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LEGEND Normal text :powerpoint Italics : Harrison’s + lecture notes
Sept 30, 2010
Types of Viral Hepatitis
Blood, body fluids
OUTLINE • Definition and types of hepatitis • Viral hepatitis as a disease TYPES A, E, B, D, C - Diagnosis – Transmission – Prevention – Treatment/management Spectrum of toxic hepatitis/drug-induced liver disease (DILI) HEPATITIS • • • means inflammation of the liver It can be caused by viruses, drugs and toxins There are many different types of viruses that can cause hepatitis • Hepatitis A, B, C, D, E • Other transfusion transmitted agents e.g. hepatitis G virus and TT virus are identified which do not cause hepatitis. • All are RNA viruses except for Hep B which is a DNA virus Each virus is prevented and transmitted differently with different symptoms
Blood, body fluids
Blood, body fluids
Source of virus
Route of Transmission
Childbirth, needles, sex, blood transfusion
Needles, blood transfusion (sex, childbirth) Yes
Needles, sex, transfusion (requires HBV coinfection) Yes
Blood transfusion (requires HBV, HCV, or HIV coinfection) No (whether it’s pathogenic to humans remains unclear) Blood donor screening
CDC fact sheets, available at www.cdc.gov
No vaccine available Blood donor screening, risk management, education
Ensure safe drinking water
HEPATITIS A • Incubation period of 4 weeks, replication is limited in the liver, but the virus is present in the liver, bile, stools and blood during the late incubation period and acute preicteric illness Despite persistence of virus in the liver, viral shedding in the feces, viremia and infectivity diminish rapidly once jaundice is apparent. Feco-oral route; but has a stage of viremia, and if it happens that patient donates blood, then patient can transmit via blood. Asymptomatic (70%) in children < 6 years Symptomatic among older children & adults; jaundice in 70% S/S lasts < 2 months Relapsing disease/cholestatic in 10-15% of symptomatic patients
VIRAL HEPATITIS A systemic infection affecting the liver Almost all caused by HAV, HBV, HCV, HDV or HEV All produce clinically similar illnesses. asymptomatic & inapparent to fulminant & fatal acute infections common to all types subclinical persistent infections to rapidly progressive chronic liver disease with cirrhosis & even hepatocellular carcinoma, common to those that are predominantly parenterally transmitted (HBV, HCV & HDV) prodromal symptoms: systemic and variable.Constitutional symptoms include anorexia, nausea, and vomiting, fatigue, malaise, arthralgias, myalgias, headache, photophobia, pharyngitis, cough, and coryza, which may precede the onset of jaundice by 1-2 weeks. Low-grade fever more present in Hep A and E types than Hep B, except when Hep B infection is heralded by a serum sickness-like syndrome Dark urine and clay-colored stools may be noticed 1-5 days before the onset of clinical jaundice. The liver becomes enlarged and tender and may be associated with right upper quadrant pain and discomfort. Splenomagaly and cervical adenopathy are present in10-20 % of patients Posticteric recovery phase is variable ranging 212 weeks in ans is usually more prolonged in Hep B and Hep C. Complete recovery is to be expected 1-2 months for Hep A and Hep E and 3-4 months after the onset of jaundice for uncomplicated self-limited infections of Hep B and Hep C. Labs: increased ALT and AST; jaundice= bilirubin level: 2.5 mg/dL,; neutropenia, lymphopenia; prolonged PT occasionally; serum immunoglobulins IgG and IgM increased
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The figure shows that antibodies to HAV can be detected during acute illness when serum aminotransferase activity is elevated and fecal HAV shedding is still occurring. During early antibody response, Ig-M is the predominant antibody and rarely persist after 6 months. During convalescence, the Ig-G class predominates. HAV: Prevention 1. General measures:
