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Approximately half the US adult population consumes herbals and dietary supplements (HDS),(1,2) with recent reports showing their use to be increasing.(3,4) Supplement users are more commonly women, non-Hispanic whites, over age 40, and have higher levels of education than non-users.(4-7) NHANES III data indicate that multivitamins and minerals are the most common supplements used, followed by calcium and fish oils.(5) However, the range of HDS is far broader and includes numerous commercial products. Although dietary supplements are perceived as safe (8), the current regulatory framework established by the Dietary Supplement Health and Education Act of 1994 (9) requires less evidence of safety prior to marketing as assessed by the Food and Drug Administration (FDA) than is required for pharmaceuticals. The FDA and other regulatory bodies can take action against a manufacturer only if there is proven adulteration or injury from its supplement. Recent cases of life-threatening hepatotoxicity from the dietary supplement OxyElite Pro (10) underscore the potential adverse consequences of this oversight process. The Drug-Induced Liver Injury Network (DILIN), supported by the National Institutes of Diabetes and Digestive and Kidney Diseases, was established in 2003 to identify, enroll, and characterize cases of drug-induced liver injury attributable to medications (excluding acetaminophen) and HDS (ClinicalTrials.gov Identifier:NCT00345930).(11) The original DILIN report identified HDS as the second most common cause for liver injury. (12) Since that report, many more cases have been accrued by the DILIN. Thus, we examined the burden and characteristics of liver injury attributable to HDS in the DILIN, and compared this injury with that due to conventional medications.

Acute liver failure (ALF) is classically defined by coagulopathy and hepatic encephalopathy (HE); however, acute liver injury (ALI), i.e., severe acute hepatocyte necrosis without HE, has not been carefully defined nor studied. Our aim is to describe the clinical course of specifically defined ALI, including the risk and clinical predictors of poor outcomes, namely progression to ALF, the need for liver transplantation (LT) and death.386 subjects prospectively enrolled in the Acute Liver Failure Study Group registry between 1 September 2008 through 25 October 2013, met criteria for ALI: International Normalized Ratio (INR)≥2.0 and alanine aminotransferase (ALT)≥10 × elevated (irrespective of bilirubin level) for acetaminophen (N-acetyl-p-aminophenol, APAP) ALI, or INR≥2.0, ALT≥10x elevated, and bilirubin≥3.0 mg/dl for non-APAP ALI, both groups without any discernible HE. Subjects who progressed to poor outcomes (ALF, death, LT) were compared, by univariate analysis, with those who recovered. A model to predict poor outcome was developed using the random forest (RF) procedure.Progression to a poor outcome occurred in 90/386 (23%), primarily in non-APAP (71/179, 40%) vs. only 14/194 (7.2%) in APAP patients comprising 52% of all cases (13 cases did not have an etiology assigned; 5 of whom had a poor outcome). Of 82 variables entered into the RF procedure: etiology, bilirubin, INR, APAP level and duration of jaundice were the most predictive of progression to ALF, LT, or death.A majority of ALI cases are due to APAP, 93% of whom will improve rapidly and fully recover, while non-APAP patients have a far greater risk of poor outcome and should be targeted for early referral to a liver transplant center.

Objective In the United States, nearly 1000 annual cases of heat stroke are reported but the frequency and outcome of severe liver injury in such patients is not well described. The aim of this study was to describe cases of acute liver injury (ALI) or failure (ALF) caused by heat stroke in a large ALF registry. Data Sources Amongst 2,675 consecutive subjects enrolled in a prospective observational cohort of patients with ALI or ALF between January 1998 and April 2015, there were 8 subjects with heat stroke. Data Synthesis Five patients had ALF and 3 had ALI. Seven patients developed acute kidney injury, all 8 had lactic acidosis and rhabdomyolysis. Six patients underwent cooling treatments, 3 received N-acetyl cysteine (NAC), 3 required mechanical ventilation, 3 required renal replacement therapy, 2 received vasopressors, 1 underwent liver transplantation, and 2 patients died—both within 48 hours of presentation. All cases occurred between May and August, mainly in healthy young men due to excessive exertion. Conclusions Management of ALI and ALF secondary to heat stroke should focus on cooling protocols and supportive care, with consideration of liver transplantation in refractory patients. This article is protected by copyright. All rights reserved.

