Hy's law

Hy's law is a rule of thumb that a patient is at high risk of a fatal drug-induced liver injury if given a medication that causes hepatocellular injury (not Hepatobiliary injury) with jaundice.[1] The law is based on observations by Hy Zimmerman, a major scholar of drug-induced liver injury.[2][3][4] Some have suggested the principle be called a hypothesis or observation.[5]

Hy's Law cases have three components:[2]

  • The drug causes hepatocellular injury, generally defined as an elevated ALT or AST by 3-fold or greater above the upper limit of normal. Often with aminotransferases much greater (5-10x) than the upper limit of normal.
  • Among subjects showing such aminotransferase elevations, they also have elevation of their serum total bilirubin of greater than 2× the upper limit of normal, without findings of cholestasis (defined as serum alkaline phosphatase activity less than 2× the upper limit of normal).
  • No other reason can be found to explain the combination of increased aminotransferase and serum total bilirubin, such as viral hepatitis, alcohol abuse, ischemia, preexisting liver disease, or another drug capable of causing the observed injury.[1]

In Zimmerman's analysis of 116 patients with hepatocellular injury and jaundice due to drug exposure, 76% went on to either require a liver transplant or died.[6] Other studies have reported a lower but still significant mortality of 10%.[7][8]

References

  1. ^ a b Reuben, Adrian (March 26, 2008). "Hy's Law Explained" (PDF). fda.gov. Retrieved December 7, 2016.
  2. ^ a b United States Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER): Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, Final, July 2009
  3. ^ Robles-Diaz M, Lucena MI, Kaplowitz N, Stephens C, Medina-Cáliz I, González-Jimenez A, Ulzurrun E, Gonzalez AF, Fernandez MC, Romero-Gómez M, Jimenez-Perez M, Bruguera M, Prieto M, Bessone F, Hernandez N, Arrese M, Andrade RJ (July 2014), "Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury", Gastroenterology, 147 (1): 109–118, doi:10.1053/j.gastro.2014.03.050, hdl:10668/1859, PMID 24704526
  4. ^ Tansel A, Kanwal F, Hollinger FB (Aug 2015), "Use of Hy's Law, R criteria, and nR criteria to predict acute liver failure or transplantation in patients with drug-induced liver injury.", Gastroenterology, 148 (2): 452, doi:10.1053/j.gastro.2014.11.046, PMID 25532807
  5. ^ Senior, John R. (22 March 2006), "How can 'Hy's law' help the clinician?", Pharmacoepidemiology and Drug Safety, 15 (4): 235–239, doi:10.1002/pds.1210, PMID 16552792
  6. ^ Zimmerman, Hyman (1999). Hepatotoxicity. Lippincott Williams & Wilkins. ISBN 978-0781719520.
  7. ^ Andrade, Raúl J.; Lucena, M. Isabel; Fernández, M. Carmen; Pelaez, Gloria; Pachkoria, Ketevan; García-Ruiz, Elena; García-Muñoz, Beatriz; González-Grande, Rocio; Pizarro, Angeles (2005-08-01). "Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period". Gastroenterology. 129 (2): 512–521. doi:10.1016/j.gastro.2005.05.006. ISSN 0016-5085. PMID 16083708.
  8. ^ Björnsson, Einar; Olsson, Rolf (2005-08-01). "Outcome and prognostic markers in severe drug-induced liver disease". Hepatology. 42 (2): 481–489. doi:10.1002/hep.20800. ISSN 0270-9139. PMID 16025496.


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