Fahmi IndrartiSub Bagian Gastroenterohepatologi, Bagian Penyakit Dalam Fakultas Kedokteran Universitas Gadjah Mada/RSUP Dr. Sardjito Yogyakarta HEPATITIS A syndrome of diverse etiology Hepatic inflammation or injury with hepatic cell necrosis Characterized by elevation of aminotransferases ~How abrupt the liver damage acute & chronic - clinically unapparent Causes of hepatitis Infection Viral Nonviral : bacterial Immune disorders Metabolic diseases Hepatic perfusion and oxygenation problems Toxic injury Medications Environmental or industrial toxins Use of chemical and herbs as complementary & alternative medicine (CAM) therapy biliary stone Persistens elevation: 300-1500.viral hepatitis.acute viral hepatitis <300 .alcoholic hepatitis.chronic hepatitis . autoimmune hepatitis. metabolic disorders. hepatotoxins. thousandfew hundred IU/mL.drug injury. chronic viral hepatitis Rapidity of improvement (ALT) Abrupt decrease: sev. . ischemia 1500-3000 IU/mL . few weeks .-low gr. pass. immunoallergic-type drug injury Persistens but fluctuating: mod.000 IU/mL .Clues for etiology Degree of elevation of aminotransferase > 10.ischemia. 2-5 days . … and physical exam .… Clues for etiology A careful history Use of medications. etc. herbals. “natural therapies”. (HCV-RNA) sev. anti-HBs. markers for * other common forms of viral hepatitis * forms of hepatitis that can have rapid and severe evolution but are treatable markers for uncommon forms . anti. IgM anti-HBc. HBsAg.… Clues for etiology …does not give a clear and obvious cause for acute hepatitis * discontinue all possible hepatotoxins * investigate viral causes by ordering IgM anti-HAV.HCV. immune disorders. drug-induced (medication or CAM therapy).… Clues for etiology Suggest chronic hepatitis The most common: chronic hepatitis C and B. alcoholic liver disease. NAFLD Other causes: metabolic disorders. exposure to industrial/environmental toxins . autoimmune hepatitis. … Clues for etiology .clinical history . … Clues for etiology .clinical history . … Clues for etiology-physical exam . VIRAL HEPATITIS The most common cause of liver disease The major cause of persistent viremia Many hepatitis episodes : inkubation Pre-interic. icteric. or convalescense . Historical Perspective “Infectious” Viral hepatitis A NANB Enterically E transmitted “Serum” B D G. ? other Parenterally C transmitted . Blood borne agents • Hepatitis B Virus (HBV) • Hepatitis D Virus (HDV) • Hepatitis C Virus (HCV) • Hepatitis G Virus (HGV) .The Agents of Viral Hepatitis Classified into two groups I. Enterically transmitted • Hepatitis A Virus (HAV) • Hepatitis E Virus(HEV) II. HEV. HCV. HDV and HGV are : Enveloped viruses Disrupted by exposure to bile / detergents Not shed in feces Linked to chronic liver diseases Associated with persistent viremia .… The agents of viral hepatitis HAV. and etc are Non enveloped viruses Survive intact when exposed to bile Shed in feces Not linked to chronic liver disease Don’t result in a viremic or intestinal carrier state HBV. Epidemiology & Risk Factors Hepatitis A Incubation period : 15-50 days Worldwide distribution : highly endemic in developing countries HAV is excreted in the stools Viremia is short lived Prolonged fecal excretion Enteric No evidence for maternal-neonatal transmission Prevalence correlates with sanitary standards & large household size Percutaneous transmission rare . secondary cases are uncommon Maternal-neonatal transmission has been documented Prolonged viremia or fecal shedding unusual .… Epidemiology & risk factors Hepatitis E Incubation period : 40 days Widely distributed : epidemic and endemic forms HEV RNA in serum and stool during acute phase The most common form of sporadic hepatitis A largely waterborne epidemic disease Intrafamilial. … Epidemiology & risk factors Hepatitis B Worldwide distribution : HBV carrier prevalence >15% in Asia Incubation period: 15 to 180 days (average 60-90 days) HBV present in blood. semen. cervicovaginal secretions. saliva. other body fluids HBV viremia lasts for weeks to months after acute infection . … Epidemiology & risk factors of Hepatitis B 1-5% of adults. hepatocellular carcinoma The risk of chronicity depends on: Age at acquisition Risk of HBV chronicity Immunocompetent adult Immunocompromised adult Early childhood Newborn <5% >50% 50% 90% . and 50% of infants develop chronic infection and persistent viremia Persistent infection linked with chronic hepatitis. cirrhosis. 