Number 3 July/September 2014

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Number 3 July/September 2014
Number 3
July/September 2014
Volume 20, Number 3, pp 141-212
July/September 2014
141
120 anniversary of the National Hospital in Sarajevo
120 godina Zemaljske bolnice u Sarajevu
142
New ICU - Central Medical Building - Clinical Center University of Sarajevo
Nova Intenzivna njega - Klinički Centar Univerziteta u Sarajevu
143
New Central Medical Building - Clinical Center University of Sarajevo
Novi Centralni Medicinski Blok - Klinički Centar Univerziteta u Sarajevu
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Content
Medical Journal (2014) Vol. 20, No. 3
Original article
Morphological characteristics of atherosclerotic lesions of coronary arteries in diabetic patients
.................. 147
Aida Hasanović, Edin Omerbašić, Aida Sarač-Hadžihalilović
The importance of intraperitoneal interleukin-6 in peritoneal solute transport rate in continuous
ambulatory peritoneal dialysis patients.................................................................................................................................. 151
Snežana Unčanin
Lymph node metastasis predictors for prostate cancer in patients with serum PSA values
ranging 2-10ng/Ml ........................................................................................................................................................................... 156
Benjamin Kulovac, Damir Aganović, Alden Prcić, Osman Hadžiosmanović, Nermina Obralić, Dženana Eminagić
Hormonal variations in correlation to the outcome of medicamentous abortion in the second trimester of
pathological pregnancy ................................................................................................................................................................... 159
Naima Imširija, Lejla Imširija, Zulfo Godinjak, Edin Idrizbegović, Fatima Gavrankapetanović, Mohammad Abou El–Ardat, Rama Admir
The effect of smoking on the results of rehabilitation in patients after cerebrovascular accident .................... 163
Senad Selimović, Edina Tanović, Haris Tanović, Ksenija Miladinović
Frequency of chromosomal aberrations among healthy population of Bosnia and Herzegovina . ...................... 167
Izeta Aganović-Mušinović, Mirela Mačkić-Đurović, Orhan Lepara
Morphometric analysis of arterial Willis ring in patients with varying degrees of occlusion of the
internal carotid artery ................................................................................................................................................................ 171
Alma Voljevica, Elvira Talović
Evaluation of clinical and laboratory characteristics of childhood lymphoma ................................................... 175
Edo Hasanbegović, Nermana Čengić, Meliha Sakić, Adela Tunić, Senada Mehadžić
Importance of noninvasive markers in the assessment of portal hypertension as a liver cirrhosis complication . . . 1 8 0
Nenad Vanis, Sanjin Glavaš, Amila Mehmedović, Rusmir Mesihović, Nađa Zubčević, Srđan Gornjaković, Azra Husić-Selimović,
Aida Saray, Nerma Zahiragić
Professional article
Antimicrobial susceptibility of common isolated microorganisms in hip surgical wound .................................... 185
Tarik Muharemović, Mersiha Bašić-Muharemović, Šukrija Zvizdić, Sadeta Hamzić
Five-year work of the birthing unit of the Clinic for Gynecology and Obstetrics; perinatal report.................... 191
Mohamad Abou El-Ardat
Review article
Oral precanceroses: clinical histopathological correlation. ............................................................................................... 194
Dedić A, Hodžić M, Avdić M, Hadžić S, Pašić E, Gojkov-Vukelić M., Kantardžić A
Case report
Staged surgical treatment of combined osteoarticular and vascular injury of the shoulder...................................... 197
Amel Hadžimehmedagić, Ismet Gavrankapetanović, Haris Vranić, Mehmed Jamakosmanović
Perivascular epithelioid cells tumor; case report of uncommon clear cell neoplasm ligamentum teres uteri...... 200
Faika Mujanović-Glamočanin, Spahić Amir
Blunt chest trauma and pericardial tamponade
................................................................................................................ 203
Dragan Milošević, Duško Golić, Dragan Rakanović, Vojislav Vujanović, Dušan Janičić
A heart murmur which saved a life
...................................................................................................................................... 205
Amir Omerbašić, Mirsad Đugum, Mirela Tuce, Aida Kriještorac, Edin Omerbašić, Mirza Halimić
Clinical picture of autoimmune hepatitis and cholangitis in a pregnant woman during pregnancy
and after delivery ......................................................................................................................................................................... 208
Lejla Imširija, Naima Imširija, Sanjin Deković, Fatima Gavrankapetanović, Edin Idrizbegović
Instructions to authors ................................................................................................................................................................ 210
Uputstva autorima ........................................................................................................................................................................ 212
Original article
Medical Journal (2014) Vol. 20, No. 3, 147 - 150 Morphological characteristics of atherosclerotic
lesions of coronary arteries in diabetic patients
Morfološke karakteristike aterosklerotičnih lezija
koronarnih arterija kod pacijenata sa dijabetesom
Aida Hasanović1*, Edin Omerbašić2, Aida Sarač-Hadžihalilović1
Department of Anatomy, Faculty of Medicine, University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina; 2Heart Center, Clinical Center
University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
1
* Corresponding author
ABSTRACT
SAŽETAK
The aim of the study was to establish the morphological characteristics of atherosclerotic lesions of coronary arteries in patients
with diabetes mellitus using coronary angiography. Diabetes is an important risk factor for the development of coronary artery disease.
In the study which included 180 patients with suspected coronary
artery disease (60 females, 120 males), we performed coronary
angiography and tested the differences between diabetic (90) and
non-diabetic (90) patients in ischemia detection by this method. All
patients underwent coronary angiography in Heart Centre of the
Clinical Center University of Sarajevo in period from June 2011 to
June 2014. Coronary angiography was performed in the right and
left anterior oblique position. Diabetic patients were found to have
a significantly higher prevalence of stenotic atherosclerotic lesions of
the coronary arteries. In 17 (19%) of our 90 diabetic patients stenosis
of the right coronary artery (RCA) was found, in 10 patients (11%)
stenosis of the circumflex branch (Cx) of the left coronary artery,
and in 63 patients (70%) stenosis of the left anterior descending artery (LAD). Stenosis of the RCA was found in 22 (24%) of our 90
non-diabetic patients. Stenosis of the CX branch of the left coronary
artery was found in 14 (16%) and stenosis of the LAD in 54 (60%)
of non diabetic patients. Stenotic atherosclerotic lesions of the large
coronary arteries were significantly more common in the left than
in the right coronary artery, but the difference between the diabetic and the non-diabetic group did not reach statistical significance.
Changes in the proximal segment of the left anterior descending artery were the most common finding in diabetic patients. The most
frequently atherosclerotic lesion of the RCA was seen in the middle
segment, rarely in the proximal and distal part. The diabetic patients
had a higher prevalence of hypertension, higher BMI and triglyceride
and cholesterol levels. Diffuse coronary artery narrowing develops
not only in patients with diabetes but also in those with non-diabetes.
These findings may prove clinically useful in the follow-up of diabetic patients, the choice of diagnostic procedures as well as in active
treatment either by aterectomy or by percutaneous angioplasty and
stenting.
Cilj istraživanja je bio angiografski utvrditi morfološke karakteristike
aterosklerotičnih lezija koronarnih arterija kod pacijenata sa dijabetes
melitusom. Dijabetes melitus je važan riziko faktor razvoja koronarne
bolesti. U ovoj studiji 180 pacijenata suspektnih na koronarnu bolest
(60 žena, 120 muškaraca) podvrgnuto je koronarnoj angiografiji i
testirane su razlike u ishemičnim promjenama između dijabetičara
(90 pacijenata) i pacijenata bez dijabetesa (90 pacijenata). Svi pacijenti
su podvgnuti koronarnoj angiografiji u Centru za srce Kliničkog
centra Univerziteta u Sarajevu u periodu od juna 2011 do juna 2014.
godine. Snimanje je vršeno u dvije projekcije: desnoj i lijevoj prednjoj
kosoj projekciji. Angiografska analiza je pokazala signifikantno veću
učestalost stenotičnih aterosklerotičnih lezija koronarnih arterija
kod dijabetičara u odnosu na grupu pacijenata bez dijabetesa.
Stenoza desne koronarne arterije uočena je kod 17 (19%) od
ukupno 90 pacijenata sa dijabetes melitusom, kod 10 pacijenata
(11%) stenoza r. circumflexus lijeve koronarne arterije i kod 63
pacijenta (70%) stenoza r. interventricularis anterior. Stenoza desne
koronarne arterije nađena je kod 22 (24%) pacijenata od ukupno
90 bez dijabetesa. Stenoza r. circumflexus lijeve koronarne arterije
uočena je kod 14 (16%), a stenoza r. interventricularis anterior kod
54 (60%) pacijenata bez dijabetesa. Stenotične aterosklerotične
lezije velikih koronarnih arterija bile su učestalije na lijevoj nego na
desnoj koronarnoj arteriji, ali razlike između dijabetičara i grupe
bez dijabetesa nisu bile značajno statistički signifikantne. Promjene
proksimalnog dijela r. interventrikularis anterior (LAD) lijeve
koronarne arterije bile su najučestaliji nalaz na koronarogramima
dijabetičara. Najčešće aterosklerotične lezije desne koronarne
arterije uočene su u srednjem, rijeđe u proksimalnom i distalnom
dijelu. Pacijenti sa dijabetesom su imali veću učestalost hipertenzije,
veći indeks tjelesne mase, veći nivo triglicerida i holesterola.
Difuzna suženja koronarnih arterija razvijaju se ne samo kod
pacijenata sa dijabetesom nego i kod onih bez dijabetesa. Ovi nalazi
dokazuju klinički značaj praćenja pacijenata sa dijabetesom, te izbor
dijagnostičkih procedura u aktivnom tretmanu ili aterektomijom ili
perkutanom angioplastikom ili stentom.
Key words: coronary arteries, diabetes mellitus, atherosclerotic lesions, coronary angiography
Ključne riječi: koronarne arterije, dijabetes melitus, aterosklerotične lezije, koronarna angiografija
148
INTRODUCTION
Coronary angiographic studies of both symptomatic and asymptomatic patients with diabetes mellitus have documented a more
diffuse narrowing of the coronary arteries than non-diabetics. Furthermore, earlier onset and accelerated progression of coronary
artery disease has been suggested by other studies (1,2). Since the
development of angiographically significant coronary artery stenosis
is a late finding in the process of coronary atherosclerosis, the factors that contribute to this process have not yet been defined (3).
Atherosclerosis is a diffuse disease with segmental lesions frequently involving particular vessels or their segments. In diabetic
patients, these lesions are more extensively, diffusely and unevenly
distributed than in non-diabetics. Diabetes mellitus (DM) as a risk
factor for atherosclerosis further increases the effect of other risk
factors, contributes to the more pronounced macroangiopathic
changes, and increases the incidence of arterial wall calcification
(1,4,5).
The ischemic heart disease in patients with diabetes shows some
specificities, such as being frequently of an asymptomatic course and
showing nonspecific ECG changes, while coronary atherosclerotic
changes in patients with diabetes mellitus regularly take up a greater
number of branches and spread onto longer segments that in percutaneous interventions require the implantation of a greater number
of stents (6,7). The incidence of myocardial infarction in patients
with diabetes is two times greater in men and three times greater in
women than in healthy individuals. Many aspects of the mechanism
of coronary artery sclerosis in patients with diabetes are unclear
(8,9,10,11).
The purpose of the present study was to compare the extent
and localization of stenosing lesions of the coronary arteries between diabetic and non-diabetic patients with a history of coronary
artery disease and to elucidate which risk factors influence the progression of coronary artery sclerosis in patients with diabetes.
MATERIALS AND METHODS
In the study which included 180 patients with suspected coronary artery disease (60 females, 120 males), we performed coronary angiography and tested the differences between diabetic (90)
and non-diabetic (90) patients in ischemia detection by this method.
All patients underwent coronary angiography in Heart Centre of
the Clinical Center University of Sarajevo (CCUS) in period from
June 2011 to June 2014. All the patients underwent angiographic
and laboratory analyses including total cholesterol and triglyceride.
In addition, patients were assessed for the prevalence of coronary
risk factors, i.e., hypertension, hyperlipidemia, smoking habits, and
family history, and for the presence of diabetes complications, i.e.,
nephropathy, a history of myocardial and cerebral infarction, and
the presence of arteriosclerotic obliterance. BMI was calculated as
the weight in kilograms divided by the square of height in meters (4).
Coronary angiography was performed by the percutaneous
transfemoral approach using the Judkins technique. Selective coronary angiography was performed in multiple projections. The aim
of the coronary angiography was to establish the coronary anatomy
A. Hasanović et al.
and the degree of the obstruction of coronary artery. The information obtained in this manner includes identifying localisation, the
presence and severity of coronary luminal obstruction, as well as an
estimate of the blood flow quality. The following parameters were
used for the assessment of morphological characteristics in global
coronary trees. The analysis included each major coronary artery:
the right coronary artery (RCA); the left anterior descending artery
(LAD); and the left circumflex artery (CX). Each of the arteries analyzed was longitudinally divided into equal thirds (proximal, medial
and distal) for more precise stenosis localization. We defined significant coronary stenosis (stenosis > 70%.).
Statistical analysis
The statistical analysis of the results was performed using
Kolmogorow-Smirnow test and the differences in the angiographic
changes of all coronary arteries obtained in diabetic and non-diabetic patients were considered significant on the level p<0,05.
RESULTS
Out of 180 patients with suspected coronary artery disease
treated in the Heart Center of CCUS the diabetic patients (90) had
a higher prevalence of hypertension, higher BMI and triglyceride, and
cholesterol levels in comparison to non diabetic patients (Table 1).
Table 1 Demographic data and risk factors in diabetic and non diabetic patients.
PATIENTS
Gender
M
Non-diabetic
58
(n=90)
Diabetic
(n=90)
62
F
Age
(mean years)
M
F
Hypertension Hyperlipidemia
n
%
n
%
Cigarette
smoking
n
%
32
67
63
52
57.7
41
45.5
55
61.1
28
66
61
60
66.6
62
68.8
39
43.3
In 17 (19%) of our 90 diabetic patients stenosis of the right coronary artery (RCA) was found, in 10 patients (11%) stenosis of the
circumflex branch (Cx) of the left coronary artery, and in 63 patients
(70%) stenosis of the left anterior descending artery (LAD). Stenosis
of the RCA was found in 22 (24%) of our 90 non-diabetic patients.
Stenosis of the CX branch of the left coronary artery was found in 14
(16%) and stenosis of the LAD in 54 (60%) of non diabetic patients
(Table 2).
Table 2 Type of vessel with coronary stenosis in diabetic and non-diabetic group.
Coronary artery
Diabetic patients (n=90)
Hyperlipidemia
N
%
N
%
RCA
17
(19)
22
24
CX
10
(11)
14
16
LAD
63
(70)
54
60
In the present study the morphological changes of small vessel
diameter and diffuse vessel narrowing developed not only in the diabetes groups but also in the non-diabetic group.
Morphological characteristics of atherosclerotic lesions of coronary arteries in diabetic patients
Statistical analysis determinated that diabetic patients had a significantly higher prevalence of stenotic atherosclerotic lesions of the
coronary arteries (p<0,001). However, some postoperative complications were significantly more prevalent among diabetics, mainly
renal failure, neurological accidents and infection. Stenotic lesions of
the large coronary arteries were significantly more common in the left
than in the right coronary artery but the difference between the diabetic and the non-diabetic group did not reach statistical significance.
Coronary angiograms of diabetic group showed the morphological
changes caused by significant stenosis of coronary arteries (> 70%).
Changes in the proximal segment of the left anterior descending artery (LAD) were the most common finding in diabetic patients. As
well as stenosis of the CX branch was found in diabetic and non-diabetic group. The most frequently atherosclerotic lesion of the RCA
was seen in the middle segment, rarely in the proximal and distal part
(Figure 1).
A
Figure 1
B
Figure 2 Coronary angiogram of the left coronary artery (left anterior oblique projection) (A) showing stenosis of the left main
coronary artery (50%) and occlusion of the CX; (B) right anterior
oblique projection showing subocclusion of CX and LAD.
149
DISCUSSION
Diabetes mellitus is frequently associated to more severe coronary artery disease, with involvement of a larger number of vessels
and more lesions. This metabolic disorder facilitates the development of coronary atherosclerosis, the frequency and severity of
which usually increases with the severity of diabetes mellitus. Due
to this relation, coronary accidents are the main cause of death in
dia-betic patients and more serious clinical manifestations of ischemic heart disease, like acute coronary syndrome and acute myocardial infarction, are up to three times more frequent in diabetics
than in non-diabetics. In addition, the diabetic patient usually has a
more depressed ventricular function (5,6).
The prevalence, localization and morphological features of atherosclerotic plaques have been thoroughly investigated in coronary
angiograms of diabetic patients involved (1,2,3,4,8,11).
Results of the present study showed that diabetic patients had
a significantly higher prevalence of stenotic atherosclerotic lesions
of the coronary arteries. In 17 (19%) of our 90 diabetic patients
stenosis of the right coronary artery (RCA) was found, in 10 patients (11%) stenosis of the circumflex branch (Cx) of the left coronary artery, and in 63 patients (70%) stenosis of the left anterior
descending artery (LAD). Our results are similar to results of the
study by Vidljak et al. Atherosclerotic lesions of the large coronary
arteries were significantly more common in the left than in the right
coronary artery, but the difference between the diabetic and the
non-diabetic group did not reach statistical significance. Changes in
the proximal segment of the left anterior descending artery (LAD)
were the most common finding in diabetic patients. The present
study also revealed that stenoses affected proximal segments of the
left anterior descending artery more frequently in diabetic patients.
The most frequently atherosclerotic lesion of the RCA was seen in
the middle segment, rarely in the proximal and distal part. Vidljak V
et al (1) determined that hemodynamic conditions were found to
be more important than diabetes for the occurrence of atherosclerotic lesions in these arteries.
The diabetic patients had a higher prevalence of hypertension,
higher BMI and triglyceride and cholesterol levels. Jakljević T et al.
(7) in the study of 286 patients with suspected coronary artery
disease and recent exercise single photon emission computed tomography (SPECT) test, performed coronary angiography with
coronary fractional flow reserve (FFR) measurement, tested the differences between diabetic (103) and non-diabetic (183) patients in
ischemia detection by this two methods and found that the diabetic
patients had a higher prevalence of hypertension, higher BMI and
cholesterol levels, as well as longer duration of hospitalization than
non-diabetic patients.
Wendler et. al (10) found that patients with diabetes mellitus
who underwent surgical revascularization had a significantly higher
prevalence of three-vessel disease, and a mean ejection fraction 5
points lower than that of non-diabetic patients. In our population,
similar differences were appreciated. The diabetics had a significantly greater number of significant coronary stenoses, and a significantly lower ejection fraction than non-diabetics. Schofer et al. (9) also
found that the mean caliber of the coronary arteries of insulin-dependent patients was smaller than in non-diabetics. In addition, the
distal beds of these patients often show diffuse disease and have
150
more extensive zones of calcification. These circumstances, although difficult to quantify and record, can make conventional surgery difficult or impossible, and compromise the intermediate and
long-term patency of coronary grafts. These unfavorable anatomic
abnormalities are more important in older patients,when diabetes is
prolonged and other vascular complications are associated.
The present study showed that he diabetic patients had a higher
prevalence of diabetes complications, i.e. nephropathy, a history of
myocardial and cerebral infarction, and the presence of arteriosclerotic obliterance.
These findings may prove clinically useful in the follow-up of diabetic patients, the choice of diagnostic procedures as well as in active treatment either by aterectomy or by percutaneous angioplasty
and stenting.
CONCLUSIONS
In the present study the morphological changes of small vessel
diameter and diffuse vessel narrowing developed not only in the
diabetes groups but also in the non diabetic group. Diabetic patients
were found to have a significantly higher prevalence of stenotic atherosclerotic lesions of the coronary arteries. Stenotic atherosclerotic lesions of the large coronary arteries were significantly more
common in the left than in the right coronary artery but the difference between the diabetic and the non diabetic group did not reach
statistical significance. Changes in the proximal segment of the left
anterior descending artery (LAD) were the most common finding in
diabetic patients. The most frequently atherosclerotic lesion of the
RCA was seen in the middle segment, rarely in the proximal and distal part. The diabetic patients had a higher prevalence of hypertension, higher BMI and triglyceride and cholesterol levels. These findings may prove clinically useful in the follow-up of diabetic patients,
in the choice of diagnostic procedures as well as in active treatment
by either aterectomy or percutaneous angioplasty, and stenting.
Conflict of interest: none declared.
REFERENCES
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A.Hasanović et al.
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characteristics of arterial supply of the conductive system of the heart in patients
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Reprint requests and correspondence:
Aida Hasanović, MD, PhD
Department of Anatomy
Faculty of Medicine University of Sarajevo
Čekaluša 90
71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 33 665 949
Email: [email protected]
Original article
Medical Journal (2014) Vol. 20, No. 3, 151 - 155
The importance of intraperitoneal interleukin-6 in
peritoneal solute transport rate in continuous
ambulatory peritoneal dialysis patients
Značaj intraperitonealnog interleukina-6 u brzini
transporta kroz peritonealnu membranu u pacijenata
na kontinuiranoj ambulantnoj peritonealnoj dijalizi
Snežana Unčanin*
Clinic of Nephrology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
Inflammatory changes are often seen in the peritoneum, even in
the absence of peritonitis, indicating that the peritoneum of a peritoneal dialysis (PD) patient may be chronically inflamed. Cytokines
orchestrate the inflammatory response, and Interleukin-6 (IL-6) is
central regulator of the inflammatory process. Effluent IL-6 may be
an excellent marker for peritoneal inflammatory status and mesothelial cell activation in PD patients. Peritoneal solute transport rates
(PSTR) for small solutes increased in parallel with the duration of
PD. Purposes of this study was to evaluate possible relationships between dialysate IL-6 levels and PSTR of small solutes evaluated using the dialysate-to-plasma ratio (D/P) of creatinine, and to establish
how they change during one year of follow-up. Methods: Sixty CAPD
patients (52%F vs. 48% M), aged 56,63 ±15,06 years were divided
into a short-term and a long-term PD group, where short-term were
defined as patients with a PD duration between 1 and 12 months,
and long-term patients with a PD duration of > 12 months. For the
analysis of peritoneal solute transport rate (PSTR) of small solute the
peritoneal functional test (PFT) (Fresenius Medical Care) was used.
Samples for the determination of dialysate interleukin 6 (IL-6) were
obtained from overnight dialysate effluent. Dialysate IL-6 was determined by use of an automated immune-chemiluminiscence method.
Values are presented as mean ± standard deviation or as median
(interquartile range). Paired Student’s t-test or Wilcoxon signed rank
test was used to compare differences between baseline and 1-year
evaluations, and Spearman rank correlation test was used for skewed
variables. Differences between groups were evaluated by use of
the Mann-Whitney test. Results: IL-6 of short-term patients (≤ 12
months) ranged from 14,95 pg/mL to 16,05 pg/mL, and Dialysate–to
plasma ratio (D/P) of creatinine from 0,64 to 0,67. Long term patients (>12 months) had a IL-6 of 27,90 pg/mL - 26,0 pg/mL, and (D/P)
creatinine of 0,65 - 0,70. There were a strong positive correlations
between dialysate IL-6 and D/P creatinine in patients on peritoneal
dialysis (≤ 12 months), at baseline (rho= 0,373; p<0,05) and after 1
year (rho =0,442; p<0,05), but not in patients treated by CAPD for
a longer time (>12 months). Conclusions: our findings indicated that
intraperitoneal inflammation, which was evaluated by measuring IL-6
in dialysate increased over the time on peritoneal dialysis. Peritoneal
solute transport rate (PSTR) of small solute was also increased over
the time. PSTR of small solute was related to interleukin-6 (IL-6 ) only
in the early phase of PD treatment, but in the follow up evaluation no
associations were observed, indicating that inflammation may not be
directly linked to the high PSTR that develops following the long term
peritoneal dialysis. Inflammation may, at least partly, be linked to development of high PSTR, which may contribute to the high transport
PD patients.
Key words: inflammation, interleukin-6, dialysate, peritoneal solute
transport rates
SAŽETAK
Upalne promjene mogu se često vidjeti na peritoneumu, u
odsustvu peritonitisa, što ukazuje da potrbušnica pacijenata na
peritonealnoj dijalizi može biti hronično upaljena. Citokini upravljaju upalnim odgovorom, a interleukin-6 (IL-6) je središnji regulator akutnog upalnog procesa. IL-6 u efluentu može biti izvanredan pokazatelj upalnog stanja peritoneuma i mezotelijalne ćelijske
aktivacije kod pacijenata na peritonealnoj dijalizi. Apsolutna brzina transporta kroz peritoneum (PSTR), za rastvorene supstance
male molekulske težine povećava se sa dužinom liječenja pritonealnom dijalizom. Svrha ovog istraživanja bila je da se procijeni
moguća veza između IL-6 u dijalizatu i (PSTR) koji se procjenjuje pomoću omjera koncentracije kreatinina u dijalizatu i plazmi,
i kako se oni mijenjaju tokom jedne godine praćenja. Metode:
šezdeset pacijenata na kontinuiranoj ambulatornoj peritonealnoj
dijalizi (CAPD) (52% žena, 48% muškaraca), starosti 56,63 ±15,06
godina, bilo je podijeljeno u grupu sa kratkoročnim liječenjem
peritonealnom dijalizom koja se definira sa trajanjem peritonealne dijalize između 1. i 12. mjeseci i dugoročnim peritonealnim
bolesnicima sa trajanjem liječenja peritonealnom dijalizom >12
mjeseci. Za analizu brzine transporta kroz peritoneum, rastvorenih supstanci male molekulske težine korišten je peritonealni
funkcionalni test (PFT) od firme Fresenius Medical Care. Uzorci za određivanje interleukina-6 u dijalizatu dobiveni su iz noćne
152
porcije dijaliznog efluenta. Dijalizat IL-6 određivan je korištenjem
automatizirane imunohemiluminiscentne metode. Vrijednosti su
prikazane kao srednja vrijednost ± standardno odstupanje ili kao
medijana (interkvartilni rang). Upareni Student’s t-test je korišten
za nezavisne uzorke u cilju procjene postojanja razlika između grupa ili Wilcoxon test rangova primjenjen je za uporedbu dobijenih
rezultata na ponovljenim mjerenjima između osnovne i 1-godišnje
procjene. U analizama korelacija (između rezultata laboratorijskih
analiza i ishoda) primjenjen je Spirmanov (Spearman) koeficijent
rank korelacije ρ (rho). Za uporedbu razlika između grupa korišten
je Man-Vitnijev U (Mann Whitney U). Rezultati: IL-6 u dijalizatu
kod bolesnika liječenih kraće (≤ 12 mjeseci) kretao se od 14,95 pg/
mL do 16,05 pg/mL, a omjer kreatinina u dijalizatu i plazmi D/P od
0,64 do 0,67. Bolesnici sa dužim dijaliznim liječenjem ( >12 mjeseci)
imali su dijalizni IL-6 27,90 pg/mL - 26,0 pg/mL, a D/P kreatinina
0,65 - 0,70. Bila je izražena jako pozitivna korelacija između dijaliznog IL-6 i D/P kreatinina u pacijenata na peritonealnoj dijalizi ≤ 12
mjeseci na početku (rho= 0,373; p<0,05) i nakon godinu dana (rho
=0,442; p<0,05), ali ne i kod pacijenata liječenih CAPD-om dužeg
INTRODUCTION
Peritoneal dialysis (PD) has been a successful form of renal replacement therapy for more than 20 years (1,2). Although peritoneal dialysis has proven its utility in renal replacement therapy (RRT)
there are still several unsolved problems which reduce the greater
acceptance of PD (3). However, peritonitis remains the major cause
of acute drop-out from PD, resulting in considerable morbidity and
transfer for haemodialysis. Severe or recurrent episodes of peritonitis and bioincompatible factors of the dialysis solutions may lead
to long-term changes in peritoneal function, leading to loss of ultrafiltration and inadequate solute clearance. The traditional solutions
used for PD are effective for dialysis, but all are acidic and lactate
buffered, and all contain glucose as the osmotic agent, leading to hyperosmolality and to the presence of reactive glucose degradation
products. Functional studies have shown that solute transport and
peritoneal surface area appear to increase in parallel with the duration of PD (4,5,6). The increased diffusive transport of small solutes
leads to rapid glucose absorption and loss of the osmotic driving
force, resulting in decreased net ultrafiltration. High peritoneal permeability has been regarded as a risk factor predicting both technical
failure and high mortality rate (7). The transport of fluid and solutes
varies between different patients and also within an individual with
time. Inflammatory changes are often seen in the peritoneum, even
in the absence of peritonitis, indicating that the peritoneum of a PD
patient may be chronically inflamed (5).
Cytokines orchestrate the inflammatory response, and available
data suggest that Interleukin-6 (IL-6) is a central regulator of the
inflammatory process (8). Interleukin-6 (IL-6) is a multifunctional protein produced by wide array of cells such as lymphoid and
non-lymphoid cells and by normal and transformed cells, including
T cells, monocyte/ macrophages, fibroblasts, mesothelial cells and
vascular endothelial cells (9). Smooth muscle cells in the tunica media of many blood vessels also produce IL-6 as a pro-inflammatory
cytokine. IL-6 is one of the most important mediators in the acutephase response, which makes it an interesting protein in the early
diagnosis of inflammation. Effluent IL-6 may be an excellent marker
S. Unčanin
trajanja (>12 mjeseci). Zaključci: naši rezultati su pokazali da se intraperitonealna upala, koja je procijenjena mjerenjem IL-6 u dijalizatu povećala sa dužinom liječenja peritonealnom dijalizom. Brzina
transporta kroz peritoneum (PSTR), za rastvorene supstance male
molekulske težine, takođe je porasla tokom vremena provedenog na peritonealnoj dijalizi. PSTR za rastvorene supstance male
molekulske težine je povezana sa dijaliznim IL-6, samo u ranoj fazi
liječenja PD-om, dok u toku perioda praćenja nije dokazana povezanost kod pacijena koji se dugoročno liječe PD-om, što ukazuje
da upala ne mora direktno biti povezana sa visokim transportnim
karakterstikama peritoneuma, koje se razvijaju nakon dugogodišnjeg liječenja peritonealnom dijalizom. Upala može bar djelimično
biti povezana sa povećanjem brzine transporta kroz peritonealnu
membranu za rastvorene supstancije male molekulske težine, a to
opet može doprinijeti pojavi pacijenata sa visokim transportnim
karakteristikama pritonelne membrane.
Ključne riječi: upala, interleukin-6, dijalizat, brzina peritonealnog
transporta
for peritoneal inflammatory status and mesothelial cell activation in
PD patients. Especially, because an increase is present in effluent
IL-6 concentrations shortly before the onset of and during peritonitis, suggesting its local production and reflecting an intraperitoneal
inflammatory state (10). Finally, inflammatory changes of the peritoneum are observed even before the initiation of PD treatment
(11), suggesting that systemic factors related to uremia may, at least
in part, be responsible for histological and functional changes of the
uremic peritoneum. It has been speculated that increased levels of
intraperitoneal pro-inflammatory cytokines such as interleukin -6,
may contribute to high peritoneal small-solute transport rate (PSTR)
in continuous ambulatory peritoneal dialysis (CAPD) patients.
Purposes of this study was to evaluate possible relationships
between dialysate IL-6 levels and PSTR of small solutes using the
dialysate-to-plasma ratio (D/P) of creatinine, and to establish how
they change during one year of follow-up.
MATERIALS AND METHODS
Sixty CAPD patients (52%F vs. 48% M), aged 56,63 ±15,06
years were divided into a short-term and a long-term PD group,
where short-term related to patients with a PD duration between
and 12 months, and a long-term patients to those with a PD duration of > 12 months. The clinical characteristics were retrieved
from patients’ files. Exclusion criteria were the presence of systemic inflammatory disease (e.g. vasculitis, disseminated neoplasia) or
peritonitis in 4 weeks prior to, or after the evaluation. All patients
were treated with conventional glucose-based PD fluids, with an
early evaluation peritoneal solute transport rate (PSTR) of small
solute (within 1 month after start of PD), and a follow-up evaluation
after about 1 year. For the analysis of peritoneal solute transport
rate (PSTR) of small solute the peritoneal functional test (PFT) (Fresenius Medical Care) was used. This computer program was used
to provide data on renal function, total Kt/V urea, creatinine clearance, water balance and transport parameters, as well as on nutritional state (12). During the PFT all patients were on CAPD and
The importance of intraperitoneal interleukin-6 in peritoneal solute transport rate in continuous ambulatory peritoneal dialysis patients RESULTS
No significant differences between the two groups of patients
were noted in any of the measured parameters except according
to duration of active treatment. Table 1 shows the patient demographics and clinical parameters as taken at the entry into the clinical
study.
Table 1 Baseline demographics of the patients.
CAPD ≤ 12 months
(n=30)
Sex (male vs. female) (n)
Age (years)
PD duration (months)
CAPD > 12 months
P
0,3014
(n=30)
17/13
12/18
53.63 ± 14.44
59.63 ± 15.32
0,1239
5.43 ± 3.08
40.67 ± 19.04
<0,0001
Body mass index (kg/m2)
24.50 ± 3.46
25.91 ± 4.01
0,1516
Primary renal disease
CAPD ≤ 12 months
CAPD > 12 months
P
Diabetic nephropathy
17
14
0.6054
Hypertensive nephropathy
4
5
1.0000
Glomerulonephritis
0
2
0.4915
Obstructive nepropathy
0
1
1.0000
Polycystic kidney disease
1
2
1.0000
Other
8
6
0.1804
There were significant differences in dialysate IL-6 levels in patients treated by CAPD longer than 12 months [27,90 pg/mL (range
22,20 - 77,80 pg/mL) ], compeered with new peritoneal dialysis
patients [14,95 pg/mL (range 10,28 - 21,80 pg/mL), p<0,001], at
baseline and 1 year later [26,0 pg/mL (range 14,60 - 67,80 pg/mL)
vs. 16,05 pg/mL (range 11,10 - 21,50 pg/mL), p<0,05], dispite significantly decreasing dialysate IL-6 levels, in the group of patients
treated by CAPD longer than 12 months, at the end of the study.
Figure 1 shows the results of the effluent concentration of IL-6
during the one year follow-up.
All values mean ±SEM
Interleukin-6 in dialysate showed no direct correlation with PD
duration and number of previous episodes of peritonitis, but dialysate IL-6 was highly correlated with comorbidity (p<0,001), and
inversely correlated with serum albumin (p<0,05 ) in the total study
population.
