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Viral hepatitis

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Viral hepatitis

  1. 1. Viral HepatitisMohammed AdemB.pharm, M.clinpharmLecturer and clinical pharmacist05/01/13 Mohammed Adem 1
  2. 2. Liver disease: syndromic approach1. Hepatocellular: injury, inflammation, and necrosis of livercells/liver parenchyma2. Cholestatic: inhibition of bile flow3. A mixed pattern : features of both hepatocellular and cholestaticdisease• The pattern of onset and prominence of symptoms can rapidly suggest adiagnosis• Laboratory pattern is characteristic05/01/13 Mohammed Adem 2
  3. 3. Hepatitis• Inflammation of liver parenchyma or hepatocytes:• The are two types : duration based– Acute hepatitis: duration for < 6 months– Chronic hepatitis: lasting for ≥ 6 months05/01/13 Mohammed Adem 3
  4. 4. Acute hepatitis: causesAcute Hepatitis< 6 monthsViral HepatitisA, B/D, C, EEBVCMV …DrugsAcetaminophenIsoniazidAlcohol …ToxinsMushroomscarbon tetrachlorideVascularHypotensionBudd-ChiariAutoimmuneHepatitisMetabolicWilsons Disease05/01/13 Mohammed Adem 4
  5. 5. Chronic hepatitis: causesChronic Hepatitis> = 6 monthsViral HepatitisB/D, CDrugsMTXINHAmiodaronealcohol NAFLDAutoimmuneHepatitisPBCPSCA1ATHHCWilsons05/01/13 Mohammed Adem 5
  6. 6. Acute viral Hepatitis• a systemic infection affecting predominantly the liver• almost all cases are caused by of the five hepatitis viral agents:HAV, HBV/HDV, HCV, HEV• all of these human Heptitis viruses are RNA viruses except HBV• HDV is a defective RNA virus05/01/13 Mohammed Adem 6
  7. 7. Acute viral Hepatitis…o Although these agents can be distinguished by their molecularand antigenic properties  all of them produce clinicallysimilar illnesses.These range from• asymptomatic and inapparent to fulminant and fatal acuteinfections common to all types, and• from subclinical persistent infections to rapidly progressivechronic liver disease with cirrhosis and even HCC , common tothe blood borne types (HBV, HCV, and HDV)05/01/13 Mohammed Adem 7
  8. 8. Acute viral Hepatitis…• Although the rates of acute infection have declined, viral hepatitis remainsa major cause of morbidity and mortality with a significant impact onhealthcare costs.• Significant therapeutic advances have occurred with hepatitis B with theapproval of new agents and updated guidelines for care.• For hepatitis C, the challenge remains of increasing successful outcomeswhile minimizing side effects of therapy05/01/13 Mohammed Adem 8
  9. 9. Acute viral Hepatitis…• Incubation period & risk factors vary with each hepatitis virus• may mimic other systemic infections• most symptoms are non-specific• most patients are asymptomatic05/01/13 Mohammed Adem 9
  10. 10. Incubation Period• Hepatitis A: 15-45 days (30)• Hepatitis B: 30-180 days (70)• Hepatitis C: 15-160 days (50)• Hepatitis D: 21-140 days (35)• Hepatitis E: 15-65 days (40)• Hepatitis G: (14- ? days)05/01/13 Mohammed Adem 10
  11. 11. Acute viral hepatitis: clinical features• Prodromal Sx of acute viral hepatitis are systemic and variable• Constitutional Sx may precede the onset of jaundice by 1–2weeks.– Anorexia, nausea, vomiting, fatigue, malaise, arthralgia, myalgia, headache,photophobia, cough and coryza– Low-grade fever• Sx and signs related to liver dysfunction– Dark urine, clay-colored– By the time of jaundice appears, these will go away or diminish– Enlarged and tender liver– Splenomegaly– Cervical lymphadenopathy05/01/13 Mohammed Adem 11
  12. 12. Mini-case 1• Eden and Bruk, Ethiopian couples returned from theirhoneymoon trip to Central America and developsnonspecific abdominal symptoms followed by clinicaljaundice.• They stayed at a resort, and ate fresh fruits and salads.Serology for hepatitis virus spread by the fecaloral routeis positive. One of the following is the most likely:• hepatitis A virus;• hepatitis B virus• hepatitis E virus• A and C• hepatitis C virus• hepatitis D virus05/01/13 Mohammed Adem 12
  13. 13. Mini-case 2E.T., a 34-year-old medical sales representative, presents to the ED at Black LionHospital with acute onset of jaundice and “dark urine.” He was in good healthuntil 2 weeks ago, when he noted feeling fatigued and weak, which he attributedto his demanding work schedule.He also recalled having a mild headache, loss of appetite, muscle pain, diarrhea,and low-grade fevers from 99°F to 101°F.He attributed these symptoms to the flu and took acetaminophen with plenty offluids. His symptoms persisted until yesterday, when they seemed to resolveunexplainably. He then noted his urine was cola-colored.This morning, he noted jaundice of his eyes and skin and sought medical attention.Mohammed Adem13
