Vito  Di Marco Gastroenterology & Hepatology Department  (Di.Bi.M.I.S.)  University of Palermo Italy  Chronic viral hepati...
Causes of liver damage in thalassemia patients IRON OVERLOAD VIRUS INFECTION
Clinical course of chronic virus related liver disease Acute Hepatitis Resolution 20 - 30 Years Chronic Hepatitis Stabilis...
Hepatitis virus infections in thalassemic patients:  the key issues <ul><li>How many patients have chronic virus infection...
Hepatitis virus infection in thalassemic patients <ul><li>Hepatitis B Virus (HBV) infection </li></ul><ul><ul><li>HBV infe...
Angelucci, E. et al. Haematologica 2008;93:1121-1123 Prevalence of anti-HCV antibodies  in different age groups Hepatitis ...
Prevalence of HCV infection in a cohort of  thalassemics  followed for 16 years  (406 patients from 5 centres) ( V. Di Mar...
  Viral genotypes in thalassemic patients  with HCV chronic hepatitis Authors Geographic Area Number of patients Genotype ...
Liver biopsy on patients with thalassemia major <ul><li>Histologic scoring systems  </li></ul><ul><ul><li>grading    grad...
Biochemical, virological and histological features of 126 patients with liver biopsy  ( V. Di Marco, M. Capra  et al. Haem...
Rates of cirrhosis in 3 groups of thalassemic patients  who underwent  liver biopsy. Authors N. of patients Mean age %  an...
Which  non-invasive  markers can replace liver biopsy to evaluate fibrosis? <ul><ul><li>a. Serologic markers </li></ul></u...
Transient Elastography by Fibroscan® <ul><li>Advantages </li></ul><ul><li>Non-invasive and painless </li></ul><ul><li>Quic...
V. Di Marco , M. Capra et al.  British Journal of Haematology, 2010 <ul><li>Correlation between </li></ul><ul><ul><li>fibr...
Causes of death in a cohort of 406 patients  with thalassemia major followed for 16 years (1993-2009)  ( V. Di Marco, M. C...
Antiviral therapy for HCV chronic hepatitis (AASLD & EASL Guidelines)  <ul><li>The therapy is indicated in patients with: ...
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 + RB...
Alfa-interferon monotherapy in thalassemic patients with chronic C hepatitis. (*) SVR: sustained virological response:  Au...
Viral genotypes  and  Sustained Virological  Response  (SVR) to alpha Interferon  0 10 20 30 40 50 60 70 80 90 100 71.6% 3...
Early Virological Response  (EVR) as predictor  of SVR .  ( Data of 23 thalassemics with chronic hepatitis C treated with ...
Combination therapy with alpha-interferon and ribavirin in thalassemic patients with chronic C hepatitis. (*) SVR: sustain...
Combination therapy with Peg-Interferon and ribavirin in thalassemic patients with chronic C hepatitis. Authors  Drugs N. ...
Changes in transfusion requirement and chelation regimen   38% 10%
Conclusions (I) <ul><li>HCV infection is common in thalassemic patients.  </li></ul><ul><li>Half of subjects with chronic ...
<ul><li>Liver biopsy remains the gold standard to evaluate inflammation  </li></ul><ul><li>and fibrosis in thalassemia pat...
Conclusions (III) <ul><li>Death related to liver cirrhosis or to hepatocellular carcinoma is  rare in thalassemic patients...
Conclusion (IV)  <ul><li>Patients with HCV hepatitis or cirrhosis should be treated with peg-interferon plus ribavirin. </...
