Dr. Minoo Saeidi Isfahan University of Medical Sciences Hepatitis Dr. Minoo Saeidi Isfahan University of Medical Sciences

Case presentation 15 year old boy presented with dark urine, fatigue, abdominal pain, loss of appetite, vomiting and pharyngitis His signs were hepatomegaly with tenderness, jaundice, exudative pharyngitis, bilateral cervical adenopathy with facial edema Lab data : Bil: 14.5 (Direct), AST: 690 Unit, ALT: 620 Unit, GGT: 413 Unit, negative serology for viral hepatitis and CMV, positive serology for acute EBV infection

Definition Presence of inflammatory cells in the liver Elevated liver enzymes Different causes (viruses, toxins, autoimmunity, drugs, shock, anoxia, Wilson, metabolic diseases) Self limited or progressive Acute or chronic

pathophysiology Direct cellular injury that elevates serum liver enzyme levels cholestasis that causes jaundice and hyperbilirubinemia Inadequate liver function that lowers serum albumin levels and prolongs the prothrombin time (PT)

Causes Acute (HAV, HEV, HBV, HCV, HDV, EBV, CMV, HSV, VZV, Adenovirus, Entrovirus, E coli, toxoplasmosis, leptospirosis, alcohol, Amantia toxin, paracetamol, autoimmunity, metabolic disorders like as Wilson) Chronic (HBV, HCV, HDV, autoimmunity, nitrofurantoin, ketoconazole, isoniazid, metyldopa, alcohol, metabolic disorders like as Wilson, alfa 1 antitrypsin deficiency, galactosemia, tyrosinemia,IBD)

Symptoms Acute (asymptomatic, malaise, fatigue, nausea, vomiting, loss of appetite, icter, dark urine, muscle pain, joint pain, fever, headache, abdominal discomfort, diarrhea, fulminant hepatic failure) Chronic (asymptomatic, right upper quadrant tenderness, fatigue, ascites, pruritus, gynecomastia, melena, hematemesis, ankle swelling, loss of libido, amenorrhea, encephalopathy)

Liver function tests

Level of enzymes and differential diagnosis

Diagnostic approach

Drugs and liver

Common causes of asymptomatic hypertransaminenia in children Hepatic origin Extrahepatic origin Obesity (non-alcoholic fatty liver disease) Duchenne/Becker muscular dystrophy (prevalence: 1:4700) Viral infections (major and minor hepatotropic viruses) Myocardiopathies Autoimmune liver disease Nephropathies Celiac disease and inflammatory bowel disease Hemolytic disorders Wilson’s disease (prevalence: 1:30000) Macro - AST (prevalence: 30% of children with isolated aspartate aminotransferasemia) Cystic fibrosis (prevalence: 1:2500) and Shwachman-Diamond syndrome (prevalence: 1:50000) Alpha1 antitrypsin deficiency (prevalence: 1:7000)

Uncommon causes of chronic hepatitis

Hepatitis A RNA virus 15 to 30 days incubation period Mainly asymptomatic Illness course 2 to 6 weeks, longer for cholestatic type (16w) Fecal oral transmission, close contact, blood Elevated liver enzymes 4 to 100× normal, leukopenia, lymphocytosis, billirubin up to 10 mg/dl Anti HAV IgM, IgG (after 4 weeks) Fulminancy rare Persistent no Carcinoma no Carrier no Prophylaxis vaccine & immunoglobulin (0.02 cc/Kg), hygiene Within 2 weeks after exposure, under 1 year old, after 40 year old, immunocompromised, sexually active, household

Serologic changes after HAV infection

treatment No specific treatment Rest unhelpful Dietary recommendation unhelpful Admission to hospital is not necessary Contact isolation in admitted patient Back to school after one week Corticosteroid no benefit Monthly liver enzymes check Mortality <0.1%

