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Hepatitis mbbch-2015
This document discusses viral hepatitis, focusing on hepatitis A, B, C, D, and E viruses. It provides details on the structure and transmission of each virus. It also summarizes the typical clinical progression and serological markers of acute and chronic infection for each virus type. The diagnosis, treatment, and complications of viral hepatitis infections are outlined.
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Hepatitis mbbch-2015
- 1. Viral Hepatitis Dr. FathallaSedky Prof of Hepatology Head of HPB Unit Faculty of Medicine, Alex UN
- 2. Viral Hepatitis -Historical Perspective AA““Infectious”Infectious” ““Serum”Serum” ViralViral hepatitishepatitis EntericallyEnterically transmittedtransmitted ParenterallyParenterally transmittedtransmitted F, G,F, G, ? other? other EE NANBNANB BB DD CC
- 3. HAV HBV HCVHDV HEV genome RNA DNA RNA RNA RNA IP 15-45 30-180 15-150 30-180 15-60 transmission Fecal oral Blood saliva Blood Saliva Blood Fecal oral diagnosis IgM anti- HAV HBsAg IgManti – HBc HBV DNA Anti HCV HCV RNA PCR IgM anti- HDV IgM anti- HEV prevention vaccine Vaccine -- -- -- chronicity No Yes Yes Yes No
- 4. Clinical types Asymtomatic; onlyelevated transaminaes. Anicteric: GI and influenza like symptoms, no jaundice. Classic: 3 stages. 1-prodromal 3-4 days. profound malaise, fever, anorexia nausea, vomiting, abdominal pain 2-icteric 1-4 weeks. -change of urine color followed by jaundice and itching. -patient feels generally better and appetite returns. -tender hepatomegaly.
- 5. Prolonged cholestasis: -classic acutehepatitis but the icteric stage is prolonged 8-29 weeks with manifestations of cholestasis. -more with HAV. Fulminanat hepatitis: -patient after a typical acute onset becomes deeply jaundiced, ominous manifestations– persistent vomiting, fetor hepaticus, drowsiness, flappy tremors, finally coma. -common with HAV , HBV , HEV, rare in HCV. Relapse: -1.8-15%especially HAV. -attack is usually milder. -precipitated by premature activity.
- 6. •Posthepatitis syndrome: -Usually, thisis a matter of weeks but it may extend to months. Features are anxiety, fatigue, failure to regain weight, anorexia, and right upper abdominal discomfort. The liver edge may be palpable and tender. -Treatment consists of reassurance after full investigation. -An isolated elevation of unconjugated bilirubin after clinical recovery is usual in patients with coexistence of Gilbert’s syndrome.
- 7. Diagnosis -SGOT , SGPT: peaklevels 1-2 days before or after onset of jaundice. -useful in early diagnosis and detection of anicteric cases. -bilirubin & ALP usually elevated. -PT prolonged. -CBC --- leucopenia, lymphopenia in anicteric stage ---aplastic anemia may occur weeks –months after acute attack.
- 8. Treatment -Bed rest. -diet: lowfat high carbohydrate diet more palatable to the patient. Symptomatic and supportive. -corticosteroids only in cholestatic HAV. Convalescence is not allowed till patient is symptom free, liver no longer tender & s bilirubin <1.5 mg/dl. -Follow up for monthly for 3ms.
- 9.
- 10. 0 1 23 4 5 6 7 8 9 10 11 12 13 Week Response Clinical illness ALT IgM IgG HAV in stool Infection Viremia Events In Hepatitis A Virus Infection
- 11. Hepatitis B Virus Double-Stranded DNA •Firstrecognized in 1960s •Scientifically classified as Hepadnavirus •Contains ddeoxyribonnucleic aacid (DNA) DNADNA PolymerasePolymerase Electron micrograph/picture of hepatitis B virusElectron micrograph/picture of hepatitis B virus
- 12. •Approximately 70% ofpatients with acute HBV infection have subclinical or anicteric hepatitis. During the prodromal period, a serum sickness- like syndrome may develop.
- 13.