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Chronic viral hepatitis and liver disease in thalassaemia

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  • 03/12/10
  • Chronic viral hepatitis and liver disease in thalassaemia

    1. 1. Vito Di Marco Gastroenterology & Hepatology Department (Di.Bi.M.I.S.) University of Palermo Italy Chronic viral hepatitis and liver disease in thalassaemia
    2. 2. Causes of liver damage in thalassemia patients IRON OVERLOAD VIRUS INFECTION
    3. 3. Clinical course of chronic virus related liver disease Acute Hepatitis Resolution 20 - 30 Years Chronic Hepatitis Stabilisation Cirrhosis Compensated Cirrhosis Decompensated Cirrhosis (Death) Liver Cancer
    4. 4. Hepatitis virus infections in thalassemic patients: the key issues <ul><li>How many patients have chronic virus infection? </li></ul><ul><li>What are invasive and non-invasive methods for the diagnosis of chronic hepatitis or cirrhosis? </li></ul><ul><li>What are the risks of developing severe liver disease? </li></ul><ul><ul><li>Development of cirrhosis </li></ul></ul><ul><ul><li>Development of hepatocellular carcinoma (HCC) </li></ul></ul><ul><li>What are the therapies for patients with chronic virus hepatitis? </li></ul>
    5. 5. Hepatitis virus infection in thalassemic patients <ul><li>Hepatitis B Virus (HBV) infection </li></ul><ul><ul><li>HBV infection is present in less than 5% of adult subjects. </li></ul></ul><ul><ul><li>Anti-hepatitis B vaccination has ruled out the risk of new virus B infections. </li></ul></ul><ul><li>Hepatitis Virus C (HCV) infection </li></ul><ul><ul><li>Hepatitis C virus is the most common viral infection. </li></ul></ul><ul><ul><li>Worldwide 20%-80% of thalassemics are seropositive for anti-HCV antibodies </li></ul></ul><ul><ul><li>HCV chronic infection is more common in thalassemics transfused before 1990. </li></ul></ul>
    6. 6. Angelucci, E. et al. Haematologica 2008;93:1121-1123 Prevalence of anti-HCV antibodies in different age groups Hepatitis virus infections in thalassemic patients
    7. 7. 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) 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%)
    8. 8. 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
    9. 9. Liver biopsy on patients with thalassemia major <ul><li>Histologic scoring systems </li></ul><ul><ul><li>grading  grade of inflammatory component (score from G1 to G3 ) </li></ul></ul><ul><ul><li>staging  degree of fibrosis (score from F0 to F4) </li></ul></ul>F1 - Mild F2 - Moderate F3 – Severe F4 - Cirrhosis <ul><li>Perl’s Prussian blue stain: semiquantitative </li></ul><ul><li>method (score from 0 to 4) for the degree and cellular distribution of iron store. </li></ul><ul><li>Liver Iron Concentration (LIC): quantitative method (0.3 -1.8 mg/g dry weight) </li></ul>
    10. 10. 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 <ul><li>Histological inflammation (Grading) </li></ul><ul><ul><li>Absent </li></ul></ul><ul><ul><li>Mild /Moderate </li></ul></ul><ul><ul><li>Severe </li></ul></ul>23 (34%) 45 (66%) 0 0 56 (96%) 2 (4%) < 0.001 <ul><li>Histological fibrosis (Staging) </li></ul><ul><ul><li>Absent </li></ul></ul><ul><ul><li>Mild/ Moderate </li></ul></ul><ul><ul><li>Severe/ Cirrhosis </li></ul></ul>23 (34%) 42 (62%) 3 (4%) 2 (4%) 37 (64%) 19 (32%) < 0.001
    11. 11. 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%
    12. 12. Which non-invasive markers can replace liver biopsy to evaluate fibrosis? <ul><ul><li>a. Serologic markers </li></ul></ul><ul><ul><ul><li>Routine laboratory tests (indirect markers) </li></ul></ul></ul><ul><ul><ul><li>Fibrogenesis markers (direct markers) </li></ul></ul></ul><ul><ul><li>b. Imaging techniques </li></ul></ul><ul><ul><ul><li>Ultrasonography </li></ul></ul></ul><ul><ul><ul><li>Transient elastography (Fibroscan) </li></ul></ul></ul><ul><ul><ul><li>Transient elastography-MRI </li></ul></ul></ul>
    13. 13. Transient Elastography by Fibroscan® <ul><li>Advantages </li></ul><ul><li>Non-invasive and painless </li></ul><ul><li>Quick and inexpensive </li></ul><ul><li>Evaluation of larger area reduces sampling errors </li></ul><ul><li>Best at identifying significant fibrosis </li></ul><ul><li>Limitations </li></ul><ul><li>Poor discrimination in mild-to-moderate fibrosis </li></ul><ul><li>Cannot be used in patients with ascites </li></ul><ul><li>Inaccurate in obese patients </li></ul>
