Hepatitis A The virus that does not cause chronic liver disease Hepatitis A “Infectious Hepatitis” First characterized in 1973 Detected in human feces Hepatovirus genus A reportable infectious disease U.S. rate of infection 4/100,000 Highest among children Risk Factors Sexual or household contact International travel Men who have sex w/ men (MSM) Intravenous drug abuse (IVDA) Daycare Transmission Unwitting contact w/ infected person Most cases unknown Primary route is fecal oral either by person to person contact or ingestion of contaminated food or water Pathogenesis After ingestion, the HAV survives gastric acid, moves to the small intestine and reaches the liver via the portal vein Replicates in hepatocyte cytoplasm – Not a cytopathic virus – Immune mediated cell damage more likely Once mature the HAV travels through sinusoids and enters bile canaliculi, released into the small intestine and systemic circulation, excreted in feces Clinical Features Incubation is usually 2 to 4 weeks, rarely 6 weeks Complete recovery within 2 months for > 50% Within 6 months for almost all others Clinical Features Low mortality in healthy people – High mortality when older than age 60 – High in presence of chronic liver disease High morbidity – Around 20% need hospitalization – Lost work days – Most become jaundiced Clinical Features Asymptomatic < 2 year old Symptomatic – 5 and older ill about 8 weeks Cholestatic – jaundice lasts > 10 weeks Relapsing w/ 2 or more bouts acute HAV over a 6 to 10 week period Acute liver failure – rare in young. When it occurs, is rapid i.e., within 4 weeks Signs and Symptoms Prodrome lasts 1-2 weeks: fatigue, asthenia, anorexia, nausea, vomiting, and abdominal pain Less common: fever, cephalgia, arthralgia, myalgia, and diarrhea Dark urine is followed by jaundice and hepatomegaly Less common: splenomegaly, cervical lymphadenopathy Diagnosis During acute infection, anti HAV IgM appears first HAV IgG antibody appears early in the course of infection and remains detectable for life, providing lifelong immunity Prevention Immunization All children 12 – 24 months Travelers, occupational exposure risk All patients w/ hepatitis B or C or those awaiting liver transplantation HIV positive patients MSM IVD users Immunize People w/ clotting factor deficiencies Lab workers handling live hepatitis A vaccine Need for post exposure prophylaxis uncommon. Administration of the vaccine is effective. If needed, administer immune serum globulin within 2 weeks 0.02 ml/Kg IM Hepatitis A Vaccine The vaccine is inactivated HAV Schedule for 2 – 18 years depends upon the manufacturer: – Havirx: 720 EL U/.5mL @ 0, 6-12 mo – Vaqta: 25 U.5mL @ 0, 6-18 mo Hepatitis A Vaccine For those over age 18: – Havirx: 1440 EL U/1mL @ 0, 6-12 mo – Vaqta: 50 U/1mL @ 0, 6-18 mo Adverse effects: rarely anaphylaxis, injection site induration, erythema, edema, fatigue, mild fever, malaise, anorexia, nausea Twinrix: – 720 El U/1mL 0, 1, 6 mo plus – 20 mcg HBV Questions? Hepatitis B The Virus The hepatitis B virus is among the smallest genomes of all known animal viruses A DNA virus that infects only humans Belongs to the family Hepadnaviridae Knowledge of the viral proteins that are perceived by the immune system as “antigens” aids understanding of the various tests used to diagnose acute, chronic, and resolved infection and verify response to immunization HBV Antigens Outer envelope contains a surface protein called hepatitis B surface antigen HBsAg is a marker of viral replication Inner core contains the genome, the DNA polymerase w/ reverse transcriptase activity, hepatitis B core antigen (HBcAg) particles. This antigen is not detectable in serum A truncated form of the major core polypeptide known as hepatitis e antigen (HBeAg) is the third antigen generated by virus activity. Marker of high infectivity Hepatitis B Antibodies Hepatitis B surface antibody is the antibody to surface antigen. HBsAb is