EPATITI CRONICHE B, C, autoimmuni

EPATITI
CRONICHE
B, C,
autoimmuni
Amedeo Lonardo
[email protected]
Reggio Emilia
7 Novembre 2012
EPATITI CRONICHE B & C
Obiettivo: La cultura e la prassi nel management clinico
delle epatiti croniche virali
• SCHEMA DELLA PRESENTAZIONE
- Impatto metabolico e rischio vascolare
- Linee guida terapeutiche
STORIA NATURALE INFEZIONE DA HCV
Extrahepatic Manifestations
Dysmetabolic
syndrome
Hepatic disease
Chronic (fatty) Hepatitis
Cirrhosis
10%-20% over 20 years
Decompensated Cirrhosis
HCC, 1-4% per year
THE METABOLIC SYNDROME IS NOT
ASSOCIATED WITH HCV
Shaheen M 2007
HCV-RELATED DYSMETABOLIC SYNDROME (1)
HCV INFECTION IS ASSOCIATED
WITH
INSULIN RESISTANCE
HCV IS ASSOCIATED WITH INSULIN RESISTANCE
Transgenic
mouse
Human study,
Japan
Shintani, Gastroenterology 2004
Kawaguchi T, Int J Molecular Medicine 2005
Human study, Italy
(Personal observation)
HCV ERADICATION IS ASSOCIATED WITH REVERSAL OF IR
Kawaguchi Am J Gastro 2007
GGT AS A MARKER OF INSULIN RESISTANCE
IN PATIENTS WITH STEATOSIS
Lonardo, J Hepatol 2006
IMPACT OF INSULIN RESISTANCE ON TREATMENT RESPONSE RATE
Romero Gomez Gastroenterology 2005
INSULIN ANTAGONIZES IFN
INSULIN
IFNα
P
IRS-2
JAK-TyK2
P
PI3K
P
STAT
P
GLUT 4
Akt
PKR
glucose
Romero-Gomez 2006
HCV-RELATED DYSMETABOLIC SYNDROME
…..If HCV is associated
with IR it must also be associated
with T2D….
La prevalenza di HCV è aumentata tra i pazienti conT2D
Lonardo A et al.
La prevalenza di diabete è aumentata nei pazienti con HCV
Author (Year)
HCV
(%T2D)
CONTROLS
(%T2D)
Allison (1994)
50
6
El-Zayadi (1998)
25.4
11.2
Mason (1999)
24
13
Mehta (2003)
7.5
1.2
Antonelli (2005)
14.4
6.9
Lecube (2004)
32
12
Wang (2007)
14
8.6
Imazeki (2008)
14
6.3
Elahawari (2011)
13.84
4.15
Meta-analysis comparing the risk of Type II diabetes in HCV infected cases
to non-infected controls in retrospective studies
White J Hepatol. 2008 November; 49: 831–844
Meta-analysis comparing risk of diabetes in HCV-infected cases to HBV-infected controls
White J Hepatol. 2008 November; 49: 831–844.
Evidence for an association between HCV &T2D
Simo 2006
HCV-RELATED DYSMETABOLIC SYNDROME (2)
HCV INFECTION IS ASSOCIATED
WITH REVERSIBLE
HYPOCHOLESTEROLEMIA
Blood Lipid values in Chronic Hepatitis C
Lonardo A et. Al. Can J Gastroenterol 2009
The removal of LDL by apheresis reduces HCV RNA levels by
77%, suggesting that the majority of infectious viral particles
are associated with lipoproteins
Schettler Eur J Clin Invest 2001
Down-regulated LDL-R, such as seen in those with high
Cholesterolemia are expected to decrease HCV entry into the
hepatocytes and possibly feature higher antiviral response rate
THE HIGHER THE PRE-TREATMENT TOT- AND LDL-CHOLESTEROL
THE GREATER THE ODDS OF RESPONDING TO ANTIVIRALS
Gopal, Hepatology 2006
RELATIONSHIP BETWEEN
RESPONSE TO IFN AND LIPIDS
Genotype3
LIVER
BLOOD
Resp
210
Resp
190
•
•
•••
••
•
•
•
NR
•
•
•
•
••
•
•
Kumar D Hepatology. 2002
•
••••
•
•
•
170
Serum Cholesterol
Percent area of steatosis
••
•
150
130
NR
110
•
••
90
BL
W2
W14
ET
••
Hofer H Am J Gastroenterol 2002
6M
HCV-RELATED DYSMETABOLIC SYNDROME (3)
HCV IS ASSOCIATED WITH STEATOSIS
STEATOSIS IN HCV INFECTION
A DISTINCT HISTOLOGY?