400
350
. CAPD ≤ 12 months
300
.
CAPD >12 months
250
200
P1<0.0001
P2=0.0545
150
100
50
0
DI IL-6 bbdijaliGbasa12
dijaliz 1 G13
DI IL-6 dijaliz 2 G25
b Baseline
1Year
Figure 1 Interleukin-6 (IL-6) concentration in dialysate
during the one year follow-up.
In patients treated with CAPD less than 12 months, IL-6 in dialysate was correlated positively with age (r=0,680, p<0,001), at
baseline and 1 year later, BMI (r=0,47, p<0,01) at baseline, but not
in patients treated by CAPD longer than 12 months.
Dialysate IL- 6 levels were significantly and inversely correlated with residual renal function (RRF) (r= - 0,543, p<0,001) at the
beginning, in long term patients during the one –year follow-up (r=
-0,363, p<0,05). Table 2 shows correlation of patient characteristics
by dialysate interleukin-6.
IL -6 in dialysate (pg/ml)
used five exchanges of 1,5-2 L glucose-containing dialysis solution
at standardized intervals. The glucose concentrations varied according to the standard program of the individual patents. Samples for
determination of dialysate interleukin 6 (IL-6) were obtained from
overnight dialysate effluent. Dialysate IL-6 was determined using an
automated immune-chemiluminescence method.
Values are presented as mean ± standard deviation or as median (interquartile range), unless otherwise specified. Paired Student’s
t-test or Wilcoxon signed ranked test were used to compare the
differences between baseline and 1- year evaluations, and Spearman
rank correlation test was used for skewed variables.
Differences between the groups were evaluated by using the
Mann-Whitney test.
Statistical analyses were performed by using the Statistical Package Med Calc for the Windows (version 12.6.1.0; MedCalc Software, Mariakerke, Belgium).
153
Table 2 Correlation of patient characteristics by dialysate
interleukin-6 (IL-6).
Baseline
1Year
I group
II group
I group
II group
variables
(CAPD≤12 months) (CAPD>12 months)
IL-6 dialysate
IL-6 dialysate
Age
0,246
0,458**
0,285
0,680**
0,212
0,330
-0,089
Body mass index
0,477**
0,092
0,060
0,277
-0,089
PD duration
Diabetic nephropathy
0,240
0,408*
-0,124
0,218
0,758**
0,525**
0,564**
0,594**
Comorbidity
0,031
0,076
0,233
0,249
Peritonitis
Albumin
-0,420*
-0,423*
-0,369*
-0,391*
-0,363*
-0,328
-0,543**
-0,058
RRF
*p<0,05; **p<0,001; RRF-residual renal function
The associations between dialysate-to-plama ratio (D/P) creatinine, and intraperitoneal Il-6 are presented in Figure 2 and 3.
There were a strong positive correlations between dialysate
IL-6 and D/P creatinine in patients on peritoneal dialysis for less
than 12 months, at baseline (r= 0,373; p<0,05) and after 1 year (r
=0,442; p<0,05), but not in patients treated by CAPD longer than
12 months.
154
S. Unčanin
140
= 0,373
p = 0,0033
Table 3 Dialysis adquacy and caracteristics of the peritoneal membrane during the one year follow-up.
Baseline
120
IL -6 in dialysate (pg/ml)
I group
100
(CAPD≤12
months)
II group
(CAPD>12
months)
1Year
p
I group
II group
80
D/P crea
0,641±0,130 0,654±0,141
0,673 0,674±0,141** 0,705±0,13††
60
Total urea
Kt/V (/week)
2,04±0,598
1,74±0,363
0,041
40
PD crea clearance
(L/1,73m2 weekly)
41,36±15,88 40,66±8,319
0,807
20
0
0.4
0.5
0.6
0.7
0.8
0.9
D/P
Figure 2 Relationship between interleukin-6 (IL-6) and dialysate-to-plasma ratio (D/P) of creatinine in short –term
patients at baseline.
1,96±0,398
1,75±0,22
p
0,318
0,007
41,73±12,14* 44,29±7,25††
0,790
Total crea clearance
85,18±34,30 62,77±36,102 0,0018 75,36±23,16** 62,91±28,59
(L/1,73m2 weekly)
0,008
nPCR (gr/24h)
0,70±0,264
0,67±0,150
0,9823
0,74±0,234*
0,74±0,17†
0,544
D/P=dialysate-to-plasma ratio creatinine; Kt/V = total weekly clearance urea (peritoeal+residual renal);
Crea= creatinine; nPCR-normalise catabolic rate
*p<0,05- statistically significant to compare values in the first group at beginning and the end of study,
**p<0,001- statistically significant to compare values in the first group at beginning and the end of study,
† p<0,05- statistically significant to compare values in the second group at beginning and the end of study,
†† p<0,001- statistically significant to compare values in the second group at beginning and the end of study.
All values mean ±SEM
DISCUSSION
140
= 0,442
p = 0,0144
IL -6 in dialysate (pg/ml)
120
100
80
60
40
20
0
0.4
0.5
0.6
0.7
D/P
0.8
0.9
1.0
Figure 3 Relationship between interleukin-6 (IL-6) and Dialysate-to-plasma ratio (D/P) of creatinine in short –term
patients after 1 year.
There were no significant changes in membrane characteristics
evulated using dialysate–to plasma ratio (D/P) of creatinine in patients on peritoneal dialysis for less than 12 months compared to patients treated by CAPD longer than 12 months at baseline and after
1 year. Dialysate–to plasma ratio (D/P) of creatinine increased over
the time, in both groups of patients, in the first group (0,641±0,130
vs. 0,674±0,141, p<0,001) and in the second group (0,654±0,141
vs. 0,705±0,13, p<0,001). At the same time, there was a significant
decrease in the parameters of dialysis adequacy (total weekly Kt/V
urea and total weekly creatinine clearance) between the first and
the second group in CAPD patients at the beginning and at the end
of the study. In both groups, nPCR increased significantly during the
follow-up, but it did not show any significant differences compared
to each other.
The measurements of dialysis adequacy, PSTR of small solute
and nutritional status are shown in Table 3.
Despite the improvement in solution delivery systems and dialysis solutions, the long-term use of PD is often limited due to reduction of the ultra filtration and solute clearance capacity of the peritoneal membrane. Previous studies have shown that solute transfer
increases and ultra filtration declines along with time on peritoneal
dialysis (13,14).
In our one-year follow–up study significant changes in dialysis-related parameters were found. The peritoneal solute transport,
which was evaluated by using the dialysate-to-plasma ratio (D/P) of
creatinine, increased over the time in all included patients. Dialysate
IL-6 levels were significantly higher in long-term patients compared
to short term patients despite significantly decreasing dialysate IL-6
levels in the group of patients treated by CAPD longer than 12
months during the evaluation. There were a strong positive correlations between peritoneal solute transport rate (PSTR) of small
solute and dialysate interleukin-6 (IL-6 ) in short term patients. The
results of this evaluation indicated that intraperitoneal inflammation
increased in patients treated with conventional glucose-based PD
solutions during the first year of PD, and that intraperitoneal inflammation could be interrelated with PSTR of small solute. In our study,
the association between dialysate IL-6 and PSTR in patients treated
by CAPD longer than 12 months, as opposed to the early asociation
between dialysae IL-6 and PSTR, hypothetically suggests that transition in cytokine effluent production may reflect two distinct phases
in the intraperitoneal inflammatory response, specifically an early
(neutrophil mediated) and late (mononuclear leukocyte mediated)
phase, which may reflect a resolved inflammation process. However,
to confirm this hypothesis, it will be necessary to perform cytokine
measurements during active inflammation (i.e. during peritonitis)
(15,16).
PSTR of small solute was related to interleukin-6 (IL-6 ) only in
the early phase of PD treatment, indicating that inflammation may
not by directly linked to the high PSTR that develops after long term
perioneal dialysis. The increased PSTR (based on small solute transport) may indicate different mechanisms of solute transport, depending on the moment it is evaluated. Our results support the hy-
The importance of intraperitoneal interleukin-6 in peritoneal solute transport rate in continuous ambulatory peritoneal dialysis patients
pothesis that there may exist two distinct types of high transporters,
specifically the early inherent high transporter (associated with high
comorbidity, inflammation and protein leakage) and late acquired
high transporter (not associated with comorbidities, inflammation
and protein leakage) (17).
The fall in residual renal function was obvious, and inversely
correlated with dialysae IL-6 levels. It could be compensated, by
increasing the delivered PD dose, which included increasing the
glucose concentrations of the conventional dialysis solutions to the
treatment.
Nutritional problems were common among PD patients (18).
They could be caused by poor appetite, inadequate food intake,
insufficient dialysis, and protein loss though the peritoneal membrane. The role of inflammation in connection with malnutrition and
atherosclerosis has been recognized only in recent years (19). Low
albumin is a strong predictive factor for mortality in CAPD (20).
Thus, it seems unlikely that inadequate dialysis would have caused
deterioration of the nutritional status.
In the present study, dialysate IL-6 was highly inversely correlated with serum albumins in the total study population. Interleukin-6
in dialysate showed high positive correlation with comorbidity in all
peritoneal dialysis patients. Thus, even if the soluble factors in the
dialysate are mainly produced locally, dialyste IL-6 seems to reflect
also systemic inflammation, which may play a role in the decline of
albumin concentrations, as a marker of deteriorating nutritional status (18, 19, 20). In short term patients, IL-6 in dialysate was correlated positively with age and body mass index (BMI). Some recent
reports assume that low grade inflammation was associated with
obesity (21).
CONCLUSION
In summary our findings indicate that intraperitoneal inflammation, evaluated by measuring IL-6 in dialysate, increased over the
time on peritoneal dialysis. Peritoneal solute transport rate (PSTR)
of small solute also increased over the time. PSTR of small solute
was related to interleukin- 6 (IL-6 ) only in the early phase of PD
treatment, but in the follow up evaluation no associations were observed, indicating that inflammation may not by directly linked to
the high PSTR that develops after long term perioneal dialysis. The
increased PSTR (based on small solute transport) may indicate different mechanisms of solute transport, depending on the moment
of evaluation. In conclusion, inflammation may, at least partly, be
linked to development of high PSTR, and this may contribute to the
high transport PD patients. Our observations need to be confirmed
in prospective studies, performed on a large number of patients,
before definitive conclusions can be drawn.
Conflict of interest: none declared.
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Reprint requests and correspondence:
Snežana Unčanin, MD, PhD
Clinic of Nephrology
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 61 245 604
Email:[email protected]
Original article
Medical Journal (2014) Vol. 20, No. 3, 156 - 158
Lymph node metastasis predictors for prostate cancer
in patients with serum PSA values ranging 2-10ng/Ml
Prediktori limfnih metastaza karcinoma prostate za
vrijednosti PSA 2-10 Ng/Ml
Benjamin Kulovac1*, Damir Aganović1, Alden Prcić1, Osman Hadžiosmanović1,
Nermina Obralić2, Dženana Eminagić2
1
Clinic of Urology, Clinical Centar University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2 Clinic of Oncology, Clinical Centar University
of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
The aim of this paper is to determine which clinical and biopsy
parameters can predict prostate cancer lymph node metastasis for
PSA values 2-10ng/ml, in the case of patients who underwent radical
retropubic prostatectomy. Material and methods: 80 patients underwent retropubic radical prostatectomy with bilateral pelvic lymphadenectomy. By application of clinical biopsy and radiologic analysis all
the patients were suspected to have organ confines disease. Each patient was subjected to transrectal ultrasound guided prostate biopsy,
and number of biopsy cores was determined by using Wienna nomogram. Serum PSA, fpsa/tpsa, PSAD, number of positive biopsy cores,
percent of positive biopsy cores, localization of positive biopsy cores,
perineural invasion and biopsy Gleason score (GS) were evaluated.
Results: out of 80 patients with PSA values 2-10ng/ml, 4 (5%) had
lymph node metastasis. All patients with lymph node metastasis had
biopsy Gleason score 7 and perineural invasion. Using multivariate
regression analysis, as significant predictors of lymph node metastasis biopsy, GS and perineural invasion were determined. Conclusion:
biopsy Gleason score and perineural invasion are statistically significant predictors of lymph node metastasis for PSA values 2-10ng/ml.
Number, percent, and localization of positive biopsy cores are on the
borderline of statistical significance.
Cilj istraživanja je utvrditi koji klinički i biopsijski parametri
mogu predvidjeti limfne metastaze karcinoma prostate za vrijednsoti PSA 2-10 ng/ml, kod pacijenta podvrgnutih radikalnoj
retropubičnoj prostatektomiji. Materijal i metode: radikalnoj
retropubičnoj prostatektomiji sa bilateralnom pelvičnom lifadenomektomijom je podvrgnuto 80 pacijenta za koje se kliničkim,
biopsijskim, radiološkim analizima predvidjelo da se radi o organ-ograničenom tumoru. Biopsija prostate je uređena pod
kontrolom transrektalnog ultrazvuka, broj biopsijskih uzoraka je
određen pema Vienna nomogramu. Evaluirani su serumski PSA,
fpsa/tpsa, PSAD, broj pozitivnih biopsija, procenat pozitivnih biopsija, lokalizacija pozitivnih biopsija, perineuralna invazija, biopsijski Gleason score (GS). Rezultati: od 80 pacijenta sa vrijednsosti
PSA 2-10 ng/ml, 4 (5%) pacijenta su imala limfne metastate. Pacijenti sa limfnim metastazama su svi imali biopsijski GS 7 i perineuralnu invaziju. Multivarijatnom regresijskom analizom kao značajni prediktori limfnih metastaza su biopsijski GS i perineualna
invazija. Zaključak: biopsijski GS i perineuralna invazija su statistički značajni preditkori limfnih metastaza za vrijednosti PSA 2-10
ng/ml. Broj pozitivnih biopsija, procenat pozitivnih biopsija, lokalizacija pozitivnih biopsija su na granici statističke signifikantnosti.
Key words: prediction, lymph node metastasis, prostate cancer,
radical prostatectomy, PSA
Ključne riječi: predikcija limfnih metastaza, karcinom prostate, radikalna prostatektomija, PSA
INTRODUCTION
more than half of the patients have a locally advanced disease or metastasis at the time of the disease detection. Pathological treatment
of surgically removed regional lymph nodes is the only method which
can provide us with 100% accurate answer on the current condition
regarding lymph node metastasis. Patient with lymph node metastasis are facing poor prognosis. Identification rate of prostate cancer
lymph node metastasis has lower values after introducing serum PSA.
Detection rate of lymph node metastasis in the 1970-1980 period
was 20-60%, while in the current data lymph node metastasis rate
is 1-9%, depending on PSA and biopsy GS values. Various author’s
Prostate carcinoma is one of the most commonly diagnosed malignancies in men; in the US it is the second cause of death. Recently,
we have had a dramatic increase in new tumor discovery. It could
be related to introduction of new, more sensitive detection methods, but also to an increase of incidence. Aside from huge incidence,
the disease is characterized by different biological activity, and often
unpredictable development, which presents a dilemma for clinicians
regarding which therapeutic modality should be used. The fact is that
Lymph node metastasis predictors for prostate cancer in patients with serum PSA values ranging 2-10ng/Ml
normograms are recommended and are being used to predict prostate cancer lymph node metastasis, which are based upon different
parameters. Pavlin’s tables are most frequently used (1-5).
MATERIALS AND METHODS
In the period of 30 months, 80 patients with PSA values 2-10ng/
ml treated at the Clinic of Urology of the Clinical Center University
of Sarajevo (CCUS) were submitted to radical retro-pubic prostatectomy with bilateral lymphadenectomy. Patients diagnosed with
prostate cancer after a trans urethral prostate resection and the
patients who received hormonal therapy, were not included in the
study. Number of biopsy samples was determined according to Vienna normogram with arithmetical mean 11 (randomizing from 8-16
samples). Biopsy samples were taken under TRUS control from the
peripheral prostate zone and singly numbered in biopsy containers.
Localization of positive samples, length of the tumor in the sample,
percentage of positive biopsies and number of positive biopsies,
GS in each positive sample, and the presence of perineural invasion
were analyzed. Sample of prostate and lymph nodes obtained after
surgical procedure was histologically processed at a definitive stage
(T stage) as well as the lymph node metastasis presence (N stage).
Serum values of PSA, FPSA/TPSA and PSAD were analyzed.
RESULTS
Table 1 Clinical and pathological characteristics of pa- tients with lymph node metastasis.
Parameters
Patient 1
Patient 2
Patient 3
Patient 4
Serum PSA ng/ml
9.0
9.8
8.9
9.5
R FPSA/TPSA
0.014
0.012
0.019
0.007
PSAD
0.21
0.28
0.24
0.18
GS biopsy
7 (4+3)
7 (4+3)
7 (4+3)
7 (4+3)
not verified
verified
verified
Peri-neural invasion verified
3
b
2
b
2
b
4
b
Localization of
1c
1c
1c
1c
positive samples
1a
1a
1a
1a
Number of positive 5
4
4
6
samples
Percentage of
31%
37%
66%
37%
positive biopsies
Tumor length in
1/2 of sample
1/2 of sample 1/2 of sample 2/3 of sample
samples
DRP
pos.
pos.
pos.
pos.
TRUS
isoechoic.
hypoechoic.
isoechoic.
hypoechoic.
Prostate volume
75
40
35
55
Tumor clinical stage G2T2b,mo,no G2T2b,mo,no G2T2b,mo,no G2T2b,mo,no
Tumor histological
G2T2c,mo,n1
G2T2c,mo,n1
G2T2c,mo,n1
G2T2c,mo,n1
stage
GS prostate sample 7 (4+3)
7 (4+3)
7 (4+3)
7 (4+3)
Table 1 shows clinical-pathological characteristics of the patients
with verified lymph node metastasis. It is important to highlight the
fact that in biopsy sample perineural invasion was verified in the patients. Digitorectal examination was positive in all four patients and
they all had positive samples basally, centrally and apically, and they
all had GS 7 (4+3). Serum PSA was within the range from 9.0 to
9.8 ng/ml, FPSA/TPSA ratio within the range from 0.007 to 0.19,
number of positive biopsies was within the range 4-6, percentage
of positive biopsies within the range 31-66%, tumor length in the
sample of three patients was one half of the sample length and in on
patient two thirds of the sample length. By using TRUS (trans rectal
157
ultrasound) in two patients one hypo echoic and one isoechoic mass
was found, and a hyperchoic mass was found in the two remaining
patients. In three patients with verified lymph node metastasis, T2b
clinical stage of the disease was determined, and one patient had
G2T2c disease stage. Average prostate volume was in the range from
35 to 75 gr. Lymph node metastasis were verified in 4 (5%) patients.
Table 2 Regression correlation analysis of independent
variable of lymph node metastasis in relation to a set of
dependent variable predictors.
t
Sig.
Unstandardized Coefficients Standardized
Coefficients
B
Std. Error
Beta
,427
,671
,389
,166
(Constant)
Age
,128
1,075
0,29
,006
,005
,125
,987
0,33
,013
,013
PSA
,120
,891
0,37
,555
,494
PSA/ratio
Primary biopsy
,006
,020
0,98
,100
,002
grade GS
Secondary biopsy
-,576
-1,551
0,12
-,172
,111
grade GS
Gleason score
,830
1,440
0,04
,109
,157
of positive
Number
,201
,633
,530
,059
,037
biopsies
Tumor length in
-,037
-,301
,76
,047
-,014
samples
Basal tumor
-,216
-,986
0,33
,054
-,054
localization
Central
tumor
-,069
-,387
0,70
,055
-,021
localization
Apical tumor
,065
,411
0,68
,063
,026
localization
DRP
-,078
-,545
0,58
,088
-,048
TRUS
,094
,832
0,40
,032
,026
,324
2,449
0,02
,069
Peri-neural invasion ,169
G stage biopsy
-,174
-1,088
0,28
,087
-,095
T stage biopsy
,232
1,529
0,13
,044
,067
,140
1,028
0,30
,002
,002
Prostate volume
G stage
,189
1,076
0,29
,095
,102
Histological
Histological T stage
,091
,559
,57
,044
,025
PSAD
,067
,529
,59
,357
,189
of
Percentage
,132
,660
,31
,004
,002
positive biopsies
By using multivariate regression analysis of twenty predictors,
biopsy GS (p<0.04) and peri-neural invasion (p<0.02) variables were
confirmed to be statistically significant predictors. Peri-neural invasion with beta coefficient is 0.169, t-test 2.44, p<0.02.
Gleason score with beta coefficient is 0.257, t-test 1.44, p<0.04,
are variables with statistically significant correlation (p<0.05).
In the statistical data processing Windows SPSS 12 program was
used. Multivariate regression analysis method was used to determine
significant predictors of lymph node metastasis, on the level of statistical significance.
DISCUSSION
Lymph node metastasis presence (N+) in patients with prostate
cancer is a weak prognostic factor. Until 1980 incidence of lymph
node metastasis was in the range between 20-60% and after introducing PSA this number decreased significantly (2.7-9%). Before the
operational procedure, it is important to monitor all clinical and biopsy parameters in order to more accurately assess the condition
of lymph node metastasis and undertake adequate therapeutic measures. Various authors regard patients with PSA<10 ng/ml and GS<6
as low risk patients for lymph node metastasis and question the need
158
for pelvic lymphadenectomy. But, a different approach prevails, which
implies that pelvic lymphadenectomy is inseparable part of the radical
prostatecomy surgical procedure and should be performed regardless of the PSA and biopsy Gleason score values. Pelvic lymphadenectomy is important in determining the stage, and has a huge influence
on therapy selection as well. It is important to point out the fact that
recent studies have shown that after performing an extensive pelvic lymphadenectomy, obturator region is not the first affected by
prostate cancer lymph node metastasis. It is determined that 20% of
patients did not have lymph node metastasis in lymph nodes removed
by standard obturator region lymphadenctomy, but they were found
after performing extensive pelvic lymphadenectomy.
As it is important whether or not there are lymph node metastases, some authors also consider the number of affected lymph nodes
to be important. Lengthy procedure and morbidity are reasons for
not performing lymphadenctomy. Following Partin’s pioneer ideas of
establishing a normogram which could predict spreading of prostate
cancer, other authors developed normograms, by using different
variables, to predict spreading of prostate cancer. In Partin’s tables
the following parameters are used: serum PSA, biopsy GS values and
clinical stage of the disease. Hamburg study indicates serum PSA
and Gleason grade 4/5 as the most important predictors for lymph
node metastasis McNeal et al. indicte to a close connection between
tumor volume, Gleason grade 4/5 and the presence of metastasis.
Houston study states the following statistically significant predictors
for lymph node metastasis: clinical stage, Gleason score, positive
basal biopsy samples, high percentage of tumor in positive biopsy
sample and maximum tumor length in biopsy sample, while Gleason
grade 4/5 was confirmed as a dominant independent predictor.
Most of the existing normograms use preoperative serum PSA
value, clinical stage and Gleason score as predictors of lymph node
metastasis,. Cagiannos added lymph node invasion prevalence of value as the fourth statistically significant predictor of nodal metastasis.
In this study 4 (5%) patients had lymph node metastasis, which
was higher in comparison with American studies (2.7%), but much
lower than in some other European studies (24%). It is important to
mention that there has not been sufficient number of studies regarding the incidence of lymph node metastasis for PSA values from 2-10
ng/ml. In this study there were no metastases in patients with PSA
2-10 ng/ml for T1c stage.
Out of the predictors used in this study lymph node metastasis
with regression multivariate analysis, perineural invasion and biopsy GS were proved as significant lymph node metastasis predictors.
Number of positive biopsies, percentage of positive biopsies, tumor
length in positive samples and localization of positive samples are
not statistically significant but still close to the border of statistical
significance, and should be taken into consideration when predicting
prostate cancer lymph node metastasis (6,7,8,9,10).
CONCLUSION
Biopsy GS and perineural invasion are statistically significant
predictors of lymph node metastasis for PSA values 2-10 ng/ml.
Number of positive biopsies, percentage of positive biopsies, and
localization of positive biopsies are on the borderline of statistical
significance.
Benjamin Kulovac et al.
Conflict of interest: none declared.
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2. Vogt H, Wawroschek F, Wengenmair H, Wagner T, Kopp J, Dorn J, et al. Sentinel
lymph node diagnostic in prostate carcinoma: I: Method and clinical evaluation. Nuklearmedizin. 2002;41(2):95-101.
3. Partin AW, Kattan MW, Subong EN, Walsh PC, Wojno KJ, Oesterling JE, et al.
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5. Wickermann D, Wawroschek F, Harzmann R. Is there need for pelvic lymph node
dissection in low risk prostate cancer patients prior to definitive local therapy? Eur
Urol. 2005:47(1):45-50; discussion 50-1.
6. Cagiannos I, Karakiewicz P, Eastham JA, Ohori M, Rabbani F, Gerigk C, et al. A
preoperative nomogram identifying decreased risk of positive pelvic lymph nodes in
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9. Graefen M, Augustin H, Karakiewicz PI, Hammerer PG, Haese A, Palisaar J, et al.
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Reprint requests and correspondence:
Benjamin Kulovac, MD, PhD
Clinic of Urology
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 298 146
Email: [email protected]
Original article
Medical Journal (2014) Vol. 20, No. 3, 159 - 162
Hormonal variations in correlation to the outcome of
medicamentous abortion in the second trimester of
pathological pregnancy
Hormonske promjene u korelaciji sa ishodom
medikamentoznog abortusa kod patoloških trudnoća
u drugom trimestru
Naima Imširija*, Lejla Imširija, Zulfo Godinjak, Edin Idrizbegović,
Fatima Gavrankapetanović, Mohammad Abou El–Ardat, Rama Admir
Clinic of Gynecology and Obstetrics, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina
1
*Corresponding author
ABSTRACT
SAŽETAK
One of the daily problems in clinical practice is how to terminate
pathologic pregnancy in the first and second trimester. It is necessary for
a modern gynecologist to find the best, the safest and the most efficient
way in accordance with the existing regulations. Surgical methods often
lead to complications such as infections, part of embryo left inside the
womb (incomplete abortion), and uterine perforation. The question is to
what extent the new drugs (mifepristone, misoprostol) improve efficiency and safety of an abortion in the first and second trimester of pathological pregnancies in respect to current protocols, and to what extent they
protect sexual health and reproductive ability of future mothers in later –
healthy pregnancies. The study was conducted at the Clinic of Gynecology
and Obstetrics of the Clinical Center University of Sarajevo. It included
90 patients with pathological pregnancies in the second trimester and was
conducted over a two-year period. The aim of the study was to establish the efficiency of mifepristone and misoprostol in the patients in the
second trimester of pathological pregnancy, and level of the hormones
(βHCG, progesterone, prolactin, testosterone, E2, androstenedione,
cortisol, FSH and LH) during and after the abortion. Results and conclusion: Success of medical abortion in combination with mifepristone and
misoprostol in the second trimester was 100% (of which 76.7% related to
complete and 23,3% to incomplete abortions), whereas frequency of the
drug side effects and complications in the procedure itself was reduced
to a minimum. A combination of 600 mg of mifepristone and 200 μg of
vaginal misoprostol proved to be the most efficient, and the abortions in
this group were the fastest with minimum side effects and complications.
During the induced abortion the hormonal status of the patients was
monitored (βHCG, progesterone, cortisol, prolactin, FSH, LH, E2, testosterone, androstenedione) and it was concluded that the highest hormone
drop was registered in βHCG and progesterone, whereas selective drop
was registered in other hormones except for pituitary gland hormones
FSH and LH, which values remained unchanged during the induced abortion. The level of the hormone drop influenced the efficiency of the abortion. This study should result in introducing medical abortion in everyday
practice of health institutions throughout Bosnia and Herzegovina.
Jedan od svakodnevnih problema u kliničkoj praksi je kako prekinuti patološku trudnoću u prvom i drugom trimestru. Za savremenog ginekologa je neophodno da u skladu sa važećim propisima
nađe najbolji, najsigurniji i najpoštedniji način. Hirurški metod nerijetko
dovodi do komplikacija kao što su infekcije, zaostali dio embriona u
uterusu (residua), pa i perforacija uterusa. Nameće se pitanje koliko
novi lijekovi (mifepriston, mizoprostol) poboljšavaju efikasnost i bezbjednost abortusa u prvom i drugom trimestru kod patoloških trudnoća
u odnosu na dosadašnje protokole, te u kojoj mjeri štite polno zdravlje
i reproduktivnu sposobnost budućih majki u narednim – zdravim trudnoćama. Ispitivanje je provedeno u Kliničkom centru Univerziteta u
Sarajevu na Ginekološko-akušerskoj klinici. U studiju je uključeno 90
pacijentica sa patološkim trudnoćama u drugom trimestru. Istraživanje
je trajalo dvije godine. Cilj istraživanja je bio utvrditi efikasnost mifepristona i mizoprostola kod ispitanica sa patološkom trudnoćom u
drugom trimestru trudnoće, te nivoe hormona (βHCG, progesteron,
prolaktin, testosteron, E2, androstendion, kortizol, FSH i LH) u toku
i nakon završenog abortusa. Rezultati i zaključak: uspješnost medikamentoznog abortusa u kombinaciji mifepristona i mizoprostola u drugom trimestru je iznosila 100% (od toga 76,7% kompletnih pobačaja,
a 23,3% inkompletnih pobačaja), dok je učestalost nus pojava lijekova
i komplikacija same procedure svedena na minimum. Kombinacija od
600 mg mifepristona i 200 μg vaginalnog mizoprostola se pokazala najučinkovitijom, te su abortusi u ovoj skupini bili najbrže završeni uz minimalne nus pojave i komplikacije. Tokom indukcije pobačaja praćen je
hormonalni status ispitanica (βHCG, progesteron, kortizol, prolaktin,
FSH, LH, E2, testosteron, androstendion) došlo se do zaključka da su
najveći pad hormona imali βHCG i progesteron, dok su ostali hormoni
selektivno padali, izuzev hormona hipofize FSH i LH čije se vrijednosti
nisu mijenjale tokom indukcije pobačaja. Nivo pada hormona je uticao
na efikasnost pobačaja. Ovakva studija bi trebala da uvede medikamentozni abortus u svakodnevnu praksu u bolničkim ustanovama širom Bosne i Hercegovine.
Key words: misoprostol, mifepristone, hormonal status, abortion
Ključne riječi: mizoprostol, mifepriston, hormonalni status, abortus
160
INTRODUCTION
Pathological pregnancies constitute a serious problem in clinical
practice. Abortions performed in the first and second trimester of
pregnancy may jeopardize future mothers’ health and their reproductive ability. In the past thirty years modern gynecologists have
intensified their efforts in finding the best, the most efficient and the
safest way to end pathological pregnancies. Pregnancy termination
in the second trimester is an even bigger problem for a modern
gynecologist. Surgical methods have been rejected due to increased
number of complications (hemorrhages, infections, part of embryo
left inside the womb (incomplete abortion), uterine perforation and
even death). Based on the USA data, the abortion mortality rate
in the first trimester was 1,6 (per 100.000 abortions) (1-3). In the
second trimester, with the application of surgical methods, it climbs
to an unbelievable 14,9 % (per 100.000 abortions) (4). The introduction of prostaglandin made a revolution and surely contributed
to safety and efficiency of an abortion in the second trimester for
both the patient and the gynecologist. In 2004, the project related
to use of misoprostol (synthetic analog of prostaglandin E1) was approved at our Clinic in combination with prepidil-gel (prosta-glandin
E2) (5). In the parallel study conducted in 2007 it was proven that
misoprostol was much more efficient, safer and more effective then
prostin M-15 (prostaglandin F2α), which was routinely used by then.
The study was conducted exclusively on pathological pregnancies.
mifepristone is a 19-nor steroid with substitutions at position 11b by
fenol group. Mifepristone is an antiprogestogen, antiglucocorticoid
and a weak antiandrogen. Mifepristone’s relative binding affinity at
the progesterone receptor is more than twice that of progesterone,
its relative binding affinity at the glucocorticoid receptor is more
than three times that of dexamethasone and more than ten times
that of cortisol, and is a weak antiandrogen (6). In medical abortion
it causes endometrial decidual degeneration, cervix softening and
dilatation and release of endogenous prostaglandins and an increase
in the sensitivity of the myometrium to the contractile effects of
prostaglandins. Mifepristone induced decidual breakdown indirectly
leads to trophoblast detachment, resulting in decreased syncytiotrophoblast production of hCG, which in turn causes decreased production of progesterone by the corpus luteum. The side effects are
rather mild, described as nausea, vomiting, diarrhea and fever (7).
Aim: the aim of this study is to show correlation in the hormone
value during medical abortion in the second trimester of pathological pregnancies.
MATERIALS AND METHODS
The study was conducted at the Clinic of Gynecology and Obstetrics of the Clinical Center University of Sarajevo. It included 90
patients with pathologic pregnancies in the second trimester and it
was conducted over a two-year period. 90 patients in the second trimester were divided in three groups of 30 patients. The first group
of 30 patients in the second trimester diagnosed with fetus mortus
in utero up to 24 weeks of gestation was given 600mg of mifepriston orally and we monitored if the miscarriage happened (complete
or incomplete). If the patients did not miscarry within 48 hours,
they were given 200 µg of misoprostol vaginally in intervals of 4
hours until the miscarriage, up to 5 doses. The second group of 30
N. Imširija et al.
patients in the second trimester diagnosed with genetic anomalies
of the fetus in the 20th week of pregnancy was given 600mg of
mifepristone orally and we monitored if the miscarriage happened
(complete or incomplete). If they did not miscarry within 48 hours
they were given 200 µg misoprostol vaginally in 4 hour intervals until
the miscarriage, up to a maximum of 5 doses. The third group of
30 patients was treated with prepidil-gel intracervically, and after 6
hours we started giving them 200 µg of misoprostol vaginally in 4
hour intervals until the miscarriage. This is a standard procedure
applicable at our Clinic in the past eight years. If after the therapy the
miscarriage in the study groups failed, we announced the induction
to be unsuccessful. All the patients were hospitalized and subjected to clinical and laboratory tests (blood count, blood sugar, urine,
urea, creatinine, APTT, INR, βHCG, progesterone, cortisol, testosterone, androstenedione, FSH, LH, E2 and prolactin). Following an
explanation of the miscarriage the patients gave their consent and
written approval. The above stated laboratory tests were done on
three occasions: before the drug administration, 24 hours following
the drug administration, and after the abortion. Determination of
βHCG, progesterone, cortisol, testosterone, FSH, LH, E2 and prolactina was done in the Clinical Laboratory of the Clinical Center
University of Sarajevo by chemiluminescent enzyme-immunological
technique on the Vitroseciq Ortoclinic Diagnostic (Siemens) machine, and determination of androstenedione was done by the same
technique on the Immulite (Siemens) machine.
