Bad Medicine: New Data Aim to Limit Drug Hepatotoxicity

William F. Balistreri, MD


December 31, 2018

In This Article

Concurrent DISI and DILI

DILI and drug-induced skin injury (DISI) may occur individually, but have rarely been reported to occur concurrently. Devarbhavi and colleagues[4] analyzed clinical and laboratory characteristics, outcome, and complications of all patients with hypersensitivity skin injury or rashes among cases of idiosyncratic DILI.

The investigators identified 255 cases of skin reactions associated with 262 drugs among 919 patients (28%) with DILI. Stevens-Johnson syndrome (SJS) and drug rash with eosinophilia and systemic symptoms (DRESS) were seen in 51 and 151 patients, respectively. The most frequently implicated drugs were antiepileptic drugs (33%), antibiotics (27%), antituberculosis agents (20%), antiretroviral drugs (8%), and nonsteroidal anti-inflammatory drugs (4%).

Overall, 31 patients died, including 27% with SJS and 12% with DRESS. Predictors of mortality included jaundice, encephalopathy, ascites, bilirubin, albumin, aspartate aminotransferase level, international normalized ratio, Model for End-Stage Liver Disease score, white blood cell count, and lymphopenia. Recovery was prolonged in patients with DRESS/SJS with significant nonskin, nonliver complications, including bone marrow suppression and bacterial infection. This study raises awareness of the potential for concomitant or sequential DILI and DISI, and the predictors of outcome.

Role of HEV Infection in Suspected DILI

Sporadic acute hepatitis E virus (HEV) infection has been reported to account for some cases of suspected DILI. The question therefore arose as to whether HEV infection initiates, potentiates, or mimics DILI.

Fontana and colleagues[5] set out to determine the incidence of presumed acute HEV infection in consecutive patients with DILI and to identify risk factors for anti-HEV serostatus. Among 1730 patients enrolled in the DILI network prospective study, 20% were reactive for anti-HEV immunoglobulin G (IgG), of whom 1.2% were also positive for anti-HEV immunoglobulin M (IgM). Participants with anti-HEV IgM were significantly older and were more likely to be male, and they were also less likely to die during follow-up than those without anti-HEV IgM (0% vs 7%). However, other clinical features, including severity scores and peak values of serum enzymes and bilirubin, were similar in the three groups.

Seroprevalence rates of anti-HEV IgG rose significantly with age, increasing from 6% in those younger 30 years to 38% in those older than 70 years. Furthermore, age-specific rates were consistently lower in those more recently enrolled, and there was a similar trend for anti-HEV IgM decreasing from 2.7% in the first 5 years to < 1% during the last 5 years. The incidence of acute HEV infection appeared to decrease, and age-specific rates of anti-HEV declined during the 14 years of the DILI network prospective study.

These results suggest a cohort effect in anti-HEV prevalence and a declining rate of acute HEV infection in the United States; however, the role of concomitant HEV infection in affecting the outcome of DILI remains uncertain.

Are DILI Outcomes Better in Teaching Hospitals?

Golikov and colleagues[6] sought to assess the variance in mortality, cost of care, and length of stay among patients with DILI in teaching and nonteaching institutions. They performed a retrospective study using the Nationwide Inpatient Sample, representing a 20% stratified sample of DILI hospitalizations acquired from 46 states, encompassing more than 97% of the US population.

The DILI-associated mortality rate in nonteaching institutions exhibited a slight upward trend from 5.04% in 2005 to 5.44% in 2011. Teaching institutions demonstrated no statistically significant difference in inpatient mortality over this 7-year period. In addition, the average mortality rate was 4.75% in nonteaching hospitals versus 4.72% in teaching institutions.

The mean cost of care demonstrated an increasing trend, with an average of $39,668 in nonteaching hospitals compared with $48,388 in teaching hospitals. Length of stay was unchanged in both settings over this 7-year period (an average of 7.37 days in teaching hospitals vs 6.35 days in nonteaching hospitals). Liver biopsy rates decreased in both settings and were found to be more common in teaching settings (4.08%) than in nonteaching hospitals (2.37%).

The investigators postulate that the increasing trend in DILI-related mortality in nonteaching institutions may be attributed to the increased recognition and diagnosis of DILI.

Searching for Effective Treatment Strategies to Limit Acetaminophen Overdose

Acetaminophen overdose is the leading cause of DILI in the United States and Europe, indicating that more effective therapeutic strategies are needed to limit its occurrence. Arnold and colleagues[7] assessed the value of the highly sulfated polysaccharides heparan sulfate and heparin in the treatment of acetaminophen-induced acute liver injury. They reported that a nonanticoagulant heparan sulfate octadecasaccharide (HS 18-mer) was protective against acute liver injury induced by acetaminophen (400 mg/kg) and improved survival in a murine model.

The HS 18-mer binds to high-mobility group box 1 (HMGB1), a DNA-binding protein released from the nuclei of necrotic hepatocytes, and decreases neutrophil infiltration to the injury site. The HS 18-mer likely potentiates the endogenous protective effect from shed syndecan-1, given that increased plasma levels of shed syndecan-1 were found in both acetaminophen overdose mice and patients. The investigators reported that the HS 18-mer administered 6 hours after acetaminophen overdose was still protective in the mouse model, demonstrating the potential benefit over the current standard of care for late-presenting acetaminophen overdose.

Discovery of HMGB1-neutralizing heparan sulfate oligosaccharides will offer a practical approach to treat acute liver injury.

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