chronic viral hepatitis and liver disease in thalassaemia
TRANSCRIPT
Vito Di MarcoGastroenterology & Hepatology Department
(Di.Bi.M.I.S.) University of Palermo
Italy
Chronic viral hepatitis and liver disease in thalassaemia
Causes of liver damage in thalassemia patients
IRON OVERLOAD VIRUS INFECTION
Clinical course of chronic virus related liver disease
AcuteHepatitis
Resolution
20 - 30 Years
ChronicHepatitis
Stabilisation
Cirrhosis
CompensatedCirrhosis
DecompensatedCirrhosis(Death)
Liver Cancer
Hepatitis virus infections in thalassemic patients: the key issues
1. How many patients have chronic virus infection?
2. What are invasive and non-invasive methods for the diagnosis of chronic hepatitis or cirrhosis?
3. What are the risks of developing severe liver disease?• Development of cirrhosis• Development of hepatocellular carcinoma (HCC)
4. What are the therapies for patients with chronic virus hepatitis?
Hepatitis virus infection in thalassemic patients
Hepatitis B Virus (HBV) infection
– HBV infection is present in less than 5% of adult subjects.
– Anti-hepatitis B vaccination has ruled out the risk of new virus B infections.
Hepatitis Virus C (HCV) infection
– Hepatitis C virus is the most common viral infection.
– Worldwide 20%-80% of thalassemics are seropositive for anti-HCV antibodies
– HCV chronic infection is more common in thalassemics transfused before 1990.
Angelucci, E. et al. Haematologica 2008;93:1121-1123
Prevalence of anti-HCV antibodies in different age groups
Hepatitis virus infections in thalassemic patients
Birth Cohort (years of birth)
Number of patients
Patients Anti-HCV+
Patients Anti-HCV+ HCV-RNA +
(1981-1990) 120 59 (50%) 28 (23%)
(1971-1980) 185 172(93%) 120 (65%)
(1961-1970) 80 73 (96%) 43 (57%)
(1951-1960) 21 18 (86%) 10 (47%)
Overall 406 324 (80%) 204 (50%)
Prevalence of HCV infection in a cohort of thalassemics followed for 16 years (406 patients from 5 centres)
(V. Di Marco, M. Capra, A. Maggio et al, submitted)
Viral genotypes in thalassemic patients with HCV chronic hepatitis
Authors Geographic Area
Number of patients
Genotype
1 (%)
Genotype
2 (%)
Genotype
3 (%)
Genotype
4 (%)
Genotype
6
(%)
Di Marco
(2005)
Italy 67 76 9 7 8
Christofidou
(1999)
Greece 28 39 7 35 17
Ramia
(2002)
Lebanon 19 37 5 21 37
Sharara
(2005)
Lebanon 20 75 25
Sievert
(2002)
Australia 27 40 20 40
Li
(2002)
China 18 77 23
Liver biopsy on patients with thalassemia major
1. Histologic scoring systems – grading grade of inflammatory component (score from G1 to G3 ) – staging degree of fibrosis (score from F0 to F4)
F1 - Mild F2 - Moderate F3 – Severe F4 - Cirrhosis
2. Perl’s Prussian blue stain: semiquantitative
method (score from 0 to 4) for the degree and cellular distribution of iron store.
3. Liver Iron Concentration (LIC): quantitative method (0.3 -1.8 mg/g dry weight)
Biochemical, virological and histological features of 126 patients with liver biopsy
(V. Di Marco, M. Capra et al. Haematologica, 2008)
Liver disease in chelated transfusion-dependent thalassemics: the role of iron overload and chronic hepatitis C
HCV-RNA negative (68 patients )
HCV-RNA positive (58 patients)
p
Age (Mean) 14 21 < 0.001
Gender (M/F) 35/33 32/26 0.6
Serum ALT ( Median, IU/mL, n.v. < 40) 27 82 < 0.001
Serum Ferritin (Median, ng/mL) 1,892 1,750 0.6
LIC (Median, mg/g dw ) 3.3 2.3 0.06
Histological inflammation (Grading) • Absent • Mild /Moderate • Severe
23 (34%)45 (66%)
0
056 (96%)
2 (4%) < 0.001
Histological fibrosis (Staging) • Absent• Mild/ Moderate • Severe/ Cirrhosis
23 (34%)42 (62%) 3 (4%)
2 (4%)37 (64%)19 (32%) < 0.001
Rates of cirrhosis in 3 groups of thalassemic patients who underwent liver biopsy.