RESULTS
Table 1 contains analyses of the average age of Group II patients
and values are presented under sub-groups. The average age of this
group was 29.67±5.47 years. The average age of Group I patients
(patients in the second trimester diagnosed with foetus mortus in
utero in 24th week of pregnancy) was 29.06±3.96 years, the average age of Group II sub-group patients (patients in the second trimester diagnosed with genetic fetus anomalies in the 20th week of
pregnancy) was 28.43±4.91 years, and the average age of Group III
sub-group patients (patients in the second trimester diagnosed with
pathological pregnancy in the 20th week) was 31.53±6.81 years.
Application of the ANOVA test proved that there was no statistically significant difference in the average age values between Group
I sub-groups, F=2.796; p=0.066.
Table 1 Average age of Group II patients.
Groups
N
X
SD
SEM
95% CI
Minimum
Maximum
Lower
Upper
30
29,06
3,96
,72
27,58
30,54
19,00
38,00
III
30
28,43
4,91
,89
26,59
30,26
19,00
38,00
III
30
31,53
6,81
1,24
28,98
34,07
19,00
45,00
Total
90
29,67
5,47
,57
28,53
30,82
19,00
45,00
The average gestation period during pregnancy termination was
17,21±2,88 weeks. The patients from Group III had the longest gestation period, 18,03±2,89 weeks, followed by patients from Group
I, which was 17,76±3,21 weeks, whereas the patients from Group
II had the smallest gestation, 15,83±2,40 weeks. The ANOVA test
proved that there was a statistically significant difference in the
length of gestation during pregnancy termination among the study
groups, F=5.295; p=0.007 (Table 2).
Hormonal variations in correlation to the outcome of medicamentous abortion in the second trimester of pathological pregnancy
Table 2 Average gestation during pregnancy termination.
X
SD
SEM
95% CI
Minimum Maximum
Groups N
Lower
Upper
I
30
17,76
3,21
0,58
16,56
18,96
13,00
24,00
II
30
15,83
2,40
0,43
14,93
16,73
13,00
21,00
III
30
18,03
2,89
0,52
16,95
19,11
12,00
25,00
Total
90
17,21
2,99
0,31
16,58
17,83
12,00
25,00
Table 3 shows analysis of the hormonal status of the patients in
the second trimester of pathological pregnancy before, during and
after abortion. It appears that the values of βHCG, progesterone,
prolactine, E2, testosterone and androstenodione statistically significantly dropped during the induction, whereas FSH and LH values
remained unchanged during the induced abortion. Analysis of the
mentioned hormones showed that Group I had a significant drop in
hormones (patients in the second semester diagnosed with foetus
mortus in utero in 24th week of pregnancy) in respect to Group II
(patients in the second trimester diagnosed with genetic fetus anomalies in the 20th week of pregnancy).
Table 3 Analysis of hormonal status during induced abortion.
Hormone
βHCG
Cortisol
Progesterone
Prolactin
Groups
I
II
I
II
I
II
I
II
I
Beginning
32174
31642
894,73
733,06
90,09
106,78
2338
1241
0,10
After 24 hours
24808
29027
866,96
655,13
67,28
89,86
2164
1039
0,10
End
7256
12629
451,76
448,96
16,40
73,78
2070
863
0,10
Result
Drop
Drop
Drop
Drop
Drop
Drop
Drop
Drop
Unchanged
FSH
II
0,10
0,10
0,10
Unchanged
LH
I
0,10
0,10
0,10
Unchanged
II
0,10
0,10
0,10
Unchanged
E2
I
10,254
8,947
8,762
Drop
II
9,914
9,355
8,454
Drop
I
3,10
2,59
1,53
Drop
Testosterone
II
2,97
2,46
1,22
Drop
Androstenodione I
13,92
13,15
9,77
Drop
II
30,64
29,30
17,77
Drop
Table 4 Relative risk of unsuccessful medical treatment of
induced abortion (Group I and II).
2,2857
Relative risk
1,1016 to 4,7427
95% CI
2,220
z statistic
P = 0,0264
Significance level
NNT (Benefit)
3,333
95% CI
1,872 (Benefit) to 15,162 (Benefit)
Analysis of the relative risk of unsuccessful medical treatment
of induced abortion showed that the relative risk of abortion was
2.28 times higher in Group I (patients in the second semester diagnosed with genetic fetus anomalies in 20th week of pregnancy) with
respect to Group II (patients in the second trimester diagnosed with
foetus mortus in utero in 24th week of pregnancy). It was also established that the patients from Group I and II, who were treated by
161
a combination of mifepriston and misoprostol had more success in
induced abortion and less side effects in respect to Group III patients
induced with prostaglandins E2 and E1.
DISCUSSION
Modern methods of medication abortion are nowadays available to women in many countries in various types and protocols.
Invention of synergistic effects of antiprogestins (mifepristone) and
synthetic analogue prostaglandin E1 (misoprostole), on early pregnancy termination and on second trimester pregnancy termination
influenced development of a new, highly effective and safe method of medicamentous abortion. Nowadays, there are established
schemes of the drugs administration in various gestation periods
provided by the World Health Organization, based on numerous
studies conducted in this field. In France, medicamentous abortion
is approved even up to seven weeks of gestation in home conditions.
The Protocol related to medicamentous pregnancy termination in
the period between weeks 9 and 12 of pregnancy is still under consideration, and for abortions in the second trimester there are several schemes in development. If an unwanted pregnancy occurs, it
is necessary to provide women with the opportunity to choose this
contemporary method of medicamentous abortion which has been
the choice of approximately half of the women in the countries in
which it is available (8-11). The success of this treatment has been
described in world literature and it rates from 60-80 in respect to
application of mifepristone alone and 96% in respect to application
of mifepristone in combination with misoprostol (8). Misoprostol
belongs to a group of drugs referred to as “prostaglandin analogs”.
In fact, it is a synthetic drug similar to prostaglandin E1 (alprostadil).
Misoprostol is a main ingredient of ciprostal which we used in our
study. It causes uterus contractions and according to the world literature the pregnancy termination success is up to 96% (in our clinical
study conducted in the period from 2004 to 2007 the success was
99%) (9). Similar to all other medicaments, in a small percentage
misoprostol can cause side effects manifested in nausea, vomiting,
diarrhea, dizziness, fever. In local application these symptoms are
minimal and almost unnoticeable (10). During the induced abortion
the patients were subjected to hormone level tests during, after and
following the induced abortion. Analysis of the hormonal status
proved that the highest drop was registered in hormone βHCG and
progesterone, while other hormones registered selective drop 24
hours following the induced abortion and after completed abortion.
Values of the pituitary gland hormones FSH and LH remained unchanged. Hormone values registered a statistically significant drop
in the patients subjected to complete miscarriages. The success of
medicamentous induced abortions in the second trimester was in
direct correlation with the level drops of certain hormones; i.e. the
higher the drop in hormone levels the shorter the induction.
CONCLUSIONS
Non surgical termination of pathological pregnancies in the first
and second trimester has significant benefits in comparison to the
surgical method. It contributes to reduction of complications (infections, bleeding, residua post abortum) and consequently to the
reduction in cervix incompetence in future pregnancies, as well as to
162
N. Imširija et al.
the reduction of side effects (bleeding, nausea, vomiting). Psychological aspects of fear in medicamentous abortion are considerably
small. Hormonal status of the studied hormones (βHCG, progesterone, prolactin, testosterone, E2, androstenodion, cortisol) is
in direct correlation with the efficiency of miscarriage, except for
pituitary gland hormones FSH and LH, which values remained unchanged.
Conflict of interest: none declared.
REFERENCES
1. Agarwal M, Das V, Agarwal A, Pandey A, Srivastava D. Evaluation of mifepristone
as a once a month contraceptive pill. Am J Obstet Gynecol. 2009;200(5).
2. Finer LB, Wei J. Effect of mifepristone on abortion access in the United States.
Obstet Gynecol. 2009;114(3):623-30.
3. Koivisto-Korander R, Leminen A, Heikinheimo O. Mifepristone as treatment of
recurrent progesterone receptor-positive uterine leiomyosarcoma. Obstet Gynecol. 2007;109(2 Pt2):512-4.
4. Winikoff B, Dzuba IG, Creinin MD, Crowden WA, Goldberg AB, Gonzales J, et
al. Two distinct oral routes of misoprostol in mifepristone medical abortion: a
randomized controlled trial. Obstet Gynecol. 2008;112(6):1303-10.
5. Kapp N, Borgatta L, Stubblefield P, Vragovic O, Moreno N. Mifepristone in second trimester medical abortion: a randomized controlled trial. Obstet Gynecol.
2007;110(6):1304-10.
6. Erenbourg A, Piccoli M, Ronfani L, Tamburlini G. Mifepristone for the treatment
of uterine leiomyomas: methodological issues and clinical implications.Obstet Gynecol. 2009; 113(3):741.
7. Imširija-Galijašević N. Obstetričke karakteristike pobačaja induciranih Misoprostolom: Magistarski rad. Sarajevo: Medicinski fakultet Univerziteta u Sarajevu, 2007.
8. El-Refaey H, Templeton A. Induction of abortion in the second trimestar by a
combination of Misoprostol and Mifepristone, a randomized comparison between
two Misoprostol regiments. Hum Reprod. 1995;10(2):475-8.
9. World health organization. Termination of pregnancy with reduced doses of Mifepristone. Br Med J. 1993;307:532-7.
10. Zhou W, Nielsen GL, Møller M, Olsen J. Short-team complications after surgically
induced abortions: A register-based study of 56117 abortions. Acta Obstet Gynecol Scand. 2002;81(4):331-6.
11.Kapamadžija A, Vukelić J, Bjelica A, Kopitović V. Abortus lekovima - savremena
metoda prekida trudnoće. Med Pregl. 2010;LXIII (1-2):63-67.
Reprint requests and correspondence:
Naima Imširija, MD, PhD
Clinic of Gynecology and Obstetrics
Clinical Center University of Sarajevo
Patriotske lige 81
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 250 250
Email: [email protected]
Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina!
Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini!
Original article
Medical Journal (2014) Vol. 20, No. 3, 163 - 166 The effect of smoking on the results of rehabilitation in
patients after cerebrovascular accident
Uticaj pušenja na rezultate rehabilitacije kod pacijenata nakon cerebrovaskularnog inzulta
Senad Selimović1, Edina Tanović*2, Haris Tanović3, Ksenija Miladinović2
JZU Aquaterm Olovo, Bosnia and Herzegovina, 2Clinic of Physical Medicine and Rehabilitation, Clinical Center University of Sarajevo, Bolnička 25, 71000
Sarajevo, Bosnia and Herzegovina, 3Clinic of Abdominal Surgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
1
*Corresponding author
ABSTRACT
SAŽETAK
The research objectives are: to analyze the prevalence of smoking as
risk factor in patients with cerebrovascular accident and to assess how
this risk factor is affecting the outcome of rehabilitation. Propose measures and procedures that will result in better rehabilitation. Materials
and methods: the study included a total of 116 patients diagnosed with
cerebrovascular infarction admitted to the Department of Physical Medicine and Rehabilitation of the Clinical Center University of Sarajevo in
a period of one year. We analyzed the gender and age distribution of
patients, duration of rehabilitation, the prevalence of smoking risk factor
and assessed the results of rehabilitation by Barthel Index at the beginning and at the end of rehabilitation in patients with and without this risk
factor. Results: from the total number of patients, most patients were
31-40 years of age, the average age of the patients was 65.45 years, 49%
of patients were male and 51% female. In 28% of patients rehabilitation
lasted from 31 to 40 days, 22% had smoking as a risk factor. Patients
who were smokers had worse results in the assessment of activities of
daily living by Barthel Index at admission and at discharge as compared to
those who did not have that risk factor (p<0.001). Conclusion: smoking
as a risk factor in patients with cerebrovascular accident is very frequent
and have direct impact on the poor outcome of rehabilitation. Therefore, in addition to other measures of secondary prevention, energetic
struggle against the risk factors such as smoking is highly recommended.
Ciljevi istraživanja su: analizirati zastupljenost pušenja kao riziko faktora kod pacijenata sa cerebrovaskularnim inzultom te procijeniti koliko
ovaj riziko faktor utiče na rezultate rehabilitacije. Predložiti mjere i postupke koji će uticati na bolje rezultate rehabilitacije. Materijal i metode:
istraživanje je obuhvatilo ukupno 116 pacijenata sa dijagnosticiranim
cerebrovaskularnim inzultom primljenih na Kliniku za fizikalnu medicinu i rehabilitaciju Kliničkog centra Univerziteta u Sarajevu (KCUS) u
periodu od jedne godine. Analizirali smo dob, spol, vrijeme provedeno
na rehabilitaciji, učestalost rizikofaktora pušenja te procjenili rezultate
rehabilitacije po Barthel indexu na početku i kraju rehabilitacije kod
pacijenata sa i bez ovog rizikofaktora. Rezultati: od ukupnog broja pacijenata najviše oboljelih je bilo od 31-40 g. života, prosječna starost pacijenata je bila 65,45 godina, 49% oboljelih je muškog, a 51% ženskog spola. 28 % pacijenata je provelo od 31 do 40 dana na rehabilitaciji, 22 %
je imalo pušenje kao rizikofaktor. U aktivnostima svakodnevnog života
lošiji rezultati po Barthel indexu su bili i prijemu i na otpustu kod pacijenata koji su imali rizikofaktor pušenje u odnosu na one koji nisu imali taj
rizikofaktor (p<0.001). Zaključak: rizikofaktor pušenje kod pacijenata
sa cerebrovaskularnim inzultom je veoma učestao te direktno utiče na
lošije rezultate rehabilitacije. Zbog toga se, uz ostale mjere sekundarne
prevencije, preporučuje energična borba protiv ovog rizikofaktora
odnosno loše navike kao što je pušenje.
Key words: rehabilitation, cerebrovascular accident, Barthel Index
Ključne riječi: rehabilitacija, cerebrovaskularni insult, Barthel index
INTRODUCTION
and that 20-30% of all stroke survivors are left dependent on others for everyday activities. Besides dramatically disrupting family life
and environment of the patient, it is a big financial burden for the
community. By the year 2020, it is expected that cerebrovascular accident, along with coronary heart disease will be the leading cause of
“healthy life years” loss (6). Cerebrovascular accident is classified by
etiology of focal brain damage, so we distinguish ischemic and hemorrhagic cerebrovascular accident (7). Knowledge of risk factors for
cerebrovascular disease and their elimination or controlling is extremely important for reducing the incidence of stroke (8). There
are two types of stroke related risk factors: risk factors that we
cannot influence, and there are risk factors that we can influence (9).
Risk factors that we cannot influence are: gender, age, race, ethnicity
and heredity (3,10). Risk factors that can be modified are:
Stroke is a neurological deficit that persists beyond 24 hours or
is interrupted by death within 24 hours (1), the definition of the
World Health Organization. Acute cerebrovascular accident (CVA)
is the third cause of death and the leading cause of disability in the
developed countries of the world: it is estimated that every 45 seconds one person suffers stroke, and every three minutes one person dies from the consequences of stroke (2,3,4). Cerebrovascular
accident is a major cause of long term disability and has a huge emotional and socio-economic impact on patients, families and health
care. Living expenses per patient with stroke are estimated at between $ 59,800 to $ 230,000 (5). It is estimated that approximately
half of all stroke survivors returned to some kind of employment,
164
a) well documented risk factors: hypertension, diabetes, smoking, dyslipidemia, atrial fibrillation and other cardiac disorders;
b) potential risk factors less documented: obesity, physical inactivity, diet, hyperhomocysteinemia, alcohol use and use of
oral contraceptives (11,12,).
Primary prevention of occurrence of stroke includes control
and treatment of risk factors that can be modified. Secondary
prevention is carried out after the occurrence of cerebrovascular
stroke in order to prevent the re-occurrence of stroke. It includes
more vigorous treatment of diseases and eliminating harmful habits
such as smoking (13).
The research objectives are: to analyze the prevalence of smoking as risk factor in patients with CVI and to assess how this risk factor is affecting the results of rehabilitation. Propose measures and
procedures that will result in better rehabilitation.
MATERIALS AND METHODS
S. Selimović et al.
The youngest patient on rehabilitation was 30 years old and the
oldest was 86 years old. The average age of the patients was 65.45
years (stand. deviation 10.368). Analysis of gender distribution
showed that cerebrovascular accident occurred in 49% of male and
in 51% of female patients.
Figure 2 Analysis of duration of rehabilitation.
We conducted a retrospective study that included a total of 116
patients diagnosed with cerebrovascular infarction admitted to the
Clinic of Physical Medicine and Rehabilitation of CCUS in the period of one year. The study was analytic-retrospective cohort study,
based on retrospective analysis of data from the history of the disease. During data acquisition, processing and presentation of the
tables, privacy of any patient was not compromised; first and last
names were not cited anywhere, or initials of the target group.
From the history of disease the following parameters were registered in the study: name, year of birth, time spent in rehabilitation,
incidence of smoking as risk factor, Barthel index at admission and
at discharge in patients with and without smoking risk factors. Assessment of activities of daily living by Barthel Index scores were
grouped as follows: 0-4 (complete dependence), 5-8 (heavy degree
of dependence), 9-12 (medium degree of dependence), 13-16 (light
dependence) and 17-20 (independence).
The majority of patien ts with cerebrovascular infarction 32
(28%) spent 31-40 days on rehabilitation at the Clinic for Physical
Medicine and Rehabilitation.
Statistical analysis
Smoking is the third most frequent stroke risk factor besides
diabetes mellitus and hypertension with a prevalence of 22% among
patients included in this study.
Results are displayed numerically, graphically and in tables with
legends and text explanation of some of the obtained values of the
variables. Statistical analysis was performed on the PC functions in
SPSS v 21.0, MS Excel 2009th. Parametric data were analyzed showing the absolute value calculation to the percentage value, the arithmetic mean with obligatory calculation of the standard deviation,
while non-parametric data was processed by chi-square test.
Figure 3 Frequency of risk factor: smoking in patients with
CVI.
RESULTS
Following the research the following results were obtained:
Figure 1 Age distribution among patients.
Figure 4 Analysis of ADL by Barthel Index at admission
and risk factor of smoking.
Table 4 shows the statistical analysis of the relationship
Barthel index at admission and risk factor of smoking.
Chi-Square
df
L evel of significance
37,552
1
P<0,001
The effect of smoking on the results of rehabilitation in patients after cerebrovascular accident
Statistical analysis shows that there is a statistically significant difference between the Barthel index at admission and risk factor of
smoking (Chi-Square: 37.552, P<0.001).
Figure 5 Analysis of ADL by Barthel Index at discharge
and risk factor of smoking.
Table 5 Shows the statistical analysis of relationship be tween the Barthel index at discharge and risk factor of
smoking.
37,552
Chi-Square
df
1
L evel of significance
P<0,001
Based on the tables and graphs of the data presented, as well
as on the basis of the calculated chi-square test (37.552), where
P<0.001, it is proven that there is a statistically significant correlation
between the Barthel index at discharge and risk factors of smoking.
DISCUSSION
Stroke is a neurological disorder that suddenly occurs after
which it can develop a variety of different clinical changes expressed in varying degrees. This disorder can end in death, but
it can also leave a smaller or larger consequences. Depending on
the level of damage, rehabilitation can be long and unpredictable
(12,13). Treatment after stroke requires a multidisciplinary approach, engagement of a patient and family, and also large economic expenses.
The study included 116 patients with stroke who were admitted on rehabilitation in a period of one year at the Department of
Physical Medicine and Rehabilitation.
We analyzed age distribution in patients as shown in Table 1.
Youngest patient at admission was 30 years old and the oldest
was 86 years old. The average age of the patients was 65.45 years
(stand. deviation 10.368). This finding is consistent with data from
the literature as well as with our previous research which states
that persons over 65 years of age frequently suffer from stroke.
Most patients were 31-40 years of age (35%), which is the active
population. This population is the most productive both as part
of the family and society. This data is not consistent with the data
from the literature probably because the patients in this age group
were more frequent rehabilitated in stationary conditions with the
aim of faster and better rehabilitation and created the impression
that most affected patients are of this age (14,15).
165
Analysis of gender distribution showed that 51% of patients
who suffered from cerebrovascular accident were female, and
there is no statistical difference in age distribution. This data differs
from the research conducted 15 years ago stating that stroke was
more frequent in male patients. For the majority of patients with
cerebrovascular infarction, 32 (28%), rehabilitation lasted from 31
to 40 days. This period is longer than usual due to a more severe form of illness after a stroke which required longer rehabilitation. This data contradicts the data from the literature suggesting
a shorter rehabilitation for patients in stationary conditions (16).
Nowadays, shorter stationary treatment with continued rehabilitation at home and ambulatory program through CBR is recommended.
In patients suffering from stroke, in our study, the risk factor of
smoking was third most frequent after hypertension and diabetes
mellitus. This risk factor was present in 22% of the patients. In our
research conducted 15 years ago, this risk factor was the second
most common, after hypertension, and was found in the range of
33-42% depending on the studied groups (12). Smoking is a risk
factor that can be modified (17-22). Health promotion and primary prevention make this proportion lower, but still high because it
includes almost one-fifth of respondents (23,24,25). Studies done
in Iran have confirmed a similar representation of smoking as a risk
factor (20%). It is believed that prevalence of smoking is affected
by a number of factors such as tradition, education, environmental effects and family (26). Many studies have confirmed that this
stroke risk factor associated with other risk factors leads to increased mortality, severe consequences upon the occurrence of
stroke and longer rehabilitation with worse results (17,21).
Figure 4 shows the activities of daily living at admission for
both groups, those with risk factor of smoking and those without
risk factor of smoking. Activities of daily living were assessed by
Barthel Index. From this chart we can see that there are statistically significant differences between these two groups (p<000.1).
Figure 5 shows the activities of daily living at discharge for both
groups, those with risk factor of smoking and those without risk
factor of smoking. The analysis showed that there was significantly
statistical difference between these two groups (p<000.1) at discharge.
When comparing the activities of daily living as shown in
graphs 4 and 5, we see that there was a significantly higher index
values between Barthel on admission and at discharge in patients
who had no risk factor of smoking. Our previous studies have
shown worse results of rehabilitation in patients with risk factor
of smoking (13,17). In particular, we noticed the existence of risk
factors in younger patients (27).
It is believed that the primary and secondary prevention of
risk factors needs to be improved especially when it comes to the
factors that we can influence. Stop smoking programs are of great
importance for primary care specialists.
CONCLUSION
Smoking as a risk factor in patients with CVA is very common
(occurring in 22% of patients) and it directly affects the poor results
of rehabilitation and the patient’s daily activities. Therefore, in addi-
166
tion to other measures of secondary prevention, energetic struggle
against this risk factor is highly recommended.
Conflict of interest: none declared.
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Reprint requests and correspondence:
Edina Tanović, MD, PhD
Clinic for Physical Medicine and Rehabilitation
Clinic Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 33 298 465
E-mail: [email protected]
Original article
Medical Journal (2014) Vol. 20, No. 3, 167 - 170 Frequency of chromosomal aberrations among healthy
population of Bosnia and Herzegovina
Učestalost pojave hromosomskih aberacija
kod zdrave populacije u Bosni i Hercegovini
Izeta Aganović-Mušinović1*, Mirela Mačkić-Đurović1, Orhan Lepara2
Center for Genetics, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina,
Department of Human Physiology, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina
1
2
*Corresponding author
ABSTRACT
SAŽETAK
Structural chromosomal aberrations (CAs) in peripheral blood
lymphocytes (PBLs) have been applied for over 30 years in occupational and environmental settings (including radiation dosimetry) as a
biomarker of early effects of human health. They can be involving the
same locus on both chromatides-chromatid aberrations (CSAs) while
chromosome type aberrations (CTAs) affect one chromatide of a
chromosome. They could be induced by different mutagens. The aim
of this study is to form baseline for chromosome aberrations frequency among healthy population of Bosnia and Herzegovina. We have
found significant effect modification by gender – female had increased
number of CAs – chromatid type, and the age infulence of both gender. Smoking habits did not influence CAs frequency of any type. The
age and smoking habits did correlate in CAs frequency for non-smokers but did not correlate for smokers. Frequency distribution of CTAs
and CSAs among male and female showed predominance of CTAs
over CSAs, independently of gender.
Strukturne hromosomske aberacije (CAs) iz limfocita perifene
krvi se koriste preko 30 godina u procjeni profesionalnog ili okolišnog okruženja (uključujući i dozimetriju zračenja) kao biomarker
ranih uticaja na zdravlje čovjeka. One mogu uključivati iste lokuse
na obje hromatide (hromatidne aberacije-CSAs) dok hromosomske
aberacije-CTAs uključuju jednu hromatidu hromosoma. Hromosomske aberacije mogu biti uzrokovane različitim mutagenima. Mi
smo uočili značajan uticaj spola na pojavu hromosomskih aberacija
– žene su imale povećan broj CAs – hromatidnog tipa, kao i uticaj
dobi kod oba spola. Pušački status nije uticao na pojavu učestalosti
CAs bilo kojeg tipa. Dob i pušački status su korelirali sa učestalošću
pojavljivanja CAs kod nepušača, dok nisu korelirali kod pušača. Ovo
se može koristiti kao bazna linija učestalosti hromosomskih aberacija u zdravoj populaciji. Distribucija učestalosti CTAs i CSAs među
spolovima pokazuje predominantnost CTAs nad CSAs, neovisno o
spolu.
Key words: structural chromosomal aberrations, chromatid aberrations, chromosome type aberrations, gender, tobacco smoking
Ključne riječi: strukturne hromosomske aberacije, hromatidne aberacije, hromosomski tip aberacija, spol, pušački status
INTRODUCTION
Other types of initial lesions (e.g. base alterations, cross-links, pyrimidine dimers, or single-strand breaks, depending on the inducer) induced by S-phase-dependent agents, including most chemical
clastogens and UV light, give rise to CTAs (1, 2, 3) .
It is obvious that chromosomal aberrations - CA generation requires one or several DNA double-strand breaks, but their formation schedule is different for CSAs and CTAs. A double-strand break
is the primary lesion for CSAs (4), and CSAs observed in cultured
PBLs are expected to reflect double-strand breaks mostly generated
in vivo in G0 stage. For lymphocyte CTAs, however, double-strand
breaks are probably formed from the initial DNA lesions in vitro in
S phase.
CSAs and CTAs have different mechanisms of formation resulting from different kinds of DNA lesions induced by different types
of clastogens (5). Therefore, information of CAs among healthy
population gives us a baseline for any other research of CAs.
Structural chromosomal aberrations (CAs) in peripheral blood
lymphocytes (PBLs) have been applied for over 30 years in occupational and environmental settings (including radiation dosimetry) as
a biomarker of early effects of human health (1). CAs include chromosomal breaks and exchanges visible in arrested metaphase-stage
cells and are usually divided into chromosome-type aberrations
(CSAs) and chromatid-type aberrations (CTAs), which differ from
each other morphologically. CSAs involve the same locus on both
sister chromatids on one or multiple chromosomes, whereas CTAs
affect one or several sister chromatids of a chromosome or several chromosomes. CSAs and CTAs are induced by different types
of environmental mutagens. In PBLs, which are mostly in a resting
G0 phase, agents that produce double-strand breaks, such as ionizing radiation and radiomimetic clastogenic chemicals, create CSAs.
168
I. Aganović-Mušinović et al.
The aim of this study is to form a baseline for chromosome
aberrations frequency among healthy population of Bosnia and Herzegovina.
MATERIALS AND METHODS
We collected whole heparinized blood from 200 persons from
Bosnia and Herzegovina. Those people had no record of cancer illness, no previous therapy of any kind (in the last three months) and
were divided in 5 age groups (20-30; 30-40; 40-50; 50-60; 60-70)
with an equal number of males and females in each group. We collected data of their smoking habits dividing them to smokers and
no-smokers.
Conventional Moorhead method was used on short-term cultures for 48 hr, with all cells being in the first division (6). Slides
from each culture were numbered and blindly scored. At least 200
well-spread metaphases with 46 ± 1 centromeres were examined.
Total CAs were subclassified as CSAs (including chromosome-type
breaks, ring chromosomes, marker chromosomes, and dicentrics)
and chromatid-type aberrations (CTAs; including chromatid-type
breaks). Gaps were not scored as aberrations.
All variables were expressed as the medians and interquartile
ranges for continuous data with or without a normal distribution,
respectively. Nonparametric data was compared between groups
using the independent samples Mann–Whitney U-test. Additionally, Spearman’s correlation was used as measure of association for
continues variables. P-value <0.05 was considered statistically significant. All statistical analyses were performed using the computer software Statistical Package for the Social Sciences, version 20.0
(SPSS, Chicago, IL).
Figure 2 Relation among age and number of aberrations at
female groups. rho-Spaerman’s correlation coefficient, p- probability
Figure 3 Relation among age and number of aberrations at
male groups. rho-Spaerman’s correlation coefficient, p- probability
As shown in Figure 1 more frequent CAs are observed to
correlate with age at both genders, whereas at females the pick is
around the age of 50 which can be in connection with hormonal
status and adjusting for menopause, males had a pick at the age of
60 and all were statistically significant using Spearman’s correlation
(p<0,01; rho=0,463; rho=0,470; rho= 0,455; respectively) (Figure
2 and 3).
Significant positive correlation among the age and number of
aberrations within all groups of healthy population (rho=0,462;
p<0,01) is evident.
Spearman’s correlation was used to define the number of CAs
among nonsmokers and it showed significance (p<0,05; rho=0,192)
- Figure 4, while it was not significant for smokers (rho=0,229; p=NS)
– Figure 5. Although the number of aberrations in smoker group is
higher 1,0 (0,0 – 2,0) when compared with non-smoker group 0,0
(0,0 – 2,0) the difference has no statistic significance (p=NS).
Figure 1 Relation among age and number of aberrations
at all groups. rho-Spaerman’s correlation coefficient, p- probability
Figure 4 Relation among age and number of aberrations at
nonsmokers. rho-Spaerman’s correlation coefficient, p- probability
RESULTS
Frequency of Chromosomal Aberrations among Healthy Population of B&H
169
DISCUSSION
Figure 5 Relation among age and number of aberrations at
smokers. rho-Spaerman’s correlation coefficient, p- probability
Mann-Whitney U test was used to determine the significance of
chromosome aberrations frequency among male and female group.
Number of aberrations at female group was 1,0 (0,0-2,0), higher
than a number of aberrations at male group 0,0 (0,0 – 2,0). The
difference has statistic significance (p=0,046) (Figure 6).
Figure 6 Relation among number of aberrations at female
and male group. rho-Spaerman’s correlation coefficient, p- probability, NS- not-significant
Figure 7 Frequency distribution of CTAs and CSAs among
male (1) and female (0).
CTAs are far more frequent than CSAs at both gender, independently of age (Figure 7).
The results of our study were used to make a baseline on chromosomal aberrations frequency on healthy population of Bosnia
and Herzegovina. We have found significant effect modification by
gender – female had increased number of CAs – chromatid type,
and the age of both gender.
Smoking habits did not influence CAs frequency of any type.
The age and smoking habits did correlate in CAs frequency for
non-smokers but did not correlate for smokers. This could be used
as a baseline for chromosome aberrations frequency among healthy
population.
Our results correlate with other investigation’s results recently
conducted in other European countries, though we did not correlate
CAs frequency and cancer risk given that the project lasted one year
and we did not have a long-lasting follow up. Frequency distribution
of CTAs and CSAs among male and female showed predominance
of CTAs over CSAs, independently of gender.
The results of the presented study based on Nordic and Italian
cohorts (5) support the conclusion that CA frequency in PBLs, as a
biomarker of cancer risk, will not be improved by separating CSAs
from CTAs. This suggests that both DNA double-strand breaks and
other DNA lesions responsible for CSAs and CTAs, respectively,
are associated with cancer risk. Authors point that the strength of
the cancer predictivity by CA frequency did not decrease in time
since the test, which is circumstantial evidence in favor of individual
susceptibility factors or long-standing exposure to dietary, environmental, or endogenous carcinogens explaining the association between CA frequency and cancer incidence.
There is no significant effect modification by sex, age at test,
or time since the test bservation. Although there was no significant
evidence of effect modification by type of occupational exposure,
a stronger association was suggested among subjects exposed to
ionizing radiation and to reactive chemicals than among unexposed
subject. Among workers exposed to ionizing radiation, an increased
risk was present for both high chromosome-type and high chromatid-type aberrations, although it was statistically significant only
for the former type of aberrations (5). A statistically significant increase in relative risk was seen in medium and high chromosomal
aberration categories in smokers but not in nonsmokers; however,
smoking did not have a significant modifying effect. The increased
risk among smokers was present for elevated chromosome-type
aberrations but not for elevated chromatid-type aberrations.
Chromosomal aberrations are usually considered to derive
from unrepaired or misrepaired DNA lesions induced by exogenous
or endogenous exposure to DNA-damaging agents. An increase in
chromosomal aberrations could also be due to genetic or acquired
conditions conferring a higher susceptibility to genetic damage.
Elevated levels of chromosomal aberrations in peripheral blood
lymphocytes may be seen as an indicator of an early phase of carcinogenesis, where various genetic alterations are also generated in
different tissues (6,7).
We showed that a high frequency of chromosomal aberrations
in peripheral blood lymphocytes, and in particular of chromosome-type aberrations, is associated with increased risk of cancer.
The fact that this association does not depend on the time elapsed
from the test is consistent with the hypothesis that the level of chro-
170
mosomal aberrations is predictive of cancer risk rather than being
an early manifestation of a clinically undetected cancer. The available
literature points toward the independence from exposure to carcinogens of the chromosomal aberration–cancer association; that
is, the prediction of cancer risk associated with chromosomal aberration frequency is the same in exposed and unexposed subjects
(5,7,8,9,10,11,12,13).
The presence of interaction between exposure to carcinogens
and the predictivity of CAs has been another issue largely debated
in the literature (14,15,16,17,18). The presence of a stronger association between CA frequency and risk of cancer in radon-exposed
workers than in other workers or controls, which has been already
reported (9,15), is not consistent with the findings of the Nordic and
Italian cohorts, in which the association between increased CA frequency and cancer risk appeared to be independent from exposure
to carcinogens or smoking habit (7). The findings from the present
study of Italian chohort (15) were not conclusive in this direction
because the predictivity of CA frequency observed in subjects exposed to various classes of carcinogens did not significantly differ
from the group of non exposed subjects.
