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A. Typesnavigator

  1. Hepatitis A (HAV)
  2. Hepatitis B (HBV)
  3. Hepatitis C (HCV)
  4. Delta Virus (HDV)
  5. Hepatitis E Virus (HEV)
  6. Hepatitis GB (G) Viruses (subtypes A,B,C)
  7. SEN Viruses
  8. Other Causes of Viral Hepatitis
    1. Epstein Barr Virus (EBV) - usually with infectious mononucleosis [33]
    2. Cytomegalovirus (CMV) - usually in immunocompromised persons [34]

B. Hepatitis A navigator

  1. Transmission
    1. Contaminated food (usually raw shellfish) or water
    2. Person to person - fecal - oral
    3. Found in feces ~3-4 weeks after exposure
    4. Highest transmission in areas of poor sanitation and hygiene
  2. Very common cause of acute hepatitis
    1. Generally self limited disease
    2. Rarely (<1%) causes fulminant hepatitis
    3. Does not cause chronic hepatitis
  3. Incubation period up to 21 days
  4. Symptoms peak at 4-5 weeks
    1. Nausea, vomiting
    2. Abdominal pain
    3. Jaundice
  5. Serological Responses
    1. IgM Abs (anti-HAV) begin 4-5 weeks
    2. IgG Abs indicative of previous infection
  6. HAV immune globulin or HAV vaccine about equally effective for post-exposure prophylaxis [6]
  7. Approved effective inactivated vaccines [1]

C. Hepatitis B Virus [2] navigator

  1. Incomplete double stranded DNA virus with 8 genotypes (A through H)
  2. Major worldwide health problem
  3. Oncogenic potential, chronic infection can cause hepatocellular carcinoma (HCC)
  4. Symptoms of Acute HBV Infection
    1. Jaundice
    2. Malaise; Flu-like Illness
    3. Arthralgias
    4. 90% of patients have self limiting illness
    5. 10% of patients have chronic active or persistent hepatitis (eventual cirrhosis)
    6. 1% of patients will progress to Fulminant Hepatic Failure
  5. Viral Coinfections
    1. Coinfection with delta virus (HDV) worsens symptoms, outcome, risk of HCC
    2. Increased risk of poor outcomes, complications, with HIV coinfection [20]
    3. Coninfection with HBV and HCV incresaes risk of death, HCC and cirrhosis [24]
  6. HBV Serology
    [Figure] "HBV Protein Expression and Serology"
    1. Surface antigen (HBsAg) - indicates chronic active or persistent infection (uncleared)
    2. Surface antibody (anti-HBs Ab) - indicates clearance of infection
    3. Core Antibody (anti-HBc Ab) - indicates previous infection
    4. Envelope Antigen (HBe Ag) - carriers are highly contagious
    5. Delta Antigen - indicates superinfection
  7. Complications [23,24]
    1. Fulminant Hepatitis [3]
    2. Chronic Hepatitis: >90% of infected children, <5% of infected adults
    3. Progression to cirrhosis in ~30%
    4. Superinfection with Hepatitis Delta Virus: increases cirrhosis and HCC risk
    5. HCC: 5-20% per year with chronic hepatitis and cirrhosis
    6. Liver failure: following cirrhosis
    7. Polyarteritis Nodosa: ~10% with chronic HBV
    8. Renal Complications - membranous nephropathy
  8. Treatment
    1. Supportive therapy - majority of patient have self-limited disease
    2. Severe acute infection may also be treated with high doses of interferon alpha (IFNa) [4]
    3. Chronic HBV should be treated to reduce risk of cirrhosis and carcinoma (see below)
    4. Many agents are approved for treatment of chronic HCV
    5. Monitor with ultrasound and serum alpha-fetoprotein (marker for HCC)
  9. Agents for HBV (HIV+ or HIV-) [20]
    1. Lamivudine
    2. Tenofovir
    3. Tenofovir + emtricitabine
    4. Adefovir
    5. Entecavir
    6. Telbivudine
    7. Pegylated IFNa
  10. Lamivudine (Epivir®)
    1. Nucleotide analog with very potent antiretroviral (anti-HIV) activity
    2. Improves inflammation, reduces fibrosis progression in chronic HBV infection
    3. 100mg qd po reduces HBV DNA 98%, normalizes ALT in ~70% persons
    4. About 15% of patients with HBeAg seroconverted to anti-HBeAb after 1 year (100mg/d)
    5. Very well tolerated
    6. Lamuvidine should be considered in ALL patients with chronic active HBV infection
  11. Adefovir (Hepsera®) [9]
    1. Activity in lamivudine resistant HBV
    2. Active against Lam resistant hepatitis B virus in HIV+ patients [10]
    3. Dose is 10mg po qd and causes 3-4 log reduction in viremia
    4. Approved as Hepsera® for use in HBV
    5. Active against HIV but at much higher (60mg) doses where kidney problems occur
  12. Tenofovir (Viread®) [11]
    1. Nucleotide RTI approved for combination therapy in resistant HIV infections
    2. Effective in patients on ART with suboptimal HIV-1 viral suppression
    3. Once daily 300mg dosing taken with food
    4. Nausea, vomiting, diarrhea are most common adverse events
    5. Often effective against HIV strains resistant to other RTIs
    6. Activity against HBV as well
  13. Pegylated IFNa for Chronic HBV [5,7]
    1. PEG-IFNa2a induces sustained complete responses (viral levels <400/mL) in ~20% versus 7% with Lamivudine in chronic HBV (HBeAg-)
    2. Reponse rate (viral load <20,000/mL) ~60% with PEG-IFNa2a versus 44% with lamivudine
    3. No benefit to combining IFNa or PEG-INFa with lamivudine in chronic HBV
  14. Prevention
    1. Immunization with recombinant surface (and pre-S) protein (Recombivax®, others)
    2. All infants should be vaccinated against HBV
    3. All persons be vaccinated against HBV