  14. 14. MH:a recent respiratory tract infection, treated successfully with levofloxacin.SH:is significant for frequenting the local bar, where he regularly ingests raw meats. Hedenies smoking and recent travel to heptitis A endemic areas, but admits tooccasional alcohol consumption.E.T. has no Hx of sexual exposure, needle use, or transfusions. His currentmedications include oral (PO) diazepam 5 mg at bedtime (HS) as needed (PRN)for “muscle spasms,” but he has not taken diazepam for “several months.” Healso has a seizure disorder sustained after a motorcycle accident 2 years beforeadmission, for which he takes phenytoin 400 mg PO HS.Mohammed Adem14
  15. 15. PE ;significant for a well-developed, well-nourished man in no acute distress. He isalert and oriented, with a temperature of 99°F. His sclerae and skin are icteric,and his abdomen is positive for a tender, enlarged liver, and right upperquadrant (RUQ) pain.Laboratory tests: reveal the following values:Hgb, 16 g/dL (12.3–16.3); Hct, 44% (37.4%–47.0%); WBC, 5,500cells/mm3(3.28–9.29 × 103); AST, 120 U/L (5–40); ALT, 240 U/L (5–40);AP, 86 U/L ( 21–91); total Bl , 3.2 mg/dL (0.2–1.0); Bl (D), 1.5 mg/dL (0–0.2); and phenytoin concentration, 12 mg/L (10–20).The albumin, PT, blood glucose, and electrolytes all are within normal limits.E.T. is negative for anti-HCV, HBeAg, HBsAg, and hepatitis B core antibody(anti-HBc), but is positive for IgM anti-HAV.What clinical features and serologic markers are consistent with viral hepatitis inE.T.?05/01/13 Mohammed Adem15
  16. 16. HEPATITIS A : HAV05/01/13 Mohammed Adem 16
  17. 17. HAV…• HAVis often a self-limiting and acute viral infection of the liverposing a health risk worldwide.•• The infection is rarely fatal.• Although vaccine preventable, HAV continues to be one of themost commonly reported infections.05/01/13 Mohammed Adem17
  18. 18. Epidemiology• Faeco-oral route– where hygiene is poor, infection is almost universal during childhood– As hygiene improves, rate of childhood infection decreases common• Close personal contact– Household, child-care centers– Identifiable risk  sexual (Promiscuous MSM); household contact with person with HAV; IDUs• Contaminated food, water– Infected food handlers, international travelers (endemic areas), immigration• Blood exposure (rare)– 45-50% have no identified source• Despite being detectable in saliva, there are no data to suggest transmissionthrough this mode of contact.NB: It almost always manifests with a self-limited clinical course05/01/13 Mohammed Adem18
  19. 19. Etiology• HAV is a RNA virus. genus Hepatovirus , Picornaviridae family.• Humans are the only known reservoir for the virus andtransmission occurs primarily through the fecal–oral route.• The virus is stable in the environment for at least a month.requires heating foods to a minimum of 85°C (185°F) for 1 minute ordisinfecting with a 1:100 dilution of sodium hypochlorite (bleach) in tap waterfor inactivation.• Multiple genotypes of the virus exist and although the clinicalimplications of infection by particular type are unknown.types I and III are the most commonly identified in human outbreaks05/01/13 Mohammed Adem19
  20. 20. Pathophysiology• HAV infection is usually acute, self-limiting, confers lifelongimmunity.• HAVs life cycle in the human host classically begins withingestion of the virus.• Absorption in the stomach or small intestine allows entry into thecirculation and uptake by the liver.• Replication of the virus occurs within hepatocytes & GI epithelialcells.• New virus particles are released into the blood & secreted into bileby the liver.• The virus is then either reabsorbed to continue its cycle orexcreted in the stool.05/01/13 Mohammed Adem20
  21. 21. Pathophysiology…• The enterohepatic cycle will continue until interrupted by antibodyneutralization.• The exact mechanism of replication & secretion is unknown. however, theinitial viral expansion does not seem to be associated with hepatic injury as peak viral fecal excretion precedes clinical signsand symptoms of infection.• On biopsy, acute hepatitis is marked by hepatocellular degeneration,inflammatory infiltrate, and hepatocyte regeneration.• Hepatocellular degeneration occurs as a result of immune-mediated injuryand not as a direct cytopathic effect of the virus.• Cytolytic T cells mediate hepatocyte lysis to eradicate the virus andmark the cellular immune response with rising hepatic enzyme levels.05/01/13 Mohammed Adem21