Drug-induced liver injury (DILI), also known as hepatotoxicity, refers to liver injury caused by drugs or other chemical agents, and represents a special type of adverse drug reaction. It has been estimated that more than 600 drugs and chemicals have been associated with significant liver injury. Many previous reviews have focused on DILI pathogenesis or have outlined the clinical features of liver injury linked to different drugs. This article briefly touches on several areas that are potentially vexing for both the novice and cognoscenti, with the goal of guiding the consultant through one of the most challenging areas of hepatology.

The purpose of this study is to describe the incidence and presenting features of patients with acute liver failure (ALF) due to ischemic hepatitis and the prognostic factors associated with short (three-week) and long-term outcomes.Retrospective cohort analysis of adult patients enrolled in the Acute Liver Failure Study Group between 1998 and 2008 with ALF due to ischemic hepatitis. Predictors of adverse outcomes three weeks after presentation were identified by univariate and multivariate analysis.Ischemic hepatitis accounted for 51 (4.4%) of the 1147 ALF patients enrolled. Mean age was 50 years, 63% were female, and only 31% had known heart disease before presentation. However, a cardiopulmonary precipitant of hepatic ischemia was identified in 69%. Three-week spontaneous survival was 71%, two patients (4%) underwent liver transplantation, and the remaining 13 patients (25%) died of multi-organ failure. Adverse outcomes were more frequent in subjects with higher admission phosphate levels (HR 1.3, 95% CI 1.1-1.6, P = 0.008) and in subjects with grade 3/4 encephalopathy at presentation (HR: 8.4, 95% CI 1.1-66.5, P = 0.04). Nineteen of the 28 short-term survivors (68%) were still alive at a median follow-up of 3.7 years whereas nine (32%) others had died at a median follow-up of 2 months.A higher admission serum phosphate level and more advanced encephalopathy are associated with a lower likelihood of short-term survival of hospitalized patients with ALF due to ischemic hepatitis. Long-term outcomes are largely determined by underlying cardiovascular morbidity and mortality.

Background & Aims The long-term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2-year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrolment in the Acute Liver Failure Study Group (ALFSG). Methods Outcomes in adult ALFSG patients that were enrolled between 1998 and 2010 were reviewed. Results Two-year patient survival was significantly higher in the 262 LT recipients (92.4%) compared to the 306 acetaminophen (APAP) spontaneous survivors (SS) (89.5%) and 200 non-APAP SS (75.5%) (P

Background & Aims Little is known about the incidence of drug-induced liver injury (DILI) and risk factors for adverse outcomes. We evaluated short-term outcomes of a large cohort of patients with DILI enrolled in an ongoing multicenter prospective study. Methods Data were collected from 660 adults with definite, highly likely, or probable DILI. Regression methods were used to identify risk factors for early liver-related death or liver transplantation and chronic liver injury. Results Patients' median age was 51.4 years; 59.5% were female and 59.1% required hospitalization. Within 6 months of DILI onset, 30 patients received liver transplants (4.5%; 95% confidence interval [CI], 3.0%–6.1%) and 32 died (5%; 95% CI, 3.2%–6.5%); 53% of the deaths were liver related. Asian race, absence of itching, lung disease, low serum albumin levels, low platelet counts, and high serum levels of alanine aminotransferase and total bilirubin at presentation were independent risk factors for reduced times to liver-related death or liver transplantation (C-statistic = 0.87). At 6 months after DILI onset, 18.9% of the 598 evaluable subjects had persistent liver damage. African-American race, higher serum levels of alkaline phosphatase, and prior heart disease or malignancy requiring treatment were independent risk factors for chronic DILI (C-statistic = 0.71). Conclusions Nearly 1 in 10 patients die or undergo liver transplantation within 6 months of DILI onset and nearly 1 in 5 of the remaining patients have evidence of persistent liver injury at 6 months. The profile of liver injury at presentation, initial severity, patient's race, and medical comorbidities are important determinants of the likelihood of death/transplantation or persistent liver injury within 6 months.

