Drug-Induced Acute Liver Failure in Children and Adults

Results of a Single-Centre Study of 128 Patients

Harshad Devarbhavi; Mallikarjun Patil; Vishnu V. Reddy; Rajvir Singh; Tarun Joseph; Deepak Ganga

Disclosures

Liver International. 2018;38(7):1322-1329. 

In This Article

Abstract and Introduction

Abstract

Background & Aims: Drugs producing acute liver failure (ALF) are uncommon and vary geographically. Here we review the implicated drugs, clinical features, laboratory characteristics and outcome of patients with drug–induced ALF (DIALF). We analysed the predictors of mortality and their relationship with MELD, King's College criteria (KCC) and ALFSG prognostic index.

Methods: We identified DIALF patients from our drug–induced liver injury (DILI) registry (1997–2017). RUCAM was used for case adjudication. Patients who fulfilled criteria for acute liver failure and drug–induced liver injury were included. Primary outcome measure was spontaneous survival or death.

Results: There were 128 cases of DIALF (14%) among 905 patients with DILI. Mean age was 38 years, 68 (53%) female and 21(16.4%) children <18 years. Combination anti–TB drugs (ATD) (n = 92, 72.4%) accounted for a majority of DIALF. Others were anti–epileptic drugs (AED, n = 11, 10%), dapsone (n = 7, 5.5%), hormones (n = 2), ferrous sulphate overdose (n = 2), acetaminophen (APAP) (n = 2), antiretroviral (n = 2), CAM (N = 2), chemotherapy agents (N = 3), amoxicillin–clavulanic acid (n = 2) and others (n = 3). Forty–four patients (34%) recovered spontaneously and 84(66%) including 13 children (62%) died. Females, ascites, albumin, bilirubin, INR and MELD were significantly associated with mortality. Mortality was 79% for ATD and 100% for APAP and iron overdose. Area under ROC was 0.76 for MELD and ALFSG index and 0.51 for KCC.

Conclusions: Fourteen percent of DILI resulted in DIALF. ATD, AED, dapsone and antiretroviral drugs are most common agents. Spontaneous survival was only 34% with an even higher mortality with ATD. Non–ATD and non–APAP drugs had a better survival (51%).INR and MELD predicted mortality.

Introduction

Acute liver failure (ALF) is characterized by sudden deterioration in liver function manifesting as encephalopathy, jaundice and coagulopathy in the absence of underlying chronic liver disease.[1]ALF is an exceedingly rare but potentially devastating cause of liver disease. Estimated incidence varies from 1.4 per million and 5.5 million per million population from Spain[2] and USA[3] respectively. The causes differ from country to country; viruses are the leading cause in low– and middle–income countries,[4] while drug–induced hepatotoxicity is a leading cause in high–income countries.[1] Indeed DILI accounts for over 50% of ALF in USA,[5] UK[6] and Sweden[7] and is the commonest indication for liver transplantation in ALF.[8,9]

In USA and European countries, acetaminophen (APAP)–induced liver injury is a leading cause of DIALF in adults (46.3%)[5] and children (14%)[10] and is a prototypical example of dose–dependent liver injury. Acetaminophen–induced ALF, however, is very rare in non–US, non–European Union countries.[1] By contrast, idiosyncratic DILI exemplified by antituberculosis drugs (ATD) or anti–epileptic drugs (AED) resulting in ALF is less common in the West. In a recent study from the acute liver failure study group (ALFSG), idiosyncratic DIALF constituted only 10.8% (n = 222) of 2070 cases of ALF between 1998 and 2013.[5] Knowledge of the drug classes that cause ALF is important in order to estimate prognosis for purpose of patient/family counselling, and help guide treatment decisions including assessment and referral for liver transplantation. Spontaneous survival in adults varies by drugs;70%in APAP–induced ALF and 33.3% in idiosyncratic DIALF, while in children, the spontaneous survival was even better at 94% (45/48) and 41% (7/17) respectively.[10]

There is paucity of data regarding DIALF, both predictable and idiosyncratic, in adults and children from outside the USA and Europe. Therefore, we analysed our experience with DIALF with regard to cause, clinical characteristics, laboratory features and outcome. Furthermore, we analysed the predictors of mortality and determined its relationship with 2 established prognostic models—model for end–stage liver disease (MELD)[11] and King's College criteria (non–acetaminophen model)[12] as well as the recent ALFSG prognostic index.[13]

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