90% of infected neonates. Viremia short lived (acute infection) or prolonged (chronic infection). parts of Africa. and Amazon basin. HDV infections occur solely in individuals at risk for HBV infection (coinfections or superinfections) . European parts of former Soviet Union. Middle East.… Epidemiology & risk factors Hepatitis D Incubation period : 4-7 weeks Endemic in Mediterranean basin. cirrhosis. hepatocellular carcinoma .… Epidemiology & risk factors Hepatitis C Incubation period :15 to 160 days (major peak at about 50 days) Prolonged viremia and persistent infection common : wide geographic distribution Persistent infection linked with chronic hepatitis. IgM 0. linear 14-45 d (30 d) B Hepadnavirus 42 nm DNA double strand. circular . B.5%) 1% Yes Yes No Yes Yes Yes --Anti-HCV Anti-HCV.5 – 1.1% Yes Yes No Yes Yes Yes HBsAg.-1 E Calicivirus 27-32 nm RNA single strand.Hepatitis A. IgM 0.0% 10-40% 30-90% (<10) 5-30%? No No No Yes Yes Yes HDAg Anti-HDV Anti-HDV. linear ? Yes No No No HAAg Anti-HAV Anti-HAV. C. G Virus Hepatitis Family Nucleic acid Incubation period (mean) Transmission . circular 30-180 d (70 d) C flavivirus ? RNA single strand. linear 14-60 d (40 d) G Flavivirus ? ? RNA single strand.0% >90% <10% (0. E. IgM 1-3-25% 50-80% 20-50% 10% ? No No Yes No No No HEAg Anti-HEV 2% (25%-?) >95% ? (<5%) ? No No ? No blood vertically sexually ? ? ----? ? Yes (? %) Yes (? %) No No Antigens Antibodies Fulminant hepatitis Healing acute hepatitis Chronic active hepatitis Liver cirrhosis Active immun Passive immun .001-0.5% >99% 0% <0..5-1. HBeAg Anti-HBs Anti-HBe Anti-HBc 0. circular 14-180 d (50 d) D Viroid 36 nm RNA single strand. D.fecal-oral route - A Picornavirus 27-32 nm RNA single strand. and myalgias . Self-limited disease Clinically a symtomatic in apparent infection fulminant. cough. fatal disease Clinical syndromes: prodromal (non specific) Malaise. coryza.Clinical Features A. nausea and vomiting Flu-like symptoms of pharyngitis. anorexia. photophobic. headache. pruritus (mild. transient) Hepatomegaly Splenomegaly (10-20%) . dark urine.… Clinical features Fever uncommon except HAV infection Prodromal symptom disappear onset jaundice. coma Reversal of sleep patterns Personality changes Cerebral edema Coagulopathy Multiple organ failure Development of ascites. drowsiness. Fulminant disease Changes in mental status (encephalopaty) Lethargy. anasarca Case fatality rate : 60% .… Clinical features B. Cholestatic hepatitis Jaundice may be striking and persist for several months prior to complete resolution Pruritus may be prominent Persistent anorexia and diarrhea in a few patients Excellent prognosis for complete resolution Most commonly seen in HAV infection .… Clinical features C. Relapsing Hepatitis Symptoms and liver test abnormalities recur weeks to months after improvement or apparent recovery Most commontly seen in HAV infection – IgM anti-HAV may remain positive.… Clinical features D. Prognosis is excellent for complete recovery even after multiple relapses (particularly common in children) . and HAV may once again be shed in stool. hypoNa. AST and ALT N ↑ during convalescence . AST & ALT ↑ ↑ ↑ the latter C. Relapsing hepatitis Bil. Self-limited disease Serum AST & ALT ↑ Serum bilirubin ↑ ALP N / mildly elevated Peripheral blood counts N / mild leukopenia B. Fulminant disease coagulopathy Leukocytosis. Cholestatic disease Bil ↑ ↑ AST & ALT N ALP ↑ D.Laboratory Features A. and hypoK common Hypoglycemia Bil. … Diagnosis-Hepatitis A . … Diagnosis-Hepatitis E . … Diagnosis-Hepatitis B . … Diagnosis-Hepatitis B . sensitive molecular methods neededs for detection. Mutations in the precore gene results in failure of HBeAg production.Serologic & virologic test of hepatitis