That study (14) confirmed previous reports of an association
between the extent of chromosomal damage and the risk of cancer.
In contrast to most previous reports, this association appeared to
be limited to the presence of CSAs, and the magnitude of the excess
risk might be lower than previously described. Also, the higher risks
found in the group exposed to ionizing radiation is a peculiar finding
of that cohort and deserves a deeper insight (14,18,19).
CONCLUSION
The possibility that the implementation of occupational preventive programs of chromosomal aberrations frequency focused on
workers with high CA frequency might have modified their risk of
cancer is a plausible explanation of these results, and it will be further evaluated with ad hoc studies, reconstructing occupational lives
of subjects with the highest frequency of CA at their first cytogenetic analysis.
I. Aganović-Mušinović et al.
7. Mitelman F, Johansson B, Mertens F. Fusion genes and rearranged genes as a linear
function of chromosome aberrations in cancer. Nat Genet. 2004;36:331-4.
8. Bonassi S, Znaor A, Norppa H, Hagmar L. Chromosomal aberrations and risk
of cancer in humans: an epidemiological perspective. Cytogenet Genome Res.
2004;104:376-82.
9. Bonassi S, Hagmar L, Strömberg U, Montagud AH, Tinnerberg H, Forni A, et
al. Chromosomal aberrations in lymphocytes predict human cancer independently
from exposure to carcinogens. European Study Group on Cytogenetic Biomarkers
and Health Cancer Res. 2000;60:1619-25.
10.Hagmar L, Brøgger A, Hansteen IL, Heim S, Högstedt B, Knudsen L, et al. Cancer
risk in humans predicted by increased levels of chromosome aberrations in lymphocytes: Nordic Study Group on the Health Risk of Chromosome Damage. Cancer
Res. 1994; 54:2919-22.
11.Hagmar L, Bonassi S, Strömberg U, Brøgger A, Knudsen LE, Norppa H, et al.
Chromosomal aberrations in lymphocytes predict human cancer—a report from
the European Study Group on Cytogenetic Biomarkers and Health (ESCH). Cancer
Res. 1998; 58: 4117-21.
12. Hagmar L, Strömberg U, Bonassi S, Hansteen IL, Ehlert Knudsen L, Lindholm C,
Norppa H. Impact of types of lymphocyte chromosomal aberrations on human
cancer risk. Results from Nordic and Italian cohorts. Cancer Res. 2004;64:2258-63.
13.Rossner P, Boffeta P, Ceppi M, Bonassi S, Smerhovsky Z, Landa K, et al. Chromosomal aberrations in lymphocytes of healthy subjects and risk of cancer. Environ
Health Perspect. 2005;113:517-20.
14. Bonassi S, Abbondandolo A, Camurri L, Dal Pra L, De Ferrari M, Degrassi F, et al.
Are chromosome aberrations in circulating lymphocytes predictive of future cancer
onset in humans? Preliminary results of an Italian cohort study. Cancer Genet Cytogenet. 1995;79:133–5.
15. Bonassi S, Ugolini D, Kirsch-Volders M, Strömberg U, Vermeulen R, Tucker JD. Human population studies with cytogenetic biomarkers: review of the literature and
future prospectives. Environ Mol Mutagen. 2005;10.1002/em.20115.
16. Bonassi S, Hagmar L, Strömberg U, Montagud AH, Tinnerberg H, Forni A, Heikkilä
P, et al. Chromosomal damage in peripheral blood lymphocytes of newly diagnosed
cancer patients and healthy controls. Carcinogenesis. 2010;31:1238-1241.
17.Smerhovsky Z, Landa K, Rössner P, Brabec M, Zudova Z, Hola N, et al. Risk of
cancer in an occupationally exposed cohort with increased level of chromosomal
aberrations. Environ Health Perspect. 2001;109: 41-5.
18.Wykes SM, Piasentin E, Joiner MC, Wilson GD, Marples B. Low-dose hyperradiosensitivity is not caused by a failure to recognize DNA double-strand breaks. Radiat
Res. 2006;165:516–24.
19.Littlefield L, McFee A, Sayer A, O’Neill P, Kleinerman R, Maor M. Induction and
persistence of chromosome aberrations in human lymphocytes exposed to neutrons in vitro or in vivo: implications of findings in ‘retrospective’ biological dosimetry. Radiat Protect Dosimetry. 2000;88:59–68.
Conflict of interest: none declared.
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4. Pfeiffer P, Goedecke W, Obe G. Mechanisms of DNA double-strand repair and
their potential to induce chromosomal aberrations. Mutagenesis. 2000;15:289-302.
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6. Moorhead PS, Nowell PC, Mellman WJ, Battips DM, Hungerford DA. Chromosome preparations of leukocytes cultured from human peripheral blood. Exp Cell
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Reprint requests and correspondence:
Izeta Aganović-Mušinović, MD
Center for Genetics
Medical Faculty University of Sarajevo
Čekaluša 90
71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 33 226 472 lok.156
Email: [email protected]
Original article
Medical Journal (2014) Vol. 20, No. 3, 171 - 174 Morphometric analysis of arterial Willis ring in
patients with varying degrees of occlusion of the
internal carotid artery
Morfometrijska analiza arterija Willisovog prstena sa
različitim stepenom okluzije unutrašnje karotidne arterije
Alma Voljevica*, Elvira Talović
Department of Anatomy, Faculty of Medicine University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
In 1664, since the time of Thomas Willis, it is known that the arterial ring at the base of the brain (later named by this anatomy) is the
most important part of the collateral cerebral blood flow. His discovery
of the valvular mechanism is particularly evident at the time of occurrence of different occlusive diseases of the internal carotid artery. In
this paper, the analysis focuses on the carotid angiogram of 75 patients
and recorded various forms of occlusive disease of the internal carotid
artery, which are presented by the method of serial angiography by
Seldinger which were excluded from the archives of the Department
of Radiology, Clinical Center University of Sarajevo. For morphometric
analysis of blood vessels, we used a specially designed software program ELLIPSE. The most prominent changes were registered in the
area of the front and rear communicating artery. The largest diameter
of the front communicating artery was seen in patients with unilateral
occlusion of the internal carotid artery, while the greatest increase of
gain in the back communicating artery was observed in patients with
bilateral occlusion of the same artery. This study confirmed so far the
repeatedly expressed assertion that the valvular mechanism of the
Willis ring is significant with all types of occlusive changes that require
arteries which are contained by it.
Još od davne 1664. godine, od vremena Tomasa Willisa, poznato
je da je arterijski prsten na bazi mozga (kasnije nazvan po ovom
anatomu) najvažniji dio kolateralnog moždanog krvotoka. Njegov
valvularni mehanizam naročito dolazi do izražaja u momentu nastanka različitih okluzivnih oboljenja unutrašnje karotidne arterije.
U ovom radu analizi je podvrgnuto 75 angiograma karotidnog sliva
pacijenata kod kojih su zabilježeni različiti oblici okluzivnih bolesti
unutrašnje karotidne arterije, prikazanih metodom serijske angiografije po Seldingeru izuzetih iz arhive Katedre za radiologiju
Kliničkog centra Univerziteta u Sarajevu. Za morfometrijsku analizu krvnih sudova korišten je posebno dizajnirani softwerski program ELLIPSE. Najizraženije promjene registrovane su u području
prednje i stražnje komunikantne arterije. Najveći promjer prednje
komunikantne arterije zabilježen je kod pacijenata sa unilateralnom
okluzijom unutrašnje karotidne arterije, dok je najveći porast vrijednosti u stražnjoj komunikantnoj arteriji zabilježen kod osoba sa
bilateralnom okluzijom iste arterije. Ovo istraživanje je potvrdilo do
sada više puta izrečenu tvrdnju da valvularni mehanizam Wilisovog
prstena dolazi do izražaja kod svih vrsta okluzivnih promjena koje
zahvataju arterije koje ga sačinajvaju.
Key words: Willis ring, cerebral arteries, serial angiography, morphometry, internal carotid artery occlusion
Ključne riječi: Willisov prsten, cerebralne arterije, serijska angiografija, morfometrija, okluzija unutrašnje karotidne arterije
INTRODUCTION
level of the anastomosed blood vessels of the brain of Willis’ circle
(for example communicating arteries) there is no mixing of blood,
due to hemodynamic balance between anastomosed arterial systems. However, under some certain conditions there is a functional
disturbance of this balance and blood can transfer from one system
to another. Thus, in flexion or extension of the head, compression
of vertebral arteries is formed, and during the rotation and lateral
flexion, the compression of internal carotid artery or compression
of common carotid artery occur (3).
In the case of occlusion of a cerebral artery, blood transferring
from one system to another can be much more intense, leading to
an increase in the diameter of collateral vessels in order that the
The intensity of research surrounding the arterial ring at the
base of the brain (circulus arteriosus cerebri Willisi) has not decreased since 1664, when for the first time, the arterial ring was described in detail and its collateral function was demonstrated (1, 2).
As known, two arterial systems are involved in the construction
of a ring: a system of internal carotid artery (arteriae Ipsilateral) and
system of vertebral arteries (arteriae vertebrales). It is also known
that the collateral function of the Willis’ circle is manifested in physiological and pathological conditions. This claim is asserted in the
study in which it was found that under normal circumstances, at the
172
blood vessels should respond functionally to current situation.
In recent years, a lot of attention has been devoted to the
assessment of hemodynamic status of cerebral circulation, and
monitoring of the condition is possible through the usage of many
modern diagnostic procedures. Some of the most frequent diagnostic procedures are MR-angiography (4), serial angiography, and
transcranial color Doppler (5, 6). By applying last two methods in
combination with compression test on the internal carotid artery, it
is possible to analyze the collateral ability of Willi’s ring.
Aim: the main goal of this study is to measure the diameters of
the blood vessels that enter the system of Willis ring among patients
with varying degrees of occlusion and stenosis of the internal carotid artery, by using a specially designed software program, whose
value could be used in clinical practice to assess the condition of the
cerebral circulation system.
A. Voljevica et al.
Figure 1 Surrounding display of Ellipse software program
used in this study.
MATERIALS AND METHODS
As for the material for this paper, there are 75 angiogram carotid
arteries of patients with disturbed cerebrovascular status displayed
by using the serial angiography method by Seldinger obtained from
the archives (retrospective study) Department of Radiology, Clinical Center University of Sarajevo. Seventy-five patients who were
treated by the method of serial angiography, were selected from a
possible 157 patients examined by the angiogram and grouped into
four categories according to the degree of narrowing, the pathological process of the affected carotid artery.
I category consisted of 28 patients who were registered as stronger unilateral or bilateral stenosis of the internal carotid artery (S)
II category consisted of 29 patients with unilateral occlusion of
the internal carotid artery (A)
III category consisted of 13 patients with unilateral internal carotid artery occlusion combined with stronger contralateral stenosis
(OS)
IV category consisted of 5 patients with bilateral occlusion (OO).
Among the categories of patients we created two subgroups;
one subgroup consisted of 40 patients who were registered as
anamnestic symptoms of cerebrovascular of insufficiency, so this
group was labelled symptomatic patients (SS), while the other subgroup consisted of 35 patients who were not registered as symptoms of cerebrovascular insufficiency, but the lesions on the internal
carotid artery was registered accidentally, so this group was labelled
asymptomatic patients (AS).
In the course of recording, a compression test on the internal
carotid artery opposite side was performed on all of the patients to
show the front and rear communicating artery. All scans obtained
were transferred to the specially designed software program Ellipse
(Figure 1). In this manner, easier storage of the images that are used
for morphometric analysis was enabled.
Morphometric measurements were used to obtain data on the
value of the diameters of the blood vessels that enter system of
Willis’ circle among patients with disturbed cerebrovascular status.
For this measurement program the Line System was used. The measurements were made on those scans that provided the best visualization of certain blood vessels. For each vessel three measurements
were made in order to obtain the mean value. All data are statistically processed, and the results are shown through charts and tables.
RESULTS
Using the specially designed software program, measurements
of the diameters of the blood vessels that enter the system of Willis
ring among patients with varying degrees of occlusion and stenosis
arteriae carotis internae (categories of subjects from I to IV) were
carried out. The obtained values were compared with values of diameters of blood vessels of Willis ring among subjects of control
category (100 subjects with normal cerebrovascular status whose
values are published in the paper: Voljevica, et al. (7).
Table 1 Diameters of blood vessels expressed in mm.
Dimeters of blood vessels expressed in mm
Blood
>60years
S (n=28)
O (n=29)
OS (n=13)
OO (n=5)
vessels
(n=100)
AcoA
1.13±0.28
1.20±0.33
1.33±0.38
1.34±0.36
1.50±0.25
A1 SS
1.78±0.41
1.63±0.51
1.90±0.42
1.84±0.67
2.02±0.60
A1 AS
1.78±0.41
1.86±0.37
2.82±0.60
2.58±0.79
1.78±0.33
PCoA SS
1.29±0.42
1.40±0.44
1.55±0.45
1.60±0.42
1.76±0.41
PCoA AS
1.29±0.42
1.25±0.32
1.45±0.66
1.39±0.64
1.95±0.32
P1 SS
1.79±0.45
1.91±0.43
2.79±0.44
2.63±0.61
2.63±0.42
P1 AS
1.79±0.45
1.92±0.49
2.41±0.59
2.62±0.58
2.66±0.39
AS - asymptomatic patients; SS - symptomatic patients; The values ± indicate
standard deviation (± SD)
Those patients with stenosis of the internal carotid artery have
the complete configuration of Willis ring increased, but there is no
statistically significant increase in the diameter of blood vessels that
enter its composition. The level of significance is p <0.05. Among
such patients inferiority of diameters of precomunacating segment
of front cerebral artery compared to the control group of subjects
were reported, which is probably caused by atherosclerotic process.
Values of diameters of other vessels were slightly higher when compared to the control group subjects.
Among patients with occlusion of the internal carotid artery
with or without contralateral stenosis, increased collateral flow
through the anterior segment of the circle of Willis’ circle was reported, resulting with a statistically significant increase of the radius
Morphometric analysis of arterial Willis Ring in patients with varying degrees of occlusion of the Internal carotid artery
of the anterior communicating artery as well as precommunicating
anterior cerebral artery compared to the control group of patients.
The level of significance is p<0.001. We have to note that these
values provided for the patients without symptoms were for about
0.2 ± 0.14 mm greater than among patients with symptoms.
Among patients with bilateral occlusion of the internal carotid
artery, increasing blood flow was identified through the rear segment of the Willis ring, resulting in a significant increase in the radius
of the rear communicating artery, and of precommunicating part of
the posterior cerebral artery. The level of significance is p<0.001.
3,00
ACoA
2,80
2,60
A1 SS
2,40
A1 AS
2,20
2,00
PCoA SS
1,80
PCoA AS
1,60
P1 SS
1,40
1,20
P1 AS
1,00
>60god
S
O
OS
OO
Figure 2 Increase of diameters of blood vessel.
Figure 1 shows the increase of the diameters of certain blood
vessels of Willis ring depending on the type of disease that affects
the internal carotid artery. The most visible changes are registered in
the front and back of the communicating artery as seen in the chart.
The anterior communicating artery shows the largest diameter in
patients with unilateral occlusion, and the largest increase in value is
achieved by back communicating artery among patients with bilateral occlusion of the internal carotid artery.
DISCUSSION
Previous studies have shown that patients with significantly reduced blood flow in the internal carotid artery or the basilar artery,
collateral arteries can maintain cerebral perfusion in the area of
vascularization court which is affected. The primary collateral, such
as arteriae cerebri anterior and arteriae cerebri posterior, respond
very quickly by greater blood flow and changing the direction of
blood flow (8).
Previous research has shown that among patients with asymptomatic internal carotid artery occlusion, the diameters of anterior
communicating artery increase so that the larger diameter of the artery may have a protective role in patients with unilateral occlusion
of the internal carotid artery (9).
Also, it was found that in patients with unilateral occlusion of
the internal carotid artery presence of collateral flow through the
posterior communicating artery circle of Willis is associated with
a lower prevalence of border infarct (border zone infarcts), and in
asymptomatic patients, increase collateral function has not been observed (9).
Based on research conducted in this area, which were based on
the morphometric measurements of the arteries of Willis ring in
173
patients with occlusion or stenosis of the corotid artery, it was determined that enhanced flow through communicating segments of
Willis ring leads to an increase in the diameter of the blood vessels.
In patients registering with unilateral stenosis, boosting flow through
the anterior communicating artery did not lead to a statistically significant increase either in the diameter of this, or of other blood
vessels that enter Willis ring. In contrast, in patients with unilateral
occlusion of the internal carotid artery with or without contralateral
stenosis, collateral flow through the anterior segment of the circle
of Willis was increased, with a statistically significant increase of the
diameter of the anterior communicating artery and precommunicating segments of anterior cerebral artery compared to the control
group subjects. The level of significance is p<0.001.
We have noted that these values in patients without symptoms
are for about 0.2 ± 0.14 mm greater than in patients with symptoms
of the disease. In patients with bilateral occlusion of the internal
carotid artery, there was a higher percentage flow through the posterior segment of the Willis ring, resulting in a significant increase
in the diameter of the rear communicating artery, and of precommunicating segments of the posterior cerebral artery. The level of
significance is p<0.001.
These results are fully in accordance with the claims of researchers (10,11,12), which, based on their research, came to the conclusion that the increased blood flow through the communicating
segment of the Willis ring leads to an increase in the caliber of the
arteries. Specifically, the authors suggest that arterial stenosis that
affects the arteries, leads to a gradual narrowing of the lumen, which
then leads to the inclusion of compensatory mechanisms, including,
dilatation of blood vessels and increased blood flow through dilated
blood vessel functioning. The same authors also found that compensatory, hemodynamic, metabolic and neural mechanisms are of
great importance and their effectiveness determines whether the
ischemic tissue can remain capable of living.
CONCLUSION
At the end we can conclude that our research confirmed previous research results related to Willis ring, and it means that protective mechanism has no match in whole organism, but for its normal
establishment of collateral circulation at the ring level the existence
of the entire configuration is necessary.
Research showed that the biggest change in diameter of back
communicating artery are noticed among asymptomatic patients
with occlusion of the inner carotid artery with and without contralateral stenosis and it goes up to 46% compared to the mean value.
In contrast, the smallest percentage changes are registrated among
asymptomatic patients with bilateral occlusion on P1 segment of
the back cerebral artery, and it goes up to 15% compared to the
mean value. Slightly bigger changes are registrated on P1 segment
of back cerebral artery among symptomatic patients with unilateral
occlusion and it goes up to 16% compared to the mean value. Identical results are obtained also among group of subjects with bilateral
occlusion on back communicating artery of asymptomatic patients
and on P1 segment of the back cerebral artery among symptomatic
patients.
Conflict of interest: none declared.
174
A. Voljevica et al.
REFERENCES
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resonance angiographic evaluation of circulus arteriosus cerebri (circle of Willis): a morphologic study in 100 human healthy subjects. Ital J Anat Embryol.
1996;101(2):115–23.
5. Baumgartner RW, Baumgartner I, Mattle HP, Schroth G. Transcranial collor-coded
duplex sonography in the evaluation of collateral flow through the circle of Willis.
Am J Neuradiol. 1997;18(1):127-33.
6. Hoksbergen AW, Legemate DA, Ubbink DT, de Vos HJ, Jacobs NJ. Influence of the
collateral function of the circle of Willis on hemispherical perfusion during carotid occusion as assessed by transcranial colour-coded duplex ulrasonography. Eur J
Vasc Endovasc Surg. 1999;17(6):486-92.
7. Voljevica A. Talović E. Morphometric analysis of Willis circle arteries. Archives of
Pharmacy Practice. 2013;4(2).
8. Abdelaziz M, Ahmed AI. Three dimensional magnetic resonance angiography of the
circle of Willis: anatomical variations in general Egyptian population. The Egyptian
Yournal of Radiology and Nuclear medicine. 2011;42(3):405-412.
9. Hendrikse J, Hartkamp MJ, Hillen B, Mali WP, van der Grond J. Collateral ability
of the circle of Willis in patients with unilateral internal carotid artery occlusion:
border zone infarcts and clinical symptoms. Stroke. 2001;32:2768–73.
10. Cassot F, Vergeur V, Bossuet P, Hillen B, Zagzoule M, Marc-Vergnes JP. Effects of anterior communicating artery dameter on cerebral hemodinamics in internal carotid
artery disease. Circulation. 1995;92(10):3122-31.
11. Hedera P, Bujdakova J, Traubner P, Pancak J. Stroke risik factors and development of
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Reprint requests and correspondence:
Alma Voljevica, MD
Institute of Anatomy „Prof. Dr Hajrudin Hadžiselimović”
Faculty of Medicine University of Sarajevo
Čekaluša 90
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 665 949 143
Fax: + 387 33 203 670
Email: [email protected]
Bosnia and Herzegovina versions of Guidelines for Patients!
Bosanskohercegovačka verzija Vodiča za pacijente!
Original article
Medical Journal (2014) Vol. 20, No. 3, 175 - 179 Evaluation of clinical and laboratory characteristics
of childhood lymphoma
Evaluacija kliničkih i laboratorijskih karakteristika
limfoma dječije dobi
Edo Hasanbegović*, Nermana Čengić, Meliha Sakić, Adela Tunić, Senada Mehadžić
Pediatric Clinic, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
The aim of this study is to evaluate the basic epidemiological and
clinical characteristics of lymphoma in childhood at the Department
of Hematooncology, Pediatric Clinic, Clinical Center University of Sarajevo (CCUS), in ten year period. Patients and Methods: the study
included 58 patients, of both gender, aged 0-15 years, diagnosed with
lymphoma at the Department of Hematooncology, Pediatric Clinic of
CCUS, in the period from January 1st 2004 to December 31st 2013.
The retrospective study of patients with lymphoma in childhood was
conducted. The results were presented using tables and charts, with
number of cases and percentages. Statistical analysis of significant differences was performed using Fisher and Chi-square test. The values
of p<0.05 or on the level reliability of 95% were considered statistically
significant. Results: our study included 58 patients, 37 (63.80%) boys
and 21 (36.20%) girls. Most of the patients were in the age group of
8-15 years, namely 38 (65.50%) patients. The leading symptom of lymphoma in childhood was lymphadenopathy, which was presented in 45
(77.58%) patients, followed by subfebrile temperature in 19 (32.75%),
paleness in 16 (27.59%), hepatosplenomegaly in 13 (22.41%), and
weight loss in 12 (20.69%) patients. The following elevated values were
noted: LDH in 16 patients with HL and 14 with NHL, and Cu in 15 patients with HL and 10 with NHL. Majority of the patients with HL were
diagnosed in stage II of disease, 12 (37.50%) patients, and 11 (34.40%)
in stage IV. Majority of patients with NHL were diagnosed in stage II, 13
(50%), and 8 (30.80%) in stage IV. Conclusion: clinical diagnostic methods and modern therapy at the Pediatric Clinic of CCUS contribute to
good prognosis for patients suffering from lymphoma in childhood.
Cilj rada je evaluirati osnovne epidemiološke i kliničke karakteristike limfoma dječije dobi na Hematoonkološkom odjelu Pedijatrijske klinike Kliničkog centra Univerziteta u Sarajevu (KCUS) u
desetogodišnjem periodu. Ispitanici i metode: istraživanje je obuhvatilo djecu kod kojih je dijagnostikovan limfom na Pedijatrijskoj klinici
KCUS-a u periodu od 01.01.2004. do 31.12.2013. Retrospektivnom
analizom oboljelih od limfoma dječije dobi, provedeno je kliničko
ispitivanje kojim je obuhvaćeno 58 pacijenta u dobi od 0-15 godina, 37 dječaka i 21 djevojčica. Dobiveni rezultati su predstavljeni tabelarno i grafički, brojem i procenatualnom vrijednošću. Fišerovim
testom je testirana razlika od normalne distribucije, a kao statistički značajna razlika smatran je (p<0.05). Rezultati: istraživanjem je
obuhvaćeno 58 djece, 37 (63.80%) dječaka i 21 (36.20%) djevojčica.
Najviše oboljelih bilo je u dobnoj skupini 8 - 15 godina i to 38 (65.50
%). Vodeći simptom limfoma dječije dobi je limfadenopatija koja je
bila prisutna kod 45 (77.58%) pacijenata, zatim subfebrilnost kod 19
(32.75%), blijedilo 16 (27.59%), hepatosplenomegalija 13 (22.41%), te
gubitak tjelesne težine kod 12 (20.69%) pacijenata. Kod 16 pacijenata
sa HL i 14 pacijenata sa NHL bile su povišene vrijednosti LDH, a Cu
u serumu kod 15 pacijenata sa HL i 10 pacijenata sa NHL. Najviše
pacijenata oboljelih od HL-a je dijagnosticirano u II stadiju bolesti i to
12 (37.50%), a u IV stadiju 11 (34.40%) pacijenata. Najviše pacijenata
oboljelih od NHL-a je dijagnosticirano u II stadiju i to 13 (50%), te
u IV stadiju 8 (30.80%). Zaključak: kliničko–dijagnostičke metode i
savremena terapija na Pedijatrijskoj klinici KCUS-u doprinose dobroj
prognozi za pacijente oboljele od limfoma dječije dobi.
Key words: Lymphoma, Hodgkin’s, Non Hodgkin’s, child
Ključne riječi: Limfom, Hodgkin, Non Hodgkin, dijete
INTRODUCTION
dren. Lymphomas are divided into Hodgkin’s lymphoma (HL) and
Non Hodgkin’s lymphoma (NHL) which are so different diseases in
epidemiology, biology, diagnostic approach, treatment and prognosis, that they are treated quite separately. NHL represent about 60%
of children’s lymphomas (1, 2).
Hodgkin’s lymphoma is the most common malignant lymphoma, characterized by hyperplasia fields of lymphoid tissue in which
there are Reed-Sternberg (RS) cells. It usually starts as a painless
lymphadenopathy, usually in the neck, and later the disease expands
In the general population, neoplasms in children represent 1% of
all malignancies. By cause of death, they are in second place right after the accidents, with a prevalence of 10,60%. In children, the most
common neoplasms are: leukemias, brain tumors and lymphomas.
Lymphomas are the primary neoplasias of the lymphatic system,
which are usually manifested by painless enlargement of the lymph
nodes. They represent 10 - 13% of newfound malignancies in chil-
176
to other lymph nodes and may cause infiltration extra - lymphatic
organs and tissues. Lymph nodes are much bigger and stronger than
in benign lymphadenopathy, which is usually seen in children. General symptoms such as fever > 38 ° C, body weight loss > 10% in the
last 6 months, night sweats, itchy skin, also called B symptoms, are
not so common in children. The etiology of the disease is not clear.
Most probably it is important influence of genetic predisposition and
environmental factors, among which socio-economic and infectious
factors are the important once. In almost 75% of the HL examples in
childhood it is possible to prove the involvement of Epstein-Barr virus. In order to determine the treatment, the stage of the disease is
determined on the basis of diagnostic biopsy and anatomical distribution. Intra-abdominal disease is normally diagnosed radiologically
(ultrasound, CT, MRI) (3).
Four types of HL are differentiated histopathologically: lymphocyte predomination, nodular sclerosis, mixed cellularity and lymphocyte depletion. Lymphocyte predomination has the most favorable
prognosis and lymphocyte depletion the least favorable. Lymphocyte depletion in children is rare.
The treatment of HL has dramatically improved in the past 40
years. With the combination therapy, which includes chemotherapy
and radiotherapy, permanent cure is achieved in 80% of the patients.
The most frequently applied protocols for the treatment of HL in
children are: ABVD (Adryamicin, Bleomycin, Vincristine, DTIC),
ChlVPP (Chlorambucil, Vinblastine, Procarbasid, Pronison), COPP
(Ciclofosfamid, Oncovin, Procarbazine, Pronison) (4, 5).
Non Hodgkin’s lymphomas (NHL) are clonal malignancies of
lymphocytes. NHL are heterogeneous group of lymphoproliferative
neoplasms marked by the emergence of malignantly altered lymphocytes in the lymph node, and rarely primary in other organs.
It is characterized by rapid growth, early dissemination and a high
degree of malignancy. Extremely rare occurs in children younger
than 2 years after which the frequency increases gradually during
childhood. Its peak is reached between the 7-10 year. NHL is 2-3
times more frequent in boys than in girls.
According to the cell lines which belong to Non Hodgkin’s lymphoma is divided into B-NHL and T-NHL group. The World Health
Organization (WHO) has classified NHL in children at four main
types: B-cell Non Hodgkin’s lymphoma (Burkitt and non-Burkitt’s
lymphoma), diffuse large B-cell lymphoma, lymphoblastic lymphoma, anaplastic large cell lymphoma.
Five-year survival in patients who were diagnosed with NHL
younger than twenty years was 86% (6, 7, 8).
The aim of the study was to evaluate the basic clinical and laboratory characteristics of lymphoma in childhood at the Pediatric Clinic of
CCUS in the ten year period.
MATERIALS AND METHODS
The study included children diagnosed with malignant lymphoma (Hodgkin and Non Hodgkin’s lymphoma), at the Department
of Hematooncology, Pediatric Clinic of CCUS, in the period from
January 1st 2004 to December 31st 2013. A total of 58 patients was
analyzed, 37 boys and 21 girls, aged 0 - 15 years. The retrospective
study of patients with childhood lymphoma was conducted. The
results were presented using tables and charts, with number of cases and percentages. Statistical analysis of significant differences was
E. Hasanbegović et al.
performed using Fisher and Chi-square test. The values of p<0.05
or on the level reliability of 95% were considered statistically significant.
The following was analyzed:
• gender and age of the patients with Hodgkin (HL) and Non
Hodgkin’s lymphoma (NHL)
• clinical features of the patients
• laboratory parameters
• histopathologic classification
• classification according to the degree of lymphoma spreading
RESULTS
Table 1 Gender distribution of children with lymphoma.
Lymphoma
boys
girls
total
p-value
HL
%
NHL
%
Total
%
17
53.10
20
76.90
37
63.80
15
46.90
6
23.10
21
36.20
32
100.00
26
100.00
58
100.00
0.724
Chi-square
test χ2
0.125
0.006
7.538
Table 1 shows the gender distribution of children with HL or
NHL in ten year period. Malignant lymphoma was diagnosed in 58
patients, 37 (63.80%) boys and 21 (36.20%) girls. There was a statistically significant difference between the groups of boys and girls
with NHL (p = 0.006; Chi-square = 7.538).
Table 2 Age distribution of children with lymphoma.
Age
Lymphoma
HL
%
NHL
%
Total
%
p-value
0-1 years
0
0
0
0
0
0
n/a
2-7 years 8-15 years
9
28.10
11
42.30
20
34.50
0.655
0.2
23
71.90
15
57.70
38
65.50
0.194
1.684
total
p-value
32
100.00
26
100.00
58
100.00
0.013
Chi-square
test χ2
6.125
0.433
0.615
0.018
5.586
Chi-square test χ2
Table 2 shows the age distribution of children with malignant
lymphoma. Most of the patients were in the age group of 8 - 15
years, 38 patients (65.50%). There was a statistically significant difference in the total morbidity of malignant lymphoma between the
age group of 2-7 and 8-15 years (p = 0.018; Chi-square = 5.586)
and morbidity of HL between the age group of 2-7 and 8-15 years
(p = 0.013, Chi-square = 6.125).
Table 3 Clinical signs and symptoms of patients with ma- lignant lymphoma.
p-value
Lymphoma
HL
NHL
Lymphadenopathy
26
19
0,297
Loss of appetite
7
3
0,206
Subfebrile temperature
9
10
0,819
Weakness
4
8
0,248
Hepatosplenomegaly
7
6
0,782
Weight loss
7
5
0,564
Paleness
11
5
0,134
Cough
3
6
0,317
Dryness of the oral mucosa
2
0
n/a
Excessive sweating
2
1
0,564
Pain in the abdomen
3
5
0,48
Pain in the bones
1
5
0,102
177
Evaluation of clinical and laboratory characteristics of childhood lymphoma
Table 3 shows the representation of symptoms of patients with
malignant lymphoma. The most frequent symptoms were lymphadenopathy (HL 26, NHL 19 patients), subfebrile temperature (HL
9, 10 NHL patients), paleness (HL 11, NHL 5 patients) and hepatosplenomegaly (HL 7, NHL 6 patients). There was no statistically
significant difference between the number of patients with HL and
NHL with these symptoms.
Table 4 Laboratory parameters.
Laboratory parameters
HL
NHL
p-value
LDH
16
14
0,715
Ferritin
4
1
0,18
Beta 2 globulin
5
4
0,739
Serum Cu
15
10
0,75
Table 4 shows nonspecific laboratory parameters. In 16 patients
with HL and 14 with NHL levels of LDH were elevated, and Cu
serum levels in 15 patients with HL and 10 with NHL. There was
no statistically significant difference between laboratory parameters
and the type of lymphoma.
p = 0.01, p < 0,05
Figure 1 Histopathological classification of Hodgkin’s
lymphoma (HL).
Figure 1 shows number of patients in relation to histopathological type of Hodgkin’s lymphoma. Most patients with HL belonged to
the histopathological type of nodular sclerosis, 16 (50.0%) patients,
and to mixed cellularity 11 (34.40%) patients. There was a statistically significant difference between the incidence of histopathological
classifications of patients with HL (p = 0.01, p <0.05).
p = 0.239, p>0.05
Figure 2 Histopathological classification of Non-Hod gkin’s lymphoma (NHL).
Figure 2 shows the relationship between the two histopathological types of Non Hodgkin’s lymphoma. B-NHL was present in
the majority of patients, 16 patients (61.50%) compared to T-NHL
which was present in 10 (38.50%) patients. There was no statistically significant difference between the incidence of histopathological
classifications of patients with NHL (p = 0.239, p> 0.05).
p = 0.804, p > 0.05
Figure 3 Classification of Hodgkin’s lymphoma (HL) according to the clinical stage of disease progression (The
Ann Arbor staging classification of Hodgkin’s lymphoma).
Figure 3 shows the number of patients classified according to
the Ann Arbor staging classification of Hodgkin’s lymphoma. Most
patients were diagnosed in stage II, 12 patients (37.50%), followed
by the 11 patients (34.40%) in stage IV and 9 (28.10%) in stage III.
There was no statistically significant difference between clinical stages of HL (p = 0.804, p> 0.05).
p = 0.152, p>0.05
Figure 4 St. Jude’s classification of Non Hodgkin’s lymphoma (NHL) according to the clinical stage of disease
progression.
