Epatologia Medica e Chirurgica

Transcription

Atti 67_SCIVAC:Atti 67_Scivac
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Organizzato da
Soc. Cons. a r.l.
Azienda con sistema qualità certificato ISO 9001:2008
Richiesto accreditamento
SOCIETÀ CULTURALE ITALIANA VETERINARI
PER ANIMALI DA COMPAGNIA
SOCIETÀ FEDERATA ANMVI
Arezzo
Centro Affari e Convegni
15-17 Ottobre 2010
67°
Congresso Nazionale Scivac
Epatologia Medica
e Chirurgica
ATTI DEL CONGRESSO
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67° Congresso Nazionale Scivac • Arezzo, 15-17 Ottobre 2010
Epatologia
Chirurgica
COMITATO SCIENTIFICO DEL 67° CONGRESSO NAZIONALE SCIVAC
PAOLA GIANELLA
Med Vet, Dr Ric, Dipl ACVIM (SAIM), Torino
GIORGIO ROMANELLI Med Vet, Dipl ECVS, Milano
GILIOLA SPATTINI
Med Vet, Dr Ric, Dipl ECVDI, Castellarano (RE)
CONSIGLIO DIRETTIVO
FEDERICA ROSSI
DEA BONELLO
ALBERTO CROTTI
WALTER BERTAZZOLO
GUIDO PISANI
DAVID CHIAVEGATO
BRUNO PEIRONE
SCIVAC
Presidente
Presidente Senior
Vice Presidente
Segretario
Tesoriere
Consigliere
Consigliere
SI RINGRAZIA LA COMMISSIONE SCIENTIFICA SCIVAC 2007/2010
MASSIMO BARONI
Med Vet, Dipl ECVN, Monsummano Terme (PT)
DAVIDE DE LORENZI
Med Vet, Dipl ECVCP, Padova
GIORGIO ROMANELLI Med Vet, Dipl ECVS, Milano
FULVIO STANGA
Med Vet, Cremona
COORDINATORE SCIENTIFICO CONGRESSUALE
Fulvio Stanga, Med Vet, Cremona
SEGRETERIA SCIENTIFICA
Monica Villa
Tel. +39 0372 403504 - E-mail: [email protected]
SEGRETERIA MARKETING, SPONSOR E AZIENDE ESPOSITRICI
Ilaria Costa
Tel. +39 0372 403538 - E-mail: [email protected]
SEGRETERIA ISCRIZIONI
Paola Gambarotti
Tel. +39 0372 403508 - Fax +39 0372 403512 - E-mail: [email protected]
ORGANIZZAZIONE CONGRESSUALE
E.V. Soc. Cons. a r.l.
Via Trecchi, 20 - 26100 CREMONA (Italia)
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SOCIETÀ CULTURALE ITALIANA VETERINARI
PER ANIMALI DA COMPAGNIA
SOCIETÀ FEDERATA ANMVI
Arezzo
Centro Affari e Convegni
15-17 Ottobre 2010
67°
Congresso Nazionale Scivac
Epatologia Medica
e Chirurgica
SCIVAC ringrazia gli Sponsor per il sostegno dato all’evento
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RELATORI
HUGUES A. GAILLOT
Med Vet, Dipl ECVDI, Alfort (F)
Hugues Gaillot si laurea nel 1989 presso la Scuola Veterinaria di Alfort (Francia). Dopo un tirocinio di 2 anni,
ha fatto parte della faculty clinica dei Piccoli Animali di
medicina Interna e Cardiologia per 10 anni. Nel frattempo ha conseguito il Master of Sciences in Genetica e un diploma in Biologia Cellulare e Molecolare. Più recentemente ha portato a termine
un’alternate residency in Diagnostica per Immagini presso le Università di Tufts (USA) e Alfort (F), diplomandosi ECVDI nel 2008. Oggi Hugues Gaillot è uno dei radiologi di “Advetia Veterinary Medical Center”,
centro di referenza di Parigi. È coinvolto nella formazione continua sia
di colleghi che di resident ECVDI, in collaborazione con il Dipartimento di Diagnostica per Immagini della Scuola Veterinaria di Alfort.
Risonanza Magnetica del Centro Robert Steiner presso il Reparto di
Radiologia dell’Hammersmith Hospital di Londra (Royal Postgraduate
Medical School). Nel 1994 ha frequentato il “Radiologic Pathology
Course” presso l’AFIP (Armed Force Institute of Pathology) del Walter
Reed Hospital di Washington DC, USA. Lo stesso anno si specializza
in Radiologia discutendo la tesi dal titolo: “Microbolle di CO2 come
mezzo di contrasto ultrasonografico intrarterioso nella valutazione
della vascolarizzazione dell’epatocarcinoma”. Nell’Ottobre 1994
prende servizio presso l’Istituto Europeo di Oncologia di Milano dove
nell’ambito della Divisione di Radiologia Diagnostica sviluppa l’attività Interventistica clinica, grazie alla collaborazione con le Divisioni
Cliniche e Chirurgiche dell’Istituto stesso. Nel 1995 in qualità di vincitore del “Bracco International Award”, frequenta il “Visiting Fellowship Program” in Risonanza Magnetica presso il centro ricerche del
Massachussets General Hospital (Boston, USA), in qualità di visiting
fellow. Membro dal 1994 della Società Europea di Radiologia Interventistica (CIRSE), nel 1998 viene nominato “Fellow”. Dal 1994 al
1999, in qualità di “tutor” Universitario presso la Scuola di Specializzazione in Radiologia dell’Università Statale di Milano, organizza lezioni di Anatomia Radiologica del Fegato e di Radiologia Interventistica. Dal Gennaio 2000 viene nominato Professore a contratto presso la Scuola di Specializzazione in Radioterapia dell’Università Statale degli Studi di Milano. Nell’ambito dell’attività Interventistica si è
dedicato con particolare attenzione alla patologia focale epatica, dalla diagnostica specifica al trattamento locoregionale, sviluppando
protocolli di trattamento chemioterapico intrarterioso con accesso per
cutaneo. Attualmente dirige l’Unità di Radiologia Interventistica dell’Istituto Europeo di Oncologia.
PAOLA GIANELLA
Med Vet, PhD, Dipl ACVIM (SAIM), Torino (I)
Si laurea con lode nel 1999 presso la Facoltà di Medicina Veterinaria a Torino. Trascorre alcuni mesi presso
la Colorado State University e presso la Texas A&M
University approcciandosi all’oncologia, alla medicina
interna e alla gastroenterologia. Nel 2000 inizia un dottorato di ricerca sull’oncologia veterinaria e comparata presso la Facoltà di Medicina Veterinaria di Torino e frequenta il reparto di gastroenterologia dell’Azienda Ospedaliera “San Giovanni Bosco” di Torino. Nel 2004 si
trasferisce all’estero e inizia un programma di Residency in Medicina
Interna della durata di 3 anni presso le Università di Berna (Svizzera) e
di Baton Rouge (USA), superando l’esame di specializzazione ACVIM
nel giugno 2007. Collabora attualmente come internista presso la Facoltà di Medicina Veterinaria di Torino e presso la Clinica Veterinaria
Malpensa di Samarate, e come gastroenterologa presso l’Ospedale
Anubi di Moncalieri.
FEDERICA ROSSI
SRV, Dipl ECVDI, Sasso Marconi (BO)
Laureata nel 1993 a Bologna, con lode, ha ricevuto il
“Premio Rotary Corsi di Laurea” per il miglior Curriculum di Laurea nell’Anno 92/93. Dopo diversi periodi di
formazione all’estero, ha conseguito nel 1997 il Dipl di Spec. in Radiologia e nel 2003 il Dipl del College Europeo in Diagnostica per Immagini (ECVDI). È autrice di oltre 40 pubblicazioni nazionali ed internazionali, revisore e coautore di testi scientifici. È Presidente della Soc.
Italiana di Diagnostica per Immagini (SVIDI) e Past-President della Società Europea (EAVDI). Ha lavorato come Ober-assistent alle Università di Berna, Philadelphia e Murdoch. Dal 2008-2009 è Prof. a contratto e consulente per la TC per la Facoltà di Med. Vet. dell’Università di
Torino. Dal 1994 lavora a Sasso Marconi (BO), svolgendo attività di referenza in Radiologia, Ecografia e TC. Dal 2010 è Presidente SCIVAC.
HEIDI HOTTINGER
DVM, Dipl ACVS, Texas, USA
Si laurea in medicina veterinaria presso la Ohio State
University nel 1990. Prosegue con uno stage in Medicina e Chirurgia dei piccoli animali presso l’Animal
Medical Center di New York City seguendo la Scuola di
medicina Veterinaria e completando, nel 1994, il residency in chirurgia dei piccoli animali presso la Michigan State University. In seguito
ricopre il ruolo di chirurgo dei tessuti molli ed istruttore all’Animal Medical Center. Dal 1996 lavora alla Gulf Coast Veterinary Specialists di
Houston in Texas. Dr. Hottinger è diplomata all’ACVS ed è attualmente partner della Gulf Coast Veterinary Specialists, dove si occupa di chirurgia oncologica e dei tessuti molli.
DAVID TWEDT
DVM, Dipl ACVIM, Colorado, USA
David C. Twedt si laurea alla Iowa State University per
intraprendere una intership e una residency in Medicina Interna con specializzazione in gastroenterologia
presso l’Animal Medical Center di New York. In seguito si unisce allo staff dell’Animal Medical Center. Ha svolto attività di
ricerca presso il Liver Research Center della Albert Einstein Medical
School. Diplomato ACVIM, è attualmente docente nel Dipartimento di
Scienze Cliniche e di Medicina Interna presso la Colorado State University. Past President del College dell’ACVIM nonché della Comparative Gastroenterology Society. Le sue pubblicazioni e i suoi campi di
ricerca abbracciano le malattie epatiche, le malattie gastrointestinali e
l’endoscopia. Destinatario di numerosi premi per l’insegnamento è anche il co-editor del Current Veterinary Therapy XIV.
FRANCO ORSI
Med Chir, Milano
Il Dott Franco Orsi si è laureato in Medicina e Chirurgia nel 1990, presso l’Università di Roma (La Sapienza), discutendo la tesi dal titolo: “Ago-biopsia toracomediastinica TC guidata: indicazioni e complicanze”.
Sia durante il Corso di Laurea che nell’ambito della Scuola di Specializzazione in Radiologia ha frequentato l’Istituto di Chirurgia Generale, l’Istituto di Chirurgia d’Urgenza e l’Istituto di Radiologia presso il
Policlinico Umberto I di Roma (Università La Sapienza), dove si è dedicato prevalentemente alla Radiologia Interventistica, sotto la guida
dei Proff Plinio Rossi e Roberto Passariello. Ha frequentato le sezioni
di Radiologia Interventistica Vascolare ed Extravascolare e l’Unità di
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PROGRAMMA SCIENTIFICO
V E N E R D Ì , 1 5 OT TO B R E 2 0 1 0
Chairperson FEDERICA ROSSI
10.20 Saluto ai partecipanti del Presidente SCIVAC, presentazione dei relatori
ed inizio lavori
10.30 Anatomia e fisiologia epatica - Paola Gianella (I)
11.20 Diagnostica di laboratorio delle malattie epatiche - David Twedt (USA)
12.10 Sindromi cliniche associate alle malattie epatiche - David Twedt (USA)
13.00 PAUSA
PRANZO
Chairperson PAOLA GIANELLA
14.30 La biopsia epatica: tecniche a confronto - Heidi Hottinger (USA)
15.20 COMUNICAZIONI BREVI
Agenesia della colecisti in un cane associata ad epatopatia
ed enteropatia infiammatorie - Veronica Marchetti (15’)
Torsione di lobo quadrato, medio di destra e cistifellea in un pastore
tedesco - Federico Massari (15’)
15.50 Considerazioni sul Farmaco Veterinario - Carlo Scotti e Roberto Villa
16.10 PAUSA
CAFFÈ
16.50 Aggiornamenti sulle principali patologie epatiche del gatto
David Twedt (USA)
17.40 Malattie associate all’accumulo di rame - David Twedt (USA)
18.30 Termine della giornata
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S A B AT O , 1 6 O T T O B R E 2 0 1 0
Chairperson GILIOLA SPATTINI
9.00 Epatite idiopatica e cirrosi (con accenni alle epatiti del Labrador)
David Twedt (USA)
9.50 L’esame ecografico delle malattie epatiche - Hugues A. Gaillot (F)
10.40 Presentazione Anagrafe Felina - Marco Melosi
10.50 PAUSA
CAFFÈ
11.20 L’esame ecografico delle patologie delle vie biliari - Hugues A. Gaillot (F)
12.10 Diagnostica per immagini avanzata: neoplasie epatiche e malattie
non vascolari - Federica Rossi (I)
13.00 PAUSA
PRANZO
Chairperson GIORGIO ROMANELLI
14.30 Utilizzo terapeutico degli agenti citoprotettivi in corso di patologia
epatobiliare - David Twedt (USA)
15.20 PAUSA
CAFFÈ
16.10 COMUNICAZIONI BREVI
Chirurgia per il trattamento di ascite in un cane con cirrosi
Stefano Nicoli (15’)
Ecocardiocontrastografia con microbolle come verifica dell’occlusione
chirurgica di uno shunt portosistemico extraepatico in un cane
Vittorio Saponaro (15’)
16.40 Presentazione VetPedia
Enrico Febbo e MariaGrazia Monzeglio
16.50 Cosa si fa in chirurgia umana: la Radiologia Interventistica
nella patologia epatica - Franco Orsi (I)
17.40 Le neoplasie epatobiliari e loro trattamento - Heidi Hottinger (USA)
18.00 Termine della giornata
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D O M E N I CA , 1 7 OT TO B R E 2 0 1 0
Chairperson GIORGIO ROMANELLI
9.00 La chirurgia delle vie biliari
Heidi Hottinger (USA)
9.50 Inquadramento clinico degli shunt porto sistemici
Paola Gianella (I)
10.40 PAUSA
CAFFÈ
Chairperson GILIOLA SPATTINI
11.20 L’esame ecografico delle patologie epatiche e biliari congenite
Hugues A. Gaillot (F)
12.00 Diagnostica per immagini avanzata: shunt porto sistemici
Federica Rossi (I)
12.40 Trattamento chirurgico degli shunt porto sistemici
Heidi Hottinger (USA)
13.30 Fine del congresso
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ESTRATTI
DELLE RELAZIONI
Questo volume degli atti congressuali riporta fedelmente quanto fornito
dagli autori che si assumono la responsabilità dei contenuti dei propri scritti.
Gli estratti sono elencati in ordine alfabetico secondo il cognome del relatore
e quindi in ordine cronologico di presentazione.
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Hugues Gaillot
DVM, MS, Dipl ECVDI, France
ULTRASONOGRAPHIC
EXAMINATION
OF LIVER DISEASES
Sabato, 16 Ottobre 2010, ore 9.50
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INTRODUCTION
Ultrasound has become a critical part of the veterinary practice. It is an essential imaging tool for diagnosing diseases of the liver parenchyma. In many
cases ultrasonography has replaced radiography as the initial imaging procedure in screening for liver diseases. However findings in ultrasound of the liver are highly non-specific. One disease can show a wide range of different ultrasonographic abnormalities. Different diseases can share exactly the same
ultrasonographic findings. Moreover, a normal ultrasonographic exam does
not exclude a liver disease. In order to reduce as much as possible the list of
differentials, ultrasonography of the liver should always be used in light of the
complete medical history, the results of the medical examination and the ancillary laboratory tests. Almost all abnormalities of the liver parenchyma will
require a fine needle aspirate or a biopsy to reach a final diagnosis.
PATIENT PREPARATION AND SCANNING TECHNIQUES
Probe frequencies ranging from 5 to 8 MHz and even higher are preferred
for most dogs and cats. A probe with more penetration with frequencies between 2 and 5 MHz may be required in larger dogs. Sectorial or microconvexe
probes are best suited to liver examination because of their triangular shaped
field of view and small footprint.
Hair clipping and application of coupling gel on the skin of the cranial abdomen and the last one or two intercostal spaces should be performed to optimize image quality. The patient can be placed in lateral or dorsal recumbency, whichever is more comfortable to the animal an operator. Sedation is usually not required.
Evaluation of the entire liver is done using two scanning planes, transverse
and longitudinal, relative to the patient spine axis. In cats and small dogs the
subcostal approach usually allows complete scanning of the liver. In deepchested dogs and patients with microhepatica the liver is hidden by the rib
cage and by the stomach and transverse colon that are located under or just
caudal to the costal arch. Gas, ingesta or feces in these organs will impede liver visualization. In such instances a right intercostal approach is needed to fully scan the liver. Consistency in the scanning protocol is critical to a good examination. Commonly used standard orientations of the images in transverse
and longitudinal planes should be respected.
For scanning the liver in longitudinal views either sagittal, parasagittal or
oblique, the probe is moved in a slow sweeping motion from lateral to contro-lateral (left to right or right to left on the animal) using subcostal windows
or intercostal windows.
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For scanning the liver in transverse views, the probe is moved form caudal
to cranial or cranial to caudal on the animal.
In any planes the operator can angle the transduceur by using the xiphoid
process or the costal arch as an anchor point.
ULTRASONOGRAPHIC ANATOMY OF THE LIVER
(PARENCHYMA)
The liver parenchyma is divided in four lobes some of them being divided
in sublobes or processes. The entire liver is composed of 7 anatomic subdivisions.
In a normal patient, liver anatomic subdivisions are in contact with each
other and show identical echotexture and echogenicity. Consequently, the separations between liver lobes are not well seen ultrasonographically. Some
anatomic landmarks are useful for localizing a particular lobe. The falciform
ligament filled with a variable amount of fat protrudes between the right and
left liver lobes dorsal to the xiphoid process. The gallbladder contacts the
quadrate lobe on its left and caudal aspects and the right medial lobe on its
right aspect; the right kidney contacts the renal fossa of the caudate process;
at the porta hepatis, the caudal vena cava and portal vein contact the isthmus
of the caudate lobe dorsally and ventrally respectively; the gastric fundus and
sometimes the spleen contact the caudal aspect of the left lateral lobe.
The diaphragm and underlying inflated lung appear as a curved hyperechoic line outlining the cranial liver contour. It is sometimes associated with
an artifactual mirror-image of the liver.
The size of the liver is difficult to assess by ultrasound particularly in dogs
because of the wide range of body conformation. Extension of the caudal aspect of the liver and location of the stomach in regard to body conformation
might be helpful to assess liver size. In deep-chested dogs the caudal liver
margin does not reach the costal arch and the stomach is located under the
costal arch. In small dogs and in cats the liver margin normally extends to the
costal arch without contacting the left kidney. An excessive overlapping of the
right kidney by the liver or a left liver reaching the left kidney are signs of hepatomegaly. Rounded caudal tips of liver lobes, that are normally pointed, are
additional signs of increased liver size.
The liver parenchyma has a uniform moderately coarse tissue echotexture
providing an homogeneous echogenicity. The liver parenchymal echogenicity
is commonly assessed by comparing the relative echogenicities between organs. These comparisons are a valuable tool for the sonographer but must be
done with caution as they are only a crude way to assess diffuse changes of
echogenicity. Comparison of organ echogenicities must be done using the
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same probe, at the same depth, with the same settings and on the same imaging frame. The liver parenchyma is isoechoic to hypoechoic to the fat-filled falciform ligament. It is hypoechoic with a coarser echotexture when compared
to the spleen. Liver echogenicity relative to the renal cortex is more variable
particularly in cats. In dogs it is commonly isoechoic to mildly hyperchoic
ULTRASONOGRAPHIC FEATURES OF LIVER
PARENCHYMAL DISEASES
Numerous liver diseases are encountered in dogs and cats. They may cause
focal, multifocal or diffuse changes of the normal ultrasound image and in
some cases they may not alter the normal sonographic appearance of the liver.
The following parameters have to be assessed during the examination: liver
size, liver lobes contour, general parenchymal echogenicity, and any alterations
of the normal echotexture giving number, size, distribution and echogenicity of
focal changes of the parenchyma.
Alteration of the normal echotexture of the liver parenchyma may be due
to a widespread parenchymal change (diffuse disorder) or a unique or multiple lesions with more or less discrete margins (focal or multifocal disorder).
Diffuse hepatic disorders
Diffuse liver diseases might be difficult to detect particularly when the
echogenicity of the parenchyma remains homogeneous and is mildly modified or when a combination of liver kidney and spleen anomalies is present.
Most of diffuse liver diseases are associated with a normal or an increased
size of the liver. A small liver is a meaningful finding as it is encountered only in a limited number of hepatic disorders. Disorders associated with a small
liver are cirrhosis, fibrosis, congenital portosystemic shunts, and congenital
portal vein hypoplasia. Diffuse hepatic disorders are classified as hyperechoic, hypoechoic or diffusely inhomogenous (mixed echogenicity) abnormalities. In each of these three categories several liver diseases are included
that may share the same pattern. A particular disease might be encountered in
two or three different categories. This emphasizes the lack of specificity of ultrasonographic changes of liver diseases.
Diffuse hyperechoic disorders
In dogs, a diffusely too bright liver will appear isoechoic to hyperechoic to
the spleen and hyperechoic to the renal cortex. In cats, hyperechogenicity of
the liver parenchyma relative to the falciform fat is the finding commonly
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used to detect diffuse liver hyperechogenicity. There may be also hyperattenuation of the ultrasound beam which can be at least partially compensated for
by increasing far gain.
A diffusely too bright liver may obscure adequate visualization of the
echogenic walls of the portal vasculature giving the impression of an “absent”
portal system. Though visualization of the portal system and comparison of
the echogenicities between organs facilitate assessment of diffuse changes,
subjective impression is also a significant component of the sonographer assessment of liver echogenicity.
A list of differential diagnoses for a liver of increased echogenicity is given:
- steroid hepatopathy
- lipidosis
- other vacuolar degenerative changes
- fibrosis
- cirrhosis
- chronic hepatitis
- lymphoma
- mast cell tumor
Diffuse hypoechoic disorders
In a liver of decreased echogenicity the portal vasculature and the wall of
the gallbladder are better visualized due to the darker background provided by
the abnormal parenchyma.
A list of differential diagnoses for a liver of decreased echogenicity is given:
- lymphoma
- leukemia
- malignant histiocytosis
- mast cell tumor
- acute hepatitis
- cholangiohepatitis (cat)
- vascular congestion
Diffuse mixed echogenicity
Diseases in this category are associated with a coarse echotexture of the liver parenchyma with uneven echogenicity. Discrete borders of the areas of different reflectivity may not be identified and it may be impossible to indicate
whether the less echogenic or the more echogenic areas or both are abnormal.
A list of differential diagnoses for a liver of diffusely mixed echogenicity
is given:
- hepatocellular carcinoma
- numerous metastasis
- necrosis
- hepatitis
- hepatocutaneous syndrome
- combination of processes
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As for diffuse homogeneous changes of the liver echogenicity, ultrasound
may lack to identify diffuse mixed echogenicity even though a diffuse inhomogenous infiltrative process of the liver is present.
Focal or multifocal hepatic disorders
Focal liver diseases include cysts, hematomas, abscesses, necrosis, benign
hyperplasia and primary or metastatic neoplasia.
Focal anechoic lesions
Focal anechoic lesions are typically echo-free structures that demonstrate
far acoustic enhancement consistent with hypoattenuating content. Differential diagnoses of such lesions include cysts, “biliary lakes”, old hematoma,
abscesses, necrosis and cystic tumors.
Cysts are usually well-defined, thin-walled, anechoic, rounded structures.
They tend to be solitary but can also appear as a cluster of anechoic lesions.
They are usually detected incidentally. However they may be clinically significant depending on their size, location and number. Kidney should always be
assessed because polycystic renal disease may accompany liver cysts.
A somewhat different cluster of anechoic lesions referred colloquially as
“biliary lakes” may be encountered. These lesions tend to be well-defined
with no visible wall, and to appear less spherical than the typical cystic lesion
with sometimes a loculated shape. They may be bile filled but it is not certain
that these lakes are truly from biliary origin. They are considered to result
from trauma or inflammatory process.
Multiple small anechoic cavities within an hyperechoic loculated mass also containing a more solid echoic component is commonly seen with biliary
cystadenoma and cystadenocarcinoma in cats.
Focal hypoechoic lesions
Focal hypoechoic lesions are relatively well-defined areas of decreased
echogenicity compared with the surrounding parenchyma and do not usually
demonstrate far acoustic enhancement. Differential diagnoses of such lesions
include nodular hyperplasia, metastasis, malignant histiocytosis, lymphoma,
primary liver tumors, abscesses, granulomas, hematomas, necrosis and complicated cyst (hemorrhagic, infected).
Nodular hyperplasia is a common finding particularly in older dogs.
They usually appear as hypoechoic nodules in the liver measuring less than
2cm in diameter. However they may have variable appearance and may form
very large masses. They cannot be diagnosed on ultrasonography alone.
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Lymphoma shows a wide range of ustrasonographic appearance either diffuse or focal. It may be seen as a unique or multiple hypoechoic nodules disseminated throughout the liver. Malignant histiocytosis is more consistently associated with the pattern of multiple hypoechoic liver nodules. Association of this
pattern with thoracic or abdominal lymphadenopathy increases the likelihood of
lymphoma or histiocytic neoplasia even though it is not pathognomonic.
Focal hyperechoic lesions
Focal hyperechoic lesions are relatively well-defined areas of increased
echogenicity relative to the surrounding parenchyma. They may exhibit distal
shadowing depending on their content. Differential diagnoses of such lesions
include nodular hyperplasia, primary neoplasia, metastasis, mineralization or
cholelithiasis, abscesses, granulomas, fat deposits or myelolipoma and gas.
Emphysematous hepatitis is an uncommon disorder typically associated
with inhomogeneous focal lesion of variable size that contains hyperechoic
foci demonstrating reverberation artifacts due to the presence of gas. Gas
within the liver can also be seen within the biliary tree following surgery.
Dystrophic mineralization of the liver parenchyma is sometimes encountered. It is characterized by small hyperechoic foci generating clean and strong
distal shadowing. It must be distinguished from lithiasis within the biliary tree.
Hepatocarcinomas display a wide range of ultrasonographic presentations. The focal form of hepatocarcinoma might be an hyperechoic solitary
mass. This appearance is not pathognomonic of a primary carcinoma and a
benign tumor (adenoma) or a non-neoplastic process cannot be ruled out
without cytologic or histologic exam.
Focal mixed lesions
Focal lesions with mixed echogenicity are areas mixing low and high reflectivity islets. Differential diagnoses of such lesions include primary liver
neoplasia, metastasis, abscesses, granulomas, hematomas and less commonly
nodular hyperplasia,
A common ultrasonographic appearance of primary liver tumors is an
inhomogeneous mass. Multiple small anechoic cavities within an hyperechoic
loculated mass also containing a more solid echoic component is commonly
seen with biliary cystadenoma and cystadenocarcinoma in older cats. Hepatocarcinomas are more commonly encountered with a focal mixed or multifocal to diffuse inhomogenous pattern rather than a focal uniformly hyperechoic lesion. However a focal mixed lesion even though large in size is not
synonymous of liver tumor. Benign hyperplasia may sometimes appear as a
large mass with mixed echogenicity depending on the presence of necrosis or
hemorrhage within the primary lesion.
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INTERVENTIONAL ULTRASONOGRAPHY
Ultrasonography changes of the liver parenchyma whichever diffuse or focal are usually not pathognomonic for a particular disorder. Moreover, some
liver diseases are associated with few or no changes of the ultrasonographic
image. Therefore cytologic or histologic confirmation is still required for a definitive diagnosis. Ultrasonographic guidance can assist fine-needle aspiration
and core biopsy. It may also assist fluid-filled cavities and abscesses drainage
as well as abdominocentesis when a small amount of fluid is present.
Fine needle aspiration
Ultrasound guided fine needle aspiration (FNA) is commonly performed
with a “freehand technique”. A 23G needle is used with a length chosen to fit
the depth of the lesion. The operator holds the transducer in one hand and the
needle in the other. With training, the operator can continuously visualize the
needle tip within the scan plane particularly if the needle is maintained nearly perpendicular to the incident ultrasound beam.
The patient should be prepared appropriately prior to any interventional
procedure. Screening for hemostatic disorders is recommended particularly in
patients with diffuse or multifocal liver lesions. Placement of an intravenous
catheter should be performed routinely.
In cooperating patients general anesthesia is usually not required for FNA.
In cases where the target is vascular, small or adjacent to critical structures,
complete anesthesia is often required. Aspiration of tissue of interest might be
performed by suction or capillarity depending on cellular cohesion and
propensity for bleeding of the tissue to be sampled.
Core biopsy
The use of an automated biopsy gun is recommended for tissue core biopsy as it provides good speed, efficiency and safety of the biopsy procedure. The
biopsy gun is equipped with a spring-trigger that automatically releases the
movement of the needle. This automated method requires only a single operator and gives satisfactory tissue samples for histopathological evaluation.
A guide-assisted technique can be also used, particularly by a non-trained
operator. This technique requires a guide that is specific for each type of transducer and a software within the ultrasound machine that will display on the
image the predicted path of the needle with accuracy. General anesthesia is required for performing safe tissue core biopsy.
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A post-biopsy scan is recommended to assess for possible hemorrhage or
hematoma. The risk of complications after ultrasound-guided biopsy is considered to be low (1.2%) and seems to be lower with fine needle aspirate.
CONCLUSION
Ultrasonography is widely used in veterinary medicine for screening for
liver parenchymal disorders. Despite its popularity, ultrasound of the liver is
not a highly sensitive tool as many diseases will show no ultrasonographic abnormalities. Ultrasonography is also a poorly specific technique as ultrasonographic findings are commonly not pathognomonic. Therefore, ultrasound
primarily serves to detect and localize liver lesions but it may also serve to obtain cytologic or histologic samples of good diagonostic quality. Finally, ultrasonography is a simple and safety modality that is beneficial in monitoring
the course of the disease and in assessing therapeutic response.
BIBLIOGRAPHY
d’ANJOU MA (2008) Chapter 6: Liver, in Penninck D, d’Anjou MA (eds), Atlas of small animal ultrasonography, 1st edition. Blackwell Publishing, pp 217-261.
LAMB CR (1991) Ultrasonographic findings in hepatic and splenic lymphosarcoma in dogs and cats. Vet
Radiol & Ultrasound 32:117-120.
NEWELL SM (1998) Correlations between ultrasonographic findings and specific hepatic diseases in cats:
72 cases (1985-1997).
RAMIREZ S (2002) Ultrasonographic features pf canine abdominal malignant of biliary cystadenomas in
cats. Vet Radiol & Ultrasound 40:300-306.
SCHWARTZ LA (1998) Hepatic abscesses in 13 dogs: a review of the ultrasonographic findings, clinical
data and therapeutic options.
THOMAS GN (2002) Liver In: Nyland T, Mattoon J, Small Animal Diagnostic Ultrasound, 2nd edition.
Philadelphia: WB Saunders, pp 93-127.
THOMAS GN (1999) Ultrasonographic evaluation of biliary cystadenomas in cats. Vet Radiol & Ultrasound 40:300-306.
THOMAS GN (1996) Hepatic ultrasonographic and pathologic findings in dogs with canine superficial necrolytic dermatitis. Vet Radiol & Ultrasound 37:200-205.
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Hugues Gaillot
ULTRASONOGRAPHIC
EXAMINATION
OF BILIARY DISEASES
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INTRODUCTION
Ultrasound has a primary role in the imaging of biliary diseases. It allows
assessment of the size, wall appearance and thickness, and luminal content of
the gallbladder. It is a sensitive tool for detecting dilation of and abnormal
content within the biliary tree. A common indication for sonographic evaluation of the biliary system is non-hemolytic icterus for which distinction between extrahepatic biliary obstruction and intrahepatic causes of jaundice has
to be done.
One additional indication of ultrasound of the biliary tract is a painful cranial abdomen with the search for an abnormal gallbladder and signs of bile
leakage.
Equipment, patient preparation and positioning, and scanning techniques
are similar to those presented for scanning the liver parenchyma.
A 12 hours fast is strongly recommended as the presence of gas in the gastric lumen may prevent visualization of the common bile duct (CBD) and adjacent structures.
It is recommended to identify the gallbladder (GB) from the beginning of
the exam of the liver in order to minimize the chance of mistakenly identifying the GB as a mass. The GB is surrounded by the liver parenchyma, embedded between the right medial and the quadrate lobes. It is located in the cranioventral abdomen on the right of midline. In dogs, the cranial aspect of the
GB commonly contacts the diaphragm.
The GB and the biliary tree are scanned using transverse and longitudinal
views successively. The transduceur position providing the best acoustic window is chosen depending on the body conformation of the patient and the region of the biliary system being imaged. For imaging the GB a ventral approach with the transduceur positioned dorsal and cranial to the xiphoid is
used while orienting the beam craniodorsally. A right oblique position can also be chosen if required. The transduceur is placed in one of the last intercostal spaces, on the right ventral thorax (few centimeters dorsal to the sternum) and angled toward the midline.
For imaging the proximal CBD and porta hepatis the ventral approach can
be used with the beam oriented more dorsally. A right lateral intercostal approach can also be used if required in order to avoid gastric and colic content.
The transduceur is then placed in one of the last intercostal spaces, on the
right dorsal thorax (few centimeters ventral to the spine) while avoiding the
inflated right caudal lung lobe.
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ULTRASONOGRAPHIC ANATOMY OF THE BILIARY
SYSTEM
The ultrasonographically relevant components of the biliary system are the
gallbladder, the cystic duct, the bile ducts (intrahepatic and extrahepatic), the
common bile duct and the major duodenal papilla.
The GB is a pear-shaped reservoir comprising a fundus, a body and a neck.
Occasionally in cats, a complete or partial duplication of the GB is seen.
The GB wall is thin and smooth measuring less than 1 mm in thickness in
cats and less than 3 mm in dogs. It may be poorly visualized on ultrasound or
appear as a thin echogenic line. The bile filling the GB lumen is commonly
anechoic and associated with far enhancement. Bile may vary in echogenicity.
GB echogenic content that does not shadow and that collects on the dependent
portion of the GB responding to gravity after patient repositioning is called
“biliary sludge”. It is considered an incidental finding particularly in dogs.
Relative little attention has been given to ultrasonographically measured
GB volume. GB volume is commonly assessed subjectively during ultrasonographic examination. No upper normal limit of the GB volume measured by
ultrasound has been established in dogs. In cats a volume of 9 ml has been
proposed as a normal upper limit. GB volume can be calculated by using averaged sonographic geometric measurements in the following volume conversion ellipse formula: V = 0.52 x (width x height x length). It is important to
recognize that considerable variability exists as several physiological and
pathological factors may influence GB volume. Fasting and anorexia are typically associated with increased GB volume. A lesion obstructing the extrahepatic biliary tree may prevent GB emptying leading to GB dilatation or, less
commonly, may prevent GB filling depending on the level of obstruction.
Moreover, loss of GB wall elasticity or reduced compliance of the peripheral
liver parenchyma may limit the GB ability to distend. Ultrasonography with
synthetic cholecystokinine stimulated GB emptying has been described as a
useful method for assessing biliary tract patency in dogs. However this timeconsuming (about 1 hour) biliary functional study is not routinely performed
in clinical situations. GB emptying study has not been described in cats.
The cystic duct is a short conical or coma-shaped dorsally directed extension
of the GB. It is prolonged with no demarcation by the CBD that receives the extrahepatic bile ducts. Extrahepatic and intrahepatic bile ducts are not seen in
normal patients. The CBD can be seen in normal patients more often in cats
than in dogs. It is considered normal if less than 5 mm wide in cats and less than
3 mm wide in dogs. It is an anechoic tubular structure void of color-flow
Doppler signal. At the porta hepatis, the proximal part of the CBD near the GB
neck is tortuous and may appear as several round anechoic structures. More
caudally, the distal part of the CBD is relatively straight as it courses ventral to
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the portal vein and dorsal to the proximal duodenum. The CBD opens into the
duodenum at the major duodenal papilla that also receives the pancreatic duct.
The major duodenal papilla is commonly seen in cats and less commonly
in dogs. It is located 2 to 3 cm distal to the pylorus and measures up to 4 by
5.5 mm (height by width). In cats, the pancreatic duct and CBD join just before they enter the major duodenal papilla. The biliary and pancreatic excretory systems are therefore intimately related in cats. In dogs the two excretory systems are not connected. The largest excretory pancreatic duct is the accessory duct which opens more distally at the minor duodenal papilla. The
pancreatic duct is the smaller duct in dogs and may be absent. When present,
it joins the duodenum at the major duodenal papilla but its opening is located
beside the CBD opening with no fusion of the two ducts.
ULTRASONOGRAPHIC FEATURES OF BILIARY DISEASES
Biliary tract content
Biliary sludge
Echogenic bile within the dependent portion of the GB (sediment) is commonly seen in healthy dogs. Its clinical significance is not fully understood. It
is considered an incidental finding. In cats, biliary sludge is rarely seen in
healthy patients. It is suspected to be an indirect sign of dysfunction of the biliary system and its presence is an indication for the search of additional ultrasonographic features of biliary disease.
