Chronic Viral Hepatitis

1. Mohssen Nassiri Toosi, MD Associate Professor of Internal Medicine Tehran University of Medical Sciences Imam Khomini Hospital Chronic Viral Hepatitis

2. Chronic Viral Hepatitis _ Definition • An ongoing, sustained inflammation of liver cells ( > six months ) • Etiology of liver cell damage can not resolved spontaneously • Recruitment of inflammatory cells and Liver cell damage is ongoing • There is continuous liver cell loss and liver cell regeneration • Production of reactive materials make damage to collagen skeleton of liver parenchyma • Destruction of liver collagenous skeleton lead to incomplete and insufficient liver cell regeneration • Liver cell loss overcome liver cell regeneration • Collagen production overcome repair

3. Chronic Inflammation and damage of liver cells lead to fibrosis What is Chronic Hepatitis? • Liver cell injury, necrosis & loss • Inflammatory cells recruitment • Edema & inflammation • Fibrosis necrosis Inflammatory cells

4. Variety of etiology (causes) of Chronic Hepatitis • Infections * • Viruses Unknown ? Fat & obesity Autoimmune dis. • Drug & Toxins * • Alcohol Ischemia • Metabolic & Inborn error metabolism disorders • Wilson • HHE • Tyrosinemia , …..

5. Just Timing course patterns of Hepatitis --- + • Acute • self-limited < 6 mo • Chronic • Persistent > 6 mo or life-long No fibrosis Fibrosis Acute hepatitis Chronic hepatitis … Time 6 months

6. Chronic Viral Hepatitis - Facts • HBV, HDV, and HCV are blood-born viral hepatitis • Relatively long incubation period (months) • Usually do not have symptoms (asymptomatic) • Detected by blood tests in high risk groups or incidentally • Usually presented with chronic presentation of liver cell failure and portal hypertension • Sometimes presented with acute or acute on chronic presentation

7. Chronic Viral Hepatitis Host Immune system Genetics Gender Age at infection Obesity Alcohol Smoking • Hepatitis virus • Genotype • Viral load • Mixed HCV infection • Co-infection • with HIV or HBV

8. Chronic Viral Hepatitis • Hepatitis virus + Host • Chronic liver cell injury • Chronic liver inflammation • Chronic liver cell necrosis • Chronic liver cell loss • Increased collagen deposition

9. Chronic Viral Hepatitis • Hepatitis virus + Host • Chronic liver cell (injury + inflammation + necrosis) + fibrosis Abnormal markers of liver cell injury (AST/ALT) + Antibody and antigen tests for virus Liver cell loss Hepatic dysfunction Abnormal PT (INR), Alb Increased collagen deposition Liver stiffness Cirrhosis, Portal hypertension +

10. Chronic Hepatitis C “The Facts” 100% (100) Exposure (Acute phase) 25% (25) 75% (75) HIV and Alcohol Resolved Chronic 80% (60) 20% (15) Stable Cirrhosis 75% (11) 25% (4) Slowly Progressive Liver failure, HCC Transplant Death The Natural History of Chronic Hepatitis C

11. * HCV Extrahepatic manifestation • Cryoglobilinemia • Monoclonal gammopathy (weakness, artheralgia, purpura, MPGN) • Lymphoma • Idiopathic Thrombocytopenic Purpura (ITP) • Arthralgia, arthritis • Porphyria cutanatarda • Sjogren,ssyn. • Lichen planus • Thyroiditis • Memberanousglomerolonephritis (GN) • Peri-arteritis Nodosa (PAN)

13. HBV infected Liver cell Cytoplasm HBV infected Liver cell Nucleus Serum virus S gene HBs Ag Virus HBs Ag = Presence of HBV infection virus C gene HBc Ag + HBe Ag Immune sys HBc Ab = Previous contact with HBV virus Virus HBe Ag = Replication of HBV virus Virus HBV-DNA = Replication of HBV virus Complete HBV virion

14. Markers for HBV • Complete virus {complex of HBs Ag, HBe Ag, HBc Ag, HBV-DNA} • Incomplete free soluble viral particles (HBs Ag, HBe Ag) • Immune system response (HBc Ab)

15. S gene = HBs Ag in liver and serum HBs Ag in serum = There is HBV infection in the body. Presence of infection C gene = HBc Ag in liver cell, no HBc Ag in serum HBc Ag in liver cell = HBc Ab in serum HBc Ab in serum = There was previous contact with HBV. HBc Ab is not protective. C gene = HBe Ag in liver and serum HBe Ag in serum = There is active viral replication. Presence of infection & Viral replication HBV-DNA = Complete HBV virion in liver and serum HBV-DNA load = Presence of complete HBV virus

16. Immunetolerant Immuneclearance Inactivecarrier Reactivation HBeAg–ve CHB HBeAg+ve CHB Immunecontrol phase Natural history of CHB HBeAg Anti-HBe HBVDNA ALT Immunetolerant Adapted from Fattovich G. Sem Liver Dis. 2003; 23: 47.

