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A. Definition and Symptoms

  1. Fulminant Hepatitis implies Severe Hepatic Failure with Jaundice
  2. Hepatic Encephalopathy (HE)
    1. Fulminant (Acute) Hepatitis: HE within 2 weeks of jaundice
    2. Subfulminant Hepatitis: hepatic encephalopathy within 3 months of jaundice
  3. Absence of Pre-existing Liver Disease
  4. Pathology
    1. Massive hepatocellular necrosis
    2. Collapse of reticulin fibers
    3. Lack of regeneration

B. Causes

  1. Overall Epidemiology [1]
    1. Acetaminophen overdose 39%
    2. Idiosynchratic drug reaction 13%
    3. Viral hepaitis A and B 12%
    4. Indeterminant 17%
  2. Hepatitis Viruses
    1. Hepatitis A virus (HAV) - 0.35% of acute cases lead to fulminant hepatitis
    2. Hepatitis B (HBV) -1% of acute HBV cases lead to fulminant hepatitis
    3. Hepatitis Delta (HDV) - coinfection of HDV with HBV increases risk of fulminant failure
    4. Hepatitis C (HCV) - acute hepatitis with fulminant failure is extremely rare [4]
    5. Hepatitis E - fulminant hepatitis can occur in pregnant patients
    6. Hepatitis G - certain strains may be associated with fulminant hepatitis [5]
    7. HAV infection of chronic HCV carries high risk of fulmonant failure [6]
  3. Alcoholism
    1. Usually with fatty change
    2. Risk of fulminant failure increased with acetaminophen use or overdose
  4. Pharmacologic Agents
    1. Acetaminophen (most common of drug causes, usually due to overdose)
    2. Isoniazid
    3. Methyldopa
    4. Niacin (very rare)
    5. Halothane
    6. NSAIDs (rare)
    7. LipoKinetix® - dietary supplement for weight loss; may cause acute hepatitis [7]
    8. Herbal weight loss agents Chaso and Onshido; likely N-nitroso-fenfluramine [3]
  5. Hepatic Ischemia
    1. Shock: Liver is very susceptible to ischemia
    2. However, "shock liver" requires cardiac congestion [8]
    3. Shock liver accompanied by extremely high transaminase levels
    4. Other causes: hypoxia, arterial or venous (including Budd Chiari) occlusion
  6. Chronic Nonviral Hepatitis
    1. Chronic Autoimmune Hepatitis
    2. Chronic Viral Hepatitis with associated autoimmunity
    3. Wilson's Disease
    4. Porphyria
  7. Other
    1. Budd-Chiari Syndrome
    2. Pregnancy associated liver disease
    3. Neoplasma associated disease
    4. Giant cell hepatitis
    5. Herpes simplex virus (HSV) - rare cause of acute hepatitis, may be fulminant [11]
  8. Pregnancy Associated Liver Disease
    1. Acute fatty liver
    2. HELLP Syndrome
    3. Eclampsia
  9. Toxins and Abused Drugs
    1. Mushrooms
    2. Carbon tetrachloride
    3. MDMA ("Ecstasy")
    4. Cocaine
  10. Hepatotoxic Effects of MDMA and Cocaine [9]
    1. MDMA liver dysfunction associated with severe (systemic) intoxication similar to cocaine
    2. MDMA also causes a liver-only toxicity, which may be focal or fulminant
    3. Liver biopsy shows central and midzonal necrosis in patients with systemic MDMA toxicity
    4. Massive hepatocyte necrosis or focal necrosis with inflammation with liver-only syndrome
    5. Steatosis and/or eosinophilic infiltration may occur

C. Fulminant Viral Hepatitis [8]

  1. Caused by HAV or HBV in most cases [1]
    1. Rapid progression of acute hepatitis A may lead to fulminant failure
    2. ~1% of HBV infection accompanied by fulminant failure
    3. Hepatitis E virus can cause fulminant failure in pregnant women
  2. Predictors of Fulminant Failure
    1. Best predictor is prothrombin time, a measure of immediate liver synthetic function
    2. Albumin level is measure of longer term (~14 day) synthetic function
    3. Bilirubin and transaminase levels are not good predictors of fulminant failure

D. Laboratory Analysis

  1. Bilirubin
  2. Prothrombin Time (PT)
    1. Most important indicator of hepatic synthetic function and outcome
    2. Albumin and transferrin levels can also be used to monitor synthetic function
    3. However, these change more slowly and do not predict outcome as well as PT
  3. Electrolytes - abnormal electrolyte balance
  4. Renal Function - assess for development of hepatorenal syndrome
  5. Glucose
    1. Fall in glucose indicates failure of hepatic gluconeogenesis
    2. In addition, failed liver does not clear insulin properly
  6. Transaminase AST and ALT are poor indicators of hepatic activity
  7. Serum Gc Protein Levels
    1. Group specific component protein
    2. Binds and sequesters actin during hepatic necrosis
    3. Depletion of Gc may cause worse microcirculatory blockade by actin/platelet complexes
  8. Acute Failure
    1. Acetaminophen levels and arterial lactate levels [10]
    2. Ceruloplasmin
    3. Urine and Blood Toxin Screens must be obtained
    4. Assess for hepatic encephalopathy
    5. Serum ammonia levels correlation moderately (r=0.5-0.6) with severity of encephalopathy [15]