- 14. Weeks after Exposure Symptoms HBeAganti-HBe Total anti-HBc IgM anti-HBc anti-HBsHBsAg 0 4 8 12 16 20 24 28 32 36 52 100 Titer Acute Hepatitis B Virus Infection with Recovery Typical Serologic Course
- 15. IgM anti-HBc Total anti-HBc HBsAg Acute (6months) HBeAg Chronic (Years) anti-HBe 0 4 8 12 16 20 24 28 32 36 52 Weeks after Exposure TiterProgression to Chronic Hepatitis B Virus Infection Typical Serologic Course
- 17. Extra hepatic manifestations -polyartritis. -glomerulonephrits. -Essentialmixed cryoglobulinemia. -Guillain-Barre syndrome.
- 18. Treatment • Acute: -Symptomatic &supportive. -Antiviral treatment (lamivudine in double dose, entecavir, tenofovir) in aggressive cases of fulminant hepatic failure.
- 19. • Licensed in1982; currently recombinant . • 3 dose series, typical schedule 0, 1, 6 months - no maximum time between doses (no need to repeat missed doses or restart) • Protection ~30-50% dose 1; 75% - 2; 96% - 3. Hepatitis B Vaccine
- 20.
- 21.
- 22. Hepatitis C Virus •First identified in 1989 • Scientifically classified as Flavivirus • Contains ribonucleic acid (RNA) Schematic view of hepatitis C virusSchematic view of hepatitis C virus Single-stranded RNASingle-stranded RNA
- 23. Natural History ofHCV Infection 100 People Resolve (15) 15% Chronic (85) 85% Cirrhosis (17) Stable (68) 80% 75% Stable (13) Mortality (4) 25% Time 20% Leading Indication for Liver Transplant
- 24. Pattern of AcuteHCV Infection with Recovery HCV RNA Symptoms +/- Time after Exposure Titer Anti-HCV ALT Normal 0 1 2 3 4 5 6 1 2 3 4 YearsMonths
- 25. Serologic Pattern ofAcute HCV Infection With Progression to Chronic Infection Symptoms +/- Time after Exposure Titer Anti-HCV ALT Normal 0 1 2 3 4 5 6 1 2 3 4 YearsMonths HCV RNA
- 26. Treatment • Acute: - Symptomatic. -Liver support. - ?? Interferon. • Liver transplant – For fulminant hepatic failure.
- 27.
- 28. Definition -Persistent inflammatory reactionin the liver for more than 6 months. -Clinically: Suspected from persistently elevated hepatic transaminases (necro-inflammatory markers) for > 6 months. -Histologically: Liver biopsy is the gold standard for diagnosis.
- 29. Etiology 1-Viral: B& D,C 2-Autoimmune. 3-Drugs. 4-Genetic: Wilson’s disease, hemochromatosis, alpha 1 anti-trypsin deficiency. 5-Alcohol (ASH( 6-fatty infiltration (NASH(.
- 30. Liver biopsy • Thegold standard for diagnosis of chronic hepatitis and evaluation of severity of liver disease. • Evaluation includes: Grading: necroinflammatory changes. Staging: extent of fibrosis. • The most commonly used currently is the METAVIR system, which grades inflammation from 0 to 4 (A 0-4) and stages fibrosis from 0 to 4 (F0-4).
- 31. Liver biopsy •Specific findingsfor specific etiology e.g: Mallory hyaline bodies in alcoholic hepatitis plasma cell infilteration in AIH ground glass hepatocyte in HBV PCR for the virus in liver tissue hepatic concentration of Cu and Fe in Wilson and hemochromatosis
- 32. Clinical picture Symptoms: -Asymtomatic. -Fatigue (mostcommon), rt hypochondrial pain, nausea, jaundice, muscle and joint pains. Signs: Tender hepatomegaly, occasionally vascular spiders.
- 33.
- 34. CHB -About 90 %of acute infection in infants become chronic. -About 10 % of acute infection in adults become chronic.
- 35. ?? • HBsAg +IgM anti-HBc • Isolated total anti-HBc • HBsAg + IgG anti-HBc • HBs Ag -ve, anti-HBs & anti- HBc +ve • Anti-HBs +ve, anti-HBc –ve • acute HBV • window period • occult infection • CHB • Cure • vaccinated
- 36. Treatment of chronicHBV Drug Generic name Drug Trade name Dose Route of administratio n Peginterferon Peg-intron Pegasys 1.5 mg/kg 180 µg/kg S.C S.C Lamivudine Zeffix 100 mg/d Oral Adefovir Hepsera 10 mg/d Oral Entecavir Baraclude 0.5 – 1 mg/d Oral Telbivudine Tyzeka 600 mg/d Oral Tenofovir Viread 300 mg/d Oral
- 37. 1st line drugs entecavir,peginterferon alfa-2a, and tenofovir because of their superior efficacy, tolerability, and favorable resistance profiles.
