Clarithromycin-Associated Acute Liver Failure Leading to Fatal, Massive Upper Gastrointestinal Hemorrhage from Profound Coagulopathy: Case Report and Systematic Literature Review

Abstract

While erythromycin has caused numerous cases of acute liver failure (ALF), clarithromycin, a similar macrolide antibiotic, has caused only six reported cases of ALF. A new case of clarithromycin-associated ALF is reported with hepatic histopathology and exclusion of other etiologies by extensive workup, and the syndrome of clarithromycin-associated ALF is better characterized by systematic review. A 60-year-old nonalcoholic man, with normal baseline liver function tests, was admitted with diffuse abdominal pain and AST = 499 U/L and ALT = 539 U/L, six days after completing a 7-day course of clarithromycin 500 mg twice daily for suspected upper respiratory infection. AST and ALT each rose to about 1,000 U/L on day-2 of admission, and rose to ≥6,000 U/L on day-3, with development of severe hepatic encephalopathy and severe coagulopathy. Planned liver biopsy was cancelled due to coagulopathies. Extensive evaluation for infectious, immunologic, and metabolic causes of liver disease was negative. Abdominal computerized tomography and abdominal ultrasound with Doppler were unremarkable. The patient developed massive, acute upper gastrointestinal bleeding associated with coagulopathies. Esophagogastroduodenoscopy was planned after massive blood product transfusions, but the patient rapidly expired from hemorrhagic shock. Autopsy revealed a golden-brown heavy liver with massive hepatic necrosis and sinusoidal congestion. Rise of AST/ALT to about 1,000 U/L each was temporally incompatible with shock liver because this rise preceded the hemorrhagic shock, but the subsequent AST/ALT rise to ≥6,000 U/L each may have had a component of shock liver. The six previously reported cases were limited by failure to exclude hepatitis E (4), lack of liver biopsy (2), and uninterpretable liver biopsy (1) and by confounding potential etiologies including disulfiram, israpidine, or recent acetaminophen use (3), clarithromycin overdose (1), active alcohol use (1), and severe heart failure (1). Review of 6 previously reported and current case of clarithromycin-associated ALF revealed that patients had AST and ALT values in the thousands. Five patients died and 2 survived.

Doxycycline vs. macrolides in combination with a β-lactam antibiotic for the treatment of community-acquired pneumonia in inpatients

“…Furthermore, more than one-fifth of the patients in the BL-M group experienced liver enzymes elevation from baseline. Although a recent meta-analysis has shown that clarithromycin has a better safety profile than erythromycin when used for the treatment of CAP [ 12 ], the risk of hepatotoxicity remains a concern with the former given the observations in our study, as well as previous reports [ 13 ]. Nonetheless, such adverse effect was more common with azithromycin than with clarithromycin in our study.…”

Effect of a combination of omeprazole and high-dose proton pump inhibitors on the treatment of patients with liver cirrhosis complicated with upper gastrointestinal hemorrhage

“…Some very important indicators of liver function are ALT, AST, total protein, total bilirubin, and total bile acids. If tests of liver function result in levels of these indicators in excess of the normal ranges, impairment of liver function and higher risks of liver diseases are implied [16,17].…”

Hepatotoxicity of Antibiotics and Antifungals and Their Safe Use in Hepatic Impairment

“…100 Cases of severe DILI leading to ALF and death have been reported. 4,[101][102][103] In the drug label, the manufacturer states hepatic failure with fatal outcome has been reported and generally has been associated with serious underlying diseases and or concomitant medications. 4,104 In terms of prescribing, no dose adjustment is needed in hepatic impairment.…”