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

Chronic viral hepatitis and liver disease in thalassaemia Chronic viral hepatitis and liver disease in thalassaemia Presentation Transcript

  • Vito Di Marco Gastroenterology & 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 Acute Hepatitis Resolution 20 - 30 Years Chronic Hepatitis Stabilisation Cirrhosis Compensated Cirrhosis Decompensated Cirrhosis (Death) Liver Cancer
  • Hepatitis virus infections in thalassemic patients: the key issues
    • How many patients have chronic virus infection?
    • What are invasive and non-invasive methods for the diagnosis of chronic hepatitis or cirrhosis?
    • What are the risks of developing severe liver disease?
      • Development of cirrhosis
      • Development of hepatocellular carcinoma (HCC)
    • 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
  • 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%)
  • 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
    • 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
    • Perl’s Prussian blue stain: semiquantitative
    • method (score from 0 to 4) for the degree and cellular distribution of iron store.
    • 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 0 56 (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 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
  • Transient Elastography by Fibroscan®
    • Advantages
    • Non-invasive and painless
    • Quick and inexpensive
    • Evaluation of larger area reduces sampling errors
    • Best at identifying significant fibrosis
    • 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) ( 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
  • 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. Sustained Virological Response (%) 1989 1994 1998 2000 2002
  • 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%
  • 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
  • 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)
  • 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%
  • 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 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.