B HBV serological & virologic markers Stage of disease/interpretation HBsAg IgM anti-HBc IgG anti-HBc with anti-HBs IgG anti-HBc alone Anti-HBs alone HBeAg Anti-HBe HBV DNA (varous methods of detection) HBV DNA in the absence of HBe-Ag Ongoing in infection Recent infection or reactivation of chronic infection Prior infection Prior infection. associated with fulminant acute infection and aggressive chronic disease . low-level infection or falsepositive test Vaccine-induced immunity Active viral replication Low replication and infectivity Active disease with active viral replication. when present in inactive disease. … Diagnosis-Hepatitis D . … Diagnosis-Hepatitis C . development of IgG anti-HBc.Serologic diagnosis Agent HAV Acute phase Total anti HAV (+) IgM anti HAV (+) Convalescence Development of IgG anti-HAV Disappearance of IgM anti-HAV HEV IgM anti HEV (+) and. late development of anti-HBs Loss of HDV RNA or antigen: development of IgG anti-HDV or loss of anti HDV Above plus usual loss of HBsAg Above usually without loss of HBsAg Loss of HCV RNA (in a minor proportion of patients): anti-HCV persistent ? HBV HDV HDV RNA (+) or HDV antigen (+) or IgM anti HDV (+) in HBsAg (+) patient Coinfection : IgM anti HBc (+) Superinfection : IgG anti HBc (+) Early presence of HCV RNA : presence of or development of anti-HCV HGV RNA (+) HDV/HBV HDV/HBV HCV HGV .or HEV RNA (in stool) IgG anti HEV may be present HBsAg (+) and IgM anti-HBc (+) Loss of HEV RNA : development of IgG anti-HEV Loss of IgM anti-HEV Loss of HBsAg: later loss of IgM antiHBc. Treatment A. Self-limited infection Outpatient care unless persistent vomiting or severe anorexia leads to dehydration Maintenance of adequate caloric and fluid intake No specific dietary recommendations A large breakfast may be best-tolerated meal Prohibitation of alcohol during acute phase Vigorous or prolonged physical activity should be avoided Limitation of daily activities and rest periods determined by the severity of fatigue and malaise No specific drug treatment. corticosteroids of no value All nonessential drugs: discontinued . … Treatment B. Fulminant hepatitis Hospitalization required As soon as diagnosis made Management best undertaken in a center with a liver transplantation program No specific therapy available Goals Continous monitoring and supportive measures while awaiting spontaneous resolution of infection and restoration of hepatic function Early recognition and treatment of life-threatening complications Maintenance of vital functions Preparation for liver transplantation if recovery appears unlikely Survival rates of about 65% or greater achieved by early referral for liver transplantation . but no clinical trials available Pruritus may be controlled with cholestyramine D. Cholestatic hepatitis Course may be shortened by short-term treatment with prednisone or ursodeoxycholic acid. Relapsing hepatitis Management identical to that of self-limited infection .… Treatment C. Prevention of Transmitted Infections HAV : immunoprophylaxis is the cornerstone of preventive efforts Pre-exposure immunoprophylaxis : inactivated HAV Vaccine dose and schedule : Adults : 2 dose regimen (1440 Elisa Units), second dose at 6-12 months after the first. Children > 2 years : 3 dose regimen (360 Elisa Units) 0,1 and 6-12 months or 2-dose regimen (720 elisa units), 0 and 6-12 months. Post-exposure immunoprophylaxis : immune globulin 0,02 ml/kg body weight, deltoid injection, as early as possible after exposure … Prevention of Transmitted Infections-Hepatitis A … Prevention of Transmitted Infections HBV : the cornerstone of immunoprophylaxis is the preexposure administration of HBV vaccine Pre-exposure Adults : 10 or 20 ug of HBsAg protein i.m. injection (in deltoid) Infants : 2.5, 5, or 10 ug doses initial inj., repeated at 1 & 6 mo Post-exposure 0,04 – 0,07 ml/kg HBiG as soon as possible after exposure vaccine doses given 1 & 6 mo later HBIG, a dose of 0.5 ml given within 12 h of birth into the ant.lat. muscle of the thigh HBV vaccine, in doses of 5-10 ug given within 12 h of birth (at another site in the anterolateral muscle) repeated at 1 & 6 mo CHRONIC COMPLICATIONS OF HEPATITIS . Fibrosis and the conversion of normal liver architecture into structurally abnormal nodules which lack normal lobular organization (WHO) . ascites. portal hypertension & varices.Diffuse process .Cirrhosis Characteristics . hepatic encephalopathy.Regeneration of hepatic cell necrosis Failure function of hepatic cells & interference blood flow in the liver Jaundice. ultimately hepatic failure . … Cirrhosis . billiary obstr.. in HBV/HCV.