Figure 4 shows the number of patients classified according to
the clinical stage of disease progression. Most patients were diagnosed in stage II, 13 patients (50.0%) and 8 (30.80%) in stage IV.
There was no statistically significant difference between clinical stages of NHL (p = 0.152, p> 0.05).
DISCUSSION
In our study, malignant lymphoma was diagnosed in 58 patients,
37 (63.80%) boys and 21 (36.20%) girls. HL was diagnosed in 32 patients, 17 boys (53.10%) and 15 girls (46.90%), which corresponds
to the literature stating approximately equal ratio of morbidity in
boys and girls. NHL was diagnosed in 26 children, 20 boys (76.90%)
178
and 6 girls (23.10%). Statistical analysis performed by using Fisher
and Chi-square test showed that there was a significant difference
between the number of boys and girls (p = 0.006; Chi-square =
7.538) suffering from NHL.
Pourtsidis A, Pedrosa MF, et al. reported 2,5-3 times more affected boys compared to girls, aged up to 15 years (9, 10).
The highest number of patients was in the age group of 8-15 years,
38 children (65.50%). In this group there were 23 patients (71.90%)
with HL and 15 (57.70%) patients with NHL. In the age group of
2-7 years, there were 20 patients, which is 34.50% of all patients.
Of these, 9 patients were with HL (28.10%), and 11 (42.30%) with
NHL. Statistical analysis showed that there was a significant difference (p = 0.013; Chi-square = 6.125) between the age groups of
patients with HL, as well as the difference between the age groups
of the total number of patients (p = 0.018, Chi-square = 5.586),
which corresponds to the literature.
Howard SC, Metzger ML, et al. stated that the greatest incidence of HL and NHL was in the age group of 2-10 years, rarely
occured before the age of two, and more often after the age of ten
(11). There was no statistically significant difference between the
age groups of patients with NHL (p = 0.43, Chi-square = 0.615) in
our study.
The main clinical symptom that dominated in HL and NHL was
painless enlargement of the lymph nodes (lymphadenopathy). In
children with HL lymphadenopathy was present in 26 cases, and in
children with NHL in 19 cases. After lymphadenopathy, the most
common associated symptoms were subfebrile temperature: HL
9, NHL 10; hepatosplenomegaly: HL 7, NHL 6; and weight loss:
HL 7, NHL 5 (all these symptoms occured equally). The difference
between HL and NHL was noticed in the occurrence of symptoms
such as loss of appetite, paleness, weakness, cough and pain in the
bones. Thus, for example, in HL: loss of appetite was registered in
7 patients, paleness in 11, compared to NHL: 3 patients with loss of
appetite and 5 with paleness. While, in NHL more symptomatology
occurred such as weakness: 8 patients, cough 6, pain in the bones
5, compared to HL: weakness 4 patients, cough 3 and pain in the
bones 1 patient, the difference was evident, but not so relevant for
statistically significant difference.
Schwartz CL, Büyükpakmukcu M, et al. reported that the most
common symptoms of lymphoma were lymphadenopathy, fever,
loss of appetite, weight loss, weakness with night sweating and itchiness of the skin (1,12).
The following non-specific laboratory parameters of lymphoma
were monitored: lactate dehydrogenase (LDH), ferritin, β2-globulin
and cuprum (Cu) in serum (2). The increase in their values indicated
to worsening of the disease and its activity. LDH was elevated in 16
cases of HL and in 14 cases of NHL. Ferritin was elevated in 4 patients with HL and in 1 patient with NHL. β2-globulin was elevated
in five patients with HL and in 4 with NHL, and Cu serum levels in
15 patients with HL and 10 patients with NHL. There was no statistically significant difference between the two groups of patients.
The study conducted by Vinjamaram S et al. found that laboratory parameters in NHL such as LDH, β2-globulin, serum Cu
were significant during the screening test, in monitoring the effects
of therapy to the final cure. Ye QD, Pan C, et al. confirmed that
laboratory parameters in HL, LDH, serum Cu, ferritin, β2-globulin
E. Hasanbegović et al.
were very important for prognosis, course and outcome of disease.
These two studies showed that these laboratory parameters for
both, HL and NHL, played a very important role in monitoring the
disease and that there was no statistically significant difference between subtypes of lymphoma, which is consistent with our research
(13,14).
From the point of pathohistology, REAL (Revised European-American Lymphoma) classification is in use now, modified and
accepted by the World Health Organization (WHO), which differs
nodular form of lymphocyte predomination and classical Hodgkin’s
lymphoma. Classical HL is divided into nodular sclerosis, lymphocyte predomination, mixed cellularity and lymphocyte depletion. It
was noticed that nodular sclerosis was represented in the majority
of cases, specifically in 16 cases (50.0%), followed by mixed cellularity in 11 patients (34.4%), while the lymphocyte predomination and
depletion were represented in a smaller number. There was a statistically significant difference between the incidence of histopathologic classifications of patients with HL (p = 0.01, p <0.05). Obralić
et. al reported that the most common was nodular type, with the
representation of 40-70%, followed by mixed cellularity (30-50%),
lymphocyte predomination (5-10%) and lymphocyte depletion with
1-5% (15). Our results correlate with the results in the international
literature.
Out of 26 patients with NHL, 16 (61.50%) had B-NHL, and
10 patients (38.50%) T-NHL. Murphy SB, et. al reported the incidence of B-NHL > 60%, or more precisely (65-70%), and of T-NHL
<40%, or more precisely (30-35%) (7). The results of our study
are approximate to the relevant literature. According to the clinical
stage of disease progression, Hodgkin’s lymphoma was classified
by the Ann Arbor classification system. Most new cases were diagnosed in stage II of the disease, 12 (37.50%), then in stage IV, 11
(34.40%), and in stage III, 9 patients (28.10%). There was no cases
of HL diagnosed in the first stage.
Xing PY, et al. noted that patients diagnosed with HL were
28.40% in stage I, 34.80% in stage II, 19.70% and 17.10% in stage III
and IV (16). According to our research, most of Hodgkin’s lymphoma (HL) was diagnosed in stage II and IV, while according to international literature, HL in children was most represented in the first and
second stage. According to the clinical stage of disease progression,
non-Hodgkin’s lymphoma was classified by St. Jude’s classification
system. The highest number of new cases were diagnosed at the
time when they were already in stage II of disease, 13 (50%). There
were 8 (30.80%) patients in stage IV and 5 (19.20%) in stage III.
Adamson P, Murphy RF, et al. reported the results according to stages: I (18%), II (21%), III (43%) and IV (18%) (17).
Non Hodgkin’s lymphoma (NHL) according to our results was
the most represented in stage II, while according to relevant international literature, NHL was the most common in stage III.
CONCLUSION
Clinical diagnostic methods and modern therapy at the Pediatric
Clinic of CCUS contribute to good prognosis for patients suffering
from lymphoma in childhood.
Conflict of interest: none declared.
179
Evaluation of clinical and laboratory characteristics of childhood lymphoma
REFERENCES
1. Büyükpakmukcu M. Non-Hodgkin’s lymphomas. In: Cancer in Children: Clinical
manegment. Fourth Edition, Voute P.A., Kalifa C, Barrett A. Eds. Oxford, Oxford
University Press 1999:119-136.
2. Pizzo A, Poplack GD. Principles of Paediatric Oncology. 5th ed. Philadelphia: Lippincott Williams - Wilkins;2005.
3. Saunders C. Hsu, Monika L. Metzger, Melissa M. Hudson et al. Comparison of
Treatment Outcomes of Childhood Hodgkin Lymphoma in Two US Centers and a
Center in Recife, Brazil. Pediatric Blood Cancer 2007;49(2):139-44.
4. DeVita VT. A selective history of the therapy of Hodgkin’s disease. Br J Hematol
2003; 122(5): 718-27.
5. Thomson AB, Wallace WH. Treatment of paediatric Hodgkin’s disease: a balance
of risks. Eu J Cancer 2002; 38(4):468-77.
6. Vats TS. Pediatric Non-Hodgkin’s lymphomas in children: diagnosis and current
management. Indian Pediatrics 2001; 38(6):583-8.
7. Cairo MS et al. Non-Hodgkin lymphoma in children. In Kufe DW. Cancer medicine
E. 6. London: BC Decker Inc, 2003; 374-87.
8. Hasanbegović E, Šabanović S. The results of Hodgkin lymphoma treatment in children in the period 1997-2006. Bosn J Basic Med Sci. 2008 Feb;8(1):72-5.
9. Pourtsidis A, Doganis D, Baka M, Bouhoutsou D, Varvoutsi M, Synodinou M, et al.
Differences between younger and older patients with childhood hodgkin lymphoma. Pediatr Hematol Oncol. 2013 Sep;30(6):532-6.
10. Pedrosa MF, Pedrosa F, Lins MM, Pontes Neto NT, Falbo GH. Non-Hodgkin’s lymphoma in childhood: clinical and epidemiological characteristics and survival analysis
at a single center in Northeast Brazil. J Pediatr (Rio J). 2007 Nov-Dec;83(6):547-54.
11. Cairo MS et al. Non-Hodgkin lymphoma in children. In Kufe DW. Cancer medicine
E. 6. London: BC Decker Inc, 2003; 374-87.
12.Schwartz CL. The management of Hodgkin disease in the young child. Curr Opin
Pediatr. 2003;15(1):10-6.
13.Vinjamaram S. Diagnosis signs and symptoms, laboratory studies in a patient with
suspected NHL. Sep 20 2006;24(27):4418-25.
14.Ye QD, Pan C, Xue HL, Chen J, Zhou M, Jiang H, ET AL. [Outcomes of 104 children with B-cell non-Hodgkin lymphoma]. Zhonghua Xue Ye Xue Za Zhi. 2013
May;34(5):399-403.
15.Obralić N. Limfomi: Morbus Hodgkin, non-Hodgkin limfomi. U Mušanović M,
Obralić N: Onkologija. Bošnjački institut, Sarajevo, Bosna i Hercegovina, 2002; 373396.
16. Office for National Statistics. Cancer Statistics registrations: Registrations of cancer
diagnosed in 2008, England. Series MB1 no.39.2011.
17. Adamson P, Bray F, Costantini AS, Tao MH, Weiderpass E, Roman E. Time trends in
the registration of Hodgkin and non-Hodgkin lymphomas in Europe. Eur J Cancer.
2007;43(2):391-401.
Reprint requests and correspondence:
Edo Hasanbegovic, MD, PhD
Pediatric Clinic
Clinical Center University of Sarajevo
Patriotske lige 81
71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 33 566 448
Email: [email protected]
Original article
Medical Journal (2014) Vol. 20, No. 3, 180 - 184
Importance of noninvasive markers in the assessment
of portal hypertension as a liver cirrhosis complication
Značaj neinvazivnih markera u procjeni portalne hipertenzije kao komplikacije jetrene ciroze
Nenad Vanis*, Sanjin Glavaš, Amila Mehmedović, Rusmir Mesihović, Nađa Zubčević,
Srđan Gornjaković, Azra Husić-Selimović, Aida Saray, Nerma Zahiragić
Clinic of Gastroenterohepatology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
Timely detection and treatment of complications associated with
liver cirrhosis, including portal hypertension and esophageal varices
results in the improvement of quality of life of already sick patients.
Frequent endoscopic exams are unpleasant for patients due to their
invasive method, and their high costs make additional burden on the
healthcare system. Recent researches have focused on the investigation of sensitivity and specificity of a numerous noninvasive parameters
in the assessment of the presence and size of the esophageal varices,
including the risk of bleeding. The objective of this study was to identify noninvasive parameters obtained through combining laboratory
reports and the results of ultrasound morphometric measures in the
assessment of esophageal varices presence in patients suffering from
liver cirrhosis. Materials and methods: The present study included 40
patients diagnosed with liver cirrhosis and portal hypertension confirmed based on laboratory tests, proximal endoscopy and abdominal
ultrasound. We analyzed the level of ammonia and the number of
platelets in blood as well as presence of splenomegaly. Results: in 90%
of the patients with liver cirrhosis and diagnosed portal hypertension
increased level of ammonia in blood was detected, in over 80% of
them reduced level of platelets in blood was registered, and over 80%
of them suffered from splenomegaly. It was also confirmed that in
over 90% of the referent patients two of the three analyzed parameters deviate from normal reference values. Furthermore, it was confirmed that affiliation to MELD score did not affect the ammonia levels
in serum (p>0,05). Conclusion: in over 90 % of the patients diagnosed
with portal hypertension and esophageal varices at least two of the
three analyzed parameters were present (hyperammonemia, thrombocytopenia and splenomegaly). It was confirmed that affiliation to
MELD score did not affect the ammonia levels in serum.
Pravrovremeno otkrivanje i tretman komplikacija ciroze jetre, među koje spada i portalna hipertenzija, te variksi jednjaka
poboljšava kvalitet života već oboljelih pacijenata. Učestali endoskopski pregledi su zbog invazivnosti pregleda neprijatni za bolesnike, a uz to zbog visoke cijene opterećuju zdravstveni sistem.
U fokusu posljednjihm istraživanja je proučavanje senzitivnosti i
specifičnosti brojnih neinvazivnih parametara u procjeni prisustva i veličine varikoziteta jednjaka, a time i rizika od krvarenja.
Cilj rada bio je identifikacija neinvazivnih parametara dobijenih
kombinacijom laboratorijskih nalaza i rezultata ultrazvučnih
morfometrijskih mjerenja u proceni postojanja varikoziteta jednjaka kod oboljelih od ciroze jetre. Podaci i metode: u studiju je
uključeno 40 pacijenata sa dijagnozom jetrene ciroze i kod kojih
je na osnovu laboratorijskih pretraga, proksimalne endoskopije i
ultrazvučnog pregleda abdomena potvrđena portalna hipertenzija. Ispitivan je nivo amonijaka i broj trombocita u krvi, te prisutnost splenomegalije. Rezultati: kod pacijenata sa cirozom jetre i
dijagnosticiranom portalnom hipertenzijom više od 90% je imalo
povišen nivo amonijaka u krvi, više od 80% smanjen broj trombocita u krvi te više od 80% pacijenata je imalo splenomegaliju.
Također je potvrđeno da kod više od 90% pomenutih pacijenata
dva od analizirana tri parametra odstupaju od referentnih vrijednosti. Potvrđeno je da pripadnost MELD klasi nema uticaja
na vrijednost NH3 u serumu (p>0,05). Zaključak: kod pacijenata
sa portalnom hipertenzijom i variksima jednjaka u više od 90%
prisutna su najmanje dva od posmatrana tri parametra (hiperamonijemija, trombocitopenija i splenomegalija). Potvrđeno je da
pripadnost MELD klasi nema uticaja na vrijednost NH3 u serumu.
Key words: liver cirrhosis, portal hypertension, esophageal varices,
ammonia level
Ključne riječi: ciroza jetre, por talna hiper tenzija, variksi jednjaka, nivo amonijaka
INTRODUCTION
treatment of portal hypertension, significantly influence the patients’
life quality. Clinical importance of portal hypertension is defined based
on the increase of portal pressure gradient to over 10-12mmHg,
(V), given that the physiological value of the portal pressure gradient
amounts to 1-5 mmHg.
Portal hypertension as a complication related to the progression of
liver cirrhosis, is a very important and complex medical issue. Timely
detection and treatment of liver cirrhosis complications, including the
181
Importance of noninvasive markers in the assessment of portal hypertension as a liver cirrhosis complication
Portal hypertension leads to the establisment of portosystemic collaterals and esophageal varices, which are the most common liver cirrhosis complications present in 50 to 80% of cases. Bleeding esophageal varices often occur in the first year after the diagnosis was set (1).
Lethality of variceal bleeding is 17−57% (2−4). The bleeding can be
predicted based on the assessment of the varices size and appearance
(red cherry spots) (5, 6), and the bleeding incidence can be reduced
by application of nonselective beta blockers (7, 8). Furthermore, it is
believed that prophylactic endoscopic variceal ligitation reduces the
incidence of the first variceal bleeding and mortality of the patients
with large varices (9, 10). Accordingly, it is recommended that patients
suffering from liver cirrhoses be subjected to endoscopic screening,
spacifically annual screening is recommended for patients with minor
esophageal varices, and once in two years for patients without varices
( 11,12). However, endoscopic exams are unpleasant for patients due
to their invasive method and their high costs make additional burden
on the healthcare system. Therefore, the researchers have recently
focused on the investigation of sensitivity and specificity of a numerous
noninvasive parameters in the assessment of the presence and size of
the esophageal varices, including the risk of bleeding.
Aim: the aim of this study was to identify noninvasive parameters
obtained through combining laboratory reports and the results of ultrasound morphometric measures in the assessment of esophageal
varices presence in patients suffering from liver cirrhosis.
Conclusion: in over 90 % of patients diagnosed with portal hypertension and esophageal varices at least two of the three observed
parameters (hyperammonemia, thrombocytopenia and splenomegaly)
were present.
MATERIALS AND METHODS
Observational, clinical and retrospective study was conducted
which included 40 randomly selected patients diagnosed with liver cirrhoses of different etiology, hospitalized and treated at Clinic for Gastroenterohepatology of the Clinical Center University of Sarajevo in
the period from 2009 to 2013. There were 65% of male and 35% of
female patients with the average age of 57.18±9,95. The patients most
represented in the sample were in the 60 to 69 age group (34%), while
the least represented were those in the age group from 30 to 39 years
(3%).
All patients were subjected to basic laboratory tests, proximal endoscopy and abdominal ultrasound. In all 40 patients the presence of
different level of oesophageal varices progression was registered, as a
complication associated with portal hypertension. The patients were
selected according to their demographic variables, sex and age, MELD
score, platelet count and level of ammonia in blood, as well as the presence or lack of splenomegaly. With regard to MELD score, platelet
count and level of ammonia in blood the measured values were registered, whereas the presence or lack of splenomegaly was identified.
Based on the measured MELD score, the patients were divided in two
groups which were monitored and compared:
Group 1: Patients with MELD score 0-15, comprising 48% of overall
sample.
Group 2: Patients with MELD score ≥16, comprising 52% of patients.
The average values of MELD score amounted to 17,23±5.9. The
average level of ammonia in blood was 76,3 ±32,1. Hyperammonemia
was present in 84% of patients included in the study.
The average platelet count was 119,7±80,84, while thrombocytopenia (<150) was present in 75% of patients.
The size of patients’ spleen was also registered as well as the presence or lack of splenomegaly. Figure 1 presents the structure of sample
based on splenomegaly presence. Spleen enlargement was registered in
75% of patients from the sample.
25%
Splenomegalia: NE
Splenomegalia: DA
75%
Figure 1 Structure of sample based on splenomegaly
presence.
Given that it would be interesting to examine the cases with deviations in two of three observed values, the patients from the sample
were divided in 4 groups: 0, 1, 2 or 3 symptoms were registered. Figure
2 presents the structure of the sample based on a number of symptoms.
8%
5%
0
1
2
54%
33%
3
Figure 2 Structure of sample based on a number of
symptoms.
The Figure shows the prevailance of patients with all three symptoms present (54%). It is also significant that 87% of patients from the
sample had two or three associated symptoms registered.
Results of the conducted descriptive analyses influenced the testing of
accuracy of hypotesis related to the outspread of thrombocytopenia,
hyperammonemia and splenomegaly in patients diagnosed with liver
cirrhosis and portal hypertension:
Hypotesis 1: hyperammonemia is present in over 90% of patients
with portal hypertension and esophageal varice.
Table 1 shows the test results based on proportion of hyperammonemia in population diagnosed with liver cirrhosis and portal hypertension.
Table 1 Unilateral test based on proportion of hyperammonemia in the basic party.
Value of parameter in sample
Predicted parameter value in population
Standard error
First type error
Level of significance
z theoretic
z empiric
0,85
0,90
0,047
0,05 (5%)
0,95 (95%)
-1,645
-1,064
Given that z empiric > z theoretic, the conclusion is that the set hypotesis can be accepted.
Hypothesis 2: thrombocytopenia is present in over 80% of the patients
with portal hypertension and esophageal varices.
182
N. Vanis et al.
Table 2 shows the test results based on proportion of thrombocitopenia in thepopulation of patients with liver cirrhosis and portal
hypertension.
Table 2 Unilateral test based on proportion of thrombocitopenia in the basic party.
Value of parameter in sample
Predicted parameter value in population
Standard error
First type error
Level of significance
z theoretic
z empiric
0,75
0,80
0,045
0,05 (5%)
0,95 (95%)
-1,645
-1,111
Given that z empiric > z theoretic, the set hypotesis is accepted on
the level of significance of 95%.
Hypotesis 3: splenomegaly is present in over 80% of the patients with
portal hypertension and esophageal varices.
Table 3 shows results of the unilateral test based on proportion
of splenomegaly in population with liver cirrhosis and portal hypertension.
Table 3 Unilateral test based on proportion of splenomegaly in the basic party.
Value of parameter in sample
Predicted parameter value in population
Standard error
First type error
Level of significance
z theoretic
z empiric
0,75
0,80
0,045
0,05 (5%)
0,95 (95%)
-1,645
-1,111
Given that z empiric > z theoretic, the set hypotesis can be accepted
on the referent level of significance.
Hypotesis 4: in over 90% of the patients with portal hypertension and
esophageal varices two of the three analyzed symptoms are present
(hyperammonemia, thrombocytopenia and splenomegaly).
Table 4 shows results of unilateral tests based on proprtion of the
patients with minimum two of the three analyzed symptoms.
Table 4 Unilateral tests based on proportion of the patients with minimum two out of three symptoms in the
basic party.
Value of parameter in sample
Predicted parameter value in population
Standard error
First type error
Level of significance
z theoretic
z empiric
0,75
0,80
0,045
0,05 (5%)
0,95 (95%)
-1,645
-1,111
In this case too z empiric > z theoretic. Accordingly the forth hypothesis is accepted on the level of significance of 95%.
Given the role of the MELD score level in patients with liver cirrhosis and portal hypertension we tested the difference between the
level of ammonia in blood in respect to a previously defined MELD
classification (relatively low (0-15) and relatively high (16 and more)
MELD score). With the purpose of the test results comparison, the
first step was to test the assumption of „normality“. Results of Kolmogorov-Smirnov tests are presented in Table 5.
Table 5 Results of Kolmogorov-Smirnov test for normality
of variables.
NH3
76,30
32,10
0,694
0,721
Means
Standard deviation
Kolmogorov-Smirnov Z
p-value
Based on the obtained p-value we can conclude that the ammonia level in blood satisfy the assumption of normality. In that regard and for
testing the difference in respect to classification based on the level of
MELD score t-test was used for standard difference between the two
independent samples. The results of the test are presented in Table 6.
Table 6 Results of t-test for standard difference of ammo nia based on MELD score classification.
Leven e's test for equality of T-test on the equality of
variances
means
Variable
F
p-value
t
p-value
NH3
Equality
of
0,140
0,710
-0,594
0,556
variances
is
purported
Based on a high p-value (p=0.556>0.05) we can conclude that there
is no significant statistical difference between the ammonia values in
groups with relatively low and relatively high MELD score values. The
results were checked with chi-square test for independence (χ2-test).
Table 7 contains the results of the test application.
Table 7 Results of χ2-test influence on MELD score class
on presence of hyperammonemia.
MELD class
0-15
16 and more
Total
Result of 2 - test
No
4
2
6
Hyperammonemia
Yes
15
19
34
Total
19
21
40
2
=1,040
p-value=0,308
Given that p-value is over 0,05, it is confirmed that the affiliation to
MELD class did not affect the values of ammonia.
DISCUSSION
Liver cirrhosis is a chronic and progressive disease leading to development of portal hypertension, and development of esophageal
varices is the most important complication of portal hypertension.
Patients diagnosed with liver cirrhosis should be regularly monitored
for the presence of esophageal varices, if the presence of portal hypertension has been identified. Given that esogastroduodenoscopy is
an invasive and costly examination, and with a view of disburdening the
endoscopic units, recent investigations have been focused on noninvasive markers for assessment of probability of the presence and level of
esophageal varices. It is very important to identify the risk of bleeding
esophageal varices with the assistance of noninvasive markers.
The present study included examinees-patients diagnosed with liver cirrhosis, of different etiology, with verified esophageal varices. Statistical analyses of the results showed that majority of male population
(65%) was represented in the sample, the represented age structure
was from 60 to 69 years (345), whereas the age structure from 30 to
39 (3%) was the least represented which corresponds to range of the
most represented liver cirrhosis in population.
The total sample was divided in two groups, according to MELD
score, with over half of the patients from the sample (52%) having
Importance of noninvasive markers in the assessment of portal hypertension as a liver cirrhosis complication
a relatively high MELD score (over 16). The presence of hyperammonemia was registered in 85% of examinees of the total sample,
whereas the presence of thrombocytopenia was registered in 75%
of the patients. Splenomegaly was registered in 75% of the patients
from the sample.
Taking into account the role of MELD score level in patients diagnosed with liver cirrhosis and portal hypertension the difference was
analyzed between the level of ammonia in blood in respect to previously defined MELD classification (relatively low (0-15) and relatively
high (16 and more) MELD score).
In over 90% of the patients with portaql hypertension and esophageal varices at least two of the three observed symptoms were present (hyperammonemia, thrombocytopenia and splenomegaly). It was
confirmed that affiliation to MELD class did not affect the ammonia
values (p>0,05).
It is evident that there is a clear correlation between the existence
of esophageal varices and increased level of ammonia in blood, and
the reduced number of platelets in blood. Furthermore, it is evident
that high percentage of the patients with the confirmed esophageal
varices suffer from spenomegaly.
In the past investigations, the most frequently used noninvasive
parameters were the number of platelets and splenomegaly. Specifically, Zaman et al. showed that patients with a platelet count under
88000/mm3 are five times more at risk of the existance of more expressed esophageal varices as opposed to patients with higher platelet
count (13). Nq FH, et al. have identified the correlation between the
existence of ascites, thrombocytopenia, hyperbilirubinemia and larger
varices in Chiness population (14). Chalasani N, et al. have also established that trombocitopeny and splenomegaly are predictors of largest
varices, where the platelet count with the highest discriminatory significance was 68000/mm3 (11).
Splenomegaly and hypersplenism are common in patients diagnosed with liver cirrhosis with portal hypertension (11), and thrombocytopenia is a normal manifestation of hypersplenism with high specificity, but low sensitivity for the presence of portal hypertension (15).
It is believed that thrombocytopenia mechanism is primarily sequestration and holding of platelets in enlarged spleen. However, Madhotra et al. established tha 32% of patients may have platelet count under
68 000/mm3 without detectable spelomegaly, which is explained with
the reduced syntesis of thrombopoetin in these patients (12). Furthermore, it was established that level of thrombopoetin and platelet count are normalized following liver transplantation (16). Other
possible factors for this phenomena are the existence of anti-platelet
antibodies in circulation and platelet – connected immunoglobulins,
which can be found in patients with liver diseases (17).
On the other hand, based on ultrasound measurements of craniocaudal projection of liver it was established that it is liable to a small
intra and inter- observatory variability unlike Doppler assessment
of the hepatic diameter (18,19). Integration of the two parameters,
platelet count and size of the ultrasound assessed spleen, resulted in
a new pathophysiology significant parameter, which can be easily calculated and applicable in clinical practice. In their retrospective and
prospective study Giannini et al. (20, 21) have showed that this index
is sensitive for predicting the presence and size of varices. The same
group of authors consider that the use of noninvasive parameters in
diagnostic algoritm is useful primarily for identification of patients not
suffering from esophageal varices. Based on the study results these
183
authors have presented cutoff value of their index of 909. In other
words, patients with index over 909 should not receive prophylactic
treatment with beta- blockers, given that there is a small probability
for these patients to suffer from esophageal varices. These patients
should only occasionally be subjected to endoscopic examination,
which is of great medico-social importance. Also, ultrasound parameters obtained through doppler assessment of hepatic diameter are
used for the assessment of portal hypertension.
The results of these studies are contradictory, but it is considered
that congestive index, obtained by division of speed of flow in port
vein and diagonal section of port vain (22- 24), as well as hepatic arterial pulsatility index (25), are in correlation with the level of portal hypertension. Hovewer, doppler ultrasound examination require better
training and ultrasound equipment with better technical possibilities.
In the present study combined laboratory and ultrasound parameters
were used in correlation with the presence of esophageal varices, and
it was confirmed with high sensitivity and specificity that in over 90%
of patients with portal hypertension and esophageal varices at least
two of the three observed parameters (hyperammonemia, thrombocytopenia and splenomegaly) were present. It was confirmed that
affiliation to MELD class did not affect the ammonia values in serum.
This study contributes to investigation of prediction of esophageal
varices presence, which has significant clinical implications.
CONCLUSION
In over 90% of patients with portal hypertension and esophageal varices at least two of the three observed parameters (hyperammonemia, thrombocytopenia and splenomegaly) were present.
It was confirmed that affiliation to MELD class did not affect the
ammonia values in serum.
It is proper to use these parameters, both individually and in combination, as criteria for the selection of patients for endoscopic
screening for esophageal varices, requiring further endoscopic treatment or monitoring.
Conflict of interest: none declared.
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Reprint requests and correspondence:
Nenad Vanis, MD, PhD
Clinic of Gastroentereohepatology
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone: + 387 33 297 911
Email: [email protected]
Professional article
Medical Journal (2014) Vol. 20, No. 3, 185 - 190 Antimicrobial susceptibility of common isolated
microorganisms in hip surgical wound
Antimikrobna osjetljivost najčešće izolovanih
mikroorganizama iz hirurških rana kuka
Tarik Muharemović¹*, Mersiha Bašić-Muharemović², Šukrija Zvizdić3, Sadeta Hamzić3
General Hospital „Prim. Dr Abdulah Nakaš“, Kranjčevićeva 12, 71000 Sarajevo, Bosnia and Herzegovina,
Institute for the Protection of Women and Motherhood of Canton Sarajevo, Josipa Vancaša 1, 71000 Sarajevo, Bosnia and Herzegovina,
3
Faculty of Medicine, University of Sarajevo, Čekaluša 90, 71000 Sarajevo, Bosnia and Herzegovina
1
2
*Corresponding author
ABSTRACT
Introduction: the development of orthopedics and traumatology
results in an increase of surgical procedures, which consequently results
in an increase of complications in terms of surgical wound infection.
There was a prevailing opinion that if patients survive the operation,
and if infection and sepsis occurs, death was almost inevitable consequence. Changes requiring surgical treatment on the hip are usually
trauma, but also a large number of congenital and acquired hip diseases.
The most frequent postoperative complication is wound infection. Infection of surgical wounds has been a significant problem since the existence of surgery. Infection of surgical wounds (Surgical Site Infections,
SSIS) is an infection that occurs 30 days after the surgery, and one year
after the implantation of operating foreign body (implant), in the part
of the body where the surgery was performed. The Center for Disease
Control and Prevention (CDC) has defined three types of these infections, adding recently a fourth type: incision, surface, deep and organic
infections. Antibiotic prophylaxis elected should act on the most common causes of surgical-site infections, but not necessarily on all possible
causes. Materials and Methods: the study is a prospective–retrospective, clinical-microbiological study, performed at the General Hospital
„Prim. Dr. Abdulah Nakaš“ in Sarajevo, from January 2007 to April
2012. The study involved the patients observed and surgically treated
at the Department of Orthopedics and Traumatology of the General Hospital „Prim. Dr. Abdulah Nakaš“ in Sarajevo. The target group
consists of 60 subjects of both sexes and different age. Each patient included in the survey was subjected to microbial processing of biological
materials taken in a standard way, prepared and microscoped. Results:
all 60 patients were divided into groups according to their diagnoses, of
which 23 (38.33%) patients were diagnosed with femur neck fracture,
15 (25.00%) with pertrochanteric fracture, 11 (18.33%) patients with
coxarthrosis, 5 (8.33%) with intertrochanteric fracture, 3 (5.00%) with
subtrochanteric fracture and 3 (5.00%) patients had other diagnosis.
Results of microbiological analysis of the number of agents from the
surgical wound, showed that one type of microorganism caused the infection detected in 50 (83.3%), and two infection agents in 10 (16.7%)
patients. Of the total of 50 patients with microbiologically proven one
type isolates from hip surgical wounds, 23 (46.0%) were diagnosed
with femoral neck fracture, 11 (22.0%) patients were diagnosed with
coxarthrosis, 9 (18.0%) with pertrochanteric fracture, 4 (8.0%) with
intertrochanteric fracture, and 3 (6.0%) with subtrochanteric fractures,
etc. Conclusion: the fracture of the femoral neck is the most common
type of injury or disease in which the microorganism is isolated from
the hip surgical wounds. Implantation of subtotal hip prosthesis is the
most common type of surgery in which microorganisms are isolated
from hip surgical wounds. The majority of patients were over 80 years.
The most common microorganism isolated from hip surgical wounds
was Acinetobaceter spp., followed by Staphylococcus aureus. Isolated
strains Acinetobaceter spp showed the highest antimicrobial susceptibility to Imipenem with 84.6%, and the highest antimicrobial resistance
to ciprofloxacin with 92.6%. Isolated strains of Staphylococcus aureus
expressed the highest antimicrobial susceptibility to vancomycin and
amikacin with 100.0%, and the highest antimicrobial resistance to sulfometoksazol-trimetoprim with 75.0%. Pseudomnas aeruginosa isolated
strains showed the highest antimicrobial susceptibility to cefazolin, with
100.0%, and the highest antimicrobial resistance to cefuroxime, ceftriaxon, cefotaxime and sulfometoksasol-trimetoprim, with 100.0%.
Key words: hip surgical wound, wound infections, antimicrobial susceptibility
SAŽETAK
Uvod: razvojem ortopedije i traumatologije povećava se broj operativnih zahvata, s čime se povećava i broj komplikacija u smislu infekcije hirurških rana. Prije je vladalo mišljenje, ako pacijenti i prežive
operaciju, te ako nastupi infekcija i sepsa, smrt je bila gotovo neizbježna posljedica. Promjene koje zahtijevaju hiruški tretman na zglobu
kuka su najčešće traume, ali i također veliki broj prirođenih i stečenih
bolesti kuka. Kao najčešća postoperativna komplikacija spominje se
infekcija rane. Infekcija hirurške rane je značajan problem od kada
postoji hirurgija. Infekcija hirurških rana (eng. Surgical Site Infections,
SSIs) je infekcija koja se javlja 30 dana nakon operativnog zahvata,
odnosno godinu dana nakon operativne ugradnje stranog tijela (implantata), na dijelu tijela na kojem je izvršena operacija. Centar za
kontrolu i prevenciju bolesti (Center for Disease Control and Pre-
186
vention, CDC) definirao je tri vrste ovakvih infekcija, a odnedavno
je dodana i četvrta vrsta, površinske, duboke incizijske i organske.
