1. Diagnostic approach to chronic hepatitis Dr. Kyaw Min Hepatic inflammation and necrosis continue for at least 6 months.

2. Learning objective At the end of the class the student should be able to: – Define hepatitis and list the causes of chronic hepatitis – Discuss the pathology and the clinical features – Relevant investigations to diagnose the cause

3. Content Definition of chronic hepatitis Clinical presentation of chronic hepatitis Classification and causes of chronic hepatitis Differentiate the causes based on pathogenesis, patient factors and investigation results

4. Definitions for Hepatitis Acute: Short term and/or severe. Chronic: Lingering or lasting - may or may not be severe Fulminant: Developing quickly and lasting a short time, high mortality rate.

5. Definition Hepatitis = inflammation of liver parenchyma with varying degrees of structural damage Chronic hepatitis = lasting 6 months or longer Mild forms Severe forms -cirrhosis

6. Causes Chronic hepatitis Autoimmune Hepatitis B +/-D Hepatitis C Drugs Wilson’s

7. Classification Based on aetiology, clinical grade, histological grade and stage

8. Histological grade = necro-inflammatory activity (minimal, mild, moderate, severe) Histological stage = extent of fibrosis (none, mild, moderate, severe, cirrhosis) Knodel Ishak scoring: based on periportal necrosis, intralobar necrosis, portal inflammation and fibrosis. – Important in predicting development of cirrhosis

11. Chronic viral hepatitis – Mild chronic hepatitis Degeneration, spotty, focal necrosis, acidophilic body Portal may have or no the infiltration of inflammation cell, mild PN or enlarged The structure is intact – Moderate chronic hepatitis(CAH) Portal area have obvious inflammation, with moderate PN Severe inflammation with BN of intralobule Form fibrous septum, most the structure of lobule reserved

12. The spectrum of clinical features of chronic hepatitis B is broad, ranging from asymptomatic infection to debilitating disease or even end-stage, fatal hepatic failure. Fatigue is a common symptom, and persistent or intermittent jaundice malaise and anorexia

13. Clinical presentation Fatigue, generally unwell Jaundice, large liver Positive blood test (Hep B/C): before blood donation, before dialysis or surgery, routine pre-employment screening Failure to recover (clinically or biochemically) from acute hepatitis Abnormal LFTs on routine check up Previous blood transfusion Previous IV drug use/vertical transmission

14. Complications of cirrhosis occur in end- stage chronic hepatitis and include ascites, edema, bleeding gastroesophageal varices, hepatic encephalopathy, coagulopathy, or hypersplenism.

16. Chronic Hepatitis B The likelihood of chronicity after acute hepatitis B varies as a function of age. Infection at birth is associated with clinically silent acute infection but a 90% chance of chronic infection. Infection in young adulthood in immunocompetent persons is typically associated with clinically apparent acute hepatitis but a risk of chronicity of only approximately 1%.

18. Development of the chronic HBV carrier state

19. ACUTECHRONIC

20. Natural History of Chronic HBV Infection Acute Infection 5-10% Chronic Carrier 90-95% Resolution 30–50 Years Chronic Hepatitis Stabilisation Progression Cirrhosis Compensated Cirrhosis Liver Cancer Death Adapted from Feitelson, Lab Invest 1994 Decompensated Cirrhosis (Death) 15-25%

21. Clinical course of HBV in adults

22. What do we expect from chronic hepatitis B? Cirrhosis –Compensated –Decompensated Complication of cirrhosis –Ascites –Variceal bleeding –Hepatic encephalopathy Hepatocellular carcinoma

23. HBV-DNA by PCR also indicates active replication of the virus HBV replication = Disease (Acute or Chronic replicative phase)

25. 2011 OSEP Leadership Mega Conference Collaboration to Achieve Success from Cradle to Career 2.0 Anti-HBc IgM: Acute or present infection Anti-HBc IgG: Chronic or past infection

26. HBeAg-negative chronic hepatitis B, HBeAg-reactive chronic hepatitis (no more than 10 5 –10 6 virions/mL) HBV DNA levels well in excess of 10 5 – 10 6 virions/mL Inactive carriers: levels of HBV DNA that are either undetectable or present at levels 10 3 virions/mL

27. Investigations 1. Deranged liver function tests 2. Serology: HBsAg + Anti-HBc IgM–Acute Hepatitis B HBsAg + IgG HBcAg HBsAg –ve (cured) HBeAg HBV DNA HBeAg+ HBeAg- HBsAg +ve (carrier) Wild type Precore Mutants

28. Precore Mutants patients with HBeAg-negative chronic hepatitis B (precore mutants) can have progressive liver injury (complicated by cirrhosis and HCC) and experience episodic reactivation of liver disease reflected in fluctuating levels of aminotransferase activity ("flares").

