Acute hepatitis

acute hepatitis with special emphasis on viruses..

1. ACUTE LIVER DISEASE (Acute Viral Hepatitis) Dr. Vijay Yadav Lecturer Internal Medicine

2. 80% 9 0% of the remaining 20% 10%

3. Introduction Definition: Acute Viral Hepatitis is defined as inflammation of liver and sudden onset of aminotransferase elevation as a consequence of diffuse necro -inflammatory liver injury which lasts for < 6 months. Acute liver disease encompasses a wide range of disorders from asymptomatic transaminitis to ALF Viral hepatitis and DILI are the most frequent causes. Acute viral hepatitis is a self-limiting disease with chance of ALF in a small percentage of patients. M.C cause: Hepatitis A and E

4. Etiology of Acute hepatitis Infectious Viral: Hepatitis A – E, EBV, CMV, Dengue, Yellow fever Bacterial: Weil’s disease, MTB, Enteric fever Protozoal : Malaria, Toxoplasmosis Helminth : E. histolytica Non-infectious Toxin: Mushroom, CCl4 Alcohol Acute fatty liver of pregnancy Acute budd chairi syndrome Metabolic: Wilson’s disease Autoimmune hepatitis Ischemic hepatitis Drugs: PCM, ATT, Phenytoin

5. Pathogenesis HAV: Survives the acidic digestion by gastric juice and reaches the portal circulation Multiplies in the hepatocytes and damages hepatocytes by immunological mechanism Excreted in feces HBV: Damages hepatocytes by immune mediated injury HCV: Binds to receptors on the hepatocyte surface Enters the cell by endocytosis Rarely causes immune mediated injury in acute phase and thus most of acute HCV infections are asymptomatic except for mild transaminesemia HDV: Causes infection only in the presence of HBV infection either as superimposed or co-infection CMV: Primary infection or as a reactivation of latent infection HSV: Neonates, Pregnancy, Immunocompromised patients a/w genital herpes infection

6. PRODROMAL PHASE CLINICAL JAUNDICE RECOVERY PHASE

7. Hepatotropic virus-general characters HAV HBV HCV HDV HEV VIRUS Group NA Entero / Picorna RNA Hepadna DNA Flavi RNA RNA Calci RNA Incubation period 15-45 days 30-180 days 15-160 days 30-180 days 15-60 days Spread Faeco -oral Parenteral Sexual Vertical Faeco -oral Chronicity Yes Yes Yes Prevention Active Passive Vaccine Immune serum globulin Vaccine Hyperimmune serum globulin No No HBV vaccine No No

8. Enterically (HAV & HEV) Parenterally (HBV, HCV, & HDV) Non-enveloped Shed in faeces Survive intact when exposed to bile Do not cause chronicity Do not have prolonged viremia Do not have carrier state M.C: HEV >> HAV Enveloped viruses Cause chronicity a/w persistent viremia Have a carrier state M.C: HBV + HDV HCV rarely causes AVH

9. HAV HBV HCV HDV HEV CMV HSV Age Any, mostly children Any age Usually adults Any age Any, Usually adults Immunocompromised Sexually active adults Symptoms Asymptomatic in children Symptomatic with jaundice Cholestatic with jaundice lasting > 10 weeks Relapsing with 2 bouts over 6-8 wks Fulminant : 0.5% Prodrome fever Arthralgia Myalgia Jaundice (30%) Maculopapular utricarial rash (10%) Acute hepatitis (20%) Fatigue N/V Asymptomatic in children Self limiting acute hepatitis mimicking flares of chronic HBV Anicteric hepatitis Icteric hepatitis FHF(20%) in pregnancy Asymptomatic Subclinical in most Mononucleosis like illness Rarely cholestatic May be seen as neonatal hepatitis

10. HAV HBV HCV HDV HEV CMV HSV Clinical Signs Tender hepatomegaly (85%) Splenomegaly (15%) Cervical LN (15%) Hepatomegaly Rashes Jaundice Fluctuating transaminases Double peak transaminases if co-infected with HBV Jaundice Hepatomegaly Splenomegaly Jaundice Hepatomegaly Splenomegaly Jaundice Hepatomegaly Splenomegaly Signs of DIC Duration Of Disease Recovery in 60% within 2 months & 100% in 6 months 95-99% resolve in 6 months Others progress to chronicity Usually resolves in 1 month (15%) Resolves in 4-8 weeks Self limiting Resolve in 6 weeks Resolves in 6-8 weeks