Severe drug-induced liver injury is a relatively rare but important public health problem. Extrapolating the incidence of this problem from clinical treatment trials is confounded by a number of issues, including the relatively small size of clinical trials, exclusion criteria for study participation, and active surveillance for liver injury. Advances in understanding the pathogenesis of drug-induced liver injury, as well as its prevention and treatment, will likely require the identification and careful characterization of severe cases in the post-marketing, "real-world" setting as part of a concerted, multi-center, well-orchestrated effort. The Drug-Induced Liver Injury Network (DILIN) represents one example of such an effort.

Drug-induced liver injury (DILI) is the most common cause of acute liver failure in the United-States. The aim of the study was to describe serum immune profiles associated with acute DILI, to investigate whether there are profiles associated with clinical features or types of DILI and/or with prognosis, and to assess temporal changes in levels. Twenty-seven immune analytes were measured in the sera of 78 DILI subjects in the Drug-Induced Liver Injury Network (DILIN) and compared with 40 healthy controls. Immune analytes (14 cytokines, 7 chemokines and 6 growth factors) were measured by BioPlex multiplex ELISA at DILI onset and after 6 months. A modeling process utilizing immune principles was used to select a final set of variables among 27 immune analytes and several additional clinical lab values for prediction of early death (within 6 months of DILI onset). Nineteen of the 27 immune analytes were differentially expressed among healthy control, DILI onset and 6-month cohorts. Disparate patterns of immune responses, especially innate and adaptive cellular (mostly TH17) immunity were evident. Low values of four immune analytes (IL-9, IL-17, PDGF-bb and RANTES) and serum albumin are predictive of early death [PPV = 88% (95% CI, 65%-100%), NPV = 97% (95% CI, 93%-100%), accuracy = 96% (95% CI, 92%-100%)]. Conclusions Acute DILI is associated with robust and varying immune responses. High levels of expression of cytokines associated with innate immunity are associated with a poor prognosis, whereas high levels of expression of adaptive cytokines are associated with good long-term prognosis and eventual recovery. Serum immune analyte profiles at DILI onset appear to be of prognostic, and perhaps, diagnostic significance.

Background & Aims The diagnosis of drug-induced liver injury relies on exclusion of other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of HEV infection among patients with drug-induced liver injury in the United States. Methods The Drug-Induced Liver Injury Network (DILIN) is a prospective study of patients with suspected drug-induced liver injury; clinical information and biological samples are collected to investigate pathogenesis and disease progression. We analyzed serum samples, collected from patients enrolled in DILIN, for immunoglobulin (Ig) G and IgM against HEV; selected samples were tested for HEV RNA. Results Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive for anti-HEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM (collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients who had anti-HEV IgM were mostly older men (89%; mean age, 67 years), and 2 were human immunodeficiency virus positive. Clinical reassessment of the 9 patients with anti-HEV IgM indicated that acute hepatitis E was the most likely diagnosis for 7 and might be the primary diagnosis for 2. Conclusions HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected to be drug induced. Serologic testing for HEV infection should be performed, particularly if clinical features are compatible with acute viral hepatitis.