19. and cirrhosis and HIV or cirrhosis

20. Therapy Interferons for Chronic Viral HepatitisSome benefit, some risk • Antiviral and immune stimulator • Many side effects: fever, anorexia, weight loss, depression, anemia, WBC / Plts drops • Not useful for those with high viral DNA, low ALT level • Not useful in immune tolerant, transplants or decompensated cirrhosis

21. Oral anti virus drugsNucleoside analogue • Directly antiviral but not immuno-stimulatory • No or less side effects, safe, oral, easy to take • Side effect : virus mutations • Stop drug without seroconversion = virus returns

23. Sustained virus clearance is closest to clinical cure. Chronic Viral HepatitisThe ultimate goals of therapy SUSTAINED VIRUSCLEARANCE HCV RNA undetectable HBV DNA undetectable HBs Ag loss HBs Abseroconversion Reduces hepatocellular carcinoma & cirrhosis Improves survival SUSTAINEDIMMUNECONTROL HCV RNA suppression HBV DNA suppression HbeAbseroconversion ON-TREATMENT HCV RNA suppression HBV DNA suppression Hbe Ag loss 1. Perrillo R, Hepatology 2006; 43: 182;2. EASL. J Hepatol 2009; 227: 242;3. van Zonneveld M, et al. Hepatol 2004; 39: 804;4. Marcellin P, et al. 20th APASL 2010: Abstract 209.

25. Course of different causes of Hepatitis Acute hepatitis + + + + + + - - - + Chronic hepatitis - + + + - + + + + - • Hepatitis A virus • Hepatitis B virus • Hepatitis C virus • Hepatitis D virus • Hepatitis E virus • Drug, alcohol, toxins • Autoimmune • Metabolic (Wilson, HHE) • Fat & obesity (NASH) • Ischemia

26. D A E Viral HepatitisVirology B C Major Hepatitis Viruses virus family, shape, size, envelope status, nucleic acid type • Hepatitis A (HAV) Picornaviridae • non-envelope Icosahedral 27 nm RNA virus • Hepatitis B (HBV) Hepadnaviridae • envelope Spherical 42 nm DNA virus • Hepatitis C (HCV) Flaviridae • envelope Spherical 55 nm RNA virus • Hepatitis D (HDV) Viroid • envelope (HBs Ag) Spherical 35 nm RNA virus • Hepatitis E (HEV) Ca;iciviridae • non-envelope Icosahedral 32 nm RNA virus

27. Risk groups for hepatitis C • Intravenous drug users (IVDU) , Intranasal cocaine ? • Needle stick • History of blood transfusion • Jail , Tattooing ? , Body piercing ? • Sharing razors or tooth brushes • Hemodialysis Endoscopy, surgery • Health care workers • Sexual contact with infected persons • Maternal transmission • Traditional practicing (Barbers) • Family contacts (Non-sexual) 27

28. HCV Transmission in IVDU Rate of HCV infection is 4 times higher than HIV infection 90% IVDU become HCV positive after 5 Yrs. Injecting HCV: 3 mo. (50-60%), 1 Yr. (80%) HBV: 3 mo. (40%), 6 Yrs. (80%) HIV: 6 mo. (30%), 6 Yrs. (30%)

29. HCV Transmission by needle stick • Comparative needle stick transmission risk: • HBV 30% • HCV 3% • HIV 0.3% • Influenced by: • Size of inoculums • Size of needle • Depth of inoculation • Type of needle (Hollow needle and cannulas)

30. HCV Non-parenteral Transmission ( percutaneous or mucous-membrane exposure ) • Sexual transmission • Limited role • Inefficient mode • Long term monogamous relationship Transmission Risk < 5% • No HCV in semen, urine, stool or vaginal secretions • Lack of appropriate target cells (CD81)

31. HCV Vertical Transmission (mother to neonate) • High maternal viral load (>million/ml) • Infrequent (<6%) • Increased by HIV co-infection • Not transmitted by breast feeding, except for nipple sore or bleeding

32. HCV Genotypes 1b 2 , 3 1b , 2 1a , 1b 2 , 3 1b , 6 1b , 3 4 3 5 1b , 3 • 170 million people (Five times more than HIV)

33. Diagnosis of Viral Hepatitis • Antibody tests Vs Antigen tests • HCV • Serum Anti-HCV antibody (ELISA test) • Srum HCV-RNA PCR is diagnostic for HCV hepatitis

35. 2 billion HBV infected = HBc Ab positive 400 million HBV disease = HBs Ag positive 70% HBV carriers are in Asia

37. Risk groups for hepatitis B • Infants born to infected mother • Household contact with chronically HBV infection • Intravenous drug users • History of blood transfusion • Sexual contact with infected persons • Hemodialysis patients • Health care workers 37

38. major protein middle protein large protein Pre-S1 Pre-S2 P S HBV-DNA smaller spherical tubular particles HBsAg partially double-strand,partially single-strand Non-soluble, nucleocapsid proteins HBcAg C converted in hepatocyte nucleus to covalently closed circular DNA CCDNA Pre-C + DNA polymerase Soluble, nonparticulate, nucleocapsid protein HBeAg X small, Nonparticulateprotein HBxAg

39. S gene Surface protein HBs Ag (envelop) C gene Capsid protein C protein Cytoplasm messenger RNA X protein X gene Nucleus Liver cell DNA polymerase P gene HBV DNA virus CCC DNA - - + + - - + + Virus DNA polymerase RNA-dependent reverse transcriptase activity DNA-dependent DNA polymerase activity Cytoplasm pregenomic RNA plus-strand DNA New DNA HBV virus minus-strand DNA HBV virion

40. Natural History of HBV Infection Observation 1 95% chronicity Immune Tolerance Adulthood Early Childhood < 5% chronicity Immune Escape Immune Clearance ? 4 2 HBeAg -ChronicHepatitis B HBeAg +ChronicHepatitis B Cirrhosis HCC Treatment ? 3 Inactive Carrier Immune Control Observation Courtesy of W. Ray Kim, MD.Chen DS, et al. J Gastroenterol Hep. 1993;8:470-475.Seeff L, et al. N Engl J Med. 1987;316:965-970.