Hy's law

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Synonyms and keywords: Hy's rule

Overview

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

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. 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.

Definition

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.

Hy’s Law cases have the following three components:

1. The drug causes hepatocellular injury, generally shown by more frequent 3-fold or greater elevations above the ULN of ALT or AST than the (nonhepatotoxic) control agent or placebo.

2. Among subjects showing such aminotransferase (AT) elevations, often with ATs much greater than 3x ULN, some subjects also show elevation of serum total bilirubin (TBL) to >2x ULN, without initial findings of cholestasis (serum alkaline phosphatase activity >2x ULN).

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.

Prognosis

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