- 38. Occult hepatitis B •Presence of HBV DNA in the serum or liver of people without HBsAg. • Anti-Hbc Abs are usually +ve. • “HBcAb-only” pattern has been associated with HCV infection.
- 39.
- 40. Treatment Indications: 1- +ve anti-HCVAbs & HCV RNA PCR. 2-Elevated transaminases. 3-Normal transaminases ----- only if there is fibrosis in liver biopsy. 4-No contraindication to treatment.
- 41. Treatment Drugs: 1-Interferon (regular, pegylated(. 2-Ribavirin. 3-DAADs(protease inhibitors, polymerase inhibitors(.
- 42. Contraindications -Interferon: Psychatric illness ,neutropenia , thrombocytopenia , CHD , arrhythmia , decomensated cirrhosis , renal transplant. -Ribavirin: During pregnancy, anemia , renal insufficiency, sever heart disease.
- 43. HCV Life Cycleand DAA Targets Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000. Receptor binding and endocytosis Fusion and uncoating Transport and release )+(RNA Translation and polyprotein processing RNA replication Virion assembly Membranous web ER lumen LD LD ER lumen LD NS3/4 protease inhibitors NS5B polymerase inhibitors Nucleoside/nucleotide Nonnucleoside *Role in HCV life cycle not well defined NS5A* inhibitors
- 44. HCV syndrome • Abattery of HCV-related diseases. 1- Mixed cryoglobulinemia. 2- B-cell lymphoma. 3- Autoimmune thyroiditis. 4- Pruritus. 5- Lichen plannus. 6- Porphyria cutanea tarda. 7- Immune thrombocytopenia.
- 45. Mixed cryoglobulinemia • Isa systemic vasculitis caused by deposition of circulating immune complexes in the small vessels. • Characterized by presence of circulating Igs that precipitate at low temperature (under 37 °C) and can solve by serum re-warming. • Type II (MC-II): Polyclonal IgG and monoclonal IgM with rheumatoid factor (RF) activity.
- 46. C/P • The mostcommon symptoms are weakness, arthralgias, and orthostatic palpable purpura. • Peripheral neuropathy represents the most frequent clinical feature after the triad, followed by renal involvement.
- 47. Lab • Serum cryoglobulins,high RF values, and reduced C4 values are the most frequent laboratory data.
- 48. HCV + jointVs. HCV + RA • Non deforming. • RF +ve. • Anti-CCP –ve. • HCV Abs +ve. • HCV RNA +ve. • Cryoglobulin +ve. • Antiviral treatment. • Deforming arthritis. • RF +ve. • Anti-CCP +ve. • HCV Abs +ve. • HCV RNA +ve. • Cryoglobulin –ve. • Interferon treatment not recommended.
- 49. Pruritic, confluent, purplepapules on the wrist of a patient with lichen planus.
- 50. Erythematous bullae, erosions,fragile skin, and scarring on the dorsal hand of a patient with porphyria cutanea tarda.
- 51. Occult hepatitis C(OCI( -Elevated transaminases. - -ve HCV antibodies. - +ve HCV RNA in low levels detected by -Amplification techniques in serum. -PBMCs. -Liver biopsy. -Progressive disease, better to be treated.
Editor's Notes
- #10 [SLIDE 7] Hepatitis A Virus Hepatitis A is caused by infection with HAV, a 27-nm RNA virus that is classified as a picornavirus. The virus can produce either asymptomatic or symptomatic infection in humans after an average incubation period of 28 days. HAV infection appears to induce lifelong protection against subsequent infection. Only one serotype has been observed among HAV isolates collected from various parts of the world. Several hepatitis A vaccines have been developed and evaluated in clinical trials and proven long-term protection against HAV infection.