protective and indicates either resolved infection or immunization HBcAb is the antibody to core antigen. This is not a protective antibody. Only those who have been exposed to the virus will have this antibody HBcAb is measured in serum as: – Anti HBc IgM (usually indicates new infection) – Anti HBc IgG (appears later) HBeAb is the antibody to e antigen. Loss of e antigen w/ gain of e antibody is called seroconversion. Not a protective antibody Epidemiology Prevalence of HBV varies markedly around the world, w/ > 75% of cases in Asia and the Western Pacific Vaccine available > 20 years, but perinatal and early life exposure continue to be a major source of infection in endemic areas Most acute HBV cases in the U.S. are seen among young adults, males > females, who use injection drugs and in those who engage in high risk sexual behaviors In the U.S., hundreds of people die each year of fulminant HBV World wide, chronic HBV and its complications including hepatocellular carcinoma account for > 1 million deaths each year Risk Factors Percutaneous and mucous membrane exposure. The virus is 100 x more infectious than HIV, 10 x more infectious than HCV and is present in all body fluids. Present on horizontal surfaces, eating utensils, personal hygiene items, etc. Babies born to infected mother Household contact Hemodialysis Receipt of blood products prior to the early 1970s Receipt of previously infected donor liver Markers of Exposure Surface antigen appears as early as 1-2 weeks following exposure, as late as 11-12 weeks HBV DNA measurable soon after HBeAg appears shortly after HBsAg Hepatitis occurs 1 – 7 weeks after appearance of HBsAg Pathophysiology Governed by interaction between the virus and host immune response Following inoculation by the HBV, cytokine release, cell injury and viral clearance follow HBsAg disappears by six months and is accompanied by sero conversion to protective HBsAb Persistent virus replication after six months ->chronic hepatitis and is the result of a compromised (newborn/HIV) or relatively tolerant immune system status Four Stages of Infection Age at time of infection predicts chronicity in most cases. Infants and young children usually become chronically infected. When acquired in adults, the virus is cleared by the healthy immune system in about 95% of cases, leading to natural immunity Immune tolerant phase, there is active viral replication. ALT and AST are normal. Immune system does not recognize HBV as “foreign” In the immune clearance phase, enzymes rise reflecting immune mediated lysis of infected hepatocytes. This phase can last for years. Seroconversion of HBeAg to HBeAb occurs Stages of Infection Low or non-replicative phase. Also known as inactive carrier (or inappropriately “healthy carrier”). Characterized by resolution of necroinflammation, normalization of enzymes and low levels of HBV DNA. This stage may last for life Reactivation. Spontaneous or immunosuppression mediated (cancer chemotherapy or high dose corticosteroid therapy) Signs and Symptoms Incubation period: a few weeks to 6 months About 30% develop jaundice 10% to 20% of patients develop serum sickness, i.e., fever, arthralgias, rash Fulminant hepatitis B occurs in < 1% of cases. 80% mortality without liver transplantation Enzyme elevations of 1,000-2,000 typical Signs and Symptoms Fatigue, RUQ discomfort may be the only symptoms Those in the immune tolerant phase are usually asymptomatic. The phase lasts until late puberty into adulthood Signs of Decompensation See section on Cirrhosis and Portal Hypertension Refer to a liver transplantation center Patient education for people with chronic liver disease should be reinforced Refer to “Ten Tips for People w/ Chronic Liver Disease” Prevention Two forms of vaccine now available. Twinrix – contains both hepatitis A and B vaccines available in an accelerated schedule or standard series Individual hepatitis B vaccine Standard schedule