Usually, biliary sludge does not shadow. If the sediment partially fills the
GB, its upper limit forms a straight line in the horizontal plane. Occasionally
some shadowing is produced and/or the sediment aggregates mimicking a
soft-tissue mass. For distinguishing such unusual appearances from a true
wall mass, an organized plug (sludge ball) or a calculi, the patient must be
repositioned. The sediment is expected to suspend before shifting toward the
dependent portion of the GB.
Biliary calculi and plugs
Calculi in the biliary tract are uncommon. They are often discovered incidentally during an ultrasonographic examination particularly when located into the GB or intrahepatic ducts. They appear as hyperechoic structures producing strong distal shadowing. Hyperechoic shadowing lesions within the
liver may correspond to intrahepatic duct calculi, dystrophic mineralization,
foreign body and gas. Calculi collect immediately into the dependent portion
of the GB after patient repositioning. When located into the CBD, calculi may
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induce an obstruction of the biliary system depending on its size and location.
Sludge balls or plugs of cholesterol and bile salts are sometimes seen within the GB. They appear as gravity dependent echogenic masses with no distal
shadowing. When located into the CBD they may induce extrahepatic biliary
obstruction as calculi do.
Gallbladder mucoceles
Gallbladder mucoceles are encountered in old dogs of small and mediumsized breeds and don’t have been described in cats. Excessive accumulation
of mucus within the GB lumen leads to GB distension. GB mucoceles are ultrasonographically characterized by hypoechoic to anechoic material (mucus)
boarding the inner surface of the wall. The inspissated bile is usually
echogenic (sludge) and centrally located within the GB as it is displaced by
the peripheral intraluminal space-occupying mucinous plugs. With progression of the mucocele the central echogenic bile typically forms a “stellate pattern” and does not collect on the dependent portion of the GB. A finely striated ultrasonographic pattern of the bile may also be seen. It appears as immobile hyperechoic fine striations radiating toward the GB center. The finely
striated pattern is described as a “kiwifruit-like pattern” and considered
pathognomonic for GB mucocele. The GB wall might be thickened, hyperechoic or hypoechoic to the liver parenchyma indicating concomitant cholecystitis. A thorough examination is required to delineate a thickened hypoechoic wall from the intraluminal peripheral immobile hypoechoic mucinous
material. End-stage GB mucocele are associated with GB overdistension and
wall necrosis. The operator must look for ultrasonographic signs of extrahepatic biliary obstruction and GB rupture during the examination.
Gallbladder wall anomalies
Gallbladder wall thickening
Thickening of the GB wall is considered when the wall thickness is greater
than 1 mm in cats and greater than 2 to 3 mm in dogs. Wall thickening is encountered with cystic mucosal hyperplasia, inflammation (cholecystitis,
cholangiohepatitis), edema (hypoalbuminemia, passive congestion from rightsided heart failure, portal hypertension, overhydration, biliary obstruction), infectious canine hepatitis, gallbladder mucocele and rarely GB neoplasia (such
as cystadenoma/carinoma, adenoid proliferation or polyps and myoma). GB
wall thickening is an abnormal but nonspecific finding. A thickened wall with
a double-rim pattern (central hypoechoic wall layer delineated by an inner and
an outer hypoechoic layers) is often seen with wall edema. Hyperechogenici-
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ty of the wall may indicate cystic changes with mural retention of mucus, mineralization associated with chronic cholecystitis, or mural gas producing “dirty
shadowing” with emphysematous cholecystitis. Free intraluminal gas appears
as hyperechoic line at the inner surface of the wall and produces reverberation
echoes (dirty shadowing) but remains in the nondependent portions of the GB
after the patient is repositioned. Uneven thickening of the wall with irregular
inner contour might be seen with chronic inflammatory polyps, acute necrotizing cholecystitis or more rarely tumors.
Gallbladder rupture
Gallbladder wall rupture and bile leakage produce bile peritonitis. Free mildly to moderately echogenic abdominal fluid is often present in variable amount
depending on the severity and duration of bile leakage into the peritoneal cavity.
An early sign of leakage is the hyperechogenicity of pericholecystic fat (falciform or omental fat) with loss of contrast indicating focal steatitis. Pain may be
detected when the transduceur is applied over the GB region. Small amount of
pericholecystic fluid may be confused with GB wall thickening. A closer inspection is required for distinguishing the wall from the surrounding fluid.
GB leakage due to one or several sites of perforation is associated with severe pre-existing wall lesion such as necrotizing cholecystitis or GB mucocele. GB rupture might also be trauma-induced (blunt trauma). A whole in the
GB with interruption of the outlining is not seen as the GB contracts or collapses. With spontaneous GB rupture secondary to a mucocele the site of rupture may appear as an irregular contour of the mixed-echogenic GB content
associated with wall discontinuity. A migrating mucocele may be found elsewhere in the abdomen with signs of steatitis and abdominal effusion.
Extrahepatic biliary obstruction
Ultrasound is commonly used for distinguishing extrahepatic biliary obstruction (EHBO) from hepatocellular disease in patients with non hemolytic
icterus. In this indication, the operator objectives are first to confirm EHBO,
and second to determine the precise level and cause of obstruction.
Despite technologic improvements in equipment and even for a well-trained
operator, ultrasound presents variable diagnostic sensitivities and specificities for
these two objectives.
Ultrasonographic features of EHBO
In dogs with acute experimental biliary obstruction, dilation of the CBD
and GB is seen by 48 hours after obstruction followed by extrahepatic ducts
(EHD) and intrahepatic ducts (IHD) dilation by 5 to 7 days.
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In cats with spontaneously occuring EHBO, the most common ultrasonographic feature (seen in almost 100% of cats) is CBD dilation. A CBD more
than 5 mm wide is a good indicator of EHBO in suspected cats. This is probably the same in dogs although it has not been studied in this specie. Absence
of dilation of the CBD does not definitely rule out EHBO particularly in a patient with high clinical suspicion. Ultrasound may have been performed to
early in the obstructive process or a peculiar level of obstruction (cystic duct
and proximal CBD) may prevent normal bile flow into the CBD and GB.
Dilation of the GB is present in approximately 50% of cats with confirmed
EHBO. This low percentage might be explained by the location, extension,
duration, and type of the cause as well as of the GB wall elasticity and the
compliance of the surrounding liver parenchyma. Therefore, EHBO cannot be
ruled out in the absence of GB dilation.
When distended, IHD appear as irregular, mildly undulating abruptly narrowing and branching anechoic tubes within the liver parenchyma. They parallel the
more linear portal veins and do not show any flow signal on color Doppler exam. When distended, EHD appear as anechoic tubes connected to the CBD at the
porta hepatis. Dilation of IHD and/or EHD along with CBD may improve the ultrasonographic detection of EHBO. In the rare case of EHBO with a peculiar level of obstruction preventing GB and CBD filling and dilation, dilated EHD
and/or IHD might be the only ultrasonographic features of obstruction.
A dilation of the CBD might be seen with non-obstructive stasis associated with inflammation (choledochitis). Furthermore, dilation of the CBD may
persist for a long while despite resolution of a previous obstruction or may be
permanent if the obstruction was prolonged. Based on the unique sign of a dilated CBD, it can be difficult to differentiate an ongoing obstructive dilation
from a dilation associated with non-obstructive stasis. Identification of a concurrent potentially obstructive lesion is therefore an important component of
the sonographic diagnosis of EHBO.
Detection of the underlying cause of EHBO
Detection of the underlying cause of obstruction requires the use of high
resolution machines and the skill of an experienced operator. Sensitivity of ultrasound in determining the cause of EHBO has been assessed in cats. It is
variable and highly dependent on the type of cause.
Obstructive choledocholithiasis is reliably diagnosed by ultrasound. The
obstructive luminal material is relatively easy to visualize. It is often located
in the distal part of the CBD, near the major duodenal papilla. Choleliths appear as hyperechoic intraluminal masses producing strong distal shadowing.
Plugs of cholesterol and bile salts may also lead to EHBO. They appear as
moderately echogenic intraluminal masses with no associated shadow.
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Other common causes of EHBO include tumors and inflammation of the
CBD, pancreas and duodenum. Acute pancreatitis affecting the body and right
limb of the pancreas with secondary duodenal and papilla inflammation and
edema is a common cause of EHBO in dogs. Combined clinicopathological
findings and ultrasonographic features of the pancreas and surrounding area
allow to reach a high level of suspicion of acute pancreatitis causing EHBO.
With other causes of obstruction such as chronic duodenitis, choledochitis,
pericholedochitis or pancreatitis and such as duodenal, CBD or pancreas neoplasia, ultrasonographic features are usually non-specific. Identification of a
mass in the anatomical region of the CBD, whatever the sonographic appearance of the mass, may indicate either an inflammatory or a neoplastic process.
Distinction between inflammatory vs neoplastic processes requires cytologic
or histopathologic assessment of the abnormal tissue or organ.
CONCLUSION
Ultrasound is widely advocated as the initial imaging tool for the diagnosis of biliary diseases in veterinary medicine. It is particularly beneficial in a
patient with non hemolytic icterus for distinguishing hepatic failure from extrahepatic biliary obstruction. Ultrasonography can rapidly provide valuable
information regarding the patency of the biliary tract. In combination with the
clinical presentation and laboratory results, it may help to make the diagnosis
of complete biliary obstruction or biliary leakage allowing for early appropriate medical treatment or surgical intervention. In challenging cases with uncertainty of extrahepatic obstructive disease, patient monitoring by follow-up
ultrasound examinations is recommended.
BIBLIOGRAPHY
BESSO JG (2000) Ultrasonographic appearence and clinical findings in 14 dogs with gallbladder mucocele. Vet Radiol & Ultrasound 41:261-271.
BRÖMEL C (1998) Prevalence of gallbladder sludge in dogs as assessed by ultrasonography. Vet Radiol
& Ultrasound 39:206-210.
FINN-BODNER ST (1993) Ultrasonographic determination, in vitro and in vivo, of canine gallbladder volume, using four volumetric formulas and stepwise-regression models. Am J Vet Res 54:832-835.
FINN ST (1991) Ultrasonographic assessment of sincalide-induced canine gallbladder emptying: an aid to
the diagnosis of biliary obstruction. Vet Radiol & Ultrasound 32:269-276.
GAILLOT H (2007) Ultrasonographic features of extrahepatic biliary obstruction in 30 cats. Vet Radiol &
Ultrasound 48:439-447.
HITMAIR K (2001) Ultrasonographic evaluation of gallbladder wall thickness in cats. Vet Radiol & Ultrasound 42:149-155.
LEVEILLE R (1996) Sonographic evaluation of the common biled duct in cats. J Vet Intern Med 10:296-299.
THOMAS GN (1982) Sonographic evaluation of experimental bile duct ligation in the dog. Vet Radiol &
Ultrasound 26:252-260.
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Hugues Gaillot
ULTRASONOGRAPHY
OF CONGENITAL
HEPTOBILIARY
DISORDERS
Domenica, 17 Ottobre 2010, ore 11.20
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INTRODUCTION
Congenital hepatobiliary disorders are mostly represented by portosystemic
shunts (PSS) in dogs and cats. Arterioportal fistulas, primary portal hypoplasia
and biliary ectasia are additional congenital hepatobiliary disorders much less
commonly encountered. Ultrasonography (US) is now widely used for congenital PSS screening. This modality is readily available, non-invasive, does
not usually require the use of general anesthesia and also allows assessment of
organs such as liver, kidneys and urinary bladder that may be secondarily affected with PSS. The sensitivity and accuracy of ultrasound for congenital portosystemic shunt is reported to be high but it is first of all dependent on the operator skills and experience.
Equipment, patient preparation, patient positioning, and scanning techniques are similar to those presented for scanning the liver parenchyma. A 12
hours fast is strongly recommended to control the gastrointestinal content (gas
and ingesta) that may prevent visualization of the portal vein (PV) and some
of its tributaries.
Additionally to the subcostal approach, a right intercostal approach may
be beneficial in a deep-chested dog and/or when the liver is very small and
contained under the rib cage.
During ultrasonographic examination the operator must visualized the entire liver including hepatic veins, intrahepatic portal veins, the main PV and
the PV tributaries.
Knowledge of the vascular anatomy and particularly the portal system is
an important prerequisite before attempting a sonographic search for vascular
malformations.
ULTRASONOGRAPHIC ANATOMY OF LIVER ASSOCIATED
VASCULAR STRUCTURES
The afferent vascular flow to the liver is dual, the larger part coming from
the PV (about four-fifths) and the remaining part coming from the hepatic artery. The outgoing venous system of the liver is composed of the hepatic veins
joining the caudal vena cava (CVC).
For the purposes of sonographic description, the liver-associated vascular
network is arbitrarily divided in three compartments: (1) intrahepatic vessels,
(2) extrahepatic PV (main PV) and hepatic artery, and (3) PV tributaries.
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Intrahepatic vessels
On B-mode imaging, only the hepatic and portal veins can be seen within
the liver parenchyma. They appear as anechoic, branching tubular structures
that taper toward the liver periphery. Portal veins can be distinguished from
hepatic veins as they demonstrate hyperchoic walls regardless of the orientation of the ultrasound beam, and converge centrally toward the main PV. At a
same level they are located ventral to the corresponding hepatic veins. Comparatively, hepatic veins have usually no visible wall and converge dorsocranially toward the CVC.
Distinction of hepatic vessels is made easier with the use of color Doppler.
Hepatic and portal veins display different color signal as their flows are in opposite direction. The hepatic veins flow is directed dorsally away from the
transduceur (commonly depicted with a blue signal) whereas the portal veins
flow is directed toward the periphery of the liver and toward the transduceur
(depicted with a red signal). The intrahepatic arteries are not seen on B-mode
but may sometimes be identified with color Doppler demonstrating a pulsatile
signal oriented toward the transduceur (red signal).
Three main hepatic branches of the PV can be visualized by ultrasound including a right branch (right lateral vein and caudate vein), a central branch
(right medial vein), and a left branch (left vein and quadrate vein).
While scanning the PV in transverse plane from the ventrum and in a caudocranial direction, the right portal branch is first seen originating from the
right aspect of the PV just cranial to the porta hepatis. This right portal branch
divides supplying portal blood to the right lateral and caudate liver lobes. The
nearly located gastroduodenal structures make the right portal branch sometimes difficult to visualize with a ventral approach. In this situation, a right intercostal approach may be beneficial.
A few centimeters cranial to the right portal branch, the central portal
branch is seen arising from the PV to the right of the GB. This central branch
corresponds to the right medial portal vein. Its origin has a relatively central
position within the liver and it is oriented craniodorsally and to the right supplying blood to the right medial liver lobe.
On the left side of the central branch origin, the PV terminates into the left
portal branch which is best visualized in a transverse plane from the ventrum.
The left portal branch is the largest branch and arises caudodorsally to the GB
neck. It courses between the GB and left hepatic veins supplying portal blood
to the left lobe (medial an lateral parts) and the quadrate lobe.
Hepatic veins distribution differs slightly from that of the portal branches.
Hepatic veins from the left lobe (medial and lateral portions), quadrate lobe
and right medial lobe converge and join the left-ventral aspect of the CVC at
a single location near the diaphragm. Left hepatic veins are best seen on US
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using a ventral approach. More caudally, the right lateral and the caudate hepatic veins enter the CVC on its right-ventral aspect at two separate locations.
Visualization of the right lateral and the caudate hepatic veins requires the use
of a right intercostal approach.
In the fetus, the umbilical venous blood from the placenta enters the liver
via the left portal branch and is immediately shunted via the ductus venosus
into the left hepatic vein and the CVC without flowing through the liver via
the fetal portal system. The ductus venosus normally closes in puppies between 2 and 6 days after birth.
Extrahepatic portal vein and hepatic artery
The normal anatomic location of the PV is relatively central in the abdomen, caudal to the liver, ventral and slightly to the left of the CVC, and ventral and to the right of the aorta. The PV shows a gently tortuous course running dorsal to the transverse colon, the junction of the right and left pancreatic limbs and the gastroduodenal junction. It reaches its maximal diameter at
the porta hepatis where it enters the liver and turns dorsal. Objective assessment of the main PV diameter can be done with a ratio comparing PV diameter (measured at the porta hepatis) to the one of the aorta (Ao). The normal
PV/Ao ratio is comprised between 0.7 and 1.25 in dogs and cats.
PV blood flow mean velocity can be measured at the porta hepatis using
spectral pulsed Doppler with an insonation angle correction comprised between 30° and 60°. The most frequently used methods are the uniform insonation method (the entire lumen of the PV is incorporated into the sample
gate and the portal flow mean velocity is calculated by the ultrasound system)
and the maximum velocity method (a small sample gate (half of the vein diameter) is placed in the center of the PV and the averaged maximum velocity is multiplied by a factor of 0.57).
The normal portal flow is hepatopetal (toward the liver) non-pulsatile and
continuous with a broad and relatively constant velocity spectrum. Mean portal
flow velocities averages 15 to 20 cm/s in dogs and 10 to 18 cm/s in cats. Inaccuracy in portal flow velocity measurements is expected with correction angles
higher than 60°. Calculated results must always be interpreted cautiously.
Between the pancreas and the porta hepatis, the main portal vein is anatomically associated with the hepatic artery that courses along its ventral-left aspect. The hepatic artery is best identified at the porta hepatis with a ventralright subcostal approach using color Doppler mode that displays its pulsatile
flow pattern directed toward the liver. It may also be imaged using a right intercostal approach, through the right kidney, as the first large branch of the
celiac artery that courses cranioventral toward the porta hepatis.
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Portal vein tributaries
Through its tributaries, the PV collects blood from the large and small intestine, the spleen, the stomach and the pancreas. Caudally the PV is formed
by the confluence of the small caudal mesenteric vein and the large cranial
mesenteric vein that drains blood from the numerous jejunal and ileal veins.
While scanning the most caudal portion of the PV in transverse section, a
slow cranial sweeping motion of the probe allows to reach the next tributary,
the splenic vein, as it enters the PV on its left aspect. The large splenic vein
is formed by the confluence of tributaries from the long hilus of the spleen
and the left gastroepiploic vein. It runs medially from the spleen between the
stomach and the transverse colon and receives the left gastric vein 1 to 2 cm
from its entry into the PV.
A few centimeters cranially, the PV receives, the small gastroduodenal
vein on its right-ventral aspect, about 1 cm from the porta hepatis. The
gastroduodenal vein is the last (most cranial) tributary of the PV. It is formed
by the cranial pancreaticoduodenal vein joined by the right gastroepiploic and
the right gastric veins.
The blood flow in each PV tributaries can be assessed using color Doppler
mode. Normal blood flow in PV tributaries is hepatopetal, directed toward the
main PV and the liver, usually directed away from the transduceur (depicted
as a blue signal).
CONGENITAL PORTOSYSTEMIC SHUNTS
Congenital portosystemic shunts (CPSS) are more often single macroscopic vascular connections between the main PV or a portal tributary and the
CVC or the azygous vein. CPSS are usually classified as intrahepatic PSS
(“IHPSS”, including patent ductus venosus) or extrahepatic PSS (“EHPSS”
including portocaval and portoazygous shunts). The diagnosis of a congenital
PSS is confirmed sonographically by the visualization of the abnormal shunting vessel connecting both circulations.
Extrahepatic PSS
Congenital EHPSS commonly affects small breed dogs and cats. They are
usually single, arising from the main PV or any tributary most often the splenic
vein or the right gastric vein.
In patients with an EHPSS, a reduction of the portal vein diameter is commonly seen cranial to the shunt origin. In some patients, the PV at the hepat-
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ic entry may even not be identified. A PV/Ao ratio of less than 0.65 is strongly suggestive of EHPSS but may also be seen with primary hypoplasia of the
PV. A PV/Ao ratio > 0.8 excludes an EHPSS. Mean PV flow velocity measured at the porta hepatis may be reduced (<15 cm/s) or reversed because the
shunt origin is caudal to the level of measurement (porta hepatis) and most of
the portal flow exits the PV before reaching the porta hepatis. However, the
small size of the PV and the cranial position of the porta hepatis secondary to
microhepatica may prevent accurate estimate of the PV flow velocity. Alternately, color Doppler can be used to identify, when present, a reversed flow
(hepatofugal flow) in the portion of the PV that is cranial to the shunt origin.
The most common type of congenital EHPSS is a splenic-caval shunt that
ususally forms a short and large single loop between the PV and the caudal
vena cava (CVC) in the vicinity of the portal entry of the splenic vein. Right
gastric-caval shunts arise from the right gastric vein near the liver hilus and
form a long vessel that follows the lesser curvature of the stomach then runs
along the left body wall in a caudomedial direction. These shunts may be associated with a second shunt loop arising from the splenic vein and the left
gastric vein. Both loops usually anastomose before entering the systemic venous circulation as a unique vessel.
The true origin of an EHPSS may be difficult to determine sonographically. Fortunately, the most important details to obtain before surgery are the
shunt termination site rather than its origin, the size of the shunting vessel and
the number of shunts.
Portocaval shunts commonly enter the CVC on its left aspect cranial to the
right renal vein. Turbulences indicated by a mosaic color Doppler pattern are
often seen at the shunt termination site. When an abnormal vessel is not easily identified, the mosaic pattern within a peculiar portion of the CVC is a useful sign helping to focus on a limited area for the search of an abnormal vessel. With portoazygous shunt the abnormal vessel dives dorsally away from
the CVC, with a flow directed dorso-cranially toward the aorta or esophagus.
The termination point of a portyoazygous shunt may be difficult or impossible to visualize by ultrasound.
Intrahepatic PSS
Congenital IHPSS are commonly seen in large breed dogs but may also affect small breed dogs and cats. With congenital IHPSS the main PV, after entering the liver, connects with a large, non-tapering, often tortuous vessel that
ultimately drains cranio-dorsally into the CVC. The sensitivity and accuracy
of US for IHPSS are higher than the one for EHPSS as the anomalous vessel,
surrounded by liver parenchyma, is often easy to identify.
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With IHPSS the main PV is always identified. Its diameter is normal or
mildly increased (PV/Ao > 0.7) and its flow is consistently hepatopetal (normal direction). The mean PV flow velocity measured at the porta hepatis may
be increased (up to 50 cm/s or more) and/or abnormally variable because the
shunt origin is cranial to the level of measurement, because vascular shunts
tend to have a low flow resistance, and because the portal vein is directly exposed to the pressure changes of the caudal vena cava.
The most common type of IHPSS is a left-divisional shunt and is considered to represent a patent ductus venosus. The anomalous vessel runs cranioventrally to the left, then turns abruptly dorsally and enters the CVC via the
left hepatic vein. A sinus-like dilation of the shunting vessel is often seen at
the site the vessel drains into the CVC.
A right-divisional IHPSS variably curves into the right liver before connecting a right hepatic vein and ultimately the CVC. Sonographically it appears as
a “mirror image” of a left-divisional shunt visualized in the right liver.
Central-divisional IHPSS are located in a more central part of the liver
usually in the right medial lobe involving the central branch of the portal vein.
The PV has a relatively straight course and often forms an aneurysmal dilation at the termination site of the short shunting vessel into the CVC.
Ultrasonographic signs associated with CPSS
Besides an anomalous blood vessel, ultrasonographic signs in patients with
CPSS include small liver, reduced visibility of intrahepatic portal branches, bilateral renomegaly and urolithiasis. The combination of these findings (microhepatica, urolithiasis and renomegaly) strongly suggests a CPSS but is encountered in less than 40% of dogs with CPSS. Bilateral renomegaly is not commonly seen in cats with CPSS.
UNCOMMON CONGENITAL HEPATIC VASCULAR
DISORDERS
Other congenital hepatic disorders than PSS are uncommonly encountered.
These include hepatoarteriovenous fistula and primary hypoplasia (HAVF) of
the portal vein (PHPV).
Hepatoarteriovenous fistulas
Congenital hepatoarteriovenous fistula (HAVF) is a rare vascular anomaly
in dogs in which one of the hepatic artery branches communicates with an in-
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trahepatic PV branch, commonly resulting in PV hypertension. Clinical presentation may resemble that of a congenital PSS with the exception of ascites
that is commonly seen in large amount with HAVF contrary to PSS.
Classic ultrasonographic features of congenital HAVF include on B-mode
(1) acites, (2) a large and tortuous anomalous intrahepatic portal branch that
connects with the main PV, (3) multiple acquired portosystemic shunts. The
main PV is clearly seen on US and may be enlarged. Color Doppler examination reveals unidirectional flow in the anomalous vessel that is directed toward the main PV. Flow in both the tortuous vessel and main PV is hepatofugal (away from the liver) rather than hepatopetal. Pulsed wave Doppler examination of both the tortuous anomalous intrahepatic vessel and the main PV
typically shows a pulsatile pattern with systolic peaks indicating an exposure
of these vessels to the arterial system. The flow velocity profile and the waveform pattern of the tortuous anomalous vessel and the main PV are similar to
those of the hepatic artery as indicated by a low pulsatile low resistance flow
pattern (broad systolic peaks followed by continuous, high velocity diastolic
flow with velocity decreasing gradually) and a parabolic flow velocity profile
(broad velocity spectrum and lack of spectral window).
Multiple acquired PSS can be seen with HAVF as the result of portal hypertension. As with any disorder leading to severe portal hypertension (either
congenital or acquired) US may show different sites of acquired PSS such as
a long splenorenal shunt reaching an enlarged gonadal vein that connects the
left renal vein or multiple small tortuous vessels encircling the left renal vein
or the caudal vena cava.
Primary hypoplasia of the portal vein
Primary hypoplasia of the portal vein (PHPV) is an hepatic vascular disorder that encompasses two different forms. Hepatic microvascular dysplasia (MVD) is usually a mild manifestation of PHPV seen in small breed
dogs, and in which multiple microscopic shunts bypassing the hepatic sinusoids are present throughout the liver. Idiopathic noncirrhotic portal hypertension (INCPH) represents a more severe form of PHPV encountered in
large breed dogs, and in which intrahepatic small portal veins (and sometimes the main PV also) are underdevelopped or absent, leading to pre-sinusoidal portal hypertension.
In dogs with MVD, US examination may be normal despite clinicopathological signs suggesting congenital PSS. Sometimes a small liver may be seen
non specifically. Final diagnosis required angiography, scintigraphy or
CTscan of the portal system to rule out a marcroscopic PSS, and histological
exam of liver biopsy specimens.
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With INCPH, US typically shows ascites and multiple acquired PSS. The
liver appears small and homogeneous. The diameter of the PV is variable as
the main PV may or may not be hypoplastic. Histological exam of liver biopsy specimens is required for distinguishing INCPH from cirrhosis. Histological exam is strongly recommended as long-term prognosis appears much
more favorable in INCPH than in cirrhotic patients.
CONGENITAL DISORDERS OF THE BILIARY SYSTEM
Congenital disorders of the biliary system are much more uncommon than
congenital vascular disorders.
A Caroli’s disease-like disorder has been described in dogs and is also recognized in cats. This disorder is characterized by marked saccular enlargement (pseudocysts) of the intrahepatic bile ducts.
US features include severe cystic dilation of connected intrahepatic bile
duct with no evidence of duct obstruction. The presence of tubular connections between the pseudocysts helps in differentiation of Caroli’s disease
from autosomal polycystic kidney/liver disease. Wall of the dilated bile ducts
an pseudocysts may appear thickened and mineralized. Biliary calculi may
be present. The GB and CBD show normal US appearance as they are not involved by the underlying process. The liver parenchyma may be hyperechoic
as a result of associated fibrosis. Patients with liver fibrosis may develop portal hypertension with sonographic signs such as ascites and multiple acquired shunts. Abnormal kidneys may also be seen (hyperechoic cortex, decreeased corticomedullary distinction, irregular contour) as renal disease,
usually tubular ectasia or other cystic disease, is commonly associated with
biliary tract changes.
CONCLUSION
Ultrasound is the first diagnostic imaging modality to perform in a young
patient with serum biochemical evidence of hepatic dysfunction. When performed by an experienced operator, US allows detection of most of congenital portosystemic shunts differentiating intrahepatic and extrahepatic shunts.
US also allows identification of hepatic arteriovenous fistulas and multiple acquired portosystemic shunts, particularly suspected in the presence of ascites.
In a few cases US does not provide a precise diagnosis. Diagnostic imaging
procedures of the portal system using a portal blood tracer such as scintigraphy, mesenteric angiography or computed tomography are indicated to confirm or definitively exclude a macroscopic portosystemic shunt.
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BIBLIOGRAPHY
d’ANJOU MA (2007) The sonographic search for portosystemic shunts. VClin Tech Samll Anim Pract
22:104-114.
d’ANJOU MA (2004) Ultrasonographic diagnosis of portosystemic shunting in dogs and cats.Vet Radiol
& Ultrasound 45:424-437.
GORLINGER S (2003) Congenital Dilattion of the bile ducts (Caroli’s disease) in young dogs. J Vet Intern Med 17:28-32.
LAMB CR (1996) Ultrasonographic diagnosis of congenital portosystemic shunts in dogs: results of a prospective study. Vet Radiol & Ultrasound 37:281-288.
LAMB CR (1994) Comparison of three methods for calculating portal blood flow velocity in dogs using
duplex-Doppler ultrasonography. Vet Radiol & Ultrasound 35:190-194.
SZATMARI V (2004) Standard planes for ultrasonographic examination of the portal system in dogs. JAVMA 224:713-716.
SZATMARI V (2004) Ultrasonographic findings in dogs with hyperammonemia: 90 cases (2000-2002).
JAVMA 224:717-727.
SZATMARI V (2001) Normal duplex Doppler waveforms of major abdominal blood vessels in dogs: a review. Vet Radiol & Ultrasound 42:93-107.
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Paola Gianella
Med Vet, PhD, Dipl ACVIM (SAIM), Torino
ANATOMIA E
FISIOLOGIA EPATICA
Venerdì, 15 Ottobre 2010, ore 10.30
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Il fegato è uno degli organi più grandi dell’organismo; nei cani e nei gatti
adulti rappresenta circa il 3.5% del peso corporeo, mentre negli animali in accrescimento il 5%. A differenza di altre specie in cui i lobi epatici sono fusi
insieme, nel cane e nel gatto i lobi sono singolarmente riconoscibili perché
profondamente fissurati, in modo da poter compiere notevoli escursioni ad
ogni atto respiratorio accomodando i movimenti diaframmatici. Le diverse
posture dell’animale, causano inoltre un “adattamento anatomico” del fegato
che può assumere forme diverse e apparire addirittura più grande in alcune
proiezioni radiografiche. Il fegato si compone di 6 lobi, i lobi sinistro e destro,
a loro volta suddivisi in porzione mediale e laterale; il lobo quadrato ed infine quello caudale con i processi papillare e caudato. Il lobo più grande e più
mobile è quello laterale sinistro che costituisce circa il 30-40% dell’intera
massa epatica e i cui bordi periferici sono irregolarmente dentellati, probabilmente a causa di questa mobilità. Inoltre, poiché la parte periferica di questo
lobo non è interessata da grosse vene, arterie o dotti biliari, risulta essere un
comodo e sicuro sito di prelievo bioptico. La maggior parte dei bordi periferici è appuntita (30° o meno), anche se in minor misura in caso di epatomegalia o nell’animale giovane che possiede un fegato più grande in proporzione all’animale adulto. A livello radiografico, l’angolo di inclinazione caudoventrale varia notevolmente, con un valore medio di circa 50°. La superficie
diaframmatica (parietale) del fegato è convessa e giace per la maggior parte a
contatto con il diaframma, quella viscerale è invece orientata caudoventralmente e a sinistra, e prende contatto con lo stomaco, il pancreas, il duodeno e
il rene destro. Il fegato è fortemente ancorato alla vena cava caudale, che lo
attraversa e, tramite il legamento coronario al diaframma. Questa è la porzione meno mobile. Esistono inoltre i legamenti peritoneali che partono dal legamento coronario e che sono più corti e meno resistenti. I legamenti triangolari destro e sinistro ancorano le parti centrali dei lobi destro e sinistro al diaframma e possono anche essere doppi. Il legamento falciforme, che è localizzato a livello della linea mediana, si riduce cranialmente ad una delicata membrana, in alcuni casi completamente assente. Nella sua parte caudale, invece,
non si ancora direttamente al fegato ma forma un cuscinetto di grasso che funge da utile contrasto radiografico nei confronti della superficie diaframmatica
del fegato. Gli ancoraggi alla superficie viscerale sono invece di maggiori dimensioni ma più lassi, come quello epatorenale tra il polo craniale del rene
destro e la fossa renale del lobo caudato. Da una prospettiva dorsoventrale, il
fegato è ruotato verso destra. La cistifellea, i grossi dotti biliari e i vasi sanguigni entrano a livello dell’ileo nel quadrante superiore destro epatico. Il fegato possiede due diversi sistemi vascolari, un sistema portale a bassa pressione e un sistema arterioso ad elevata pressione. Il sistema portale drena sangue dallo stomaco, dall’intestino, dal pancreas e dalla milza e rappresenta circa i 4/5 del sangue afferente; il restante quinto è fornito dalle arterie epatiche.
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Queste arterie sono diramazioni dell’arteria epatica comune e sono in numero da due a cinque. Il sistema efferente epatico è invece costituito dalle vene
epatiche. A livello fetale, il dotto venoso consente uno shunt tra la vena ombelicale e il sistema venoso epatico; pochi giorni dopo la nascita diventa fibrotico, si occlude e prende il nome di legamento venoso. La vena porta, i dotti biliari, le arterie epatiche, i vasi linfatici e i nervi sono contenuti all’interno
di una porzione del piccolo omento detta legamento epatoduodenale. Il flusso totale ematico a livello epatico è circa il 20-25% della gittata cardiaca. La
vena porta accomoda circa il 70% di tale flusso e a livello ilare si divide in
due branche principali; quella destra che irrora la porzione destra del fegato,
e quella sinistra, molto più grande e più lunga che irrora la porzione centrale
e sinistra del fegato. Le vene portali intraepatiche si ramificano poi ulteriormente per terminare a livello delle aree portali da cui originano le venule che
distribuiscono il sangue portale ai capillari sinusoidi. Anche l’arteria epatica
entra nel fegato a livello dell’ileo. Le sue diramazioni si accompagnano a
quelle della vena porta per connettersi poi a livello terminale con quelle del
sistema venoso e sinusoidale. Il sistema biliare epatico è nutrito solo dal sangue arterioso mentre il parenchima epatico riceve sangue sia arterioso che venoso. Il sangue sinusoidale si riversa nelle vene centrali del lobulo epatico, anche dette vene terminali epatiche, nelle diramazioni della vena epatica ed infine nella vena cava caudale3.
Nei cani il fegato giace interamente all’interno della gabbia toracica e
quindi non è palpabile; un’eccezione è invece costituita dall’epatomeglia soprattutto nelle razze brachicefaliche che possiedono una gabbia toracica più
ampia e un diaframma più piatto. Nelle razze dei cani da corsa, che possiedono una conformazione toracica molto profonda, il fegato diventa palpabile solo in caso di grave epatomegalia. Nei gatti sani, invece, è sempre possibile palpare il bordo ventrale del fegato, o, in caso di epatomegalia, l’intero organo. Lo stomaco giace in contatto con la superficie epatica, di conseguenza,
qualsiasi modificazione epatica ne causa una dislocazione. Questa potrebbe
essere una possibile spiegazione del perché il vomito è spesso il segno clinico principale in pazienti con malattia epatica. Il sistema biliare serve per collezionare bile da ogni singolo epatocita ed è organizzato come la struttura di
un albero in cui nella parte prossimale avviene la produzione di bile e nella
parte distale il suo immagazzinamento. In ogni lobulo epatico gli epatociti si
dispongono a raggiera attorno ad una vena centrale, collegata a diverse aree
portali. Il sangue scorre dalla vena centrale alle aree portali, mentre la bile
fluisce dalle aree centrali alle aree portali e al dotto biliare comune. Le membrane laterali che connettono le cellule epatiche adiacenti contengono una regione specializzata detta membrana canalicolare. Lo spazio tra le membrane
canalicolari di epatociti adiacenti è sigillato da strette giunzioni intercellulari
e dà origine alle ramificazioni più piccole dell’albero biliare, i canalicoli.
