The liver and skin are two of the commonest

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1 AMERICAN ASSOCIATION FOR THE STUDY OFLIVERD I S E ASES HEPATOLOGY, VOL. 63, NO. 3, 2016 LIVER INJURY/REGENERATION Drug-Induced Liver Injury Associated With Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis: Patient Characteristics, Causes, and Outcome in 36 Cases Harshad Devarbhavi, 1 Sujata Raj, 2 Venu H. Aradya, 1 Vijaykumar T. Rangegowda, 1 Girish P. Veeranna, 1 Rajvir Singh, 3 Vishnuvardan Reddy, 1 and Mallikarjun Patil 1 The liver and skin are the organs most commonly involved in serious adverse drug reactions. Rarely a drug reaction can affect both organs concurrently. The association of drug-induced liver injury (DILI) and Stevens-Johnson syndrome (SJS) or toxic epidermal necrosis (TEN) is even rarer and not well studied. We describe our experience of DILI occurring in association with SJS/TEN including the etiologic agents, clinical and biochemical characteristics, and outcome. We identified patients who developed DILI in association with SJS/TEN from a registry of DILI patients from a single center. Causality assessment for DILI and SJS/TEN was carried out with the Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis, respectively. Among 748 consecutive patients with DILI from 1997 to March 2015, 36 (4.8%) had associated features of SJS/TEN. The mean age was 32 years (females 19). Children and patients with human immunodeficiency virus constituted 25% (n 5 9) and 22% (n 5 8), respectively. Only a small number of high-risk drugs such as antiepileptic agents, sulfonamides, and antiretroviral drugs accounted for the majority of cases. Overall mortality was 36% (n 5 13),whichroseto45.5%inthepresenceofjaundice.Mortality was less in children 11% (n 5 1) and human immunodeficiency virus patients 12.5% (n 5 1). Conclusions: DILI associated with SJS/TEN is rare and associated with a high death rate, particularly in those with jaundice; however, children and human immunodeficiency virus infected individuals have a favorable outcome; a small group of drugs contributed to a disproportionate number of cases, and causality with Roussel Uclaf Causality Assessment Method and the Algorithm for Drug Causality for Epidermal Necrolysis was highly probable or probable in all cases. (HEPATOLOGY 2016;63: ) SEE EDITORIAL ON PAGE 700 The liver and skin are two of the commonest organs involved in idiosyncratic drug reactions. The reactions generally occur in isolation but may rarely occur concurrently, as with the drug rash with eosinophilia and systemic symptoms syndrome. The outcome in such cases is variable, and prognostic factors have not yet been identified. Druginduced Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare and characterized by severe skin and mucus membrane involvement. (1) The overall annual incidence of SJS or TEN has been reported to be between one and two cases per million. (2) Mortality in patients with SJS/TEN is also high, with reported figures ranging between 22% 3,(4) and 30%. (1) It may be higher in the presence of Abbreviations: AIDS, acquired immune deficiency syndrome; ALDEN, Algorithm for Drug Causality for Epidermal Necrolysis; ; DILI, drug-induced liver injury; HIV, human immunodeficiency virus; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrosis. Received May 10, 2015; accepted September 30, Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/ /hep.28270/suppinfo. Copyright VC 2015 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI /hep Potential conflict of interest: Nothing to report. 993

2 DEVARBHAVI ET AL. HEPATOLOGY, March 2016 visceral involvement. (1,5) Factors that can influence the incidence and outcome include age, offending agent, presence of comorbidities such as human immunodeficiency viral (HIV) infection, ethnicity, and geography. (3,6) There is limited information regarding the characteristics, natural history, and outcome of liver injury in the presence of SJS/TEN. Reports of extracutaneous involvement are limited to liver biochemical abnormalities without clinical jaundice or alteration in synthetic function. In a recent retrospective study, SJS with liver involvement was associated with a mortality of 22% and hepatic involvement was characterized predominantly by biochemical abnormalities without clinical jaundice. (4) The Drug-Induced Liver Injury Network recently described nine cases (with four deaths) among a cohort of 889 patients with drug-induced liver