- #15 [SLIDE 34] Acute Hepatitis B Virus Infection with Recovery: Typical Serologic Course Serologic markers of HBV infection vary depending on whether the infection is acute or chronic. The first serologic marker to appear following acute infection is HBsAg, which can be detected as early as 1 or 2 weeks and as late as 11 or 12 weeks (mode, 30‑60 days) after exposure to HBV. In persons who recover, HBsAg is no longer detectable in serum after an average period of about 3 months. HBeAg is generally detectable in patients with acute infection; the presence of HBeAg in serum correlates with higher titers of HBV and greater infectivity. A diagnosis of acute HBV infection can be made on the basis of the detection of IgM class antibody to hepatitis B core antigen (IgM anti‑HBc) in serum; IgM anti‑HBc is generally detectable at the time of clinical onset and declines to subdetectable levels within 6 months. IgG anti‑HBc persists indefinitely as a marker of past infection. Anti‑HBs becomes detectable during convalescence after the disappearance of HBsAg in patients who do not progress to chronic infection. The presence of anti‑HBs following acute infection generally indicates recovery and immunity from reinfection.
- #16 [SLIDE 35] Progression to Chronic Hepatitis B Virus Infection: Typical Serologic Course In patients with chronic HBV infection, both HBsAg and IgG anti‑HBc remain persistently detectable, generally for life. HBeAg is variably present in these patients. The presence of HBsAg for 6 months or more is generally indicative of chronic infection. In addition, a negative test for IgM anti‑HBc together with a positive test for HBsAg in a single serum specimen usually indicates that an individual has chronic HBV infection.
- #20 Vaccine advisory groups that have endorsed this strategy include the Immunization Practices Advisory Committee to the U.S. Public Health Service (ACIP), the American Academy of Pediatrics (AAP), the American Academy of Family Physicians (AAFP), and the American College of Physicians (ACP).
- #22 [SLIDE 1] Hepatitis C Virus HCV is an enveloped, single‑stranded RNA virus, approximately 50 nm in diameter, that has been classified as a separate genus in the Flaviviridae family. Before HCV was visualized, the virus genome was cloned and sequenced. The 5&apos; end of the genome codes for core and envelope proteins, followed by nonstructural proteins, which extend to the 3&apos; end. The ability of HCV to undergo rapid mutation in a hypervariable region(s) of the genome coding for envelope protein allows it to escape immune surveillance by the host; thus, most persons infected with HCV develop chronic infection.
- #25 [SLIDE 52] Acute HCV Infections with Recovery: Typical Serologic Course The incubation period for acute hepatitis C has been reported to average 6 – 7 weeks, but may range 2 – 26 weeks. Children and adults with acute hepatitis C are typically either asymptomatic or exhibit mild clinical illness. In adults with acute HCV infection, studies have shown up to 40% had some symptomatic illness and 15 –30% had jaundice. The course of acute hepatitis C is variable, although its most characteristic feature is fluctuating alanine aminotransferase (ALT) patterns. Normalization of ALT may occur and suggest full recovery although symptomless ALT elevations can follow, indicating chronic infection. Fulminant hepatic failure following acute hepatitis C is rare.
- #26 [SLIDE 53] Progression to Chronic HCV Infection: Typical Serologic Course Persistent HCV infection develops after the onset of acute hepatitis C in most persons (&gt;85%). Chronic hepatitis C develops in 60 – 70% of HCV-infected persons, and 10 – 20% of these individuals may develop cirrhosis over the course of 20 – 30 years. Chronic hepatitis C progresses at a slow rate without symptoms in the majority of patients during the first two decades subsequent to infection. Usually chronic hepatitis C is not diagnosed until symptoms, such as fatigue appear with advanced liver disease.
- #44 DAAs, direct-acting antivirals; ER, endoplasmic reticulum; HCV, hepatitis C virus; LD, luminal domain. The elucidation of the life cycle of the hepatitis C virus (HCV) allowed for the identification of potential targets of antivirals that directly interrupt HCV replication. From the binding of the virus to the plasma membrane and its endocytosis through the membrane, all the way through uncoating and generating the membranous web to translation and replication, viral assembly, and transport and release again into the extracellular space, one may envision a variety of potential targets. The most obvious targets are the NS3/4 serine protease and the NS5B HCV polymerase. Therefore, our first DAAs have been protease inhibitors and nucleoside or nonnucleoside polymerase inhibitors. Also interesting was the recent discovery of NS5A inhibitors that are inhibitors of the NS5A protein. However, the function of this protein in the hepatitis C life cycle is not yet well understood. Therefore, the inhibitory drugs may help to elucidate the involvement of this protein in the HCV life cycle rather than vice versa.