D. Hepatitis C Virus (HCV) [4,12] navigator

  1. Single stranded, RNA flavivirus virus
  2. Main cause of chronic viral hepatitis and need for liver transplantation in developed world [13]
  3. HCV Serotypes
    1. Type 1a (I)
    2. Type 1b (II) ~60% of cases
    3. Type 1c
    4. Type 2a (III) - associated with mixed cryoglobulinemia
    5. Type 2b (IV)
    6. Type 3a (V)
    7. Serotypes have importance for response to IFNa based therapy
  4. Epidemiology and Coinfection [12,23,24]
    1. Over 170 million chronically infected patients worldwide
    2. Causes ~280,000 deaths per year
    3. About 170,000 new cases per year in USA
    4. Prevalence 4.1 million (1.6%) in USA; highest rate (4.3%) in ages 40-49 years [16]
    5. 40% of asymptomatic infection is histologically active and progressive
    6. ~50% of acutely infected patients will develop chronic HCV
    7. ~20% of these will develop hepatic cirrhosis and some will require transplant
    8. Main association currently with intravenous drug abuse (IVDA) in developed countries
    9. Low risk of sexual transmission with monogamous partners in stable relationships
    10. Severity of disease correlates with ALT elevations, increases with age
    11. Coexisting occult HBV infection may exacerbate HCV and reduce IFN responses [14]
    12. Coexisting HIV infection associated with very poor prognosis [20]
  5. Detection
    1. All persons with high risk behavior should be screened for HCV [15]
    2. Second or third generation ELISA tests used for screening
    3. Viral load (HCV RNA) detection by PCR or branched chain assay
    4. PCR detection is more sensitive than branched chain DNA assay
    5. HCV RNA level and genotyping should be used to confirm all HCV infections [35]
    6. Viral load is useful for antiviral therapy assessment but not prognosis
    7. Liver biopsy generally recommended for assessment of patients prior to therapy
  6. Associated with Autoimmune Hepatitis
    1. May have LKM1+ antibodies (Ab) with hepatitis C infection
    2. Antinuclear Ab (ANA)
    3. Anti-smooth muscle Ab
    4. Cryoglobulins
  7. Extrahepatic Associations
    1. Cryoglobulinemia
    2. Membranoproliferative Glomerulonephritis
    3. Porphyria cutanea tarda
    4. Possible: autoimmune thyroiditis, Mooren corneal ulcers
  8. Hepatocellular Carcinoma (HCC) [23]
    1. Increased risk in HCV+ patients with cirrhosis
    2. ~30 year latency between infection and development of HCC
    3. In HCV+ cirrhotic patients, 38% developed HCC within 7 years
    4. Overlal risk of HCC is 1-4% per year in patients with HCC and cirrhosis
    5. IFNa therapy (6MU 3X/week) reduced risk of HCC to 4% in 7 years
  9. IFNa Treatment [4,17,18,19,20]
    1. Pegylated IFNa (PEG-IFNa) improved efficacy and side effects versus standard IFNa
    2. Combination ribavirin + IFNa effective in patients who fail or relapse after IFNa [21]
    3. Standard of care in HCV+ (HIV- or HIV+) is PEG-IFNa + ribavirin
    4. Ribavirin dosed according to HCV genotype except in HIV coinfection
    5. Reduces HCV replication (reduced HCV RNA levels) and improves organ dysfunction
    6. IFNa therapy reduces risk of developing HCC in HCV carriers
    7. Viral serotypes generally correlate with treatment response
    8. Side effects of IFNa therapy are common, mainly flu-like symptoms
  10. Prognosis in Chronic HCV Infection [23,24]
    1. Hepatomegaly in ~70%
    2. Presentation: chronic hepatitis in ~20%, chronic active hepatitis in 25%, cirrhosis ~50%
    3. HCC develops in 1-4% per year in cirrhosis with HCV
    4. IFNa treatment reduces risk of HCC by >50% [37]
    5. Coinfection with HBV and HCV greatly increases risk of developing HCC
    6. Coinfection of SEN D or SEN H with HCV reduces response to IFNa/ribavirin therapy [22]
    7. Hepatitis G virus coinfection does not affect severity of liver disease
    8. Transplanted livers are uniformly reinfected with HCV
  11. Empiric therapy with combination antiviral therapy for mild chronic HCV is is more cost effective than periodic liver biopsy and institution of therapy later [25]