29. Hepatitis B ± D Treatment – All patients with chronic active hepatitis B should receive antiviral agents – Interferon-α (PEGylation) – Lamivudine – Ribavirin 100 mg orally daily – Adefovir dipivoxil 10 mg orally Pegylated Interferon, long acting

30. Hepatitis B +/-D Treatment – given to avoid progression to cirrhosis – Interferon-α + Lamivudine best combination

31. Treatment Seroconversion from HBeAg to anti-HBe occurs in approximately 20%, Relapse after successful therapy is rare (1 or 2%).

32. PEG IFN b LamivudineAdefovirEntecavir Route of administration Subcutaneous injection Oral Duration of therapy 48–52 weeks52 weeks48 weeks TolerabilityPoorly tolerated Well toleratedWell tolerated; creatinine monitoring recommended Well tolerated HBeAg loss 1 year 29–30%20–33%23%22%

33. Side effects Interferon: flu like symptoms, bone marrow suppression, rash, alopecia, numbness, autoimmune reactions. Lamivudine alone: Mutant side effects Adefovir: rare nephrotoxic

34. Serologic Pattern of Acute HCV Infection with Recovery Symptoms +/- Time after Exposure Titer anti-HCV ALT Normal 012345 61234 Years Months HCV RNA

35. Serologic Pattern of Acute HCV Infection with Progression to Chronic Infection Symptoms +/- Time after Exposure Titer anti-HCV ALT Normal 012345 61234 Years Months HCV RNA

37. Hepatitis C Clinical features – All ages affected and both sexes affected equally – Commonly asymptomatic – Risk factors for hep C infection present – Severity very variable – Extrahepatic manifestations: Sjögren's syndrome, lichen planus, porphyria cutanea tarda. Diagnostic tests – Anti HCV, HCV RNA – Biopsy: Fat, lobular component, lymphoid aggregates High-level HCV RNA (>2 million copies/mL )

38. recombinant immunoblot assay (RIBA) test to help confirm a hepatitis C infection.

39. Hepatitis C Treatment – Pegylated Interferon-α with ribavirin Prognosis – Usually very slow progression – cirrhosis in 20-30% within 3 decades – Variable prognosis depending on age, race and development of cirrhosis

40. Laboratory examination Liver function – Serum transaminase ALT(alanine transferase) ↑ AST(aspartase transferase) ↑ ALP (Alkaline phosphatase) ↑ in chronic hepatitis LDH (Lactate dehydrogenase) ↑ – Serum protein Albumin ↓ In chronic hepatitis Ig ↑↑ The ratio of A/G ↓ – Bilirubin Urobilinogen ↑in early stage of AIH

41. Urobilinogen and urobilin ↑in icteric stage Urobilin is positive and urobilinogen may be negative in cholestatic hepatitis – Prothrombin time may be prolonged especially in fulminant hepatitis – Blood amonia examination Detection of the markers of hepatitis virus – Hepatitis A Serologic marker – Anti-HAVIgM: recent infection – Anti-HAVIgG: past infection

42. Marker of feces – HAV particles may be detected by RIA or IEM – Isolation of HAV may use tissue culture or animal inoculation – Hepatitis B Sero-immunologic marker – HBsAg anti-HBs – HBcAg anti-HBc – HBeAg anti-Hbe Molecular biological marker – DNAp – HBV DNA – Immune tissue chemistry examination – Hepatitis C Serological marker – Anti-HCVIgM – Anti-HCVIgG