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Questa regione escretoria costituisce circa il 15% della superficie epatocellulare. La maggior parte delle molecole viene escreta attraverso questa membrana dotata di sistemi di trasporto attivi specializzati, contro un elevato gradiente di concentrazione. I canalicoli a loro volta trasportano la bile a livello dei
tratti portali che drenano nei canali di Hering. Dai canali di Hering fluisce nei
dotti intraepatici, nei dotti interlobari, settali, ed infine ilari, i quali raccolgono la bile che si forma in ogni singolo lobo epatico. I dotti ilari formano poi
il dotto biliare comune (coledoco), il quale sbocca a livello duodenale nella
papilla del Vater, protetta dal reflusso di contenuto duodenale dallo sfintere di
Oddi. Il flusso biliare è influenzato da un trasporto attivo dovuto alla peristalsi (contrazione della cistifellea e chiusura/apertura dello sfintere di Oddi) solo nel dotto biliare comune4. Il dotto coledoco ha un diametro di 2-3 mm nel
cane e nel gatto e non sempre è facilmente visibile ad un’indagine ecografica. Tuttavia, in caso di ostruzione del dotto biliare comune, la dilatazione che
ne consegue diventa visibile e funge da segno ecografico caratteristico. La papilla duodenale maggiore è localizzata 3-6 cm caudalmente al piloro, a seconda della taglia dell’animale. Nei gatti, il dotto pancreatico e il dotto biliare comune sboccano nel duodeno insieme a livello della papilla duodenale maggiore. Questa particolarità anatomica spiega come mai in questa specie l’associazione tra pancreatite e colangite/colangioepatite si verifica con una certa frequenza. Nei cani invece, il dotto biliare e quello pancreatico sboccano separatamente. La cistifellea è connessa al dotto biliare comune attraverso un corto dotto cistico; è localizzata tra i lobi quadrato e destro mediale. Può talvolta essere doppia. Nelle proiezioni radiografiche laterali standard si visualizza
caudalmente al diaframma e sopra il margine dello xifoide. La sua posizione
è sempre un utile indicatore delle dimensioni epatiche. La sua funzione è
quella di immagazzinare e concentrare la bile; si pensi infatti che la bile viene concentrata fino a 10 volte nella cistifellea e nei grossi dotti biliari grazie
al riassorbimento attivo di sodio, ioni bicarbonato e acqua8. Nei cani e nei gatti sani la cistifellea completamente repleta è in grado di contenere circa 1 ml
di bile/kg di peso corporeo. Meno della metà di bile prodotta viene immagazzinata e concentrata a questo livello, mentre più del 50% viene immediatamente rilasciata nel duodeno attraverso il dotto biliare comune6. Il maggiore
stimolo alla contrazione della cistifellea è l’ormone colecistokinina (CKK)7,
che viene secreto dalla mucosa duodenale sotto l’influenza di grassi o proteine (aminoacidi). La cistifella non si contrae improvvisamente, come la vescica urinaria, ma gradualmente nel giro di 1 o 2 ore. Inoltre, mostra uno svuotamento incompleto e variabile in seguito al pasto (5%-65%)6. A livello istologico il fegato è costituito da unità funzionali emodinamiche o acini, diversi
dai lobuli, unità anatomiche il cui nome è invece puramente descrittivo. Il
concetto di acino, proposto da Rappaport, è costituito dalla vena porta al centro e da diverse vene epatiche, anche dette vene terminali epatiche, alla peri-
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feria. Le diramazioni delle arterie e della vena porta entrano nel fegato attraverso le aree portali. Il sangue portale viene così distribuito dalle grosse vene
portali attraverso gli acini fino ai capillari sinusoidi. In accordo con questo
concetto di acino, le unità circolatorie epatiche si dividono così in 3 zone. La
zona 1, la più vicina all’area portale, riceve sangue con il più elevato contenuto di ossigeno, nutrienti e fattori di crescita; la zona 3, la più distante dall’area portale, riceve invece sangue con la più bassa concentrazione delle suddette sostanze. In caso di shock o ipossia non compensati, gli epatociti localizzati in zona 3 diventano necrotici. Come risultato si ha una necrosi epatocellulare centrolobulare. Il tipo cellulare predominante è la cellula epiteliale o
epatocita (60% di tutte le cellule epatiche). Vi sono poi altri tipi di cellule quali quelle endoteliali, quelle epiteliali dei dotti biliari, quelle del Kupffer e
quelle stellate. Gli epatociti sono disposti in sottili foglietti cellulari attorno ad
una vena centrale e sono in contatto bilateralmente mediante numerosi villi
(membrana sinusoidale) con i capillari sinusoidi. La membrana sinusoidale
costituisce il 70% dell’intera superficie cellulare. Una porzione delle membrane cellulari laterali adiacenti forma i canalicoli biliari (come precedentemente accennato). La membrana canalicolare costituisce circa il 15% della
membrana epatocitaria e possiede specializzate funzioni escretorie. La membrana sinusoidale è separata dai capillari sinusoidi da uno strato di cellule sinusoidali. Tra gli epatociti e le cellule sinusoidali si trova lo spazio perisinusoidale di Disse, che consente il drenaggio della linfa. Lo strato di cellule endoteliali è fenestrato e permette lo scambio di grosse molecole tra lo spazio di
Disse e il sangue sinusoidale. Le cellule sinusoidali (endoteliali e di Kupffer)
sono molto efficienti nel rimuovere endotossine e batteri. Questa funzione, insieme alle numerose funzioni di detossificazione proprie degli epatociti e alle funzioni escretorie biliari, rende il fegato un organo fondamentale nel controllo delle sostanze tossiche provenienti dal tratto gastrointestinale. Sebbene
la funzione di tutti gli epatociti sia simile, esistono alcune differenze funzionali legate alla loro dislocazione. Per esempio, gli enzimi del ciclo dell’urea
si trovano in quantità preponderante negli epatociti di Zona 1, attorno all’area
portale; l’incorporazione dell’ammoniaca nella glutammina e il metabolismo
dei farmaci via citocromo p450 si verificano negli epatociti localizzati attorno alla vena centrale; il metabolismo dei lipidi e delle proteine non è confinato ad una zona particolare, mentre l’accumulo di rame colpisce soprattutto gli
epatociti di Zona 3. Il fegato possiede una notevole capacità di rigenerazione
e di riserva funzionale e la rimozione fino al 70% di parenchima epatico non
causa sintomatologia clinica. Tuttavia, in caso di epatopatia, la capacità rigenerativa diminuisce mentre aumenta la tendenza a produrre tessuto non funzionale (i.e. fibrosi epatica). La crescita epatica e la rigenerazione sono regolate da diversi fattori di crescita; tra questi il fattore di crescita epatocitario è
il più importante (HGF = hepatocyte growth factor). È prodotto dalle cellule
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stellate in seguito alla stimolazione di alcune sostanze come l’insulina e il fattore di crescita insulino-simile. In aggiunta, l’apporto ematico è indispensabile. Si pensi infatti ai pazienti con PSS nei quali una ridotta crescita epatica
causa microepatia e ridotta funzionalità, problemi che si risolvono brevemente dopo l’intervento chirurgico. Come precedentemente accennato, il fegato
svolge un ruolo importante in numerosi processi metabolici e nel mantenimento dell’omeostasi, poiché risponde alle richieste dei tessuti extraepatici attraverso un adattamento metabolico. Per esempio, le concentrazioni plasmatiche di glucosio e di numerose proteine sono regolate dal fegato e possono ridursi in caso di disfunzione epatica. Relativamente al metabolismo lipidico,
poi i trigliceridi provenienti dal tessuto adiposo o i chilomicroni intestinali,
vengono convertiti in lipoproteine a livello epatico per poter essere agevolmente trasportati. Altre funzioni metaboliche comprendono la biotrasformazione di prodotti endogeni (i.e. ammoniaca e ormoni steroidei) e la rimozione di prodotti tossici esogeni (i.e. sostanze chimiche, endotossine provenienti dai batteri intestinali). Numerose sostanze tossiche vengono escrete direttamente dal fegato (i.e. metalli pesanti), mentre altre sono modificate e poi successivamente escrete per via renale (i.e. conversione dell’acido urico in allantoina, conversione dell’ammoniaca in urea, trasformazione e coniugazione
degli steroidi). In aggiunta, grosse molecole (>300 Da) vengono invece escrete per via biliare dopo essere state coniugate e rese più idrofiliche. Un’altra
importante funzione metabolica del fegato è la produzione di acidi biliari. Circa il 50% di produzione di bile dipende dalla secrezione attiva epatocitaria di
sali biliari nei canalicoli. Gli acidi biliari vengono prodotti dal fegato a partire dal colesterolo, consentendone quindi un’escrezione. I due acidi formati
sono l’acido colico e l’acido chenodeossicolico, detti acidi primari. Prima di
essere escreti nella bile vengono resi idrofilici attraverso la coniugazione con
glicina e taurina. Come precedentemente accennato, una piccola porzione di
membrana epatocitaria (circa il 15%) circonda i canalicoli e contiene sistemi
di trasporto attivi. L’escrezione attiva degli acidi biliari contribuisce alla formazione di un notevole gradiente di concentrazione tra gli epatociti e i canalicoli. Il gradiente osmotico così indotto causa escrezione di acqua nei canalicoli, la quale diventa quindi la maggior forza drenante del flusso biliare.
Quando la bile raggiunge l’intestino, gli acidi biliari coniugati vengono parzialmente trasformati dalla flora batterica e deconiugati dalla glicina e dalla
taurina o idrossilati. Gli acidi biliari secondari, deossicolico e litocolico, sono
prodotti dall’idrossilazione dell’acido colico e dell’acido chenodeossicolico
rispettivamente. L’acido litocolico viene scarsamente assorbito, ma è epatotossico e può causare grave colestasi. Una piccola frazione di acidi biliari viene riassorbita (acidi biliari terziari) e trasformata in acido sulfolitocolico a livello epatico. Gli acidi biliari coniugati vengono attivamente riassorbiti nell’ileo. Gli acidi biliari non coniugati vengono assorbiti in tutto il tratto intesti-
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nale attraverso una diffusione passiva. Tutti gli acidi biliari riassorbiti vengono trasportati al fegato attraverso il flusso ematico portale, ove vengono riassorbiti a livello dei sinusoidi dalle cellule epatiche (90% ad ogni passaggio),
e se necessario, riconiugati e riescreti nei canalicoli. Solo una piccola frazione di acidi biliari si perde in questo circolo enteroepatico che si ripete 10-15
volte al giorno. La frazione persa viene sintetizzata nuovamente dal fegato.
Una parte della produzione di bile si verifica per secrezione epatocitaria di sodio nei canalicoli, seguita da una secrezione passiva di acqua. Il restante 30%
della bile viene prodotto dalle cellule epiteliali dei dotti biliari intraepatici attraverso l’escrezione di acqua, bicarbonato e cloro.
La bilirubina è un pigmento che determina la colorazione gialla-marrone
della bile. È il prodotto finale del catabolismo dell’eme. L’eme si trova nell’emoglobina dei globuli rossi e in numerosi sistemi enzimatici (i.e. citocromi, catalasi, perossidasi). Sebbene la quantità di emoproteine epatiche sia esigua se paragonata a quella emoglobinica, la produzione di bilirubina dall’eme
epatico è circa il 30% della produzione totale, poiché il turnover epatico dell’eme è notevolmente elevato (2 ore-4 giorni verso 98 giorni dell’emoglobina).
La bilirubina plasmatica viene eliminata dal fegato attraverso l’escrezione biliare dopo un processo di coniugazione; non viene riassorbita a livello intestinale. La bilirubina non coniugata è idrofobica e si lega alle albumine plasmatiche. Raramente, in caso di dismicrobismo intestinale, viene deconiugata dagli enzimi batterici e riassorbita nel piccolo intestino attraverso il circolo enteroepatico. La degradazione batterica della bilirubina nel colon dà origine alle stercobiline, pigmenti neri e marroni che conferiscono alle feci la loro normale colorazione. Gli animali sani possiedono in circolo solo bilirubina non
coniugata. La colestasi causa un accumulo di bilirubina coniugata nel plasma
che viene ri-escreta dal fegato e anche dai reni. La presenza di bilirubina nell’urina dei gatti è anormale ed indica sempre una malattia epatica. Al contrario, il rene dei cani, soprattutto maschi, possiede tutto il corredo enzimatico
necessario alla produzione e alla coniugazione della bilirubina. Quindi le urine dei cani maschi sani possono contenere concentrazioni misurabili di bilirubina. L’urobilinogeno è un prodotto incolore, di cui una piccola frazione è
riassorbita a livello portale. La maggior parte viene escreta dal fegato mentre
una piccola parte dai reni. In caso di ostruzione biliare extraepatica una minor
quantità di bilirubina raggiunge il tratto intestinale e la quantità di urobilinogeno nelle urine è ancora inferiore. La misurazione dell’urobilinogeno nelle
urine è quindi stata utilizzata per differenziare colestasi da forme diverse di ittero. Tuttavia, a causa di variazioni fisiologiche ed errori tecnici, tale parametro non ha significato clinico. La bilirubina viene allontanata dalla circolazione, coniugata ed escreta con la bile dal fegato. Tale clearance è tuttavia un
processo non efficiente se paragonato a quella degli acidi biliari10. Mentre gli
acidi biliari sono quasi completamente eliminati al primo passaggio, la biliru-
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bina ne richiede diversi per essere eliminata completamente. Di conseguenza,
la bilirubina è ugualmente distribuita in tutto il torrente circolatorio, mentre
gli acidi biliari sono concentrati soprattutto a livello di sangue portale (mentre hanno una bassa concentrazione a livello sistemico). Questo spiega i diversi pattern di reazione di bilirubina e acidi biliari in caso di epatopatia. In presenza di colestasi, tutti i componenti della bile compresi bilirubina e acidi biliari entrano nella circolazione sistemica attraverso la linfa epatica. Tale processo non è dovuto alla clearance epatica o alla perfusione portale epatica. Al
contrario, in caso di malattie caratterizzate da shunts porto sistemici, le elevate concentrazioni portali di acidi biliari raggiungono la circolazione sistemica
causandone un aumento della concentrazione plasmatica. Invece, la concentrazione di bilirubina non è influenzata da una perfusione epatica anomala.
Gli animali con shunt porto sistemico non mostreranno mai ittero.
Oltre alle funzioni metaboliche il fegato possiede anche funzioni di immagazzinamento di svariate sostanze (i.e. glicogeno, vitamine, ioni metallici) ed
ematopoietiche in caso di anemia.
BIBLIOGRAFIA CONSULTATA
1.
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4.
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6.
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8.
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10.
Slatter D. The liver and biliary system in Slatter-Textbook of Small Animal Surgery. Third Edition,
vol.1 Saunders. 2003 pg. 513-514.
www.vin.com
Cullen JM et al. Morphological classification of parenchymal disorders of the canine and feline liver; reversible hepatic injury and amyloidosis. In: WSAVA Standards for clinical and histological
diagnosis of canine and feline liver disease. Edinburgh, Churchill Livingstone, 2006;77-84.
Abiru H, Sarna SK, Condon RE. Contractile mechanism of gallbladder filling and emptying in dogs.
Gastroenterology 1994; 106(6):1652-61.
The liver as an organ in Textbook of medical physiology. 11th ed. Guyton and Hall.
Rothuizen J, de Vries-Chalmers H, van Papendrecht R. et al. Post prandial and cholecystokinin-induced emptying of the gall bladder in dogs. Vet Rec 1990; 126:505-507.
Westfall SG, Deshpande YG, Kaminski DL. Role of glucagon and insulin in canine bile flow stimulated by endogenous cholecystokinin release. Am J Surg 1989; 157:130-136.
Center SA. Serum bile acids in companion animal medicine. Vet Clin North Am Small Anim Pract
1993;23(3):625-657.
Armstrong PJ, Rothuizen J. Hepatology. Vet Clin North Am Small Anim Pract 2009; 39(3):419-437.
Rothuizen J, van den Brom WE, fevery J. The origins and kinetics of bilirubin in healthy dogs, in
comparison with man. J Hepatol 1992; 15:25-34.
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Paola Gianella
Med Vet, PhD, Dipl ACVIM (SAIM), Torino
INQUADRAMENTO
CLINICO DEGLI SHUNT
PORTO-SISTEMICI
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Gli shunt porto-sistemici (PSSs) sono malformazioni vascolari che causano un “dirottamento” del sangue proveniente dalla circolazione venosa addominale verso la circolazione venosa sistemica bypassando i capillari sinusoidi
e il parenchima epatico1,2. In condizioni normali, il sangue proveniente da stomaco, intestino, milza e pancreas entra nella vena porta, perfonde il fegato attraverso la rete dei capillari sinusoidi, per poi dirigersi nelle vene epatiche
ed infine nella vena cava caudale1. Se è invece presente una comunicazione
anomala tra la circolazione venosa sistemica e quella venosa portale (shunt
porto-sistemico), le sostanze assorbite dall’intestino (nutrienti, ormoni trofici
intestinali e pancreatici, prodotti batterici e tossine di derivazione intestinale)
non vengono metabolizzate e detossificate dagli epatociti3. La riduzione
del flusso ematico e della funzionalità epatica che ne conseguono causano una
diminuzione dell’accumulo epatico di proteine e di glicogeno, una disfunzione del metabolismo proteico e lipidico, una disfunzione del sistema reticoloendoteliale, un alterato metabolismo dell’ammoniaca e di altre tossine, atrofia epatica ed eventualmente insufficienza epatica. Infatti, la riduzione dei
fattori epatotrofici presenti nella circolazione venosa addominale, quali ormoni (insulina, glucagone) e fattori di crescita che inducono in particolare la produzione locale dell’HGF (hepatocyte growth factor), contribuisce a causare
uno scarso sviluppo epatico sia in termini di funzionalità che di massa. Come
regola generale i PSSs possono essere congeniti o acquisiti, cioè secondari a
malattie epatiche ed ipertensione portale. Nei cani il dotto venoso, che trasporta il sangue ossigenato placentare alla circolazione sistemica fetale bypassando la circolazione epatica, generalmente si chiude entro pochi giorni dalla nascita. Un’anomala pervietà di tale vaso, o un’anomala comunicazione tra il sistema venoso vitellino e quello cardinale del feto, danno origine a shunt congeniti porto-sistemici rispettivamente intra- ed extraepatici1,2. Generalmente
gli shunt congeniti sono singoli, anche se alcuni animali possono averne due
o più. Circa il 20% dei cani con PSS presenta invece shunt multipli acquisiti,
secondari all’ipertensione portale cronica. Un aumento della pressione portale causa infatti l’apertura di vasi sanguigni fetali, cui fa seguito una riduzione
della pressione idrostatica delle vene portali. Gli shunt acquisiti sono generalmente multipli, tortuosi ed extraepatici, e sono frequentemente localizzati nella regione perirenale. Le cause più comuni sono la cirrosi epatica, l’ipertensione portale non cirrotica, le malformazioni epatiche artero-venose e l’ipoplasia
venosa portale congenita. I tipi più comuni di shunt congeniti sono invece
quello portocavale intraepatico, come il dotto venoso persistente, e quello portocavale extraepatico, come lo shunt porta-azygos. Altri tipi di malformazioni
vascolari riportati in letteratura sono quelli macroscopici veno-arteriosi (le
malformazioni epatiche arterovenose) e quelli microscopici veno-parenchimatosi (displasia microvascolare o ipoplasia venosa portale epatica). In una piccola percentuale di cani con PSS congenito, la vena porta pre-epatica è assen-
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te. Poiché la vena azigos è molto più piccola della vena cava, il flusso attraverso lo shunt porta-azigos è ridotto e questi pazienti tendono ad avere segni
clinici meno gravi, spesso apparenti non prima dei 5-7 anni di età. In rari casi, esiste solo una comunicazione tra la vena porta e una vena sistemica, senza la presenza di una normale continuazione vasale a livello epatico, cranialmente alla porzione di shunt. Misurazioni quantitative hanno rivelato che, nella maggior parte dei casi, più del 95% del sangue portale bypassa il fegato.
Una compensazione avviene però, almeno in parte, grazie ad un aumento del
flusso epatico arterioso. In questo modo la richiesta epatica di ossigeno viene
soddisfatta e mantenuta. La gravità dei segni clinici dipende sempre dalla
quantità e dalla provenienza del flusso ematico che bypassa il fegato e può
comprendere una sintomatologia variabile (encefalopatia epatica, segni gastrointestinali cronici, delle basse vie urinarie, coagulopatie e ritardi dell’accrescimento)4. Negli animali con shunt porto-sistemici, la concentrazione di
tossine endogene ed esogene che sono normalmente metabolizzate o eliminate dal fegato (ammoniaca, glutammina, acidi grassi a catena corta, tossine
encefalopatiche intestino-associate, ormoni, sostanze benzodiazepino-simili, aminoacidi aromatici…) aumenta, mentre le normali funzioni del metabolismo epatico (gluconeogenesi, ciclo dell’urea, ciclo dell’acido urico…) diminuiscono (vedi sopra). I PSS intraepatici congeniti sono descritti in circa il 2533% dei cani, mentre singoli PSS extraepatici congeniti in 66-75% di cani e
gatti; la localizzazione portocavale sembra essere la più frequente3,5. La maggior parte degli shunt intraepatici viene riscontrata in cani di grossa taglia,
mentre la maggior parte degli shunt extraepatici nei cani di piccola taglia5. Alcuni shunt extraepatici, come quello portoazygos o portofrenico, possono essere associati a segni clinici meno gravi (vedi sopra), probabilmente a causa di
una minor frazione di shunt, o di una compressione diaframmatica o gastrica
(replezione) intermittenti. Cani con ipoplasia portale epatica venosa senza
ipertensione possono mostrare segni clinici simili a cani con PSS congenito,
sebbene la sintomatologia sia meno grave, evidente in età avanzata e la prognosi a lungo termine con la sola terapia medica migliore. Due razze frequentemente predisposte sono il Cairn terrier e lo Yorkshire terrier6,7. Animali con
PSS e con ipoplasia portale epatica venosa senza ipertensione presentano le
stesse modificazioni istologiche e gli stessi segni clinici. Tra le razze maggiormente riportate essere predisposte allo sviluppo di PSS extraepatici ricordiamo lo Yorkshire terrier, l’Havanese, il Maltese, il Dandie Dinmont terrier, il
Carlino e lo Schnauzer piccolo5,12. Nei gatti, sebbene gli shunt extraepatici
siano frequentemente riportati1, non mancano segnalazioni di shunt congeniti intraepatici13. Persiani, siamesi, himalayani, burmesi e domestici a
pelo corto sono razze in cui gli shunt porto-sistemici sono stati segnalati di frequente. Tra i cani di grossa taglia ricordiamo gli Irish wolfhound, i Retriever,
gli Australian cattle dog e gli Australian shepherd. Un’ereditarietà è stata
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dimostrata per lo shunt intraepatico congenito sinistro negli Irish wolfhound14,
e per i cani di razza maltese, mentre in uno studio condotto in Australia, gli
Australian cattle dog maschi presentavano di frequente lo shunt intraepatico
destro15. Si pensa inoltre che anche i cani di razza Yorkshire possano avere una
trasmissione di tipo ereditario, che nei Cairn terrier è stata documentata per
l’ipoplasia venosa portale epatica non associata ad ipertensione (carattere autosomico). La maggior parte della sintomatologia associata agli shunt congeniti porto-sistemici è riconducibile all’encefalopatia epatica. Si tratta di una
sindrome neuropsichiatrica che annovera una serie di anomalie neurologiche
che si manifestano con la perdita della funzionalità di più del 70% del parenchima epatico8. Più di 20 differenti sostanze si accumulano in circolo in elevate concentrazioni in caso di insufficienza epatica, alterando molteplici
aspetti della funzionalità del sistema nervoso centrale. Per esempio, gli aminoacidi aromatici causano una diminuzione della sintesi dei neurotrasmettitori DOPA e aumentano la produzione dei falsi neurotrasmettitori; gli acidi biliari rendono invece la barriera emato-encefalica più permeabile; le benzodiazepine endogene causano un’iperpolarizzazione della membrana neuronale; il
triptofano causa una neuro inibizione attraverso un’azione tossica diretta; la
glutammina altera il trasporto aminoacidico attraverso la barriera emato-encefalica; i falsi neurotrasmettitori esercitano un’azione sinergica con l’ammoniaca e gli acidi grassi a catena corta e diminuiscono la detossificazione dell’ammoniaca nel ciclo cerebrale dell’urea. Tuttavia, in base a numerosi studi, l’ammoniaca può essere considerata la sostanza più importante poiché un aumento della sua concentrazione scatena una serie di eventi metabolici implicati
nello sviluppo dell’encefalopatia epatica non solo nel cane, ma anche nell’uomo e nel ratto8,9,10. L’ammoniaca causa un aumento delle concentrazioni cerebrali di triptofano e di glutammina, una diminuzione di ATP disponibile,
un’aumentata eccitabilità, un’aumentata glicolisi, edema cerebrale e una diminuzione della NA, K-ATPase microsomiale a livello cerebrale. Le terapie volte alla diminuzione di ammoniaca riducono la gravità dei segni clinici dell’encefalopatia epatica, anche se non esiste una relazione diretta tra la gravità dell’encefalopatia epatica e i livelli di ammoniemia, suggerendo quindi il ruolo di
altre neurotossine nella patofisiologia dell’encefalopatia epatica11. In altre parole, l’encefalopatia epatica è una disfunzione cerebrale che coinvolge diversi
sistemi di neurotrasmissione a livello cerebrale, e poiché l’integrità cerebrale
non è compromessa a meno che non si tratti di stadi molto avanzati, i sintomi
neurologici sono completamente reversibili con la correzione del problema
epatico. I più importanti sistemi di neurotrasmissione che vengono coinvolti
sono il glutammato, la dopamina/noradrenalina, e il sistema acido gamma
amino butirrico/benzodiazepine. I segni clinici dell’encefalopatia epatica sono
variabili. Nel primo stadio sono aspecifici (apatia, diminuita attenzione,
svogliatezza) e spesso vengono riconosciuti a posteriori, quando è presente
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una sintomatologia più tipica. Successivamente possono comparire atassia,
tremori, aggressività, anomalie dell’andatura, movimenti di circolo, cecità, salivazione, stupore, inattività, pressione del capo contro gli ostacoli, coma.
L’epilessia non è frequente ma si può verificare occasionalmente in associazione ad altri sintomi. L’epilessia da sola, in assenza di altri sintomi, non è mai
causata dall’encefalopatia epatica. La fluttuazione della sintomatologia tra lo
stadio 1 e quelli più avanzati è caratteristica; generalmente uno o più giorni di
grave sintomatologia si alternano ad almeno una o più settimane con assenza
quasi totale della sintomatologia. In aggiunta alla sintomatologia neurologica
causata dall’encefalopatia epatica, si possono osservare una serie di sintomi
non neurologici quali poliuria, vomito, diarrea, perdita di peso, crescita stentata e disuria (cristalli di biurato di ammonio). Tra i fattori che precipitano la
sintomatologia da encefalopatia epatica ricordiamo: pasti ricchi di proteine,
deficienza di zinco e di arginina (gatti), ipopotassiemia, alcalosi, ipovolemia,
ipossia, emorragie gastrointestinali, infezioni, azotemia, costipazione, farmaci e trasfusioni di sangue stoccato (che contiene livelli elevati di ammoniaca).
A causa inoltre di un’aumentata sensibilità cerebrale ai sedativi, analgesici ed
anestetici, è possibile che si sviluppi coma anche utilizzando dosaggi normali. La maggior parte di cani e gatti valutati per uno shunt porto-sistemico congenito si presenta alla visita veterinaria con segni clinici acuti o cronici già all’età di 1-2 anni o meno, sebbene alcuni pazienti abbiano un’età superiore ai
10 anni5,16. Negli studi riportati in letteratura, nei cani non è ancora emersa una
chiara predisposizione per il genere maschile o femminile, mentre nei gatti i
maschi sembrano essere colpiti più di frequente3,17. In anamnesi viene riportato un paziente sottopeso (11%), intollerante agli anestetici, ritardato mentalmente o letargico, che mostra comportamenti bizzarri (41-90%; soprattutto pressione del capo contro ostacoli, sguardo fisso e perso nel vuoto, vocalizzi casuali, cecità intermittente, aggressività, stazione quadrupedale fissa
contro pareti od ostacoli…)3,4,17. Alcuni animali, soprattutto cani, si presentano con un’anamnesi di ematuria, stranguria, pollachiuria, o ostruzione urinaria (20-53%). A causa di una diminuita produzione di urea, un’aumentata
escrezione di ammoniaca, e un diminuito metabolismo dell’acido urico, si
possono formare calcoli di urato di ammonio (30% dei pazienti), eventualmente associati ad infezioni batteriche5. Poliuria e polidipsia sono frequenti
nei cani, e come cause sono state proposte varie teorie, compresa un’aumentata secrezione di ACTH, una riduzione del gradiente di concentrazione della
midollare causato da bassi livelli di BUN, un aumento del flusso ematico renale, e una polidipsia psicogena secondaria all’encefalopatia epatica. Una correlazione tra l’insorgenza dei segni clinici e l’ingestione del pasto è stata riportata nel 30-50% dei pazienti4. Vomito, pica, anoressia, diarrea o sanguinamenti gastrointestinali sono anche frequenti nei cani (30%)17, ma meno nei
gatti. Lo ptialismo è estremamente comune nei gatti (75%) e si crede essere
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causato dall’encefalopatia epatica o da problemi gastrointestinali4,18. In uno
studio, 75% dei cani con malformazioni epatiche artero-venose e con PSS
congenito associato a grave ipoalbuminemia presentavano ascite18. Come regola generale, l’ascite è frequente nei pazienti con una concomitante enteropatia proteino-disperdente, la quale può essere associata ad ulcere/sanguinamenti gastrointestinali o IBD con o senza linfangectasia. L’ascite sembra essere maggiormente riscontrata nei pazienti con shunt porto-sistemico intraepatico (osservazioni personali del Dr. Berent AC, vedi anche ref. 17). Altri difetti congeniti riportati negli animali con PSS congenito sono soffi cardiaci e
criptorchidismo (fino al 30% nei gatti e al 50% nei cani a seconda degli studi)1,4. Sono inoltre state documentate, soprattutto nei gatti, colorazioni anomale dell’iride (color rame inappropriato per la razza). I segni clinici associati ad
una malformazione epatica artero-venosa sono la somma di quelli causati dallo shunt e dall’ipertensione portale. Questo problema è stato segnalato nei cani di tutte le taglie e in un piccolo numero di gatti4,19. Oltre all’ascite (75%),
sono stati riportati soffi cardiaci (20%), crescita stentata, letargia, segni gastrointestinali e talvolta un rumore di flusso ematico turbolento a livello della
fistola (auscultazione epatica). Segni di encefalopatia epatica sono riportati
meno frequentemente rispetto ai pazienti con shunt porto-sistemici. Per quanto concerne le alterazioni di laboratorio, l’anomalia più frequente è la presenza di un’anemia da lieve a moderata, microcitica, normocromica non rigenerativa (60-72% dei cani e 30% dei gatti). La causa dell’anemia microcitica è
ancora sconosciuta, anche se si pensa a meccanismi di alterato trasporto del
ferro, diminuita concentrazione sierica del ferro, diminuita capacità totale di
chelazione del ferro e aumentati accumuli epatici di ferro nelle cellule del
Kupffer1. Generalmente la microcitosi si risolve dopo la fissazione dello shunt.
Al contrario, la microcitosi non viene riportata nei cani con displasia microvascolare - ipoplasia portale venosa4. Altre anomalie riscontrabili nell’emogramma sono le cellule a bersaglio eritrocitarie nei cani e i poichilociti nel gatto20.
Inoltre, la leucocitosi osservata può essere secondaria a stress o inadeguata
clearance epatica di batteri ed endotossine3. Le anomalie del profilo biochimico sono anche molto comuni nei pazienti con PSS. Nei cani quelle più frequenti includono l’ipoalbuminemia (50%), la diminuzione della BUN (70%),
l’ipocolesterolemia e l’ipoglicemia (da diminuita sintesi epatica). Valori di albumina inferiori a 1.3 g/dl generalmente indicano una prognosi infausta. Sono inoltre riportati lievi-moderati aumenti delle concentrazioni sieriche di
ALP e ALT. Al contrario, nei gatti l’ipoalbuminemia e l’ipocolesterolemia non
sono frequenti, mentre sono tipici una diminuzione della BUN e un innalzamento degli enzimi epatici21. Tuttavia, queste anomalie sono tipiche di qualsiasi malformazione vascolare epatica, senza essere patognomoniche per nessun disordine in particolare. La ALP è generalmente molto più elevata della
ALT nel caso di PSS e generalmente tale aumento è causato dall’isoenzima
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osseo negli animali in accrescimento4. Per quanto riguarda l’esame delle urine, è frequente il riscontro di un peso specifico diminuito (>50% ipostenuria
o isostenuria) dovuto alla polidipsia e al diminuito gradiente di concentrazione della midollare e cristalluria di biurato di ammonio. L’iperammoniuria,
causata da un ciclo epatico dell’urea malfunzionante, insieme ad un inappropriato metabolismo dell’acido urico, è responsabile di un’eccessiva escrezione di ammoniaca e di urati con formazione di cristalluria (26-57% di cani e
16-42% di gatti)22 o di calcoli (30% di cani in uno studio)5. La proteinuria può
essere presente e si pensa essere secondaria a sclerosi glomerulare o ad un’altra glomerulopatia. In uno studio di 12 cani, tutti mostravano evidenza di moderata-grave glomerulofibrosi o glomerulonefrite membranoproliferativa23.
Questo legame tra la presenza di una malattia epatica grave e la glomerulonefrite è stato osservato da tempo in medicina umana e si pensa essere secondario all’accumulo renale di antigeni che bypassano la clearance epatica. Nella
maggior parte dei cani con PSS sono presenti prolungamenti dei tempi di coagulazione, anche se i sanguinamenti spontanei sono rari a meno che non venga eseguita una chirurgia. In uno studio sembra che la mortalità post-operatoria fosse aumentata nei cani che presentavano un peggioramento della coagulopatia dopo l’intervento24. Poiché gli epatociti sintetizzano la maggior parte
dei fattori della coagulazione, gli animali in insufficienza epatica si pensa abbiano carenze di uno o più di questi fattori. In ogni caso, circa il 65-80% di
questi fattori deve essere perso prima che si verifichi un aumento del tempo di
protrombina (PT) o del tempo di tromboplastina parziale attivata (PTT). Inoltre, il fegato è anche coinvolto nella clearance dei fattori attivati, in modo da
favorire la rigenerazione dei fattori inattivati e dei fattori fibrinolitici. I cani
con PSS possono avere prolungati PTT, senza aumenti del PT, potenzialmente a causa di un’alterata sintesi epatica, anomalie qualitative, e clearance dei
fattori di coagulazione25. I fattori che sono stati visti essere deficitari sono i fattori II, V, VII e X, suggerendo quindi che anche il PT dovrebbe essere prolungato. Una spiegazione certa comunque manca25. I cani con PSS
possono inoltre mostrare una trombocitopenia perioperatoria, che suggerisce
la presenza di una coagulopatia da consumo. Gli acidi biliari pre- e post-prandiali sono ampiamente utilizzati per valutare la funzionalità epatica negli animali con PSS. La concentrazione degli acidi biliari è influenzata dalle contrazioni della cistifellea, dalla velocità di trasporto intestinale, dalla deconiugazione nell’intestino tenue, dalla velocità e dall’efficacia dell’assorbimento nell’ileo, dal flusso ematico portale, dalla funzionalità degli epatociti e dal trasporto canalicolare. Sebbene un aumento degli acidi biliari postprandiali sia
sensibile al 100% nell’individuazione del PSS nei cani e nei gatti26, in un esiguo numero di pazienti gli acidi biliari postprandiali sono normali mentre
quelli preprandiali sono aumentati. I cani di razza Maltese, inoltre, hanno acidi biliari aumentati senza che sia presente un sottostante problema epatico. È
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comunque importante ricordare che gli acidi biliari non sono specifici per gli
shunt porto-sistemici poiché un loro aumento è stato osservato in corso di malattie epatobiliari, colestasi, glucocorticoidi, antiepilettici, collasso tracheale,
crisi convulsive e malattia gastrointestinale20. Un altro test che può essere utilizzato in caso di sospetta falsa negatività degli acidi biliari è la misurazione
dei livelli plasmatici di ammoniaca. La sensibilità dell’ammoniaca basale negli animali a digiuno si avvicina al 100%27 e quindi il test di tolleranza dell’ammoniaca è raramente necessario. La concentrazione degli acidi biliari è
stata considerata anche da alcuni autori essere meno sensibile e meno specifica dell’ammoniaca per la diagnosi di shunt porto-sistemico27. Nei cuccioli di
Irish wolfhound è possibile avere risultati falsi positivi a causa di un difetto
congenito nel metabolismo dell’ammoniaca5.
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Tobias KM. Portosystemic shunts. In: Bonagura JD, Twedt DC, editors. Current veterinary therapy
XIV. 14th edition. St Louis (MO): Saunders Elsevier; 2009. p.581-586.
Tams TR. Disease of the liver and hepatobiliary system. In: Tams TR, editor. Handbook of small animal gastroenterology. 2nd edition. St Louis (MO): Elsevier Science; 2003. p. 330-335.
Mathews KG, Bunch SK. Vascular liver diseases. In: Ettinger SJ, Feldman ED, editors. Textbook of
veterinary internal medicine: disease of the dogs and cat. 6th edition. St Louis (MO): Elsevier Saunders; 2005. p. 1453-64.
Winkler JT, Bohling MW, Tillson DM, et al. Portosystemic shunts: diagnosis, prognosis and treatment of 64 cases (1993-2001). JAAHA 2003; 39:169-185.
Christiansen JS, Hottinger HA, Allen L, et al. Hepatic microvascular dysplasia in dogs: a retrospective study of 24 cases (1987-1995). JAVMA 1985; 207:1048-1054.
Schermerhorn T, Center SA, Dykes NL, et al. Characterization of hepatoportal microvascular dysplasia in a kindred of cairn terriers. JVIM 1996; 10(4):219-230.
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Holt DE, Washabau RJ, Djali S, et al. Cerebrospinal fluid glutamine, tryptophan, and tryptophan metabolite concentrations in dogs with portosystemic shunts. Am J Vet Res 2002; 63:1167-71.
Fisher JE. On the occurrence of false neurochemical transmitters. In: Williams R, Murray-Lyons I,
editors. Artificial liver support. Tunbridge Wells (UK): Pitman Medical; 1975. p. 31-48.