E. Treatment

  1. Supportive Care - Intensive Care Unit
    1. Replete Coagulation Factors
    2. Glucose Infusion
    3. Treat Sepsis
    4. Aspiration Precautions
  2. Correct electrolyte abnormalities
  3. Intracranial Pressure (ICP)
    1. Avoid maneuvers that might increase ICP
    2. Consider placement of intracranial bolt to measure ICP
  4. Glucocorticoids - severe alcoholic hepatitis
  5. Prostaglandins may be helpful in drug / toxin induced fulminant failure
  6. Hepatic Encephalopathy [12]
    1. Reduce gut flora - metronidazole, others
    2. Acidify gut with lactulose - to block ammonia (and other bases) from crossing to blood
    3. Reverse benzodiazepine receptor ligands with flumazenil
  7. Transplantation
    1. Transplant team should be involved early
    2. Efficacy is very good with improving outcomes
    3. MELD score is used to determine urgency for transplant

F. Complications

  1. Metabolic acidosis (early)
  2. Hypoglycemia
  3. Renal Failure
    1. Mild to moderate insufficiency
    2. Hepatorenal syndrome - severe failure with oliguria / anuria
    3. Currently, only intravenous dopamine and transplantation improve urine production
  4. Coagulopathy - severe bleeding diathesis
  5. Hepatic Encephalopathy
    1. Deteriorating mental status with delirium
    2. Waxing and waning mental status
    3. Cerebral edema
    4. Increased intracranial pressure
    5. Reduced cerebral perfusion pressure
    6. Mortality ~90% in patients with poor prognosis, rapid decline
  6. Cerebral Edema [13,14]
    1. Brain edema leads to increased intracranial pressure (ICP) in ~80% of patients
    2. Cerebral edema is also found in chronic liver disease (with deterioration)
    3. May lead to brainstem herniation
    4. Neurological deterioration / encephalopathy should prompt rapid evaluation
  7. Elevated ICP (Intracranial Hypertension) [14]
    1. Found in severe liver failure
    2. Contributes to hepatic encephalopathy
    3. Mannitol given as 1gm/kg over 20 minutes can have some efficacy initially
    4. Mannitol is of minimal efficacy in patients with renal dysfunction
    5. Hyperventilation can improve condition usually temporarily
    6. Reduction in plasma volume with ultrafiltration can be helpful
    7. However, cerebral edema usually recurs with increased intracranil hypertension
    8. Ultimately, brain herniation will occur unless transplantation is carried out
    9. Transient hypothermia for 10-14 hours to 32-33°C core temperature can be helpful [14]
  8. Infection - usually respiratory tract
  9. Hepatopulmonary Syndrome - Hypoxemia

Resources

calcMELD Score

References

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  2. Atillasoy E and Berk PD. 1995. Ann Rev Med. 46:181 abstract
  3. Adachi M ,Salto H, Kobayashi H, et al. 2003. Ann Intern Med. 139(6):488 abstract
  4. Farci P, Alter HJ, Shimoda A, et al. 1996. NEJM. 335(9):631 abstract
  5. Heringlake S, Osterkamp S, Trautwin C, et al. 1996. Lancet. 348:1626 abstract
  6. Vento S, Garofano T, Renzini C, et al. 1998. NEJM. 338(5):286 abstract
  7. Favreau JT, Ryu ML, Braunstein G, et al. 2002. Ann Intern Med. 136(8):591
  8. Seeto RK, Fenn B, Rockey DC. 2000. Am J Med. 109(2):109 abstract
  9. Jonas MM and Graeme-Cook FM. 2001. NEJM. 344(8):591
  10. Bernal W, Donaldson N, Wyncoll D, Wendon J. 2002. Lancet. 359(3306):558
  11. Bliss SJ, Moseley RH, Del Valle J, Saint S. 2003. NEJM. 349(19):1848 (Case Discussion) abstract
  12. Riordan SM and Williams R. 1997. NEJM. 337(7):473 abstract
  13. Donovan JP, Scharfer DF, Shaw BW Jr, Sorrell MF. 1998. Lancet. 351(9104):719 abstract
  14. Jalan R, Damink SWMO, Deutz NEP, et al. 1999. Lancet. 354(9185):1164 abstract
  15. Ong JP, Aggarwal A, Krieger D, et al. 2003. Am J Med. 114(3):188 abstract