Chronic hepatitis

a short take on chronic hepatitis

1. CHRONIC VIRAL HEPATITIS

2. Introduction Chronic hepatitis represents a series of liver disorders of varying causes and severity in which hepatic inflammation and necrosis continue for at least 6 months . Milder forms are nonprogressive or only slowly progressive, while more severe forms may be associated with scarring and architectural reorganization, which, when advanced, lead ultimately to cirrhosis, etc.

3. Older Classification 1. Chronic persistent hepatitis 2. Chronic active hepatitis 3. Chronic lobular hepatitis

4. Newer Classification The classification of chronic hepatitis is based on 1. Cause 2. Histologic activity or grade 3. Stage or degree of progression

5. CAUSES OF CHRONIC HEPATITIS 1 . Viral (HBV, HCV, HDV ) 2. Drugs (alpha-methyldopa, isoniazid ) 3. Alcoholic liver disease 4. Non-alcoholic steatohepatitis 5. Metabolic causes a. Primary biliary cirrhosis b. Sclerosing cholangitis c. Alpha-1-antitrypsin deficiency d. Wilson’s disease e. Haemochromatosis 6. Autoimmune hepatitis a. Type I ( antiactin / lupoid ) b. Type II (anti-liver kidney microsomal ) c. Type III (anti-soluble liver antigen) 7. Cryptogenic

6. By Grade Histologic Activity Index(HAI) HAI Score Knodell-Ishak score

7. By Stage

8. Hepatitis B Virus HBV is a DNA virus that belongs to the hepadnavirus family. Eight genotypes of HBV have been identified and labeled A through H . HBV (with or without cirrhosis) causes 60% to 80% of HCC worldwide. HBV-related mortality is estimated between 500,000 and 1,000,000 deaths worldwide per year. HBV is an indication for l5% to 10% of the cases of liver transplantation.

9. Pathophysiology HBV liver damage is immune mediated. Modes of transmission Horizontal transmission Parenteral or percutaneous routes (e.g., needlestick injury, injection drug use, hemodialysis , transfusions) Sexual contact (e.g., men who have sex with men, sexual promiscuity, or intercourse with HBV-infected partners) Vertical transmission: Mother to infant

10. Chronic hepatitis B runs an indolent course, sometimes for decades. Fatigue is a common symptom but frequently overlooked because of its subjectivity. The disease may only become clinically apparent late in the natural course, with symptoms typically associated with ESLD . Chronic HBV infection is a dynamic process that occurs in different phases

11. Clinical course of HBV Acute hepatitis B infection Chronic HBV infection 3-5% of adult-acquired infections 95% of infant-acquired infections Cirrhosis Chronic hepatitis 12-25% in 5 years Liver failure Hepatocellular carcinoma 6-15% in 5 years 20-23% in 5 years

12. Chronic hepatitis B immune tolerant patients and chronic hepatitis B with low replication should not be treated.

13. Three main groups: 1. IFNs , 2. Nucleoside analogs ( entecavir ), 3. Nucleotide analogs ( tenofovir ).

14. The ideal treatment outcome is HBsAg loss with seroconversion , unfortunately this goal is rarely achieved . Therefore , in patients who are HBeAg positive at baseline, the expected outcome is loss of HBeAg with anti-e seroconversion , clearance of HBV DNA, and normalization of liver enzymes.

15. In patients who are HBeAg negative at baseline, the expected outcome is clearance of HBVDNA and normalization of liver enzymes. In patients who are HBeAg positive at baseline, treatment should be prolonged at least 6 months after HBeAg loss/ seroconversion . These patients should be monitored, given the possibility of reactivation.

16. In patients who are HBeAg negative at baseline , treatment should be continued indefinitely or until HBsAg loss/ seroconversion is achieved.

17. Antiviral resistance is a phenomenon observed with the use of nucleoside and nucleotide analogs . Resistance should be considered in patients with an HBV DNA level increase (.1 log10) from the lowest level of suppression achieved while on therapy .

18. Tenofovir and entacavir have a high genetic barrier for resistance ( lowest susceptibility ) when compared to other nucleoside and nucleotide analogs and are therefore the preferred oral therapeutic agents

19. First Line Entecavir (ETV ) oral nucleoside ( guanosine ) analog Dose: 0.5 orally and 1 mg orally in case of lamivudine resistance for 48 weeks. Tenofovir ( TDF) oral nucleotide (acyclic) analog Dose: 300 mg daily

20. INTERFERONS A ntiviral, antiproliferative and immunomodulatory effects. IFN-α and -β bind to the same receptor and have predominantly antiviral effects. IFN-γ binds to a separate receptor and has more marked immunoregulatory action but less potent antiviral effects. Pegylation reduces rate of absorption,renal clearance, decreases immunogenecity and increases half life.

21. IFN- α 2a and 2b—SC either 10 million units thrice weekly or 5 million units daily for 4-6 months or peginterferon α 2a 180 mcg weekly or 2b 100 mcg weekly for 48 weeks

22. Second Line Telbivudine ( LdT ) oral nucleoside ( thymidine ) analog Dose: 600 mg daily Adefovir (ADV) oral nucleotide (adenosine) analog Dose : 10 mg daily orally for 48 weeks Lamivudine oral nucleoside (dideoxy-3¢- thiacytidine ) analog Dose : 100 mg daily orally for 48 weeks

23. Hepatitis C Classification HCV is an RNA virus that belongs to the flavivirus family. There are six HCV genotypes with multiple subtypes

24. Epidemiology HCV is a global health problem with approximately 180 million carriers worldwide . The incidence of hepatitis C has declined in the last 30 years.