E. Hepatitis D Virus (HDV) navigator

  1. RNA virus requires helper function from HBV
  2. Causes acute or chronic hepatitis in setting of HBV
    1. May cause severe exacerbation of chronic hepatitis
    2. When coinfects with HBV, more likely to cause a fulminant course
    3. ~80% of patients with D infection will go on to cirrhosis
  3. High dose IFNa2b therapy appears effective in ~70% of patients
    1. Relapse rate with discontinuation of therapy is high
    2. Responses are generally good during therapy
    3. PEG-IFNa + ribavirin should be used first line

F. Hepatitis E Virus (HEV) navigator

  1. Self limited, enterically transmitted acute viral hepatitis
  2. Occurs as epidemic outbreaks in underdeveloped countries
  3. No reported cases in USA or Canada
  4. Symptoms: jaundice, malaise, anorexia, abdominal pain, hepatomegaly
  5. HEV in Pregnancy
    1. May cause fulminant failure in pregnant patients
    2. Preganant women with jaundice caused by acute HEV have higher maternal mortality, worse obstetric outcomes than jaundiced pregnant women with other acute viral hepatidites [8]
  6. Detection of anti-HEV antibodies by ELISA or RIA to identify infected patients
  7. Recombinant HEV vaccine appears 95% effective at preventing infection [36]
  8. No specific therapy

G. Hepatitis GB Virus Cnavigator

  1. Formerly Hepatitis G Virus, HGV
  2. At least 3 distinct viruses exist in this group, types A, B and C
  3. All are RNA Flaviviruses related to HCV
    1. ~10% of HCV+ patients also have HGV
    2. Does not affect response or progression of HCV to IFNa
  4. Risk Factors
    1. HCV Infection
    2. Detected in ~3% of patients on long term hemodialysis
    3. Transfusion is major mode of transmission (high rates of HGV in hemophiliacs)
  5. HGV serum antibodies to E2 appear to clear infection
  6. Diagnosis by detection of anti-E2 antibodies
  7. Effect on HIV Progression
    1. HGV coinfection with HIV leads to lower HIV viral loads [26]
    2. GB Virus C coninfection slows progression [26] and improves survival in AIDS [27,28,29]
    3. GB Virus may stimulate a Th1 cytokine profile and thereby slow HIV progression [30]
    4. May compete for viral replication and/or budding mechanisms
  8. Some strains of HGV-C (HGV) may be associated with fulminant hepatic failure [31]

H. TTV Virus [31,32]navigator

  1. Novel single stranded DNA virus, 3739 nucleotides
  2. Unclear association with chronic liver disease / transfusion hepatitis
  3. Relatively high seroprevalence, ~10% across different populations
  4. May be associated with some cases of chronic hepatitis
  5. However, high prevalence of virus is found, usually in the absence of any liver damage [32]

