Title

Obesity Increases Risk for Abnormal LFTs with Amoxicillin in Women, But Not in Men

Authors

Kennedy Forest MS-IV, Tiffany Knecht MS-I, Shaopeng Gu M.S., Eric A. Larson M.D., and Russell A. Wilke M.D., Ph.D.

Introduction

The obesity epidemic is an escalating concern for clinicians worldwide due to potential clinical consequences including metabolic dysfunction–associated steatotic liver disease (MASLD). MASLD causes liver injury through multiple mechanisms that result in inflammation within hepatic sinusoids including localized HLA-mediated immune system activation. In a subset of patients, MASLD can therefore lead to the development of metabolic dysfunction-associated steatohepatitis (MASH) with advanced fibrosis and eventual cirrhosis. Further, repeated liver insults can accelerate disease progression in an already inflamed steatotic liver. Commonly prescribed medications, such as antibiotics, also hold the potential to cause immune-mediated liver injury through the formation of drug-protein adducts that can trigger immune system activation. For some drugs, HLA gene variants alter the risk for this adverse reaction. It is possible that the rising incidence of obesity and its associated conditions may contribute to the increasing occurrence of liver injury related to antibiotic use due to their similar mechanism of immune-mediated inflammation in the liver.

Methods

We conducted a retrospective observational cohort study, using the All of Us Research Program biobank based at the NIH, to quantify the relationship between body mass index (BMI) and risk for drug-induced liver injury (DILI) with amoxicillin, one of the most commonly prescribed antibiotics in the U.S. A standardized laboratory-based phenotyping algorithm was applied to the de-identified longitudinal electronic health record (EHR) data available for a total of 41,982 All of Us study participants who had been exposed to amoxicillin during the course of their routine clinical care between February 1984 and December 2021. Patients were excluded if their EHR data contained any diagnostic codes for alcohol-related hepatic cirrhosis or infectious hepatitis.

Results

Within the 41,982 study subjects exposed to amoxicillin in the All of Us database, a subset of 121 case patients developed abnormal LFTs (alanine aminotransferase greater than 5xULN or alkaline phosphatase greater than 2xULN) within 1 month after amoxicillin exposure. In females, mean BMI was greater in the case patients (34.5 + 8.9 kg/m2) than in drug-exposed controls (31.5 + 8.4 kg/m2) (p < 0.01; n = 50 cases versus 26,389 controls). ICD-9 and ICD-10 codes for morbid obesity, MASLD and MASH were present at a much greater frequency within the EHR data of female case patients (56.0%) than the EHR data of female controls (28.9%).

Conclusion

In women, obesity is a risk determinant for abnormal LFTs with amoxicillin. This increase in risk for liver injury may represent a convergence between the chronic inflammation seen with MASLD and MASH and acute inflammation due to DILI.

References

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