25. HCV infection is the most common chronic blood-borne infection Transmission by transfusion of blood products (and their derivatives) and organ transplantation has been reduced to near zero in developed countries due to sensitive screening methods.

26. Genotype 1 accounts for 75% and genotypes 2 and 3 account for 20% of HCV infections in the United States.

27. 70% of cases of chronic hepatitis, 40% of cases of ESLD, 60% of cases of HCC, and 40% of liver transplantations.

28. Pathophysiology The liver damage that ensues after HCV infection is immune mediated. Modes of transmission include: Parenteral (e.g., transfusion, injection drug use, body piercing, needlestick injury) Sexual (high-risk sexual practices) and from mother to offspring ( vertical transmission ), although at a much lower frequency than HBV

29. Clinical Presentation The incubation period varies from 15 to 150 days. Acute hepatitis can be silent, especially in children and young adults.

30. Symptoms may also vary from mild illness to ALF. Malaise, fatigue, pruritus , headache abdominal pain, myalgias , arthralgias , nausea, vomiting, anorexia, and fever are common but nonspecific symptoms. Chronic hepatitis runs an indolent course, sometimes for decades . Fatigue is a common symptom. The disease may only become clinically apparent late in the natural course, when symptoms are associated with advanced liver disease.

31. Risk factors

32. Natural history

33. Diagnostic Testing Antibodies against HCV (anti-HCV) may be undetectable for the first 8 weeks after infection. These antibodies are detected by enzyme immunoassay (EIA ). Antibodies do not confer immunity . The test has a sensitivity of 95% to 99% and a lower specificity. A false-positive test (anti-HCV positive with HCV RNA negative ) may be detected in the setting of autoimmune hepatitis (AIH) or hypergammaglobulinemia . A false-negative test (anti-HCV negative with HCV RNA positive ) may be seen in immunosuppressed individuals and in patients on hemodialysis .

34. HCV RNA can be detected by PCR in serum as early as 1 to 2 weeks after infection (qualitative and quantitative assays). It is expressed in international units per milliliter (IU/ mL ), with lower limits of detection approaching 10 IU/ mL. HCV RNA determination is useful for both diagnosis and treatment purposes.

35. HCV genotypes and subtypes can be detected by commercially available serologic and molecular assays. HCV genotype influences the duration, dosage, and response to treatment. Liver biopsy is useful to score the degree of inflammation (grade) and fibrosis (stage) in the liver of chronically infected patients. It is useful to grade the amount of liver steatosis and guides treatment decisions.

36. Treatment Goals Endpoints Viral eradication Prevention of disease progression Sustained loss of HCV RNA in serum (3-6 months post- Tx ) Normalization of liver enzymes Improved liver histology Improved quality of life

37. Treatment outcome in HCV is determined by a number of pretreatment and ontreatment factors Pretreatment factors Viral genotype, IL-28B genotype (CC allele), viral load, treatment naïve or previous treatment failure, advanced liver disease (amount of liver fibrosis), metabolism (obesity, steatosis , and insulin resistance), race/ethnicity On-treatment factors Adherence to the prescribed regimen, dose and duration of ribavirin , pIFN -a, and protease inhibitors boceprevir and telaprevir Rapidity of viral clearance

38. Treatment In patients with genotype 1 (all subtypes), the standard of care is to use triple therapy including pIFN , ribavirin , and a direct antiviral agent (DAA ). DAAs currently approved are boceprevir and telaprevir . The chosen treatment regimen takes into consideration prior exposure and response to pIFN and ribavirin , presence of cirrhosis, and selected DAA Side effects of IFN-based therapy include flu-like symptoms, neuropsychiatric disorders , endocrine dysfunction, and bone marrow suppression.

39. HEPATITIS D Classification HDV is a circular RNA virus and is the only member of the genus Delta virus . Originally, it was considered a subviral particle resembling plant pathogens, viroids , and virusoids .

40. Epidemiology It is found throughout the world and is endemic to the Mediterranean basin, the Middle East, and portions of South America. Outside these areas, infections occur primarily in individuals who have received transfusions or in injection drug users. HDV requires the presence of HBV for infection and replication.

41. Pathophysiology HDV infection clinically presents as a coinfection ( acute hepatitis B and D ), as a superinfection ( chronic hepatitis B with acute hepatitis D) that may progresses to chronic infection and cirrhosis, or as a latent infection (i.e., in the liver transplantation setting).

42. Risk Factors High-risk groups are similar to HBV (see Epidemiology under Hepatitis B Virus section). Prevention Although there is no vaccine to prevent HDV in carriers of HBV, both infections can be prevented by timely administration of the HBV vaccine.

43. Clinical Presentation In patients with coinfection , the course is transient and self-limited. The rate of progression to chronicity is similar to the one reported for acute HBV. In superinfection , the HBV carriers may present with a severe acute hepatitis exacerbation with frequent progression to chronic HDV.

44. Diagnostic Testing Diagnosis is made by finding HDV RNA or HDV antigen in serum or liver and by detecting antibody to the HDV antigen in the setting of acute or chronic HBV. TREATMENT IFN-a is the treatment of choice for chronic hepatitis D .

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