TRANSCRIBED BY: Faye Bautista COPYREAD BY:
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Europe Early adulthood Sexual Percutaneous Other Moderate Mediterranean E.and post-exposure with immune globulin Active Immunization: Hepatitis A Vaccine • Highly immunogenic • Administered in 2 doses • Passively transferred maternal antibody interferes with immune response • Recommended for patients with CLD Passive Immunization: Immune Globulin • Effective pre-exposure or within 2 weeks post-exposure • Maybe given to children < 2 years who are traveling to countries endemic to Hep A • Concurrent administration with hepatitis A vaccine reduces vaccine immunogenicity HAV: Management 1. Pre-exposure immunization with hepatitis A vaccine 3. Good hygiene Safe drinking water * HAV inactivated by boiling for 1 minute. Drugs 4. reaching low levels within 9-12 months Serologic testing not available routinely HEPATITIS B HBV: Epidemiology & Transmission • 350M chronically infected worldwide • Especially endemic in Asia Why Should Filipinos Be Aware of Hepatitis B? • The Philippines is hyperendemic to HBV infection • One in four carriers of the hepatitis B virus will eventually die of liver cancer or liver failure • Hepatitis B is the most common cause of liver cancer and liver cirrhosis among Filipinos • Liver cancer is the 4th most common cause of cancer among Filipinos(2nd among men and 7th among women) and is the 2nd leading cause of cancer-related deaths in the Philippines TRANSCRIBED BY: Faye Bautista COPYREAD BY: Page 2 of 6 . Diet: high protein diet can improve health status 3. America W.g. Europe Childhood Birth Toddlers Preschool Horizontal High • • • Asia Pacific Africa Perinatal Horizontal Table shows that incidence varies with mode of transmission Low incidence countries: early adulthood and sexual contact Highly endemic: newborns and toddlershorizontal. blood transfusion as cause= effaced Geographic prevalence of chronic hepatitis B may be impacted by migration e. Activity 2. but both fall rapidly after acute infection. contact with formaldehyde and chlorine and ultraviolet radiation Proper disposal of sewage 2. SF Bay Area prevalence: 5-6 % • • • • • • Behaves like Hep A but with higher morbidity and mortality especially in pregnant patients First described in India Increased ALT when symptomatic Diagnosis done through inference Both IgM anti HEV and IgG HEV can be detected. sexual contact= rare. Pre. Hospitalization: not recommended unless obviously jaundiced and vomiting HEPATITIS E Serologic Course • • • • 8-9M hepatitis B carriers in the Philippines 10 – 40% progress to cirrhosis in 10 years 3 – 6% of cirrhotics transform to HCC 4 – 10% deaths annually Geographical variation in mechanisms of HBV transmission Endemicity Location Age at time of infection Mode of transmission Low N.
4-4.0 5.1 2.6-8.5 Outcome of HBV Infection: effect of age at infection Figure shows that infants are generally asymptomatic and that as one ages.0 5. HBV Infection Markers Acute Infection HBsAg Chronic Infection HBsAg HBeAg / AntiHBe AntiHBc Recovery Anti HBs HBeAg Anti Hbe HBcAg AntiHBc TRANSCRIBED BY: Faye Bautista COPYREAD BY: Page 3 of 6 .3-12.0 0.4-8.0-19.6-5.0-13. Transmission of HBV IV.0 4.4-13. Disease Outcome In either case. fulminant hepatitis (1%) or develop a chronic infection (1-2 % of immunocompetent adults higher in neonates. II.7 1.8 5.2-0.0 5. % 10.elderly and immunocompromised) that usually lasts throughout life.Country Taiwan Vietnam China Africa Philippines Thailand Japan Indonesia South Korea India Russia US HBsAg Positive.0 2.0 4. the patient may recovery from the infection (>90 %) & develop lifelong immunity.7-10.0-16.0 4. becomes symptomatic due to immune response III.