Tobias KM, Rohrbach BW. Association of breed with the diagnosis of congenital portosystemic
shunts in dogs: 2400 cases (1980-2002). J Am Vet Med Assoc 2003;223(11): 1636-1639.
Schunk CM. Feline portosystemic shunts. Semin Vet Med Surg (Small Anim) 1997; 12:45-50.
Kerr MG, van Doorn T. Mass screening of Irish wolfhound puppies for portosystemic shunts by the
dynamic bile acid test. Vet Rec 1999; 144(25):693-6.
Krotscheck U, Adin CA, Hunt GB, et al. Epidemiologic factors associated with the anatomic location of intrahepatic portosystemic shunts in dogs. Vet Surg 2007;36:31-36.
Worley DR, Holt DE. Clinical outcome of congenital extrahepatic portosystemic shunt attenuation
in dogs aged five years and older: 17 cases (1992-2005). JAVMA 2008; 232: 722-727.
Berent A, Weisse C. Portosystemic shunts and portal venous hypoplasia. Standards of Care. Emergency and Critical Care Medicine 2007; 9(3):1-11.
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Broome CJ, Walsh VP, Braddock JA. Congenital portosystemic shunts in dogs and cats. N Z Vet J
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Chanoit G, Kyles AE, Weisse C, et al. Surgical and interventional radiographic treatment of dogs
with hepatic arteriovenous fistulae. Vet Surg 2007; 36:199-209.
Willard MD, Twedt DC. Gastrointestinal, pancreatic, and hepatic disorders. In: Willard MD, Tvedten H, Turnwald GH, editors. Small animal clinical diagnosis by laboratory methods. 3rd edition.
Philadelphia: WB Saunders Company; 1999. p. 172-207.
Schunk CM. Feline portosystemic shunts. Semin Vet Med Surg (Small Anim) 1997; 12:45-50.
Johnson CA, Armstrong PJ, Hauptman JG. Congenital portosystemic shunts in dogs: 46 cases (19791986). JAVMA 1987; 191:1478-1483.
Tisdall PC et al. Glomerulopathy in dogs with congenital portosystemic shunts. Aust Vet J 1997; 73:
52-54.
Kummeling A. et al. Prognostic implications of the degree of shunt narrowing and of the portal vein
diameter in dogs with congenital portosystemic shunts. Vet Surg 2004; 33:17-24.
Kummeling A. et al. Coagulation profiles in dogs with congenital portosystemic shunts before and
after surgical attenuation. JVIM 2006; 20:1319-1326.
Center SA. Serum bile acids in companion animal medicine. Vet Clin North Am Small Anim Pract
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513-541.
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Heidi Hottinger
LIVER BIOPSY
TECHNIQUES
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Before performing any procedure on the liver, even biopsies, it is important to have a good understanding of the liver anatomy. This will allow full
evaluation of all liver lobes so that representative samples can be collected
and important lesions will not be missed. It will also minimize complications
during biopsy procedures due to the close proximity or involvement of important structures and organs, such as the caudal vena cava, gall bladder and bile
duct, portal vein, right kidney and stomach. A review of the general anatomy
in a veterinary text book is recommended, but a few important points should
be stressed to aid in the review.
The liver is composed of 6 lobes: the right lateral, right middle, quadrate,
left middle, left lateral and caudate lobes. The caudate lobe is further divided into the caudate process which sits against the cranial pole of the right
kidney, and the papillary process which molds to the lesser curvature of the
stomach. The caudal vena cava passes through the caudate process of the
caudate lobe and the right middle lobe. The gall bladder sits between the
quadrate lobe and the right middle lobe. Several ligaments provide stabilization of the liver lobes to the diaphragm and viscera and will often need to be
dissected free to allow mobilization of the liver lobe of interest. These ligaments are reflections of the peritoneum and include the falciform, hepatorenal, hepatogastric and coronary ligaments.
Prior to performing a liver biopsy technique, a coagulation panel should be
evaluated in addition to other diagnostic tests. Coagulopathies are common
with both liver and biliary disorders. Clotting factors are made in the liver and
the Vitamin K utilized in creating the factors requires bile for absorption from
the intestinal tract. Patients with biliary obstruction should be pretreated with
injections of Vitamin K1 preferably 24 hours prior to surgery. Patients with
Liver Anatomy: Ventral Surface
LL:
LM:
Q:
RM:
RL:
C:
G:
CVC:
PV:
CHA:
63
Left lateral liver lobe
Left middle liver lobe
Quadrate liver lobe
Right middle liver lobe
Right lateral liver lobe
Caudate liver lobe
• Papillary process
• Renal process
Gall Bladder
Caudal Vena Cava
Portal vein
Hepatic artery
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hepatic parenchyma disease may have deficiencies of clotting factors, which
may require specific techniques or equipment for proper hemorrhage control
or replacement with fresh frozen plasma if severe. It should also be kept in
mind that the liver is quite friable and diseased livers are often more friable
than normal. For this reason, the liver should be handled very gently to avoid
trauma and iatrogenic hemorrhage and all instruments should be delicate, in
good repair and sharp.
There are 3 main catagories of techniques that can be used to sample or
biopsy the liver. The first are the percutaneous techniques (fine needle aspirate and needle core biopsy), the second is laparoscopic (typically with a clam
shell forcep) and the third is by open abdominal exploratory techniques
(wedge, guillotine and punch are the most common). Choice of technique is
dependent of many factors which relate to the patient as well as the operator
and technique. Factors relating to the patient include liver size and texture; focal, multi-focal or diffuse disease; presence of abdominal effusion, coagulation status and whether the patient is suitable for anesthesia. Operator and
technique factors include availability of necessary equipment, experience
with the chosen technique, complication rates of the chosen technique, and
size of specimen required.
Percutaneous Techniques. These techniques can be performed blindly, or
preferably with ultrasound guidance. They are best utilized when hepatomegaly is present as well as diffuse or uniform disease. They should NOT
be chosen to sample a cavity mass. They should also be avoided if a coagulopathy is present or if there is a good chance that the disease could be corrected surgically (eg. EBDO, PSS, large solitary mass that can be excised).
Heavy sedation is recommended for these techniques. Should the patient
move or struggle during sample collection, the sharp needles or biopsy instruments can cause laceration of the liver, blood vessels or bile ducts.
Fine Needle Aspirate (FNA). The advantages of this technique are that it is
easy to perform using a 22-25 Ga needle with syringe, and it is relatively safe.
It should not be performed in patients with a platelet count <20,000/ul. The
disadvantages are that it does not reveal architecture and can miss fibrosis and
infiltrative diseases that are not extensive. For example, the finding of hepatocytes with vacuoles may lead to a diagnosis of hepatic lipidosis, but additional disease such as lymphsarcoma or cholangiohepatitis that is associated
with the hepatic lipidosis may be missed. Basically, you can’t eliminate a diagnosis if it was not found on a FNA. Positive findings are important, negative findings suggest moving on to a more definitive biopsy technique. Studies that have looked at the accuracy of liver FNA results compared to surgical
biopsies found <40% correlation for most diseases (neoplasia, chronic hepatitis, cholangitis, fibrosis, cirrhosis, portovascular anomalies).
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Needle Core Biopsy. This technique allows for an actual biopsy of the liver tissue
compared to cytology so architecture can be
evaluated and infiltrative disease is more
likely to be found. Disadvantages and cautions must also be carefully recognized with
this technique. It should be used in conjunction with ultrasound guidance rather than
blindly because significant or fatal damage
can occur if the larger biopsy needle punctures the vena cava, portal vein or gall bladder. Ultrasound guidance can also improve
the probability of collecting a representative sample. Samples collected with this technique may be fragmented or too
small to properly interpret and it is difficult to monitor the patient for hemorrhage from the biopsy sites. For this reason, this technique is not recommended in patients with platelet counts <60,000-80,000/ul and the patients should
be monitored closely for about 2 hours after the procedure. The ultrasound
should be repeated 30 minutes post-procedure to evaluate for possible hemorrhage (fluid in the abdomen) and patient heart rate, mucous membrane color,
blood pressure and attitude should be closely followed. To increase the rate of
positive yield from this technique, a 14 Gauge biopsy instrument is recommended and at least 3 core samples should be collected. The samples should
be carefully handled and placed into tissue cassettes or onto cardboard before
placing into formalin. Use a 25 Ga. needle to gently roll the tissue from the
channel of the biopsy instrument onto the cassette or cardboard and do not allow the sample to dry out before placing in formalin. It should be recognized
that the ultrasound can be insensitive to some infiltrative disease processes, so
this technique can still miss lesions and disease processes that direct visualization can better access. It can be very useful, however, for lesions deep within the liver parenchyma that visual inspection can miss.
Laparoscopic Liver Biopsy. This technique has the advantages of direct
visualization of liver pathology as well as confirmation of hemorrhage control. Multiple representative samples can be collected and larger biopsy specimens are collected compared to needle core biopsies. Disadvantages are that
the samples are very superficial in origin, still somewhat limited in size and
the patient must undergo general anesthesia. Anesthesia considerations for
these patients are very important. The liver is necessary to metabolize drugs
and anesthetic agents so they may have longer recovery periods and increased
sensitivity to anesthetic agents and narcotics. Increased abdominal pressure
from insufflation can decrease lung volume so most patients will require me-
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chanical ventilation. A final disadvantage
is the need for specialized equipment and
experience with the technique. To collect
liver biopsies with a laparoscopic technique, a clam shell biopsy instrument is
recommended. Hemostatic control is
achieved with gelatin sponge. Patients can
be positioned in dorsal or lateral recumbancy, but I prefer dorsal and will describe that approach. Two 5 mm ports will be used for the technique, one located just caudal to the umbilicus (so that the falciform ligament is avoided)
and a second more laterally placed working port. Abdominal insufflation
should be maintained at 10-12 mm Hg pressure with CO2. All liver lobes and
surfaces should be visually inspected and a minimum of 2 biopsy samples
should be collected. The gelatin sponge is placed into each biopsy site and additional pieces are placed as needed to control hemorrhage. After samples are
collected, the abdomen should be carefully inspected to ensure hemostasis.
Lavage and suction may be necessary if you are uncertain about hemorrhage
control. Keep in mind that the increased abdominal pressure of insufflation
and hypotension from anesthesia may suppress hemorrhage. Bleeding can occur once the abdominal pressure is decreased and blood pressure is restored
after anesthesia, so careful postoperative monitoring is still required.
Surgical Liver Biopsy. Open surgical techniques allow optimal visualization of all lobes and surfaces so that biopsy sites can be carefully selected.
They also provide the largest and usually the most diagnostic samples. Hemostasis can be managed with a variety of techniques so this is the optimal approach for patients with a concern of clinical bleeding. Several techniques can
be utilized to biopsy the liver at the time a laparotomy, including the guillotine technique, wedge biopsy and punch biopsy. Hemostasis options include
gelatin sponge or similar hemostatic agents, digital pressure, suture ligatures,
hemostatic clips, omentum and falciform ligament. The disadvantages of
these techniques are that they require general anesthesia, a surgical incision
and lesions deep within the hepatic parenchyma may not be visualized.
Guillotine technique. This method allows for large tissue samples, but it is
limited to lesions that are located on the edge of a liver lobe, preferably near
a tip or fissure. An encircling ligature is tied around the chosen tip of the liver. The liver parenchyma crushes or fragments under the ligature and vasculature is entrapped and ligated. Unfortunately, most lesions are not conveniently positioned near a tip or fissure which limits the usefulness of this technique. It can also be associated with significant frustration if the ligature is cut
or slips off the tissue when the sample for biopsy is transected and removed.
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Wedge biopsy. The wedge biopsy also allows for large tissue samples and
it is slightly more versatile in that the location of sampling does not have to
be at a tip or along a fissue, but it still requires the lesion to be close to the
edge of a liver lobe. Multiple ligatures placed as through-and-through overlapping mattress sutures are used to surround the lesion and ligate the hepatic parenchyma and vessels. Monofilament, absorbable suture on a taper needle should be used. This technique can also be associated with the frustration
of cut or slipped ligatures when the biopsy sample is removed.
Punch biopsy. I personally prefer the punch biopsy technique because it
is very quick, easy and allows sampling of tissue anywhere throughout the
lobes of the liver, not just on an edge. The biopsy defect is small enough to
allow control of hemostasis even in patients with coagulopathies. Multiple
biopsy sites can be collected in the time required to collect a single sample
by the guillotine or wedge techniques. The disadvantage is that it will yield
smaller samples than the other surgical techniques. The tools required include a 4 mm sharp skin biopsy punch and a gelatin hemostatic agent. To collect a liver sample, simply choose the site of interest, place the punch over
the region and spin in one direction with very gentle pressure to cut through
the capsule. Then direct the punch at an angle, spin again, and lift the sample out while still holding the punch at an angle. The angular spin and retraction allows the cutting edge of the biopsy punch to cut the deep base of the
biopsy core. The sample can be removed from the punch with a gentle but
forceful shake over a moistened gauze sponge. A rolled piece of gelatin
sponge is inserted into the biopsy site and help in place with a gauze sponge
and gentle pressure for 30-60 seconds. Patients with a coagulopathy may require 2 minutes of steady pressure to completely control hemorrhage. Gently
roll the gauze off the biopsy site to prevent dislodging the gelatin and clot. If
hemorrhage continues, use a second
piece of cellulose sponge and additional
pressure. Multiple sites can be biopsied
throughout the liver with this technique.
It is rapid and easy and requires minimal
investment in supplies. The size of the
biopsy is sufficient for pathologic diagnosis form most disorders except possibly copper storage deficiency.
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Heidi Hottinger
HEPATOBILIARY
NEOPLASIA
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Hepatobiliary cancer is relatively rare in the dog and cat compared to other types of cancer, but as a surgical veterinarian, they will still need to be managed fairly frequently. The most common tumors are hepatocellular adenomas
(hepatomas), hepatocellular carcinomas, hemangiosarcoma, cholangiocarcinomas, biliary cystadenomas, biliary cystadenocarcinomas and rarely hepatic
carcinoids. Benign nodular hyperplasia can result in large masses that can create diagnostic confusion and may at times require resection. Rarely, tumors of
other cell types may also arise in the liver, such as osteosarcomas, anaplastic
carcinomas, fibrosarcomas, myelolipomas, etc. Metastatic nodules commonly develop in the liver due to the duality of blood flow from the portal vein
and hepatic artery as well as the low pressure sinusoidal filtering mechanism
of the liver. Systemic cancers such as lymphosarcoma and mast cell tumors
may also have hepatic involvement. Most hepatobiliary cancers are found incidentally or may be associated with vague clinical signs such as lethargy,
vomiting, diarrhea, inappetance and anemia. Serum alanine aminotransferase
(ALT) and serum alkaline phosphatase (ALP) may be elevated or normal. Total bilirubin is rarely elevated. Radiographs, ultrasound and CT scans can be
very helpful in the diagnosis of hepatobiliary neoplasia. Biopsy may be indicated in situations of numerous masses in the liver or small nodules. For larger masses, biopsy is only indicated if it will affect the owner’s willingness to
treat. Otherwise, surgical excision and definitive biopsy is the diagnostic and
therapeutic action of choice. Biopsy should be avoided in cavitary lesions as
it may initiate hemorrhage and a positive diagnosis is often difficult since
most of the mass tends to be clotted blood. Also keep in mind that a cavitary
lesion does not always mean the tumor is a hemangiosarcoma. Adenomas and
adenocarcinomas can hemorrhage and develop large cavitary components.
Multi-nodular disease on ultrasound exam does not necessarily equate to
metastatic disease either. Only definitive histologic biopsy can make that distinction. I have been surprised on numerous occasions as to the positive results of a biopsy compared to the presumed poor prognosis based on the initial ultrasound or visual impressions. Tumor size should also not be cause for
poor prognosis. For solid tumors, the large size typically indicates less aggressive behavior or it could not have achieved such a large size.
Prognosis for a particular tumor type may have impact on owner willingness to pursue surgery, so a little basic knowledge about the most common hepatic tumors is important.
• Hepatocellular adenomas may be very large and typically have a solid,
diffuse echogenic texture. They are benign in nature and complete surgical excision can achieve cure. Surgical excision is advised because it
can be difficult to differentiate them from hepatocellular carcinoma and
regenerative nodules on biopsy. Large masses can also develop abscessation or they may rupture and hemorrhage.
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• Hepatocellular carcinomas come in 3 varieties. Multi-nodular and diffuse forms are not amenable to surgical excision and carry a much poorer prognosis. Massive, solitary hepatocellular carcinoma carries a much
more favorable prognosis. The tumor is slow growing and slow to metastasize. If surgical excision is possible, long-term control or cure can be
achieved for most patients. It will have a solid tissue, homogenous
echogenic texture on ultrasound exam. Chemotherapy following surgical
excision is not generally recommended, however long-term supplementation with s-adenosyl L-methionine (SAMe) is recommended.
• Hemangiosarcoma that arises as a primary mass in the liver can be
amenable to surgery if it is a solitary lesion. Prognosis is still very guarded, with an average survival of 2-6 months. These tumors tend to have a
cavitary appearance on ultrasound examination and free fluid in the abdomen is also a common finding due to hemorrhage. However, a lack of
abdominal fluid does not preclude a diagnosis of hemangiosarcoma.
• Biliary cystadenomas and cystadenocarcinomas are most commonly
seen in cats. They can be solitary or multiple, small or massive. Larger masses may appear polycystic, like a grape cluster and are typically amenable to removal. They can also cause a cystic sacculation in the
wall of the common bile duct, which carries a less favorable prognosis.
The benign and malignant forms of the disease can both carry a favorable prognosis if surgical resection is possible. Both benign and malignant growths have the potential for recurrence, however, so the patient
should be monitored long term.
Before considering surgery to remove a hepatobiliary cancer, the veterinarian must have a strong grasp of the anatomy of both systems. A review of
the general anatomy in a veterinary text book is strongly recommended. It is
also important to keep in mind some basic but very important patient principles when planning surgery on the liver.
• Of primary importance is the fact that the liver is instrumental in metabolizing many anesthetic agents and drugs. Doses of some medications
may need to be altered depending on the degree and type of compromise
to liver function. Narcotic dosing must be especially monitored to prevent overdose. A complete blood count, serum chemistry profile and
urine analysis are recommended on all patients.
• A coagulation panel is recommended as coagulopathies are common
with both liver and biliary disorders. Clotting factors are made in the liver and the vitamin K utilized in creating the factors requires bile for absorption from the intestinal tract. Patients with biliary obstruction
should be pretreated with injections of Vitamin K1 preferably 24 hours
prior to surgery. Patients with hepatic parenchyma disease may have de-
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•
•
•
•
ficiencies of clotting factors, which will require replacement with fresh
frozen plasma if severe.
Proper perioperative antibiotic therapy is important. The liver is a low
oxygen tension system, so anaerobes are prevalent. The biliary tree has
direct communication with the intestinal tract, resulting in an enterobacter flora (E. coli, Strep. spp., Proteus spp., Klebsiella spp.). Antibiotic
choices should include the cephalosporins, which are excreted in high
concentrations in the bile, and chloramphenicol, amoxicillin and the fluoroquinilones, which reach high levels in the liver parenchyma.
At the time of surgery, it should be kept in mind that the liver is extremely friable, and diseased livers are often more friable than normal.
For this reason, the liver should be handled very gently to avoid trauma
and iatrogenic hemorrhage. The liver also receives significant blood
flow, requiring the surgeon to be familiar with hemostasis techniques,
especially if a coagulopathy is present. Hepatic hemorrhage can often
be controlled with digital pressure, patching with the falciform ligament
or omentum, ligation of the causative vessels with through-and-through
mattress sutures, hemostatic agents such as gelatin sponges, stapling
equipment and tissue sealing devices.
When performing any procedures on the liver and biliary system, the
surgeon should also remember to collect representative liver biopsies
separate from the tumor, unless a biopsy has been recently evaluated.
Patients undergoing major surgery on the liver should be monitored
closely for the first 12-24 hours following surgery. It is not uncommon
for their temperatures to progressively drop several hours after surgery,
especially cats. Should this occur and not be rectified, it can lead to
death of the patient. External heat sources are important postoperative
and patient temperature should be monitored until the patient is up and
moving around. Narcotics may need to be partially reversed so the use
of pure agonist narcotics is recommended since agonist/antagonist narcotics cannot be reversed.
Before you are able to perform surgery on the liver, a proper abdominal incision must be created. This means a midline incision that extends from the
xiphoid to the caudal abdomen or pubis. An incision of this size is imperative
to allow proper visualization of the liver and safe working space. The falciform ligament/fat should also be removed when the incision is created or it
will block visualization and access to the liver and it will also become traumatized and potentially result in painful steatitis in the postoperative period.
It is also important to have proper abdominal retraction so that the incision
can be held open. Balfour retractors are one of the best options, but paired
Gelpi retractors can be used in cats and very small dogs—one at either end of
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the incision. Once the abdomen is properly exposed, you are ready to begin
surgery on the liver.
Many liver tumors are quite large and may raise concern as to the amount
of liver that can be safely excised. Fortunately, the liver has tremendous regenerative potential, allowing 70% of the liver to be safely excised if the remaining 30% is apparently normal. When evaluating the potential for successful removal of a liver mass, the size of the tumor is typically not the limiting
factor. Location of a tumor within the liver carries much greater impact on
surgical success. Tumors located near the edge of a liver lobe are easier to remove than those located up near the hilus. Tumors in the left side of the liver
are typically associated with more options for excision than those on the right.
The left lateral liver lobe is much more mobile at its hilus than other lobes so
a complete lobectomy is much more easily performed. The left middle lobe is
not as mobile at the hilus but the hilus is fairly remote from other important
structures. The right side of the liver is more intimately associated with the
gall bladder and common bile duct and the caudal vena cava and portal vein
run through the caudate and right middle lobes. Dissection of hepatic
parenchyma from these important structures is required to perform complete
lobectomies, so excision of most tumors on the right are limited to the ability
to remove them via a partial lobectomy rather than complete.
Various techniques can be used to perform partial or complete liver lobectomies. Dissection of the supporting hepatic ligaments of the lobe of interest
is important to allow proper retraction and visualization. Suture ligatures can
be used to perform partial lobectomies, but excision at the hilus should not rely on a single ligating suture. Dissection of the hilar tissues should be performed so that major vessels (which are usually quite large) can be individually ligated. Stapling equipment and/or vessel sealing equipment has become
much more common for liver lobectomies and their use allows for faster and
safer surgery for the patient. The most common stapling equipment is the TA
stapling devices. These instruments lay 2 or 3 alternating rows of staples
across the tissue. Staple size is chosen by the thickness and compressibility of
tissue that must be enclosed in the staples. I prefer to use the vascular cartridges when placing them across the hilus of a lobe where the vessels are
quite large. The vascular staples close tightly, place 3 alternating rows rather
than 2 and only come in a 30 mm length cartridge. This means that the hilus
must be dissected free of extraneous tissues. Partial lobectomies can use the
larger 55 mm cartridges that will span a larger area of hepatic parenchyma.
The vessels are smaller mid-lobe, so the larger bite of the staples is typically
adequate to control hemorrhage. Individual areas of continued bleeding can
then be controlled with hemostatic clips or gelatin sponge. My preferred
method is to use a combination of surgical staples and the LigaSure Vessel
Sealing System (Valleylab, USA). The LigaSure applies a precise amount of
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pressure and bipolar energy to the tissues between the electrodes, which causes the collagen and elastin in the vessel walls to fuse and transform into a single structure, basically sealing or obliterating the vessel lumen. It can seal
vessels up to 9 mm in diameter and will cause a thermal spread of approximately 2 mm. It can seal other tissues as well as vessels, but they must contain collagen and elastin for the device to be effective. Ultrasonic coagulation
devices can also be used and they result in a statistically similar amount of
thermal spread. The ultrasonic coagulation devices tend to be more cost prohibitive than the LigaSure device, so they are not as common in the veterinary
setting. I use the LigaSure to help dissect the hepatic parenchymal tissue near
the hilus of the liver lobe that I am removing. The electode jaws should be
gradually closed while activating the current until they are completely closed
and the machine indicates that the seal is complete (a beep will sound). I do
not like to use the LigaSure across the hilus of the lobe in most patients because the vessels approach or exceed the maximal size of the unit. Also, you
may only partially cross the vessel when going through the tissue, resulting in
excessive hemorrhage as the vessel partially seals and is partially open. Once
the LigaSure has helped to dissect all the tissue from the hilar region, I then
use a TA stapling device with the vascular cartridge to cross and staple the hilar vessels. Hemoclips and gelatin sponge can be used to control any additional hemorrhage that may be present after removal of the liver lobe and tumor.
Surgery for tumors of the liver and biliary tree requires familiarity with the
anatomy of both systems and proper anesthetic monitoring and recovery due
to the critical condition of many of these patients. The ability to provide blood
or plasma transfusion is often necessary and special equipment may be required at the time of surgery. With proper preparation and appropriate client
education as to the risks of surgery, results can be extremely rewarding for
many patients.
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Heidi Hottinger
SURGERY OF THE
BILIARY SYSTEM
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Surgery on the biliary system requires technical skill at the time of surgery
due to complex anatomy, difficult exposure and delicate tissues. The condition of the patient as well as associated liver disease can add additional challenges. A good grasp of biliary anatomy, proper patient preparation and monitoring, experience with biliary surgical techniques and appropriate instrumentation is important for successful results.
The anatomy of the biliary system can seem confusing at first, but is actually quite simple. Intralobar ducts feed into bile canaliculi and then into lobar
ducts within the liver. The lobar ducts coalesce into hepatic ducts, which carry bile from each of the liver lobes and empty into the common bile duct. The
common bile duct runs between the cystic duct of the gall bladder and the
duodenum and allows bile to flow in 2 directions; retrograde to the gall bladder for storage and normograde to the duodenum. The common bile duct
empties into the duodenum at the major duodenal papilla, next to the pancreatic duct. The gall bladder lies between the quadrate and right medial liver
lobes and communicates with the common bile duct via the cystic duct.
From: Miller’s Anatomy of the Dog1.
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Patients with biliary disease (primarily obstructive disease) may have malabsorption of Vitamin K1, resulting in deficiencies of Factors VII, IX and X.
Pretreatment with Vitamin K1, 0.5 – 1 mg/kg SC for 24-48 hours preoperatively, may help alleviate clotting deficiencies at the time of surgery. Patients that
also have primary hepatocellular disease may be unable to produce Factors
VII, IX and X despite administration of Vitamin K1, so plasma or whole blood
transfusions may be required at the time of surgery if intraoperative hemorrhage is a problem. Postoperative hemorrhage can also present as a problem,
necessitating blood products in the postoperative period. Intraoperative hemostatic tools are necessary during surgery regardless of clotting capabilities
when performing surgery on the biliary tract to help prevent intraoperative
and postoperative hemorrhage.
Proper surgical techniques and instruments are also important for successful surgery on the biliary system. The gall bladder is thin walled and contains limited smooth muscle. Puncture of the gall bladder wall with a needle
will often result in leakage of bile from the puncture site due to inadequate
closure from contracture. Leakage along a suture line can result from choosing needles that are too large or are not swedged onto the suture. Cutting needles can also be associated with leakage because they create a V-shaped cut
in the tissues, resulting in a larger hole than the suture material can fill.
Small, taper needles swedged onto the suture material should be chosen
when performing surgery on the ball bladder or common bile duct. The thinwalled gall bladder wall can be easily traumatized as well, especially if it is
diseased. Fine, atraumatic forceps and gentle tissue handling are just as important for surgical success as an understanding of the surgical techniques
and indications for their use. The most common reasons to perform biliary
surgery include trauma and extrahepatic biliary obstruction.
Trauma to the biliary system can result in laceration, rupture or avulsion
of the common bile duct, hepatic ducts or gall bladder. Clinical symptoms of
bile peritonitis may not become evident for days or weeks post trauma, and
will typically include anorexia, vomiting, weight loss, abdominal pain, lethargy, dehydration and eventually icterus and sepsis.
Extrahepatic biliary obstruction will often require surgical intervention to
alleviate the obstruction. Common causes of obstruction will be inspisated bile
and calculi. Obstruction can also result from inflammation at the duodenal
papilla associated with acute pancreatitis. Chronic pancreatitis can cause scarring and eventual obstruction at the papilla. A disease that has increased significantly in prevalence over the past few years is the phenomenon of biliary
mucoceles. This condition is seen with many different types of liver disease
and chronic pancreatitis patients, but the cause appears to be a primary prob-
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lem in the gall bladder wall called mucinous hyperplasia. It is especially prevalent in Shetland sheepdogs, dachunds and miniature schnauzers but can occur
in any breed. The condition is diagnosed on ultrasound examination by a characteristic stellate pattern within the gall bladder. The mucocele is formed when
bile salts and liquid are resorbed from the bile, leaving primarily the mucoid
component. On examination of the mucocele, a lamellar pattern, similar to the
rings on a tree will be noted. Symptoms can be chronic or acute, depending on
the type of liver disease that may be present. The disease is often silent until
the wall of the gall bladder becomes devitalized and undergoes pressure necrosis and rupture occurs. A cause or predisposing factors for this condition has
Biliary mucocele: lamellar appearance to the inspisated bile.
Biliary mucocele with stellate appearance on ultrasound.
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not been identified at this time. Surgical intervention is carries the most favorable prognosis for long-term management. For most patients, removal of the
gall bladder is the surgical procedure of choice. Some patients will have more
progressive disease and pieces of the mucocele will be located within the common bile duct and sometimes even in the hepatic ducts. If this situation is present, retrograde lavage of the bile ducts through the duodenal papilla is necessary to establish proper bile flow. Advanced stages of the disease may also be
associated with peritonitis, which will require specific surgical and postoperative management for that condition. Biliary mucoceles can have a very good
prognosis, even with underlying liver disease, if they are able to undergo surgical treatment and proper supportive care during the postoperative period.
Anesthesia, surgery and recovery must be carefully monitored and postoperative pancreatitis has been noted as a potential risk factor.
Common Bile Duct Procedures Occasionally, surgery will be indicated on
the common bile duct. The typical problem will be laceration or avulsion of
the duct. Surgical repair requires fine instruments and small gauge suture material, such as 5-0 or 6-0 absorbable monofilament (PDS, Maxon, Biosyn,
Monocryl). The duct should be cannulated for proper closure and the cannula then left in place as a percutaneous stent for the first several postoperative
days. The stent is typically placed through the duodenal papilla into the common bile duct. The stent can be run through the wall of the duodenum and the
duodenum pexied to the body wall where the stent passes through.
Cholecystotomy A cholecystomy involves opening and then closing the
gall bladder. This procedure is typically performed to remove inspissated bile
or calculi from the gall bladder. I feel it is also important to flush the cystic
and common bile duct, as the same inspisated bile or calculi may be in the
duct and occluding bile flow. This flushing is best accomplished by opening
the duodenum over the duodenal papilla and passing a red rubber catheter into the common duct, retrograde fashion. It is very difficult to pass a catheter
into the common duct from the gall bladder due to the sharp bend and incomplete valve that is present at the junction of the cystic and common ducts. Also, most obstructive material is lodged at the sphincter of Odi and can only be
removed by retrograde lavage back into the gall bladder, similar to urethral
calculi. The gall bladder should be opened on the convex edge, away from the
liver parenchyma. Hemorrhage from the cut edges is a good indication of viability. Lack of hemorrhage typically means a non-viable, necrosing gall
bladder—typically the case with biliary mucoceles. Closure of the gall bladder should be performed with 4-0 to 5-0 monofilament, absorbable suture material (PDS, Biosyn, Maxon, Monocryl) in a single layer, simple continuous
appositional pattern.
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Obstruction in bile duct.
Retrograde Lavage of bile duct.
Cholecystectomy A cholecystectomy involves complete removal of the
gall bladder. Indications for this technique include cholecystitis, necrosis of
the gall bladder from obstruction, neoplasia, trauma, and biliary mucoceles.
When possible, I recommend emptying of the gall bladder and retrograde
flushing of the common bile duct, as above, prior to removal of the gall bladder if potential for bile duct obstruction is present. It is not uncommon for advanced stage mucoceles to have the same inspisated material within the bile
duct that is present in the gall bladder, the same with inspisated bile. If the gall
bladder is removed without removing obstructing material from the ducts, the
patient will still be obstructed and will not show improvement postoperative.
To remove the gall bladder, it must be dissected free from its fossa in the liver. Gelatin sponge or other hemostatic agents may be necessary to help control oozing from the hepatic parenchyma in the fossa. The gall bladder should
be dissected to the level of the cystic duct. The cystic duct and cystic artery
should then be ligated with suture material or surgical hemostatic clips. Dietary changes will need to take place postoperatively for these patients. Low
fat diets will be important since they no longer have a storage reservoir for
bile and bile salts. Instead, the bile continuously trickles into the intestines as
it is produced. A low fat, high carbohydrate diet will aid tremendously in recovery and long-term quality of life.
Cholecystoenterostomy Anastomosis of the gall bladder to the intestines is
indicated in cases of extrahepatic biliary obstruction and common bile duct
trauma. In this procedure, the gall bladder is anastomosed to the proximal
duodenum, if possible, as this is closest to the normal anatomic location of
bile entry into the intestines. The gall bladder will often need to be dissected
from its fossa to facilitate proximity to the duodenum. If it is not possible to
anastamose to the duodenum, the jejunum can be used, choosing the most
proximal section that will mobilize to the gall bladder. The anastamosis
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should correspond to the length
of an incision from the fundus of
the gall bladder to the infundibulum (approximately 2-3 cm).
The stoma will contract approximately 50%, so this initial large
size is necessary to prevent stricture. A common error when creating the cholecystoenterostomy
that can lead to an increased rate of dehiscence is differing incision lengths in
the gall bladder and intestine. An incision is often made in the duodenum if
retrograde lavage of the common bile duct was attempted. This incision may
be longer than the length required for an anastamosis with the gall bladder for
ease of accessing the Sphincter of Odi at the duodenal papilla. The temptation
is to partially close this incision until it is the same length as the incision in
the gall bladder and then create the anastamosis. This is an accepted technique, but increased tension results at the “T” junction of the incisions and
this increased tension, as well as the tissue trauma required to pass several
loops of suture for closure of the corner defect can lead to dehiscence at that
location. The consequences of a dehiscence are so severe that the risk of using this technique may be too great.
The better options would be to increase the incision length in the gall bladder to match the incision in the duodenum, or close the duodenal incision and
create the anastamosis further down the duodenum or jejunum. Like patients
with a cholecystotomy, these patients will require a low fat diet as bile will
flow continuously into the intestines due to limited ability to distend the gall
bladder with the sizeable stoma.
In summary, surgeryof the biliary tree can be very successful and quite
rewarding. Unfortunately, complications can be quite devastating, so it is very
important to know the surgical anatomy as well as surgical techniques, use
careful tissue handling and have
proper instruments available. Proper patient preoperative preparation,
careful anesthesia and close postoperative monitoring are also important to
success. Remember when performing
any surgical technique on the liver or
biliary tree to collect bile cultures
and always BIOPSY several areas of
Paired incisions in gall bladder
the liver to evaluate for underlying
and intestine are preferred.
liver disease.
From: Fossum Small Animal Surgery2
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REFERENCES
1.
2.
Evans, HE, Christensen, GC, eds. Miller’s Anatomy of the Dog, 2nd ed. Philadelphia, Saunders
Company, 492-501.
Fossum, TW. Surgery of the liver. In: Fossum, TW, ed, Small Animal Surgery,2nd ed. St. Louis, Mosby, Inc. 450-473.
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Heidi Hottinger
SURGICAL TREATMENT
OF PORTOSYSTEMIC
SHUNTS
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Any discussion of congenital portosystemic shunts (CPSS) must first start
with an understanding of the physiology of the condition. This understanding
will allow a better understanding of the preoperative management and current
surgical recommendations. When blood bypasses the liver through a CPSS,
many things happen which result in the clinical and laboratory changes that
we will look for in a CPSS patient.
First, the liver does not receive nutrition or hepatotropic factors, resulting
in microhepatia. The liver is also responsible for metabolizing and storing
energy sources delivered from the intestinal circulation. CPSS patients will
not receive proper building blocks for growth and development and they will
have poor energy reserves, which can result in stunted growth, lethargy and
possibly hypoglycemia in young toy breeds. And finally, factors that would
normally be filtered from the intestinal blood flow by the liver will enter into the systemic circulation, creating false neurotransmitters. These factors include NH3, methionine/mercpatans, short chain fatty acids, γ-aminobuteric
acid (GABA), and altered ratios of branched chain: aromatic ring amino
acids. These false neurotransmitters are responsible for the symptoms of hepatic encephalopathy, many GI symptoms and increased urate crystals in the
urine as they are excreted.
PREOPERATIVE MEDICAL MANAGEMENT
Control of clinical symptoms and a decrease in false neurotransmitters is
the goal of medical management. This preoperative management not only
makes the patient a better surgical candidate, but it also dramatically decreases the rate of postoperative seizure syndrome. Postoperative seizure syndrome
typically occurs at 36 hours postoperative and progresses to status epilepticus
very quickly. Valium does not control the seizures. Continuous propofol infusion for 24-48 hours is the treatment of choice but is only associated with a
60-70% success rate. Residual neurologic symptoms or seizures may remain
in successfully managed patients. Because treatment has limited success, it is
preferable to prevent the syndrome.
