Acute liver failure induced by idiosyncratic reaction to drugs: Challenges in diagnosis and therapy

Abstract

Acute liver failure (ALF) requires urgent attention to identify etiology and determine prognosis, in order to assess likelihood of survival or need for transplantation. Identifying idiosyncratic drug-induced liver injury (iDILI) may be particularly difficult, but the illness generally follows a subacute course, allowing time to assess outcome and find a liver graft if needed. Not all drugs that cause iDILI lead to ALF; the most common are antibiotics including anti-tuberculous medications, non-steroidal anti-inflammatory agents and herbal and dietary supplements (HDS). Determining causality remains challenging particularly if altered mentation is present; identifying the causative agent depends in part on knowing the propensity of the drugs that have been taken in the proper time interval, plus excluding other causes. In general, iDILI that reaches the threshold of ALF will more often than not require transplantation, since survival without transplant is around 25%. Treatment consists of withdrawal of the presumed offending medication, consideration of N-acetylcysteine (NAC), as well as intensive care. Corticosteroids have not proven useful except perhaps in instances of apparent autoimmune hepatitis caused by a limited number of agents. Recently developed prognostic scoring systems may also aid in predicting outcome in this setting.

Keywords: acute liver failure; drug-induced liver injury; hepatotoxicity; idiosyncratic.

Figure 1

Etiology of acute liver failure in the United States, from the ALFSG registry, 1998–2016, including 2,436 patients. Acetaminophen and DILI are the most common specific etiologies.

Figure 2

Idiosyncratic drug-induced liver injury involves the interplay of host, drug and environment. Reproduced with permission from Nat Rev Gastroenterol Hepatol. 2011;8:202–11.

Figure 3

Drug classes causing idiosyncratic DILI-related ALF, by frequency (reference 1). The largest categories are antibiotics, both general as well as those specific to tuberculosis treatment.

Figure 4

a. Trends in overall outcome, transplant listing and transplantation in acute liver failure in the US over time, 1998–2013, 2070 patients; note difference in patient count shown in other Figures/Tables—2,436 from 1998–2016. b. Trends over time in intensive care support including ventilator or pressor use, as well as transfusion of blood or plasma. c. Use of NAC for APAP and non-APAP ALF and overall use over time from 1998–2013. An increase of NAC use for non-APAP ALF was observed after 2006. (Figures 4a–c reproduced from reference , Ann Intern Med 2016:164:724–732 with permission.) Number *Legacy sites have enrolled at least one subject in each of the 16 years of the registry. They include: Northwestern University, University of California at San Francisco, University of Michigan, University of Washington, and the University of Texas Southwestern Medical Center. Note that p-values represent trends over time tested with the Cochran-Armitage test.

Figure 4

a. Trends in overall outcome, transplant listing and transplantation in acute liver failure in the US over time, 1998–2013, 2070 patients; note difference in patient count shown in other Figures/Tables—2,436 from 1998–2016. b. Trends over time in intensive care support including ventilator or pressor use, as well as transfusion of blood or plasma. c. Use of NAC for APAP and non-APAP ALF and overall use over time from 1998–2013. An increase of NAC use for non-APAP ALF was observed after 2006. (Figures 4a–c reproduced from reference , Ann Intern Med 2016:164:724–732 with permission.) Number *Legacy sites have enrolled at least one subject in each of the 16 years of the registry. They include: Northwestern University, University of California at San Francisco, University of Michigan, University of Washington, and the University of Texas Southwestern Medical Center. Note that p-values represent trends over time tested with the Cochran-Armitage test.

Figure 4

a. Trends in overall outcome, transplant listing and transplantation in acute liver failure in the US over time, 1998–2013, 2070 patients; note difference in patient count shown in other Figures/Tables—2,436 from 1998–2016. b. Trends over time in intensive care support including ventilator or pressor use, as well as transfusion of blood or plasma. c. Use of NAC for APAP and non-APAP ALF and overall use over time from 1998–2013. An increase of NAC use for non-APAP ALF was observed after 2006. (Figures 4a–c reproduced from reference , Ann Intern Med 2016:164:724–732 with permission.) Number *Legacy sites have enrolled at least one subject in each of the 16 years of the registry. They include: Northwestern University, University of California at San Francisco, University of Michigan, University of Washington, and the University of Texas Southwestern Medical Center. Note that p-values represent trends over time tested with the Cochran-Armitage test.