Background & Aims
The drug-induced liver injury network (DILIN) is conducting a prospective study of patients with DILI in the United States. We present characteristics and subgroup analyses from the first 1257 patients enrolled in the study.
Methods
In an observational longitudinal study, we began collecting data on eligible individuals with suspected DILI in 2004, following them for 6 months or longer. Subjects were evaluated systematically for other etiologies, causes, and severity of DILI.
Results
Among 1257 enrolled subjects with suspected DILI, the causality was assessed in 1091 patients, and 899 were considered to have definite, highly likely, or probable DILI. Ten percent of patients died or underwent liver transplantation and 17% had chronic liver injury. In the 89 patients (10%) with pre-existing liver disease, DILI appeared to be more severe than in those without (difference not statistically significant; P=.09) and mortality was significantly higher (16% vs 5.2%; P<.001). Azithromycin was the implicated agent in a higher proportion of patients with pre-existing liver disease compared to those without liver disease (6.7% vs. 1.5%, p=0.006). Forty-one cases with latency ≤ 7 days were caused predominantly by antimicrobial agents (71%). Two most common causes for 60 DILI cases with latency >365 days were nitrofurantoin (25%) or minocycline (17%). There were no differences in outcomes of patients with short vs long latency of DILI. Compared to individuals younger than 65 y, individuals 65 y or older (n=149) were more likely to have cholestatic injury, although mortality and rate of liver transplantation did not differ. Nine patients (1%) had concomitant severe skin reactions; implicated agents were lamotrigine, azithromycin, carbamazepine, moxifloxacin, cephalexin, diclofenac, and nitrofurantoin. Four of these patients died.
Conclusion
Mortality from DILI is significantly higher in individuals with pre-existing liver disease or concomitant severe skin reactions compared to patients without. Further studies are needed to confirm the association between azithromycin and increased DILI in patients with chronic liver disease. Older age and short or long latencies are not associated with DILI mortality.
Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.
Glycerol phenylbutyrate (GPB) lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion in the form of phenylacetyl glutamine, which is excreted in urine. This randomized, double-blind, placebo-controlled phase II trial enrolled 178 patients with cirrhosis, including 59 already taking rifaximin, who had experienced two or more hepatic encephalopathy (HE) events in the previous 6 months. The primary endpoint was the proportion of patients with HE events. Other endpoints included the time to first event, total number of events, HE hospitalizations, symptomatic days, and safety. GPB, at 6 mL orally twice-daily, significantly reduced the proportion of patients who experienced an HE event (21% versus 36%; P = 0.02), time to first event (hazard ratio [HR] = 0.56; P < 0.05), as well as total events (35 versus 57; P = 0.04), and was associated with fewer HE hospitalizations (13 versus 25; P = 0.06). Among patients not on rifaximin at enrollment, GPB reduced the proportion of patients with an HE event (10% versus 32%; P < 0.01), time to first event (HR = 0.29; P < 0.01), and total events (7 versus 31; P < 0.01). Plasma ammonia was significantly lower in patients on GPB and correlated with HE events when measured either at baseline or during the study. A similar proportion of patients in the GPB (79%) and placebo groups (76%) experienced adverse events. Conclusion: GPB reduced HE events as well as ammonia in patients with cirrhosis and HE and its safety profile was similar to placebo. The findings implicate ammonia in the pathogenesis of HE and suggest that GPB has therapeutic potential in this population. (Clinicaltrials.gov, NCT00999167). (Hepatology 2014;59:1073-1083)
Ipilimumab is a first-in-class immunological checkpoint blockade agent and monoclonal antibody against Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) that has demonstrated survival benefit and durable responses in patients with metastatic melanoma. To date, solid organ transplant recipients have been excluded from clinical trials with cancer immunotherapies on the basis of their concurrent treatment with immunosuppressive agents. We present the first case to our knowledge of a patient with advanced cutaneous melanoma receiving ipilimumab status post orthotopic liver transplantation with a partial response. Transaminitis was observed 4 months after administration of ipilimumab that resolved with close observation. No evidence of graft rejection has been observed to date. This case advocates for further investigation of the safety and efficacy of cancer immunotherapies in solid organ transplant recipients.
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