is given: – Time 0 – 1 mo – 6 mo Prevention Educate to avoid IVDU, high risk sexual activity Prevent peri natal transmission. Serology of pregnant women for HBsAg is standard of practice in U.S. If pregnant female has high viremia, refer to hepatologist for treatment during the 3rd trimester to reduce risk of transmission to neonate Babies of HBsAg mothers receive hepatitis B immune globulin with 12 hours of birth and begin the vaccine series immediately Treatment approved medications as of July Six 2008 – Interferon alpha – Pegylated interferon – Lamivudine – Adefovir Dipivoxil – Entecavir – Telbivudine – Tenofovir approved Refer to hepatologist The Cholestatic Liver Diseases Adults Cholestatic Liver Disease Etiologies Immune Mediated: PBC, PSC, autoimmune cholangitis, liver allograft rejection, graft-versus-host disease Infectious: acute viral hepatitis Genetic and Developmental: cystic fibrosis, Alagille’s syndrome (syndrome w/ paucity of intrahepatic bile ducts), fibro polycystic liver disease Cholestatic Liver Disease Etiologies Neoplastic: Cholangiocarcinoma Drug-Induced Ductopenia: amoxicillin, amitriptyline, cyproheptadine, erythromycin, tetracycline, thiabendazole Ischemic Idiopathic Pathogenesis of Cholestatic Disorders Immune response (inflammation, auto-antibody) or hepatotoxic injury to bile ducts Bile duct injury by bile acids - > Retention of bile acids in hepatocytes -> Liver cell damage, apoptosis, necrosis, fibrosis, cirrhosis - > liver failure Complications of Chronic Cholestasis Pruritisbelieved to be 2/2 increased opioid receptor tone, or centrally mediated Fatigue Bone disease: osteopenia, osteoporosis Fat soluble vitamin deficiency Malabsorption (Sprue, bile salt deficiency, pancreatic insufficiency) Pruritis in Cholestasis Therapy: – Urso in AICP, PBC (15-30mg/Kg/day) – Opiate antagonist naltrexone (50mg/day) – 5-HT3 antagonist odansetron – SSRI sertaline – Bile acid sequesterant cholestyramine 4gm t.i.d. to q.i.d. – Antihistamines rarely effective – Rifampin 150mg to 300mg b.i.d. Fatigue in Cholestasis High prevalence in Primary Biliary Cirrhosis unrelated to disease severity or duration Pathogenesis – ?decreased hypothalamic cortico-tropin- releasing hormone – ?CNS accumulation of manganese Prognosis worse No effective treatment Bone Disease in Cholestasis Clinical manifestations: low bone density, fractures of axial and/or appendicular skeleton Pathogenesis: hyperbilirubinemia impairs osteoblast proliferative activity Therapy: bisphosphonates, calcium, vitamin D, weight bearing exercise, estrogens appear to be safe 1. Primary Biliary Cirrhosis A chronic and progressive disease of unknown etiology affecting primarily middle-aged women Primary Biliary Cirrhosis Affects all races 9:1 ratio female > male, age 20 – 65 Characterized by small intrahepatic bile duct destruction and cholestasis In the presence of cirrhosis, male > likely than female to develop hepatocellular carcinoma PBC Laboratory Findings Alk Phos 2x to 20x ULN in > 90% of patients AST-ALT 1x to 5x ULN > 90% Bilirubin – variable. When elevated, may indicate advanced cirrhosis or 2nd condition Hypercholesterolemia in 80% of patients Hypercholesterolemia Unique in PBC Hypercholesterolemia – No obvious increase in heart disease – Some lipid lowering agents cause rise – Cholestyramine or Urso may mobilize cholesterol deposits PBC Laboratory Findings IgM 1x to 5x ULN > 90% Anti mitochondrial antibody > 1:20 titer >90% Anti nuclear and/or smooth muscle antibody > 1:80 may be seen in “overlap syndrome” Liver biopsy helpful to grade and stage disease, determine if cirrhosis present PBC Treatment Slowly progressive, even if asymptomatic Ursodeoxycholic acid only effective therapy. May improve natural history Transplant curative Manage disease specific complications Effects of Ursodeoxycholate Urso is a hydrophilic bile acid having multiple anti-inflammatory and immunomodulatory actions Urso