Victor J. Navarro

ACG Clinical Guideline: The Diagnosis and Management of Idiosyncratic Drug-Induced Liver Injury

Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction and it can lead to jaundice, liver failure, or even death. Antimicrobials and herbal and dietary supplements are among the most common therapeutic classes to cause DILI in the Western world. DILI is a diagnosis of exclusion and thus careful history taking and thorough work-up for competing etiologies are essential for its timely diagnosis. In this ACG Clinical Guideline, the authors present an evidence-based approach to diagnosis and management of DILI with special emphasis on DILI due to herbal and dietary supplements and DILI occurring in individuals with underlying liver disease.

Liver injury from herbals and dietary supplements in the U.S. Drug‐Induced Liver Injury Network

The Drug‐Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight U.S. referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by HDS increased from 7% to 20% (P < 0.001) during the study period. Bodybuilding HDS caused prolonged jaundice (median, 91 days) in young men, but did not result in any fatalities or LT. The remaining HDS cases presented as hepatocellular injury, predominantly in middle‐aged women, and, more frequently, led to death or transplantation, compared to injury from medications (13% vs. 3%; P < 0.05). Conclusions: The proportion of liver injury cases attributed to HDS in DILIN has increased significantly. Liver injury from nonbodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399–1408)

Hepatic histological findings in suspected drug‐induced liver injury: Systematic evaluation and clinical associations

Drug‐induced liver injury (DILI) is considered to be a diagnosis of exclusion. Liver biopsy may contribute to diagnostic accuracy, but the histological features of DILI and their relationship to biochemical parameters and outcomes are not well defined. We have classified the pathological pattern of liver injury and systematically evaluated histological changes in liver biopsies obtained from 249 patients with suspected DILI enrolled in the prospective, observational study conducted by the Drug Induced Liver Injury Network. Histological features were analyzed for their frequency within different clinical phenotypes of liver injury and to identify associations between clinical and laboratory findings and histological features. The most common histological patterns were acute (21%) and chronic hepatitis (14%), acute (9%) and chronic cholestasis (10%), and cholestatic hepatitis (29%). Liver histology from 128 patients presenting with hepatocellular injury had more severe inflammation, necrosis, and apoptosis and more frequently demonstrated lobular disarray, rosette formation, and hemorrhage than those with cholestasis. Conversely, histology of the 73 patients with cholestatic injury more often demonstrated bile plugs and duct paucity. Severe or fatal hepatic injury in 46 patients was associated with higher degrees of necrosis, fibrosis stage, microvesicular steatosis, and ductular reaction among other findings, whereas eosinophils and granulomas were found more often in those with milder injury. Conclusion: We describe an approach for evaluating liver histology in DILI and demonstrate numerous associations between pathological findings and clinical presentations that may serve as a foundation for future studies correlating DILI pathology with its causality and outcome. (Hepatology 2014;59:661–670)

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self‐treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose‐exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well‐compensated, chronic noncirrhotic HCV who failed interferon‐based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady‐state exposures for silybin A and silybin B increased 11‐fold and 38‐fold, respectively, with a 5‐fold increase in dose, suggesting nonlinear pharmacokinetics. No drug‐related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy: A Randomized Controlled Trial

CONTEXT The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. OBJECTIVE To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. INTERVENTION Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. MAIN OUTCOME MEASURES The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. RESULTS After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, -4.3 [95% CI, -17.3 to 8.7] U/L for placebo, -14.4 [95% CI, -41.6 to 12.7] U/L for 420-mg silymarin, -11.3 [95% CI, -27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, -0.05 to 0.18] log10 IU/mL for placebo, -0.03 [95% CI, -0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, -0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. CONCLUSION Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00680342.

Factors Associated with Severe Impact of Lipodystrophy on the Quality of Life of Patients Infected with HIV-1

A standardized questionnaire was used to assess the impact of lipodystrophy (LD) on quality of life (QoL). Eighty-four consecutive asymptomatic human immunodeficiency virus type 1 (HIV-1)-infected outpatients with clinical LD completed a modified version of the Dermatology Life Quality Index (DLQI) survey to measure the impact of body fat changes on their QoL. Body changes influenced dressing for 55 patients (65%), produced feelings of shame for 41 (49%), and disrupted sexual life for 23 (27%). There was a greater impact on the DLQI due to body changes among women, injection drug users, patients with abdominal or breast lipoaccumulation, and patients with a high number of non-LD side effects. Multivariate proportional odds model analysis showed that the severity of non-LD-associated side effects and the presence of breast lipoaccumulation were associated with impaired psychosocial functioning. Specific characteristics of patients, antiretroviral-based side effects, and breast lipoaccumulation exert a greater impact on QoL in HIV-1-infected patients with LD.

