Acute & chronic hepatitis

1. Acute & chronic hepatitis Dr. Fathalla Sidkey Prof of Hepatology Faculty of Medicine, Alex UN

2. Acute hepatitis • Viral : - Hepatotrophic: A, B, C, D, E ……. - Non-hepatotrophic: CMV, EBV. • Ischemic. • Drug induced. • Autoimmune.

3. Clinical picture Asymtomatic; only elevated transaminaes. Anicteric: GI and influenza like symptoms, no jaundice. Classic: 3 stages. 1- prodromal 3-4 days. profound malaise, fever, anorexia nausea, vomiting, abdominal pain 2- icteric 1-4 weeks. - change of urine color followed by jaundice and itching. - patient feels generally better and appetite returns. - tender hepatom,egaly. 3- convalescent.

4. Prolonged cholestasis: - Classic acute hepatitis but the icteric stage is prolonged 8-29 weeks with manifestations of cholestasis. - More with HAV. Fulminant hepatitis: -Patient after a typical acute onset becomes deeply jaundiced, ominous manifestations– persistent vomiting, fetor hepaticus, drowsiness, flappy tremors, finally coma. - Rare in HCV. Relapse: - 1.8-15 % especially HAV. - Attack is usually milder. - Precipitated by premature activity.

5. Post-hepatitis syndrome: - Usually, this is a matter of weeks but it may extend to months. Features are anxiety, fatigue, failure to regain weight, anorexia, and right upper abdominal discomfort. The liver edge may be palpable and tender. - Treatment consists of reassurance after full investigation.

6. Diagnosis - SGOT , SGPT: peak levels 1-2 days before or after onset of jaundice. Levels > x 10 ULN. - Useful in early diagnosis and detection of anicteric cases. - Bilirubin & ALP usually elevated. - PT prolonged.

7. Treatment - Bed rest. • Diet: low fat high carbohydrate diet more palatable to the patient. • Symptomatic and supportive. • Convalescence is not allowed till patient is symptom free & s bilirubin <1.5 mg/dl.

8. HAV • RNA virus. • Oral-fecal transmission. • Incubation period: 15 to 45 days. • Jaundice > 70 % in adults. • Fulminant hepatic failure < 1 %. • Peak infectivity occurs 2 weeks before and at least 1 week after the initial symptoms. • No chronicity. • Vaccination is available.

9. HAV

10. Chronic hepatitis

11. Definition - Persistent inflammatory reaction in the liver for more than 6 months. - Clinically: Suspected from persistently elevated hepatic transaminases (necro-inflammatory markers) for > 6 months. - Histologically: Liver biopsy is the gold standard for diagnosis.

12. Etiology • Viral: B& D, C • Autoimmune. • Drugs. • Genetic: Wilson’s disease, hemochromatosis, alpha 1 anti-trypsin deficiency. • Alcohol (ASH) • fatty infiltration (NASH).

13. Liver biopsy • The gold standard for diagnosis of chronic hepatitis and evaluation of severity of liver disease. • Evaluation includes: • Grading: necro-inflammatory changes. • Staging: extent of fibrosis. • The most commonly used currently is the METAVIR system, which grades inflammation from 0 to 4 (A 0-4) and stages fibrosis from 0 to 4 (F0-4).

14. Liver biopsy • Specific findings for specific etiology e.g: - Mallory hyaline bodies in alcoholic hepatitis. - Plasma cell infiltration in AIH. - Ground glass hepatocyte in HBV. - PCR for the virus in liver tissue - Hepatic concentration of Cu and Fe in Wilson and hemochromatosis

15. Clinical picture Symptoms: - Asymptomatic. - Fatigue (most common), rt hypochondrial pain, nausea, jaundice, muscle and joint pains. Signs: Tender hepatomegaly, occasionally vascular spiders.

16. HBV

17. HBV genotypes • 10 genotypes (A-J) • Genotype A: better response to interferon. • Genotype C: delayed HBeAg seroconversion and higher risk of HCC.

18. Perinatal transmission • In the absence of prophylaxis, the risk of perinatal transmission is between 85% and 90% for infants born to HBeAg-positive mothers and 30% for infants born to HBeAg-negative mothers. • Although HBsAg can be detected in breast milk, there is no evidence that HBV infection can be transmitted by breast- feeding.

19. HBV Serology

20. Acute HBV • Incubation period: 1 to 4 months. • Blood borne infection. • Approximately 70% of patients have subclinical or anicteric hepatitis and only 30% have icteric hepatitis. • During the prodromal period, a serum sickness–like syndrome manifesting as fever, skin rash, and arthralgia may develop. • Less than 1% of patients with acute hepatitis B develop acute liver failure.

21. Symptoms HBeAg anti-HBe Total anti-HBc Titer IgM anti-HBc anti-HBs HBsAg 0 4 8 12 16 24 28 32 52 100 20 36 Weeks after Exposure Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course

22. Treatment • Symptomatic & supportive. • Antiviral treatment (lamivudine in double dose, entecavir, Tenofovir) in severe acute HB. • Characteristics of severe acute hepatitis B: • Coagulopathy (INR > 1.5). • Protracted course (persistent symptoms or marked jaundice for > 4 weeks). • Signs of acute liver failure.

23. CHB • About 90 % of acute infection in infants become chronic . • About 10 % of acute infection in adults become chronic.