administration in the setting of pro-apoptotic stimuli (bile salts, ethanol, TGF-beta, FAS ligand) inhibits in vitro apoptosis (programmed cell death) Reduces mitochondrial membrane permeability Monitor for and Treat PBC Associated Disorders Sicca Keratoconjunctivitis Scleroderma, CREST syndrome Gallstones Arthropathies: – Rheumatoid, psoriatic arthritis, Raynaud’s phenomenon, Hypertrophic osteodystrophy, Avascular necrosis, Chondrocalcinosis Thyroid disease, renal tubular acidosis PBC Associated Disorders Malabsorption Celiac Sprue – 6% of PBC patients have Celiac Sprue – 3% of Sprue patients have PBC Bilesalt deficiency Pancreatic insufficiency Manage PBC Complications Standard liver disease recommendations PBC specific symptom management Refer for liver transplantation 2. Primary Sclerosing Cholangitis Rare One of the most important cholestatic liver diseases in the western world Chronic, cholestatic liver disease characterized by – Inflammation – Obstruction – Fibrosis of both intrahepatic and extrahepatic bile ducts Primary Sclerosing Cholangitis PSC Many patients will progress to cirrhosis Highly variable in and between individuals Usually fatal important complication is cholangiocarcinoma Etiology largely unknown, though evidence points to immune system involvement PSC No specific treatment Treatment aimed at management of disease associated conditions Prevalence unknown Almost half are asymptomatic at diagnosis No specific diagnostic marker for PSC PSC Clinical Features Labs: – Two- fold increase in alk phos, most have increased AST and ALT – Albumin and protime normal in early disease – Bilirubin initially normal, but gradually increases and fluctuates widely w/ extrahepatic biliary strictures, infection, obstructing stone sludge or stone PSC Clinical Features Imaging – Endoscopic retrograde cholangiography is the gold standard Magnetic resonance cholangio- pancreatography demonstrates intrahepatic duct changes – Diagnostic method of choice – Less invasive, lower risk – High cost – Claustrophobia, metal implants may preclude PSC Clinical Features Histology Liver biopsy for staging the disease Liver biopsy to rule out other potentially treatable causes of cholestasis PSC Patient Presentation Large bile duct PSC may have asymptomatic elevation of LFTs. Can be cirrhotic w/ no symptoms Symptomatic patients will have cholestasis-type symptoms plus: – Abdominal pain – Weight loss – Hepatomegaly – Acute cholangitis PSC Associated Diseases Inflammatory bowel disease, most often ulcerative colitis These patients have increased risk for colorectal carcinoma 25% have another autoimmune disease PSC Complications Related to cholestasis: pruritis, fatigue, fat soluble vitamin deficiency, osteoporosis Related to cirrhosis: liver failure, peristomal varices Extra-hepatic disease: IBD, pancreatitis, sprue, diabetes, thyroid disease PSC specific PSC Disease Specific Complications Fever Abdominal pain Dominant stricture Gall stones Cholangiocarcinoma PSC Prognosis Factors of Importance: – Older age – Increasing bilirubin – Histological advanced stage – Child-Pugh-Turcotte Class C PSC Treatment Goal Improve Quality of Life Medical support Endoscopic treatments Surgical interventions Liver transplantation – PSC recurrence is more frequent than PSC Case Study Asymptomatic elevation in AP noted on routine lab Middle aged male w/ Hx ulcerative colitis on mesalamine 59 209 -----------------------------------------< 1.0 64 500 Negative viral serologies; U/S normal MRCP reveal narrowing and strictures of intrahepatic and extrahepatic biliary tree “Pruned Tree” appearance High risk for cholangiocarcinoma, colon cancer Treatment is transplant Reference Broome, U and Berguist. Primary sclerosing cholangitis. In Zakim and Boyer’s Hepatology: A textbook of liver disease, 5th Ed., Boyer, T.D., Wright, T.L., & Mans, M.P. Saunders Elsevier: Canada, 821-854.
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