occasionally a gap of several weeks or longer may separate the disappearance of HBsAg and the appearance of anti-HBs. Rarely. Because HBcAg is sequestered within an HBsAg coat. HBeAg appears transiently. isolated antiHBc represents a cross-reacting or false positive immunologic specificity. improve symptoms • Arrest / reverse hepatic fibrosis: improve long term prognosis • Treatment is available but not all individuals need it TRANSCRIBED BY: Faye Bautista COPYREAD BY: Page 4 of 6 . In part because the sensitivity of immunoassays for HBsAg and anti-HBs has increased. anti-HBc may represent serologic evidence of current or recent HBV infection. beginning within the first 1 to 2 weeks after the appearance of HBsAg and preceding detectable levels of anti-HBs by weeks to months. and the presence of HBeAg during chronic hepatitis B is associated with ongoing viral replication. do not denote severity of disease rather the degree of liver cell damage such that HbSAg titers would be highest among the immunocompromised than the chronically infected and levels would be lowest for acute fulminant hepatitis. however. however. HBeAg seroconversion. HBsAg becomes undetectable 1 to 2 months after the onset of jaundice and rarely persists beyond 6 months. its presence is thought to reflect the stimulation of a related clone of antibody-forming cells. occasionally. Circulating HBsAg precedes elevations of serum aminotransferase activity andclinical symptoms and remains detectable during the entire icteric or symptomaticphase of acute hepatitis B and beyond. isolated anti-HBc does not necessarily indicate active virus replication. children and adolescents • Host factors that contribute to decreased immunogenicity: age.and inflammatory liver injury. Figure shows a persistence of HbsAg and anti HBc beyond 6 months V. smoking. and blood containing anti-HBc in the absence of HBsAg and antiHBs has been implicated in the development of transfusion-associated hepatitis B. this window period Is rarely encountered. most instances of isolated anti-HBc represent hepatitis B infection in the remote past. HBsAg carrier mothers who are HBeAg-positive almost invariably (>90%) transmit hepatitis B infection to their offspring.detection in serum is the most sensitive test for Hep B infection HbSAg= acute or chronic HBV infection. Anti-HBc ofthe IgM class (IgM anti-HBc) predominates during the first 6 months after acutei nfection. 6 months on the deltoid. 1. whereas IgG anti-HBc Figure shows HbsAg is the first serological marker to be detected with appearance of IgM anti-HBc weeks prior the appearance of anti -HBs SALIENT POINTS: HBV DNA. • Protective anti-HBs response in 90% of healthy adults and >95% of infants. antibody toHBsAg (anti-HBs) becomes detectable in serum and remains detectable indefinitely thereafter. Treatment Objectives for CHB • Stop HBV replication. obesity & immune suppression • 0.the first virologic marker detectable in serum isHBsAg. By contrast. isolated anti-HBc represents low level hepatitis B viremia. anti-HBc may persist in the circulation longer than antiHBs. Persistence of HBeAg in serum beyond the first 3 months of acute infection may be predictive of the development of chronic infection. In typical cases. After HBsAg disappears. anti-HBc is predominantly of the IgG class.which is a qualitative marker of HBV replication and relative infectivity.After a person is infected with HBV. anti-HBc is readily demonstrable in serum. infectivity. years after HBV infection. In some persons. but it has no clinical relevance and does not signal imminent clearance of hepatitis B.05 mL in the thigh immediately after birth with the vaccine series started at 12 h of life VI. HBV: Prevention • Single most effective preventive measure is immunization (recombinant Hep B Vaccine IM) at 0. ideally permanently • Improve hepatitis: normalize ALT’s. IgM anti-HBc= early onset denotes acute or recent infection in cases where HbsAg in serum is too low. its disappearance may be a harbinger of clinical improvement and resolution of infection.06 mL/kg IM immediately HBIg (Hep B Immunoglobulin) after exposure in unvaccinated patients • For perinatal exposure HBIg 0. Mothers For example. During this “gap” or “window” period. with HBsAg below the detection threshold. Therefore. Recent and remote HBV infections can be distinguished by determination of the immunoglobulin class of anti-HBc. HbeAg= nucleocapsid protein. HBcAg is notdetectable routinely in the serum of patients with HBV infection.The replicative stage in the liver is thought to be the stage of highest infectivity. whereas HBsAg carrier mothers with anti-HBe rarely (10 to 15%) infect their offspring. anti-HBs= protective antibody. Because variability exists in the time of appearance of anti-HBs after HBV infection. Early during the course of acute hepatitis B.appears 1-2 weeks after the appearance of HbsAg preceding detectable levels of anti-HBs by weeks to months IgG anti-Hbc=In patients who have recovered from hepatitis B in the remote past as well as those with chronic HBV infection.
