Hy's law

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:

Synonyms and keywords: Hy's rule


Hy's law is a prognostic indicator based on observations by Hyman J. Zimmerman that drug-induced hepatocellular injury with jaundice is a grave illness, with an estimated mortality rate of 10 to 50 percent.

Hy’s Law is essentially a translation of Hy Zimmerman’s observation that pure hepatocellular injury sufficient to cause hyperbilirubinemia is an ominous indicator of the potential for a drug to cause serious liver injury. Thus, a finding of ALT elevation, usually substantial, seen concurrently with bilirubin >2xULN, identifies a drug likely to cause severe DILI (fatal or requiring transplant) at a rate roughly 1/10 the rate of Hy’s Law cases.[1][2]

Hy’s Law cases have the following three components:
  1   The drug causes hepatocellular injury, generally shown by a higher incidence of ≥3xULN of ALT or AST than the (nonhepatotoxic) control drug or placebo.
  2   Among trial subjects showing such AT elevations, often with ATs much greater than 3xULN, one or more also show elevation of serum TBL to >2xULN, without initial findings of cholestasis (elevated serum ALP).
  3   No other reason can be found to explain the combination of increased AT and TBL, such as viral hepatitis A, B, or C; preexisting or acute liver disease; or another drug capable of causing the observed injury.

Historical Perspective

Recognition of the importance of altered liver function, in addition to liver injury, began with Zimmerman’s observation that drug-induced hepatocellular injury (i.e., aminotransferase elevation) accompanied by jaundice had a poor prognosis, with a 10 to 50 percent mortality from acute liver failure in pretransplantation days.[3] The reason for this now seems clear. Because the liver has a large excess of bilirubin-excreting capacity, injury to hepatocytes sufficient to cause jaundice or even mild hyperbilirubinemia (i.e., a bilirubin >2xULN) represents an extent of liver injury so great that recovery may not be possible in some patients. Zimmerman’s observation that hepatocellular injury sufficient to impair bilirubin excretion was ominous has been used at the Food and Drug Administration (FDA) over the years to identify drugs likely to be capable of causing severe liver injury. The observation of the critical importance of altered liver function has been referred to informally as Hy’s Law.[4][5]




Differentiating Hy's law from Other Diseases

Epidemiology and Demographics

Risk Factors


Natural History, Complications, and Prognosis

Natural History



Without a hepatic transplant, patients meeting criteria for Hy's Law face a case fatality rate of 10% to 50%.[6]


Diagnostic Criteria

History and Symptoms

Physical Examination

Laboratory Findings

Imaging Findings

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Medical Therapy




  1. "http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf" (PDF). External link in |title= (help)
  2. "http://www.fda.gov/OHRMS/DOCKETS/98fr/07d-0396-gdl0001.pdf" (PDF). External link in |title= (help)
  3. "Hepatotoxicity: The Adverse Effects of Drugs and Other Chemicals on the Liver - Hyman J. Zimmerman - Google Boeken".
  4. "http://www.fda.gov/downloads/Drugs/ScienceResearch/ResearchAreas/ucm122149.pdf" (PDF). External link in |title= (help)
  5. Reuben, A.; Zimmerman, HJ. (2004). "Hy's law". Hepatology. 39 (2): 574–8. doi:10.1002/hep.20081. PMID 14768020. Unknown parameter |month= ignored (help)
  6. "http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM174090.pdf" (PDF). External link in |title= (help)

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