HCV
ALCOHOL
Fat Distribution
Focal
Pansteatosis
Acinar (zone 3)
Fat globules size
Mixed
Large
Large > small
Fibrosis Distribution Peri-portal
NAFLD
Pericentral Perisinusoidal (zone 3)
Lonardo, JVH 2006
Author
PREVALENCE
OF STEATOSIS
IN CHRONIC HEPATITIS C
* excluded from the final analysis
Prevalence
%
Scheuer
Fiore
Czaja
Hourigan
Adinolfi
Fujie
Rubbia-Brandt
Clouston
Hwang)
Adinolfi
Petit
Monto
La Torre
Hui
1992
1996
1998
1999
1999
1999
2000
2001
2001
2001
2001
2002
2002
2002
29/54
73/121
31/60
91/148
65/158
21/43
41/101
56/80
55/106
86/180
66/123
171/297
33/69
90/122
53.7
60.3
51.7
61.5
41.1
48.8
40.6
70.0
51.9
47.7
53.6
57.6
47.8
73.7
Akuta
Serfaty
Romero-Gomez
Asselah
Ohata
Sanyal
Poynard
Hu
Rubbia-Brandt
Sharma
Patton
Hézode
2002
2002
2003
2003
2003
2003
2003
2004
2004
2004
2004
2004
320/394
60/142
63/131
135/290
56/161
110/1536
935/1428
214/324
315/755
90/225
277/574
141/176
81.2
42%
48.1
46.5
34.8
7.2*
65.5
66.0
41.7
40.0
48.3
80.1
3,696/6,576
56.20
TOTAL
Lonardo, JVH 2006
(year) Steatosis/total
n/n
PREVALENCE OF STEATOSIS IN
VARIOUS CHRONIC LIVER DISEASES
Prevalence of Steatosis (%)
60
56
50
40
30
20
27
27
16
10
0
Type 1
Autoimmune
Hepatitis
Chronic
Hepatitis B
Cryptogenic
Hepatitis
Cronic
Hepatitis C
Lonardo, JVH 2006
Meta-analysis of the prevalence of hepatic steatosis in
HBV versus HCV infected patients.
Machado Journal of Gastroenterology and Hepatology 26 (2011) 1361–1367
HBsAg seropositivity was not associated with increased mortality risks of
atherosclerosis related/cardiovascular diseases during 17-year follow-up.
C.-H. Wang et al. / Atherosclerosis 211 (2010) 624–629
Steatosis and HCV viral load are independently associated with carotid
atherosclerosis in 326 patients with chronic hepatitis C
Adinolfi Lonardo & Loria Atherosclerosis 2012; 221:496– 502
PREVALENCE OF STEATOSIS
ACCORDING TO THE GENOTYPES
p < 0.01
AUTHOR , year
GENOTYPE
“ 3”
“NON-3”
75.6
48.8
Genotype Genotype
3
non 3
Rubbia-Brandt, 2000
Hui, 2002
Poynard, 2003
Rubbia-Brandt, 2004
Sharma, 2004
Patton, 2004
Cholet, 2004
Hézode, 2004
117/134
19/26
33/34
61/84
109/178
43/61
33/43
79/93
553/900
71/198
39/84
194/437
206/577
66/193
50/71
62/83
TOTAL
494/653 1241/2543
Lonardo, JVH 2006
EXTENT OF STEATOSIS ACCORDING TO THE GENOTYPE
100
Genotype 3
Genotype non 3
SUBJECTS (%)
80
p< 0.01
60
40
NS
p<0.01
20
0
<33%
33-66%
Data pooled from: Rubbia-Brandt, 2004; Patton, 2004, Sharma, 2004
Including 179 patients with HCV Genotype 3 and 471 with Genotype non-3
>66%
Lonardo, JVH 2006
Steatosis impairs SVR in
genotypes other than 3
P=0.33
90
P<0.001
80
P<0.001
70
SVR %
Steatosis
No steatosis
60
50
40
30
20
10
0
HCV Genotypes
3
(n = 134)
non-3
(n = 900)
1, 4, 5, 6
(n = 746)
Poynard et al, Hepatology 2003;38:75-85
“VIRAL STEATOSIS”
24.0
r = 0.786
P < 0.001
16.0
8.0
0.2
0
25
50
75
100
% of hepatocytes with steatosis
“METABOLIC STEATOSIS”
Genotype 1
36
BMI (Kg/ m2)
Serum HCV RNA levels
(Eq/ml x 106)
Genotype 3a
30
24
Normal BMI
r = 0,689
p < 0.0001
18
0
25
50
75
100
% of hepatocytes with steatosis
Adinolfi LE Hepatology 2001
Progression rate of fibrosis (per yr)
STEATOSIS IMPACTS ON NATURAL HISTORY OF HCV
INFECTION - ALCOHOL