Authors
N. of patients
Mean age
%
anti-HCV +
%
HCV-RNA +
LIC
(mg/g dry weight
(median, range)
%
with cirrhosis
MJ Cunnigham
.( Blood 2004)
232 20 81 (35%)
53 (23%)
7.8 (0.9-43) 10%
D Prati
(Haematologica,2004 )
117 26 107 (91%
80 (66%)
6.0 (0.6-29) 8%
V Di Marco
(Haematologica,2008 )
126 17 84 (67%)
58 (46%)
2.4 (0.3-22) 11%
Which non-invasive markers can replace liver biopsy Which non-invasive markers can replace liver biopsy to evaluate fibrosis?to evaluate fibrosis?
a. Serologic markers• Routine laboratory tests (indirect markers)• Fibrogenesis markers (direct markers)
b. Imaging techniques• Ultrasonography• Transient elastography (Fibroscan)• Transient elastography-MRI
Advantages• Non-invasive and painless
• Quick and inexpensive
• Evaluation of larger area reduces sampling errors
• Best at identifying significant fibrosis
Transient Elastography by Fibroscan®
Limitations
• Poor discrimination in mild-to-moderate fibrosis
• Cannot be used in patients with ascites
• Inaccurate in obese patients
V. Di Marco , M. Capra et al. British Journal of Haematology, 2010
Correlation between• fibrosis stage and LIC (A) • fibrosis stage and LSM (B)
Noninvasive assessment of liver fibrosis in thalassaemia major patients by transient
elastography
Causes of death in a cohort of 406 patients with thalassemia major followed for 16 years (1993-2009)
HCV-RNA negative
( 202 patients )
HCV-RNA positive
(204 patients)p
Age (mean, years) at start of follow-up
15 19 n.s.
Gender (M/F) 98/105 105/93 n.s.
ALT (IU/mL) 37 78 0.002
Ferritin (ng/mL) 1713 1878 n.s
Overall Death 14 (7%) 33 (16%) 0.004
Death for heart disease 6 (3%) 18 (9%) 0.02
Death for Infection 3 3 n.s.
Death for Cirrhosis/HCC 0 10 (5%) 0.001
Death for Accident 2 - n.s.
Death for HIV/AIDS 1 - n.s.
Death for other causes 2 2 n.s
(V. Di Marco, M. Capra, A. Maggio et al, submitted)
Antiviral therapy for HCV chronic hepatitis(AASLD & EASL Guidelines)
• The therapy is indicated in patients with: – elevated transaminases, – positive blood tests for anti-HCV and HCV-RNA – clinical evidence of significant liver fibrosis or cirrhosis.
• The main goals of the treatment are:– the eradication of virus C; – the control of liver inflammation and liver fibrosis– the prevention of cirrhosis;
• Treatment can be defined efficacy if:– serum HCV-RNA remains negative almost 6 months after the
end of therapy.
Milestones in Therapy of HCV
6%
16%
41% 39%
61%
0
10
20
30
40
50
60
70
IFN 24 wk IFN 48 wk IFN + RBV PEG IFN PEG IFN + RBV
McHutchison JG 1998; Poynard T 1998; Zeuzem S 2000;Lindsay K 2001; Manns M 2001; Fried MW 2002.
Sus
tain
ed V
irolo
gica
l Res
pons
e (%
)
1989 1994 1998 2000 2002
Alfa-interferon monotherapy in thalassemic patients with chronic C hepatitis.
Authors Cuntries N. of patients
Mean age
Pts with cirrhosis
IFN dose Months of therapy
Rate of SVR(*)
Clemente
(1994)
Italy 51 14 0 % 3 MU/mq t.i.w.
15 37%
Di Marco
(1997)
Italy 70 14 15% 3 MU/mq t.i.w.