43. Molecular biologic marker – HCV RNA may be detective by RT-PCR 1-2 weeks after infection of HCV – Quality of HCV RNA – Immune tissue chemistry method detect HCAg within liver cells – Hepatitis D HDAg anti-HDV HDV RNA – Hepatitis E Anti-HEVIgG,Anti-HEVIgm RT-PCR HEV particais: IF IEM

44. Ultra-sound examination Liver biopsy Other laboratory examination – Blood routine – Urine routine

45. AUTOIMMUNE HEPATITIS Chronic hepatitis of unknown etiology Can progress to cirrhosis Characteristics include: – presence of autoimmune antibody – evidence of hepatitis – elevation of serum globulins

46. Autoimmune Clinical features – More females affected – Usually aged 14-25 or post menopausal – 25% present with acute hepatitis – Associated with other autoimmune diseases Cause unknown Classified as type 1 (“lupoid”), type 2 and type 3

47. Clinical features Type I auimmune hepatitis is the classic syndrome Fatigue, malaise, anorexia, amenorrhea, acne, arthralgias, and jaundice are common. Occasionally arthritis, maculopapular eruptions (including cutaneous vasculitis), erythema nodosum, colitis, pleurisy, pericarditis, anemia, azotemia, and sicca syndrome (keratoconjunctivitis, xerostomia) occur.

48. CLINICAL PRESENTATION Hepatomegaly Jaundice Stigmata of chronic liver disease Splenomegaly Elevated AST and ALT Elevated PT Non-specific symptoms: malaise, fatigue, lethargy, nausea, abdominal pain, anorexia

49. DIAGNOSIS Elevated AST and ALT Elevated IgG Rule out other causes: – Wilsons disease – Alpha 1 antitrypsin deficiency – Viral hepatitis (A, B, C) – Drug induced liver disease (alcohol, minocycline, nitrofurantoin, INH,, methyldopa, etc) – PBC, autoimmune cholangitis Presence of autoimmune antibodies Liver biopsy

50. Autoimmune Treatment – Corticosteroids +/-azathioprine – Only treat after biopsy – Huge reduction in symptoms + prolongs life Prognosis – Variable course with relapses – Cirrhosis almost inevitable – 63% 10 year survival rate

51. Other causes of chronic hepatitis Commonly females aged >40 Associated with arthritis, glomerulonephritis, vasculitis Present with jaundice + hepatomegaly Isoniazid, methyldopa, nitrofurantoin, dantrolene, propylthiouracil + more Diagnosis from history + raised serum liver enzymes Improvement after stopping drug Drugs

52. Wilson’s disease – Rare inborn error of copper metabolism – Presents in childhood with liver + basal ganglia involvement – Biopsy shows CAH or cirrhosis – Treat with long term penicillamine

53. Kayser-Fleischer Ring

54. Scheme of diagnosis and management History (Alcohol, IVDU, Sexual promiscuity, family history –autoimmune disease, Wilson’s disease) + physical examination (Tattoo, needle marks, K- F ring) CHRONIC HEPATITIS Double check medications HBsAg/anti-HCV tests Positive Consider antiviral therapy Negative Exclude Wilson’s + other rare causes Autoantibodies Positive Corticosteroids

55. IFN-, PEG IFN-PEG IFN-IFN-, PEG IFN- Type of HepatitisDiagnostic Test(s)AutoantibodiesTherapy Chronic hepatitis BHBsAg, IgG anti- HBc, HBeAg, HBV DNA Uncommon IFN-α, PEG IFN-α, lamivudine, adefovir, entecavir Chronic hepatitis CAnti-HCV, HCV RNAAnti-LKM1 PEG IFN-α plus ribavirin Chronic hepatitis DAnti-HDV, HDV RNA, HBsAg, IgG anti- HBc Anti-LKM3 IFN-α, PEG IFN-α Autoimmune hepatitis ANA (homogeneous), anti-LKM1(±), Hyperglobulinemia ANA, anti-LKM1, anti-SLA Prednisone, azathioprine Drug-associated—UncommonWithdraw drug CryptogenicAll negativeNonePrednisone (?), azathioprine (?)

56. Conclusion Chronic hepatitis commonly presents with non-specific symptoms or abnormal blood tests Common causes are viral hepatitis B + C and autoimmune disease A logical investigative pathway should be followed to diagnose the cause Treatment and prognosis depends on the underlying cause