Antibiotik izabran za profilaksu trebao bi djelovati na najčešće uzročnike infekcija hirurškog mjesta, ali ne mora nužno djelovati na
sve moguće uzročnike. Materijal i metode: istraživanje je prospektivno - retrospektivno, kliničko-mikrobiološka studija, izvedena u
Općoj bolnici „Prim. dr. Abdulah Nakaš“ u Sarajevu, u periodu od
pet godina i četiri mjeseca, tj. od januara 2007. godine do aprila 2012.
godine. U istraživanje su uključeni ispitanici operisani i observirani na
Odsjeku za ortopediju i traumatologiju Hirurškog odjeljenja Opće
bolnice „Prim. dr. Abdulah Nakaš“ u Sarajevu. Ciljanu skupinu čini
60 ispitanika, oba spola i različite životne dobi. Od svakog pacijenta
(ispitanika) uključenog u istraživanje vršena je mikrobiološka obrada
bioloških materijala uzetih na standardan način nakon čega se pravio
preparat koji se bojio po Gramu, te mikroskopirao. Rezultati: svih
60 pacijenata podijeljeni su u grupe prema dijagnozama, od čega je
prelom vrata femura imalo 23 (38.33%) pacijenata, peritrohanterni
prelom 15 (25.00%), koksartrozu 11 (18.33%) pacijenata, intertrohanterni prelom 5 (8.33%), subtrohanterni prelom 3 (5.00%) i ostalo 3 (5.00%). Rezultati mikrobiološkog ispitivanja broja uzročnika iz
hirurških rana, pokazuju da je jedan uzročnik infekcije dokazan kod
50 (83.3%), a dva uzročnika infekcije kod 10 (16.7%) ispitanika. Od
ukupno 50 pacijenata sa mikrobiološki dokazanom jednom vrstom
INTRODUCTION
The development of orthopedics and traumatology results in
an increase of surgical procedures, which consequently results in an
increase of complications in terms of surgical wound infection (1).
There was a prevailing opinion that if patients survive the operation, and if infection and sepsis occurs, death was almost inevitable
consequence. Because of that the surgery was reserved only for
life endangered patients. In the late years of the 19th century, with
the advent of Louis Pasteur and application of sterilization methods
by Joseph Lister, surgeons were able to operate with significantly
reduced risk of infection. Consequently, surgeons become more
confident and began to explore the operational procedures in which
they previously were not allowed to engage. Later, in the twentieth
century, administration of the antibiotic prophylaxis has begun (2,3).
Changes requiring surgical treatment on the hip are usually trauma, but also a large number of congenital and acquired hip diseases.
Commonly referred congenital hip disease are:
•Congenital (developmental) dislocation of the hip,
•Epiphiseolisis of the femoral caput,
•Legg-Calve-Perthes disease, etc. (4).
Most frequently referred acquired diseases are:
•Inflammatory diseases (acute septic arthritis, chronic rheumatoid arthritis, tuberculosis of the hip joint, etc.),
•Posttraumatic conditions (femoral neck pseudoarthrosis,
post-traumatic arthrosis of the hip, post-traumatic necrosis of
the femoral head, collum angle changes, etc.),
•Degenerative Diseases (coxarthrosis, hip neurogenic arthropathy, etc.),
T. Muharemović et al.
izolata iz hirurške rane kuka, 23 (46.0%) bilo je sa dijagnozom prelom vrata femura, 11 (22.0%) pacijenata imalo je dijagnozu koksartroza, 9 (18.0%) imalo je dijagnozu pertrohanterni prelom, 4 (8.0%)
bilo je sa dijagnozom intertrohanterni prelom i 3 (6.0%) bilo je sa
dijagnozom subtrohanterni prelom i ostalo. Zaključak: prelom vrata
femura najučestaliji je tip povrede ili oboljenja kod kojeg je izolovan
mikroorganizam iz hirurške rane kuka. Implantacija parcijalne proteze kuka najučestaliji je tip operativnog zahvata kod kojeg je izolovanmikroorganizam iz hirurške rane kuka. Najveći broj pacijenata
bio je starosne dobi preko 80 godina. Najčešće izolovani mikroorganizam iz hirurške rane kuka je Acinetobaceter spp., a potom slijedi
Staphylococcus aureus. Izolovani sojevi Acinetobaceter spp. iskazali
su najvišu antimikrobnu osjetljivost na Imipenem sa 100.0%, a najvišu
antimikrobnu rezistenciju na ciprofloxacin sa 92.6%. Izolovani sojevi
Staphylococcus aureus-a iskazali su najvišu antimikrobnu osjetljivost
na vankomicin i amikacin sa 100.0%, a najvišu antimikrobnu rezistenciju na Sulfometoksazol-trimetoprim sa 75,0%. Izolovani sojevi
Pseudomnas aureus-a iskazali su najvišu antimikrobnu osjetljivost na
cefazolin, sa 100.0%, a najvišu antimikrobnu rezistenciju cefuroxime,
ceftriaxon, cefotaxime i sulfometoksasol-trimetoprim, sa 100.0%.
Ključne riječi: hirurška rana kuka, infekcije rane, antimikrobna osjetljivost
•Other diseases (idiopathic aseptic necrosis of the femoral head
in adults, acetabular protrusion, Coxa saltans, hip chondromatosis, etc.) (4).
The most frequently mentioned postoperative complication is
wound infection (1). Infection of surgical wounds has been a significant problem since the existence of surgery. Surgical Site Infections
(SSIS) are infections that occur not later than 30 days after the surgery, and one year after the implantation of operating foreign body
(implant) in the part of the body where the surgery was performed
(5).
The Center for Disease Control and Prevention (CDC) has defined three types of these infections, recently adding a fourth type
of infection: incision, surface, deep, and organic (6,7).
Nosocomial infections continue to be a major health, economic
and social problem (8). Growing number of surgical procedures in
the area of the hip joint result in an increase of postoperative complications of which infection is the most frequently referred. It is
important to make distinction between superficial wound infection
and deep infection. The rate of deep infections in patients fitted with
orthopedic implants ranges from 0.6 to 2.3% , while the infection
rate in some institutions rnges up to 10% (9). As a possible causes
of infection of surgical wounds of patients undergoing hip surgery,
the most commonly isolated pathogens are certain representatives
of Gram - positive cocci and Gram - negative bacill (10).
Frequently referred Gram - positive cocci are Staphylococcus
aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Enterococcus faecalis, Enterococcus spp, and other, while frequently
referred Gram - negative bacilli are Haemophilus influenzae, Enterobacteriaceae (Escherichia coli, Shigella spp, Salmonella, Enterobacter
spp, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris, Cit-
Antimicrobial susceptibility of common isolated microorganisms in hip surgical wound
187
robacter spp, Hafnia spp, Serratia spp), Pseudomonas aeruginosa,
Acinetobacter spp, etc. Among mushrooms, which are potentially
possible causes of wound infections, the most commonly isolated is
Candida albicans (11).
The most common cause of serious infections of surgical
wounds, affecting not only the skin, is Staphylococcus aureus. It is
estimated that about 50% of severe infections after orthopedic surgical procedures is caused by S. aureus, and about 50% of these infections are caused by methicillin- resistant S. aureus (MRSA), which
is resistant to most antibiotics of certain groups (12,13).
Risk-factors for the development of infections are comorbidities (diabetes, rheumatoid arthritis), extreme obesity, immunosuppressive therapy, older age, use of corticosteroids before surgery,
malnutrition, inadequate sterilization, inadequate handling of sterile
material, concomitant infection or recent surgery. The above risk factors significantly increase the chance of infection after surgery on
the hip (14).
Infections after the hip surgery may occur as early and late infections. Early infections occur, not later than one month following
the operation, and late infections occur more than one month after surgery. Described are also cases when the infection was first
demonstrated several years after surgery (15).
When selecting antibiotics in surgical prophylaxis, it is important
to take into account certain specific circumstances. With pure selective surgical procedure, in which there is no damage to the tissue
that contains the normal micro flora, antibiotics are not indicated. In
these cases, the risk of possible side effects resulting from the application of antibiotics is greater than the benefit of any prophylaxis.
Exceptions are only the procedures in which bone or joint implants
are implanted (16).
Antibiotic prophylaxis elected should act on the most common
causes of surgical-site infections, but not necessarily on all possible
causes. The choice of antimicrobial drug depends mostly on anatomical accommodation of surgical procedure, duration and type of
surgery. In addition, a drug used in prophylaxis should be different
from the drugs used in the treatment of the same anatomical region,
in order to prevent the emergence of bacterial resistance and preserve those drugs which are effective in the treatment of infection
of each anatomical region (17).
The aim of the study is to show the antimicrobial susceptibility
of microorganisms isolated from the hip surgical wounds.
disease, accompanying diseases, etc.
Each patient included in the survey was subjected to microbial processing of biological materials taken in a standard way, prepared and
microscoped (18).
During the wound treatment the collected material was inoculated in culture medium and incubated under appropriate conditions
and for appropriate time. Isolation and identification of infectious
agents was carried out using the standard microbiological methods.
Swabs taken from the relevant biological materials were sown on
blood agar, Endo agar or McConkey agar, and incubated for 24-48
hours at the temperature of 35-37 C. The samples taken were processed in accordance with the primary and secondary microbiological studies. The agents were identified based on the characteristic
appearance of colonies, biochemical and antigenic test strains. For
each isolated microorganism species testing of their antimicrobial
susceptibility / resistance to appropriate antimicrobials was done
(18).
In our study, samples of surgical wounds were not analyzed for
the presence of anaerobic pathogens.
Each of the isolated pathogens is examined by the appropriate
disk diffusion method for its sensitivity / resistance to the appropriate representatives of the group of antimicrobial drugs, the method
according to the Kirby - Bauer by the NCCLS (18). Based on the
collected data the statistical analysis was performed. SPSS 17.0 program for Windows (SPSS Inc., Chicago, IL, USA) was used for the
statistical analysis of the data.
MATERIALS AND METHODS
The study is a prospectively - retrospective, clinical- microbiological study, performed at the General Hospital „Prim. Dr Abdulah
Nakaš“ in Sarajevo, from January 2007 to April 2012. The study involved patients observed and surgically treated at the Department
of Orthopedics and Traumatology of the General Hospital „Prim.
Dr Abdulah Nakas“ in Sarajevo. The target group consisted of 60
subjects of both sexes and different age.
From an objective medical examination, anamnesis and available
medical documentation, insight into the type of disease and injury
was obtained, as well as the type of surgical treatment. In addition,
basic information about the patient was collected as well as information on type of therapy, presence of complications of the underlying
RESULTS
All 60 patients were divided into groups according to their diagnoses, of which 23 (38.33%) patients were diagnosed with femur neck fracture, 15 (25.00%) with pertrochanteric fracture, 11
(18.33%) patients with coxarthrosis, 5 (8.33%) with intertrochanteric fracture, 3 (5.00%) with subtrochanteric fracture and 3 (5.00%)
patients had other diagnosis (Figure 1).
Figure 1 Rate of representation between types of injuries
or illnesses.
From the total of 60 patients treated for isolated microorganisms
from surgical wounds, 21 (35.0%) belonged to the age group up to
74 years, 13 (21.7%) patients belonged to the age group of 75-79
years, while 26 (43.3%) patients belonged to the age group of 80
and over (Figure 2).
188
T. Muharemović et al.
Figure 2 Rate among type of injury or disease by age of
patients.
Table 1 Type of surgical procedure.
TYPE OF SURGICAL PROCEDURE
No.
%
26
43.3
Partial hip repleacement
12
20.0
Osteosinthesis with condylar plate
10
16.6
Total cementless hip repleacement
4
6.7
Total cemented hip repleacement
4
6.7
Osteosinthesis with angular plate
4
6.7
Other procedures
Total
60
100.0
From the total of 60 patients surgically treated for microorganisms isolated from hip surgical wounds, in respect to the type of
surgery, during the investigation there was a total of 26 (43.3%) patients with implantation of partial endoprosthesis, 4 (6.7%) patients
with implantation of total bone cement prosthesis, 10 (16.6%) with
implantation of total prosthesis without bone cement, 12 (20.0%)
patients underwent the surgery osteosynthesis with a condylar
plate, in 4 (6.7%) patients surgery osteosynthesis with angular plate
was performed, while 4 (6.7%) patients were assigned to the group
of other surgical procedures (Table 1).
Results of the microbiological analysis of the number of pathogens isolated from the hip surgical wound showed that one pathogen was proved as a cause of the infection detected in 50 (83.3%)
patients, and two pathogens in 10 (16.7%) patients. Of the total
of 50 patients with microbiologically proven one type isolates from
hip surgical wounds, 23 (46.0%) were diagnosed with femoral neck
fracture, 11 (22.0%) patients were diagnosed with coxarthrosis, 9
(18.0%) with pertrochanteric fracture, 4 (8.0%) with intertrochanteric fracture, and 3 (6.0%) with subtrochanteric fractures, etc.
Of the total of 10 patients with microbiologically proven two
types of isolates from hip surgical wound, 3 (30,0%) patients were
diagnosed with fracture neck of femur, 6 (60.0%) with pertrohanter-
Table 2 Overview of microbial positive isolates (one or two
isolated pathogens).
Femoral neck fractures
Number of isolated microorganism
ONE
TWO
TOTAL
20
3
23
(40.0%)
(30.0%)
Coxarthrosis
11
(22.0%)
0
(0.0%)
11
Pertrohanteric fractures
9
(18.0%)
6
(60.0%)
15
Intertrohanteric fractures
4
(8.0%)
1
(10.0%)
5
Other
6
(12.0%)
0
(0.0%)
6
TOTAL
50
(83.3%)
10
(16.7%)
60
(100%)
TYPE OF INJURY OR DISEASE
nic fracture, and 1 (10,0%) patient with two agents was from the intertrochanteric fracture group (Table 2). It did not happen that two
pathogens causing the hip wound infection were isolated in patients
diagnosed with coxarthrosis.
Out of the total of 70 isolated and identified bacterial isolates,
the most represented was the bacterium Acinetobacter spp in 27
(45.8%) cases, followed by Staphylococcus aureus in 20 (33.9%)
cases, Pseudomonas aeruginosa in 7 (11.9%) cases, Enterococcus
faecalis in 6 (10.2%) cases, Proteus mirabillis in 3 (5.1%) case, Staphylococcus epidermidis in 3 (5.1%) case, and 2 (3.4%) cses with isolates of Klebsiella spp, and 1 (1.7%) isolate of Serratia marcescens
and Streptococcus viridans, respectfully (Figure 3).
Figure 3 Frequency rate of microorganism species isolated
from hip surgical wounds.
Table 3 Results of antimicrobial susceptibility testing of isolated Acinetobacter species strains.
S
Antibiotik
Total tested (100,0%)
No
I
R
%
No
%
No
%
37,0
3
11,1
14
51,9
3,7
14,8
11,1
11,1
7,4
11,1
11,1
23,1
84,6
16,7
1
0
0
0
0
0
0
3
1
6
3,7
0,0
0,0
0,0
0,0
0,0
0,0
11,5
3,8
25,0
25
23
24
24
25
24
24
17
3
14
92,6
85,2
88,9
88,9
92,6
88,9
88,9
65,4
11,5
58,3
80,8
0
0,0
5
19,2
Broj
Amoxicil lin +
10
Clav. Kiselina
27
Ampicilin
27
1
Cefalotin
27 4
Cefazolin
27 3
Cefuroxim
27 3
Ciprofloksacin
27
2
Ceftriaxon
27 3
Cefotaxime
27 3
Gentamicin
26 6
Imip enem
26 22
Sulfometoksazol -trimetoprim
4
24
Meropenem
26
21
Table 4 Results of antimicrobial susceptibility testing on
Staphylococcus aureus isolated strains.
Antimicrobial susceptibility of common isolated microorganisms in hip surgical wound
Table 5 Results of antimicrobial susceptibility testing on
Pseudomonas aeruginosa isolated strains.
S
Antibiotik
Total tested (100,0%)
I
No
%
No
R
%
No
%
Amoxicillin +
Clav. Kiselina
7
3
42,9
2
28,6
2
28,6
Ampicillin
Ampicillin + Sulbactam
Cefalotin
Cefazolin
Cefuroxim
Ciprofloksacin
Ceftriaxon
Cefotaxime
Gentamicin
Imipenem
Sulfometoksaz. -trimetoprim
Meropenem
7
7
7
7
7
7
7
7
7
7
7
7
1
4
1
7
0
1
0
0
1
6
0
6
14,3
57,1
14,3
100,0
0,0
14,3
0,0
0,0
14,3
85,7
0,0
85,7
0
0
0
0
0
0
0
0
2
0
0
0
0,0
0,0
0,0
0,0
0,0
0,0
0,0
0,0
28,6
0,0
0,0
0,0
6
3
6
0
7
6
7
7
4
1
7
1
85,7
42,9
85,7
0,0
100,0
85,7
100,0
100,0
57,1
14,3
100,0
14,3
DISCUSSION
All 60 patients were divided into groups according to their diagnose, of which 23 (38.33%) patients were diagnosed with fracture neck of femur, 15 (25.00%) with peritrohanteric fracture, 11
(18.33%) patients with coxarthrosis, 5 (8.33%) with intertrochanteric fracture, 3 (5.00%) with subtrochanteric fracture and 3 (5.00%)
were diagnoses otherwise. According to a research conducted by
the Department of Health of the State of New York in September
2011, which included 167 hospitals, and where 26,286 hip operations were reported in the period of January-December 2010, the
percentage of infection was 1.12%. The above percentage is related
only to hip aloarthroplastic surgery. Of these 31% were superficial,
42% deep and 27% infection organic space. A similar percentage
was also reported in 2008 and 2009. From the isolated pathogen in
New York, USA, Staphylococcus aureus was the most frequent with
54.4% followed by MRSA with 26.4%, Enterococcus spp with 9.2%,
etc. (19). Most authors still describe the percentage of infection of
1-2%, but it generally refers to a deep infection. Some authors refer
to the percentage of infection of approximately 10%, which is very
rare (20,21,22).
Out of the total of 70 isolated and identified bacterial isolates,
the most represented was the bacterium Acinetobacter spp in 27
(45.8%) cases, followed by Staphylococcus aureus in 20 (33.9%)
cases, Pseudomonas aeruginosa in 7 (11.9%) cases, Enterococcus
faecalis in 6 (10.2%) cases, Proteus mirabillis in 3 (5.1%) case, Staphylococcus epidermidis in 3 (5.1%) case, and 2 (3.4%) cses with isolates of Klebsiella spp, and 1 (1.7%) isolate of Serratia marcescens
and Streptococcus viridans, respectfully.
The percentage of patients with an isolate obtained from the hip
surgical wounds was far greater in the operations that were carried
out immediately due to trauma than in those patients in whom surgery was elective. Infections were common in patients with comorbidity and elderly patients.
Care of the patients who develop surgical site infections after
discharge, is significantly more expensive than the care of the patients without infection, given that the patients with infection visit
the general practitioner and emergency hospital centers 7.5 times
more often, than those without infection. It is therefore necessary
189
to develop a strategy for the prevention of these infections, as well
as all other infections incurred in health care institutions, as part of
national programs developed so far in many countries, aimed at patient safety.
Frequently used ceftriaxone, applied in perioperative prophylaxis, expressed antimicrobial susceptibility in 21 (35.0%) patients,
and cefazolin, a drug that is the method of choice in preoperative
prophylaxis, showed sensitivity in 20 (33.3%) patients.
CONCLUSION
Femoral neck fracture is the most common type of injury or
disease with positive isolate from the hip surgical wounds, represented in 23 (38.3%) cases. Implantation of partial hip endoprothesis is the most common type of surgical procedure in which the
microorganism were isolated from hip surgical wounds, represented
in 26 ( 43.3% ) cases. The largest number of patients aged over 80,
a total of 26 (43.3%), was with positive isolation. Most frequently
isolated microorganism from the hip surgical wounds is Acinetobaceter spp (45.8% of cases), followed by Staphylococcus aureus in
33.9%, Pseudomonas aeruginosa in 11.9% and Enterococcus faecalis
in 10.2% of cases. Acinetobaceter spp isolated strains expressed the
highest antimicrobial susceptibility to Imipenem, with 84.6%, and
the highest antimicrobial resistance to ciprofloxacin, with 92.6%.
Staphylococcus aureus isolated strains expressed the highest antimicrobial sensitivity to vancomycin and amikacin with 100.0%, and
the highest antimicrobial resistance to sulfometoksasol-trimetoprim,
75.0%. Pseudomnas aeruginosa isolated strains showed the highest
antimicrobial susceptibility to cefazolin, with 100.0%, and the highest
antimicrobial resistance to cefuroxime, ceftriaxon, cefotaxime and
sulfometoksasol-trimetoprim, with 100.0%.
Conflict of interest: none declared.
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udžbenike i nastavna sredstva; 1998;533-619.
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Scheckler WE. Infection Control Reference Service. 2nd ed. Philadelphia: W.B.
Saunders; 2001;343-5.
3. Prpić I. et al. Infekcije u kirurgiji za medicinare. Zagreb: Školska knjiga; 2002;58-63.
4. Pećina M. Et al. Ortopedija. Zagreb: Naklada Ljevak; 2004;286-324.
5. Centers for Diesase Control and Prevention, Surgical Site Infection (SSI)
http:/www.cdc.gov/ncidod/dhqp/ FAQ_SSI html (10. Januar 2011).
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razvoj KCUS; 2001;217-219.
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GC, editor. Hospital epidemiology and infection control. Baltimore: Wiliams and
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8. Roy MC, Perl TM. Basic of surgical-site infection surveillance. Infect control Hosp
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19. Van Kasteren ME, Manniën J, Ott A, Kullberg BJ, de Boer AS, Gyssens IC. Antibiotic
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Reprint requests and correspondence:
Tarik Muharemović, MD
General Hospital „Prim dr. Abdulah Nakaš“
Kranjčevićeva 12
71000 Sarajevo
Bosnia and Herzegovina
Email: [email protected]
Bosnia and Herzegovina is high risk region for fatal CVD events!
Bosna i Hercegovina pripada visoko rizičnom regionu za fatalne KV ishode!
Professional article
Medical Journal (2014) Vol. 20, No. 3, 191-193 Five-year work of the birthing unit of the Clinic for Gynecology and Obstetrics; perinatal report
Petogodišnji rad porođajne sale Klinike za ginekologiju i
akušerstvo; perinatalni izvještaj
Mohamad Abou El-Ardat*, Ejub Bašić, Nermin Hadžić, Fatima Gavrankapetanović,
Lejla Imširija, Eldar Mehmedbašić, Amela Hodža
Clinic of Gynecology and Obstetrics of the Sarajevo University Clinical Center, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
The Clinic of Gynecology and Obstetrics of the Clinical Center
University of Sarajevo is a tertiary level of health care with over
3,500 infants born every year. The birthing unit of the Clinic provides 24/7 service throughout the year. It has the most contemporary equipment for vaginal delivery, with 10 beds and rooms for
delivery in the presence of a husband (spause). Also, there are ORs
that can be accessed directly from the delivery room, if required.
This paper provides a presentation of the work of the birthing unit
within the Clinic in the period from 2009 to 2013, frequency of deliveries ending in surgical procedures, manner and number of deliveries, and presentation of other manual methods and interventions
applied during delivery. Over the five year period (2009-2013) a
total of 17,157 women gave birth in the birthing unit of the Clinic of
Gynecology and Obstetrics of CCUS, or to be specific, there were
5.526 (32.21%) Caesarean sections (C-sections) and 11.631 (or
67.79%) vaginal deliveries. Over the five-year period, 17.356 babies
were born in the Clinic of CCUS. Most of the babies were born in
2009. The highest number of twins was recorded in 2013 (n=89),
and triplets in 2010 (n=7). The highest perinatal mortality rate was
recorded in 2013 (7.4 ‰), and the lowest in 2010 (4.3 ‰). In the
last three years, the perinatal mortality was around 7 ‰, which
matches the perinatal mortality rates in European hospitals. Following the period of low birth rate, in the past few years the number
of deliveries in the Clinic recovered, nearing the average from 2009.
The C-section rate is still very high. However, this number stabilized
in 2013 at around 30%, which exceeds all epidemiological indicators.
Perinatal mortality has been stable over the last three years, coinciding with the European Union incidence rate.
Klinika za ginekologiju i akušerstvo Kliničkog centra Univerziteta u Sarajevu (KCUS) predstavlja tercijalni nivo zdravstvene zaštite sa preko 3500
poroda na godišnjem niovu. Porođajna sala Klinike za akušerstvo je organizovana tako da pruža usluge 24h dnevno u toku cijele godine. U porođajnoj sali se nalazi najsavremenija oprema za vaginalni porod, sa ukupno 10
porođajnih kreveta, sa prostorijom za porod uz prisustvo supruga (partnera). U sklopu Klinike za ginekologiju i akušerstvo nalaze se i operacione
sale do kojih se direktno dolazi iz porođajne sale, u hitnim slučajevima.
Ovim istraživanjem je dat detaljni prikaz rada porođajne sale Klinike za
ginekologiju i akušerstvo od 2009-2013 godi-ne, učestalost operativnog
dovršetka poroda, način i broj poroda, te prikaz ostalih manuelnih tehnika
i inetervencija koje su primjenjene tokom poroda. U petogodišnjem periodu (2009-2013. godine) u porođajnoj sali Klinike za ginekologiju i akušerstvo KCUS-a porođeno je ukupno 17157 žena. Od ukupnog broja poroda
carskim rezom je porođeno 5526 (32,21%) žena, a vaginalno je porođeno
11631 (67.79%) žena. U petogodišnjem periodu na Klinici za akušerstvo
KCUS rođeno je 17356 beba. Najveći broj beba je rođen u 2009. godini. Najveći broj gemina je bilo u 2013. godini (n=89), dok je najveći broj
tripleta zabilježen u 2010 godini (n=7). Najveći perinatalni mortalitet je
zabilježen u 2013. godini (7.4‰), a najmanji u 2010. godini (4.3 ‰). Perinatalni mortalitet se kretao u istim vrijednostima od oko 7‰ u posljednje tri
godine što se poklapa sa vrijednostima perinatalnog mortaliteta evropskih
porodilišta. Nakon pada broja poroda, posljednjih godina broj poroda na
Klinici za akušerstvo se oporavlja te se vraća na prosječni broj iz 2009. godine. Procenat carskih rezova i dalje je jako visok, ali je u 2013. godini došlo
do stabilizacije sa prosječnih oko 30%, što prevazilazi sve epidemiloške
parametre. Perinatalni mortalitet je u posljedne 3 godine konstantan te se
podudara sa incidencom porodilišta Evropske unije.
Key words: delivery, Caesarean section, perinatal mortality
Ključne riječi: porod, carski rez, perinatalni mortalitet
INTRODUCTION
officially opened on 25 November 2010. The Birthing Center of the
Clinic of Gynecology and Obstetrics provides 24/7 service throughout the year. It has the most contemporary equipment for vaginal
delivery, with 10 beds and rooms for delivery in a the presence of a
husband (spause).
Also, there are ORs that can be accessed directly from the delivery room in case of emergency.
The Clinic of Gynecology and Obstetrics of CCUS is a tertiary
level of health care with over 3,500 infants born every year. During
the 1992-1995 war, the building of the Clinic was destroyed and the
Clinic was moved to another location within CCUS. In 2010, the
original building of the Clinic in Jezero (Sarajevo) was restored and
192
Figure 1 Delivery room.
For centuries pregnancy has been causing fear of negative outcome for either the mother or the baby. Unfortunately, this was very
common in the past. All of us, who have ever been present at a
delivery, know that there is nothing more natural and normal than a
natural birth. We also know that nothing is abnormal as an abnormal
birth. It is unbelievable how one can become the other in the blink of
an eye (1).
Research objective: thorough presentation of the work of the
Birthing Center within the Clinic of Gynecology and Obstetrics in the
period from 2009 to 2013, frequency of deliveries ending in surgical
procedures, manner and number of deliveries, and presentation of
other manual methods and interventions applied during delivery.
MATERIALS AND METHODS
The research was carried out at the Clinic of Gynecology and
Obstetrics of CCUS in the period from 2009 to 2013. A database
has been created using the data collected from the birthing center, which keeps all delivery-related data (parity, delivery method,
interventions during delivery, information about infants). The data
were entered into MS Excel and then exported to the SPSS software
(v20.0) for statistical analysis. Chi-squared test was used for statistical evaluation of qualitative data.
Research findings: over the five year period (2009-2013) a total of
17,157 women gave birth in the Birthing Center of the Clinic for Gynecology and Obstetrics of CCUS, namely there were 5,526 (32.21%)
Caesarean sections (C-section), and 11,631 (67.79%) vaginal deliveries.
Table 1 Number of deliveries (vaginal–C-section) during
the observed period.
2009
2010
2011
2012
2013
Vaginal delivery
2,809
1,995
2,148
2,101
2,578
%
71.88%
66.68%
64.66%
65.33%
69.32%
No.
1,099
997
1,174
1,115
1,141
C-section
%
28.12%
33.32%
35.34%
34.67%
30.68%
No.
3,908
2,992
3,322
3,216
3,719
Total
%
100.00%
100.00%
100.00%
100.00%
100.00%
The highest birth rate was recorded in 2009 (3,908), and the
lowest in 2010 (2,992). The average number of deliveries during
the period under review was 3,431. The chi-squared test showed a
statistical difference in the number of deliveries during the analyzed
years, χ2=163.577; df=4; p<0.05.
The C-sections rate grew linearly in the period from 2009
(28.12%) to 2011, when the highest number of C-sections was recorded (35.34%). After that, the trend of C-sections began to drop,
especially in 2013 (30.68%).
M. Abou El-Ardat et al.
Graph 1 Number of deliveries during the observed period.
Graph 2 C-section percentage share vs. total number of de liveries.
Table 2 shows the frequency of surgeries per year during the
period under review. The Chi-squared test showed that there was a
statistical difference in the number of surgeries compared to the period under review, χ2=31.118; df=4; p<0.05. The highest number of
surgeries was recorded in 2013 (355), and the lowest in 2010 (222).
It is also important to say that the most usual procedure was manual
exploration of the uterus. Frequency of forceps delivery dropped
over the years and reached zero in 2013.
Table 2 Frequency of obstetric surgical procedures over the
five-year period.
2009
2010
2011
2012
2013
Manual aid – breech birth
12
12
14
15
31
7
2
13
21
30
VE
Forceps
1
3
3
3
0
Manual exploration of
201
163
204
197
244
uterus
Lysis placentae manualis
58
42
53
49
50
Obstetric surgeries - total
279
222
287
285
355
Over the five-year period, 17,356 babies were born in the Clinic
of Gynecology and Obstetrics of CCUS. Most of the infants were
born in 2009. The highest number of twins was recorded in 2013
(n=89), and triplets in 2010 (n=7).
Table 3 Number of infants born during the observed period.
Singleton
Twins
Triplets
The highest preterm birth rate was recorded in 2012 (11.29%),
and the lowest in 2013 (4.65%).
Table 4 Number of full-term and preterm births.
2009
2010
2011
2012
2013
Full-term
3675
2826
3128
2907
3546
Preterm
257
220
237
370
173
6.54%
7.22%
7.04%
11.29%
4.65%
2009
3802
66
1
2010
3405
72
7
2011
3365
72
2
2012
3156
59
1
2013
3628
89
2
Five-Year Work of the Birthing Center of the Clinic for Gynecology and Obstetrics
Statistically speaking, the frequency of infants born weighing between 500 and 1000g remained stable during the observed period.
Table 5 Birth weight overview.
500-1000g
1000-2500g
>2500g
2009
32
257
3643
2010
30
220
2796
2011
33
237
3095
2012
31
240
3006
2013
23
323
3465
The highest perinatal mortality rate was recorded in 2013 (7.4‰),
and the lowest in 2010 (4.3‰). In the last three years, the perinatal mortality was around 7‰, which matches the perinatal mortality
rates in European hospitals.
Graph 3 Perinatal mortality analysis.
193
at 16.65‰ in 1996 and 9.60‰ in 2007 (2). The study on C-Section
and perinatal mortality rate carried out at the Maichin Dom (7) in
Bulgaria in the period from 1976 to 2000 showed that C-section rate
growth from 4.8% to 24.4% reduced the perinatal mortality from
27.7‰ to 11.4‰. In normal pregnancies, perinatal mortality was
between 8 and 11% with a C-section frequency between 15 and
16%. In high-risk pregnancies the perinatal mortality rate remained
the same, but with the C-section frequency it was between 24 and
26%. “No correlation between caesarean section rates and perinatal
mortality of singleton infants over 2,500 g” is a study carried out in
Island, which provided new information about obstetrics trends (8).
Island is one of the countries with the lowest perinatal mortality rate.
The data were collected from the Island birth registry for the period
of 20 years, i.e. 1987-2006. Perinatal mortality stood at ca 2‰ per
annum, ranging between 0.8 and 4.1‰. The C-section delivery rate
ranged between 11.9% and 16.7%, without correlating with the perinatal mortality rate. Among primiparae, the C-section delivery rate
increased from 13.1 to 17.8% without correlating with the perinatal
mortality, which stood at ca 1.7‰.
CONCLUSION
DISCUSSION
The Birthing Center of the Clinic of Gynecology and Obstetrics is
a 24/7 institution staffed with experienced obstetricians. In 2012, at
the Clinic for Gynecology and Obstetrics, 3,216 women gave birth,
of which 35% were subject to C-section. During the 2009-2013 period, 17,157 women gave birth in this Center: 32.21% through C-section, and 67.79% via vaginal birth. The highest number of births was
recorded in 2009, and the lowest in 2010. The highest C-section rate
was recorded in 2011 (35.34%) and the lowest in 2009 (28.12%).