0.6
p=0.02
0.5
0.4
0.3
0.2
0.1
0
Steat-/Alc-
Steat-/Alc+
Steat+/Alc-
Steat+/Alc+
Serfaty L. Am J Gastroenterol 2002
Impact of steatosis on liver fibrosis
progression in chronic hepatitis C
A retrospective study on repeated liver biopsies
Fartuex, Hepatology 2005;41:82-87
STEATOSIS IMPACTS ON NATURAL HISTORY OF HCV INFECTION
HCC
% Cumulative incidence
Steatosis (+)
n=90
P=0.0012
Steatosis (-)
n=71
Follow-up (months)
Ohata K Cancer 2003
Impact of steatosis on the natural course of
chronic hepatitis C virus infection
Lonardo & Loria Journal of Viral Hepatitis, 2006, 13, 73–80
Independent predictors of SVR
Harrison SH Hepatology 2010;52:864-874
LA SINDROME METABOLICA
Age
HCV+
(years)
HCV+
69 (HCV + NAFLD)
48 13
47 11
28
63
Shaheen, 2007
239
39 0.82
16,7
Hanouneh,
2008
228
52
(47-55)
26
108 (genotype1b)
90 (gt 2)
5510
5511
41
22
90
47 13
4,4
Author,
year
Sanyal, 2003
Persico, 2007
S.-Baroni, 2007
Targher, 2007
Series
75 (HCV)
MS
%
60
3416
25
Lonardo, 2008
97
53.00
(43.5057.0
)
4,4
Tsochatzis,
2008
95
43.412.3
5,01
MS%
General
population
USA
7-44
ITALY
3-25
GREECE
5-43
IS THE
PREVALENCE
OF THE MS
REDUCED
IN HCVPOSITIVE
INDIVIDUALS ?
Lonardo Adinolfi Petta Craxì & Loria,
The HCV-associated dysmetabolic syndrome
HCV
Steatosis
Visceral fat
hypertrophy
Acquired, reversible
hypocholesterolemia
Insulin resistance
La sindrome metabolica da HCV - 4
Ipertrofia del grasso mesenterico in corso di
infezione da HCV
Mostafa Gut 2010;59:1135e1140.
CONCLUSIONS
• HCV is associated with insulin resistance- diabetes
risk, reversible hypocolesterolemia hypertrophy of
visceral fat and steatosis
• Individual components of this “HCV-associated
dysmetabolic syndrome” impact on the course of
viral infection
• Therefore, they are a potential therapeutic target
Louis Pasteur
The microbe is nothing: the terrain is everything
PARTE SECONDA
• Virological assessment
Diagnosis of HCV infection is based on detection of anti-HCV antibodies by EIA and HCV
RNA by a sensitive molecular method (A1).
For the diagnosis of acute hepatitis C, HCV RNA testing is required as HCV RNA appears
before anti- HCV antibodies may be detectable (A2). The use of real-time polymerase chain
reaction (PCR) detects minute quantities of HCV RNA (as few as 10 international units
(IU)/ml) and accurately quantifies HCV RNA levels up to approximately 107 IU/ml.
HCV RNA detection and quantification should be made by a sensitive assay (lower limit of
detection of 50 IU/ml or less), ideally a real-time PCR assay, and HCV RNA levels should be
expressed in IU/ml (C1).
The HCV genotype must be assessed prior to antiviral treatment initiation and will
determine the dose of RBV and treatment decision (A1).
Assessment of liver fibrosis
Assessment of the severity of liver disease is recommended before beginning therapy.
Identifying patients with cirrhosis is of particular importance, as their prognosis and
likelihood to respond to therapy are altered, and they require surveillance for HCC (A1).
As liver disease can progress in patients with repeatedly normal ALT levels, disease severity
evaluation should be performed regardless of ALT levels (B2).