Review article: drug-induced liver injury – its pathophysiology and evolving diagnostic tools

Aliment Pharmacol Ther 2011; 34: 11–20

LiverTox: A Website on Drug-Induced Liver Injury

LiverTox is a freely available website ( http://LiverTox.nih.gov ) that provides up-to-date, comprehensive, and easily accessed clinical information on liver injury due to prescription and over-the-counter medications, herbals, and nutritional supplements. LiverTox includes introductory sections on the clinical course, diagnosis, phenotypic patterns, outcomes, severity scales, and causality grading systems for drug-induced liver injury (DILI). The bulk of LiverTox comprises individual sections on specific medications, including background information on the agent, a concise description of its potential and pattern of hepatotoxicity, and extensive annotated references linked to PubMed citations. For agents that cause liver injury, representative case reports are provided. Finally, LiverTox allows for submission of clinical cases of hepatotoxicity to the website, which will be added to a database that can be accessed and analyzed. LiverTox is an ambitious effort aimed not only at providing clinical information on DILI but also at stimulating and assisting future research into its cause, prevention, and treatment.

The effect of hla class I (A and B) and class II (DR) compatibility on liver transplantation outcomes : An analysis of the OPTN database

The purpose of this study was to explore the relationship between human leukocyte antigen (HLA) compatibility and liver transplantation outcomes by analyzing the effect of HLA compatibility on 5‐year graft survival. We analyzed first liver transplants between 1987 and 2002 in the Organ Procurement and Transplantation Network (OPTN) database, where A, B, or DR loci data were available. Graft failure was defined as retransplantation or death from transplant‐related cause. We evaluated associations between total and locus‐specific match levels and 5‐year graft survival. Multivariable Cox proportional‐hazard models were used to evaluate statistical interactions and adjust for the effect of potential confounders. Among 29,675 first‐time transplants, the overall degree of HLA match had no effect on 5‐year graft survival, even after controlling for potential confounders. Univariate and multivariable analyses showed that the 0 HLA antigen mismatch cohort of patients had higher 5‐year graft failure rates than the other 6 antigen mismatch groups. However, this occurred in a small group with a disproportionately large number of live donors and split‐liver recipients. When these recipients were excluded from the analysis, the effect was no longer seen. Finally, multivariable, locus‐specific analyses showed no association between 5‐year graft survival and degree of match/mismatch and the A, B, or DR loci. In conclusion, this careful examination of the OPTN database, with respect to HLA match or mismatch and liver graft survival, reaffirms that HLA matching has no clinically significant impact on this outcome. Liver Transpl 12:652–658, 2006.

Psychosocial adjustment to orthotopic liver transplantation in 266 recipients.

Although the survival rate of patients undergoing orthotopic liver transplantation (OLT) is highly satisfactory, one of the most important objectives for liver transplantation teams at the present time is to achieve the best possible quality of life and psychosocial functioning for these patients after transplantation. We present the preliminary results of a study designed to determine which domains of psychosocial functioning are most affected in liver transplant recipients, and to examine the factors associated with poorer adjustment after OLT, using a utility‐based standardized measure. Patients who had undergone liver transplant more than 12 months previously were eligible. They were administered the Psychosocial Adjustment to Illness Scale (PAIS), and they provided the answers themselves. Multivariate regression models showed that attitudes toward health care were poorer in women (β = 0.916, P < .001), in patients who were employed at the moment of transplantation (β = 0.530, P = .032), and in patients of lower social class (β = 0.722, P = .026) than in men, unemployed patients, and patients of higher social class. Sexual functioning was worse in women (β = 0.907, P = .001) and older patients (β = 0.999, P < .001) than in men or younger patients. Psychological distress was higher in women (β = 0.981, P = .001) than in men, and lower in currently employed patients (β = −0.937, P = .001) than in the unemployed. Only gender remained significantly associated with the total PAIS score (β = 0.969, P < .001), with women showing a poorer overall psychosocial adjustment to OLT. In conclusion, there seems to be no doubt that liver transplantation improves quality of life, but special attention should be paid to female recipients, who seem to have more difficulty than their male counterparts in adjusting to the psychosocial consequences of the procedure. (Liver Transpl 2004;10:228–234.)