Drug-Induced liver injury with hypersensitivity features has a better outcome: A single-center experience of 39 children and adolescents

Abstract

Drug-induced liver injury (DILI) is rare in children and adolescents, and, consequently, data are remarkably limited. We analyzed the causes, clinical and biochemical features, natural history, and outcomes of children with DILI. Consecutive children with DILI from 1997 to 2004 (retrospective) and 2005 to 2010 (prospective) were studied based on standard criteria for DILI. Thirty-nine children constituted 8.7% of 450 cases of DILI. There were 22 boys and 17 girls. Median age was 16 years (range, 2.6-17). Combination antituberculous drugs were the most common cause (n 5 22), followed by the anticonvulsants, phenytoin (n 5 10) and carbamazepine (n 5 6). All of the 16 children (41%) who developed hypersensitivity features, such as skin rashes, fever, lymphadenopathy, and/or eosinophilia, including the 3 with Stevens-Johnson syndrome, survived. Those with hypersensitivity presented earlier (24.5 versus 35 days; P 5 0.24) had less severe disease (MELD, 16 versus 29; P 5 0.01) and had no mortality (0/16 versus 12/23; P < 0.001), compared to those without hypersensitivity. The 12 fatalities were largely the result of antituberculous DILI (n 5 11). The presence of encephalopathy and ascites were associated with mortality, along with hyperbilirubinemia, high international normalized ratio, and serum creatinine. According to the Roussel Uclaf Causality Assessment Method, 18 were highly probable, 14 probable, and 7 possible. Thirty-two children were hospitalized. Conclusion: DILI is not uncommon in children and accounts for 8.7% of all patients with DILI. Antituberculous drugs and anticonvulsants are the leading causes of DILI in India. Overall mortality is high (30.7%), largely accounted by antituberculous drugs. Children with DILI and hypersensitivity features present early, have less severe disease, and, consequently, a better prognosis, compared to those without, and are often associated with anticonvulsants or sulfonamides. (HEPATOLOGY 2011;54:1344-1350 T he last decade has seen an increasing number of reports on drug-induced liver injury (DILI) in adults across all regions of the world.

An Update on Drug-induced Liver Injury

“…Features of immunoallergic or hypersensitivity reactions are observed more commonly in children, with 41% of 39 children in one study demonstrating immunoallergic features. 16 Presence of hypersensitivity features is often associated with good prognosis 16 ; a similar observation was made by the Spanish DILI group in whom this reaction was seen in 23% of their 461patients. 18 An indirect evidence for a better outcome was provided by Bjornsson et al who observed eosinophilia including liver eosinophilia in their patients.…”

“…9 Patients presenting with hypersensitivity DILI have a milder disease and a better survival, particularly in children. 16,18 Hypersensitivity DILI is often accompanied by immunoallergic features such as skin rashes, eosinophilia or lymphadenopathy. These characteristics may aid in the differentiation of hypersensitivity DILI from the metabolic idiosyncrasy variety (Table 3).…”

“…It is likely that skin rashes draw a patient earlier to a hospital resulting in earlier discontinuation of the offending drug and an earlier diagnosis. 16 Failure to stop the drug with the onset of DILI often results in high morbidity, mortality or chronicity. 18,32 Drug-induced Liver Injury Severity Index Elevated transaminases or alkaline phosphatase alone without jaundice or hyperbilirubinemia qualifies as mild disease.…”

“…9 DILI is a leading cause of acute liver failure (ALF) in the Western world, with paracetamol being the commonest drug followed by antimicrobials. 12,13 In India antituberculosis drugs are the commonest cause of druginduced ALF in adults and children, [14][15][16] contributing to 5.7-22% of all cases of ALF. [14][15][16] Paradoxically, many could be preventable, as empirical treatment for tuberculosis in 43-60% drives most of the reasons for antituberculous ALF.…”

“…12,13 In India antituberculosis drugs are the commonest cause of druginduced ALF in adults and children, [14][15][16] contributing to 5.7-22% of all cases of ALF. [14][15][16] Paradoxically, many could be preventable, as empirical treatment for tuberculosis in 43-60% drives most of the reasons for antituberculous ALF. 14,17 A brief summary of drugs causing hepatotoxicity and other demographic characteristics are depicted in Table 1.…”