Abadžić’s research findings showed that the number of C-sections in
the Clinic of Gynecology and Obstetrics of the CCUS in 1996 was
8.57%, and 27.75% in 2007. This indicates that the number of C-sections tripled over the 12-year period (2). The growth trend continued in 2012. We have been witnesses of increase in C-section births
in the last few years. When it comes to developed countries, Australia and the USA have the highest C-section rate (28.5% and 29.1%)
(3). Similar trends have occurred in Latin America, especially in Mexico (25.7%) and Brazil (27.9%) and other developing countries including India (Kerala) (21.4%) (4,5). Even though the “optimum C-section
rate” is still a subject of many discussions, the World Health Organization (WHO) has proposed the rate of 15% (5). Fatušić et al.
in their retrospective study carried out in the Clinic of Gynecology
in Tuzla, reviewed the medical documents on C-section deliveries
performed over the course of a five year period (1984-1988). Their
findings showed no C-section epidemics. During that period, 6.47%,
or 1,819 of C-sections were performed. Out of the total percentage,
90.22% (1,641) were unplanned C-sections, while 9.78% (178) were
planned in advance (6). As already stated, during the observed period, 17,356 infants were born. The perinatal mortality rate grew and
stands at 7‰ as of 2011 (the same trend was preserved in 2013). In
her research, Abadžić proved that the perinatal mortality rate stood
Following the period of low birth rate, in the past few years the
number of deliveries in the Clinic of Gynaecology and Obstetrics „recovered“, nearing the average from 2009. The C-section rate is still
very high. However, this number stabilized in 2013 at around 30%,
which exceeds all epidemiological indicators. Perinatal mortality has
been stable over the last three years, coinciding with the European
Union incidence rate.
Conflict of interest: none declared.
REFERENCES
1. Dornan J. Managing Obstetric Emergencies and Trauma course manual; RCOG
press-London; 2007 (Foreword xix;178-179)
2. Abadžić N. Perinatološki parametri i karakteristike gravida porođenih carskim rezom,
Magistarski rad, Medicinski fakultet, Univerzitet u Sarajevu, 2012.
3. Berghela V, Baxter JK, Chauhan SP. Evidence-based surgery for cesarean delivery. Am
J Obstet and Gynecol. 2005;193(5):1607-17.
4. Cesarean section history, US National Library of medicine, Part 1, 2009.
5. Cyr RM. Myth of the ideal cesarean section rate: commentary and historic perspective. Am J Obstet and Gynecol. 2006;194(4): 932-6.
6. Fatušić Z. Minimalna hirurška trauma u toku Carskog reza, Perinatalni dani BiH 2007.
99-109
7. Dimitrov A. Rate of cesarean section and perinatal infant mortality at “Maichin dom”.
Akush Ginekol (Sofia). 2003;42(6):3-6.
8. Jonsdottir G, Smarason AK, Geirsson RT, Bjarnadottir RI. No correlation between
cesarean section rates and perinatal mortality of singleton infants over 2.500 g. Department of Obstetrics and Gynecology, Landspitali University Hospital, Reykjavik,
Iceland. Acta Obstet Gynecol Scand. 2009;88(5):621-3.
Reprint requests and correspondence:
Mohamad Abou El-Ardat, MD
Clinic of Gynecology and Obstetrics
Clinical Center University of Sarajevo
Patriotske lige 81, 71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 33 250 285
Email: [email protected]
Review article
Medical Journal (2014) Vol. 20, No. 3, 194 - 196
Oral precanceroses: clinical histopathological
correlation
Oralne prekanceroze: kliničko patološka korelacija
Dedić A¹*, Hodžić M¹, Avdić M², Hadžić S¹, Pašić E¹, Gojkov-Vukelić M.¹, Kantardžić A¹
1
Department of Periodontology and Oral Medicine, Faculty of Dentistry University of Sarajevo, Bolnička 4a, 71000 Sarajevo, Bosnia and Herzegovina; ²Department of Periodontology, New Mowsat Hospital, Kuwait
*Corresponding author
ABSTRACT
SAŽETAK
Oral precanceroses are on the rise in the world and in our country. Precancerous oral lesions represent morphologically altered tissue in which cancerization occurs at a much higher probability than
in the seemingly unaltered oral mucosa of the contralateral side. This
paper points to a number of etiopathogenetic mechanisms, with a
special focus on the proto-oncogenic and oncogenic mechanisms. The
aim of this paper is to present the clinical-histopathologic correlation
of leukoplakia and lichen. The significance of progression of dysplasia
and strategic diagnostic protocol are important for early detection
of oral precanceroses. With strategic diagnostic protocol and recommendations for doctors, we expect to overcome numerous dilemmas
in the differential diagnosis of oral precanceroses. Sophisticated histopathological methods and a multidisciplinary approach are the gold
standard for exact diagnosis.
Key words: oral precanceroses, oncogene, histopathological findings
Oralne prekanceroze imaju tendencu rasta u svijetu i kod nas.
Prekancerozne oralne lezije označavaju morfološki promijenjeno
tkivo u kojem se kancerizacija pojavljuje s mnogo većom vjerovatnoćom nego u naizgled nepromijenjenoj oralnoj sluznici kontralateralne strane. Rad ukazuje na brojne etiopatogenetske mehanizme
sa posebnim fokusom na protoonkogene i onkogene. Cilj rada je
prezentirati kliničko-patohistološku korelaciju leuko-plakije i lichena.
Značaj progresije displazije i strateški dijagnostički protokol su značajni za ranu detekciju oralnih prekanceroza. Uz strateški dijagnostički
protokol i preporuke za ljekare, očekujemo prevazilaženje brojnih
dilema u diferencijalnoj dijagnozi oralnih prekanceroza. Sofisticirane
patohistološke metode i multidisciplinaran pristup su zlatni standard
za egzaktnu dijagnozu.
INTRODUCTION
antigens in the epithelial cells may be the earliest initial indicators of
premalignant or malignant orientation of the oral epithelium (2).
According to the World Health Organization (WHO), oral precanceroses are divided into: oral precancerous lesions and oral precancerous conditions. Oral precancerous lesions are pathological
changes that can transform into malignant lesions. Precancerous oral
lesions represent morphologically altered tissue in which cancerization occurs at a much higher probability than in the seemingly unaltered oral mucosa of the contralateral side (1).
Possible etiopathogenetic mechanisms for cancerization of oral mucosa
It has been shown that free radicals play the primary role in the
development of premalignant and malignant diseases of all tissues,
including the oral mucosa. Free radicals are byproducts of oxygen
which are released together with the energy necessary for living cells
in the process of oxidation of tissue, and are generally very unstable.
Free radicals can damage all cellular elements. In the initial stages of
premalignant and malignant diseases, they damage the cellular DNA,
and then run a number of cellular reactions which release additional
free radicals. They are constant irritants during the long latency period of development of malignant tumors. Therefore, they are slowly
but surely destroying the affected tissue in the premalignant stage.
The latest research confirms the importance of secretory status in
etiopathogenesis of premalignant and malignant diseases. It is important to note that the differences in the expression of blood group
Ključna riječ: oralne prekanceroze, onkogen, patohistološki nalaz
Oncogenes
Oncogenes are genes whose activities lead to the disturbance of
the regulation of cell division, causing malignant tumors. They occur
through mutation of normal cellular genes, the so-called proto-oncogenes involved in controlling the cell cycle. Protein products of
proto-oncogenes play a key role in the regulation of proliferation
and differentiation of cells. Proto-oncogenes are responsible for autonomous growth of malignant cells that are unresponsive to normal
control mechanisms even without any external growth factors (3).
Proto-oncogenes become oncogenes through translocation or transposition
(1); amplification (2); dotted mutation (3).
From: Pavlica M.,Web udžbenik: Genetika,2012.(2)
195
Oral precanceroses: clinical histopathological correlation
Clinical histopathological correlation
of oral precanceroses
Erythoplakia
Cause unknown;
Smoking is associated with the emergence of erythroplakia
Age: Usually occurs between 50 and 70 years of age
High risk localization: Oral cavity floor, tongue, retromolar region, the soft palate
Histopathology:
Squamous cell carcinoma 50%
High degree of dysplasia or Ca in situ 40%
Mild to moderate dysplasia 10%
Biopsy required
(4,5)
Clinical - histopathological correlation
Erythroplakia – buccal mucosa
Erythroplakia – tongue
Progression of dysplasia
From: Regezi J. A., Sciubba, J. J., Jordan, R. C. K. Oral pathology: Clinical
pathologic correlations. 2008. St. Louis,Mo: Saunders Elsevier (4)
Lichen ruber planus
Erythroplakia - ph finding
Leukoplakia
Risk factors
Smoking, alcohol, nutrition, unknown
Localization: Vestibulum, buccal and palatal mucosa, alveolar
ridge, lips and tongue, oral cavity floor
Locations with a high risk for malignant transformation:
Oral cavity floor > tongue > lips > palate > cheeks > vestibulum >
retromolar region
Age: Usually over 40 years of age
Microscopic diagnosis
Hyperkeratosis - 80%
Dysplasia - 12%
Ca in situ - 3%
(4,6,7)
Cause unknown;
Destruction of basal keratinocytes by T cells
Clinical presentation
Adults; relatively common (0.2-2% of the population); parasites for
a long time
Characteristic white keratosis stretch marks
Form: reticular, erosive (ulcerative), plaque, papular, erythematosus
(atrophic)
Pain: in erosive forms (ocasionally in erythematosus form)
Potential risk for malignant transformation
Increased in erosive forms of lichen (0.4 to 2.5%)
Pathology
Combination of mucositis and hyperkeratosis. IgM deposition in the
basal membrane, and less frequently of IgA and C3
Therapy
Observation, local and systemic corticosteroids, or other immunosuppressive drugs - Levamisole tbl.
(4,8,9)
Clinical - histopathological correlation
Erosive form
of lichen (10)
Bullous form
of lichen (10)
Clinical - histopathological correlation
Proliferative
verrucous
leukoplakia
Hyperkeratosis
Idiopathic
leukoplakia
of the lateral
side of tongue
Mild degree
of dysplasia
Leukoplakia
of the tongue,
cobblestone
form
High degree
of dysplasia
Hyperkeratosis,
lymphocytic infiltrate
and basal
Immunohistochemical
detection of CD3 antigen
with T cell dominance
in the inflammatory
infiltrate (4)
Strategic clinical and diagnostic protocol
Anamnesis
Visual perception
Visual observation
Early detection - Toluidine Blau test
Assessment of quantitative and qualitative salivary status
Native, microbiological and Ph finding of Candida albicans
Clinical - histopathological correlation (efflorescence → biopsy)
Ph finding of dysplasia (mild, moderate, severe)
196
A. Dedić et al.
Idiopathic leukoplakia: Diagnosis and management
CONCLUSION
Early detection of efflorescence initiation is significant in prevention of development of oral precanceroses. Procedures for sophisticated diagnostic histopathological methods constitute fundamental
knowledge and a gold standard relevant in the exact verification of
oral precanceroses. A multidisciplinary approach is a clinical imperative in the treatment of oral precanceroses.
Conflict of interest: none declared.
REFERENCES
From: Regezi J. A., Sciubba, J. J., Jordan, R. C. K. Oral pathology: Clinical pathologic
correlations. 2008. St. Louis,Mo: Saunders Elsevier (4)
Recommendations for doctors
How to identify precanceroses?
Inspection and visualization of efflorescence
Macroscopic morphological characteristics of efflorescence (at the
level of mucosal tissue, below and above the level of mucosal tissue)
Time factor → risk factor → length of efflorescence
White lesions: PLAQ → EROSION → ULCUS → COBBLESTONE
→ NODULES → INDURATION
Imbalance of humoral and cellular immunity
Can not be removed
1. Cekić A. et al. Oralna medicina. Zagreb: Školska knjiga; 2005.
2. Pavlica M. Web udžbenik: Genetika, 2012.
3. Radović S, Dorić M, Tomić-Ćuk I, Babić M, Kuskunović S. Dijagnostičke procedure u
patologiji. Medicinski fakultet Univerziteta u Sarajevu. 2012., Sarajevo
4. Regezi JA, Sciubba, JJ, Jordan RCK. Oral pathology: Clinical pathologic correlations.
2008. St. Louis, Mo: Saunders Elsevier.
5. Reichart PA, Philipsen HP. Oral erythroplakia-a review. Oral Oncol. 2005;41:551-561.
6. Scully C, Sudbo J, Speight PM: Progress in determining the malignant potential of oral
lesions. J Oral Pathol Med. 2003;32:251-256.
7. Zakrzewska JM, Lopes V, Speight P, Hooper C. Proliferative verrucous leukoplakia: a report of ten cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.
1996;82(4):396-401.
8. Boisnic S, Frances C, Branchet MC, Szpirglas H, Le Charpentier Y. Immunohistochemical study of oral lesions of lichen planus: diagnostic and pathophysiologic aspects, Oral Surg Oral Med Oral Pathol. 1990;70(4):462-5.
9. Barker JN, Mitra RS, Griffiths CE, Dixit VM, Nickoloff BJ. Keratinocytes as initiators
of inflammation. Lancet 1991;337:211-214.
10. Dedić A. Autoimune oralne bolesti: praktikum. Sarajevo: Institut za naučnoistraživački rad i razvoj KCUS; 2010.
- Monitor the efflorescence
- Control check-ups (every 3 months)
- Continuous motivation and education for oral hygiene
- Risk factors - smoking, alcohol, UV rays - CAUTION
- Medications - side effects - CAUTION
- Complete dental treatment of the patient until prosthetic restoration (fixed prosthetics) (10).
This strategic doctrinal code of ethics and diagnostic
aims at overcoming the many dilemmas in differential
diagnosis of precancerous lesions
Erythroplakia
of the tongue
Squamous
carcinoma
of the tongue
Reprint requests and correspondence:
Amira Dedić, MD, PhD
Department of Periodontology and Oral Medicine
Faculty of Dentistry in Sarajevo
University of Sarajevo
Bolnička 4a
71000 Sarajevo
Bosnia and Herzegovina
Phone:+387 33 214 249
Email: [email protected]; [email protected]
Case report
Medical Journal (2014) Vol. 20, No. 3, 197-199 Staged surgical treatment of combined osteoarticular
and vascular injury of the shoulder
Fazni hirurški tretman kombinovane koštano zglobne i
vaskularne ozljede ramena
Amel Hadžimehmedagić1*, Ismet Gavrankapetanović2, Haris Vranić1,
Mehmed Jamakosmanović2
Clinic for Cardiosurgery, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina, 2Clinic for Orthopedics
and Traumatology, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
1
*Corresponding author
ABSTRACT
SAŽETAK
This case report describes a staged surgical treatment of combined osteoarticular and vascular injury of the right shoulder. Initial
surgical treatment at Trauma Department of the Regional Hospital
failed. Humeral head was still out of joint, axillar artery suture caused
acute arterial occlusion, and brachial plexus was compressed so the
patient was referred to our hospital. After completed diagnostics
surgery was indicated. Our plan was to resolve both injuries in two
stages so we decided to proceed with the operative treatment of the
vascular injury in the first stage, and postpone final fracture treatment for the second stage. Implantation of reversible shoulder endoprosthesis was postponed until it was evident that neurovascular
recovery was achieved. In the treatment of these combined injuries
we recommend staged procedure.
Prikaz slučaja opisuje fazni hirurški tretman kombinovane koštano-zglobne i vaskularne ozljede desnog ramena. Primarni hirurški tretman
u regionalnoj bolnici nije dao zadovoljavajući rezultat. Glavica humerusa je
i dalje zauzimala izvanzglobnu poziciju, a neadekvatan šav aksilarne arterije
je izazvao akutnu arterijske okluziju i kompresiju brahijalnog pleksusa, te
je pacijent je upućen u našu bolnicu. Nakon kompletiranja dijagnostike indiciran je hirurški tretman. Naš plan je osmišljen tako da se hirurški zbrinu
obje povrede, ali u dvije faze, tako smo odlučili da se vaskularne ozljede
zbrinu u prvoj fazi, i odloži tretman završne obrade loma za drugu fazu.
Implantacija ramene endoproteze je odgođena do momenta kada je bilo
nedvojbeno da je postignut potpuni neurovaskularni oporavak. U tretmanu ovakvih kombinovanih povreda preporučujemo faznu proceduru.
Key words: humeral neck fracture, axillary artery lesion, arthroplasty
INTRODUCTION
Proximal humeral fractures represents only 5% of all fractures
seen at the emergency departments, and 15% of them are associated with axillary artery and nerve structures injuries (1). This injuries
can lead to heavy bleeding, neurological palsy and severe perypheral
limb ischemia. Early diagnosis and exact treatment is fundamental
for the restoration of peripheral circulation and motor function.
Possibility of unexpected intraoperative events and problematic
outcome, implicates to have high index of suspicion when dealing
with proximal humeral fractures even when typical clinical signs of
neurovascular injury are absent (2). This is even more difficult when
history of blunt low-energy trauma is present in a healthy young
patient. This report involves a patient suffering from osteoarticular
and associated neuro-vascular injury of the right shoulder.
CASE REPORT
A 31 year old male sustained an anatomical humeral neck frac-
Ključne riječi: prelom vrata humerusa, lezija aksilarne arterije, artroplastika
ture after blunt trauma, falling from height (Figure 1).
Figure 1 Anteroposterior radiograph at regional medical
center after initial procedure.
198
Initial treatment was performed in a regional medical center two
weeks before admission to our hospital. According to a written report, initially absent clinical signs of associated neurovascular injury
led to conservative treatment and Dessault immobilization for two
days. Unsuccessful conservative treatment and immobilization was
followed by surgical treatment of humeral head migrated in the axillary fossa. When the conservative treatment failed, open reduction
and stabilization of the fracture was indicated. In such position sharp
bony fragment lacerated the mid-portion of the axillary artery and
made complete compression of the axillary vein.
Surgical approach to the fracture site revealed vascular lesion
and severe bleeding which resulted in a direct suture of arterial
vessel wall. This was followed by unsuccessful attempt to perform
reduction of the humeral head. This "unexpected" intraoperative
diagnosis of vascular injury caused a switch in surgical plan and the
patient was referred for a final treatment at Clinic for Orthopedic
and Traumatology of the Clinical Center University of Sarajevo.
Pulselessness, signs of the first degree forearm ischemia, and
compromissed deep venous blood flow were noticed at the admission. Signs of mild neurological injury with generalized motor
weakness in the arm, neuropraxia of the brachial plexus, were also
present. MRC scale 2 was found most likely due to direct consequences of the injured artery. We explaned it primarelly by ischemic syndrome and due to developing hematoma causing swelling
and compression on the nerve structures placed in common fascial
sheath. No other motor deficiency was detected in the right arm.
The patient suffered from severe pain as a result of a swollen
and tender shoulder. The x-ray confirmed fracture dislocation with
the humeral head migration into the axillary fossa (Figure 2).
Figure 2 Anteroposterior radiograph at admission showing
head dislocation into axillary fossa.
MATERIALS AND METHODS
Transfemoral angiography showed 6 cm length of interruption
of the arterial tree at the midportion level of axillary artery with rich
blood vessel collateral network feeding distal arterial tree (Figure 3).
Upon evaluation of clinical and radiological findings, two staged
surgery was suggested. We concluded that dislocated humeral head
A. Hadžimehmedagić et al.
Figure 3 Angiogram showing complete obliteration of the
flow through right axillary artery.
still positioned in the axillary fossa caused segmental arterial thrombosis with complete obliteration of the flow after the initial suture of
the vessel wall. The likelihood of the avascular necrosis was high and
preoperative strategy was to remove humeral head and perform
vascular reconstruction of the vessel in the first stage.
Figure 4 Intraoperatively taken image showing a vascular necrosis of humeral head.
We used the same surgical approach through the deltoid-pectoral groove. As expected, approach to humeral head showed its avascular necrosis due to lasting dislocation in axillary fossa (Figure 4).
Once the humeral head was removed an extensive arterial bleeding
occurred. Bleeding was control by clamping after extending the surgical approach along Morencheim line through the pectoral muscle.
After resection of the damaged and trombosed segment of artery
(4 cm in length), an arterial reconstruction was performed using
synthetic graft (PTFE 7 mm in diameter). Interposition of the graft
was done in a usual way by a proximal and distal termino-terminal
eversive anasthomosis using Prolen 6/0 suture.
Postoperatively a normal radial artery pulse was found. Signs
of ischemia, cyanosis and venous obstruction were resolved, with
Staged surgical treatment of combined osteoarticular and vascular injury of the shoulder
only mild paresthesias present. The patient was discharged with a
"hanging shoulder" and the second stage treatment was postponed
until a neurological and a vascular recovery was confirmed with angiography and EMG (Figure 5).
Figure 5 Angiogram taken upon neurovascular recovery
showing functional synthetic graft.
A follow up angiogram (Figure 5) showed a potent graft and
”hanging shoulder”. Twelve weeks after the first stage we performed
the second stage surgical treatment. By using lateral approach to the
shoulder, total arthroplasty was done with hydroxyl apatite coated
cementless reverse total endoprosthesis (total reverse endoprosthesis Lima LTO s.p.a) (Figure 6).
Figure 6 Anteroposterior radiograph showing reverse
shoulder endoprosthesis in place.
Postoperatively the shoulder was placed in 0°- abduction, 0°rotation and in sling for 2 weeks. Recovery was assisted by physiotherapy with the aim to achieve active-assited flexion/abduction up
to 90°, avoiding external rotation and with 45° of internal rotation.
Unrestricted motion was allowed after 8 weeks when active flexion
was 70°, abduction 95°, internal rotation 30° and external rotation
20°. Patient was pain free, clinical examination and radiograph taken
199
showed no loosening. Neurovascular status of the right arm was
equal when compared to the other non-injured arm.
DISCUSSION
Proximal humeral fractures represents only 5% of all fractures
seen at the emergency departments, and 15% of them are combined
with neurovascular injury. Treatment of uncommon injuries provided in inexperienced medical center reveals several pitfalls that could
and should be avoided in the future and by that provide favorable
treatment outcomes for the patient. In order to avoid delay in diagnosis and reduce risk of increasing severity of the injury, Doppler
ultrasound scanning initially and arteriography if necessary should be
routinely part of the initial procedure when dealing with proximal
humeral fractures (3,4). This diagnostic procedure, along with close
clinician follow up is necessary in patients suffered from proximal humeral fractures even when no significant clinical signs of neurovascular injury are present (4,5).
CONCLUSION
When dealing with major neurovascular artery injury secondary
to displaced proximal humeral fractures requiring arthroplasty we
recommend staged procedure, where major vascular injury involving arterial reconstruction should be resolved first, followed by final
treatment of the fracture involving arthroplasty in the second stage.
Furthermore, follow up of this and other similar reported cases will
in the future give us better and long term results in the cases in
which primary implantation of reverse shoulder endoprosthesis was
performed.
Conflict of interest: none declared.
REFERENCES
1. Palm DS, Parikh PP, Schoonover B, Lebamoff D, McCarthy MC. Axillary arterial entrapment and brachial plexus injury due to proximal humeral fracture. Injury Extra.
2013;44(8):67–69.
2. Goyal VD, Sharma V, Kalia S, Sehgal M. Axillary Artery Injury Caused by Fracture of Humerus Neck and Its Repair Using Basilic Vein Graft. Case Rep Surg.
2014;2014:430583.
3. Stenning M, Drew S, Birch R. Low-energy arterial injury at the shoulder with progressive or delayed nerve palsy. J Bone Joint Surg Br. 2005;87(8):1102–6.
4. Yagubyan M, Panneton JM. Axillary artery injury from humeral neck fracture: a rare
but disabling traumatic event. Vasc Endovascular Surg. 2004;38(2):175–84.
5. Modi CS, Nnene CO, Godsiff SP, Esler CN. Axillary artery injury secondary to
displaced proximal humeral fractures: a report of two cases. J Orthop Surg (Hong
Kong). 2008;16(2):243-6.
Reprint requests and correspondence:
Amel Hadžimehmedagić, MD, PhD
Clinic for Cardiosurgery
Clinical Center University of Sarajevo
Bolnička 25
71000 Sarajevo
Bosnia and Herzegovina
Phone:l +387 33 297 682
Email: [email protected]
Case report
Medical Journal (2014) Vol. 20, No. 3, 200-202 Perivascular epithelioid cells tumor; case report of uncommon clear cell neoplasm ligamentum teres uteri
Perivaskularni epitelioidni stanični tumori; prikaz
slučaja neuobičajene svijetlostanične neoplazije
ligamentum teres materice
Faika Mujanović-Glamočanin1*, Spahić Amir2
Department for Gynecology and Obstetrics, Cantonal Hospital Travnik, Kalibunar bb, 72270 Travnik, Bosnia and Herzegovina,
Department for Pathology, Public Hospital Travnik, Kalibunar bb, 72270 Travnik, Bosnia and Herzegovina
1
2
*Corresponding author
ABSTRACT
SAŽETAK
Neoplasms with perivascular epithelioid cell differentiation are mesenchymal tumors that consist of histologically and immunohistochemically different perivascular epithelioid cells (PEComa). PEComa are
described in different organs and are considered to be widely present
tumors. Clinical presentation is not specific and accurate preoperative
diagnosis is hard to achieve. PEComa can be very aggressive disease
and lead to appearance of metastasis even after couple of years. At this
moment surgical resection appears to be the most adequate manner
of treatment, while radiotherapy and chemotherapy (without surgical
resection) did not show significant results. Case report in our study describes a patient with non specific symptoms, extreme general weakness
and CT scan showing large tumor mass in projection of right ovary.
Final diagnosis was made after surgery by histopathological analysis with
immunochemical profile. According to the WHO data 200 cases of this
neoplasm was described so far, and this was the first case documented
in Bosnia and Herzegovina.
Neoplazme sa perivaskularnom epitelioidnostaničnom diferencijacijom (PEComa) su mezenhimalni tumori sastavljene od histološki i imunohistohemijski različitih perivaskularnih epitelioidnih stanica. PEComi
su opisani u različitim organima i smatraju se sveprisutnim tumorima.
Klinička prezentacija nije specifična i tačnu preoperativnu dijagnozu
je teško odrediti. PECom može biti vrlo agresivna bolest i dovesti do
metastaza i nakon nekoliko godina. Hiruško odstranjenje tumora za
sada se čini najadekvatnijim načinom liječenja, dok samo chemio i radio terapija (bez hiruškog tretmana) nisu pokazali značajne rezultate.
Prikaz slučaja u našoj studiji je pacijentica sa nespecifičnim simptomima, izražene opšte slabosti organizma i CT prikazom velike tumorske
mase u projekciji desnog jajnika. Do konačne dijagnoze PEComa dođe
se postoperativno patohistološkom i imunohistohemijskom analizom.
Prema podacima WHO do sada je objavljeno 200 slučajeva ove naoplazme, a predmetni slučaj je prvi registrovani u Bosni i Hercegovini.
Key words: perivascular epithelioid cells tumor, mesenchymal tumors
INTRODUCTION
The term PEComa as a concept was firstly introduced by Zamboni in 1996, and in 2003 the WHO defined PEComa as a mesenchymal tumor. One hypothesis states that the neoplasm is derived from undifferentiated neural crest cells with smooth muscle
cells and melanocytes. The second assumption is that a PEComa
has myoblastic origin, and the third one that it is of pericytic origin. Neoplasms with perivascular epithelioid-cell differentiation are
mesenchymal tumors composed of histologically and immunohistochemically different epithelioid perivascular cells (1,2,3).
The family of neoplasms with perivascular epithelioid-cell differentiation includes:
•angiomyolipoma (AML)
•clear cell “sugar” lung tumor (CCST),
•lymphangioleiomyomatosis (LAM),
•clear cell myomelanocytic tumor of falciform ligament / ligamentum teres (CCMMT),
Ključne riječi: perivaskularni epitelioidni stanični tumori, mezenhimalni tumori
•uncommon clear cell tumors.
Up to date PEComa were described as pancreas, rectal, abdominal serosa, uterine, external female genital organs, and thigh and
heart tumors. Some of these lesions according to the WHO classification were listed as renal (AML), liver (AML) and lung (CCST,
LAM) tumors.
Epidemiologically, neoplasms with perivascular epithelioid cell
differentiation are extremely rare. In 80-90% of cases they occur in
women of 46 years on average. There are reports for approximately 200 neoplasms with perivascular epithelioid cell differentiation
(4,5,6,7,8,9).
Neoplasms with perivascular epithelioid cell differentiation
(PEComa) which were previously reported developed in retroperitoneum, abdominal-pelvic region, uterus and gastrointestinal
tract. Clinically, clear cell myomelanocytic tumors of the falciform
ligament / ligamentum teres (CCMMT) are presented as painful abdominal mass. Uterine PEComa are presented with a vaginal bleeding. Other neoplasms with a perivascular epithelioid cell differenti-
Perivascular epithelioid cells tumor; case report of uncommon clear cell neoplasm ligamentum teres uteri
ation (PEComa) are basically painless masses. Clinical presentation
is nonspecific, and therefore the exact diagnosis is difficult to make.
Accurate diagnosis requires histopathology and immunohistochemical analysis, and it is set following surgical procedure. Grade of tumor malignancy is determined by the tumor size; (larger than 5 cm)
mitotic activity (higher than 1/50 HPF) and necrosis (10). Immunohistochemical PEComa demonstrates expression of the myogene
and melanocytic marker, such as HMB45, HMSA-1, Melan A/ Mart,
Mitf and actin. Surgical treatment followed by chemotherapy and
radiotherapy shows significant results.
CASE REPORT
Patient R.A, 50 years old, in menopausal age.
Personal history: patient is complaining of weakness during the
last year, weight loss of about 20 kg, pain in lower abdomen, sedimentation rate test rises to three digit values (125/135), and chronic sideropenic anemia. Cervical cone biopsy performed five years
ago (CIN III), patient was positive to hepatitis C antigen.
Gynecological finding: multipara, vaginal portion of the uterus
shows scaring, uterus is visualized with right adnexa, size of baby
head, can be moved, left tube and ovary shows no pathological
changes.
Abdominal CT prior to surgical procedure: in the area of right
ovary there is a clearly marked area of soft tissue density which in
contrast sequence receives contrast medium and its central parts
are hypodense. The diameter of this area is 65x60 mm. Urine bladder has normal position, shape and width of the wall. Parenchymatous organs and digestive tube without changes. There are no
pathologically enlarged nodes along large blood vessels.
Work diagnosis: Tumor ovarii lateris dextri.
Surgical procedure was suggested and performed: Tumerectomia. Hysterectomia totalis abdominalis cum adnexectomiam bill.
Surgical finding: between right ovary, uterine fundus and posterior
wall of the urine bladder there is a tumor, size about 10 cm, closely
linked to all surrounding organs and especially to the urine bladder
wall, in a shape of cauliflower, of fragile consistency. Surgically primary location of the tumor can not be precisely defined.
After the surgery patient received the course of antibiotics, analgesics and fluid compensation, Clivarin 0,25, and three doses of full
blood type „O“ RhD negative.
Postoperative course went without complications, patient afebrile, regular diuresis, peristaltic returned.
Surgically removed tumor mass consisted of grayish tissue particles, of moderately hard consistency and homogenous structure
with area of necrosis and hemorrhage with the largest tissue sample
size measuring 85x50x20mm, and the smallest one 10x5mm.
Microscopically, perivascular epithelioid cells (PECs) are characterized with perivascular location, often with radial pattern of
the cells around the blood vessel lumen while the stroma among
the aggregates of the neoplastic cells is scarce and infiltrated with
abundant inflammatory cells dominated with lymphocytes (Figure
2). Typically, perivascular epithelioid cells in immediate perivascular
localization are mostly epithelioid and spindle cells that remind of
smooth muscle cells. Most of the changes had relative relation of
epithelioid and spindle cells (Figure 1).
201
Figure 1 PEComa. Ratio of epithelioid and spindle cells
(H&E, x10).
Figure 2 PEComa. Perivascular radial pattern PECs (H&E,x10).
Perivascular epithelioid cells (PECs) have clear to granular, slightly eosinophilic cytoplasm, round to oval nuclei with small nucleoli, even though hyperchromasia and irregularity of nuclei is visible
(Figure 4). Tumor cells demonstrate emphasized nuclear atypia,
frequent mitotic activity and presence of necrotic degenerative
changes (Figure 3). Perivascular epithelioid cells (PECs) form nest
like architecture (Figure 1, Figure 4).
Figure 3 PEComa shows a picture of atypia, pleomorphism of nuclei with coarse chromatin, small nucleoli and mitoses (HE, x20).
Figure 4 PEComa has clear to granulated, easily eosinophil- ic cytoplasm (HE,x20).
202
Single perivascular epithelioid cells (PECs) demonstrate emphasized pleomorphy in their forms with large nuclei of vesicular
and bizarre shapes, granular chromatin with prominent one or
two nucleoli and frequent mitotic activity (6MF/10HPF) (Figure3).
Immunohistochemical profile of neoplastic cells demonstrate positivity to Vimentine and SMA, respectively focal positivity to S-100,
HHF35 and Calponin (courtesy and approval of Professor Svjetlana Radovic, Institute for Pathology, Faculty of Medicine, University of Sarajevo). Following the obtained histopathological diagnosis
of neoplastic mass the patient was referred to the Oncologist who
prescribed chemotherapy and radiotherapy after cystoscopy and
abdominal CT.
Cystoscopy: regular finding.
Abdomen CT: no residual disease, urinary bladder normal position, form, size, width of the wall. After urination negligible amount
of residual urine.
Gynecological finding: palpatory and in specula normal findings.
Vaginal scar regular finding. PAP smear showed inflammation.
Applied chemotherapy: VI Taxotera cycles a 120 mg, Gemcitabin
1600 mg with standard hydration and premedication and post-medication. During IV cycle patient had neutropenia, pretibial edema
and diarrhea. After diuretic therapy with potassium, antibiotics, B
vitamin the chemotherapy was resumed.
Applied radiotherapy: irradiated lesser pelvis with box isocentric
technique with TT 46 Gy, and endocavitary boost on HDR with TD
20 Gy.
Control CT of the abdomen: no secondary metastatic changes.
Laboratory findings were within referral ranges.
Gynecological finding and control cystoscopy showed no pathological findings. Patients felt well, no complaints, gained 20 kilograms.
Further treatment: control visits to Oncologist and Gynecologist
every six months.
DISCUSSION
Neoplasms with perivascular epithelioid cell differentiation are
mesenchymal tumors that consist of histologically and immunohistochemically from different perivascular cells. There are reports by
the WHO for approximately 200 neoplasms and up to date there
has been no reports of this neoplasm in Bosnia and Herzegovina.
Cases of this neoplasm were reported in uterus, falciform ligament,
small and large intestines, pancreas and pelvic wall respectively in
vulva, thigh and heart, while this report describes a case of PEComa in retrovesical area with intimate relation to surrounding organs.
Clinical symptoms were non specific. Location of the tumor was
established before the surgical procedure via CT scan of pelvis and
abdomen and after that a surgical procedure was done based on
the work diagnosis: Tu ovarii lat.dex. During the surgery a primary
location of the tumor could not be established due to the intimate
contact with urinary bladder, uterus and right ovary, and it was reported that the tumor was located in retrovesical area. The urinary
bladder wall remained intact during the surgery and the uterus was
detached from the tumor and surgically removed. Tumor size was
about 10 cm. Histologically it had mitotic potential and areas of necrosis pointed to the highly malignant mass.