Hepatitis E RNA virus 35 to 60 days incubation period Clinical course resemble to hepatitis A Fecal oral transmission (mainly water) Fulminancy 1 to 20% (pregnancy) HEV IgM & IgG, Virus PCR Persistent no Carcinoma no Carrier no Prophylaxis hygiene

Hepatitis B DNA virus 60 to 180 days incubation period Sexual, transfusion, perinatal transmission Fulminancy < 1% (co infection with HDV) Persistent (HBsAg positive for more than 6 mo) 5 to 10% (90% in perinatal infection) Carcinoma yes Prophylaxis vaccine & HBIG

Body fluid concentration of virus High (blood, wound exudates, serum) Moderate (semen, saliva, vaginal fluid) Low or not detectable (urine, feces, breast milk, tear, sweat)

HBV antigens Pre S1 Pre S2 Surface (s) basis of hepatitis B vaccine Pre core (e) good indicator of active replication Core (c ) may have role in virus replication X transcriptional power of virus Polymerase virus replication Virus entrance to hepatocyte

Markers in hepatitis B infection HBsAg : Acute or chronic infection HBeAg : Acute hepatitis B   Persistence implies: continued infectious state ,increased severity of disease HBV DNA : viral replication Anti HBsAb : previous exposure, vaccination Anti HBeAb Anti HBcAb

Treatment Patients with positive HBsAg, positive HBeAg and HBV DNA in the serum with abnormal serum aminotransferases and chronic hepatitis on liver biopsy should be treated Aim of treatment : the seroconversion of HBeAg and the reduction of HBV DNA to undetectable levels by PCR Normalization of the serum ALT level and histological improvement in inflammation and fibrosis : good response

Treatment Lamivudine 100 mg/Kg Interferon alfa 2b (normal LFT and decompensated liver failure) HBIG (0.5 cc) + vaccine Neonate of mother with positive HBsAg Needle stick with HBsAg positive patient Sex partner of newly diagnosed patient with positive HBsAg

Neonate of HBsAg + mother HBIG 0.5 ml Hepatitis B vaccine Vaccine at 1 and 6 mo HBsAg check between 9 to 15 mo Within 12 hours of birth

Hepatitis D RNA virus 60 to 180 days incubation period Co infection or super infection with HBV Fulminancy (co infection) 2 to 20% Persistent (super infection) 2 to 70% Carcinoma no

Hepatitis C RNA virus Incubation period of 30 to 60 days Fulminancy rare Persistent 85% Carcinoma yes (7 to 15%) Anti HCV IgM & IgG, virus PCR Asymptomatic and accidental detection 50%

Treatment Treat when liver biopsy is consistent with chronic hepatitis, abnormal LFT for more than 6 mo, detectable HCV RNA in serum Treat abnormal biopsy and normal LFT Treat cirrhosis on the base of HCV hepatitis Uncompensated cirrhosis liver transplant Aim of treatment : stop progression of active liver disease and prevent the development of hepatocellular carcinoma

Treatment Ribavirin 800 to 1200 mg/Day for 6 to 12 mo + INF alfa 1a 180 microg/w Experience in children is not sufficient

Autoimmune hepatitis Female predominance Associated with other autoimmune diseases like as Coombs positive hemolytic anemia, pernicious anemia, thyroiditis Genetically predisposed patient Type 2 in teens, jaundice and very high level of liver enzymes with other features of autoimmune disorders, go to cirrhosis, high level of serum gamma globulins, often high PT, Anti LKM Type 1 ANA & ASMA positive Type 3 Anti soluble liver Ag positive ASMA: anti smooth muscle antibody LKM: liver kidney microsomal

Treatment Prednisolone 30 mg is given daily for 2 weeks, followed by a slow reduction and then a maintenance dose of 10-15 mg daily Azathioprine should be added, 1-2 mg/kg daily, as a steroid-sparing agent and in some patients as sole long-term maintenance therapy Therapy induce remission in over 80% of cases Treatment is lifelong in most cases