  22. 22. Risk Factors• Ingestion of contaminated food substances– Large outbreaks as well as sporadic cases have been traced tocontaminated: Food , Water, Milk• Family member who is affected• Poor personal hygiene• Institutional resident who is affected• Child care centers• Neonatal intensive care units• MSM, IVDU05/01/13 Mohammed Adem 22
  23. 23. Clinical presentations…Mohammed Adem23
  24. 24. Clinical presentations…Signs and symptoms• Symptoms and severity of HAV vary according to age• Children <6 years of age typically are asymptomatic.• The preicteric phase brings nonspecific influenza-like Sx: anorexia,nausea, fatigue, and malaise• Abrupt onset of anorexia, N, V, fever, headache & RUQabdominal pain• Icteric hepatitis is generally accompanied by dark urine, acholic (light-colored)stools, and worsening of systemic Sx.• Pruritus is often a major complaint of icteric patientsMohammed Adem24
  25. 25. Clinical presentations• Incubation period : 15–45 days ; Mean: ~4 weeks• Viremia occurs within 1-2 weeks of exposure as patients begin toshed the virus. viral shedding in feces,• Peak fecal shedding of the virus precedes the onset of clinical Sx& elevated liver enzymes.• Acute hepatitis follows, beginning with the preicteric orprodromal period.The phase is marked by an abrupt onset of nonspecificsymptoms, some very mildMohammed Adem25
  26. 26. Clinical presentations…• unusual Sx : chills, myalgia, arthralgia, cough, constipation, diarrhea, pruritus,and urticaria. Non-specific• Liver enzyme levels rise within the first wks of infection, peaking~ in the 4thwk and normalizing by the 8thwk.• Conjugated bilirubinemia, or dark urine, precedes the onset ofthe icteric period.Mohammed Adem26
  27. 27. Clinical presentations…• The concentration of virus declines at this point andpatients are generally considered noninfectious~ 1 week after the onset of jaundice.• GI Sx may persist or subside during this time and somepatients may have hepatomegaly.• Duration of the icteric period varies and corresponds todisease duration. It averages between 7 and 30 days.Mohammed Adem27
  28. 28. Clinical presentations…Physical examination• Icteric sclera, skin, and secretions• Mild weight loss of 2–5 kg• HepatomegalyMohammed Adem28
  29. 29. Clinical presentations…Laboratory findings• Positive-serum IGM ,• IgG replaces IgM and indicates host immunity following the acute phase.• Mild elevations of serum bilirubin, -globulin, and ALT , AST values to about 2Xnormal in acute anicteric disease• Elevations of AP, - GGT and total bilirubin in patients with cholestatic illness• Serum HAV becomes detectable 5 - 10 days before the onset of symptomsand can persist for monthsMohammed Adem29
  30. 30. Prognosis• HAV does not lead to chronic infections.• Some pts may experience Sx for up to 9 months.• Virtually all previously healthy patients with hepatitis A recovercompletely from their illness, with no clinical sequelae.• Complete clinical and biochemical recovery is to be expected in 1–2months.• No chronic carrier state• fatality rate: ~ 0.1%Mohammed Adem30
  31. 31. Complications• Rarely, patients experience complications from HAV, includingrelapsing hepatitis, cholestatic hepatitis, and fulminant hepatitis• Relapsing hepatitis :– Recurrence of symptoms– Elevated liver enzyme levels– Jaundice (occasionally)– Fecal excretion of HAV– Even when this occurs, hepatitis A remains self-limited and does not progress to chronic liverdisease.• Cholestatic hepatitis– Characterized by protracted cholestatic jaundice and pruritus• Fulminant hepatitis (massive hepatic necrosis): Rare 0.1% yet high fatality– Primarily in older adults (50), younger children and in persons with underlying chronic liver disease05/01/13 Mohammed Adem31
  32. 32. Diagnosis• History: particular attention to risk factors• Clinical Criteria:acute onset of fatigue, abdominal pain, loss ofappetite, intermittent nausea and vomiting, jaundice• Laboratory:serum aminotransferases, and serologic testing for anti-HAV antibodies.IgM anti-HAV is the diagnostic test of choice• Appears very soon after infection• Disappears 3–6 months later• Incidental presence of rheumatoid factor can yield false-positive results• IgG anti-HAV appears later in the acute phase but persists for decades05/01/13 Mohammed Adem 32