Assessment of the severity of liver fibrosis is important in decision making in patients with
chronic hepatitis C (A1).
Liver biopsy is still regarded as the reference method to assess the grade of inflammation
and the stage of fibrosis (A2).
Transient elastography can be used to assess liver fibrosis in patients with chronic hepatitis
C (A2).
Evaluation of genetic
polymorphisms
Although the predictive value is low,
determination of IL28B polymorphisms seems to
be useful in identifying a patient’s probability of
response to PEG-IFN-a and RBV treatment.
Determination of IL28B polymorphisms may
assist in evaluating a patient’s likelihood of
response to treatment with PEG-IFN-a/RBV (B2).
STORIA DI IL-28
In 2009, three different genomewide search studies
demonstrated that in patients with HCV infection, a
high genetic variability in the genomic region 3 kb
upstream of the gene codifying for IL28B on
chromosome 19 correlates with the response to
antiviral treatment with PEG-IFN alpha plus ribavirin.
In particular, possession of the favourable CC
genotype at the SNP rs12979860 was associated with
a 2.5-fold increase in the likelihood of SVR in patients
with HCV genotype 1 (1-3).
[1] Ge D,. Nature 2009;461:399–401.
[2] Suppiah V, Nat Gen 2009;41:1100–4.
[3] Tanaka Y, Nat Genet 2009;41:1105–9.
Effect of rs12979860 genotype on 3-level treatment outcome in
Caucasian chronic HCV patients treated with PEG-IFN/RBV
McCarthy JJ Gastroenterology 2010;138:2307–2314
Association between rs12979860 genotype and HCV genotype
McCarthy JJ Gastroenterology 2010;138:2307–2314
STORIA DI IL-28
A fourth GWAS study [4], showed the same CC-genotype to
be associated with spontaneous viral clearance in patients
with a documented acute infection.
This finding has been subsequently confirmed both in studies
evaluating patients from different cohorts [5-7]
These data further imply that this locus is directly involved in
the pathogenesis and in the response to HCV treatment.
[4] Thomas DL, Nature 2009;461:798–801.
[5] Rauch A, Gastroenterology 2010;138:1338–45.
[6] Tillmann HL, Gastroenterology 2010;139:1586–92.
[7] Mangia A. J Hepatol 2010;52:S452.
IFN-/ and IFN- signaling pathways.
Lange & Zeuzem J Hepatol 2011;55: 692–701
FUNZIONE DI IL-28
Extremely interestingly, IL28B encodes
interferon (IFN) lambda, a cytokine which
shares the same intracellular pathways of IFNalpha, the drug we have been using in
combination with ribavirin for the treatment
of patients with chronic hepatitis C for the
past 25 years.
IL-28 AND INTER-ETHNIC VARIATIONS IN
VIROLOGIC RESPONSE
The variability of this genomic region in patients with different responses
to interferon-based antiviral treatment may largely explain, though not
completely, the differences in the rates of virological response registered
across different ethnicities.
A lower rate of SVR has been reported patients of African American
ancestry < European Americans,
Latin < Caucasian American patients.
European subjects < individuals of Asian origin.
Such differences now appear mostly related to the different frequency of
specific polymorphic variants in the genomic region upstream of the gene
for IL28B.
Results of current therapies and predictors of response
Nave patients
SVR is achieved in 40–54% of patients
infected with HCV genotype 1 treated with PEGIFN-a/RBV at approved doses for 48 weeks (A1).
SVR is achieved in 65–82% of patients
infected with HCV genotypes 2 or 3 treated with
PEG-IFN-a/RBV at approved doses for 24 weeks
(A1).
Naive patients - Strongest baseline
predictors of SVR are:
• a. HCV genotype (A1).
• b. Genetic polymorphisms located in
chromosome 19 (IL28B), particularly in genotype
1 patients (A1).
• c. Stage of liver fibrosis (A1).
Relapsers and non-responders
• Relapsers - Patients who achieve an end-of-treatment viral
response (undetectable HCV RNA at the end of treatment) but
subsequently relapse, and do not achieve an SVR. The relapse
rate after treatment with PEG-IFN-a and RBV is approximately
15–25%, but varies depending on, when HCV RNA becomes
undetectable during therapy.
• Relapsers respond to re-treatment with PEG-IFN-a/RBV in 32–
53% of the patients .