A combination of medication and strict diet for a minimum of 2 weeks
preoperative has proven to be very successful. Medical management can be
used longer than 2 weeks, but patients typically become refractory to medical
management within 18-24 months. It should be stressed to owners that medical management must be followed VERY STRICTLY prior to surgery, even
if the pet had minimal symptoms, as their life could actually depend upon it.
Typical treatment goals are to decrease absorption of enteric toxins, decrease
the interaction of enteric bacteria with nitrogenous substances and decrease
oxidative hepatocyte damage.
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1. Lactulose 1 mL/4-5 kg, BID-TID, titrate until stool is soft. Changes intestinal pH which traps NH3 and other toxins, creates an osmotic gradient to decrease GI transit time allowing decreased absorption, and alters intestinal flora that metabolizes proteins & amino acids.
2. Antibiotic therapy: Neomycin at 10-15 mg/kg BID, or Metronidazole
at 10 mg/kg BID. Goal is to alter GI flora that breakdown nitrogenous
substances (proteins).
3. Dietary protein alteration. Components of false neurotransmitters
originate primarily from meat protein sources, so diets that have moderate protein restriction using protein sources originating from dairy,
soy and vegetables should be utilized. Commercial liver specific diets
are available and should be tried first before allowing owners to choose
appropriate dietary options for the pet. Caution should be used to avoid
diets that are too protein restricted or the patient may become hypo-albuminemic, which has been associated with a poor surgical prognosis.
Diets that are too low in protein may also result in protein starvation,
causing the body to utilize muscle resources to meet protein demands.
Muscle constitutes a meat source of protein and false neurotransmitters
may actually increase, contributing to hepatic encephalopathy.
4. Anti-oxidants, such as s-adenosyl-L-methionine (SAMe).
SURGICAL TECHNIQUES FOR CPSS
Surgical therapy is the treatment of choice for CPSS. Occlusion of the vessel allows for return of normal bloodflow to the liver. Unfortunately, most patients with a CPSS cannot tolerate complete occlusion of the vessel at the time
of surgery because the hepatic vasculature has not been able to properly develop such that it can handle the additional bloodflow. Portal hypertension develops, which results in the development of multiple acquired shunts or death.
The liver has the capacity to regenerate, so gradual return of bloodflow allows
vascular development that can eventually handle all of the portal bloodflow.
For this reason, techniques that create gradual vascular occlusion, rather than
acute complete ligation, is recommended for CPSS. Several techniques have
been described, which include ameroid constrictors, cellophane bands, hydraulic occluders and thrombogenic coils. The two most common techniques
used clinically are cellophane bands and ameroid constrictors.
Ameroid constrictors contain an inner band of ameroid and an outer stainless steel sheath (Research Instruments NW Inc, Sweet Home, OR). Ameroid
is a hygroscopic substance consisting of compressed casein that expands with
exposure to water. The initial theory for these constrictors was that the
ameroid would swell and slowly occlude the vessel. Studies have shown that
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the actual mechanism of action to occlude
the vessel is an inflammatory response.
This inflammation, fibrosis and intravascular thrombosis can occur at variable
rates—some patients as rapidly as 6 days,
other patients may not completely occlude at all. Because ameroid constrictors
may occlude the vessel too rapidly, they
have been associated with a relatively high rate of multiple acquired shunt development (17% for extrahepatic shunts, 40% for intrahepatic shunts). The
ring is also bulky and heavy and can hang on the vessel causing it to kink or
twist, rapidly occluding the lumen. The rings are associated with many benefits, however, in that they do not require measurement of portal pressures during surgery (although this information may be useful in predicting long term
outcome) and gradual occlusion of the shunt can be achieved with a single
surgery. Placement of the ring can be a bit tricky at times because a fair
amount of dissection must take place around the vessel to allow placement
and the ameroid “key” can be difficult to insert into the channel that completes the ring.
Cellophane Bands were first reported to be used clinically in 1990. The
initial recommendations suggested folding the cellophane into 3 layers, then
placing it around the vessel and using hemoclips to fix the cellophane
around the vessel. It was recommended to occlude the vessel to a diameter
of 2.5-3 mm using a metal rod. The cellophane caused occlusion of the vessel by an inflammatory response, similar to ameroid, but it occurs at a more
gradual rate. The technique has now evolved such that a single strip of cellophane, or 3 strips placed on top of one another, can be used for the occlusion. The folded cellophane tended to be bulky and did not lay nicely on the
vessel wall. The recommendation for 2.5-3 mm diameter closure has also
been altered. Some surgeons now just lay the cellophane on the vessel with
minimal attenuation of the lumen. I still prefer to measure portal pressures
and create a change of approximately 2-4 cm of H20. I tend to be in the minority in measuring portal pressures so it is definitely not necessary for successful use of the technique. Studies reporting clinical use of cellophane
bands show a slower occlusion rate and minimal development of multiple
acquired shunts compared to ameroid constrictors. Dissection around the
vessel does not have to be as extensive for placement of the cellophane compared to ameroid and it is very light weight so kinking or mechanical distortion of the vessel are not a concern. The drawbacks of cellophane are the
potentially variable rates of occlusion and very large vessels may not reach
complete occlusion.
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Hydraulic occluders have primarily
been used in research with little clinical
application. The occluder consists of an
injection port positioned under the skin
with a length of length of tubing that has
a stretch resistant cuff at the end. The cuff
is placed around the vessel and secured
with suture. Gradual inflation with the
cuff is then achieved by percutaneous injections of fluid into the port under the skin. The occluders are made of silicone so minimal inflammation develops. This means that the cuff must remain in place long term to maintain the occlusion of the shunting vessel. Cuff
damage or diffusion of fluid across the membrane are concerns for long-term
use of this device, so it has not gained widespread clinical use.
Thrombogenic Coils are placed into the vessel lumen via catheter access
and guide wires under fluoroscopic guidance. These have primarily been used
for intrahepatic shunts that are less amenable to surgical attenuation. The coils
are constructed of flexible metallic strips and polyester fibers that stimulate
thrombus development. Several problems are associated with their use. They
rapidly create a thrombus, which can cause too much occlusion of the vessel
and resulting portal hypertension. To alleviate this problem, multiple procedures are often required to deploy a few coils at each event, allowing for more
gradual occlusion. Coil migration is also a major complication, which can potentially be fatal. Deployment of caval wall expandable stents are now being
used to prevent migration of the coils out of the shunting vessel and into the
cava. This adds additional expense and multiple procedures may still be required, but stent migration has been shown to be alleviated with this technique. Due to the high rate of complications, multiple procedures and expensive equipment required for this technique, not to mention considerable experience with interventional radiology, this technique is not widely used. It can
be very beneficial, however, for intrahepatic shunts that are not amenable to
surgery or would be associated with high surgical risk.
POSTOPERATIVE PATIENT MANAGEMENT
As discussed, surgery is the treatment of choice for CPSS, but immediate
correction of the condition does not occur at the time of surgery. Gradual attenuation of the shunting vessel should take place over several weeks or
months, which dramatically decreases the rate of postoperative complications
(portal hypertension, seizures, multiple acquired shunts). This means that
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shunting continues for several weeks. The liver also needs time to regenerate
once hepatic bloodflow has been re-established. Most patients with CPSS will
also have some degree of microvascular dysplasia (MVD) within the liver,
which has more recently been termed portal venous hypoplasia (PVH). This
condition allows shunting of blood on a microscopic level within the liver.
PVH can be present without a CPSS, but all CPSS have PVH to some degree.
Most dogs will not experience complications from their PVH, but a few may
require some degree of medical management long-term following surgery.
Short and long-term postoperative management has evolved to meet the needs
of the recovering and potentially abnormal liver of CPSS patients.
1. Dietary management should continue for a minimum of 2 months postoperative or longer, depending on the measured fall of bile acid values.
2. Lactulose should continue for 4-8 weeks postoperative.
3. Antibiotics should continue for 2-4 weeks postoperative.
4. Anti-oxidants, such as SAMe, should continue throughout life.
5. Bile acid values, fasting and 2 hour postprandial, should be measured
approximately 2 months postoperative. If the values have not begun to
fall, medical management should continue and they should be checked
again in 2 months. Once values have begun to fall, fasting and 2 hour
postprandial bile acids should be evaluated again in 6 months, then annually for 2-3 years to establish a normal baseline for the patient (values may not completely fall to normal in many patients),and to ensure
that associated PVH does not begin to create problems for the patient
later in life.
As outlined above, understanding the disease mechanisms and goals of
treatment make the diagnostic and treatment protocols for CPSS much easier
to pursue and trouble-shoot. Surgical treatment of extrahepatic CPSS is associated with a 92-95% success rate, but that rate is dependent upon a well-orchestrated pre and postoperative course in addition to proper surgical techniques.
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Franco Orsi
Med Chir, Milano
INTERVENTIONAL
RADIOLOGY
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Clinical needs for local tumor control, by means of minimally invasive approach more than classical invasive, risky and expensive surgical ones, represents the main reason for the very fast developing of new hyper-technological branches in Oncology.
Due to the high specialization required for most of the interventional procedures in Oncology, the appellative of “Interventional Oncology” has been
proposed very recently to define this field.
Common elements of different approaches in this branch is image guidance
for very precise treatments and the low invasiveness compared with more
classical options.
For academic purposes Interventional Radiology may be divided in two
different main fields: Vascular treatments and Percutaneous procedures.
The use of blood flow for delivering drugs and/or particles directly and selectively to the tumor is the aim of all Vascular treatments in Interventional
Radiology and they are mainly oriented for liver tumor control.
Percutaneous procedures include all image-guided tumor ablative techniques which required percutaneous insertion of dedicated devices (such as
needle for radiofrequency).
Moreover, a totally new locoregional therapy for tumor ablation has been
very recently added to the IR armamentarium: High Intensity Focused Ultrasound (HIFU-see dedicated chapter).
VASCULAR TREATMENTS
Introducing the multimodal approach for hepatic lesions
Hepatic lesions represent a main challenge in clinical oncology, both for
primary and metastatic tumours. This is mainly due to the crucial role this organ represents for the prognosis. In hepatocellular carcinoma, the simultaneous presence of cirrhosis and tumour lesions in the majority of patients, limits the indication for an aggressive local approach, because of the high risk of
post-treatment liver failure.
Moreover the high rate of new nodule development after any local treatment (>80% after 4 years), plays a key role in the decision making on treatment strategy.
Regarding liver metastases, local treatments such as surgery for liver
metastases (mainly from colorectal cancer) after systemic chemotherapy
seems to induce better results than chemotherapy alone.
Minimally invasive local techniques are therefore being continuously developed in order to supplement the surgical resection.
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Super-selective bland arterial embolization with micro-particles
HCC: The intra-arterial treatment using transarterial chemoembolization
(TACE) and transarterial embolization (TAE) is considered a palliative therapy for multifocal HCC not suitable for surgical resection or percutaneous ablation therapies, but the efficacy of intra-arterial treatment in patient with single HCC is not well defined. However, it is not clear whether embolization
alone gives the same survival advantage nor whether specific patient characteristics affect outcome or any particular technique in performing transarterial therapy is better than any other.
The aim of this study, is to assess feasibility and local response in patients
affected by unresectable hepatocellular carcinoma, treated with TAE by using
very small sized fine-calibrated microparticles (40 and 100 microns).
Between October 2007 and september 2009 63 HCC patients underwent
100 TAE, and a total of 87 target lesions were embolized with a super-selective technique. Embolization was preformed by using very small size fine-calibrated micro-particles of 40 μ and/or 100 μ in diameter. In all cases liver perfusion scintigraphy was performed by injecting Tc-99 labelled albumin
macro-aggregates (MAA) via the main hepatic artery, just before treatment,
in order to rule out pulmonary shunting. MDCT was performed in order to assess the early local result after embolization.
Median follow-up for all 63 patients was 26 months (range, 1-38 months).
Of the 63 patients, 4 have died: one died within 24 hours after intervention
and three patient died for liver progressive disease. Up to now 29 out of 63
patients have at least one year follow up with an overall survival rate of 96%.
Local outcomes on target lesions at 1 year follow-up in these 29 patients are:
6 complete response (CR), 5 partial response (PR), 7 stable disease (SD), and
9 progressive disease (PD) for new lesions (i.e. new nodules) while 2 PD on
treated lesions.
Bland embolization is an effective therapeutic modality in the treatment of
unresectable HCC. In our initial experience with Embozene ™ 40 and 100
µm we observed a very good handiness in embolization, obtaining good results in lesion and disease control, at a median follow-up of 12 month. Microparticles 40 and 100 µm in diameter are very effective in local response,
with good clinical outcomes, but patients must be selected very carefully in
order to reduce major complications.
Metastases: The aim of this new field is to assess the feasibility and efficacy in metastatic lesion control with a new kind of coated small particles: 40
and 100 microns EMBOZENE®.
Between October 2007 and september 2009 42 patients with liver metastatic disease underwent TAE: 10 CRC, 17 NET, 5 breast cancer, and 10 from
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other malignancies. Technique used was the same as in primary liver cancer
for vascular access and microspheres injection. The intent was not curative only in patients with NET mets because of radionuclide therapy. The real purpose
in fact was to obtain a “debulking” effect. At the moment response assessment
is feasible in 38 patients following RECIST criteria: 12 PD, 15 SD, 8 PR and
3 CR with a mean follow-up of 13 month. 3 pt were lost at follow-up.
Yttrium-90 internal radiation therapy for hepatic malignancy
Surgical resection is the only potentially curative strategy in the treatment
of patients with hepatic malignancy. Unfortunately, due to advanced stage,
underlying liver disease, or medical co-morbidities, most patients are inoperable at this time of presentation. As a result, various loco-regional therapies
have emerged for otherwise unresectable hepatic tumors. Radioembolization
(i.e. intra-arterial administration of 90Y microspheres-SIR-Spheres®) is a therapeutic option that allows preferential delivery of radiations into the tumor
without significant liver toxicity.
SIR-Spheres® (SIRTEX Medical, Australia) is a resin-based microsphere,
of 20-40 μm-diameter, and a typical dose of 3-8 milion per injection.
90
Y is a pure β-emitting radioisotope, it has a high average energy (0.936
MeV), limited tissue penetration (mean 2.5 mm; max 11 mm), and short halflife (64 h), making it an ideal transarterial liver-directed agent. 90Y is selectively injected into the whole liver parenchyma, or in one liver lobe, via the
main lobar hepatic arterial branches.
Prior to radioembolization, detailed imaging (CT, PET/CT) and therapy
planning must be completed. All patients that are considered for 90Y internal
radiation therapy must undergo a preliminary hepatic angiography in order to
assess local vascular anatomy. At the end of angiography, simulation of treatment is performed by injecting 99mTc-macroaggregated albumin, in all hepatic arterial branches, and nuclear medicine scan is carried out (MAA scintigraphy). This work-up aims to determine the presence of hepato-pulmonary
shunting, and the amount of the dose to administer to the patient. Up to 2008,
29 patients with liver metastases (from colorectal cancer in 11 pts, breast cancer in 10 pts, uterine cancer in 3 pts, other cancers in 5 pts) have been treated
with SIR-Spheres® in our Institute.
Once vascular hepatic anatomy was assessed, for each patient a dosimetric
evaluation, based on 99mTc-MAA images (WB and SPECT, 30 min p.i.) and CT
scans, has been performed in order to estimate the activity to be safely injected.
Concerning the efficacy profile, revaluation CT and PET/CT (6, 12 and 18
weeks after treatment) documented objective response in 83% of patients,
with complete response in 3 of them.
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In our experience we observed that the optimal dose to normal liver is up
to 40-50 Gy, but the optimal response to the treatment has been achieved in
those lesions with high T/NT ratio at MAA scintigraphy. SIRT can be considered as a 2nd or 3rd line therapy for liver secondary lesions, but it must be
considered only in a multi-disciplinary and multi-treatment behaviour.
Percutaneous thermal ablation
Hepatocellular carcinoma and colorectal liver metastases are the two most
common malignant liver tumors. While surgical resection remains the gold
standard of therapy, only a few patients are suitable candidates for curative
surgical resection, because of the presence of liver malignancy in unresectable
locations, the number and anatomic distribution of tumor lesions, or the presence of extrahepatic disease, poor liver function or medical comorbidities.
From experiences reported in literature, despite the limitations of the data,
reasonable safety of the procedure has been established, with mortality and
morbidity rates in the largest series of 0.2% and 1.7% respectively. The major complications described are peritoneal bleeding, hepatic abscesses, intestinal perforation, large biloma, acute cholecystitis. Tumor seeding is probably
over-emphatisized and can be avoid by a hot withdrawal of the electrode.
Candidate patients with HCC and cirrhosis have to be in Child’s class A
or B; tumour has to be single or, if multiple, with no more than three nodules,
without vein thrombosis or extra-hepatic spread. The dimensions of the nodules should preferably be below 3–3.5 cm. By using combination therapy (hepatic artery occlusion and RFA; RFA and Pringle manoeuvre during surgery)
larger tumours can be treated. RFA is considered a safe bridge to liver transplantation in several recent papers.
Tumors close to the gall bladder or subcapsular adjacent to hollow organs
should be preferably treated by a laparoscopic or open approach; RFA of a lesion close to the hilum plate puts the patient at high risk of biliary injury. Up
to 2008, in our institute we treated 108 patients, 76 with liver metastases (follow up 2 – 98 months, median 46) and 32 with HCC (follow up 2-94 months,
median 42); RF was performed with ultrasound and/or CT guidance under
conscious sedation and requires 3 days of hospitalization. In our experience
we had a very low percentage of complications, less than 1%, and no mortality. To assess the results a contrast-enhanced CT is performed after one
month: coagulation necrosis appears as a non-enhancing low density area in
both arterial and portal phases; on MR T2 hypointense images and loss of enhancement on gadolinium enhanced MR correspond to complete necrosis.
FDG-PET allows for detection of pathological increase of glucose metabolism, as it happens in solid tumor. If a residual non-ablated tumor or tumor regrowth is detected a re-treatment with RF can be performed.
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Liver bland embolization associated with radiofrequency
thermal ablation
Tumor size, site and morphology may affect the local results of liver radiofrequency ablation (RFA). We are evaluating feasibility, safety and local
effectiveness of a single session combined approach for treating difficult liver lesions with bland embolization (TAE) immediately prior to RFA. Nineteen patients (9 males; mean age 66.5 years) with liver lesions (8 metastases
from CRC, 2 HCC, 2 CCC, 3 breast mets and 4 mets from different origin)
underwent the combined approach (TAE and RFA) in the same session. TAE
was performed with 40 µm Embozene™ injected within segmental or subsegmental arteries supplying the lesion, until cessation of blood flow. RFA
was then performed under US/CT guidance with 3.5 to 5 cm Lee-Veen needle, according to the lesion size (mean diameter 38.2 mm; range 25-70 mm).
Technical success was 100%. We obtained an area of coagulation necrosis larger than needle size (mean diameter 73 mm; range 44-108 mm). All lesions were completely ablated with a safe margin.
Combined approach for treating difficult liver lesions seems to be feasible
and safe. TAE with micro-particles performed immediately before RFA allows for a larger area of coagulation necrosis, improving the volume of ablation. Even if long-term clinical results are needed, this technique could be a
useful therapeutic option for patient with large or difficult liver lesions appropriate for localized treatment.
HIFU (High Intensity Focused Ultrasound)
High intensity focused ultrasound (HIFU) is a highly precise medical procedure using focused ultrasound energy for burning and destroy the tumor tissue at depth within the body, selectively and without harming overlying and
adjacent structures within the path of the beam. Unlike radiofrequency or
cryoablation, which are also used to ablate tumors, HIFU is completely noninvasive and can be used to reach tumoral areas that are deep within the body,
if there is an acoustic window for allowing for the transmission of ultrasound
energy. First devices never used widely in clinical practice were trans-rectal
probes, which have been used predominantly to treat the prostate cancer. Extracorporeal devices are significantly larger and can be used to treat a variety
of problems, most commonly intra-abdominal solid tumors. As a result, these
extracorporeal devices use transducers with a longer focal length and use both
ultrasound or MRI for targeting the organ. Several studies on HIFU treatment
of HCC and secondary liver metastases in human clinical trials have been already published. Wu et al. used an extracorporeal HIFU device to treat 68 pa-
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tients with liver malignancies showing complete tumor ablation in 30 cases in
which surgical excision followed HIFU treatment. HIFU has also been used
for palliation in patients with advanced-stage liver cancer by Li CX et al. observing after treatment 87% of symptomatic improvement. In Oxford, UK, in
2005 a total of 22 patients with liver metastases were treated with HIFU revealing a favourable adverse event profile when compared to open or minimally invasive techniques. To date, both animal and human subject investigations show significant promise in the treatment of hepatic malignancies with
HIFU. Hence this therapy can be applied to treat many patients who can not
undergo conventional treatment techniques due to either absolute and relative
contraindication or tumor location.
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Federica Rossi
Med Vet, Spec Rad Vet, Dipl ECVDI
Sasso Marconi (BO)
DIAGNOSTICA PER
IMMAGINI AVANZATA:
NEOPLASIE EPATICHE
E MALATTIE
NON VASCOLARI
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La Diagnostica per Immagini avanzata delle malattie neoplastiche e non
vascolari del fegato include l’Ecocontrastrografia, la Scintigrafia, la Tomografia Computerizzata e la Risonanza Magnetica.
ECOGRAFIA CON MEZZO DI CONTRASTO
Si tratta di una modalità innovativa che consente di studiare la perfusione
del fegato e di lesioni epatiche in modo non invasivo. Richiede l’utilizzo di un
mezzo di contrasto ecografico e di un sistema ecografico dedicato, in grado di
ricevere e selezionare il segnale ultrasonoro prodotto dal mezzo di contrasto.
Le piccole microbolle contenute nel preparato hanno un diametro molto piccolo, nell’ordine di pochi micron, pertanto sono in grado, dopo l’iniezione in
una vena periferica, di attraversare il filtro polmonare e di raggiungere il circolo sistemico. La normale perfusione epatica, studiata con eco-contrastrografia, è stata descritta nel cane1. La distribuzione epatica avviene tramite la
successione di due fasi, una fase precoce (early phase) che include a sua volta una fase arteriosa (wash in) e venosa (wash out) e una fase tardiva (sinusoidal phase). Il parenchima epatico si presta bene allo studio con il mezzo di
contrasto in quanto una lesione focale può essere confrontata con il parenchima adiacente per valutare differenze o similitudini nella perfusione. Il fegato
è l’organo per il quale i pattern di perfusione sono stati meglio caratterizzati
e in cui la differenziazione di lesioni maligne e benigne sulla base del tipo di
perfusione ha oramai sufficiente evidenza scientifica2,3. Possono essere studiate lesioni primarie già visualizzate mediante l’ecografia basale, o ricercare
la presenza di metastasi. Le lesioni maligne presentano generalmente un rapido wash out e rimangono ipoperfuse nella fase tardiva. Le lesioni benigne,
escludendo le cisti, gli ematomi e le lesioni necrotiche, presentano una perfusione simile a quella del parenchima epatico normale. Il rilievo di noduli disseminati ipoperfusi con rapido wash out in un paziente con HSA splenico indica la presenza di metastasi epatiche. Nonostante si possa considerare l’ecografia con mezzo di contrasto una metodica affidabile per la caratterizzazione
delle lesioni epatiche, non da sempre risultati facili da interpretare pertanto
non deve essere sempre considerata una alternativa alla esecuzione di un prelievo dalla lesione, che risulta spesso necessario per tipizzare il tipo di neoplasia e adottare una corretta strategia terapeutica.
SCINTIGRAFIA
È una metodica che può essere utilizzata per quantificare la funzionalità
epatica e studiare le vie biliari. Richiede la disponibilità di particolari radio
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farmaci (99m Tc-mebrofenina) e di un sistema di rilevazione e produzione delle immagini (gamma camera e computer). Il paramento che consente di valutare la funzionalità epatica è il HEF (hepatic extraction fraction), che esprime
la percentuale di radiofarmaco che gli epatociti sono in grado di metabolizzare dopo la somministrazione endovenosa del radioisotopo. Il picco di radioattività epatica viene raggiunta dopo 6-8 minuti. Dopo un tempo medio di 19
minuti, il radiofarmaco viene escreto nelle vie biliari e dopo 1 ora la radioattività deve essere osservata nella colecisti e nelle vie biliari. In caso di insufficienza epatica, si possono osservare alterazioni morfologiche del fegato, ridotto uptake del radiofarmaco dal circolo ematico e rallentato wash out. Il rallentamento o la assenza del transito nelle vie biliari indica una ostruzione delle vie biliari, che può esser dimostrata precocemente, anche prima di essere
visibile ecograficamente.
TOMOGRAFIA COMPUTERIZZATA (TC)
All’esame TC, il fegato si visualizza nell’addome craniale, a contatto con
il diaframma. La presenza di grasso periepatico consente di distinguere le porzioni periferiche dei lobi. La cistifellea appare come una struttura piriforme a
contenuto ipodenso. Viene sempre effettuata anche una scansione dopo la
somministrazione di un mezzo di contrasto iodato non-ionico, che è estremamente utile per aumentare il contrasto tra i parenchimi addominali ed evidenziare i vasi. Sono ben visibili i vasi addominali che attraversano l’area epatica (aorta, vena cava caudale ed aorta) ed i vasi intraepatici (vene sovra epatiche e vasi portali). A livello dell’ilo epatico, a destra e a sinistra della vena
porta, si identificano i linfonodi portali.
Rilievi TC occasionali che riguardano il fegato sono calcoli della colecisti,
cisti epatiche, dilatazione della colecisti e delle vie biliari in corso di lesioni
duodenali o del pancreas.
La TC viene impiegata frequentemente per l’approfondimento del paziente con neoplasia epatica, sia per studiare la lesione primaria che per completare la stadiazione del soggetto, cioè valutare i linfonodi regionali e ricercare
eventuali metastasi a distanza. Per questo motivo, nella maggior parte dei casi la scansione include anche il torace. Le neoplasie maligne del fegato si presentano spesso come masse solitarie anche voluminose localizzate in sede variabile. L’aumento della attenuazione della lesione dopo la somministrazione
del mezzo di contrasto (cosiddetto enhancement) è variabile, spesso la massa
si presenta eterogenea per la presenza di aree di necrosi. Gli emangiosarcomi
epatici tendono a presentarsi come voluminose masse con una abbondante
componente emorragica. È importante studiare il rapporto della lesione con i
vasi principali (aorta, vena cava caudale, vena porta) e con gli organi adiacen-
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ti, per valutarne la possibile resezione chirurgica. Se la neoplasia interessa le
vie biliari, si può perdere la normale visualizzazione della colecisti, e possono essere visibili calcificazioni o segni di ostruzione delle vie biliari. I linfonodi portali, se metastatici, appaiono ingranditi e talvolta eterogenei. La scansione ad alta risoluzione del polmone è la tecnica migliore per mettere in evidenza noduli anche di piccole dimensioni, causati dalla disseminazione metastatica della neoplasia.
Il fegato, in quanto organo molto vascolarizzato e con funzione di filtro, è
spesso sede di metastasi, che provengono da neoplasie localizzate nel pancreas, milza, mammella, surrenali, apparato gastro-enterico, tiroide, ossa e polmoni. Le metastasi epatiche si presentano come noduli ipoperfusi di solito numerosi e rotondeggianti, ben visibili nella scansione effettuata dopo la somministrazione del mezzo di contrasto.
RISONANZA MAGNETICA (RM)
La letteratura Veterinaria riporta un utilizzo sporadico di questa tecnica per
la valutazione delle malattie epatiche, ma è probabile che in futuro, analogamente a quanto succede in Medicina Umana, vi sia una maggior diffusione
della RM epatica, legata anche al miglioramento tecnologico delle apparecchiature a disposizione. Risultati incoraggianti vengono dallo studio che ha
valutato la specificità della RM diretta e post contrasto nella caratterizzazione di lesioni epatiche5. Tuttavia, il basso numero dei soggetti studiati richiede
che questi primi dati siano validati da studi numericamente più significativi.
BIBLIOGRAFIA
1.
2.
3.
4.
5.
Ziegler LE, O’Brien RT, Waller KR et al. Quantitative contrast harmonic ultrasound imaging of normal canine liver. Vet Radiol Ultrasound 2003;44:451-4.
O’Brien RT, Iani M, Matheson J et al. Contrast harmonic ultrasound of spontaneous nodules in 32
dogs. Vet Radiol Ultrasound 2004;45:547-53.
O’Brien RT. Improved detection of metastatic hepatic hemangiosarcoma nodule qith contrast ultrasound in three dogs. Vet Radiol Ultrasound 2007;48:146-8.
Daniel GB. Hepatic scintigraphy. In: Daniel GB, Berry CR, editors. Textbook of veterinary nuclear
medicine, 2° edizione. Knoxville (TN), 2006;p-208-228.
Clifford CA, Pretorius ES, Weisse C et al. Magnetic resonance imaging of focal splenic and hepatic
lesions in the dog. J Vet Intern med 2004;18:330-338.
Indirizzo per la corrispondenza:
Clinica Veterinaria dell’Orologio - Centro Oncologico Veterinario - Via Gramsci ¼
Sasso Marconi (BO) - Tel e fax: 051 6751232 - Email: [email protected]
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Federica Rossi
Med Vet, Spec Rad Vet, Dipl ECVDI
Sasso Marconi (BO)
DIAGNOSTICA PER
IMMAGINI AVANZATA:
SHUNT
PORTO-SISTEMICI
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La Diagnostica per Immagini avanzata delle malformazioni vascolari epatiche include le seguenti tecniche: Eco-contrastrografia, Scintigrafia, Tomografia Computerizzata e Risonanza Magnetica.
ECOGRAFIA CON MEZZO DI CONTRASTO1
I mezzi di contrasto ecografici di seconda generazione sono stati utilizzati
per lo studio della perfusione epatica in pazienti con shunt porto-sistemico
(PSS). La metodica prevede l’iniezione di una piccola quantità di mezzo di contrasto contenente microbolle in una vena periferica in un paziente non sedato. La
valutazione della distribuzione del mezzo di contrasto avviene grazie all’utilizzo di particolari sistemi ecografici che consentono di sopprimere il segnale ultrasonoro prodotto dal parenchima e visualizzare solamente quello prodotto dalle microbolle. L’esame viene condotto in real-time, per poter studiare in questo
modo le diverse fasi di perfusione (fase arteriosa e fase venosa). Durante la fase
arteriosa, in un paziente con shunt porto sistemico si visualizzano le arterie epatiche, che sono più numerose ed hanno un andamento maggiormente tortuoso.
Il picco di perfusione del parenchima epatico è più precoce (TTP medio di circa 7 secondi) rispetto ad un soggetto con fegato normale (TTP medio di circa 22
secondi). L’esame con eco-contrasto consente di valutare le alterazioni di perfusione epatica in un soggetto con PSS, tuttavia non fornisce informazioni morfologiche aggiuntive riguardo la morfologia dei vasi anomali addominali.
SCINTIGRAFIA2
È un metodo rapido e non invasivo che consente di diagnosticare uno PSS.
Questa metodica si avvale dell’utilizzo di un radiofarmaco (generalmente
99m
TC pertecnectato, al dosaggio di 5-20 mCi per il cane e 5-10 mCi per il gatto) che viene infuso nel colon, per via rettale. Il radioisotopo viene riassorbito dalle vene coliche, che drenano nelle vene mesenteriche e poi nella vena
porta. In un soggetto con PSS, il radioisotopo passa direttamente dal sistema
portale al cuore, bypassando il fegato, e arriva quindi al fegato successivamente attraverso la circolazione arteriosa. Vengono acquisite, mediante l’utilizzo di una gamma camera, una serie di immagini per un tempo di 2-3 minuti (generalmente 1 immagine/secondo). La scintigrafia consente di calcolare
la frazione di shunt, un valore che normalmente è inferiore al 15%, che è proporzionale della quantità di sangue che viene deviata dalla vena porta alla circolazione sistemica, pertanto può essere un indice della gravità della malattia.
Cani con PSS hanno normalmente una frazione di shunt superiore al 60%. Uno
svantaggio della scintigrafia è l’utilizzo di un prodotto radioattivo, che impo-
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ne di isolare l’animale per almeno 24 ore dopo la procedure (l’emivita del
99m
TC è di 6 ore). Inoltre, non da informazioni sulla morfologica e la sede dello shunt, non consente di differenziare tra PSS intra-ed extraepatici, e di identificare shunts secondari o soggetti con displasia microvascolare.
TOMOGRAFIA COMPUTERIZZATA (TC)3
È considerata il gold standard per lo studio del sistema portale in medicina umana ed è senza dubbio la più informativa tra tutte le tecniche di imaging
avanzate anche nei piccoli animali, consente di:
1. confermare la diagnosi di anomalia vascolare mettendo in evidenza anche vasi di difficile visualizzazione all’ecografia a causa della posizione (interferenze con gas) o delle piccole dimensioni
2. studiare con estrema precisione tutta l’anatomia vascolare dell’addome
identificando anche shunt multipli e malformazioni vascolari complesse
3. evidenziare la presenza di shunt secondari o altri segni secondari di
ipertensione portale
4. ottenere ricostruzioni biplanari e tridimensionali estremamente utili per
una valutazione pre-operatoria. La precisa rappresentazione della anatomia vascolare in quel soggetto consente di velocizzare il reperimento intraoperatorio del vaso e di evitare l’esecuzione di metodiche più invasive (come per esempio la portografia intraoperatoria).
5. calcolare il volume epatico e confrontarlo nei pazienti sottoposti a chirurgia per il follow up
Tecnica di esame: l’esame TC va condotto in anestesia generale con paziente intubato e monitorato. Il paziente viene posizionato in decubito sternale con arti moderatamente estesi, va particolarmente curato l’accurato posizionamento grazie all’ausilio di cuscini di gommapiuma e sacchi di sabbia. La
scansione viene effettuata dall’area cardiaca all’addome caudale, iniziando
con una scansione diretta. Seguono più scansioni effettuate con il mezzo di
contrasto (iodato non ionico), con l’obiettivo di studiare la vascolarizzazione
epatica sia in fase arteriosa che venosa. Ciò consente di diagnosticare anche
le fistole artero-venose. È importante che, durante i pochi secondi necessari
ad ottenere le diverse scansioni, l’animale mantenga l’apnea, in modo da evitare artefatti da movimento. Per garantire un esame diagnostico, viene effettuata un primo studio che consente di valutare i tempi di perfusione nella fare arteriosa e venosa nel soggetto in esame (cosiddetta test injection). Viene
iniettata una piccola quantità di mezzo di contrasto iodato (circa 185 mg/Kg)
e viene eseguita una scansione ottenendo 1 immagine al secondo sempre nello stessa sede, in un punto dell’addome in cui è possibile visualizzare i prin-
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cipali vasi (aorta, vena cava caudale e vena porta), generalmente al livello della regione pancreatica. Le immagini ottenute vengono utilizzate per costruire
curve di perfusione dei tre vasi e programmare in modo preciso la scansione
finale. Per questa scansione si utilizza una quantità superiore di mezzo di contrasto (generalmente 800 mg/Kg) che viene iniettato mediante una pompa da
infusione regolata con velocità di infusione di 5 ml/min. Si effettua una prima scansione durante la fase arteriosa (con direzione caudo-craniale) e una
seconda durante la fase venosa (con direzione cranio-caudale), programmate
in base ai tempi di perfusione calcolati grazie alla test injection.
Interpretazione: in caso di malformazione artero-venosa, si osserva un
enahancement molto precoce, in fase arteriosa, nel sistema portale, inoltre si
possono visualizzare vasi di connessione tra l’arteria epatica ed il sistema portale. Gli shunt porto-sistemici si visualizzano nella fase venosa. La conoscenza della esatta anatomia vascolare consente di identificare la comunicazione
anomala, che si presenta spesso come un vaso tortuoso, che origina dalla vena porta o da una sua tributaria e termina nella vena cava caudale, in una vena sovraepatica o nella vena azigos. Può essere misurato il diametro residuo
della vena porta ed il volume epatico, elementi utili per un eventuale confronto dopo il trattamento chirurgico. Vanno ricercati shunt secondari, indice di
ipertensione portale, piccoli vasi visibili attorno alla vena porta, nella radice
del mesentere e nella regione perirenale.
RISONANZA MAGNETICA (RM)
Con tecnica angiografica (MRA) è stata utilizzata in uno studio4 per visualizzare il sistema portale in cani con PSS, senza necessità di utilizzare mezzo di
contrasto, grazie a speciali sequenze (time-of flight e phase-contrast). Attualmente la RM non viene ancora utilizzata routinariamente con questo scopo.
BIBLIOGRAFIA
1.
2.
3.
4.
Salwei RM, O’Brien RT, Matheson JS. Use of contrast harmonic ultrasound for the diagnosis of congenital portosystemic shunts in three dogs. Vet Radiol Ultrasound 2003;44:310-5.
Daniel GB, Berry CR. Scintigraphic detection of portosystemic shunts. In: Daniel GB, Berry CR,
editors. Textbook of veterinary nuclear medicine, 2° ed. Knoxville (TN), 2006;232-53.
Frank P, Mahaffey M, Egger C et al. Helical computed tomographic portography in ten normal doggs
and ten dogs with a portosystemic shunt. Vet Radiol Ultrasound 2003;44:392-400.