… Cirrhosis Classification Morphologic less useful. PBC Mixed Etiologic Most usefull clinically Excessive alcohol use & viral hepatitis .hemochromatosis. Fe+Cu deposit. in alcoholic. Macronodular: nodular variation > 3 mm.. considerable overlap Micronodular: uniform nodules Ø < 3 mm. 1-antitrypsin def. hepatic vein obstr. … Cirrhosis-etiologies . umbilical herniation . Dupuytren’s contractures. palmar erythema. weight loss. malaise. muscle wasting. anorexia. azure lunules). jaundice Neurologic: hepatic encephalopathy. clubbing. nail changes (clubbing. hepatic osteodystrophy. peripheral neuropathy Musculoskeletal: reduction in lean muscle mass. fever Dermatologic: spider telangiectasis.Clinical features … Cirrhosis General features: fatigue. hypertrophic osteoarthropathy (synovitis. and periostitis). white nails. muscle cramps. feminization=acquisition of estrogeninduced characteristics (spider telangiectases. hepatorenal syndrome Endocrine: hypogonadism.Clinical features Renal: secondary hyperaldosteronism-leads to sodium and water retention.… Cirrhosis . palmar erythema. hepatic glomerulosclerosis. and primary biliary cirrhosis). Wilson’s disease. gynecomastia. diabetes. changes in body hair patterns). renal tubular acidosis (more frequent in alcoholic cirrhosis. elevated parathyroid hormone levels-may be due to hypovitaminosis D and secondary hyperparathyroidism . … Cirrhosis Potential complications of cirrhosis Ascites permagna Spontaneous bacterial peritonitis Variceal hemorrhage Hepatic encephalopathy Hepatorenal syndrome Hepatopulmonary syndrome Hepatocellular carcinoma . . … Cirrhosis-ascites However. ascites can occur secondary to a number of pathological conditions . … Cirrhosis . Diagnosis Physical examination Laboratory evaluation Imaging modalities … Cirrhosis Management Most cases: focuses on treatment of complication Specific treatment Alcohol avoidance for alcohol induced cirrhosis Antiviral drug Liver transpantation Screening for HCC (every 6 months) Serial USG Serum alpha feto protein . Karsinoma Hepatoselulare (KHS) . Merupakan 40% dari tumor ganas hati 70-80% berkaitan dengan sirosis hati Insiden + 250.k. C Prognosis buruk. alkohol Negara berkembang : Insiden tinggi Usia lebih muda berkaitan dg hepatitis B.rata2 kelangsungan hidup 3-4 bl .000 kasus pertahun meski sangat berbeda di beberapa negara Negara maju : Insiden rendah Sering pada usia tua Berkaitan dg sirosis o. C Aflatoksin yg dikaitkan oleh jamur apergilus florus Sirosis hati terutama makronoduler .Etiologi Hepatitis virus B. Diagnosis Anamnesis Pemeriksaan fisik Biokimia darah : Alfa fetoprotein meningkat pada 60-80% kasus PIVKA II (Protein Induced by Vit. K Absence Antagonist II) Bilirubin Alkali fosfatase Transaminase . Radiologi : pada hampir 30% terjadi peninggian USG : mendeteksi nodul gambaran tidak khas Angiography : sangat vaskuler. Dd tumor metastase = sedikit vaskularitas CT Scan dan MRI Canggih Informasi perluasan tumor & hubungannya dg vasa2 Patologi anatomi : diambil sel hati dg jalan biopsi aspirasi dg jarum halus (AJH) dg bimbingan USG . belum metastase.Terapi Keberhasilan terapi tergantung : Besar/kecil/perluasan tumor Ada/tidak latar belakang sirosis Transplantasi Operasi berhasil baik bila : tumor kecil. tidak ada sirosis Dengan skining yg baik kelangsungan hidup 50-60% . satu lobus. Radioterapi : Jarang Hanya untuk mengurangi nyeri pd metastase tulang Kemoterapi : Keberhasilan diragukan Embolisasi (TAE) dengan alkohol Suportif : mengurangi penderitaan Upaya pencegahan : mencegah penularan virus hepatitis B & C .