• Non-responders - Patients who fail to achieve a decline of 2 log
HCV RNA IU/ml after 12 weeks of treatment or who never
achieve undetectable HCV RNA during a minimum of 24 weeks
of treatment.
Indications for treatment
main recommendations
All treatment-nave patients with compensated disease because of HCV
should be considered for therapy (A2)
Treatment should be initiated promptly in patients with advanced fibrosis
(METAVIR score F3–F4), and strongly considered in patients with moderate
fibrosis (METAVIR score F2) (B2)
Patients infected with HCV genotype 1 who fail to eradicate HCV after
prior therapy with PEG-IFN-a and RBV should not be re-treated with the same
drug regimen, because SVR rates are low (9–15% for all genotypes and 4–6%
for genotype 1) (17, 18).
These patients should wait for approval of new combination therapies,
which have been shown to result in higher SVR rates of between 30% and
60%, depending upon the type of previous non-response and the stage of
liver disease (19).
Interferone
Effetti collaterali più frequenti
S. simil-influenzale
(cefalea, febbre, astenia, dolori osteo-muscolari),
Tossicità midollare
(piastrinopenia, neutropenia, anemia)
Disfunzione erettile.
Ribavirina
Effetti collaterali più frequenti
anemia, tosse, astenia, diarrea, dolore toracico ed
addominale, cefalea, nausea, vomito, teratogenicità.
Monitoring of treatment efficacy is based on the repeated
measurement of HCV RNA levels
Monitoring of safety and treatment dose
reductions – main recommendations
• At each visit, the patients should be assessed for clinical
side effects, such as severe fatigue, depression,
irritability, sleeping disorders, skin reactions and
dyspnoea.
• Haematological and biochemical side effects of PEGIFNa and RBV include neutropenia, anaemia,
thrombocytopenia and ALT flares.
• Thyroid stimulating hormone and free thyroxine levels
should be measured every 12 weeks while on therapy
and patients should be advised about the risk of
teratogenicity with RBV and the need for contraception
during and 6 months after treatment.
Full adherence to both PEG-IFN-a and
RBV is associated with improved SVR rates
• Thus the full dose should be reinstituted as soon
as possible to attain and sustain maximum
exposure to each drug
• Patients should be informed of the preventive
and therapeutic measures to relieve their side
effects, for example, using antipyretics,
analgesics or antidepressants, and the use of
growth factors may help limit dose reductions.
Full adherence to both PEG-IFN-a and
RBV is associated with improved SVR rates
Patients with a history and/or signs of
depression should be seen by a psychiatrist
before therapy (C2).
Patients who develop depression during
therapy should be treated with antidepressants.
Preventive antidepressant therapy in selected
subjects may reduce the incidence of depression
during treatment, without any impact on the
SVR (B2).
Main recommendation of treatment in patients
with severe liver disease
Patients with compensated cirrhosis should
be treated, in the absence of contraindications,
to prevent short to mid-term complications
(A1).
Assiduous monitoring and management of
side effects, especially those linked to portal
hypertension and hypersplenism, is required.
Growth factors are particularly useful in this
group (C2).
Main recommendation of treatment in
patients with severe liver disease
Patients with cirrhosis should undergo regular surveillance for
HCC, irrespective of SVR (B1).
Antiviral therapy is indicated in patients with Child–Pugh A in
whom the indication for transplantation is HCC (B2).
In patients with Child–Pugh B cirrhosis, antiviral therapy is
offered on an individual basis in experienced centres, preferentially
in patients with predictors of good response (C2).
•Patients with Child–Pugh C cirrhosis should not be treated with the
current antiviral regimen, because of a high risk of life-threatening
complications (C1).
TERAPIA: Le nuove terapie
Cosa c’è già disponibile
- Boceprevir
- Telaprevir
The current American Association for the Study of Liver
Diseases (AASLD) Practice Guidelines (2011) recommend
triple therapy with a protease inhibitor, peginterferon, and
ribavirin as the standard treatment for hepatitis C.
Both telaprevir and boceprevir have been studied in treatment
naïve and previous partial responders, but
only telaprevir has been studied in prior null responders.
QUANTO MI COSTI !
The 12-week regimen of telaprevir therapy has a
wholesale acquisition cost (WAC) in 2011 of $49,200
(added to $17,175 WAC for 24 weeks of peginterferon plus
ribavirin [PR] or $34,349 for 48 weeks of PR).
The boceprevir WAC in 2011 is $26,410 for the 24-week
regimen (added to $20,037 WAC for PR for 28 weeks,
$25,762 for 36 weeks, or $34,349 for 48 weeks).