injury (DILI). (7) We therefore undertook this study to investigate the association between DILI and SJS/TEN, to identify the drugs responsible, and to characterize the clinical and laboratory features and the outcome. Patients and Methods We identified consecutive cases of SJS/TEN from the DILI registry at a single center over an 18-year period from 1997 to March 2014 ( retrospective, prospective). The details of the registry and definition used for DILI have been described. (8,9) Briefly, DILI was defined as a rise in aspartate aminotransferase or alanine aminotransferase more than three times the upper limit of normal in the presence of symptoms. In the absence of symptoms, DILI is defined as aspartate aminotransferase or alanine aminotransferase greater than five times the upper limit of normal or alkaline phosphatase greater than two times the upper limit of normal or serum bilirubin >2 mg/dl with any degree of elevation of transaminases or alkaline phosphatase. Severe DILI was defined as bilirubin >2 mg/dl associated with an international normalized ratio >1.5 or ascites, encephalopathy, or death (per international consortium guidelines). (10) Competing causes of liver injury were excluded by negative serological tests for hepatitis A, B, C, and E as well as antinuclear and anti smooth muscle antibodies. The patterns of liver injury were characterized as hepatocellular, cholestatic, or mixed based on the ratio of serum transaminases to alkaline phosphatase as described. (10) SJS, TEN, and overlap syndrome were defined according to standard criteria: skin detachment <10% (SJS), 10%-30% (overlap syndrome), and >30% (TEN) plus widespread purpuric macules or flat atypical targets (Fig. 1). (1,5) All patients admitted either to the Gastroenterology or the Dermatology intensive therapy unit or the intensive care unit or to the burns ward underwent detailed evaluation for potential exposure to medications. Once identified, the potential offending agent was promptly discontinued. Alternative drugs were introduced as clinically indicated. This was particularly true for seizure disorders, when second-generation antiepileptic drugs were instituted instead of first-generation drugs. A dermatology consultation was obtained in all cases of skin rashes with DILI. The diagnosis of SJS/TEN was established by careful dermatological evaluation, and appropriate therapy was instituted. Treatment included supportive measures in the form of aggressive intravenous fluid administration, local saline compresses, topical antimicrobials, and betamethasone. Steroids, either 100 mg methylprednisolone or 500 mg hydrocortisone, were administered to 14 patients for a short term (4-7 days) according to the discretion of the treating dermatologist (10 in survivors and four in nonsurvivors). Intravenous broadspectrum antibiotics were administered when deemed necessary. Three patients (in the nonsurvivor group) underwent amniotic membrane transplantation for ocular surface injury. ARTICLE INFORMATION: From the 1 Department of Gastroenterology, St. John s Medical College Hospital, Bangalore, India; 2 Department of Dermatology, St. John s Medical College Hospital, Bangalore, India; 3 Hamad Medical Center, Doha, Qatar ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Harshad Devarbhavi, M.D. Department of Gastroenterology St. John s Medical College Hospital Bangalore, India. harshad.devarbhavi@gmail.com. 994

3 HEPATOLOGY, Vol. 63, No. 3, 2016 DEVARBHAVI ET AL. FIG. 1. Features associated in patients with DILI and SJS/TEN. (A) Multiple bullae on face and hemorrhagic crusts on both lips in a patient with SJS. (B) Denuded areas covering the entire back in a patient with TEN. (C) Hematoxylin and eosin stained section of skin showing epidermal necrosis (arrow) and subepidermal separation with scanty infiltrate (arrowhead). (D) Hematoxylin and eosin stained section of post mortem liver biopsy in a patient with lamotrigine-induced DILI and SJS showing cholestasis and scanty infiltrate. (E) Hematoxylin and eosin stained section of a post mortem liver biopsy in a patient with carbamazepine-induced DILI and SJS showing severe portal inflammation with lymphocytes, polymorphs, plasma cells, and occasional eosinophils. Causality assessment for DILI was carried out according to the Roussel Uclaff Causality Assessment Method. (10) The drugs implicated in SJS/TEN were analyzed according to the Algorithm for Drug Causality for Epidermal Necrolysis (ALDEN; in