Keratins 8 and 18 (K8/K18) provide anti-apoptotic functions upon liver injury. The cytoprotective function of keratins explains the overrepresentation of K8/K18 variants in patients with cirrhosis. However, K8/K18 variant-associated susceptibility to acute liver injury, which is well-described in animal models, has not been studied in humans.We analyzed the entire coding regions of KRT8 and KRT18 genes (15 total exons and their exon-intron boundaries) to determine the frequency of K8/K18 variants in 344 acute liver failure (ALF) patients (49% acetaminophen-related) and 2 control groups (African-American [n = 245] and previously analyzed white [n = 727] subjects).Forty-five ALF patients had significant amino-acid-altering K8/K18 variants, including 23 with K8 R341H and 11 with K8 G434S. K8 variants were significantly more common (total of 42 patients) than K18 variants (3 patients) (P.001). We found increased frequency of variants in white ALF patients (9.1%) versus controls (3.7%) (P = .01). K8 R341H was more common in white (P = .01) and G434S was more common in African-American (P = .02) ALF patients versus controls. White patients with K8/K18 variants were less likely to survive ALF without transplantation (P = .02). K8 A333A and G434S variants associated exclusively with African Americans (23% combined frequency in African American but none in white controls; P.0001), while overall, K18 variants were more common in non-white liver-disease subjects compared to whites (2.8% vs 0.6%, respectively; P = .008).KRT8 and KRT18 are important susceptibility genes for ALF development. Presence of K8/K18 variants predisposes to adverse ALF outcome, and some variants segregate with unique ethnic and race backgrounds.

Background: Drug-induced liver injury (DILI) is an uncommon adverse drug reaction of increasing importance to the medical community, pharmaceutical industry, regulatory agencies and the general public. Objectives: The Drug-Induced Liver Injury Network (DILIN) was established to advance understanding and research into DILI by initiating a prospective registry of patients with bona fide DILI for future studies of host clinical, genetic, environmental and immunological risk factors. The DILIN was also charged with developing standardized nomenclature, terminology and causality assessment instruments. Methods: Five clinical sites, a data coordinating centre and senior scientists from the National Institute of Diabetes and Digestive and Kidney Diseases initiated the DILIN prospective study in September 2004. Eligible patients are required to meet minimal laboratory or histological criteria within 6 months of DILI onset and have other competing causes of liver injury excluded. Patients in the general community setting with pre-existing HIV, hepatitis B virus or hepatitis C virus infections and/or abnormal baseline liver biochemistries are eligible for enrolment. In addition, subjects with liver injury due to herbal products are eligible to participate. Control patients without DILI are also to be recruited in the future. Results: All referred subjects undergo an extensive review of available laboratory, pathology and imaging studies. Subjects who meet pre-defined eligibility criteria at the 6-month study visit are followed for 2 years to better define the natural history of chronic DILI. Causality assessment is determined by a panel of three hepatologists who independently assign a causality score ranging from 1 (definite) to 5 (unlikely) as well as a severity score ranging from 1 (mild) to 5 (fatal). During the first 3 years, 367 subjects were enrolled into the DILIN prospective study. Conclusion: DILIN is a multicentre research network charged with improving our understanding of the aetiologies, risk factors and outcomes of DILI in the US. The network is meeting the targeted enrolment of ten patients per month and is developing a repository of clinical data and biological samples for future studies of DILI pathogenesis and outcome.

The development of coagulopathy in acute liver failure (ALF) is universal. The severity of the coagulopathy is often assessed by determination of the prothrombin time and International Normalized Ratio (INR). In more than 1,000 ALF cases, the severity of the coagulopathy was moderate in 81% (INR 1.5–5.0), severe in 14% (INR 5.0–10.0), and very severe in 5% (INR > 10.0). Certain etiologies were associated with more severe coagulopathy, whereas ALF caused by fatty liver of pregnancy had the least severe coagulopathy. Management consisted of transfusions of FFP in 92%. Overall, FFP administered during the first week of admission amounted to 13.7 ± 15 units. Patients who received an ICP monitor had significantly more FFP transfused than those managed without ICP monitor (22.7 ± 2.4 vs. 12.3 ± 0.8 units FFP; P