HCV targets of BOCEPREVIR and TELAPREVIR
Safety
DYSGEUSIA
boceprevir
ANEMIA
NEUTROPENIA
Safety
RASH
Telaprevir
ANEMIA
GASTROINTESTINAL
DISORDERS
Mild Rash (Grade 1)
Grade 1 (Mild):
localized skin
eruption and/or
a skin eruption
with limited
distribution,
with or without
associated
pruritus
Moderate Rash (Grade 2)
Grade 2 (Moderate):
diffuse skin
eruption involving
up to 50% of body
surface area, with
or without
superficial skin
peeling, pruritus,
or mucous
membrane
involvement with
no ulceration
Severe Rash (Grade 3)
Grade 3 (Severe):
either generalized skin
eruption involving either
>50% of body surface area
OR rash presenting with
systemic symptoms or
ulceration of mucous
membranes, epidermal
detachment, etc.
Estimating
BodySurfaceArea
(BSA)
9
%
1
%
Front
18%
Back
18%
9%
18
%
18
%
9%
Adult body
Grade 4 (life-threatening):
Toxic epidermal necrolysis
(TEN), Stevens-Johnson
syndrome (SJS), skin
eruption with generalized
bullous eruption
BSA
Arm
9%
Head
9%
Neck
1%
Leg
18%
Anterior trunk
18%
Posterior trunk
18%
Hettiaratchy S, et al. BMJ 2004;329:101–3
Treatment of acute hepatitis C
PEG-IFN-a monotherapy for 24 weeks is
recommended in patients with acute hepatitis C
and obtains viral eradication in > 90% of
patients (B2).
Patients failing to respond should be
retreated according to the SoC for chronic
hepatitis C (C2).
HBV
PREVALENZA
Storia naturale dell’epatite cronica B
INFEZIONE CRONICA
1.
Fase precoce elevata replicazione virale (epatite cronica HBeAg positiva)
Fase tardiva replicazione virale bassa o assente con sieroconversione da
HBeAg ad anti-HBe e remissione bioumorale ed istologica di malattia epatica
(portatore cronico inattivo).
Dopo sieroconversione da HBeAg ad anti-HBe la maggior parte dei pazienti
diventano portatori inattivi del virus B, tuttavia in una proporzione di pazienti si
osserva la progressione ad epatite cronica HBeAg negativa dovuta a mutanti
HBeAg minus che blocca/riduce la sintesi di HBeAg.
2.
Caratteristica principale dell’ epatite cronica HBeAg negativa è l’andamento
fluttuante delle transaminasi e della viremia con talora periodi anche
prolungati di remissione bioumorale e virologica. La remissione spontanea
sostenuta della malattia è molto rara.
3.
Complicanze cliniche maggiori dell’epatite cronica B sono l’evoluzione verso la
cirrosi e HCC. La progressione a cirrosi sembra essere più rapida nell’ epatite
cronica HBeAg negativa che in quella HBeAg positiva.
.
Diagnosi e gestione del portatore inattivo
HbsAg<1000 UI/ml
+
HBV-DNA <2000 UI/ml
La storia naturale del portatore cronico
inattivo in assenza di cofattori di malattia
(alcol, superinfezioni con altri virus,
obesità) è benigna con sopravvivenza
simile alla popolazione
generale.
Portatore
inattivo
No Treatment
Follow-up every 6-12 months
Brunetto MR AASLD 2009
INFEZIONE CRONICA
4. Il rischio di HCC varia a seconda dell’area geografica e dello stadio della malattia alla
diagnosi.
Esso è > nei soggetti con infezione cronica da HBV di razza asiatica o africana, (più
precoce acquisizione dell’infezione virale e più lunga durata della malattia).
Il paziente cirrotico ha un aumentato rischio di HCC rispetto al paziente con
epatopatia cronica senza cirrosi.
5. Alti livelli di replicazione virale e attività di citolisi epatica persistenti nel tempo sono
i più importanti fattori prognostici di progressione a cirrosi, scompenso epatico,
HCC e morte epatocorrelata.
6. Altri fattori predittivi di progressione di malattia sono:
•
’età più avanzata alla diagnosi,
•
sesso maschile,
•
severità della fibrosi epatica alla diagnosi
•
severità della cirrosi compensata alla presentazione,
•
coinfezioni HBV/HDV e/o HBV/HCV e
•
abuso di alcol.