Seguin B, Tobias KM, Gavin PR et al. Use of magnetic resonance angiography for diagnosis of portosystemic shunts in dogs. Vet Radiol Ultrasound 1999;40:251-8.
Clinica Veterinaria dell’Orologio - Centro Oncologico Veterinario - Via Gramsci ¼
Sasso Marconi (BO) - Tel e fax: 051 6751232 - Email: [email protected]
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David C. Twedt
LABORATORY
DIAGNOSIS OF LIVER
DISEASE
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The detection of abnormal liver biochemical tests in the asymptomatic as
well as the symptomatic patient is a common finding on a routine blood screen.
In humans it is reported that up to 4% of asymptomatic persons have increased
serum liver enzymes. In a study of 1,022 blood samples taken from both
healthy and sick dogs and cats 39% had ALP increases and 17% had ALT increases. The identification of liver biochemical abnormalities should suggest
certain diagnostic possibilities and should guide a protocol for further investigation. Liver biochemical abnormalities are often nonspecific; the measured
enzymes can be isoenzymes from another tissue or the same enzyme from a
different tissue source. An understanding of the liver biochemical tests is essential when evaluating the patient in question. Liver biochemical test abnormalities are categorized into groups that reflect 1) hepatocellular injury, 2)
cholestasis or 3) tests of impaired metabolic function or synthetic capacity.
LABORATORY TESTS
It is important to understand basic liver related laboratory tests in order to
determine the possible etiologies for abnormal levels and to develop a course
of action. Many liver tests are not specific only to the liver but can be abnormal from primary non-hepatic disease as well. Evaluation of liver biochemical tests must be interpreted in light of the history, medications and clinical
findings. The magnitude and duration of increase is also dependent on the
type, severity and duration of the stimulus and the species. They do not prognosticate the irreversibility of liver disease at one point in time. Also because
the liver is involved in so many functions no single laboratory test in this category reflects the complete functional state of the liver.
Indicator of Hepatocellular Injury. A common presentation is the isolated increase in either alanine aminotransferase (ALT) or aspartate aminotransferase activity (AST). Canine and feline hepatocyte cytoplasm is rich in ALT
and contains lesser amounts of AST. Altered permeability of the hepatocellular membrane caused by injury or a metabolic disturbance results in a release
of this soluble enzyme. Conceptually ALT and AST should be thought of as
hepatocellular “leakage” enzymes. Subsequent to an acute diffuse injury, the
magnitude of increase crudely reflects the number of affected hepatocytes. It
is however neither specific for the cause of liver disease or predictive of the
outcome. The plasma half-life of ALT activity is 2.5 days and AST about 1
day, however ALT concentrations may take many days to decrease following
an acute insult (possibly 2 weeks or longer). ALT elevations greater than 2X
normal or persistent increases should be investigated. ALT increases are characteristic of chronic hepatitis in the dog.
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Specific Evaluation of Increased ALT. Persistent ALT increases should be
investigated or when they are greater than twice normal. The most important
diagnosis to make is chronic hepatitis. Early diagnosis and prompt therapy
improves patient survival. Hepatitis often begins in dogs 2-5 years of age with
only ALT increases. Females are over-represented and breed associated hepatitis is well known. Dogs with significant hepatitis usually also have concurrent bile acid abnormalities. ALT elevations in young dogs under 1 year of age
is sometimes associated with portal vascular anomalies and bile acid concentrations should be obtained to exclude that possibility. Occasionally I see
young dogs evaluated prior to elective surgery having unexplained ALT increases for unknown reason that correct over time. Occasionally we will see
dogs with mild increases in ALT and no histological evidence of disease and
this probably reflects mild membrane changes not seen with light microscopy.
A variety of tissues, notably skeletal muscle and liver, contain high aspartate aminotransferase activity (AST). Hepatic AST is located predominately
in hepatocyte mitochondria (80%) but also soluble in the cytoplasm. Skeletal
muscle inflammation invariably causes a serum AST increase (and ALT to a
much lesser extent) that exceeds the serum ALT activity and can be further defined as muscle origin by the measurement of the serum creatine kinase activity (CK) a specific muscle enzyme. Clinical experience in veterinary medicine
indicates that there is value in the interpretation of the serum activities of ALT
and AST for liver disease. Following an acute injury resulting in a moderate
to marked increase in the serum ALT and AST concentrations, the serum AST
will return to normal more rapidly (hours to days) than the serum ALT (days)
due to their difference in plasma half-life and cellular location. By determining these values every few days following an acute insult, a sequential “biochemical picture” indicative of resolution or persistent pathology is obtained.
Markers of Cholestasis and Drug-Induction. Alkaline phosphatase
(ALP) and gamma-glutamyltransferase (GGT) show minimal activity in normal hepatic tissue but can become markedly increased in the serum subsequent to increased enzyme production stimulated by either impaired bile flow
or drug-induction. These enzymes have a membrane bound location at the
canalicular surface; ALP associated with the canalicular membrane and GGT
associated with epithelial cells comprising the bile ductular system. With
cholestasis, surface tension in the canuliculi and bile ductules increases and
these surface enzymes are then up-regulated in production.
Specific Evaluation of Increased ALP. Elevations in only ALP in the dog
is a common observation. It has a high sensitivity (80%) but a low specificity (51%). This is because of the multiple isoenzymes of ALP that can be induced into production. Alkaline phosphatase is present in a number of tissues
but only two are diagnostically important, bone and liver. The plasma half-life
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for hepatic ALP in the dog is around 70 hours in contrast to 6 hours for the
cat and the magnitude of enzyme increase (presumably a reflection of the synthetic capacity) is greater for the dog than the cat. Bone source from osteoblastic activity occurs in young growing dogs before their epiphysial plates
close or in bone lesions (ie osteogenic sarcoma). In the adult dog without
bone disease, an increased serum ALP activity is usually of hepatobiliary origin. However a recent study identified some dogs with osteogenic bone tumors to have increased ALP concentrations. ALP increase in those dogs indicates a poorer prognosis suggesting probable diffuse bone metastasis. GGT is
not found in bones.
An increase in the serum ALP and GGT activity can also be associated
with of glucocorticoids (endogenous, topical or systemic), anticonvulsant
medications and possibly other drugs or herbs in the dog. There is remarkable
individual variation in the magnitude of these increases and there is no concomitant hyperbilirubinemia. A moderate to marked increase in serum ALP
activity without concurrent hyperbilirubinemia is most compatible with druginduction and warrants a review of the patient’s history (topical or systemic
glucocorticoids) or evaluation of adrenal function. The increased ALP has
long been attributed to a glucocorticoid-stimulated production of a novel ALP
isoenzyme in the dog that can be distinguished from the cholestatically-induced hepatic ALP isoenzyme by several procedures. It was initially thought
that the glucocorticoid-associated isoenzyme could be used as a marker of exogenously administered corticosteroids or increased production of endogenous glucocorticoids. The glucocorticoid-associated isoenzyme has a very
high sensitivity in animals with Cushing’s disease but a low specificity. Unfortunately, the glucocorticoid-associated isoenzyme is also associated with
hepatobiliary disease as well.
A common condition observed in older dogs is an idiopathic vacuolar hepatopathy associated with increased ALP steroid isoenzyme. Investigation for
hyperadrenocorticism is negative in these cases. It is postulated that other adrenal steroids may also be responsible in some cases. It is known that progesterones bind to the hepatocyte corticosteroid receptors and can induce ALP
production. Scottish Terriers also have yet unexplained increases in serum
ALP concentrations causing an idiopathic hyperalkalinephosphatasemia.
Lastly, hepatic neoplasia and benign hepatic nodular hyperplasia both are
sometimes associated with only ALP increases. Abdominal ultrasound should
be performed to rule out neoplasia such as hepatic adenoma, adenocarcinoma
or bile duct carcinoma. Multiple hyper or hypoechoic nodules in the liver of
older asymptomatic dogs suggests nodular hyperplasia but wedge biopsy confirmation is advised.
Increased serum GGT activity is associated with impaired bile flow in the
dog and cat and glucocorticoid administration in the dog. Bone does not con-
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tain GGT, therefore growth and bone disease are not associated with increased
serum GGT activity. The administration of anticonvulsant medications to
dogs is reported not cause an increase in the serum GGT activity. Colostrum
and milk have high GGT activity and nursing animals develop increased
serum GGT activity. As a marker of hepatobiliary disease, the measurement
of serum GGT activity does not appear to provide a diagnostic advantage over
the serum ALP determination in the dog, however it is reported to be a more
sensitive marker in cats having biliary tract disease.
Evaluation of Liver Function. On a routine biochemical profile it is important to note the liver function tests including bilirubin, albumin, glucose,
BUN, and cholesterol. Albumin is exclusively made in the liver and if not lost,
sequestered or diluted, a low concentration would suggest significant hepatic
dysfunction. It may take greater than 60% hepatic dysfunction for albumin
concentrations to decline. Major clotting factors are also made in the liver (except factor 8) therefore prolonged clotting time suggests hepatic dysfunction.
Liver disease and abnormal function tests suggests hepatic failure and a
guarded prognosis. Serum bilirubin will be affected by pre-hepatic (hemolytic disease) hepatic disorders or post-hepatic disorders (extra-hepatic obstructive disorders like choleliths, pancreatitis and mucoceles). A CBC should be
first performed to rule out hemolytic disease. Because the liver has a great reserve capacity the PCV must be quite low (in the teens) for icterus to develop. With pre-hepatic causes ruled out then further diagnostic liver evaluation
is indicated including imaging and possibly biopsy.
One of the most sensitive function tests we have readily available in small
animals are serum bile acids. The fasting serum total bile acid concentration
(FSBA) is a reflection of the efficiency and integrity of the enterohepatic circulation. Pathology of the hepatobiliary system or the portal circulation results in an increased FSBA prior to the development of hyperbilirubinemia,
negating its usefulness in the icteric patient. An increase is not specific for a
particular type of pathologic process but is associated with a variety of hepatic insults and abnormalities of the portal circulation.
The current suggestion for the determination of the FSBA is to differentiate between congenital portal vascular anomalies and liver insufficiency
prior to the development of jaundice. The determination of FSBA can contribute to the decision to obtain histological support for the diagnosis of this
last group of hepatic diseases. When the fasting value is greater than 25
µmol/L for the dog and cat, there is a high probability that the histology findings will define a lesion. When the FSBA concentration is normal or in the
“gray zone” the FSBA should be followed by a 2-hour postprandial serum total bile acid (PPSBA) looking for an increase greater than 25 µmol/L. The diagnostic value of determining PPSBA concentration is increased sensitivity
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for the detection of hepatic disease and congenital portal vascular anomalies.
When using these guidelines it is prudent to recognize that a small number
of healthy dogs have been reported with PPSBA values above 25 umol/L and
dogs with mild liver disease may have normal bile acids.We have occasionally observed the measurement of a FSBA value higher than the PPSBA value. The reason for this non sequitur is unclear but probably multifactorial. It
has been shown that (1) the peak PPSBA concentration for individual dogs
is variable, (2) fasted dogs store about 40% of the newly produced bile in the
gallbladder and (3) a meal stimulates the release of only between 5 to 65%
gallbladder bile. Undoubtedly these physiologic variables in addition to
physiological variation in intestinal transit time and concurrent underlying
intestinal disease contribute to the dichotomy. Recently, urinary bile acids
have become available as a diagnostic tool. Identifying increased urinary bile
acids provides similar information to what is obtained from serum bile acids
and neither test appears to be better than the other. The advantage of urinary
bile acid measurements would be for the screening of litters of young puppies for suspected inherited vascular anomalies where urine collection is
simpler than paired serum samples.
Blood ammonia is also used as a liver function test. Ammonia produced in
the intestine must be metabolized by the liver urea cycle. Ammonia is influenced by portal blood circulation and hepatic function. Ammonia is more sensitive for screening for portosystemic shunting and less sensitive for detecting
liver disease unless advanced.
In summary, there are a variety of markers with variable sensitivity and
specificity that reflect hepatic tissue and portal vasculature pathophysiology.
We support the conclusion of another study that found that the optimal test
combination is the serum ALT activity and bile acid concentrations. This pairing provided the best sensitivity and specificity, respectively. Clinical experience indicates that elevated serum AST concentration along with an elevated
ALT helps to support a diagnosis of hepatocellular disease and that the PPSBA concentration enhances the evaluation of hepatic function.
MANAGEMENT STRATEGIES
In the asymptomatic patient with an increased liver biochemical test(s) the
increased value should be confirmed at least once to exclude a spurious result
from laboratory error and to avoid unnecessary and costly additional testing.
A careful history is essential to exclude drug associated enzyme elevations.
The signalment of the patient may also provide an insight to the possible etiology of the enzyme increase. For example old dogs frequently have benign
nodular hyperplasia, neoplasia or systemic disease while younger to middle
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aged dogs more commonly have chronic hepatitis. There are also certain
breeds that are predisposed to developing chronic hepatitis. A careful physical examination may also provide clues to the diagnosis. The most common
cause of abnormal liver enzymes is not primary liver disease but rather reactive hepatic changes occurring secondary to other non-hepatic diseases. These
would include such conditions as intra-abdominal disorders (IBD, nutritional
abnormalities), cardiovascular disease or metabolic derangements as just a
few examples. Generally these secondary changes are reversible once the primarily disease is treated. Successful resolution of the non-hepatic disease and
continued abnormal liver enzymes would be a strong indication for further investigation of the liver.
If no likely explanation for the laboratory abnormalities can be found there
are two courses of action that one can take; either begin a diagnostic evaluation of the patient starting with bile acid determinations, or re-evaluate the patient’s liver enzymes at a later date. A rational wait period for re-evaluation is
4-6 weeks giving consideration to the half-life of liver enzymes and the time
needed for recovery from an acute occult hepatic injury. It is best not to delay
retesting beyond 6-8 weeks in the event that an active disease process may
progress.
DIAGNOSTIC STRATEGIES
Once further work up has been elected, if the patient is not icteric, the next
diagnostic step should be evaluation of urine or serum bile acids. Abnormal
bile acids indicate hepatic or circulatory abnormalities and that the patient
should undergo further evaluation at this time.
Imaging. Routine abdominal radiographs are helpful in determining liver
size and shape and for detection of other intra-abdominal disorders. Ultrasonography is noninvasive, readily available and is the most informative initial imaging modality for liver disease. It often complements the clinical and
laboratory findings and is useful for identifying focal liver lesions, diffuse liver disease or biliary disease. Frequently, fine needle aspiration (FNA) for cytological evaluation is performed in conjunction with ultrasound. Although
FNA is safe and easy to perform, one must be cautious in the interpretation of
the results and use the FNA findings in conjunction with clinical signs and
other diagnostics to make a diagnosis. The sensitivity and specificity is not
very high when results are compared to histopathology. We find the best correlation with hepatic neoplasia and diffuse vacuolar hepatopathies and the
poorest in patients with chronic hepatitis.
Liver Biopsy. Although our diagnostic techniques continue to improve, in
most instances imaging and biochemical testing cannot replace a liver biopsy.
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This is by far the best examination for a definitive determination of the nature
and extent of hepatic damage and to appropriately direct the course of treatment. The method for liver biopsy procurement may be surgery, needle biopsy or laparoscopy. Each has certain advantages and disadvantages and the decision of which procedure to use should be made in light of all the other diagnostic information, always considering what is in the best interest of the patient and client.
SUMMARY
Abnormal liver enzymes should not be ignored and should be investigated
in a systematic manner as previously discussed. Asymptomatic animals with
no evidence of significant or treatable disease or in situations where financial
constraints limit further work up the patient should be fed a quality maintenance diet for the patient’s stage of life and the possibility of instituting specific liver support therapy should be explored.
Address for correspondence:
David Twedt, Professor, Department of Clinical Sciences Colorado State University
Fort Collins, CO 80523 USA - E-mail: [email protected]
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David C. Twedt
IMPORTANT CLINICAL
SYNDROMES
ASSOCIATED WITH
LIVER DISEASE
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Abnormal liver enzymes are a common encounter in the dog and can be
due to a number of etiologies. The following discussion includes some of the
more common conditions I encounter causing abnormal liver enzymes. This
section does not however include chronic hepatitis and this in included in the
following section.
REACTIVE HEPATOPATHIES
The so-called “reactive hepatopathies” which occur secondary to non-hepatic disease can result in increased serum biochemical hepatic tests and histomorphologic abnormalities. Most of the reactive hepatopathies cause increases in laboratory tests that evaluate hepatocellular integrity (ALT, AST)
and tests of hepatic cholestasis (ALP, GGT). In most cases there are little if
any changes in tests that evaluate hepatic function (bilirubin, albumin, glucose, and BUN). Most of the animals with secondary liver disease also retain
normal serum bile acid concentrations, which again supports a concept that
there is generally minimal hepatocellular dysfunction in most of these disease conditions.
This group is characterized by nonspecific hepatocellular degeneration or
necrotic changes without evidence of significant chronic progressive inflammation. Again, these changes are usually secondary to manifestations of a primary non-hepatic disease. The reason the liver often undergoes these changes
revolves from the fact that the liver is involved in many metabolic and detoxification functions. Endogenous toxins, anoxia, metabolic changes, nutritional changes and endogenous stress related glucocorticoid release are examples
of conditions responsible for the majority of these changes. Non-specific mild
liver changes routinely also occur following general anesthesia.
A good example that helps explain this concept is inflammatory bowel disease in which it is not unusual to observe mild inflammatory changes around
portal triads presumed to be the result of abnormal portal uptake of gastrointestinal “toxins”. Throughout the liver and closely associated with portal areas are Kupffer cells (fixed macrophages) that function to filter the blood of
injurious toxins, inflammatory mediators and bacteria. When this macrophage
system is abnormally insulted Kupffer cells release their own inflammatory
mediators that in turn insult the hepatocytes.
Another example could be the sick septic dog having vacuolar change
thought to be due to endogenous cortisol release for endogenous stress and
hepatic cholestasis from presumed endotoxin or cytokine alteration of bilirubin metabolism.
Histological findings associated with secondary reactive changes include
descriptors such as vacuolar degeneration, hydropic degeneration, swollen he-
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patocytes, lipidosis, intracellular or intrahepatic cholestasis, mild multifocal
hepatitis and periportal or variable hepatic necrosis. These changes are devoid
of the typical progressive chronic inflammatory cell infiltrates characteristic
of chronic hepatitis.
In a review of consecutive liver biopsies at Colorado State University histology grouped as non-specific reactive changes made up the largest category
of abnormalities (approximately 25%) In this group we were able to identify
an associated disease in many that could explain the likely cause for the hepatic enzyme increases and histological changes observed. Concurrent diseases identified included neoplasia, gastrointestinal, renal, autoimmune, dermatologic, dental, infectious and cardiac disease as a few examples. In some
cases an underlying disease is not identified. The ALT values on the average
are 1-2 X normal and the ALP values 1-3 X normal. It is interesting to note
that in a series of 32 dogs having reactive hepatopathies, 8/8 cases in which
serum bile acids were run, all were within the normal reference range again
suggesting hepatic function remains intact.
This category appears to be the most common histological change to occur in dogs and is by far the most common cause of elevated liver enzymes.
Based on this fact, dogs presented with elevations in ALT and ALP should always have primary non-hepatic disease ruled out first. These changes are usually very reversible and no specific hepatic therapy is required short of treating the primary disease. The liver changes resolve once the primary etiology
is successfully treated. Therapy providing good liver support such as antioxidants may be warranted.
VACUOLAR HEPATOPATHIES
The histological reports of diffuse vacuolar hepatopathy are often very
frustrating in determining the underlying etiology. When hepatocytes become
injured one response is for them to swell and become vacuolated. Hepatocellular vacuoles distending the cytosolic compartment may contain, fat, glycogen, intracellular water (edema) or other metabolic wastes or intermediates.
Vacuolar hepatopathies may occur in conjunction with hydropic degeneration
in which there is cytosolic swelling but devoid of distinct vacuoles. A number
of conditions discussed above causing reactive hepatopathies can be responsible for vacuolar hepatopathies or lesions may develop as a result of secondary chronic stress (presumed to be endogenous steroid induced) resulting
from concurrent disease.
Glucocorticoid (steroid) hepatopathies occur in the dog secondary to exogenous or endogenous glucocorticoids. On histology the vacuolar lesions
contain glycogen that is not easily differentiated from other vacuolar contents
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without specialized histopathology processing. The development of steroid
hepatopathies is linked with marked increases in ALP. The glucocorticoid associated ALP (G-ALP) is unique to the dog and dogs having steroid hepatopathies are associated with a large component of G-ALP. Experimentally
when steroids are administered to dogs there is initially an increase in ALP
but latter G-ALP increases and may comprise the majority of ALP concentration. Determining the G-ALP portion of ALP has been suggested as a screening test for hyperadrenocorticism but unfortunately many other conditions are
also associated with increased G-ALP which is most likely secondary to
chronic stress of the disease. Hence, many will question the diagnostic usefulness of G-ALP.
Dogs having hyperadrenocorticism or those given corticosteroids have
considerable individual sensitivity or variation in liver lesions and ALP concentrations. Dogs given 4 mg/kg prednisone will have liver lesions in 2 to 4
days and marked increases in ALP to follow. Rarely if ever total bilirubin
increases but bile acid concentrations may become slightly abnormal and
possibly as high as 40-50 µmol/L. Topical steroid administration can also
cause steroid hepatopathies and may take a month or longer for values to return to normal once medication is discontinued. A single dose of methylprednisolone acetate (Depo-medrol®) can alter adrenocortical function for
five weeks or longer.
Dogs having increased ALP and evidence of vacuolar hepatopathy should
always be investigated for hyperadrenocorticism. The diagnosis of canine
Cushing’s disease requires specific testing such as a low dose dexamethasone
test or ACTH stimulation test.
Idiopathic vacuolar hepatopathy is a frustrating diagnosis frequently observed in older dog. In all intense purposes they appear typical of steroid hepatopathies based on histology and abnormal ALP but without clinical or laboratory evidence of Cushing’s disease. The liver of these dogs contains excess
glycogen and they have laboratory finding predominately G-ALP isoenzymes. One is unable to make the diagnosis of Cushing’s disease based on
lack of typical clinical signs and normal conventional adrenal testing (i.e.
ACTH stimulation or LDDS). We have recently investigated several dogs having vacuolar hepatopathy and increased ALP without overt Cushing’s disease
to have abnormal concentrations in some of the other adrenal steroids (i.e. sex
hormones such as progesterone, estradiol, DHEAS or 17a-Hydroxy-progesterone). It has been documented that progestin steroids have been shown to
bind to hepatic glucocorticoid receptors and will induce a steroid hepatopathy
when given orally to dogs. There is now speculation that increases in progestin steroid hormones may result in the hepatic changes and ALP increase.
Clinically we have found many of these dogs fail to have increases in GGT
concentrations in spite of significant ALP elevations. It appears those most, if
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not all of these dogs, live a normal life with out adverse consequences from
their liver disease. Obviously further investigation is required into this syndrome. We have observed several dogs following empirical ketoconazole or
lysodren therapy to have decreases in ALP supporting aberrant adrenal steroid
production. The reason for abnormal progestin levels may be secondary to adrenal adenomas (incidentalomas), adrenal enzyme deficiency converting precursors to cortisol or unapparent adrenal masses. Some adrenal adenomas
have been shown to secrete high levels of 17 hydroxyprogesterone in dogs.
Some have also suggested administering melatonin (4-6 mg/da) and report
improvement in liver enzymes and hepatic changes. More studies are required
to confirm this finding.
Recently we have identified a disproportionate number of Scottish terriers
suggesting a breed predisposition for this condition. We are currently investigating these and other dogs with ultrasound to rule out hepatic or adrenal
masses and an ACTH stimulation test with concurrent adrenal panel that includes progestins. We currently send our samples to the University of Tennessee Diagnostic Laboratory.
The benefit of specific treatment for the idiopathic vacuolar hepatopathies
has not been adequately evaluated. With no clinical signs I question the value
of therapy in most cases. Some cases may become hypertensive or develop
proteinuria and this should be evaluated. Some have suggested melatonin 3
mg bid (<15 kg bw) for antigonatropic hormone effect or Flaxseed hull products with lignans which competes with estridiol production or alternatively
lysodren (often can be given at low doses. Trilostane is not recommended as
17 OH progesterone will increase.
HEPATIC NODULAR HYPERPLASIA
This is a benign process causing an increase in hepatic values and histomorphologic changes that include macroscopic or microscopic hepatic nodules containing vacuolated hepatocytes. Liver function remains unchanged.
Grossly, the appearance may be suggestive of chronic hepatitis or neoplasia.
The etiology is unknown but appears to be an aging change in dogs; most of
those affected are greater than 10 years of age.
Laboratory findings include an ALP increase, but some may have mild increases in ALT and AST concentrations as well. Ultrasound may be normal or
may demonstrate larger nodules (many can be only microscopic and not observed on ultrasound). Biopsy confirms the diagnosis, however a wedge section is preferred, as a needle biopsy may not demonstrate the nodules. There
is no specific therapy.
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HEPATIC NEOPLASIA
In the dog liver tumors can be either metastatic or primary. Metastatic tumors are more common and would include the carcinomas and sarcomas. Hepatocellular ademoma is common in dogs and generally restricted to a single
liver lobe. Previous terminology calls these tumors as hepatomas human terminology that is incorrect. These tumors are very slow growing and often are
found as an incidental finding on ultrasound as a work up for abnormal liver
enzymes. There is no spread to this tumor. Often we will just watch them using ultrasound every several months and if they grow in size rapidly then surgery can be suggested. If they become large they may not lend to resection or
may become necrotic and rupture causing abdominal bleeding. Hepatocellular carcinomas are malignant neoplasms that can be either solitary (more
slowly growing) or diffuse having a poor prognosis. Sometimes telling the
difference from adenoma and carcinoma is difficult FNA or a biopsy sample.
It has also been reported that large liver masses may be associated with hypoglycemia due to production of an insulin like factor. The more diffuse cholangiocellular and hepatic carcinomas have poorer prognosis and do not respond
well to chemotherapy.
PORTAL VEIN HYPOPLASIA
Portal vein hypoplasia (PVH), also referred to as microvascular dysplasia,
is associated with abnormal microscopic hepatic portal circulation. The primary defect is characterized by hypoplastic small intrahepatic portal veins.
With paucity in size or presence of portal veins there is a resultant increased
arterial blood flow in attempt to maintain hepatic sinusoidal blood flow. The
hepatic arteries become torturous and abundant in the triad (portal arterialization). Sinusoidal hypertension occurs and lymphatic and venous dilation results opening up of embryologic sinusoidal capillaries forming microscopic
acquired shunts transporting some of the blood into the central vein by-passing the sinusoidal hepatocytes. This results in abnormal hepatic parenchymal
perfusion and hepatic atrophy. These changes are similar to congenital macroscopic portosystemic shunts that also result in decreased portal blood flow. If
an intrahepatic or extrahepatic macroscopic shunt is not observed then PVH
becomes the probable diagnosis. Angiography or transcolonic portal scintigraphy fails to demonstrate macroscopic shunting. A liver biopsy shows characteristic changes (wedge or laparoscopic).
This condition was first described in Cairn terriers, Yorkshire Terriers and
Maltese but other mostly small breeds can have PVH. Serum bile acids are elevated (usually moderate) and variable liver enzyme increases (mostly ALT).
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There is no therapy and treatment for hepatic encephalopathy is uncommon.
Antioxidant supplementation is used by some. The long-term prognosis is uncertain but is thought to be good.
Portal vein hypoplasia with fibrosis, portal hypertension, formation of acquired portosystemic shunts (PSS) and ascites occurs as rare variant of the
congenital PVH. These dogs have moderate to marked fibrosis of the portal
tracts, proliferation of arterioles and bile ductules in the portal area. There is
minimal to little inflammatory changes. This condition has also been referred
to as idiopathic non-cirrhotic portal hypertension or congenital hepatic fibrosis because of the significant portal fibrosis.
This condition is observed in younger dogs most under 3 years of age.
There is no breed prevalence however Doberman Pinschers, Cocker Spaniels
and Rottweilers may be over represented. The clinical presentation is similar
to dogs having either congenital PSS except most dogs have ascites. The liver enzymes are generally increased with a hypoalbuminemia and very high
bile acid concentrations reflecting shunting. Ultrasound may be helpful showing microhepatia, hepatofugal portal blood flow and multiple extrahepatic
collateral shunts. Portal contrast studies demonstrate acquired portal shunts
and pressure measurements document portal hypertension. The prognosis for
this condition is generally guarded but some dogs are reported to have a prolonged survival using anti-fibrotic agents, ascites management and hepatic encephalopathy therapy.
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David C. Twedt
UPDATE ON FELINE
HEPATOBILIARY
DISEASE
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Liver disease is common in the cat and the finding of icterus is a frequently a clinical clue that the cause is primary liver disease. The types of liver disease as well as differences in laboratory tests for the cat are very different
from disorders observed in the dog.
LABORATORY TESTING
A sick cat may become icteric (jaundice) without having primary liver disease. This is because of the complexities of bilirubin metabolism combined
with cat’s weak ability to conjugate compounds. It is this complex pathway
that can result in icterus without evidence of significant structural liver disease. Cats with clinically icteric (bilirubin > 3.0 mg/dl) most often have primary hepatobiliary disease when hemolytic disease is ruled out. Cats having
biochemical icterus (bilirubin < 3.0 mg/dl) do not always have primary hepatobiliary disease and many have other primary non-hepatic disorders with the
liver being secondarily affected. When evaluated 180 feline cases having elevated total bilirubin concentrations (> 0.2 mg/dl) and categorized them into
three groups; prehepatic disease (mean bilirubin 4.1), hepatobiliary disease
(mean 3.54) and secondary hyperbilirubinemia (mean 1.21). From this cats
with bilirubin greater than 3 were likely to have primary hepatobiliary disease
while cats with bilirubin less than 3 could have elevations secondary to some
primary non-hepatic disorder.
A study evaluating the utility of liver biochemistries in the diagnosis of feline liver disease found the best predictive tests for primary liver disease includes ALP, GGT, total bilirubin and bile acids. The ALT and AST are quite
variable and elevations don’t always predict primary inflammatory liver disease or hepatic lipidosis, both of which cause more cholestatic (increases in
ALP, GGT) than hepatocellular (increases in ALT, AST) damage. ALP is also
unique in cats in that the half-life of the enzyme is short (6 hours) and the feline liver is reported to contain only one-third the concentrations found in dogs.
ALP is also not induced by corticosteroids nor do they cause a steroid hepatopathy. Gamma-glutamyl transpeptidase (GGT) is a similar enzyme to ALP
that increases with cholestasis and is more sensitive for feline inflammatory
bile duct disease than ALP. Presumably this is because GGT is found in higher concentrations in the bile ducts than the hepatocyte where ALP predominates. Cats with cholangitis usually have higher elevations in GGT than ALP.
LIVER DISEASES
The incidence of liver disease in the cat is unknown but at Colorado State
University several large categories were observed in reviewing 175 liver biop-
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sies and include: Lipidosis (both idiopathic and secondary, 26%), Cholangitis
(25%), Neoplasia (20%) and Reactive hepatopathies (16%).
Hepatic Lipidosis. Hepatic lipidosis can occur as either a primary idiopathic disease syndrome or secondary to a number of other primary disease
conditions. Lipid accumulation in the liver is simply the result of nutritional,
metabolic or toxic insults to the liver and the degree of lipid accumulation can
be quite variable and the process is reversible. For example, a common secondary disease associated with significant hepatic triglyceride accumulation is diabetes mellitus. Hepatic lipid accumulation can also result secondary to any
number of other disease syndromes associated with anorexia and weight loss
such as pancreatitis, inflammatory bowel disease or other major organ dysfunction. These secondary conditions generally have less severe lipidosis than
idiopathic hepatic lipidosis in which there is no identifiable etiologic factor.
In the idiopathic form cats will present with an acute history of rapid
weight loss (up to 40-60% body weight over 1-2 weeks), depression and
icterus. The weight loss is significant with loss of muscle mass while abdominal and inguinal fat stores are often spared. These cats generally have a total
aversion to any type of food. The diagnosis of idiopathic hepatic lipidosis is
supported by the clinical history and laboratory findings. Icterus and marked
elevations in ALP are consistent findings. GGT concentrations are normal or
only moderately increased in these cats. Icterus with a very high ALP and normal GGT should be a clue to probable idiopathic lipidosis given with appropriate clinical features. A definitive diagnosis requires a liver biopsy or hepatic cytology. A fine needle aspirate of the liver with cytological evidence of
many vacuolated hepatocytes helps support a diagnosis. Be aware that cytological diagnosis does not always correlate with histology. A hepatic tissue
biopsy confirms the diagnosis of lipidosis but not the cause.
The therapy for idiopathic hepatic lipidosis requires aggressive management. Initial therapy requires re-hydration with balanced electrolyte solutions.
Administration of high glucose containing solutions and lactate-containing
fluids should be avoided. Adequate nutrition then becomes the most important part of the therapy for hepatic lipidosis. Nasogastric tubes can be used but
due to the small size feeding is limited to liquid diets and they are less tolerated than larger tubes. I suggests placement of a 20 French red rubber
esophageal feeding tube. The nutritional recommendations for idiopathic hepatic lipidosis are empirical and poorly documented. In general, dietary fat
and protein should not be restricted in these cats because calories and protein
are so important in providing nutritional balance. There is also no good data
on the benefit of various dietary supplements. Some suggest arginine (1000
mg/day), thiamine (100 mg/day) and taurine (500 mg/day) for 3-4 weeks.
There is some evidence that L-carnitine supplementation (250-300 mg/day) in
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cats may protect against hepatic lipid accumulation (at least in weight reduction studies in cats) and consequently may be an appropriate dietary adjunct
for cats with lipidosis. Cats with lipidosis are often cobalamin deficient and
improve faster with high doses of cobalamin given 250 µg SQ weekly. Other
therapies suggested include S-adensosylmethionine (SAMe) a nutraceutical
that is a naturally occurring molecule found in all living organisms and is involved in the metabolism of glutathione (GSH). The benefit of SAMe or other antioxidants in hepatic lipidosis is unknown. Another antioxidant hepatoprotectant is milk thistle or its extract silybin (available as a silybin-phosphatidylcholine combination, Marin™), is also a safe hepatic support therapy.
The prognosis must be guarded however with aggressive nutritional therapy many if not most cats recover. Several complications that can occur with
therapy include a re-feeding syndrome and vomiting. The re-feeding syndrome is associated with the development of an often life-threatening electrolyte disturbances that occurs within 24 to 48 hours of enteral feeding. To
avoid these problems electrolyte abnormalities should be first corrected and
then by feeding small frequent meals usually starting out with 25% of the daily calculated caloric needs and gradually increasing the diet volume over 3 to
7 days. We have also used mirtazapine (Remaron™) a tetracyclic antidepressant that has both antiemetic and appetite stimulant effects (approximate dose
is 1/8 of a 15 mg tablet every 3 days) with encouraging preliminary success.
When the cat is consuming adequate calories without the need for tube supplementation the feeding tube can be removed.
Feline Inflammatory Liver Disease (Cholangitis). Cholangitis is an inflammatory disorder of the hepatobiliary system. It is a disease complex that
may be concurrently associated with duodenitis, pancreatitis, cholecystitis
and/or cholelithiasis. The terminology is somewhat confusing however the
histological classification of the WSAVA Liver Standardization Group has
been separated diseases into three histological groups; neutrophilic cholangitis, lymphocytic cholangitis and cholangitis associated with liver flukes.
Neutrophilic Cholangitis. This classification has previously been referred
to as suppurative or exudative cholangitis /cholangiohepatitis and is the most
common type of biliary tract disease observed in cats in North America. Neutrophilic cholangitis is thought to be the result of biliary tract infection ascending from the gastrointestinal tract. In the acute neutrophilic form (ANF),
the lesions are exclusively neutrophilic or suppurative but over time it is
thought that cases may progress to a chronic neutrophilic form (CNF) having
a mixed inflammatory pattern containing variable numbers of neutrophils,
lymphocytes and plasma cells.
The ANF is thought to be the result of an ascending bacterial infection.
Usually coliforms (E. coli) are cultured from the liver or bile. Cats may have
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evidence of a fever, anorexia, vomiting or lethargy. A leukocytosis is generally identified on the CBC. The ALT and ALP are increased but variable and
these cats are frequently icteric. Ultrasound should be performed to rule out
pancreatitis and biliary obstruction. A liver biopsy is required for histology
and will confirm the diagnosis. The liver should always be cultured because
of the relationship of bacteria and cholangitis. If obstruction is identified surgery becomes indicated to decompress and flush the biliary system. Therapy
includes fluid and electrolyte therapy as needed. Antibiotics are a critical part
of the therapy as well. Ampicillin, ampicillin-clavulanic acid, cephalosporins
and metronidazole have been suggested as effective antibiotics. Unless a culture and sensitivity says otherwise ampicillin or ampicillin-clavulanic acid are
my choice because of the likelihood of E. coli and the fact that both are concentrated in the bile. It is recommended that cats be treated for at least 1
month or even longer with antibiotics. Short duration of therapy may result in
reoccurrence of clinical signs. Ursodeoxycholic acid (Actigall 10-15
mg/kg/day) should be used as well. Abdominal discomfort and vomiting may
be associated with hepatobiliary pain and buprenorphine (Buprenex™)
should be administered.
