Concomitant drug‐induced liver and skin reactions: An Indian experience
Authors: Einar S. Björnsson, Jon Hjaltalin Ólafsson
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. See Article On Page 993. Although the liver and skin are the organs most commonly affected by drug‐related reactions, there has been lack of systematic analysis of adverse drug reactions (ADRs) leading to concomitant involvement of these organs. Stevens‐Johnson syndrome (SJS) and toxic epidermial necrolysis (TEN) can be life‐threatening ADRs. SJS and TEN are considered by some to represent different severities of the same disorder.1 SJS is defined by an area of skin detachment of <10% of the body surface, whereas TEN involves >30%, usually involving mucosal surfaces.1 SJS/TEN overlap is defined as an area of the skin affecting 10%‐30% of the body surface. SJS/TEN is the result of delayed‐type allergic reactions and involves T cells.2 In a recent study from Korea, SJS/TEN patients with concomitant liver involvement had approximately 20% mortality, but this study was limited to only 11 patients with SJS/TEN.3 In this issue of Hepatology, Devarbhavi et al., from Bangalore, India, publish the largest cohort to date of patients with drug‐induced liver injury (DILI) in association with SJS/TEN.4 Consecutive patients were identified from a registry of DILI patients at a single center from 1997 to 2014.4 Overall, 36 of 748 (4.8%) of these DILI patients had associated features of SJS/TEN (mean age: 32 years; 53% females). All patients admitted either to Gastroenterology or Dermatology intensive care units (ICUs), general ICU, or burn wards had undergone detailed assessment of potential exposure to drugs. If drugs were considered a possible etiology, the suspected agent was discontinued. A dermatological consultation was obtained in all patients and appropriate therapy instituted. Overall, 9 (25%) patients were children <18 years of age and 8 (22%) had human immunodeficiency virus (HIV)/acquired immune deficiency syndrome. Antiepileptic drugs were the major etiological agents, mostly aromatic agents, such as phenytoin and carbamazepine, but also lamotrigine and levetiracetam. Sulfonamides (18%), nevirapine (16%), and others consitituted the rest. A high proportion was on multiple agents (61%). Median duration between drug initiation and onset of rash was 24 days (range, 5‐50). Approximately 60% developed severe liver injury. In comparison with other DILI patients identified during the study period, DILI patients with concomitant SJS/TEN had more severe liver dysfunction indicated by a high proportion with jaundice (61%), international normalized ratio 2.1, and Model for End‐Stage Liver Disease (MELD) score of 20. Mortality was high and overall 36% died. Deaths were caused by sepsis and multiorgan failure contributed both by liver and/or skin injury. A higher mortality was observed in those with concomitant jaundice (46%) and ascites (31%). Bilirubin levels and MELD score were also significantly higher among nonsurvivors versus survivors. Thus, mortality was high in patients who had severe hepatic dysfunction. Overall, 77% of those who died had jaundice, indicating that liver involvement is an important determinant of prognosis in these patients. Although it is conceivable that hepatic dysfunction is an important determinant in the prognosis of patients who also have severe skin reactions, some issues need to be adressed in further studies. Patients with SJS/TEN were recruited among a cohort of DILI patients. Thus, patients with SJS/TEN with and without jaundice would need to be compared in order to convincingly demonstrate this. It is conceivable that profound systemic inflammatory response resulting from the skin detachment and/or sepsis might account for the liver involvement, rather than the effects of an idiosyncratic drug reaction on the liver. Therefore, the liver might be an "innocent bystander." However, as pointed out by the investigators, sepsis‐induced cholestasis is characterized by mild elevation in aminotransferases,5 whereas in the study by Devarbhavi et al. mean aminotransferase levels were 8‐10 times elevated above the upper limit of normal. The liver tests were also obtained within 2 days from admission, but sepsis‐induced liver dysfunction occurs late in the course of the disease.5 Patients with SJS/TEN without known liver involvement do also have high mortality. During a 10‐year observational study on SJS/TEN patients admitted to a dermatological ICU in France, 18% mortality was observed.6 The 36% mortality in the Indian study can be compared to 44% mortality among patients with DILI and concomitant severe cutaneous reactions in the DILIN study.7 Among 9 patients, 4 with SJS/TEN and DILI died associated with diclofenac, azithromycin, lamotrigine, and carbamazepin.7 All these patients were treated with steroids during the course of their liver and skin disorder.7 In the study by Devarbhavi et al.,4 39% were treated with systemic steroids according to the discretion of the treating dermatologist (10 in survivors and 4 in nonsurvivors). In a Korean study of patients with concomitant SJS/TEN and DILI, use of systemic corticosteroids was not found to significantly affect either recovery from liver injury or mortality.3 Systemic steroids are frequently used in patients with SJS/TEN, even if no controlled studies exist confirming steroids as first‐line treatment in SJS/TEN. Other therapies being increasingly used are immunoglobulins, cyclosporin, or biological drugs.8 In these two studies,4 there are several similarities. Almost half of the patients had been treated with antiepileptic drugs; median latency to onset was 24 days in the Indian study and 14 days in the DILIN study. The patients in both studies who had the longest duration of treatment were only treated with the offending drug for approximately 2 months. Thus, it seems that patients with SJS/TEN and concomitant DILI have, in general, shorter duration of drug therapy than DILI patients without skin reactions. Interestingly, HIV patients had lower mortality (12.5%) as well as children (11%). The reason for this is unclear, although lack of severe comorbidities in the HIV patients and children might have played a role. The strengths of the Indian study published in this issue are several, such as presence of well‐characterized patients with complete follow‐up. The diagnosis of SJS/TEN was made by dermatology faculty in an inpatient setting. Also, prospective recruitment of cases was undertaken during the last 10 years of the study period. Close collaboration between hepatologists and dermatologists in this setting cannot be overestimated. As in all clinical studies, there were limitations and most of these were acknowledged by the investigators. A proportion of the patients were identified retrospectively. A control group of SJS/TEN cases without liver involvement was lacking. It is also unclear whether the skin disease preceded the liver injury. It would be helpful in future studies to know the latency to onset of: (1) liver enzyme elevations; (2) skin disease; and (3) clinical symptoms of liver disease, such as jaundice.Figure 1: Drug‐induced toxic epidermal necrolysis.In recent years, the understanding of the pharmacogenomics of DILI and severe skin reactions has increased considerably. Studies on genetic susceptibility to hepatotoxicity support the role for the innate immunity in the pathogenesis of these ADRs.9 So far, we do not know whether the same or other types of genetic susceptibilities will imply a risk for concomitant severe skin reactions and DILI. If it would be possible to predict susceptibility to these severe ADRs, it might prevent treatment of high‐risk patients with certain drugs. In summary, this important collaboration between hepatologists and dermatologists in India has resulted in an important contribution to the fields of both DILI and severe cutaneous reactions. Concomitant involvement of the liver and SJS/TEN is associated with poor prognosis, which illustrates the clinical importance of this disorder. Further studies are needed to identify patients at particular risk for this type of ADR.