12 40%
Spiliopoulou
(1999)
Grecee 13 14 7.5% 3 MU t.i.w.
18 75%
Sievert
(2002)
Australia 28 26 3.5% 3 MU t.i.w.
6 28%
(*) SVR: sustained virological response:
Viral genotypes and Sustained Virological Response (SVR) to alpha Interferon
0
1020
3040
50
6070
8090
100
71.6%
33.3%
Genotypes 1 & 4
(n= 109)
Genotypes 2 & 3
(n= 30)
28.4 %
66.%
Therapy: alpha IFN 3 MU/mq for 48 weeks NR
SVR
(p < 0.001)
V. Di Marco et al, Gastroenterology 2007
Early Virological Response (EVR) as predictor of SVR . (Data of 23 thalassemics with chronic hepatitis C treated with alpha-interferon)
Negative HCV RNA
Yes
No
Week 12 of therapy14 SVR(87%)
2 NR (13%)
0 SVR(0%)
7 NR (100%)
16 patients
7 patients
(V. Di Marco, data from Blood, 1997)
Combination therapy with alpha-interferon and ribavirin in thalassemic patients with chronic C hepatitis.
Authors Patients N. of patients
Mean age
Doses of IFN
Dose of Ribavirin
Months of
therapy
SVR
(*)
Rate of SVR
(*)
Telfer
(1997)
No
responders
8 25 3 MU t.i.w.
1 g day
6 2/8 25%
Relapsers 3 25 3 MU t.i.w.
1 g day
6 3/3 100%
Li
(2002)
Naive 18 16 3 MU/mq t.i.w.
16 mg/kg day
12 13/18 72%
Sherker (2002)
Naive 3 28 3 MU t.i.w.
1 g day
12 3/3 100%
(*) SVR: sustained virological response:
Combination therapy with Peg-Interferon and ribavirin in thalassemic patients with chronic C hepatitis.
Authors Drugs N. of patients Months of therapy
Patients with SVR
Inati A et al, Br J Haematol. 2005
Peg-IFN alone 12 12 33%
Peg-IFN plus Ribavirin
8 12 63%
S.M. Kamal et al . EASL 2006
Peg-IFN alone 39 12 46%
Peg-IFN plus Ribavirin
39 12 64%
Paul Harmatz, Haematologica, 2008
Peg-IFN plus Ribavirin
4 (genotypes 2 - 3)
6 25%
Peg-IFN plus Ribavirin
12 (genotypes 1- 4)
12 50%
Changes in transfusion requirement and chelation regimen
0
20
40
60
80
100
Increase intransfusion and
chelation regimen
No increase intransfusion and
chelation regimen
PEG-IFN
PEG-IFN + RBV
38%
10%
Conclusions (I)
HCV infection is common in thalassemic patients.
Half of subjects with chronic HCV infection develop chronic
hepatitis.
Adult patients with active HCV infection have frequently a moderate or severe liver fibrosis and 20% of them have a cirrhosis.
Liver biopsy remains the gold standard to evaluate inflammation and fibrosis in thalassemia patients with chronic viral hepatitis.
Transient Elastography could also be used to define the presence of cirrhosis in centers with high expertise on this field.
Magnetic resonance imaging is a feasible alternative to liver biopsy
for liver iron measurement
In the near future we will use:
TE for the liver fibrosis definition MRI (T2*) for iron overload measurement of the liver and the heart
Conclusions (II)
Conclusions (III)
Death related to liver cirrhosis or to hepatocellular carcinoma is rare in thalassemic patients without HCV infection
Development of hepatocellular carcinoma is associated with the presence of cirrhosis and active HCV infection.
Conclusion (IV)
Patients with HCV hepatitis or cirrhosis should be treated with peg-interferon plus ribavirin.
The sustained virological response is more common in patients • without cirrhosis, • infected with genotypes 2 or 3, • with early suppression of viral load on therapy.
In thalassemic patients treated with interferon and ribavirin the blood transfusions can increase because of ribavirin-associated haemolysis.
Combination antiviral therapy can increase the number of patients cured by virus C and can reduce the risk of liver related death.