The CNF (neutrophilic, mixed or lymphocytic-plasmacytic) cholangitis
may be the result of progression of the acute neutrophilic cholangitis. In the
chronic stage the liver lesions are associated with the presence of a mixed inflammatory infiltrates in the portal areas consisting of neutrophils, lymphocytes and plasma cells. Possibly fibrosis, ductular proliferation or extension
of inflammation into the hepatic parenchyma can occur as well.
There is also a direct relationship between chronic cholangitis and inflammatory bowel disease and chronic pancreatitis. One study found 83% of affected cats had inflammatory bowel disease and 50% had concurrent chronic
pancreatitis. The association of the three together has been referred to as “feline triaditis”. In a yet published study we have identified over 50% of affected cats to have evidence of bacteria in and around bile ducts of these cats suggesting that resident bacteria may be responsible for the chronic inflammation. Affected cats are older and have signs that wax and wan and weight loss
and vomiting may be present. Physical findings identify jaundice in most. The
laboratory findings are variable. Most cats are icteric and there are variable increases in ALP/GGT or ALT/AST. Hyperglobulinemia is observed in over
50% if the cases. Ultrasound may reveal pancreatic, bile duct or gallbladder
changes. The liver generally has a mixed echoegnicity pattern with prominent
portal areas. A liver biopsy confirms the diagnosis.
The primary treatment recommended is immunosuppressive therapy using
prednisolone at 2-4 mg/kg daily and then slowly tapering over 6 to 8 weeks
to 0.5-1 mg/kg given once or every other day. This therapy does not appear to
resolve this chronic disease but generally slows the progression and may min-
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imize the clinical signs. Based on recent observations of bacteria and around
bile ducts antibiotic therapy may be a better option. Ursodeoxycholic acid is
a nontoxic hydrophilic bile acid that when administered changes the bile acid
milieu. Ursodeoxycholic acid (10-15 mg/kg/day) is nontoxic and suggested
for these cats as it is reported to increase bile flow (choleresis), change bile
acid concentrations to less toxic concentrations, reduce inflammation and fibrosis and improve liver enzymes. Liver support therapy such as SAMe, Silybin or other antioxidants may be of benefit in the long-term management. The
disease is slow and progressive often scattered with periodic flair ups. Approximately 50% of the cases will have a prolonged survival.
Lymphocytic Cholangitis. This is a condition is a very chronic inflammatory biliary tract condition that is progressive over months and years. Some
describe it as being acute or chronic in nature. The pathology of the liver is
characterized by a consistent moderate to marked infiltration of small lymphocytes predominately restricted to the portal areas, often associated with
variable portal fibrosis and biliary proliferation. The later stages result in considerable distortion of liver architecture. The bile ducts can also become irregular with dilation and fibrosis. In some cases lymphocytic infiltrates in the
portal areas may be confused with well-differentiated lymphocytic lymphoma. It is postulated that lymphocytic cholangitis could be the result of immune mediated mechanisms. Bacteria id believed not to be primarily involved
in this disease.
Persian cats appear to be over-represented, suggesting a possible genetic
predisposition. The most common clinical features observed late in the disease include ascites, jaundice, and hypergammaglobulinemia (in almost all
cases). In advanced cases, ultrasonographic examination often demonstrates
dramatic changes intra and extra-hepatic bile ducts with marked segmental dilations and areas of stenosis that may lead the operator to believe there is an
obstruction. Ascites and hepatic encephalopathy occur late in the disease as a
result of acquired portal hypertension and hepatic dysfunction.
The treatment for the chronic lymphocytic cholangitis involves using anti-inflammatory or immunosuppressive therapy in addition to supportive therapy as described with neutrophilic cholangitis. Some report lymphocytic
cholangitis had a better response when treated with ursodeoxycholic acid than
with corticosteroids. This finding may not be completely unexpected because
ursodeoxycholic acid has been shown to have a positive treatment effect in
humans having chronic primary biliary cirrhosis having a very similar histologic pattern to these chronic cases.
Complications of Cholangitis Syndromes. The following are conditions
often observed with the cholangitis cases. Bile sludge and or cholithiasis often occur with inflammatory biliary tract disease. Thick inspissated bile or
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choleliths are thought to be the result of deconjugation of the normally soluble conjugated bilirubin from the action of bacterial enzymes or inflammatory products present in the biliary tree. The certain bacteria such as E. coli are
capable of producing the enzyme beta glucuronidase that can deconjugate
bilirubin resulting in pigment precipitation. Choleliths in cats are primarily
bilirubin pigment stones that contain various amounts of calcium and other
precipitates. Some choleliths may be radiopaque if enough calcium is incorporated in the cholelith. Primary cholesterol choleliths as occur in humans do
not naturally occur in cats or dogs. Bile sludge or choleliths may block bile
flow and can cause complete obstruction. Obstructive choleliths should be removed surgically. Occasionally a clear viscous fluid devoid of bile pigments
is seen in the gallbladder of some cats thought to be the result of severe intrahepatic cholestasis and reabsorption of intraductal bile.
Bile sludging is best managed by treating the primary cholangitis, treating
any biliary tract infection, and by the use of choleretic agents to increase the
flow of bile. Ursodeoxycholic acid (Actigall®) should be prescribed. Corticosteroids have a similar effect on bile flow and may also be useful. Complete
obstructions may require surgery and in rare conditions a cholecystoduodenostomy or cholecystojejunostomy is required.
Cholecystitis is inflammation of the gall bladder and occurs frequently in
the cholangitis syndrome. Radiographically gas within the gall bladder may
be observed due to bacterial fermentation. Characteristic thickening of the
gall bladder wall may be seen with ultrasound examination. Rarely is there
the need for a surgical cholecystectomy if the primary disease is adequately
identified and treated.
Feline triaditis is a syndrome that has been observed in many cats having
cholangitis. This condition is associated with a concurrent chronic cholangitis-cholangiohepatitis, chronic pancreatitis and duodenitis. Since the common
bile duct and pancreatic ducts join a common channel before they enter the
duodenum extension of inflammation and luminal contents in both directions
is common. Chronic fibrosing pancreatitis with ductal inflammation and
nodular hyperplasia is reported frequently with inflammatory biliary disease
in the cat. Some of these cats to also have lymphocytic-plasmacytic infiltrates
within the duodenum (IBD) as well.
Each part of the traid alone can have a similar clinical presentation often
associated with chronic intermittent vomiting, lethargy, and anorexia. Liver
enzymes are variable and pancreatic amylase and lipase concentrations are
not helpful however fPLI levels may be abnormal.
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David C. Twedt
COPPER ASSOCIATED
LIVER DISEASE
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There is increasing recognition that inflammatory liver disease in dogs is
associated with abnormal hepatic copper (Cu) concentrations. Abnormal hepatic Cu accumulation results as either a primary metabolic defect in Cu metabolism unique to some breeds or as a secondary event associated with
chronic hepatic cholestasis resulting in a decrease in biliary excretion of hepatic Cu. Regardless of the cause at a certain concentration Cu contributes to
hepatocellular damage.
NORMAL COPPER METABOLISM
Copper is an essential trace element required as a redox co-factor for many
different enzymes. Copper enters the body through the diet and approximately 30% is absorbed by the upper small intestine with unabsorbed copper passing through the feces. Although the exact details of intestinal Cu absorption
is not completely delineated it is clear that copper is taken up in the intestine
through an active transport mechanism shared with zinc. Intestinal copper is
quickly bound to the cytosolic protein metallothionein. Intestinal Cu is subsequently transported to the liver bound to albumin and transcuprein. The liver
is responsible for the uptake and storage of copper, as well as the regulation
of excretion of this metal into the bile. Hepatic copper is either complexed to
ceruloplasmin, an acute phase reactant protein, and transported to peripheral
tissues for utilization, or Cu is redistributed among the various metallothioneins in the liver. Metallothioneins are cysteine-rich, cytosolic proteins capable of binding several metal ions, including copper. Metallothioneins function are to protect the hepatocyte against the toxicity from free Cu catalyzing
oxygen free radicals and also to mediate Cu transport into the bile for removal
from the body. The normal hepatic copper concentrations in dogs are maintained at approximately 200-400 µg/g dry weight liver.
Recently there has been characterization of the genetic regulation of copper
excretion by the liver. A specific gene in humans ATP7b is a copper-transporting
ATPase expressed within the secretory pathway of hepatocytes and plays a critical role in copper excretion and ceruloplasmin production. A second gene encoding COMMD1 (MURR1) is expressed in the liver suggesting that this protein also plays a role in hepatic copper transport and biliary copper excretion.1
Wilson disease in humans is an inherited mutation in the gene encoding human
ATP7b and results in hepatic copper overload and decreased Cu-ceruloplasmin
production. Bedlington Terriers also have an inherited disorder of copper homeostasis. These animals have impaired copper excretion into bile but no abnormality in copper incorporation into ceruloplasmin suggesting that the defect occurs
distal to the function of ATP7b in intracellular copper transport.2 This disorder
has recently been shown to result from deletion of a gene on dog chromosome
10 encoding a small cytosolic protein termed COMMD1 (MURR1).3
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COPPER HEPATOXICITIES IN DOGS
Bedlington Terriers. Hepatic copper toxicity was first identified in Bedlington Terriers in 1975. It was subsequently shown that affected Bedlington Terriers have an inherited autosomal recessive defect, which results in reduced biliary
excretion of copper with hepatic metallothionein sequestration of Cu in hepatic
lysosomes. It is suspected that over 50% of Bedlington Terriers are carriers for
this defect. Clinically affected dogs have a progressive hepatic Cu accumulation
occurring with age ranging from 1,000 to 12,000 µg/g dry weight of liver. The
extent of hepatic damage tends to parallel the increasing hepatic Cu concentrations. The morphological changes extend from focal necrosis to chronic hepatitis that may ultimately lead to cirrhosis. In some cases, acute hepatic necrosis and
Cu associated hemolytic anemia and acute liver failure may occur.
The pathogenesis of hepatic damage is thought to occur when the metallothionein sequestration ability for Cu becomes exceeded and free copper is
released. The mitochondria appear to be the first organelle to become damaged resulting in mitochondrial electron leak initiating lipid membrane peroxidation and eventual cellular death.4
The excess hepatic copper is sequestered in lysosomes bound to metallothionein proteins. Routine stained histological sections may show abundant
golden-brown refractile hepatocellular lysosomal granules that contain the sequestered Cu. These granules are nonspecific for copper, but may indicate abnormal copper accumulation. A more reliable semi-quantitative estimation involves histochemical staining for hepatic Cu. Reliable tissue bound copper
stains include rhodanine and rubeanic acid. The copper tends to accumulate
in a centrilobular location. A grading system of 1-4 estimating the quantity of
Cu granules correlates roughly with quantitative determination of hepatic Cu
when the values approach >750 µg/g dry liver weight.
Definitive determination of the amount of hepatic Cu requires a quantitative
analysis of tissue Cu. Hepatic copper content is measured using atomic absorption spectroscopy and can be determined on needle biopsy samples, although
larger samples provide better accuracy. Samples for analysis should be placed
in a Cu free container (such as a serum blood tube) for analysis. Normal canine
hepatic Cu concentrations are less than 400 µg/g dry weight liver. The concentration at which abnormal hepatic Cu contributes to hepatic damage is unknown. It is possible to take adequate size biopsy sample embedded in paraffin
for histology and de-paraffinize the sample to obtain a quantitation of copper.
Morphologic evidence of inflammatory hepatic injury in Bedlington Terriers begins when concentrations reach approximately 2,000 µg/g dry weight
although sub-cellular morphologic changes are found with lower Cu concentrations. Homozygous affected dogs have increased copper concentrations but
should be older than one year of age prior to having a biopsy. This is because
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the heterozygous carrier dogs normally increase in copper concentrations out
of the normal range until around 6-9 months of age before concentrations fall
back into the normal range. Genetic testing (VetGen.com) is also available for
Bedlington Terriers to determine if they are free of disease. This test involves
an anonymous microsatellite marker closely linked to the copper toxicosis locus.5 Allele 1 is linked with a healthy gene and allele 2 is linked with disease.
The results are reported as 1/1 disease free, 1/2 heterozygous carriers and 2/2
affected dogs. The genetic testing is not 100% accurate but detects approximately 90-95% of affected dogs. A liver biopsy is required to completely confirm if the dog is phenotypic affected.
Doberman Pinscher. Doberman hepatitis is a form of chronic hepatitis. The
incidence is unknown but may occur in as high as 4 to 6% of dogs. The high percent suggests a genetic predisposition.6 Females seem to be over-represented.
The disease begins in young dogs (1-3 years) with increased ALT concentrations
and having sub-clinical hepatitis. Clinical evidence of liver disease usually begins around 4-7 years of age with chronic hepatitis and cirrhosis. Copper appears
to be associated with the disease and recent studies suggest that copper is often
increased prior to development of clinical hepatitis. Cu64 isotope studies demonstrate affected dogs have an impaired biliary excretion of copper.7 Copper chelator therapy in sub-clinical dogs normalized copper concentrations with improvement in the grade of histological damage. In affected dogs the copper concentrations generally range from 1000-2000 µg/g DW liver. At this point no specific
gene has been identified for this disease to determine the mode of genetic transmission. The above evidence suggests a primary defect in copper metabolism in
the breed but awaits further conformation. An autoimmune mechanism is also
suggested but this too requires further investigation.
Dalmatians. A retrospective study summarizes 10 Dalmatians suspected of
having hepatic copper toxicosis.8 Two of the dogs were related and all presented for gastrointestinal clinical signs, had elevated liver enzymes and
necroinflammatory hepatic changes associated with copper-laden hepatocytes
most prominent in a centrilobular location. The mean hepatic copper concentration was 3,197µg/d dry weight liver. In 5 of these 9 dogs, hepatic copper
concentrations exceeded 2,000 µg/d DW liver with several dogs having copper levels as high as those observed in Bedlington Terriers. These findings
support the hypothesis that a primary metabolic defect in hepatic copper metabolism occurs in the Dalmatian breed. The mechanism and genetic basis of
this condition is under further study.
West Highland White Terriers. The “Westie” breed has been associated with
liver disease and hepatic copper accumulation. The clinical findings appear to
be different than other breeds associated with copper accumulation. Dogs reported showed evidence of hepatitis or cirrhosis and had increased hepatic copper ranging from 1000-3000 µg/g dry weight liver. Twenty-four dogs described
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ranged from 3-7 years of age. Some dogs in this report had high copper concentrations but no evidence of liver disease while others did.9 While the Bedlington
Terrier tends to accumulate Cu with age it was not apparent in this group of
dogs. Affected dogs that were bred produced offspring with elevated copper
concentrations supporting a genetic defect. Several dogs were treated with zinc
therapy and showed reduction in hepatic copper concentrations.
Labrador Retrievers. Chronic hepatitis is reported to be common in this
breed and there is evidence that copper accumulation is associated with some,
but not all the cases. We find females are more commonly affected and the diagnosis is generally made between 2 to 7 years of age. Hepatic copper concentrations generally range between 750 to 2000 µg/g dry weight liver. The
histological location of the Cu being centrilobular suggests that Cu elevation
is probably not secondary to cholestasis. It appears that copper chelation is
beneficial in some dogs with hepatitis and copper accumulation.
Other Breeds. The Skye Terrier, Anatolian Shepherd, and possibly the
Keeshond as well as other breeds have also been reported with liver disease
and increased copper accumulation. The exact mechanism or extensive description in specific breeds is lacking.
SECONDARY COPPER ACCUMULATION
Copper may also concentrate in the liver secondary to cholestatic liver diseases. Because copper is excreted via the bile, cholestatic liver disease often results in copper accumulation in the periportal areas. The copper accumulation
occurs in Kupffer cells and hepatocyte lysosomes. The magnitude of Cu concentrations from cholestasis is not as high as those found in the breeds thought to
have a genetic basis. In a Review of 17 liver biopsies from breeds not yet identified to have inherited Cu copper associated liver disease (including 2 Standard
Poodles, 2 Cocker Spaniels, 5 mixed breeds and the remainder single dogs of different breeds), the mean copper concentration was 984 µg/g dry weight liver.
TREATMENT CONSIDERATIONS
Regardless of the cause of hepatic Cu accumulation it has been shown that
unbound Cu plays a role in hepatocellular damage. Medical strategies should
be considered when abnormal Cu concentrations are identified in dogs presenting with liver disease. This is true not only for dogs with hereditary Cu
accumulation but also for dogs having secondary copper accumulation as
well. Copper at toxic concentrations initiates oxidative membrane damage
causing either hepatocellular necrosis or apoptosis. Removing copper from
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the liver and preventing the resultant oxidative damage is the basis of therapy.
The treatment possibilities are threefold: (1) to decrease further absorption of
copper from the gastrointestinal tract by feeding a Cu deficient diet or blocking dietary Cu uptake, (2) to enhance hepatic Cu removal using specific chelator therapy and/or (3) to protect the liver from copper catalyzed oxidative
damage using antioxidant agents. A specific therapeutic plan requires careful
case evaluation and individual formulation.
Decreasing Copper Absorption. Dietary Restriction. The restriction of
dietary Cu is recommended but does little to lower hepatic Cu in diseased
dogs having significant hepatic Cu accumulation. This is in part because of
the large amounts of hepatic Cu present in the liver at the time of diagnosis
and the fact that placing a dog in a negative copper balance using diet alone
is almost impossible. All commercial diets contain copper at concentrations
that meet minimum daily requirements that are far in excess of what should
be given to a dog with a metabolic defect in copper metabolism. Homemade
diets can be prepared that do not to contain excess Cu but because of the minimal immediate impact of diet on the management of the affected dog, diet
tends to be less of a therapeutic consideration. Of more importance is to feed
a balanced diet, without excessive copper content and with acceptable palpability that meets other nutritional requirements. Heavily Cu supplemented diets or copper containing vitamin-mineral supplements should be avoided.
Blocking Copper Absorption. Zinc therapy decreases intestinal absorption
of dietary Cu by inducing synthesis of intestinal epithelial protein metallothionein. Copper binds more tenaciously to the increased metallothionein than
does zinc and prevents its intestinal movement into the blood.10 Metallothionein bound copper is eventually lost into the feces when intestinal epithelial
cells are sloughed as they die off. Thus, a mucosal block of Cu absorption is
achieved. There is a suggestion that zinc therapy also decreases hepatic stores
of Cu. Zinc therapy given to West Highland White Terriers and Bedlington
Terriers showed a reduction in hepatic Cu concentrations, although it took
several years to achieve a therapeutic response. In this study the approximate
9 kg dogs were given an inducing dose of 100 mg of elemental zinc acetate
bid for 1-2 months then the dose was reduced to 50 mg of elemental zinc bid
thereafter. Serum zinc concentrations were monitored with a goal of no more
than a two-fold increase of serum concentrations (< 300 µg/ml). In this study
serum zinc levels remained in the suggested therapeutic range and there was
no evidence of toxicity. In humans Galzin™ (zinc acetate capsules) containing 25 or 50 mg of elemental zinc is used for this purpose. Doses given to humans range from 25-50 mg tid which is lower than those recommended in the
dog study. The author is currently using 25 to 50 mg zinc acetate bid as a
maintenance dose. In humans, combination therapy using zinc and chelators
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showed no benefit over single therapy. It is recommended that in affected
dogs chelator therapy be used first to decrease copper concentrations before
zinc therapy is initiated. Zinc may be beneficial in dogs with early sub-clinical hepatitis and elevated copper concentrations less than 1000 µg/g dry
weight liver, however there are no studies to substantiate this.
Chelating Agents. Excretion of copper from the body is enhanced by
cupruretic agents (Cu chelators). Treatment using Cu chelators has had a
proven beneficial effect in dogs having increased hepatic Cu concentrations.
These specific chelators bind with Cu in blood or tissues and promote their
removal through the kidneys.
D-penicillamine. D-penicillamine (PCA) (Cuprimine®) has consistently been
shown to be an effective copper chelator and is a recommended therapy for Wilson disease in humans. In Wilson disease patients, PCA removes most but not
all the excess hepatic Cu. Even after prolonged therapy urinary copper excretion
declines even though there are remaining elevated hepatic copper concentrations. There is speculation that there may be several pools of hepatic Cu in Wilson disease, some of which may not be effected by PCA. There is also now speculation that PCA may detoxify the remaining Cu in the liver, either by the formation of a chelate that is nontoxic or by inducing the synthesis of hepatic metallothionine that binds and detoxifies Cu. In spite of the abnormal hepatic Cu
concentrations histological damage does not progress in those Wilson disease
treated patients. The dose of penicillamine in dogs is 10-15 mg/kg bid given on
an empty stomach. In some dogs vomiting is a problem at the onset of therapy
and may improve if the PCA is given with a small amount of food. One should
then eventually attempt to medicate without food. In a Bedlington Terrier study
there was an average of 900 µg/g dry weight copper lost per year. Once the patient has been decoppered, zinc therapy can be initiated or PAC therapy titrated
to once every several days or longer. Other side effects to PCA are uncommon
however the author has observed cutaneous and renal manifestations.
Trientine. A second chelator, trientine (Syprine® a 2,2,2 tetramine) acts by
increasing urinary excretion of copper.11 Although it has an overall effect in
humans somewhat less than PCA, it is considered an effective chelator and is
reserved for patients that are intolerant to PCA. In our dog studies we found
trientine to have similar effects to PCA. It appears that trientine’s chelation
affinity for copper is greater in the serum while PCA has greater affinity for
tissue copper. We have observed trientine to have far fewer GI side effects
than PCA. The does is 10-15 mg/kg bid given on an empty stomach.
Antioxidant Therapy. Abnormal concentrations of hepatic copper promotes cellular oxidative damage and membrane lipid peroxidation.12 A recent
study by this investigator found that affected Bedlington Terriers with copper
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hepatoxicity and subcellular evidence of morphologic damage have increased
concentrations of hepatic markers of oxidative damage (lipid conjugated dienes
and melondialdehyde) and reduced mitochondrial concentrations of vitamin
E.13 In these dogs the Cu accumulation was thought to catalyze the formation of
reactive free radicals causing membrane peroxidation. In another in vivo study
using laboratory animals it was demonstrated that vitamin E therapy (d-alpha
tocopherol) had protective properties against Cu hepatotoxicity. Vitamin E, a
major membrane bound intracellular antioxidant, functions to quench membrane lipid peroxidation damage when free radicals are formed. Based on these
preliminary studies it is suggested that vitamin E therapy may have a protective
benefit in affected dogs with abnormal hepatic Cu concentrations and oxidative
damage. A dose range of 100 to 400 IU of d-alpha tocopherol given daily is suggested. The supplement appears to be safe and free of side effects in this dose
range. Other antioxidants or glutathione may also be beneficial however vitamin C has been shown to act as a pro-oxidant in the presence of increased concentrations of copper and should not be supplemented.
SUMMARY
The abnormal accumulation of hepatic Cu can occur as a primary disease
or secondary to cholestatic liver disease. Because of Cu’s both direct and indirect effects on hepatocellular morphology and function, attempts should be
directed at depleting abnormal hepatic Cu by either blocking Cu absorption
or through chelation therapy.
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Wijmenga C, et.al. Proc Nutr Soc 2004; 63:31.
van De Sluis B, et.al. Hum Mol Genet 2002; 11(2): 165.
Haywood S, et.al. Anal Cell Pathol 1996;10 (3): 229.
Yuzbasiyan-Gurkan V, et.al. Am J Vet Res 1997; 58 (1): 23.
Speeti M, et.al. Vet Pathol 1998; 35:361.
Mandigers PJJ, et.al. J Vet Intern Med 2004; 18 (5): 647.
Webb CB, et. al. J Vet Intern Med 2002; 16 (6):665.
Thornburg LP, et.al. Vet Rec 1986;118(4);110.
Brewer GJ, et. al. J Am Vet Assoc. 1992; 201(4):564.
Twedt DC, et.al. J Am Vet Med Assoc 1988;192(1):52.
Spee B, et.al. Comp Hepatol 2005; 1:3.
Sokol RJ, et.al. Gastroenterology 1994; 107(6):1788.
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David C. Twedt
IDIOPATHIC HEPATITIS
AND CIRRHOSIS
IN DOGS
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Chronic hepatitis is an etiologic diverse and morphologically variable
condition associated by mixed inflammatory cell infiltrates. It is characterized by hepatocellular apoptosis or necrosis, a variable mononuclear or
mixed inflammatory infiltrate, regeneration and fibrosis. The proportion and
distribution of these components vary widely. Plasma cells, lymphocytes
and macrophages predominate with a lesser number of neutrophils. Because
we see non-specific mild portal inflammation as a common non-specific reactive change I always ask the pathologist to tell me the severity of inflammation and chronicity of the disease. The presence of fibrosis in the hepatic biopsy usually denotes to me more serious consequences. As damage progresses cirrhosis can result with diffuse fibrosis, alteration in hepatic lobular architecture with the formation of regenerative nodules and abnormal
vascular anastomoses.
Cirrhosis, a sequel of some chronic hepatitis cases, is often associated with
portal hypertension, ascites and multiple portosystemic collateral veins. Some
may show manifestations of liver failure, e.g., hyperbilirubinemia, coagulopathies, edema due to hypoalbuminemia, ascites and hepatoencephalopathy.
Inflammation in the liver has been given a number of different classifications
(ie chronic active hepatitis, cholangiohepatitis etc) but the WSAVA liver standardization group believes we are not able to subclassify hepatitis and suggests we call the condition simply chronic hepatitis. This type of chronic inflammation is uncommon in the cat as their inflammatory disease is directed
at bile ducts causing cholangitis.
ETIOLOGY
The etiology of this chronic inflammatory condition is generally never
determined. Copper associated chronic hepatitis has been documented in a
number of breeds as an inherited etiology. The hepatic copper accumulation increases to a level that then becomes toxic to the hepatocyte causing
cellular death. The copper accumulation may also result as secondary copper retention from altered biliary copper excretion (see copper associated
hepatitis below).
Infectious causes of chronic hepatitis have been associated with leptospirosis and experimental and spontaneous infectious canine hepatitis virus
infection. Chronic liver injury has also been reported in dogs with aflatoxicosis and various drug-induced hepatitis. Some dogs treated with anticonvulsant
drugs primidone, phenytoin and phenobarbital can develop chronic hepatitis.
We have also observed dogs treated with NSAIDs to have hepatitis and there
may be a casual relationship in some cases. More commonly however we see
acute liver necrosis as a NSAID related drug reaction.
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Alpha1-antitrypsin (AAT- also referred to as alpha one protease inhibitor)
deficiency in the serum leading to accumulation of AAT in the hepatocytes, is
known to cause chronic hepatitis and cirrhosis in man. Investigations by researchers in Sweden using immunostaining for AAT in hepatocytes found
some dogs with chronic hepatitis to be positive. The breed most often associated with AAT accumulation was the cocker spaniel.
Finally immune associated hepatitis may occur in the dog. Circulating autoantibodies are important diagnostic markers used to identify autoimmune
liver disease in humans. It appears that autoantibodies (ANA, antimitochrondial antibodies [AMA], smooth muscle antibodies [SMA], liver membrane
autoantibodies [LMA]) are of a minor importance in classifying canine chronic hepatitis and thought to occur in most cases secondary to the liver damage.
Nonetheless, immune-mediated mechanisms are thought to be associated
with certain cases of chronic hepatitis and this is supported by the fact that
some dogs respond favorably to immunosuppressive therapy.
There is lastly a lobular dissecting hepatitis characterized by a rapid diffues spread of inflammation throughout the liver lobule. This condition is
observed in younger dogs and is associated with hepatic encephalopathy
and ascites.
BREED PREDISPOSITION
There are a number of breeds that have an increased incidence and suspected genetic basis. Some of these breeds have copper associated chronic
hepatitis (discussed below). Other breeds not yet associated with copper include the standard poodle, Cocker spaniel and Scottish terrier. The mechanism of their hepatitis is unknown.
COPPER ASSOCIATED HEPATITIS
Abnormal hepatic copper accumulation may be the result of either a primary metabolic defect in copper metabolism or as a secondary event from
abnormal hepatic function altering hepatic copper excretion. When we reviewed a number of dogs having chronic hepatitis not associated with genetic copper accumulation we found many dogs had increases in both copper and iron hepatic concentrations. A number of these dogs were also deficient in hepatic zinc. The interrelationship of the heavy metals and liver
disease needs further investigation. The diagnosis of abnormal Cu accumulation requires a liver biopsy.
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CLINICAL FINDINGS
The incidence of chronic hepatitis makes up approximately one fourth of
the cases having liver biopsies at Colorado State University (based on a review of 150 consecutive liver biopsies). Chronic hepatitis is more common in
female dogs. The average of presentation ranges from 4 to 10 years. It is interesting to note that in both our series and in studies by others it is uncommon to observe chronic hepatitis/cirrhosis in dogs older than 10 years of age.
As a general rule old dogs (> 11 years of age) don’t generally present with
chronic hepatitis/cirrhosis or if they do they are at or near end stage disease.
The clinical signs parallel the extent of hepatic damage. Early in the disease there are usually no or minimal clinical signs. Only after the disease progresses do the clinical signs specific for liver disease becomes evident. Frequent early signs are gastrointestinal associated with vomiting, diarrhea and
poor appetite or anorexia. Ascites, jaundice and hepatic encephalopathy may
then occur as the disease progresses. With development of these late signs the
long-term prognosis is generally poor.
The laboratory findings include consistently elevated ALT and ALP. The
magnitude of rise need not be marked however. One report found 75% of the
cases at diagnosis had abnormal bilirubin elevation (mean elevation of 2.6
mg/dl). Serum proteins are variable. As the lesions become more severe albumin levels decline. Serum bile acids are abnormal in most cases having significant chronic hepatitis and measurement of bile acids appear to be a good
screening test for the patient with unexplained elevations in ALT and ALP. In
our study all dogs evaluated with chronic hepatitis had abnormal bile acid
concentrations. In a second study only 8/26 dogs with chronic hepatitis had
normal fasting bile acids. However, postprandial samples were not determined in these cases. Determining postprandial bile acids has been shown to
increase the sensitivity of this test.
A presumptive diagnosis is made based on the clinical features and persistent increases of ALP and ALT values. A definitive diagnosis requires a hepatic biopsy showing characteristic morphological patterns. Needle aspirates are
not helpful in making the diagnosis of chronic hepatitis because it is important to see the architecture of the liver and location and extent of the inflammation. One must work with the pathologist when making the diagnosis of
chronic hepatitis and to be certain that characteristic abnormalities found in
chronic hepatitis are present
Prognosis. There is little information of the prognosis with and without
therapy. The prognosis in dogs with advanced chronic hepatitis and cirrhosis
is guarded. In a study by Strombeck found mean survivals ranging from 6 to
16 months with therapy. This study also identified that dogs with hypoalbuminemia, hypoglycemia and coagulopathies have very guarded prognostic
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factors and many died within 1 week of diagnosis. A second study of 79 dogs
found that dogs with cirrhosis had a survival of less than one month and dogs
with chronic hepatitis had a mean survival in the range of about 20 to 30
months. Most of these dogs were not advanced in their disease and had
concurrent corticosteroid treatment. Low albumin, ascites and hepatic encephalopathy are all poor prognostic indicators.
THERAPY
I have four general goals in therapy of CH: 1) remove the etiology, 2) provide an adequate diet, 3) specific therapy and 4) providing general liver support. First the therapy for chronic hepatitis involves removing the primary etiology if it can be identified. Short of treating the primary etiology all other
therapies suggested are unproven in the management of CH in dogs. Much of
the therapy is directed at providing adequate liver support. This often involves
the use of multiple therapies.
Diet therapy should be considered in all cases however only general guidelines can be given. First, palatability is important to assure adequate energy
requirements are met. Next, there is a misconception about diet and liver disease that liver patients should be placed on a protein restricted diet. Protein
restriction should only be instituted in the patient that has clinical evidence of
protein intolerance (i.e. hepatic encephalopathy). The goal of dietary therapy
is to adjust the quantities and types of nutrients to provide nutrient requirements but to avoid the production of excess nitrogen by-products associated
with liver disease. As a general recommendation one should feed a highly digestible protein source contributing 15 to 20% of dry matter basis (DM). High
carbohydrate and moderate fat content is important to supply caloric needs.
Mineral supplementation containing high concentrations of both copper and
iron should be avoided and involves feeding the lowest copper content available (ideally < 5 mg/Kg (ppm) copper DM).
Decreasing inflammation for CH in the dog is unproven although the author’s clinical impression suggests anti-inflammatory therapy is beneficial in
some cases. The treatment of chronic hepatitis is quite controversial and there
are as yet no good controlled studies in animals to support corticosteroids use
in every case. In a study by Strombeck found that some dogs with chronic
hepatitis tended to have a prolonged survival when treated with corticosteroids. This retrospective study is one with a wide diversity of diseases and
concurrent therapies. But none-the-less, it appears that corticosteroids offer
benefit in at least some cases (possibly around 25%). A suggested dose of 1
to 2 mg/kg/day using either prednisone or prednisolone should be instituted.
When clinical improvement is suspected or after several weeks the dose is
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then gradually tapered eventually to a dose of 0.5 mg/kg/day or every other
day. The only accurate way to evaluate a response to any therapy is to re-biopsy the patient in 6 months to 1 year because the patient will develop a concurrent steroid hepatopathy with increased liver enzymes making laboratory determination of any improvement impossible. The steroid hepatopathy along
with the negative clinical signs from steroids I am now tending to use other
immunosuppressive therapy. Azathioprine is an effective immunosuppressant
drug that has shown to increase survival in man when treated for chronic hepatitis in conjunction with corticosteroids. There are no studies in dogs and
azathioprine has been associated with a drug-induced hepatopathy. I now tend
to use cyclosporine in cases having CH because of its excellent immune suppression and the fact that a generic form is available and less expensive. I have
observed resolution in a number of dogs treated with cyclosporine alone at a
dose of 5 mg/kg bid however I advise monitoring blood levels.
CH associated with abnormal hepatic copper accumulation requires copper chelator or zinc therapy. Hepatic copper levels of greater than 1000 µcg/g
dry weight liver should have chelator therapy for at least some period of time.
Chelators bind with copper either in the blood or the tissues and then promote
copper removal through the kidneys. Refer to paper on copper associated hepatopathies.
Other therapy for CH includes ursodeoxycholic acid (Ursodiol-Actigall™.
This drug is a synthetic hydrophilic bile acid that essentially changes the bile
acid pool from the more toxic hydrophobic bile acids to less toxic hydrophylic
bile acids. Ursodeoxycholic acid has been shown to increase bile acid dependent flow, reduce hepatocellular inflammatory changes, fibrosis and possibly
some immunomodulating effects. The hepatoprotective characteristics makes
one believe ursodeoxycholic acts as an antioxidant. The dose for ursodeoxycholic acid is 15 mg/kg daily. Antioxidants can also be given to provide liver
support promoting optimal hepatic function. Vitamin E, d-alpha tocopherol is
a membrane bound antioxidant. S-Adensosyl-methionine (SAMe) [Denosyl™] is a precursor of the antioxidant glutathione in the hepatocyte. Milk
thistle has been used for centuries as a natural remedy for liver disease. Silymarin is the active extract consists of bioflavonoligans that have been reported to work as antioxidants, scavenging free radicals and inhibiting lipid peroxidation. Marin™ (Nutramax Labs) contains silybin-phosphatidylcholine
that increases absorption.
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David C. Twedt
THERAPEUTIC USE
OF CYTOPROTECTIVE
AGENTS IN CANINE
AND FELINE
HEPATOBILIARY
DISEASE
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There are a number of cytoprotective agents that are used in the management
of liver disease. The common ones used in veterinary medicine are discussed below. Although there are many other agents that have been used the ones below
are safe and have some scientific evidence for benefit. There is however few published reports showing benefit in clinical disease and much of the information
gathered is generated from in vitro studies. Whenever using any therapy the patient should be carefully monitored for adverse side effects.
Ursodeoxycholic Acid. Ursodeoxycholic acid (Ursodiol) is a choleretic
agent that was developed to dissolve gallstones but later found to have positive effects in patients with chronic hepatitis. This drug is a synthetic hydrophilic bile acid that essentially changes the bile acid pool from the more
toxic hydrophobic bile acids to less toxic hydrophylic bile acids. Ursodeoxycholic acid has been shown to increase bile acid dependent flow, reduce hepatocellular inflammatory changes, fibrosis and some immunomodulating effects. The hepatoprotective characteristics, much like antioxidants, makes ursodeoxycholic a good adjunct therapy. The dose for ursodeoxycholic acid is
15 mg/kg daily. No toxicity has been observed in dogs and cats at this dose.
There has been a concern raised by some that it should not be used if there is
any possibility of a bile duct obstruction for fear of biliary rupture. Although
with bile obstruction surgical correction is indicated ursodeoxycholic acid is
not a prokinetic and will not worsen the disease. In fact in experimental bile
duct obstruction in a rat study found there is less secondary “toxic” changes
in the liver of rats given ursodiol than placebo. Although there is only one case
report of a dog treated only with ursodeoxycholic acid that dog did have
changes in the bile acid pool and improvement in laboratory enzymes. This
drug has also been shown in controlled studies to be beneficial in primary biliary cirrhosis in humans. I will routinely supplement ursodeoxycholic acid in
cases having hepatitis or cats having cholangitis.
