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A. Types [1]

  1. Autoimmune Hepatitis [4]
    1. Some cases are associated with true Systemic Lupus Erythematosus (SLE)
    2. Most cases are ANA+ (anti-nuclear antibody)
    3. Type I most common: anti-smooth muscle, anti-soluble liver antigen (SLA), ANA+, pANCA+
    4. Type II: uncommon Anti-LKM1 (Liver-Kidney Microsomal) Ab+
    5. LKM1 has been identified as Cytochrome P450 2D6
    6. These are autoimmune diseases, often coexist with other autoimmune disorders
  2. Chronic Hepatitis B Virus (HBV)
    1. sAg+ HDV-
    2. sAg+ HDV+
  3. Chronic Hepatitis C Virus (HCV)
    1. Anti-LKM 1 negative
    2. Anti-LKM 1 positive
  4. Chronic Viral Hepatitis, Indeterminant
  5. Cryptogenic Chronic Hepatitis
    1. ~10% of patients with cryptogenic liver disease have keratin 8 mutations [5]
    2. ~10% of patients who undergo liver transplantation
  6. Drug-Induced Chronic Hepatitis [8]
    1. Isoniazid (INH)
    2. Rifampin (particularly when combined with pyrazinamide) [10]
    3. HMG-CoA Reductase Inhibitors (mild)
    4. Niacin (nicotinic acid)
    5. Methotrexate (Rheumatrex®, others)
    6. Alcohol
    7. Alpha-methyldopa (Aldomet®)
    8. Nitrofurantoin
    9. Troglitazone (Rezulin®; withdrawn from market) [23,24]
    10. Zileuton (Zyflo®; withdrawn from market)
    11. Tacrine (Cognex®; withdrawn from market)
    12. P450 enzyme activation with toxic metabolite generation is often seen
    13. Women tend to be more susceptible than men
  7. Steatohepatitis [3,13,16]
    1. Fatty liver with lobular hepatitis
    2. Alcoholism is the most common cause
    3. Non-alcoholic patients are typically obese, middle-aged women with insulin resistance
    4. Insulin resistance or frank diabetes
    5. Hyperlipidemias, particularly with elevated triglycerides, appear to contribute
    6. Non-alcoholic form is generally benign, but cirrhosis and portal hypertension can occur
    7. No convincing response to ursodeoxycholic acid [3]
    8. Pioglitazone (Actos®), a PPARg agonist, leads to metabolic and histologic improvement in non-alcoholic steatohepatitis [6]
    9. In non-alcoholic disease, weight loss and exercise critical
  8. Drugs of Abuse [12]
    1. Alcohol (ethanol) abuse
    2. Cocaine
    3. Glue sniffing (toluene and trichlorethylene)
    4. Phencyclidine (Angel Dust)
    5. MDMA (Ecstasy) - stimulant related to cocaine
    6. Hepatotoxic Mushrooms
  9. Other causes of Chronic Hepatitis
    1. Hemochromatosis
    2. Alpha1-Antitrypsin Deficiency (may be excerbated by viral infections)
    3. Wilson's Disease - Ceruloplasmin Deficiency
    4. Chinese Herbal Medication Jin Bu Huan
    5. Granulomatous Hepatitis
  10. Need for and priority of liver transplant determined by MELD score

B. Evaluation [2]

  1. Determine extent of liver damage
    1. Parenchymal cell function: AST (SGOT), ALT (SGPT)
    2. Biliary system function: alkaline phosphatase (heat stabile), 5'-nucleotidase (5'NT), GGT
    3. Presence of jaundice: total, conjugated, unconjugated bilirubin
    4. Liver synthetic function: albumin level, prothrombine time (PT)
    5. Over 30% of adults with initially elevated AST, ALT or bilirubin levels will be reclassified as normal on retesting [25]
  2. Determining cause of chronic hepatitis is critical
  3. Medications should always be considered first
    1. Drug induced hepatitis is common
    2. Stopping drug often results in rapid normalization of liver function
  4. Alcoholism is very prevalent and should be ruled out
  5. Viral hepatitis serologies are then obtained
  6. Ultrasound and/or computerized tomography (CT) to rule out gallstones
  7. If no cause is found, consider, in order of decreasing likelihood:
    1. Iron studies - hemochromatosis
    2. ANA and other autoantibodies
    3. Ceruloplasmin levels
    4. Alpha-1 antitrypsin levels
  8. Liver biopsy may be required to confirm diagnosis [11,15]