After the surgical procedure, followed by histopathological diagnosis with immunohistochemical finding and completed oncologi-
F. Mujanović-Glamočanin et al.
cal treatment which obviously gave favorable results, general status
of the patient was satisfying, taken into account referral laboratory
blood findings, brining the weight back to normal values and no recidive and no metastasis of this neoplasm. Patient is still under the
supervision of the Gynecologist and Oncologist.
CONCLUSION
There are difficulties in therapeutical work due to the rare nature of the disease and therefore an international study is needed to
resolve this issue.
Conflict of interest: none declared.
REFERENCES
1. World Health Organization Classification of Tumours 2013, Pathology & Genetics,
Tumours of Soft Tissue and Bone, Chapter 9: Tumours of Uncertain Differentiation
221-223.
2. World Health Organization Classification of Tumours 2002, Pathology & Genetics,
Tumours of Soft Tissue and Bone, Chapter 9: Tumours of Uncertain Differentiation
221-223.
3. Beak JH, Chung MG, Jung DH, Oh JH. Perivascular epithelioid cell tumor (PEComa)
in the transverse colon of an adolescent: a case report. Tumori. 2007; 93(1):106-8.
4. Folpe AL, Kwiatkowski DJ. Perivascular epithelioid cell neoplasms: pathology and
pathogenesis. Hum Pathol. 2010;41(1):1-15.
5. Bonetti F, Martignoni G, Colato C, Manfrin E, Gambacorta M, Faleri M, et al. Abdominopelvic sarcoma od perivascular epithelioid cells. Report of four cases in
young women, one with tuberous sclerosis. Mod Pathol. 2001;1486):563-8.
6. Goh SG, Ho JM, Chuah KL, Tan PH, Poh WT, Riddell RH. Leiomyomatosis-like
lymphangioleiomyomatosis of the colon in a female with tuberous sclerosis. Mod
Pathol. 2001;14(11):1141-6.
7. D´Andrea V, Lippolis G, Biancari F, Ruco LP, Marzullo A, Wedard BM, et al. A uterine pecoma: a case report. G Chir. 1999;20(4):163-4.
8. Folpe Al, Goodman ZD, Ishak KG, Paulino AF, Taboada EM, Meehan SA, Weiss SW.
Clear cell myomelanocytic tumor of the falciform ligament/ligament teres: a novel
member of the perivascular epithelioid clear cell family of tumors with a predilection for choldren and young adults. Am J Surg Pathol. 2000;24(9):1239-46.
9. Folpe AL, McKenney JK, Li z, Smith SJ, Weiss SW. Clear cell myomelanocytic tumor
of the thigh: report of a unique case. Am J Surg Pathol. 2002;26(6):809-12.
10.Tazelaar HD, Batts KP, Srigley JR. Primary extrapulmonary sugar tumor (PETS): a
report of four cases. Mod Pathol. 2001;14:615-22.
Reprint requests and correspondence:
Faika Mujanović-Glamočanin, MD
Department for Gynecology and Obstetrics
Cantonal Hospital Travnik
Kalibunar bb
72270 Travnik
Phone: +387 61 726 000
E-mail: [email protected]
Case report
Medical Journal (2014) Vol. 20, No. 3, 203 - 204
Blunt chest trauma and pericardial tamponade
Tupa trauma grudnog koša i tamponada perikarda
Dragan Milošević1*, Duško Golić1, Dragan Rakanović1,Vojislav Vujanović1, Dušan Janičić2
Clinic of Anesthesia and Intensive Care, Clinical Center Banja Luka, Zdrave Korde 1, 78000 Banja Luka, Bosnia and Herzegovina,
Clinic of Thoracic Surgery, Clinical Center Banja Luka, 12 beba 1, 78000 Banja Luka, Bosnia and Herzegovina
1
2
*Corresponding author
ABSTRACT
SAŽETAK
Blunt chest trauma can cause a spectrum of cardiac injuries,
ranging from asymptomatic arrhythmias to rupture of the cardiac
chambers or great blood vessels. Pericardial tamponade is an acute
life-threatening complication of blunt chest trauma with a high mortality rate despite aggressive treatment. It is generally accepted that
early recognition, prompt diagnosis and immediate treatment of cardiac tamponade are critical for survival of those patients. The case
in our study was a male, aged 44, admitted to ICU after blunt chest
trauma, 40 minutes after an accident.
Tupa trauma grudnog koša može izazvati širok spektar srčanih
ozljeda, od asimptomatskih aritmija do rupture srčanih šupljina i velikih krvnih sudova. Tamponada perikarda se javlja kao jedna od akutnih
- životno ugrožavajućih komplikacija tupe traume i praćena je visokim
mortalitetom uprkos agresivnom tretmanu. Opšte prihvaćen stav je
da su rano prepoznavanje, brza dijagnostika i hitan tretman presudni
za preživljavanje ovakvih pacijenata. Slučaj iz naše studije je muškarac,
44 godine star, primljen u JIL nakon tupe traume grudnog koša, četrdeset minuta nakon incidenta.
Key words: blunt chest trauma, pericardial tamponade, early recognition, treatment
Ključne riječi: tupa trauma grudnog koša, tamponada perikarda,
rana dijagnoza, tretman
INTRODUCTION
ography showed no signs of pulmonary effusion, pneumothorax or
broken ribs. ECG showed microvoltage, central venous pressure
was 22 mmH2O. Paradoxal pulse was present. Complete blood
count and urine output was normal. Haemodynamic instability was
still present and we reasonable suspected pericardium tamponade
and decided to perform surgergical procedure, specifically the left
thoracotomy. Initial treatment and diagnostic procedure took twenty minutes.
In the operating theatre, before induction of anesthesia, arterial blood pressure was 76/46 mmHg, heart rate 135 bpm, oxygen
saturation 89%. For premedication we used fentanil 100 mcg, and
“crush” induction technique with barbiturate, succinil holin, and rapid intubation with double lumen endotracheal tube (“left” tube). The
patient’s position was right lateral due to performing left antero-lateral thoracotomy. Fluid resuscitation was performed with caution
due to the presence of cardiogenic shook (Hartman sol.500 ml).
After thoracotomy and collapsed left lung, the surgeon performed
pericardiocentesis with fenestration and got approximately 300 ml
of hemorrhagic fluid from the pericard. From that moment patient’s
condition rapidly improved with established haemodynamic stability TA 135/89, mmHg, heart rate 90 bpm, ECG normovoltage
and central venous pressure 13 mmH2O. There were no signs of
miocard trauma. After double chest drainage, and chest closing, the
laparoscopic exploration of abdominal cavity was performed wich
confirmed the ultrasound examination result. Following the surgical
procedure the patient was awaken at ICU, with hemodynamic stability. The following day the patient was transferred to the thoracic
surgery department with stabile vital signs. On the third and fifth
postoperative day the thoracic drain was extracted, and ten days
Trauma is a leading cause of death, morbidity and hospitalisation in developed civilisations. According to the USA data trauma is
responsible for one hundred tousand deaths per year (1). The same
source indicates that incidence of chest trauma is 12 on one million population per day, with 33% of them requiring hospitalisation.
Chest trauma causes 50% motrality in polytrauma patients, of whom
25% accounted for blunt chest trauma (1,2).
Blunt chest trauma can affect one or more structures of chest: wall,
ribs, clavicula, sternum, thoracic cavity with pleura, lungh, tracheobronchial elements, esophagus, heart and great blood wesseles (2).
High central venous pressure, low arterial pressure, silent heart
sounds – classic signs of pericard tamponade, are not allways present,
and can be unreliable signs in life treatened polytrauma patients (3).
CASE REPORT
A male, aged 44, was admitted at ICU after blunt chest trauma,
forty minutes after an accident at work (he was hit in the chest by a
trunk). Upon the admission he was conscious, hypotensive (80/50
mmHg), tachycardic (130 bpm), tachypnoic (respiratory rate 22/
min), with swollen neck vessels, auscultator clear respiratory sound,
silent heart sound, and oxygen saturation 90%. We perform initial
treatment of polytrauma (oxygen via mask, kristalloid infusion 1000
ml), with radiographic and ultrasound examination of the thoracic
and abdominal cavity. Ultrasound evaluation of abdominal and chest
showed no presence of fluid, parenchymal organs preserved echo
structure, while pericard was not suitable for analysis. Chest radi-
204
after the accident he was discharged from hospital.
The surgical procedure lasted for approximately 50 minutes,
and the overall time from the accident to postoperative time at ICU
amounted to less than two hours.
Figure 1 Left thoracotomy, pericard fenestration.
DISCUSSION
Pericardium tamponade is an acute life-threatening condition requiring percutaneous or surgical pericardiocentesis (4). Existing signs
of cardiac tamponade may be unreliable, and the presence of normal clininical parameters can not exclude cardiac tamponade development. Initial chest radiography is not reliable in many cases, and
even the ultrasound examination, despite its high specifity (90%), is
not always superior diagnostic procedure (5-9). These procedures
may delay urgently needed surgical intervention. Laboratory findings
in many cases may show normal values. CK levels determination has
low sensitivity, specifity and low positive predictive values (9,10).
D. Milošević et al.
REFERENCES
1. Centres for Disease Control and Prevention. Accidents/Unintentional Injuries.
CDC Web site. Available at: http://www.cdc.gov/nchs/FASTAT/acc-inj.htm. Accessed May 2013.
2. Goalay TJ, Dente CJ, Feliciano DV. Toso vascular trauma at an urban level I trauma
center. Prespect Vasc Surg Endovasc Ther. 2006;18(2):102-12.
3. Varahan SL, Farah GM, Caldeira CC, Hoit BD, Askari AT. The double jeopardy of
blunt chest trauma: a case report and review. Echocardiography 2006;23(3):235-9.
4. Karmy-Jones R, Jurkovich GJ, Nathens AB, Shatz DV, Brundage S, Wall MJ Jr, et al.
Timing of urgent thoracotomy for hemorrhage after trauma: a multicenter study.
Arch Surg. 2001 ;136(5):513-8.
5. Cook AD, Klein JS, Rogers FB, Osler TM, Shackford SR. Chest radiographs of
limited utility in the diagnosis of blunt traumatic aortic laceration. J Trauma.
2001;50(5):843-7.
6. Paydar S, Johari HG, Graffarpasand F, Shahidian D, Debhozorgi A, Ziaeian B, et
al. The role of rutine chest radiography in initial evaluation of stable blunt trauma
patients. Am J Emerg Med. 2012;30(1):1-4.
7. Breen JF. Imaging of pericardium. J Thorac Imaging. 2001;16(1):47-54.
8. Chirillo F, Totis O, Cavarzerani A, Bruni A, Farnia A, Sarpellon M, et al. Usefulness of
transthoracic and transoesophageal echocardiography in recognition and management of cardiovascular injuries after blunt chest trauma. Heart. 1996;75(3):301-6.
9. Ansari MZ, Chaudhry MA, Signal A, Joshi R. Unusual cardiac injury following blunt
chest trauma. Eur J Emerg Med. 20018(3):229-31.
10. Sybradni KC, Cramer MJ, Burgersdijk C. Diagnosing cardiac contusion: old wisdom
and new insights. Heart. 2003;89(5):485-9.
11.Fitzgerald M, Spencer J, Johnson F, Marasco S, Atkin C, Kossmann T. Definitive
management of acute cardiac tamponade secundary to blunt trauma. Emerg Med
Australas. 2005;17(5-6):494-9.
12.Baum VC. The patient with cardiac trauma. J Cardiothorac Vasc Anesth
2000;14(1):71-81.
CONCLUSION
Fundamental history, rapid available diagnostic based on clinical
condition, and inability to establish hemodinamic stability after fluid
resuscitation are sufficient for a reasonable doubt accompanied by
urgent surgical treatment as a basic condition for survival (11,12).
Physicians who treat polytraumatic patients must think about possibility of cardiac tamponade developing. The time is a very important
facor, which in our case was less than two hours from the accident
to postoperative treatment at ICU (4). It depense on functioning of
all the links in the chain from the first aid to intrahospital treatment.
Pericardium tamponade is an acute life – threatening condition, relatively easy to treat when timely recognised.
Conflict of interest: none declared.
Reprint requests and correspondence:
Milošević Dragan MD, MSc
Clinic of Anesthesia and Intensive Care
Clinical Center Banja Luka
Zdrave Korde 1
78000 Banja Luka, RS
Bosnia and Herzegovina
Phone:+387 51 343 238
Email: [email protected]
Case report
Medical Journal (2014) Vol. 20, No. 3, 205 - 207
A heart murmur which saved a life
Šum na srcu koji je spasio život
Amir Omerbašić1*, Mirsad Đugum1, Mirela Tuce1, Aida Kriještorac1, Edin Omerbašić2,
Mirza Halimić2
„Poliklinika Atrijum“, Džemala Bijedića 185, 71000 Sarajevo, Bosnia and Herzegovina,
Heart Center, Clinical Center University of Sarajevo, Bolnička 25, 71000 Sarajevo, Bosnia and Herzegovina
1
2
*Corresponding author
ABSTRACT
SAŽETAK
A 45-year old female appears with symptoms of breathlessness and rapid fatigue which has progressed. She is diagnosed
with COPD (chronic obstructive pulmonary disease), anemia and
anxiety-depressive syndrome. She takes bronchodilators and iron
supplements but does not feel any better. With auscultation a
pansystolic murmur grade 2/6 is found in the tricuspid valve area
without progression to other areas. Echocardiography reveals a
gigantic tumor that takes up almost the entirely left atrium and
partly protrudes into the left ventricle. Within an hour the patient
was operated. The tumor was removed entirely, with dimensions
of 7x5x4 cm, connected with a thin stem to the interatrial septum.
Postoperative the patient feels very well.
Pacijentica, 45 godina, javlja se sa simptomima otežanog disanja i
brzog zamaranja koji progrediraju, te je šest mjeseci vođena pod dijagnozom HOBP–a (hronične opstruktivne bolesti pluća), anemije i
anksiozno-depresivnog sindroma. Prethodno pacijentica bez ikakavih kliničkih simptoma. Istoj se ordiniraju bronhodilatatori i preparati
željeza nakon kojih se pacijentica ne osjeća bolje. Auskultacijom srca
čuje se pansistolni šum stepena 2/6 u području trikuspidne valvule bez
širenja. Ultrazvukom srca otkriva se gigantski tumor koji zauzima skoro
u cjelosti lijevu pretkomoru i jednim svojim dijelom prolabira u lijevu
komoru. U roku od jednog sata od postavljanja dijagnoze pacijentica
biva operirana. Operativnim zahvatom se odstrani tumorska masa u
cjelosti, dimenzija 7x5x4 cm koja je bila vezana tankom peteljkom za
interatrijalni septum. Postoperativni tok prolazi uredno.
Key words: Left atrial myxoma, echocardiography, heart murmur
Ključne riječi: Miksom lijevog atrija, ehokardiografija, srčani šum
INTRODUCTION
tole, partially obstruct the inflow of blood to the ventricles, or may,
depending on body position (left side body position) completely and
permanent obstruct the valve, resulting drop of pressure and/or
short–term loss of consciousness. They, however, can fully let the
blood flow into the ventricle, if the patient lies horizontally on the
back, which means that these patients tolerate that position of the
body much better than those one who have a real mitral stenosis
(5). Auscultatory finding, called “tumor plop”, is a typical low - frequency noise, which can be heard at the beginning or middle of
diastole and seems to arise due to a sudden stop of the tumor after
hitting the wall of the chamber. Myxoma may be clinically manifested
with peripheral or pulmonary embolism, as well as with general signs
or symptoms that include fever, weight loss, cachexia, weakness, arthralgia, rash, thickened fingers, Raynaud’s phenomenon, hypergammaglobulinemia, anemia, polycythemia, leukocytosis, increased sedimentation, thrombocytopenia or thrombocytosis. Not surprisingly,
the myxoma is often mistakenly diagnosed as endocarditis, collagen
vascular disease or tumors outside the heart (6).
Two-dimensional transthoracic or transesophageal echocardiography is useful in the diagnosis of cardiac myxoma and allows the
determination of localization of the tumor and its size, which is very
important while planning surgical removal.
The method of choice in the treatment of patients with myxoma is surgical removal of the tumor with cardiopulmonary bypass.
Primary benign tumors account for about 75% of all tumors of
the heart, of which 27% are endocardial myxoma, 75% are with the
localization in the LA. Myxoma are the most common type of primary tumors of the heart, they occur in all age groups, they make
one-third to one-half of all cases of tumors found at the autopsy
and about three-quarters of all tumors treated surgically. Very often they are found in patients “post–mortem” after a stroke. The
diagnosis is not always easy to set up because of its uncharacteristic
symptoms. Atrial myxoma are often associated with the processes
of embolization in 30–40% of cases. They are more often represented in middle–aged women (1,2,3,4).
Pathological, myxoma have a gelatinous structure, composed of
myxoma cells immersed in the stroma which is rich with glycosaminoglycans, with an average diameter of 4-8 cm. Most are solitary
tumors localized in the atrium, especially the left one, where they
grow near the fossa ovalis attached to the interatrial septum. In
most cases myxoma are represented with obstructive, embolic or
constitutional signs and symptoms. The most common clinical presentation mimics mitral valve disease or stenosis due the prolapse
of the tumor through the mitral valve or mitral regurgitation due a
trauma caused by the tumor. Depending on their weight, shape and
insertions, the tumor can rhythmically and intermittently in the dias-
206
A. Omerbašić et al.
Myxoma recurrences occur in approximately 12–22 % in hereditary
forms and about 1–2% in other forms. Recurrence of the tumor
probably arises because of multifocal lesions in the first and inadequate resection in another form.
CASE REPORT
We present a case of a 45 year old female who was scheduled
for a medical examination because of breathlessness and rapid fatigue. Further investigation discovered that the patient had a weight
loss of 10 kg within the last 6 months, she often felt palpitations and
bloating in the stomach. The symptoms were present for six months
during which the patient went to several medical examinations in different institutions of health and was diagnosed with COPD (chronic
obstructive pulmonary disease) and anemia. After taking bronchodilators and iron supplements, which were prescribed from different
doctors, she didn’t feel any better and was afterwards diagnosed
with anxiety - depressive syndrome. During the physical examination in our clinic a pansystolic murmur grade 2/6 was found in the
tricuspid valve area, without further progression to other areas. This
heart murmur was not found until then and it was a indication for
us to do a transthoracic echocardiography (TTE). Blood pressure
(120/80 mmHg), heart rate (62/min) and ECG of the patient were
normal.
Figures 1, 2 and 3 show a large left atrial mass attached to the
interatrial septum with severe mitral insufficiency.
Figure 1
Figure 2
Figure 3
Echocardiography revealed a gigantic tumor, with dimensions of
67 x 53 mm, that took up almost the entirely left atrium and partly
protruded into the left ventricle. Tumor mass followed the kinetics
of the left ventricle and gave the impression that it was connected
with a thin stem to the interatrial septum. Dimensions of the left
atrium were slightly increased (LAD 4.8 cm) with the presence of
severe mitral regurgitation, moderate tricuspid insufficiency, pulmonary hypertension and a small pericardial effusion.
An emergency surgery was performed. The tumor was removed entirely, with dimensions of 7.0 x 5.5 x 4.0 cm, connected
with a thin stem to the interatrial septum. Histopathologic analysis
confirmed a myxoma.
Figure 4 shows the extracted tumor from the left atrium.
Figure 4
Postoperative the patient had episodes of atrial fibrillation that
were successfully treated with cardioversion after which the patient
was in a permanent sinus rhythm without need for a pace maker and
without any symptoms.
DISCUSSION
Left atrial myxoma gives a different clinical picture and can imitate a range of cardiovascular diseases. The clinical picture depends
on the localization, mobility and size of the tumor (7). Symptoms
may be completely missing, but sudden death is also possible. Myxoma of the heart is often followed by a series of general symptoms
207
A heart murmur which saved a life
and nonspecific laboratory tests, so-called paraneoplastic syndrome.
Fatigue, periodic fever, weight loss, joint pain and skin rash often appear. In this case, the patient did not show characteristic symptoms
of atrial myxoma even though he had such dimension.
Sometimes the occurrence of shortness of breath (dyspnea),
coughing and coughing up blood (hemoptysis) is possible. Fatigue,
malaise and edema of the lower extremities is common. Sometimes
accumulation of free fluid in the abdomen (ascites), dizziness and
fainting appears (8). The patient in this case presented only shortness of breath and fatigue and misled the doctors to think more of
a respiratory problem rather than cardiovascular one.
Although „tumor plop“, a late diastolic murmur, is usually found
in the case of left atrial myxoma, we heard a pansystolic murmur
grade 2/6 because of its large dimensions.
Laboratory test are not specific and can show leukocytosis, anemia, increased sedimentation, CRP and interleukin 6. Our patient
had only anemia.
Diagnosis is based on ultrasound findings (echocardiography),
transthoracic as in our case, or transesophageal , and finally confirmed by pathological examination.
CONCLUSION
This case shows a patient who was misdiagnosed only due lack
of basic methods of physical examination, in this case, auscultation
of the heart. Auscultation of the heart is a very important part of
the physical examination that can not be left out. Each newly discovered heart murmur should undergo a ultrasound of the heart
in order to timely detect difficult diagnosis. In this case we want to
emphasize the importance of basic physical examination and ultrasound of the heart as a primary method of testing the origin of any
heart murmur. The importance of this case lies in the fact that a
myxoma tends to embolic incidents and sudden cardiac death and
as such should be promptly detected and removed. This case is also
significant because the gigant tumor mass did not make any embolic
process or lead to sudden cardiac death, which is very rare for a
myxoma with such large dimensions.
Conflict of interest: none declared.
REFERENCES
1. Arhiva pacijenata Poliklinika Atrijum, Sarajevo 2013. godina
2. Arhiva pacijenata KCUS – Centar za srce, Sarajevo 2013. godina
3. Jurilj R, Božić I. Ehokardiografija: Bolest endokarda. Medicinska naklada Zagreb
2007;14:326.
4. Harrison TR, et al. Načela interne medicine. Oboljenja kardiovaskularnog sistema.
Izdanje 15, Beograd i Banja Luka 2004;240:1373.
5. Burke AP, Virmani R. Cardiac myxoma: a clinicopathologic study. Am J Clin Pathol.
1993;100(6):671-80.
6. Vrhovac B, et al. Interna medicina. Kardiovaskularni sistem: Tumori srca. Zagreb
1997; V.12:699
7. Internet stranica: http://www.stetoskop.info/Miksom-srca-1029-c37-sickness.htm
8.Internet stranica: http://www.simptomi.rs/index.php/bolesti/17-tumori-i-maligne-bolesti/645-miksom-miksomi-tumo-tumori-srce-srca-leva-pretkomoa-trijalni-simptomi-medicina-zdravlje-lekar-trudnoca-bolesti-ishrana-dijeta-dijagnoza-uzrok-posledica-lecenje-terapija-beograd-srbij
Reprint requests and correspondence:
Amir Omerbašić, MD
Poliklinika Atrijum
Džemala Bijedića 185
71000 Sarajevo
Bosnia and Herzegovina
Email: [email protected]
Our contribution to the reduction of cardiovascular diseases in Bosnia and Herzegovina!
Naš prilog redukciji kardiovaskularnih bolesti u Bosni i Hercegovini!
Case report
Medical Journal (2014) Vol. 20, No. 3, 208-210 Clinical picture of autoimmune hepatitis and
cholangitis in a pregnant woman during
pregnancy and after delivery
Klinička slika autoimunog hepatitisa i holangitisa
kod trudnice tokom trudnoće i nakon poroda
Lejla Imširija*, Naima Imširija, Sanjin Deković, Fatima Gavrankapetanović,
Edin Idrizbegović
Clinic of Obstetrics, Clinical Center University of Sarajevo, Patriotske lige 81, 71000 Sarajevo, Bosnia and Herzegovina
*Corresponding author
ABSTRACT
SAŽETAK
A primigravida diagnosed with autoimmune hepatitis and cholangitis was monitored at the Clinic where she gave birth on her due
date. During the entire pregnancy she was subjected to regular and
multi disciplinary controls followed by immunosuppressive therapy in
correlation with the liver tests. The required findings were generally
accurate during the entire pregnancy but the expected deterioration
in the liver test findings occurred following the delivery.
Prvorotka sa dijagnozom autoimunog hepatitisa i cholangitisa je
praćena na klinici za porodiljstvo gdje je i porođena u terminu. Tokom cijele trudnoće je redovno, multidisciplinarno kontrolirana te je
ordinirana imunosupresivna terapija u korelaciji sa nalazom jetrenih
proba. Traženi nalazi su tokom cijele trudnoće uglavnom bili uredni ali
je nakon poroda došlo do očekivanog pogoršanja u nalazima jetrenih
proba.
Key words: pregnancy, autoimmune hepatitis, cholangitis
Ključne riječi: trudnoća, autoimuni hepatitis, cholangitis
INTRODUCTION
CASE REPORT
Autoimmune hepatitis is a chronic inflammatory disease involving the loss of tolerance to the liver tissue which results in destruction of the liver parenchyma. It is characterized with necroses and
inflammation in periportal parts of lobules, hypergammaglobulinemia and presence of auto antibodies. The disease is more frequent
in women and immunogenetics connection with haplotype A1-B8DR3 or DR4 has been registered (1–3). Extra hepatitis syndromes
are also frequently present. There is no specific test for diagnosing
autoimmune hepatitis but there is a set of diagnostic criteria based
on which the International Association for Autoimmune Hepatitis
in 1999 formulated a numeric system for diagnosing potential or
positive disease (4). Sclerosing cholangitis is a chronic progressive
holistic disease of intrahepatic and extrahepatic bile ducts. Diffuse
inflammation, fibrosis and obliteration of the entire biliary tree finally result in secondary biliary liver cirrhosis. Incidence rates are from
2 to 8 per 100,000 people (5). These two patological conditions
of hepatobiliary system especially deteriorate during the pregnancy and particulary after delivery. This report describes a case of a
pregnant woman whose pregnancy was monitored at the Clinic of
Obstetric of the Clinical Center University of Sarajevo.
A primigravida, previously diagnosed with autoimmune hepatitis and cholangitis, reported to the admission unit of the Clinic of
Obstetric, Clinical Center University of Sarajevo (CCUS). She was
diagnosed with the disease at the age of 15 and had been under
regular control of the responsible Hepatologist. Her pregnancy was
monitored by practitioners of the Pathology department, which
involved accurate and regular control of the liver enzymes and
parameters for the purpose of the therapy adjustment. The team
responsible for monitoring the patient’s condition also included two
Hepatologists and the Clinic Internist.
During the pregnancy she was under intensive clinical and laboratory controls which involved monitoring of all parameters related
to the disease. The patient gave spontaneous birth at 40 week of
gestation, following the spontaneous rupture of the membranes.
The second and third stage of the labor went well and 24 hours
later she was discharged from the Clinic of Obstetrics.
One month after delivery, in a good general health and in a
proper obstetric status, the patient was referred under further responsibility of the practicing Hepatologist.
Clinical picture of autoimmune hepatitis and cholangitis in a pregnant woman during pregnancy and after delivery
Figure 1 Values of ASAT during the pregnancy and after delivery.
Figure 2 Values of ALAT during pregnancy and after de- livery.
Figure 3 Values of GGT during pregnancy and after deliv- ery.
Descriptive-statistical analysis was used for presenting values
of liver enzymes in the patient during pregnancy and after delivery.
The average AST values ranged from approximately 32,78 U/L
during the pregnancy, while after delivery their value significantly increased and amounted to 60 U/L (p<0,05). The average ALT value
during the pregnancy (48,9 U/l) and after delivery (124,75 U/L),
significantly differ, and it also significantly increased after delivery.
Although GGT value statistically significantly increased after deliver
(during the pregnancy 158,09 U/L; after delivery 188 U/L), the av-
209
erage value during delivery was also significantly higher then the reference values. The same related to ALP values during the pregnancy
and after delivery. The values of liver enzymes during the pregnancy were maintained within certain borders through application of
medicamentous therapy, but their value statistically significantly increased immediately after delivery.
Figure 4 Values of ALP during pregnancy and after delivery.
Figure 5 Values of PV during pregnancy and after delivery.
Whereas average PV values during the pregnancy (1,07) and after delivery (13,37) statistically significantly differ (p<0,05), there
was no statistically significant difference in the value of bilirubin
during the pregnancy and after delivery (Figure 6).
Figure 6 Levels of bilirubin during pregnancy and after de livery.
210
L. Imširija et al.
CONCLUSION
During the pregnancy the patient received the therapy consisting of Decortin, Imuran and Ursofalk. Dosage of Decortin was reduced during the pregnancy and before delivery, and due to high values of the liver enzymes after delivery it was again restored to 5mg.
Imuran was administered by mid pregnancy in a dosage of 50-100
mg. It is important to note that Ursofalk was administered continuously, starting from the third trimester until after delivery in a dosage
of 1500mg. Only this triple therapy could partly maintain the liver
enzymes in their reference values, or in the values under control of
the practitioner, and clinically stable condition of the patient could
be maintained by adjusting the dosage.
Incidence of pregnant women with AIH and Cholangitis is small
but it can be connected with serious complications during pregnancy and after delivery. Therefore, those pregnant women must be
treated in third level institutions. Regular pregnancy monitoring by
a team comprising not only a Gaenecologist but also a Hepatologist
and an Internist may result in a positive outcome, as described in the
present case report.
DISCUSSION
REFERENCES
Pathogenesis of autoimmune hepatitis has not been fully explained, but there is a generally accepted concept that external factors constitute a “trigger” for development of autoimmune hepatitis
in the presence of the genetic predisposition. However, the disease
most often occurs spontaneously sui generis without prior exposure to a virus or some other agent. Autoimmune liver diseases as
well as other autoimmune diseases are more frequent in women
(6). Women are four times more likely to develop autoimmune
hepatitis. It is likely that hormones play important role, taking into
account that some autoimmune diseases develop after menopause,
while other improve during pregnancy and deteriorate after delivery
(7). Nevertheless, the most significant part in the development of
autoimmune hepatitis as well as other autoimmune diseases is attributed to certain haplotypes of alleles of the main histocompatible
complex which point to crucial importance of class II antigens in the
clinical expression of these diseases (1-3). The manner in which certain alleles of human leukocyte antigen (HLA) participate in the development of autoimmunity has not yet been established. Structural
analysis of molecule of the major histocompatibility complex and
the complex with peptides is the bases for studying associations with
certain autoimmune diseases and for therapy consideration. This research has shown that functions of hormones excreted during pregnancy successfully stabilize autoimmune hepatitis and cholangitis,
while the clinical picture deteriorates after pregnancy which requires
timely action of a practitioner in adjustment of the therapy to be
used by a puerpera.
1. Agarwal K, Czaja AJ, Jones DE, Donaldson PT. Cytotoxic T lymphocyte antigen-4
(CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis.
Hepatology. 2000;31(1):49–53.
2. Manns MP, Vogel A. Autoimmune hepatitis, from mechanisms to therapy. Hepatology. 2006;43(2 Suppl 1):S132-44.
3. Heathcote EJ. Management of primary biliary cirrhosis – the American Association
for the Study of Liver Diseasespractice guidelines. Hepatology. 2000;31(4):100513.
4. Kaya M, Angulo P, Lindor KD. Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system. J Hepatol.
2000;33(4):537-42.
5. Kneser JM, Bantel H, Manns MP. Diagnostic and therapeutic management of autoimmune hepatitis. Hepatology Rev. 2005;2:80-7.
6. Vergani D, Alvarez F, Bianchi FB, Cançado EL, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus statement from the committeefor autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol.
2004;4184):677-83.
7. Poupon R. Autoimmune overlapping syndromes. Clin Liver Dis. 2003;7(4):865-78.
Conflict of interest: none declared.
Reprint requests and correspondence:
Lejla Imširija-Idrizbegović, MD, MSc
Clinic of Obstetrics
Clinical Center University of Sarajevo
Patriotske lige 81
71000 Sarajevo
Bosnia and Herzegovina
Phone: +387 61 190 622
Email: [email protected]
Instructions to authors
211
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REFERENCES
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Bosna i Hercegovina
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214
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215
Instructions to authors
Novi Evropski vodič za prevenciju tromboembolizma kod A Fib
CHA2DS2-VASc skor za procjenu rizika od tromboembolizma kod A Fib!
Risk factor-based point-based scoring
system - CHA2DS2 -VASc
Risk factor
Score
Congestive heart failure/LV dysfunction
1
Hypertension
1
Age >75
2
Diabetes mellitus
1
Stroke/TIA/thrombo-embolism
2
Vascular disease*
1
Age 65–74
1
Sex category (i.e. female sex)
1
Maximum score
9
*Prior myocardial infarction, peripheral artery disease, aortic plaque. Actual rates of stroke in contemporary cohorts may vary from these estimates.
Major i non-major riziko fakori za procjenu tromboembolizma kod A Fib!
Risk factors for stroke and
thrombo-embolism in non-valvular AF
Major risk factors
Previous stroke
TIA or systemic embolism
Clinically relevant non-major
risk factors
CHF or moderate to severe LV systolic
dysfunction [e.g. LV EF � 40%]
Hypertension
Age �75 years
Diabetes mellitus
Age 65-74 years
Female sex
Vascular disease
AF = atrial fibrilation; EF = ejection fraction (as documented by echocardiography, radio nuclide ventriculography, cardiac catheterization,
cardiac magnetic resonance imaging, etc.); LV = left venticular; TIA = trasient ischaemic attack.
Algoritam antikoagulantne terapije nakon procjene CHA2DS2VASc i major risk faktora!
Choice of
Anti-coagulant
Atrial fibrilation
Yes
Valvular AF*
Yes
No (i.e. non-valvular AF)
<65 years and lone AF (including females)
No
Assess risk of stroke
(CHA2DS2-VASc score)
* Includes rheumatic valvular
AF, hypertrophic
cardiomyopathy, etc.
0
** Antiplatelet therapy with
aspirin plus clopidogrel, or less effectively - aspirin only,
may be considered in patients
who refuse any OAC
1**
�2
Oral anticoagulant therapy
Assess bleeding risk (HA S-BLED score)
Consider patient values and preferences
No antithrombotic therapy
NOAC
VKA
NOAC - Novel Oral Anticoagulants, VKA - Vitamin K Antagonists
Prijedlog mreže Primarne Perkutane Koronarne Intervencije
za Bosnu i Hercegovinu!
Prijedlog mreže Primarne Perkutane Koronarne Intervencije
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