  33. 33. Differential diagnosis1. Other hepatitis viruses2. Other viral illnesses frequently affect the liver– Infectious mononucleosis , Cytomegalovirus , Herpes simplex1. Many drugs and certain anesthetic agents2. Alcoholic hepatitis3. Acute Cholecystitis4. Disorders in pregnancy that may be confused with viralhepatitis• Acute fatty liver of pregnancy , Cholestasis of pregnancy , Eclampsia ,1. Many, many more…05/01/13 Mohammed Adem33
  34. 34. Treatment• Mainstay of therapy is supportive care.• Specific treatment is not necessary.– Most patients hospitalized with hepatitis A excrete little if any HAV– Likelihood of HAV transmission from these patients during theirhospitalization is low.Nonetheless, universal precautions are recommended.Mohammed Adem34
  35. 35. TreatmentDesired Outcome• The ultimate goal of therapy is complete clinical resolution.• Other goals: reducing complications, normalization of liver function,and reducing infectivity and transmission.• The majority of pts are expected to fully recover without clinicalsequelae.• clinical resolution within 6 months of the infection, & a majoritywill have done so by 2 months.• Rarely, Sx persist for longer or patients relapse.Mohammed Adem35
  36. 36. Treatment…General Approach• In pts who develop liver failure, transplant is the only option.• Prevention and prophylaxis are key to managing the virus.• Immunoglobulin: for pre- and postexposure prophylaxis offers passive immunity.• Active immunity is achieved through vaccination.Children and at-risk adults  to reduce the overall incidenceMohammed Adem36
  37. 37. Treatment…• Most patients hospitalized with hepatitis A excrete little if anyHAV. Likelihood of transmission is low• Prevaccination serologic testing to determine susceptibility isgenerally not recommendedif the cost of the test is less than that of the vaccine andif the person is from a moderate to high endemic area and likely to have priorimmunity• Prevaccination serologic testing of children is not recommended.• postvaccine serologic testing is not recommended.Due to high vaccine responseMohammed Adem37
  38. 38. Prevention• HAV is easily preventable with vaccination.• vaccine programs have targeted children as the most effectivemeans to control HAV.• vaccination programs among children from high-incidence states >70% reduction in the annual incidence of new HAV infections• Two vaccines for HAV are available and are incorporated into theroutine childhood vaccination schedule.05/01/13 Mohammed Adem38
  39. 39. Prevention… Recommendation for HAV Vaccine05/01/13 Mohammed Adem39
  40. 40. Prevention…• Routine prevention of HAV transmission includeswith soap and water after using the bathroom,Regular hand washing changing a diaper, and before food preparation.• For travelers to countries with high endemic rates of HAV, evenshort-term stays in urban and upscale resorts are not risk free.contaminated waterfresh produce, and any uncooked foods pose a risk05/01/13 Mohammed Adem40
  41. 41. Vaccines• Havrix and Vaqta: are available for pediatric and adult use. USAthe two inactivated virus vaccines. 1995• The differences in the two vaccines are in the use of apreservative and in expression of antigen content.• Vaqta: formulated without a preservative anduses units of HAV antigen to express potency.• Havrix: uses 2-phenoxyphenol as a preservative andantigen content is expressed as enzyme-linked immunosorbent assayunits.• Pediatric dosing is indicated for children 1 to 18 years of age, andadult dosing is for patients ages 19 years and older05/01/13 Mohammed Adem41
  42. 42. Vaccines …• Although high seroconversion rates of 94% are achieved with thefirst dose, both vaccines recommend a booster shot to achieve thehighest possible antibody titers.• In situations of postexposure prophylaxis, previously onlyimmunoglobulin was indicated but recent guidelines changesallow the use of vaccines for this indication.The change to the use of the vaccine is advantageous asvaccination confers the benefit of long-term immunity against HAV.• Both vaccines may be given concomitantly with immunoglobulinand the two brands are interchangeable for booster shots.05/01/13 Mohammed Adem42
  43. 43. Recommended dosing of the Vaccines05/01/13 Mohammed Adem43