I. SEN Viruses [22]navigator

  1. Family of 8 new viruses similar to circoviruses
  2. Single stranded, circular, non-enveloped DNA viruses, average 3900 nucleotides
  3. SEN D and SEN H transmitted parenterally, can cause post-transfusion hepatitis
  4. Coinfection of SEN D or SEN H with HCV reduces response to IFNa/ribavirin therapy

References navigator

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  2. Ganem D and Prince AM. NEJM. 2003. 350(11):1118
  3. Vento S, Garofano T, Renzini C, et al. 1998. NEJM. 338(5):286 abstract
  4. Flamm SL. 2003. JAMA. 289(18):2413 abstract
  5. Lai CL, Ratziu V, Yen MF, Pynard T. 2003. Lancet. 362(9401):2089 abstract
  6. Victor JC, Monto AS, Surdina TY, et al. 2007. NEJM. 357(17):1685 abstract
  7. Marcellin P, Lau GKK, Bonino F, et al. 2004. NEJM. 351(12):1206 abstract
  8. Patra S, Kumar A, Trivedi SS, et al. 2007. Ann Intern Med. 147(1):28 abstract
  9. Adefovir. 2002. Med Let. 44(1145):103
  10. Benhamou Y, Bochet M, Thibault V, et al. 2001. Lancet. 358(9283):718 abstract
  11. Drugs for HIV Infection. 2001. Med Let. 43(1119):103 abstract
  12. Poynard T, Yuen MF, Ratziu V, Lai CL. 2003. Lancet. 362(9401):2095 abstract
  13. Alberti A, Noventa F, Benvegnu L, et al. 2002. Ann Intern Med. 137(12):961 abstract
  14. Cacciola I, Pollicino T, Squadrito G, et al. 1999. NEJM. 341(1):22 abstract
  15. Alter MJ, Seeff LB, Bacon BR, et al. 2004. Ann Intern Med. 141(9):715 abstract
  16. Armstrong GL, Wasley A, Simard EP, et al. 2006. Ann Intern Med. 144(10):705 abstract
  17. Interferon Plus Ribavirin. 1999. Med Let. 41(1054):53 abstract
  18. Manns MP, McHutchison JG, Gordon SC, et al. 2001. Lancet. 958(9286):858
  19. Pegylated Interferon. 2001. Med Let. 43(1107):54 abstract
  20. Koziel MJ and Peters MG. 2007. NEJM. 356(14):1445 abstract
  21. Barbaro G, Di Lorenzo G, Belloni G, et al. 1999. Am J Med. 107(2):1125 abstract
  22. Rigas B, Hasan I, Rehman R, et al. 2001. Lancet. 958(9297):1961
  23. Schiff ER. 2006. Lancet. 368(9539):896 abstract
  24. Amin J, Law MG, Bartlett M, et al. 2006. Lancet. 368(9539):938 abstract
  25. Wong JB and Koff RS. 2000. Ann Intern Med. 133(9):665 abstract
  26. Yeo AET, Matsumoto A, Hisada M, et al. 2000. Ann Intern Med. 132(12):959 abstract
  27. Xiang J, Wunschmann S, Diekema DJ, et al. 2001. NEJM. 345(10):707 abstract
  28. Tillmann HL, Heiken H, Knapik-Botor A, et al. 2001. NEJM. 345(10):715 abstract
  29. Williams CF, Klinzman D, Yamashita TE, et al. 2004. NEJM. 350(10):981 abstract
  30. Nunnari G, Nigro L, Palermo F, et al. 2003. Ann Intern Med. 139(1):26 abstract
  31. Simmonds P, Davidson F, Lycett C, et al. 1998. Lancet. 352(9123):191 abstract
  32. Naoumov NV, Petrova EP, Thomas MG, Williams R. 1998. Lancet. 352(9123):195 abstract
  33. Auwaerter PG. 1999. JAMA. 281(5):454 (Case Discussion) abstract
  34. Amory JK, Rosen H, Sukut C, et al. 2006. NEJM. 354(14):1516 (Case Discussion) abstract
  35. Scott JD and Gretch DR. 2007. JAMA. 297(7):724 abstract
  36. Shrestha MP, Scott RM, Joshi DM, et al. 2007. NEJM. 356(9):895 abstract
  37. International IFN-a Hepatocellular Carcinoma Study Group. 1998. Lancet. 351(9115):1535 abstract