24. Acute (6 months) Chronic (Years) HBeAg anti-HBe HBsAg Total anti-HBc Titer IgM anti-HBc 0 4 8 16 20 24 28 36 12 32 52 Weeks after Exposure Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course

25. Extra hepatic manifestations • Polyartritis nodosa. • Glomerulonephrits. • Essential mixed cryoglobulinemia. • Guillain-Barre syndrome.

26. Treatment of chronic HBV

27. Treatment of chronic HBV • 1stline drugs entecavir, peg interferon alfa-2a, and Tenofovir because of their superior efficacy, tolerability, and favorable resistance profiles.

28. Treatment Chronic HBV HBV DNA < 2,000 IU/ml HBV DNA > 2,000 IU/ml ALT abnormal ALT normal No treatment No treatment Liver biopsy if patient is > 35-40 y Observe In absence of biopsy Treat

29. Treatment duration

30. Treatment of cirrhosis • Patients with compensated or decompensated cirrhosis need treatment, with any detectable HBV DNA level and regardless of ALT levels. • ANA with high barrier to resistanceshould be used. • Patients should be assessed for liver transplantation.

31. Resistance

32. Prevention Avoiding unnecessary drug use. Choosing drugs that suppress viral replication as completely and rapidly as possible because drug-resistant populations are established and expand through replication. Avoid combination of drugs with cross resistance: 1- Lamivudine & telbivudine. 2- Adefovir & tenofovir.

33. HBV + HCV coinfection • Treatment of HCV with direct-acting antivirals (DAAs) may cause reactivation of HBV. Patients fulfilling the standard criteria for HBV treatment should receive NA treatment. • HBV infected patients - not fulfilling treatment criteria – receiving DAAs should be monitored and tested for HBV reactivation in case of ALT elevation.

34. Occult HBV • The detection of HBV DNA in the absence of HBsAg. • HBV DNA is detected in the liver in most cases, but is undetectable or present at low concentrations in the serum. • Anti-HBcAbs are usually +ve. • More common among patients with cirrhosis or HCC. Many of these patients probably had chronic HBV infection for decades, leading to liver damage, but HBsAg is no longer detectable when cirrhosis or HCC is diagnosed.

35. HBV in pregnancy

36. Post-exposure prophylaxis • Vaccinated: - Anti HBs Ab > 10 mIU/ml no treatment. - Anti HBs Ab < 10 mIU/ml HBIG + booster dose. • Not vaccinated: HBs Ag , anti HBcAb, anti HBs Ab. - Anti HBs Ab > 10 mIU/ml no treatment. - Anti HBs Ab< 10 mIU/ml HBIG + vaccinate.

37. Post-exposure prophylaxis • Vaccination should be provided as soon as possible, not later than seven days after exposure; HBIG should be administered not later than within 72 hours. • Test HBV infection markers (HBsAg, anti-HBc IgM) at 6, 12 and 24 weeks post-exposure.

38. HDV • RNA virus. • Blood borne infection. • Coinfection with acute HBV infection or as superinfection in patients with preexisting chronic HBV infection. • Incubation period: 1 to 4 months. • Diagnosis: anti-HDV Abs (IgM, IgG) & HDV RNA • Treatment Pegylated interferon 48 weeks.

39. HCV • RNA virus. • Blood borne. • 7 genotypes. • Incubation period: 15 to 150 days. • Acute cases are usually asymptomatic.

40. Vertical transmission • 5.8% in HCV RNA +ve, HIV –ve mothers; maternal coinfection with HIV increased this risk to 10.8%. • Whereas infants born to mothers with a viral load of approximately 5 log IU/mL or greater have a 14% risk of infection. • Neither breast- feeding, nor mode of delivery (i.e., vaginal vs. cesarean) has been associated with increased risk.

41. Acute HCV

42. Spontaneous clearance • Of persons recently infected with HCV, approximately 27% clear infection spontaneously. • Predictors of spontaneous clearance: • Symptomatic patients (jaundice). • IL28B CC genotype.

43. Treatment of acute HCV • Monitoring for Spontaneous Clearance: All patients with acute HCV should have HCV RNA monitoring every 4 to 8 weeks for a minimum of 16 weeks. (6 months). • If the decision is made to treat a patient with acute HCV infection, the same regimens should be used as recommended for the initial treatment of patients with chronic hepatitis C.

44. Natural course

45. Factors that accelerate progression • Male gender. • Older age at infection. • Duration of infection. • Alcohol use. • Insulin resistant diabetes mellitus. • Steatosis. • HIV infection and other immunosuppressive states.

46. Treatment of chronic HCV Drugs: • Interferon (regular, pegylated). • Ribavirin. • DAAs (protease inhibitors, polymerase inhibitors).

47. Key Data for HCV treatment decisions • HCV treatment history • Interferon and ribavirin regimen? • Protease inhibitor? Sofosbuvir? • Fibrosis stage? • Options for fibrosis assessment • If cirrhosis, is it decompensated? Child Pugh B or C? Transplant evaluation?

48. HCV Life Cycle and DAA Targets Receptor bindingand endocytosis Transportand release Fusion and uncoating ER lumen Virionassembly (+) RNA LD LD LD Translation andpolyprotein processing Membranousweb RNA replication NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside ER lumen NS5A* inhibitors *Role in HCV life cycle not well defined

49. DAAs

50. DAAs