INFEZIONE CRONICA
PROFILI SIEROLOGICI DELL’INFEZIONE CRONICA
DA HBV
Fase
ALT
HBeAg
AntiHbe
HBV-DNA
IU/ml
Immunotolleranza
v.n. o poco
elevate
+
-
Livelli molto
elevati
>200.000
20 bilioni
Epatite cronica
HBeAg positiva
Sempre
elevate
+
-
Livelli elevati
>200.000
2 bilioni
Epatite cronica
HBeAg negativa
Elevate e
spesso
fluttuanti
-
+
Livelli
moderati
spesso
fluttuanti
>2.000
20 milioni
Portatore cronico
inattivo
v.n.
-
+
Livelli bassi
<2.000
DIAGNOSI E MONITORAGGIO
• Identificazione dei marcatori di presenza e
severità della malattia
• Identificazione della fase di infezione
• Considerare i co-fattori che influenzano la
progressione di malattia (sesso, età, steatosi,
alcol,co-infezione da HCV, HDV, HIV)
• BIOPSIA EPATICA per pz con HBV-DNA>2000
e/o incremento delle ALT.
DOES WAIST CIRCUMFERENCE DRIVE HISTOLOGICAL
WORSENING IN HBV ?
Factors associated with superimposed NAFLD subtypes
Factors associated with superimposed NASH
Factors associated with hepatic fibrosis
Bondini S, Liver International ISSN 1478-3223
EASL CLINICAL PRACTICE GUIDELINES
PERDITA DI HBsAg/anno
HBeAgpositive
HBeAg-negativi
PEG-IFN
3-4%
3%
Lamivudina
1%
0
Adefovir
0
0
Entecavir
2%
0
Telbivudina
0
0
Tenofovir
3%
0
EASL CLINICAL PRACTICE GUIDELINES
VALUTAZIONE PRE-TRATTAMENTO
• Assessment globale : età e condizioni generali
• HBV-DNA>2000 UI/ml /circa 10.000 copie/ml
• ALT ai limiti superiori di norma
• Biopsia epatica o tecniche non invasive validate (es.
fibroscan): moderata o severa attività necroinfiammatoria e/o
fibrosi
EASL CLINICAL PRACTICE GUIDELINES
INDICAZIONI AL TRATTAMENTO
• Pazienti con cirrosi compensata e HBV-DNA > 2000 UI/ml: con
o senza elevazione delle ALT candidato al trattamento
• Paziente con cirrosi scompensata rapida soppressione
antivirale con NUCs (nucleoside/nucleotide = lamivudine,
adefovir and entecavir) analogues
EASL CLINICAL PRACTICE GUIDELINES
INDICAZIONI AL FOLLOW-UP
• Pazienti immunotolleranti: alti livelli di HBV-DNA, ALT normali
scarsa progressione in cirrosi o HCC follow-up
• Pazienti con infezione cronica moderata: elevazione
moderata delle ALT (2 x v.n.) e moderata progressione
istologica follow-up
ENTECAVIR (Baraclude)
• Cpr bianche: 0,5 mg, rosa: 1 mg
• una volta al giorno.
• 0,5 mg (pazienti non trattati prima con un analogo
nucleosidico)
• 1 mg (pazienti già curati in precedenza con lamivudina e che
hanno sviluppato una"resistenza“)
• effetti collaterali più comuni (riscontrati nel 9% dei pazienti)
sono stati affaticamento (6%), sonnolenza (4%) e nausea (3%).
Adefovir (Hepsera)
• Cpr da 10 mg
• 10 mg una volta al giorno
• La durata del trattamento varia a seconda
delle condizioni del paziente e della risposta al
trattamento, che devono essere controllate
ogni sei mesi.
• effetti collaterali (osservati in più di un
paziente su 10) sono un aumento della
creatinina ed astenia (debolezza).
EPATITE AUTOIMMUNE
Spettro delle epatopatie autoimmuni
EPATITE AUTOIMMUNE
Abbreviations: AIH, autoimmune hepatitis; ANA, antinuclear antibodies; IgG,
immunoglobulin G; LKM, liver/kidney membrane microsome; NAFLD, nonalcoholic
fatty liver disease; SLA, soluble liver antigen; SMA, smooth muscle antibodies;
ULN, upper limit of normal.
Criteri diagnostici di epatite autoimmune
Probable AIH: ≥ 6 points;
Definite AIH: ≥ 7 points; maximum number of points for all
autoantibodies is 2; total is 8 points.