Clevudine HEPATITIS D + + - + + + + + + - + - - + + - TOXIC HEPATITIS AND DRUG-INDUCED LIVER INJURY When to Suspect? • Appearance of symptoms and signs of liver disease in the setting of intake of prescription or non-prescription medications or dietary supplements – anorexia. carbamazepine. HAART Granulomatous hepatitis Incomplete virus that requires HBV for its replication. acetaminophen. Simplified Approach in Patients Presenting with Acute Hepatitis HBsAg IgM antiHAV IgM antiHBc + + AntiHCV Diagnostic Interpretation Acute hepatitis B Chronic hepatitis B Acute hepatitis B (HBsAg below detection threshold) Acute hepatitis A Acute hepatitis C Acute hepatitis A & B Acute hepatitis A superimposed on chronic hepatitis B Acute hepatitis A & B (HBsAg below detection threshold) VII. Transfusion and transplant from infected donor before routine screening implemented 1990s. Serologic markers: Anti-HCV present but problem presents because chronicity cannot be identified. Most sensistive indicator of HCv infection is Anti-HCV RNA. nausea. Enhances severity of HBV infection (acceleration of chronic hepatitis to cirrhosis. diclofenac. steroids. halothane. oxacillin. Thymosin α • 3. HDB RNA and HDB antibody tests are available but are seldom used. Entecavir • 6. Interferon α / PEG IFN α • 2. Treatment Options for CHB • 1. benzene derivatives. microvesicular steatosis) or idiosyncratic (isoniazid.Telbivudine • 7. Either coinfects with HBV or superinfects a chronic Hep B carrier. antiinflammatory and anti-apoptosis pathways) Drug-induced acute hepatitis or hepatocellular injury Methotrexate. Exposures Known to Be Associated With Hepatitis C (HCV) Infection • • • • • • Intravenous (IV) or injecting drug use. abdominal pain. paracetamol Fatty liver disease Ethanol. occasionally fulminant acute hepatitis) A high index of suspicion is needed to determine infection. fatigue. sulfonamides) High index of suspicion Detailed medication history and compatible chronology Awareness of a drug’s hepatotoxic potential Exclusion of other causes of liver damage Detection of the presence of subtle data that favors a toxic etiology Types Hepatic adaptation Mediated by survival genes (anti-oxidant. Lamivudine • 4. mushroom poisoning. INH. methyldopa. mostly hemodialysis patients Occupational exposure to blood (mostly needle sticks) Iatrogenic (unsafe injections) Birth to HCV-infected mother Sex with infected partner – Multiple sex partners TRANSCRIBED BY: Faye Bautista COPYREAD BY: Page 5 of 6 .• • Criteria: activity/progression of disease + increased transaminases HBV infected individuals can work and 80-90 % do not show disease activity. phenytoin. malaise. HEPATITIS C Serologic Course Figure shows the mild clinical course of HCV marked by fluctuating elevations of serum aminotransferases with 50% likelihood of chronicity leading to cirrhosis. Adefovir dipivoxil • 5. or jaundice • Include DILI in the differential diagnoses of any patient who presents with liver dysfunction Diagnosis: Challenging because there are no specific markers o Straightforward acute liver injury after overdosage to known hepatotoxins such as acetaminophen or paracetamol Rechallenge with a drug suspected of being the cause of previous episode of acute liver injury Diagnosis of exclusion Dose-related(carbon tetrachloride.
Allopurinol. elevated baseline transaminases. chronic HBV and HCV. amoxicillin-clavulanic acid Anti-Tb Drug Toxicity • Mainly idiosyncratic • INH+RIF > INH > PZA > RIF • RIF+PZA is extremely toxic when used alone • PZA toxicity more prolonged • Toxicity often in peripartum women and Asian men • Higher risk with acetaminophen. TMP-SMZ Cholestasis Estrogen. pyrazinamide. captopril. quinidine. sulfonamides. possibly HIV TRANSCRIBED BY: Faye Bautista COPYREAD BY: Page 6 of 6 .
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