  44. 44. Vaccines … monitoring issues• Response to the vaccine as determined by detection of anti-HAVafter vaccination.• Vaccine efficacy may be reduced in certain pt groups.eg. In HIV infected pts, greater immunogenic response may correlate with higher baseline CD4 counts.females and patients with CD4 counts >200 high response rate• most common S/E: soreness & warmth at the injection site, headache, malaise, pain• Reported serious A/E: causality not yet establishedanaphylaxis, Guillain-Barré syndrome, transverse myelitisReported brachial plexus neuropathy, multiple sclerosis,encephalopathy, and erythema multiforme.Note: the incidence of these events was similar in the general population. Vacc vs unvaccThe vaccine is considered safe05/01/13 Mohammed Adem44
  45. 45. Vaccines … Twinrix• Twinrix is a bivalent vaccine for HAV and HBV. in 2001• It is approved for people ages 18 and older and is given at 0, 1,and 6 months.• Although seroconversion exceeds 90% for HAV after the firstdose , the full three-dose series is required for maximal HBV seroconversion.• The combined vaccine offers the advantage of immunizationagainst both types of hepatitis in a single vaccine.05/01/13 Mohammed Adem45
  46. 46. Immunoglobulin/Ig• Used in persons for whom vaccination is not an option.pre- or postexposure prophylaxis• provides protection by passive transfer of antibody• is preferred forchildren <12 months of age andpostexposure prophylaxis in patients aged >40 years, pts with chronic liver disease,and persons allergic to any part of the vaccine.• most effective if given in the incubation period of the infection. Receipt of Ig within the first 2 weeks of infection will reduce infectivity and moderate theinfection in 85% of patients.Note: Patients who receive at least 1 dose of the vaccine at least 1 month earlierdo not need pre- or postexposure prophylaxis with Ig.05/01/13 Mohammed Adem46
  47. 47. Ig…• International travelers are the major patient population receivingpreexposure prophylaxis with Ig.• vaccination or prophylaxis with Ig is recommended for travelers tocountries with high endemic rates of HAV. A/E like anphylaxis IgA deficiency• Patients who had an anaphylaxis reaction to Ig should not receiveit. There is no C/I for use in pregnancy or lactation.• Dosing of Ig is the same for adults and children.• a single dose of 0.02 mL/kg IM: For postexposure prophylaxis and for short-term preexposure coverage of <3 months,05/01/13 Mohammed Adem47
  48. 48. Ig…• For long-term preexposure prophylaxis of 5 monthsa single dose of 0.06 mL/kg is used.• People recently exposed to HAV and not been previouslyvaccinated  Ig is indicated fora) close personal contact with an HAV-infected person;b) all staff and attendees of daycare centers when HAV is documented;c) common source of exposure (food handler)d) classroom contacts of an index case patient; ande) schools, hospitals, and work settings where close personal contact occurred with thecase patient• Ig can be given concomitantly with the HAV vaccine. the response isprotective05/01/13 Mohammed Adem48
  49. 49. Ig…• The MMR (measles, mumps, and rubella) vaccine should be delayed for a minimum of3 months after receipt of Ig.• The varicella vaccine must be delayed for 5 months.• Ig should not be given to patients who received the MMR within 2 weeks or thevaricella vaccine within 3 weeks.• In situations where the benefits of Ig outweigh the benefits of the othervaccines, revaccination can be performed after Ig administration.• For the MMR, revaccination should be at least 3 months later, and for thevaricella vaccine, at least 5 months later.• Ig does not interfere with inactivated vaccines and may be administered safely withother vaccines traditionally given to travelers to some developing countries, such as theoral poliovirus or yellow fever vaccine.05/01/13 Mohammed Adem49
  50. 50. Pharmacoeconomic Considerations• The costs of an HAV outbreak are significant, yet routine vaccination of allindividuals is not cost-effective. So,• targeting at-risk populations, the majority of cases can be prevented.Children play a pivotal role in disease persistence• Using vaccine is cost-effective in children and offers the most benefit to thepersonal contacts of children.• The use of the combined HAV-HBV vaccine is effective in reducing costsassociated with HAV among persons who are at increased risk for infection.05/01/13 Mohammed Adem50
  51. 51. References• Harrison’s principle of internal medicine 18thed• Joseph T dipro; Pharmacotherapy apathophysiologic approach 8thed• Applied therapeutics the clinical use of drugs 9thed05/01/13 Mohammed Adem 51

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