SJS/ TEN), (11) a causality assessment tool that is specific to SJS/TEN. ALDEN is a particularly useful tool in discriminating the culprit from innocent drugs when patients are on multiple drugs. Similar to the Roussel Uclaf Causality Assessment Method, the assigned scores for ALDEN helps categorize probability of disease into very probable, probable, possible, unlikely, and very unlikely. (11) Drugs were also categorized as high risk or highly suspected as described. (2,11) When patients are on multiple drugs, causality assessment is complicated; application of ALDEN criteria is particularly helpful in such cases, avoiding the implicated drugs and continuing or reintroducing nonimplicated drugs. (11) The study was approved by the institutional ethical review board. STATISTICAL ANALYSIS Variables are summarized as appropriate: means/ medians and standard deviations for continuous variables and frequencies and percentages for categorical variables. Fisher s exact test was used to compare categorical variables and t test, for continuous variables. P < 0.05 (two-tailed) was considered statistically significant. Data were analyzed using the SPSS 21.0 statistical package (SPSS Inc., Chicago, IL). Results Thirty-six cases of SJS/TEN were identified from a cohort of 748 patients with DILI during the period 995

4 DEVARBHAVI ET AL. HEPATOLOGY, March 2016 TABLE 1. Baseline Characteristics of Patients With DILI and SJS/TEN Variable Number Mean (6 Standard Deviation) Range Age (years) Gender 36 Male 17 (47.2) Female 19 (52.8) Jaundice (61%) Encephalopathy 36 4 (11%) Ascites 36 5 (14%) Serum protein (g/dl) Serum albumin (g/dl) Total bilirubin (mg/dl) Direct bilirubin (mg/dl) AST (U/L) ALT (U/L) ALP (U/L) GGT (U/L) INR Serum creatinine (mg/dl) MELD score Hemoglobin (g/dl) WBC count (10 3 /dl) Platelet count (10 5 /dl) Values are in frequency and percentages in parenthesis for categorical variables and means 6 standard deviation for continuous variables. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, c- glutamyltransferase; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; WBC, white blood cell to March The demographic and clinical characteristics are shown in Table 1. Although females outnumbered males (19:17) in occurrence of disease and mortality (61.5% versus 38.5%), the differences were not significant. Twenty-one patients (58%) experienced severe DILI. Our cohort of patients with SJS/TEN and DILI had more severe liver dysfunction as indicated by the presence of jaundice (61%, n 5 22), high bilirubin (11.7 mg/ dl), international normalized ratio 2.1, and Model for End-Stage Liver Disease score of 20. Eight patients (22%) had HIV/acquired immune deficiency syndrome (AIDS), and nine (25%) were children <18 years. Table 2 highlights the differences between survivors and nonsurvivors. The overall mortality was 36% (n 5 13) but was greater in those with jaundice and ascites (Table 2) and least in those with HIV/AIDS infection (n 5 1, 12.5%) or children (n 5 1, 11%). Deaths were caused by sepsis and multiorgan failure contributed both by liver-related and/or skin-related injury. Presence of ascites (31% versus 4%, P ), elevated bilirubin (176 versus 8.5, P ), and Model for End-Stage Liver Disease score (256 versus 17, P ) were significant predictors of mortality in our cohort of patients. Elevated bilirubin is highly associated with mortality. Seventy-seven percent of patients who died had jaundice, and overall 45% of patients with jaundice died. The demographic and laboratory characteristics in children are presented in Supporting Table S1. According to ALDEN, 19 (52.7%) were categorized as very probable and 17 (47.2%) as probable. The average duration between drug initiation and onset of rash (drug rash interval) was days (range 5-50 days). Figure 2 depicts the drug exposure to skin rash interval of the drugs causing SJS/TEN and DILI. The distribution pattern of liver injury was as follows: mixed, 50% (n 5 18); hepatocellular, 36% (n 5 13); cholestatic, 14% (n 5 5). According to the Roussel Uclaf Causality Assessment Method criteria, 18 DILI episodes were listed as probable and another 18 as highly probable (definite). The drugs implicated are listed in Table 2. Antiepileptic drugs were the major causes and contributed to 47% (n 5 17) of cases. These were primarily aromatic agents (n 5 15, 88%), although newer antiepileptic drugs, levetiracetam (n 5 1) and lamotrigine (n 5 1), also contributed. Sulfonamides (18%, n 5 7), nevirapine (15.7%, n 5 6), and others constituted the rest. Fourteen (39%) patients were on single agents and 22 (61%) on multiple agents. Discussion Our study is one of the few efforts to investigate the characteristics of DILI when associated with SJS/ TEN. 996