    14. 14. V. Di Marco , M. Capra et al. British Journal of Haematology, 2010 <ul><li>Correlation between </li></ul><ul><ul><li>fibrosis stage and LIC (A) </li></ul></ul><ul><ul><li>fibrosis stage and LSM (B) </li></ul></ul>Noninvasive assessment of liver fibrosis in thalassaemia major patients by transient elastography
    15. 15. Causes of death in a cohort of 406 patients with thalassemia major followed for 16 years (1993-2009) ( V. Di Marco, M. Capra, A. Maggio et al, submitted) 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
    16. 16. Antiviral therapy for HCV chronic hepatitis (AASLD & EASL Guidelines) <ul><li>The therapy is indicated in patients with: </li></ul><ul><ul><li>elevated transaminases, </li></ul></ul><ul><ul><li>positive blood tests for anti-HCV and HCV-RNA </li></ul></ul><ul><ul><li>clinical evidence of significant liver fibrosis or cirrhosis. </li></ul></ul><ul><li>The main goals of the treatment are: </li></ul><ul><ul><li>the eradication of virus C; </li></ul></ul><ul><ul><li>the control of liver inflammation and liver fibrosis </li></ul></ul><ul><ul><li>the prevention of cirrhosis; </li></ul></ul><ul><li>Treatment can be defined efficacy if: </li></ul><ul><ul><li>serum HCV-RNA remains negative almost 6 months after the end of therapy. </li></ul></ul>
    17. 17. 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. Sustained Virological Response (%) 1989 1994 1998 2000 2002
    18. 18. Alfa-interferon monotherapy in thalassemic patients with chronic C hepatitis. (*) SVR: sustained virological response: 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%
    19. 19. Viral genotypes and Sustained Virological Response (SVR) to alpha Interferon 0 10 20 30 40 50 60 70 80 90 100 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
    20. 20. 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 therapy 14 SVR (87%) 2 NR (13%) 0 SVR (0%) 7 NR (100%) 16 patients 7 patients (V. Di Marco, data from Blood, 1997)
    21. 21. Combination therapy with alpha-interferon and ribavirin in thalassemic patients with chronic C hepatitis. (*) SVR: sustained virological response: 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%
    22. 22. 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%
    23. 23. Changes in transfusion requirement and chelation regimen 38% 10%
    24. 24. Conclusions (I) <ul><li>HCV infection is common in thalassemic patients. </li></ul><ul><li>Half of subjects with chronic HCV infection develop chronic hepatitis. </li></ul><ul><li>Adult patients with active HCV infection have frequently a moderate or severe liver fibrosis and 20% of them have a cirrhosis. </li></ul>
    25. 25. <ul><li>Liver biopsy remains the gold standard to evaluate inflammation </li></ul><ul><li>and fibrosis in thalassemia patients with chronic viral hepatitis. </li></ul><ul><li>Transient Elastography could also be used to define </li></ul><ul><li>the presence of cirrhosis in centers with high expertise on this field. </li></ul><ul><li>  </li></ul><ul><li>Magnetic resonance imaging is a feasible alternative to liver biopsy </li></ul><ul><li>for liver iron measurement </li></ul><ul><li>In the near future we will use: </li></ul><ul><li>TE for the liver fibrosis definition </li></ul><ul><li>MRI (T2*) for iron overload measurement of the liver and the heart </li></ul>Conclusions (II)
    26. 26. Conclusions (III) <ul><li>Death related to liver cirrhosis or to hepatocellular carcinoma is rare in thalassemic patients without HCV infection </li></ul><ul><li>Development of hepatocellular carcinoma is associated with the presence of cirrhosis and active HCV infection. </li></ul>
    27. 27. Conclusion (IV) <ul><li>Patients with HCV hepatitis or cirrhosis should be treated with peg-interferon plus ribavirin. </li></ul><ul><li>The sustained virological response is more common in patients </li></ul><ul><ul><li>without cirrhosis, </li></ul></ul><ul><ul><li>infected with genotypes 2 or 3, </li></ul></ul><ul><ul><li>with early suppression of viral load on therapy. </li></ul></ul><ul><li>In thalassemic patients treated with interferon and ribavirin the blood transfusions can increase because of ribavirin-associated haemolysis. </li></ul><ul><li>Combination antiviral therapy can increase the number of patients cured by virus C and can reduce the risk of liver related death. </li></ul>

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