C. Treatment

  1. Glucocorticoids
    1. Effective for autoimmune hepatitis associated with autoantibodies
    2. Recommended for alcoholic hepatitis with encephalopathy
    3. Effective in idiopathic granulomatous hepatitis
    4. Generally poor liver enzyme responses in sarcoidosis with hepatic involvement
    5. Treatment with glucocorticoids may worsen hepatitis C virus (HCV) infection
    6. Usual dosing: 0.3-1mg/kg po qd prednisone or prednisolone initially
    7. Slow taper (10mg/wk to 30mg/d, then 5mg/wk to 10mg/d) following liver enzymes [9]
    8. Combination with azathioprine (1-2mg/kg) recommended for long-term therapy [15]
  2. Azathioprine
    1. Low doses (1mg/kg/d) combined with glucocorticoids maintain long term remissions
    2. Higher doses (2mg/kg/d) may allow reduction or discontinuation of glucocorticoids
    3. Azathioprine 50mg/d may be effective / tolerated in patients with combined auto- immune hepatitis and HCV infection [7]
  3. Interferon for Viral Hepatitis
    1. Interferon alpha (IFNa) is approved for chronic hepatitis B and C treatment
    2. Side effects include flu-like symptoms and depression
    3. Liver biopsy usually required prior to initiation of treatment
    4. Treatment of autoimmune hepatitis with interferon may lead to exacerbations [15]
    5. IFNa reduces risk of developing liver carcinoma in HCV+ and HCV/HBV+ persons [19]
    6. Treatment of HCV infection is complicated by variable disease course [14]
  4. Lamuvidine for Chronic HBV Hepatitis [21,22]
    1. Nucleotide analog, potent antiretroviral 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
  5. Other Agents [9]
    1. Methotrexate 15mg/wk orally is effective in idiopathic granulomatous hepatitis [18]
    2. Cyclophosphamide - generally useful with cryoglobulinemia
    3. Cyclosporine - eg. 2mg/kg per day in resistant cases
    4. Ursodeoxycholic Acid (Actigall®) 13-15mg/kg/d po for cholestatic aspects [15]
  6. Therapeutic goal is usually complete normalization of liver enzymes [9]
    1. Maintenance of normal enzymes over long term can lead to reversal of fibrosis [17]
    2. In patients with HCV infection and persistently normal enzymes, IFNa not advised [14]

References

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  2. Roche SP and Kobos. 2004. Am Fam Phys. 69(2):299 abstract
  3. McCullough AJ. 2006. NEJM. 355(22):2361 abstract
  4. Krawitt EL. 2006. NEJM. 354(1):54 abstract
  5. Ku NO, Gish R, Wright TL, Omary MB. 2001. NEJM. 344(21):1580 abstract
  6. Belfort R, Harrison SA, Brown K, et al. 2006. NEJM. 355(22):2297 abstract
  7. Bellary S, Schiano T, Hartman G, Black M. 1995. Ann Intern Med. 123(1):32 abstract
  8. Lee WM. 2003. NEJM. 349(5):474 abstract
  9. Zum Bushenfelde KH and Lohse AW. 1995. NEJM. 333(15):1004 abstract
  10. Jasmer RM, Saukkonen JJ, Blumberg HM, et al. 2002. Ann Intern Med. 137(8):640 abstract
  11. Bravo AA, Sheth SG, Chopra S. 2001. NEJM. 344(7):495 abstract
  12. Jonas MM and Graeme-Cook FM. 2001. NEJM. 344(8):591
  13. Tilg H and Diehl AM. 2000. NEJM. 343(20):1467 abstract
  14. Levine RA. 1998. Ann Intern Med. 129(4):323 abstract
  15. Arribas JR, Storch GA, Clifford DB, Tselis AC. 1996. Ann Intern Med. 125(7):577 abstract
  16. Sheth SG, Gordon FD, Chopra S. 1997. Ann Intern Med. 126(2):137 abstract
  17. Dufour JF, DeLellis R, Kaplan MM. 1997. Ann Intern Med. 127(11):981 abstract
  18. Knox TA, Kaplan MM, Gelfand JA, Wolff SM. 1995. Ann Intern Med. 122(8):592 abstract
  19. International IFN-a Hepatocellular Carcinoma Study Group. 1998. Lancet. 351(9115):1535 abstract
  20. Galperin C and Gershwin ME. 1997. JAMA. 278(22):1946 abstract
  21. Dienstag JL, Perrillo RP, Schiff ER, et al. 1995. NEJM. 333:1657 abstract
  22. Lai CL, Chien RN, Leung NWY, et al. 1998. NEJM. 339(2):61 abstract
  23. Gitlin N, Julie NL, Spurr CL, et al. 1998. Ann Intern Med. 129(1):36 abstract
  24. Neuschwander-Tetri BA, Isley WL, Oki JC, et al. 1998. Ann Intern Med. 129(1):38 abstract
  25. Lazo M, Selvin E, Clark JM. 2008. Ann Intern Med. 148(5):348 abstract