Vitamins. The liver is the major organ for vitamin metabolism. Both vitamin storage as well as the conversion of provitamins to their metabolically active state takes place in the hepatocytes of the liver. Consequently, practitioners must contemplate the vitamin status of patients with liver disease. The fatsoluble vitamins (i.e., A, D, E, and K) are prone to be deficient because they
require bile salts to form intestinal micelles for absorption. In cholestatic liver disease, bile acids abnormally excrete into the intestine, which affects the
uptake of fat-soluble vitamins. The water-soluble vitamins (i.e., B vitamins,
vitamin C) are generally found in high concentrations in the liver where many
are stored as coenzymes. In patients with liver disease, an increased demand
for these vitamins, altered conversion to the vitamin’s active form, or decreased hepatic storage may occur.
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Vitamin E (alpha-tocopherol) functions as a cellular membrane-bound antioxidant. Evidence now shows that oxidative damage occurs during liver disease from free radical generation. While cellular damage in liver disease is
probably multifactorial, free radicals may play an important role in initiating
or perpetuating this damage. Free radicals are molecules with an unpaired
electron that form by the injurious effects of certain drugs or various other
toxic agents or events. Abnormal concentrations of bile acids and the accumulation of heavy metals, such as copper and iron, have been shown to cause free
radical generation in the liver. If not inactivated, free radicals damage cellular
macromolecules via lipid peroxidation and thus participate in cellular injury
when produced in excess.
Normally, an extensive system of cytosolic and membrane-bound enzymatic and nonenzymatic antioxidants prevent oxidative damage by scavenging or quenching free radicals that are formed. Vitamin E is a major membrane-bound intracellular antioxidant that protects membrane phospholipids
from peroxidative damage when free radicals are formed. Evidence shows
that dietary supplementation with vitamin E reduces oxidant injury to hepatic tissue. Bedlington terriers with copper-associated hepatopathy have oxidant
damage in their mitochondria and reduced mitochondrial vitamin E concentrations. Vitamin E has also shown a protective effect in the liver from copper-related oxidant damage and bile acids.
Vitamin E is inexpensive and safe when supplemented at a dose of 10
IU/kg/day. d-Alpha-tocopherol, the natural form of vitamin E, is recommended because of greater uptake, dispersion, and bioactivity compared with the
more common synthetic dl-alpha-tocopherol formulation. d-Alpha-tocopherol is also retained in tissues by a two-to-one ratio over the synthetic formulation. With significant cholestatic liver disease, I suggest a water-soluble
formulation.
Ascorbic acid (vitamin C) is an important soluble intracellular antioxidant
that helps convert oxidized tocopherol radicals back to active alpha-tocopherol. Vitamin C is also necessary for the synthesis of carnitine, which is important for transport of fat into mitochondria. People with liver disease often
have low hepatic vitamin C concentrations in part because people can’t synthesize vitamin C, but dogs and cats can. Although vitamin C supplementation may be a beneficial adjunct in treating liver disease, supplementation of
excessive amounts of vitamin C may be deleterious in patients with increased
hepatic copper or iron concentrations. This is because ascorbate is believed to
promote oxidative damage caused by these transition metals.
Vitamin K stores in the liver can become depleted with advanced liver disease and can result in serious coagulopathies. Deficiency can occur from reduced intestinal absorption from cholestatic liver disease or as the result of
advanced liver dysfunction with a failure of hepatic conversion to the vitamin
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K-dependant coagulation factors (i.e., factors II, VII, IX, and X). This can result in prolongation of coagulation as measured by prothrombin time or activated partial thromboplastin time and can cause significant bleeding. Vitamin
K supplementation is warranted in patients with liver disease to maintain hepatic stores. With severe cholestasis or overt coagulation abnormalities, parenteral vitamin K1 (phytonadione) at 0.5 to 2.0 mg/kg every 12 hours subcutaneously for two to three dosages (or until normalization of prothrombin
time) is recommended for dogs and cats with hepatic disease. Vitamin K1 supplementation is recommended for 24 to 36 hours before invasive procedures,
such as hepatic biopsy or feeding tube placement.
B vitamins are important in many metabolic functions and may become
deficient in both dogs and cats with liver disease. However, deficiencies are
difficult to diagnose or analytically document. Because the B vitamins are water-soluble, they are relatively nontoxic and supplementation using a B-complex formulation recommended in patients with liver disease.
Cats are particularly prone to vitamin B12 deficiency. Subnormal concentrations of vitamin B12 (cobalamin) is reported in cats with liver disease and,
in particular, idiopathic hepatic lipidosis.24 Cats with cholangiohepatitis frequently have concurrent inflammatory bowel disease or chronic pancreatitis
and subsequent cobalamin deficiency. The recommended dose of cobalamin
for cats is 250 µg given subcutaneously weekly until normal cobalamin concentrations are maintained. It should be noted there is not enough vitamin B12
in the B-complex formulations to correct a B12 deficiency in cats.
Nutraceuticals. A nutraceutical is not quite a foodstuff and not quite a
drug—it appears to lie somewhere in between. The North American Veterinary Nutraceutical Council defined a nutraceutical as “a non-drug substance
that is produced in a purified or extracted form and administered orally to patients to provide agents required for normal body structure and function and
administered with the intent of improving the health and well being of animals”. Because nutraceuticals are not classified as drugs, they are not subject
to Food & Drug Administration approval showing purity, safety, and efficacy.
Consequently, “buyer beware” when purchasing nutraceuticals as some may
not be what they are labeled to be.
Many nutraceuticals available for use in animals are listed as nutritional
supplements. Typical categories of nutraceutical products used in pets include
antioxidants, omega fatty acids, amino acids, chondroprotective agents,
herbals, and probiotics. Although some nutraceuticals have shown a potential
for improving veterinary care, little information is known about the purity,
dosage, safety, side effects, and effectiveness of the substance for the prescribed disease treated. The nutraceutical industry, with a few exceptions, has
done little to answer these important questions. Below are some nutraceutical
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compounds used in the management of liver disease that have shown at least
some scientific evidence for both effectiveness and relative safety.
S-adenosylmethionine (SAMe) is a naturally occurring molecule synthesized in all living cells and is essential in intermediary metabolism. It has both
hepatoprotective and antioxidant properties. SAMe is produced from the
amino acid methionine and subsequently initiates one of three metabolic pathways. The transmethylation pathway is essential in phospholipid synthesis,
which is important in membrane structure, fluidity, and function. The transsulfuration pathway generates sulfur-containing compounds, such as glutathione, which participates in many metabolic processes and plays a critical
role in cellular detoxification mechanisms.
Depletion of hepatic glutathione can indirectly cause toxic effects in
these cells by increasing oxidative stress. The aminopropylation pathway
yields products that have anti-inflammatory effects and polyamines important in DNA and protein synthesis.
The liver normally produces abundant SAMe, but evidence also suggests
conversion from methionine to SAMe is hindered in liver disease and results
in the depletion of glutathione concentrations. Orally administered SAMe
(but not oral glutathione) has been shown to increase intracellular glutathione
levels in hepatocytes and prevent glutathione depletion when exposed to toxic substances. Thus, SAMe in part acts as an antioxidant replenishing the glutathione stores. Preliminary veterinary studies suggest that SAMe supplementation increases hepatic glutathione concentrations in normal cats and prevents glutathione depletion in dogs with steroid-induced hepatopathy. SAMe
treatment following acetaminophen administration prevented hepatic glutathione depletion.
N-acetylcysteine, the acetylated variant of the amino acid L-cysteine, is an
excellent source of sulfhydryl groups and is converted in the body into
metabolites capable of stimulating glutathione synthesis, promoting detoxification, and acting directly as free radical scavengers. N-acetylcysteine has
historically been used as a mucolytic agent in a variety of respiratory illnesses; however, it appears to also have beneficial effects in other conditions characterized by oxidative stress or decreased glutathione concentrations. Nacetylcysteine is currently the mainstay of treatment for acetaminophen-induced hepatotoxicity. It also appears to have some clinical usefulness as a
chelating agent in the treatment of acute metal poisoning, both as an agent capable of protecting the liver and kidney from damage and as an intervention
to enhance elimination of the metals.
Although N-acetylcysteine is produced as a drug, it is also available as a
nutritional supplement. The oral dose recommended for acetaminophen toxicity is 70 mg/kg three times a day. When given intravenously, a loading dose
of 140 mg/kg is given and followed by the 70 mg/kg dosing. N-acetylcysteine
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is reported to have extremely low toxicity with few side effects. I use Nacetylcysteine IV when the patient is vomiting or too sick to take oral SAMe
which is my preference as a maintenance therapy.
Phosphatidylcholine is a phospholipid used as a nutritional supplement for
its hepatoprotective effects. A building block for cell membranes, phosphatidylcholine is one of the components required for normal bile acid transport. It is thought to be hepatoprotective by improving membrane integrity
and function. In vitro studies have shown phosphatidylcholine increases hepatic collagenase activity and may also help prevent fibrosis. Clinical trials indicate that phosphatidylcholine protects the liver against damage from alcohol, viral hepatitis, and other toxic factors that operate by damaging cell membranes. In two animal studies using baboons given alcohol and supplemented
with 60% phosphatidylcholine, both fibrosis and cirrhosis were largely prevented in the phosphatidylcholine-treated group.
Several forms of phosphatidylcholine supplements are available, and no
major side effects have been reported other than occasional nausea or diarrhea. Based on the multiple mechanisms of action of phosphatidylcholine,
this nutrient may be beneficial for chronic liver disease because oxidative
stress, cytokine alterations, and fibrosis ensue. Given the apparent safety of
phosphatidylcholine and its acceptable cost, animal studies would appear to
be worthwhile. Phosphatidylcholine is rapidly absorbed, enhances absorption
of other compounds, and is included as a carrier in one silybin product.
L-carnitine is a vitamin-like substance found in most cells. Synthesis of
carnitine is predominately in the liver, and, consequently, liver disease may
result in deficiency states. The primary function of L-carnitine is to transport
long-chain fatty acids across the inner mitochondrial membrane into the mitochondria for ß-oxidation to form acetyl CoA fragments. These fragments
then enter the citric acid cycle for energy production. Carnitine deficiency
may result in hepatocyte triglyceride accumulation and lead to accumulation
of toxic acetyl CoA metabolites that impair mitochondrial respiration and
function. Clinically, carnitine deficiency has been associated with increased
ammonia concentrations, hypoglycemia, and fatty livers.
In a study where carnitine was given to obese cats undergoing rapid weight
loss from caloric restriction, researchers found it protected against hepatic
triglyceride accumulation. Some studies suggest that L-carnitine deficiency
may play a role in the pathogenesis of idiopathic feline hepatic lipidosis; however, carnitine concentrations were higher in the plasma, liver, and muscle
than in control cats. A deficiency of carnitine may lead to impaired mitochondrial function; however, these studies failed to show carnitine deficiency in
cats with hepatic lipidosis.32 Supplementation of 250 mg of carnitine a day in
lipidosis cats is reported to be associated with better survival rates, but this is
not yet documented.
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Silymarin a product of milk thistle grows wild throughout Europe and
has been used there for more than 2,000 years as a medical remedy for liver disease. The active extract of milk thistle is silymarin, which is classified
as a nutraceutical in the United States. Mounting evidence suggests that
milk thistle has medicinal benefits for various types of liver disease as well
as a protective effect against hepatotoxins. A recent poll of liver patients at
one U.S. hepatology clinic found that 31% were also using alternative
agents for their disease and that milk thistle was the most commonly used
nontraditional therapy.
Silymarin is the active extract in milk thistle. A standard milk thistle extract is approximately 70% silymarin and contains four flavonoid stereoisomers—and the most biologically potent one is silybin (silibinin). An abundance of both in vivo animal and in vitro experimental data shows the antioxidant properties and free radical scavenging properties of silymarin. Specifically, silymarin inhibits lipid peroxidation of hepatocyte and microsomal
membranes and protects against gene damage by suppressing hydrogen peroxide, superoxide anions, and lipoxygenase. Silymarin also increases hepatic
glutathione content and appears to retard hepatic collagen formation. Evidence also suggests that silymarin has hepatoprotective effects through the inhibition of Kupffer cell function by inhibiting leukotriene B4 production and
hepatotoxin binding to receptor sites on hepatocyte membranes, which provide additional stability against xenobiotic injury.
Several human trials have assessed the efficacy of silymarin in the treatment of liver disease. The data are somewhat difficult to interpret because of
the limited number of patients, poor study design, variable etiologies, and
lack of standardization of preparations with different dosing protocols. However, compelling evidence in many studies suggests that silymarin has a therapeutic effect in acute viral hepatitis, alcoholic liver disease, cirrhosis, and
toxin- or drug-induced hepatitis. To date, limited clinical studies have evaluated the efficacy of silymarin in liver disease in dogs and cats. In one placebo-controlled experimental study of dogs poisoned with the Amanita phalloides mushroom, silybin had a significant positive effect on liver damage and
survival outcome.
The purity and potency of commercial milk thistle products vary by manufacturer, and the therapeutic dosage for dogs and cats is unknown. Suggested doses for silymarin range from 50 to 250 mg/day. Milk thistle is reported
to have an extremely low toxicity and has been used extensively in clinical patients with little concern for side effects. When the active isomer silybin is
complexed with phosphatidylcholine, oral uptake and bioavailability is
greater. I recently performed a pharmacokinetic study evaluating a commercially available complex (Marin—Nutramax Labs) in normal cats, which
found no clinical outward signs of toxicity at 5 mg/kg daily and showed evi-
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dence of some oxidative protection in red blood cells. A new compound Denamarin™ is available containing SAMe and silybin-phosphatidylcholine and
is available in a chewable formulation. It appears that the combination of both
compounds has good absorption, appears to be very stable and SAMe is not
easily oxidized.
David Twedt Professor, Department of Clinical Sciences Colorado State University
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COMUNICAZIONI
BREVI
Le comunicazioni sono elencate in ordine alfabetico
secondo il cognome dell’autore presentatore.
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AGENESIA DELLA COLECISTI IN UN CANE ASSOCIATA
AD EPATOPATIA ED ENTEROPATIA INFIAMMATORIE
V. Marchetti, MV, PhD, SPCAA-GE1, S. Citi, MV, SRV1,
V.M. Innocenti, MV1, L. Campora, MV2, G. Guidi, MV1
1
Dipartimento di Clinica Veterinaria, Università di Pisa, Pisa, Italia
2
Dipartimento di Patologia Animale, Università di Pisa, Pisa, Italia
Tipologia: Caso Clinico
Area di interesse: Medicina interna
Introduzione. L’agenesia della colecisti (AC) è una rara anomalia congenita
riportata nell’uomo con un’incidenza fra lo 0.01% e lo 0.075%; legata ad un
alterato sviluppo della parte cistica del diverticolo epatico, decorre in modo
asintomatico nel 77% dei casi, ed è frequentemente una diagnosi incidentale
Nel cane, sono stati segnalati 3 casi (due maltesi ed un chihuahua), due giovani ed un adulto, paucisintomatici, con epatopatia caratterizzata da proliferazione duttulare e fibrosi. Nel presente lavoro si descrive il caso di una AC
in un cane adulto con epatopatia ed enteropatia infiammatorie.
Descrizione del caso. Un cane American Staffordshire, femmina, di 21 mesi di
età, viene riferito per un consulto a seguito del rilievo di un aumento significativo
degli enzimi epatici riscontrato in corso di accertamenti anestesiologici per una
ovariectomia. All’anamnesi il proprietario riferisce di episodi ricorrenti di nausea
e di un comportamento inaspettatamente calmo del cane anche da cucciolo; alla
visita clinica il paziente appare in buono stato di salute. Il profilo ematobiochimico completo evidenzia significativo aumento di ALP (1790 UI/L, 77-200 UI/L),
GGT (38 UI/L, 2.9-12.6 UI/L), AST (130 UI/L, 40-68 UI/L), ALT (2012 UI/L,
31-95 UI/L), moderato aumento di bilirubina totale (0.68 mg/dL, 0.13-0.30
mg/dL) e sideremia (234 mg/dL, 90-180 mg/dL). I restanti parametri, l’esame
delle urine, il profilo coagulativo e gli acidi biliari urinari sono nella norma. L’ecografia addominale evidenzia un fegato normale in dimensioni, con parenchima
iperecogeno, diffusamente disomogeneo. Non viene visualizzata la colecisti in sede né in localizzazione ectopica. Le restanti vie biliari extraepatiche appaiono normali in forma e dimensioni. La mucosa del piccolo intestino è diffusamente iperecogena ed il duodeno, dilatato da contenuto liquido, presenta piccoli foci iperecogeni mucosali e stratigrafia rispettata. I restanti organi addominali risultano nella norma. Il quadro ecografico suggerisce un’epatopatia ed enteropatia infiammatorie. Viene proposta una indagine laparotomica per accertare l’assenza della colecisti, eseguire prelievi bioptici epatici ed intestinali, nonché l’ovariectomia. In
sede chirurgica fegato e vie biliari extraepatiche appaiono nella norma e viene
confermata l’assenza della colecisti. Vengono eseguite biopsie epatiche, marginali e non, usando la tecnica del punch, e biopsie intestinali. L’esame istopatologico evidenzia una diffusa proliferazione di duttuli biliari associata a modesto infil-
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trato linfocitico periduttulare ed esili ponti di fibrosi porto-portali. Gli epatociti
mostrano una degenerazione idropico-vacuolare diffusa e modesta, non associata
a colestasi intra od extracellulare. La diagnosi conclusiva è di colangite cronica
proliferativa associata a modesta fibrosi epatica. A livello intestinale viene diagnosticata una modesta flogosi linfoplasmocitica con danno epiteliale di grado lieve,
senza segni di dilatazione linfatica. Nel periodo postchirurgico il paziente è sottoposto a terapia con amoxicillina-acido clavulanico, acido ursodeossicolico, S-adenosilmetionina, silimarina nonché a terapia antinfiammatoria con metilprednisolone a 1 mg/kg bid a scalare per 40gg e dietoterapia specifica per epatopatici. A
seguito della terapia il paziente mostra maggior vivacità e scomparsa dei segni di
nausea. Agli esami di controllo, 3 settimane dopo la fine della terapia antifiammatoria, si evidenzia un miglioramento del quadro enzimatico (ALP 313 UI/L, GGT
14 UI/L, ALT 327) e normalizzazione della sideremia. All’ecografia il quadro intestinale appare normalizzato, mentre persistono le alterazioni del parenchima
epatico. A 5 mesi dalla diagnosi, mantenendo la terapia con acido ursodeossicolico, S-adenosilmetionina e dieta, il paziente è in ottime condizioni cliniche.
Conclusioni. In questo caso di AC, a fronte di una sintomatologia lieve, i quadri di laboratorio, ecografici e istopatologici suggerivano un’epatopatia importante con aspetti flogistici non segnalati in precedenza. L’incremento degli
enzimi e della sideremia trovano correlazione con la colangite e la fibrosi. È
stato ipotizzato che la colangite possa ricondursi ad una discinesia biliare ed
una disfunzione dello sfintere di Oddi, con possibile reflusso duodenale. La
mancanza di un quadro colestatico istopatologico rende più probabile la seconda ipotesi. L’assenza di un flusso biliare intermittente può predisporre ad
una duodenite sia per una mancanza dell’effetto tampone della bile sia per
un’azione irritante dei sali biliari sulla mucosa. Nel nostro caso, senza un’evidente sintomatologia intestinale, erano presenti segni ecografici e istopatologici di enterite, non segnalata nei casi precedenti. Dopo la terapia steroidea i
segni ecografici intestinali sono scomparsi e sarebbe stato interessante eseguire biopsie di controllo sia epatiche sia intestinali. Il mantenimento della terapia con S-adenosilmetionina e acido ursodeossicolico trova i suoi presupposti
nella ricerca di un’azione di protezione di membrana, una riduzione della tossicità ed un’aumento della secrezione della bile.
Bibliografia
Liptak JM, Swinney GR, Rothwell TLW, et al. Aplasia of the gallbladder in a dog. JSAP, 2000;41:175-177.
Austin B, Tillson DM, Kuhnt LA. Gallbladder agenesis in a maltese dog. JAAHA, 2006;42:308-311.
Kamishina H, Masaaki K, Okamura Y et al. Gallbladder agenesis in a chihuahua. JVetMedSci, 2010:in
press.
Dott.ssa Veronica Marchetti - Dipartimento di Clinica Veterinaria, Università di Pisa,
Via livornese lato monte, 56122 San Piero a Grado (PI), Italia - E-mail [email protected]
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Pagina 153
TORSIONE DI LOBO QUADRATO, MEDIO DI DESTRA
E CISTIFELLEA IN UN PASTORE TEDESCO
F. Massari, DMV1, S. Verganti, DMV2, B. Secchiero, DMV, PhD1,
F. Orifici, DMV3, G. Romanelli, DMV, DECVS1
1
Libero professionista, Nerviano (MI), Italia
2
Libero professionista, Newmarket, United Kingdom
3
Libero professionista, Brugherio (MI), Italia
Area di interesse: Chirurgia
Introduzione. La torsione dei lobi epatici è una condizione patologica poco
comune già descritta in letteratura in diverse specie. I lobi di sinistra sembrano essere più interessati.1 Segnalazioni di torsione di cistifellea rimangono ad
oggi ancora più sporadiche.2
Lo scopo del lavoro è di riportare un caso di torsione di lobo quadrato, medio
di destra e cistifellea, senza alterazioni anatomiche congenite in un cane adulto.
Descrizione del caso. Un Pastore Tedesco femmina di 11 anni era riferito per
una neoformazione di origine non chiaramente identificata al quadrante addominale craniale. Il paziente aveva subito una splenectomia, 2 anni prima, per
un linfoma splenico di basso grado.
Alla visita clinica il cane appariva in buone condizioni generali, magro ma
con addome disteso. Mucose, TRC, T°, FC e FR erano nella norma. L’appetito era conservato senza vomito o diarrea. L’ematologia indicava una modica
leucocitosi (22,8 x 109 cell/L) e neutrofilia (19,6 x 109 cell/L) con spostamento a sinistra ed il profilo biochimico un aumento delle ALT (471 U/L). Il
liquido addominale risultava essere un trasudato modificato.
Lo studio TC dell’addome segnalava megalia della cistifellea (17x8,3x10
cm), con sedimento iperdenso declive, versamento addominale e una fine disomogeneità densitometrica dei lobi epatici medio di destra e quadrato che si
presentavano ipodensi rispetto al restante parenchima e privi di impregnazione in fase contrastografica. A livello del corno uterino di destra si evidenziava una neoformazione tondeggiante di 4x3,8x4,5 cm ed entrambe le ovaie erano cistiche e megaliche.
La diagnosi citologica della biopsia ad ago sottile dei lobi alterati era compatibile con un processo infiammatorio sub acuto/cronico misto. Vista la non
chiara natura del processo si consigliava una celiotomia esplorativa.
Durante l’ispezione addominale venivano drenati circa 2000 ml di liquido siero emorragico e apparivano evidenti una sovradistensione della colecisti e dei
lobi epatici medio di destra e quadrato, torti di circa 200° in senso orario sul
proprio asse.
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Pagina 154
Si eseguiva una lobectomia mediante l’ausilio di una Stapler TA 60 senza detorcere i lobi.
Prima di suturare l’addome si eseguivano un’ovarioisterectomia ed una gastropessi. La cavità addominale veniva abbondantemente lavata con soluzione fisiologica tiepida e suturata come di routine.
Il quadro istopatologico era compatibile con iperplasia mucinosa cistica della colecisti con grave ipertensione portale epatica e colestasi cronica extraepatica. La neoformazione uterina risultava essere un leiomioma.
La leucocitosi monitorata nei 2 giorni successivi alla chirurgia tendeva a rientrare nella norma ed il paziente era dimesso in terza giornata. A 9 mesi dalla
chirurgia il paziente era in ottime condizioni generali.
Conclusioni. La torsione di lobi epatici è una condizione patologica già segnalata in letteratura. Le cause fisiopatogenetiche più accreditate ad oggi
sembrerebbero essere legate a neoplasie localizzate all’apice di un lobo, episodi traumatici o agenesia delle strutture legamentose di sostegno.3 La presenza di un’imponente quantità di trasudato modificato sembra giustificabile dalla permanenza iniziale di una vascolarizzazione arteriosa senza un drenaggio
venoso. La secondaria stasi vascolare comporta un “ristagno” ematico con
trombosi diffusa. Il fatto che la torsione includesse la sola cistifellea non ha
creato alterazioni sistemiche. Il dotto cistico, non incluso nel peduncolo torto, permetteva alla restante parte del fegato di riversare la bile nel duodeno
portando tuttavia la cistifellea a sovradistendersi. Il solo innalzamento delle
ALT giustifica la necrosi intraepatica conservando tuttavia la sua funzionalità nel parenchima non coinvolto.
I risultati ottenuti suggeriscono che la prognosi per pazienti con torsione di lobi epatici, con o senza colecisti, è ottima a lungo termine se trattata in maniera tempestiva. A conoscenza degli Autori questo è il primo report in letteratura che descriva la torsione di cistifellea con lobo quadrato e medio di destra.
Bibliografia
1.
2.
3.
Schwartz SGH, Mitchell SL, Keating JK, Chan DL Liver lobe torsion in dogs: 13 cases (1995–2004)
J Am Vet Med Ass, 228:242-247, 2006.
Corfield GS, Read RA, Nicholls PK, Lester N Gall bladder torsion and rupture in a dog Aust Vet J
2007;85:226-231.
Jubb KVF. Kennedy PC, Palmer N. Pathology of Domestic Animals. New York: Academic Press,
1993(2);324-325.
Dott. Federico Massari - Clinica Veterinaria Nerviano, Via Lampugnani 3, 20014 Nerviano
(MI), Italia - Tel 0331415263 - Cell 339/4848578 - E-mail [email protected]
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Pagina 155
CHIRURGIA PER IL TRATTAMENTO DI ASCITE
IN UN CANE CON CIRROSI
S. Nicoli, DMV1,2
1
Dipartimento di Patologia Animale - Università di Torino, Torino, Italia
2
Clinica Veterinaria Pirani, Reggio Emilia, Italia
Introduzione. L’ipertensione portale rappresenta, sia in medicina veterinaria
sia in medicina umana, una grave complicazione nei pazienti affetti da cirrosi epatica. L’aumento pressorio cronico a carico del circolo portale, per l’aumentata resistenza al flusso ematico nel parenchima epatico alterato, determina una serie di eventi patologici differenti in relazione alla specie. Il segno clinico importante nell’uomo è il sanguinamento delle varici esofagee. Nei nostri pazienti, nei quali la cirrosi epatica è evento più raro, l’aspetto più eclatante è lo sviluppo di un’imponente ascite. In medicina umana, per il trattamento dei sintomi e per la decongestione del circolo portale, sono riportati
trattamenti medici e/o chirurgici. In questo lavoro è descritta l’applicazione di
una di queste tecniche chirurgiche in un cane cirrotico con ascite.
Descrizione del caso. Cane dalmata femmina intera di 7 anni di età riferito
presso la nostra struttura per alterazioni dei parametri biochimici di funzionalità epatica. La raccolta dei dati anamnestici mostrava l’insorgenza, da alcuni
mesi, di sintomatologia neurologica riconducibile ad encefalopatia epatica, responsiva al trattamento medico e, in tempi più recenti, la comparsa di progressiva distensione addominale. All’EOG si evidenziava stato di nutrizione medio-scadente ed imponente distensione addominale; lo stato neurologico del
paziente appariva nella norma. Gli esami di laboratorio mostravano innalzamento dei valori di ALT e ALP, ipoproteinemia con ipoalbuminemia, ipocolesterolemia e grave anemia microcitica ipocromica. L’esame ecografico addominale evidenziava abbondante raccolta liquida in addome e microepatia associata a completa disorganizzazione del parenchima. L’esame chimico-fisico
del liquido addominale raccolto per centesi lo identificava come trasudato.
Considerato che l’imponente raccolta liquida addominale era motivo di scarsa
qualità di vita della paziente si decideva, in accordo con i proprietari, di sottoporre l’animale ad un intervento chirurgico di decongestione del circolo portale. Tra le tecniche riportate in letteratura si sceglieva in particolare l’anastomosi porto-cava latero-laterale. Dopo approccio celiotomico, la vena porta e la vena cava caudale erano isolate per un tratto a facile accessibilità per la successiva anastomosi. Su ciascuna di esse si applicava una pinza vascolare a presa
tangenziale (Satinsky) al fine di eseguire una venotomia longitudinale di ugual
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Pagina 156
lunghezza su entrambe. Dopo abbondante lavaggio del lume endovasale, si
eseguiva l’anastomosi mediante sutura continua in polipropilene doppio armato 5/0. Ad anastomosi ultimata la sutura vascolare veniva protetta da materiale emostatico. Prima della chiusura della breccia laparotomica, che avveniva
come di routine, si eseguivano prelievi bioptici multipli. Il decorso post-operatorio avveniva senza complicanze e le dimissioni avvenivano in quinta giornata. Si prescrivevano: regime dietetico povero di proteine, lattulosio ed antibioticoterapia (neomicina e metronidazolo). La diagnosi istologica era di cirrosi
epatica “ultimo stadio”. La paziente era sottoposta a controlli periodici presso
il veterinario curante fino al suo decesso, avvenuto 6 mesi dopo la chirurgia,
per il progredire della patologia epatica. Durante questo periodo non si registravano recrudescenze della raccolta liquida addominale.
Conclusioni. Le epatiti croniche nel cane riconoscono predisposizione di razza (ad es. Dalmata), nessuna predisposizione di sesso e si sviluppano in pazienti di età compresa tra 5 e 7 anni. L’eziopatogenesi non è ancora chiara. Il
15% delle epatopatie croniche evolve nel cane in cirrosi (“end stage”) ed ipertensione portale, con conseguente ascite. Questo è il segno clinico più eclatante, con netto peggioramento delle condizioni di vita del paziente. In medicina umana, ai pazienti colpiti da cirrosi epatica che manifestano segni clinici legati all’ipertensione portale, sono spesso proposti trattamenti chirurgici
volti a decongestionare il circolo portale. Nel cane di norma si fa ricorso solo alla terapia medica, il cui obiettivo è il controllo dell’encefalopatia epatica;
l’ascite è di regola gestita mediante centesi ripetute.
Nel caso descritto l’intervento chirurgico palliativo, eseguito per una patologia non tumorale, si è rivelato efficace nel contrastare la formazione di ascite; si suppone che, in casi molto selezionati di neoplasia endoaddominale non
operabile e in grado di interferire con il circolo portale, questo intervento possa esitare in un risultato analogo.
Bibliografia
1.
2.
3.
4.
5.
Keefe F, Mason MM, Boria T. - Use of the portocaval shunt in the treatment of ascites in a dog. - J
Am Vet Med Assoc. 1961 Feb 15;138:200-3.
Scott RC, Wilkins RJ, Greens RW. - Abdominal paracentesis and cystocentesis. - Vet Clin North Am.
1974 May;4(2):413-417.
Kyles AE, Gregory CR, Adin CA. - Re-evaluation of a portocaval venograft without an ameroid constrictor as a method for controlling portal hypertension after occlusion of intrahepatic portocaval
shunts in dogs. - Vet Surg. 2004 Nov-Dec;33(6):691-8.
Gutierrez OH, Burgener FA. - Production of nonsurgical portosystemic venous shunts in dogs by
transjugular approach. -Radiology. 1979 Feb;130(2):507-9.
Zemel G, Katzen BT, Becker GJ, Benenati JF, Sallee DS. - Percutaneous transjugular portosystemic
shunt. - JAMA. 1991 Jul 17;266(3):390-3.
Dott. Stefano Nicoli, Via Filippo Re, 31, 41100 Modena (MO), Italia
Cell 340 9332925 - E-mail [email protected]
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Pagina 157
ECOCARDIOCONTRASTOGRAFIA CON MICROBOLLE COME
VERIFICA DELL’OCCLUSIONE CHIRURGICA DI UNO SHUNT
PORTOSISTEMICO EXTRAEPATICO IN UN CANE
V. Saponaro, DVM, PhD1, L. Lacitignola, DVM, PhD1,
F. Staffieri, DVM, PhD1, A. Crovace, DVM, Prof.1
1
Dipartimento delle Emergenze e dei Trapianti d’Organo,
Sezione di Chirurgia Veterinaria. Facoltà di Medicina Veterinaria,
Università degli studi di Bari, Valenzano (BA), Italia
Introduzione. Lo shunt portosistemico (SPS) è una comunicazione macroscopica tra il circolo portale e quello sistemico a varia localizzazione. Pertanto il semplice passaggio di microbolle da un circolo all’altro, dimostra con
massima accuratezza l’esistenza di SPS.
Descrizione del caso. Un Labrador Retriever maschio, di 6 mesi è stato riferito a causa di encefalopatia epatica. Gli esami di laboratorio supportavano il sospetto di SPS. È stata quindi eseguita ecografia addominale che, anche se ha evidenziato dei segni indiretti di SPS extraepatico, non ha permesso la visualizzazione diretta dello shunt. È stato programmato l’intervento
chirurgico con l’intento, oltre al trattamento, di completare l’iter diagnostico con una portografia e di verificare l’utilità di un’ecocardiocontrastografia intraoperatoria. Dopo aver effettuato una laparotomia mediana, il chirurgo ha incannulato una vena digiunale, mentre l’ecografista posizionava una
sonda settoriale phased array da 3.5 MHz sulla finestra apicale sinistra senza spostare il paziente dal decubito dorsale.
La rapida iniezione di 2 ml di soluzione fisiologica agitata, unita in siringa
con 0.5 ml del sangue del paziente ha permesso la visualizzazione di un
chiaro ecocontrasto positivo in atrio e ventricolo destro apparso dopo pochissimi secondi. Successivamente l’esplorazione dell’addome ha permesso
il reperto di un vaso anomalo tra la vena porta e la vena renale destra ed il
chirurgo ha potuto confermarlo quale unico shunt ripetendo l’esame ecocontrastografico previa occlusione provvisoria: il risultato è stato questa
volta l’assenza di ecocontrasto. Onde escludere che l’ecocontrasto negativo
fosse dovuto ad alterata condizione emodinamica, l’occlusione è stata rilasciata ed ha permesso nuovamente la comparsa di microbolle nelle camere
cardiache destre. La portografia realizzata successivamente per permettere
di valutare l’utilità del test precedente, ha confermato l’esito della procedura. Lo shunt è stato completamente occluso in quanto erano presenti i criteri per tale opzione.
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Conclusioni. Lo SPS può essere confuso all’esame clinico ed agli esami di
laboratorio con altre patologie non operabili. Fin’ora è stato indagato mediante differenti tecniche diagnostiche. In un recentissimo studio condotto su
20 cani sani, è stata proposta un’iniezione intrasplenica di microbolle seguita da ecografia vascolare come tecnica complementare nella diagnosi dello
SPS. La comparsa delle bolle nelle camere destre cardiache costituisce
un’immagine di più oggettiva interpretazione rispetto a quelle angiografiche
che possono dare raramente dei falsi negativi. Pertanto si sottolinea l’utilità
di un’ecocardiocontrastografia intraoperatoria nel management chirurgico di
uno SPS extraepatico. Nel nostro caso è stata facile da realizzarsi, non stancante ed utile. Ha permesso dapprima di accertare la presenza di SPS e dopo
l’occlusione, di escludere che ci fosse un secondo shunt, o ancora che quello occluso avesse dei rami lasciati al di fuori della legatura. A quanto nella
conoscenza degli autori questo è il primo caso in cui viene decritta questa
tecnica in cani affetti da SPS.
Bibliografia
1.
2.
3.
4.
5.
6.
7.
Szatmári V, Rothuizen J, Voorhout G. Standard planes for ultrasonographic examination of the portal system in dogs. JAVMA 2004;224:49-57.
Santilli RA, Gerboni G. Diagnostic imaging of congenital porto-systemic shunt in dogs and cats: a
review. The Veterinary Journal 2003;166:7-18.
D’Anjou M-A, Penninck D, Cornejo L, et al. Ultrasonographic diagnosis of portosystemic shunting
in dogs and cats. Veterinary Radiology & Ultrasound 2004;45:424-437.
Chetboul V, Pouchelon J-L, Tessier-Vetzel D. Echocardiographie et écho-Doppler: aspect normal in
Chetboul V, Pouchelon J-L, Tessier-Vetzel D et al. Echographie et Doppler du chien et du chat. Masson Paris, 2005;56-57.
Arndt JW, Oyama MA. Agitated saline contrast echocardiography to diagnose a congenital heart defect in a dog. Journal of Veterinary Cardiology 2008;10:129-132.
Gomez-Ochoa P, Llabrés-Diaz F, Ruiz S, et al. Ultrasonographic appearance of the intravascular
transit of agitated saline in normal dogs following ultrasound guided percutaneous splenic injection.
Veterinary Radiology & Ultrasound 2010; in press.
Scrivani PV, Yeager AE, Dykes NL, et al. Influence of patient positioning on sensitivity of mesenteric portography for detecting an anomalous portosystemic blood vessel in dogs: 34 cases (19972000). JAVMA 2001;219:1251-1253.
Dott. Vittorio Saponaro - Sezione Chirurgia Veterinaria, Facoltà di Veterinaria di Bari,
Str. Provinciale per Casamassima km 3, 70010 Valenzano (BA), Italia
Cell 329/5360321 - E-mail [email protected]
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Epatologia Medica e Chirurgica

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