*Histology
– Compatible with AIH: chronic hepatitis with lymphocytic infiltration
without features considered typical.
– Typical of AIH:
1. Interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in portal
tracts and extending in the lobule.
2. Emperipolesis (active penetration by one cell into and through larger
cell).
3. Hepatic rosette formation.
– Atypical: showing signs of another diagnosis like NAFLD.
Standard treatment
The American Association for the Study of Liver Diseases
practice guidelines recommends either monotherapy with
prednisone at a starting dose of 40–60 mg daily, or a lower
dose of prednisone (30 mg daily) combined with azathioprine
(1–2 mg/kg body weight can be considered evidence-based.
Complete Remission
• Characterized by the disappearance of clinical
symptoms and complete normalization of all
inflammatory parameters including histology.
• Can be achieved in 65%–75% of patients after 24
months of treatment. As the histological resolution of
inflammation lags behind the biochemical response by
3 - 6 months, therapy has to be continued beyond the
normalization of aminotransferase levels. At least 3
years of continuous therapy is recommended.
WARNING:
Long-term use of azathioprine may increase your risk
of certain types of cancer (e.g., skin cancer, lymphoma).
You must be closely monitored by your doctor during
treatment and regularly afterwards if your doctor stops
treatment with this medication.
Azathioprine may also cause serious (rarely fatal) blood
disorders (decreased bone marrow function leading to
anemia, low number of white blood cells and platelets).
It can lower your body's ability to fight an infection.
The risk of these side effects is higher in patients
receiving this medication to prevent kidney transplant
rejection than in patients treated for rheumatoid arthritis.
To reduce the risk of side effects, use this medication at
the lowest effective dose.
Keep all medical and laboratory appointments.
Tell your doctor immediately if you develop any of the
following: unusual skin changes, change in the
appearance/size of moles, unusual growths/lumps,
swollen glands, swollen or painful abdomen,
unexplained weight loss, night sweats, unexplained
itching, signs of infection (e.g., fever, persistent
sore throat), easy bruising/bleeding, or unusual tiredness.
Conclusion
AIH is a chronic inflammatory disease of the liver occurring worldwide
in both sexes and across all age groups.
The pathogenesis is complex, combining environmental and genetic
factors.
The diagnosis is based on a combination of elevated transaminases, the
presence and pattern of typical autoantibodies, and a liver biopsy
showing interface hepatitis and other typical features.
Response to treatment can also help to establish the diagnosis.
Simplified criteria can be used to make a bedside diagnosis with
relatively high accuracy.
Treatment consists of corticosteroids or other Immunosuppressive
regimens according to the severity of the disease, the response to
treatment, and the tolerance to therapy.
GRAZIE PER L’ATTENZIONE!
1. Quale delle seguenti affermazioni è
vera ?
a Farmaci non sono mai causa di epatite cronica
b Il virus dell’epatite B cronicizza nella maggior
parte dei pazienti con infezione acuta
C il virus dell’epatite C cronicizza nella maggior
parte dei pazienti con infezione acuta
d Alcol non è mai causa di epatite cronica
e Diabete non è mai causa di epatite cronica
2. Terapia antivirale dell’epatite C
3. Epatite C
a)Non recidiva mai dopo trapianto
b)Recidiva occasionalmente dopo trapianto
c) Recidiva dopo trapianto solo se
sostenuta da genotipi epatotossici (1a e 1b)
d)Recidiva regolarmente dopo trapianto
e)Recidiva dopo trapianto solo se sostenuta da
genotipo 3
4. Epatite B
a)
La vaccinazione dei conviventi ha un ruolo
fondamentale
b)
La vaccinazione dei portatori di HBsAg è
dannosa
c)
La vaccinazione dei portatori di HBsAg è
controindicata
d)
Vanno vaccinati solo i conviventi dei
portatori inattivi di HBsAg
e)
La vaccinazione è suggerita solo se il caso
indice è HBeAb positivo
5. Epatite A (HAV)
a)La vaccinazione anti HAV è sconsigliabile nelle
epatiti croniche virali
b)E’ la causa piu’ frequente di epatite cronica (in
Italia)
c) E’ la causa piu’ frequente di epatite cronica (in
Africa sub-sahariana)
d)E’ tipicamente appannaggio delle età piu’
avanzate della vita
e)Nessuna delle precedenti è corretta