11. HAV HBV HCV HDV HEV CMV HSV Fulminant hepatitis Mostly in adults 55% in 1 st week & 90% within 4 weeks < 0.5% overall In < 1% Within 4 weeks High mortality (80%) HBV+HDV > 50% cases Very rare 5-10% 20% in pregnancy Occurs with MODS in immunocompromised patient May develop in neonate as adrenal insufficiency In pregnancy as well Extra-hepatic manifestations Rash Arthralgia Nephritis Cutaneous vasculitis Rash Arthritis Hematuria Proteinuria PAN GN Nephrotic syndrome Cryoglobulinemia Cryoglobulinemia GN Lichen planus Sicca syndrome PCT None Arthralgia Pancreatitis Acalculous cholecystitis Rash DIC

12. Investigations Complete blood count Neutropenia & lymphopenia Relative lymphocytosis Pancytopenia (aplastic anemia) Renal function tests Liver function tests ↑ Serum bilirubin: 5-20 mg/ dL (both UB & CB equally) ↑ AST/ALT (ALT >> AST): 400 – 4000 in icteric phase Diminishes gradually in recovery phase Anicteric hepatitis ( N bilirubin but ↑ AST/ALT ) ALP: Increased but < 3 x UNL Albumin: Normal PT/INR: usually normal; poor prognosis if increased

13. Viral serology: HAV IgM , HAV RNA HBsAg , IgM anti- HBc , HBV DNA, HBeAg Anti-HCV(4-6 weeks), HCV RNA (1-2 weeks), HCV genotyping HDV RNA, anti-HDV antibodies HEV IgM EBV Capsid antigen, CMV DNA , HSV, VZV serology Dengue serology and NS1 antigen Leptospirosis: Microscopic agglutination test (MAT): Gold standard ELISA, PCR : confirmatory Enteric fever: Blood C/S, Typhi dot IgM Malaria: MP antigen, Thick and Thin smear

14. Alcoholic hepatitis: ↑ AST/ALT – 2:1; calculate DF ↑ γ GGT Acute fatty liver of pregnancy: USG abdomen Acute budd-chiari syndrome: Doppler USG & Hepatic venography Wilson’s disease: Serum ceruloplasmin , 24 hr urinary copper Slit lamp exam for KF rings Autoimmune hepatitis: ANA, Anti-LKM Ab , ASMA, Anti SLA, serum IgG levels Ischemic hepatitis: Rapid rise & fall in AST.ALT (>1000) and LDH within 1-3 days of insult Drugs: Serum APAP & plot in Rumack -Matthew nomogram Treat Hypophosphatemia Modified ATT regimen if ATT induced liver injury

15. Rumack -Matthew nomogram

16. N- acetylcysteine is administered within 8 – 10 hours of ingestion as per toxicity line on Rumack -Matthew nomogram . ORAL Loading dose: 140mg/kg Maintenance dose: 70mg/kg every 4 hours for a total of 17 doses. INTRAVENOUS Loading dose: 150mg/kg over 1 hour Maintenance dose : 14mg/kg/ hr for 4 hours and then 7mg/kg/ hr for 16 hours For late presenters(>8hrs) LD: 140mg/kg over 1 hr MD: 14mg/kg/ hr for 44 hrs

17. Complications Hepatitis A: Relapsing hepatitis Cholestatic hepatitis Hepatitis B: Serum sickness Hepatitis C: Porphyria cutanea tarda (PCT) Lichen planus Essential mixed cryoglobulinemia Fulminant hepatitis HBV + HDV > 50% cases HEV – 20% in pregnancy Drug induced Chronic hepatitis Aplastic anemia

18. Management- Hepatitis A Pre-exposure prohylaxis Post-exposure prohylaxis Inactivated HAV vaccines containing single HAV antigen given IM into deltoid in a 2 dose regimen ( 0, 6-18 months) Combination vaccines (HAV >720 ELISA unit + 20 μ g HBsAg ) given in a 3 dose regimen (0, 1, & 6 months) Given in chronic hepatitis B and C infections Immune serum globulin 0.02 ml/kg/dose given on deltoid within 14 days of exposure Effective in outbreak of hepatitis in school or nursery.