5 HEPATOLOGY, Vol. 63, No. 3, 2016 DEVARBHAVI ET AL. TABLE 2. Description of Survivors Versus Nonsurvivors in DILI With SJS/TEN Cases Variables Survivors (n 5 23) Nonsurvivors (n 5 13) P Male:females 12 (52.2):11 (47.8) 5 (38.5):8 (61.5) 0.43 Age (years) Jaundice 12 (52.2) 10 (76.9) 0.14 Ascites 1 (4.3) 4 (30.8) 0.03 Encephalopathy 2 (8.7) 2 (15.4) 0.54 Age <18 years 8 (34.8) 1 (7.7) 0.07 HIV 7 (30.4) 1 (7.7) 0.12 Serum protein (g/dl) Serum albumin (g/dl) Total bilirubin (mg/dl) Direct bilirubin (mg/dl) AST (U/L) ; 333 ( ) ; 531 ( ) 0.24 ALT (U/L) ; 317 ( ) ; 346 ( ) 0.35 ALP (U/L) ; 275 ( ) ; 270 ( ) 0.43 GGT (U/L) ; 356 ( ) ; 170 ( ) 0.52 INR Serum creatinine (mg/dl) MELD score Hemoglobin (g/dl) WBC count (10 3 /dl) ; 7.6 ( ) ; 14.6 (2-26.9) 0.19 Eosinophils (%) Platelet count (10 5 /dl) Implicated drugs* Phenytoin 7 1 Nevirapine 6 0 Carbamazepine 2 2 Phenobarbitone 1 1 Dapsone 2 3 Cotrimoxazole 3 0 Allopurinol 2 0 Leflunomide 0 3 Lamotrigine 0 1 Oxcarbazepine 1 0 Levitericetam 0 1 Levofloxacin 1 0 Ceftriaxone 0 1 Values are frequency and percentages in parentheses for categorical variables and means 6 standard deviation with median and range for continuous variables. *Two patients were on two drugs each: nevirapine1cotrimoxazole and phenytoin1oxcarbazepine. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, c- glutamyltransferase; INR, international normalized ratio; MELD, Model for End-Stage Liver Disease; WBC, white blood cell. Our experience showed that a small number of drugs were responsible for a majority of cases. These include first-generation antiepileptic agents, sulfonamides, and antiretroviral drugs (mostly nevirapine). This finding is in agreement with a recent multicenter study from Europe. (11) The first-generation antiepileptic drugs (carbamazepine or phenytoin), despite their propensity for liver injury, are commonly used because of lower costs, efficacy record, and wide experience (Table 3). (12,13) The availability and increasing use of second-generation antiepileptic drugs with fewer toxic effects will likely see a drop in the frequencies of DILI and SJS, although lamotrigine and levetiracetam, both second-generation antiepileptic drugs, were also responsible. Further, lamotrigine carries a black box warning for SJS in the United States. In addition, our study further suggests that mortality is higher when DILI in SJS/TEN is associated with severe hepatic dysfunction (high Model for End-Stage Liver Disease score). Further, 77% (10/13) of patients who died had jaundice, indicating that liver involvement is an important determinant of prognosis in these patients. Although this study has a biased group of patients with DILI and SJS/TEN, it indicates the impact of liver disease on mortality. Further studies of patients with and without jaundice and with SJS/TEN are required to convincingly demonstrate the impact of liver dysfunction on mortality. Given the severity of 997

6 DEVARBHAVI ET AL. HEPATOLOGY, March 2016 FIG. 2. Durations (days) between drug exposure and onset of skin reaction. disease in patients with DILI and SJS/TEN, there is need for continued vigilance and early recognition of adverse effects, with prompt withdrawal of the offending drug. (14) This may be even more applicable with drugs that have long half-lives such as leflunomide and nevirapine. (14) The strengths of our study are that the diagnosis of SJS/TEN was made by dermatology faculty in an inpatient setting. All patients had complete follow-up and were admitted, treated, and followed up until recovery or death. This is deemed important by an international consortium of experts (5) and obviates the need for photographs of skin and mucous membranes for confirmation of diagnosis of SJS/TEN. (5) The limitations include the fact that a proportion of patients were diagnosed prior to 2004 and were identified retrospectively, as well as the absence of a comparison group without jaundice. Our cohort consisted of a relatively higher proportion of patients with HIV/AIDS (8/36). This is consistent with other reports demonstrating not only a 1000-fold higher incidence of SJS/TEN in HIV/ AIDS infection but also a greater risk of DILI compared to non-hiv individuals (15,16) ; but the lower mortality in this group was surprising. It is likely that HIV patients receiving highly active antiretroviral treatment are monitored more closely for DILI, resulting in an early diagnosis and treatment. This may be especially true for patients receiving nevirapine as there is a high index of suspicion. Indeed, there is a report of nevirapine-induced SJS and fulminant liver failure that was diagnosed 13 days before elevation of liver enzymes and liver dysfunction. (17) Furthermore, the absence of comorbidities such as liver and kidney disease or malignancies that increase risk of dying in those with HIV and SJS/TEN (18) may have played a role in the low mortality in our cohort. A favorable outcome in children with SJS/TEN has been reported by Levi and colleagues (7.5% mortality), (19) but no information regarding associated DILI was provided. The better outcome in children in SJS with or without DILI may be ascribed to the use of lower doses of medication, lack of comorbidities and drug interactions, and differential susceptibility to certain drugs. (20) Similar to the study by Levi et al., (19) our cohort of children with DILI and SJS/TEN was primarily exposed to aromatic antiepileptics (n 5 7) or sulfonamides (n 5 2). Causality assessment in patients with DILI and SJS/TEN may be confounded by polypharmacy. However, the ALDEN assessment method with inclusion of drug notoriety and the assessment of half-life of the drug at the time of presentation may be helpful in identifying potential offending agents from innocent bystanders. Further studies are needed to determine its utility in DILI without SJS/TEN. Sepsis-associated cholestasis (21) and systemic inflammatory response syndrome (22) by way of a bystander effect may pose a diagnostic challenge. However, the liver test abnormalities produced as a consequence are mild, and transaminases are rarely elevated two-fold to three-fold. In addition, these occur later in the course of the disease. As can be seen in Recruitment Period TABLE 3. Depiction of Offending Drugs Against Recruitment Periods Drugs Implicated (N 5 2) Phenytoin (n 5 1), dapsone (n 5 1) (N 5 6) Phenytoin (n 5 1), dapsone (n 5 1), leflunomide (n 5 3), ceftriaxone (n 5 1) (N 5 14) Phenytoin (n 5 2), carbamazepine (n 5 2), phenobarbitone (n 5 2), nevirapine (n 5 2), allopurinol (n 5 2), cotrimoxazole (n 5 2), zidovudine (n 5 1), levofloxacin (n 5 1) (N 5 11) Phenytoin (n 5 2), carbamazepine (n 5 1), dapsone (n 5 2), lamotrigine (n 5 1), nevirapine (n 5 3), cotrimoxazole (n 5 1), oxcarbazepine (n 5 1) (N 5 7) Phenytoin (n 5 2), dapsone (n 5 1), nevirapine (n 5 1), carbamazepine (n 5 1), levetiracetam (n 5 1), cotrimoxazole (n 5 1) 998

7 HEPATOLOGY, Vol. 63, No. 3, 2016 DEVARBHAVI ET AL. Table 1, the mean transaminase levels in our series were eight to 12 times the upper limit normal together with significant elevation of bilirubin and international normalized ratio, and the tests were done within 1-2 days of admission. SJS/TEN is an immunologically mediated disease, and it is highly likely that the same process affected both organs concurrently (as DILI is not due to direct toxicity). (1) In conclusion, some patients with DILI also develop SJS/TEN from the same medication. Those patients who develop severe DILI in combination with SJS/ TEN have poor outcomes. However, children and HIV-infected individuals appear to have a better outcome overall. A small group of drugs, primarily antiepileptics, antiretrovirals, and sulfonamides, accounted for most cases. The medications of notoriety for developing SJS/TEN as in the ALDEN scoring system are also responsible for a majority of the patients who develop DILI in the setting of SJS/TEN. Acknowledgment: We gratefully acknowledge the help of Dr. Keyur Sheth and Dr. Ravi Kiran in the management of these patients and in maintaining the DILI database. REFERENCES 1) Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331: ) Mockenhaupt M, Viboud C, Dunant A, Naldi L, Halevy S, Bouwes Bavinck JN, et al. Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The Euro SCAR-study. J Invest Dermatol 2008;128: ) Schneck J, Fagot JP, Sekula P, Sassolas B, Roujeau JC, Mockenhaupt M. Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective Euro SCAR-Study. 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N Engl J Med 2013;369: Supporting Information Additional Supporting Information may be found at onlinelibrary.wiley.com/doi/ /hep.28270/suppinfo. 999