Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation

Abstract

Background Drug-induced liver injury (DILI) is increasingly recognized as a common cause of acute hepatitis. The clinical impact of DILI following liver transplantation (LT) is not known. Aims To describe the frequency, clinical presentation, and outcomes of DILI among LT recipients. Methods LT recipients with possible DILI were identified using electronic pathology and clinical note database retrieval tools. Diagnostic criteria were applied to identify cases of DILI. Results Among 1689 LT recipients, 29 individuals with DILI (1.7%) were identified. Mean age was 52 years with 52 % women. Major indications for LT were primary sclerosing cholangitis (28%), cholangiocarcinoma (14%), and hepatocellular carcinoma (14%). Severity of DILI was mild or moderate in 92% of cases. Nausea or diarrhea (31%), jaundice (24%), and pruritus (10%) were the most common symptoms at diagnosis. Mean ALT was 204±263 U/L, AST 108 ± 237 U/L, ALP 469 ± 689 U/L, and TB 1.9±10.3 mg/dL. Median duration of medication use until DILI diagnosis was 57 days, and major classes of agents were antibiotics (48%), immunosuppressive agents (14%), and antihyperlipidemic drugs (7%), Trimethoprim-sulfamethoxazole was the most common single implicated agent (n=11). Serum liver enzymes improved within a median time of 34 days (range, 5-246 days) after drug withdrawal. Hepatic re-transplantation or death did not occur. Among 50 cases with possible DILI explained by other causes, 13 (26%) individuals had no alternate diagnosis despite histology compatible with DILI. Conclusions DILI is a rare yet under-recognized event among LT recipients. The majority of cases are not clinically severe, and resolve following drug cessation without hepatic retransplantation or death.

Drug-drug interactions with oral anti-HCV agents and idiosyncratic hepatotoxicity in the liver transplant setting

“…The frequency and risk factors for DILI in 1689 consecutive LT recipients from Mayo Clinic seen over a 15 year period were also recently reported (118). A diagnosis of “Definite DILI” was based on the presence of clinical criteria and a compatible liver biopsy after rigorous exclusion of competing causes using expert opinion for causality assessment (103).…”

Pathogenesis of Idiosyncratic Drug-Induced Liver Injury and Clinical Perspectives

“…In support of the “danger hypothesis” (Figure 2) administration of tumor necrosis factor (TNF) to hepatocyte cultures as well as in animal models of DILI can potentiate the hepatotoxicity of multiple drugs (53). In addition, the greater frequency of DILI in immunosuppressed liver transplant recipients (1 in 100 patient years) compared to the general population (1 in 10,000 patient years) suggests that specific patient populations may be at increased risk of idiosyncratic DILI (20). However, a plausible explanation as to why the majority of patients with an acute or chronic illness who receive multiple medications including antibiotics do not develop DILI remains unclear.…”

“…However, recent studies that use natural language processing algorithms which can search for key words in a text field such as “hepatotoxicity” or “toxic hepatitis” have demonstrated an improved sensitivity and specificity for DILI (18). In addition, the linking of clinical, laboratory and pathology databases with text searching algorithms may allow for more real time identification of idiosyncratic DILI cases (19, 20). …”

Systematic investigation of elevated cholestatic enzymes during the third posttransplant month

“…Approximately a quarter of all cases of drug‐induced liver injury occur in months 1 to 3 after LT . The common culprits include antibiotics (42%), immunosuppressive agents (14%), antihyperlipidemic agents (7%), antivirals (7%), antifungals (3%), and miscellaneous agents (21%), with trimethoprim‐sulfamethoxazole as the commonest cause .…”