19. Management- Hepatitis B Supportive with monitoring for ALF (<1% cases) In adults, 90 -95% (99%) resolve with the development of anti HBs antibody --- thus, no role of antiviral therapy The remaining 5 -10% develop chronic hepatitis B Vertical transmission leads to chronic hepatitis B in 90 % of children & recovery is rare. Role of antiviral proven in severe acute hepatitis B that may progress to ALF. Entecavir or Tenofovir until 3 months after HBsAg seroconversion or 6 monhs after HBeAg seroconversion .

20. Management- Hepatitis B Pre-exposure prophylaxis Post-exposure prophylaxis HBV vaccine: prepared from HBsAg given IM at 0, 1, and 6 months Response is measured by anti-HBs levels ≥ 10 mIU /ml Protected antibody response is > 90% after 3 rd dose. Infants born to HBsAg + mother: HBV vaccine & HBIg 0.5 ml within 12 hours of birth at two separate sites Sexual partners + Needlestick injury: HBIg (0.04 – 0.07 ml/kg) + 1 st dose of HBV vaccine at different sites within 48 hours but no more than 7 days 2 nd dose HBIg after 30 days and complete the vaccination schedule

21. Management- Hepatitis C In typical acute hepatitis C, recovery is rare. Progression to chronicity is the rule. 50-85%: develop chronicity 60-70%: Chronic hepatitis after 10 years 30%: Cirrhosis after 20-30 years 15%: HCC after 40 years Interferon α 3 million units SC three times a week + Ribavarine

22. HDV, HEV: supportive HSV: IV acyclovir CMV: Ganciclovir , Cidofovir , Foscarnet Leptospirosis: Ceftriaxone, Doxycycline Enteric fever: Ceftriaxone, Azithromycin, Ofloxacin Malaria: Artesunate , Artemether Acute budd-chiari syndrome: Anticoagulation, surgical shunts, liver transplantaion Wilson’s disease: D- penicillamine , Trientene Autoimmune hepatitis: Steroids, Azathioprine Ischemic hepatitis: correction of underlying cause that caused circulatory collapse APAP toxicity: N- acetylcysteine

23. General Measures ? Bed rest ?Physical isolation to a single room & bathroom Fecal incontinence for hepatitis A and E Uncontrolled, voluminous bleeding for hepatitis B and C Universal precaution for HBV & HCV Avoiding direct, ungloved hand contact with blood & other body fluids High calorie diet – mainly in morning as nausea predominant during evening Avoid hepatotoxic drugs Cholestyramine for pruritis Maintain proper sanitation, hygeine & avoidance of overcrowding in hepatitis A and E

24. Prevention HAV: Clean drinking water, proper sewage disposal Public education about the hygiene Active & passive immunization HBV: Screening the transfused blood & blood products for HBsAg Using disposable syringes & needles Using safety precautions & practicing safe sex Active & passive immunization HCV: Screening for anti-HCV No active & Passive immunization available HDV: Same as HBV but vertical transmission is extremely rare HEV: Same as HAV HEV vaccine has been recently shown to be effective and is awaiting commercial availability

25. Points not to be forgotten Viral hepatitis (HAV & HEV) and DILI (PCM & ATT) are the most frequent causes of AVH. M.C cause of parenterally mediated AVH: HBV + HDV Hepatocyte injury is mainly via immune mediated injury. 3 stages of clinical features. Rate of fulminancy is least in isolated HAV, HBV, & HCV. Rate of fulminancy is high with combined HBV + HDV & HEV in pregnancy (both 20%). Acute hepatitis is rare in HCV & Chronic hepatitis is rare in PCM overdose. HAV is associated with relapsing & cholestatic variant. 95-99% of acute hepatits B resolve spontaneously but 90% of vertically transmitted children develop chronic hepatitis. Progression to chronicity is the rule in acute hepatitis C; only 15% undergo spontaneous remission. HDV is always co-infected with HBV as it uses HBsAg as its envelope. Use Rumack -Matthew nomogram for APAP toxicity as a guide to treatment. Both active & passive immunization are available for HAV & HBV. HBV vaccine is given in HDV infection. Avoid hepatotoxic drugs