The Hidden Everyday Pharmacologic Liver Toxicities

As a second-year resident, I’m still getting used to the feeling of signing my name to medication lists that seem to grow longer every day. I add a statin here, adjust a diabetes medication there, continue a proton-pump inhibitor (PPI) because the patient was taking it before admission and stopping it feels risky at 3 a.m. I rarely think about the cumulative long-term consequences of those decisions. I think about guidelines, indications, hemoglobin A1c goals, and atherosclerotic cardiovascular disease scoring, not hepatic bandwidth. 

It wasn’t until recently that I realized how often those routine choices quietly shape a patient’s liver health. In a routine primary care clinic visit, I saw a woman in her 70s with type 2 diabetes, obesity, and chronic kidney disease who had mildly elevated aminotransferase levels for over a year. Never high enough to trigger alarm. Never normal enough to ignore. 

Using the framework outlined in an Annals of Internal Medicine review by Tran and colleagues (1), I worked through the standard evaluation alcohol history, viral serologies, imaging, and common causes of drug-induced liver injury (DILI). The work-up was unremarkable, yet her aspartate aminotransferase and alanine aminotransferase levels drifted up and down year after year. 

When I reviewed her medication list with my attending, the pattern became harder to ignore. A statin, PPI, sulfonylurea, glucagon-like peptide-1 (GLP-1) receptor agonist, and bisphosphonate, all while taking over-the-counter supplements purchased to “support metabolism.” None of them individually seemed dangerous. None would appear on a board question as the obvious culprit; however, the liver does not metabolize medications in isolation. We are trained to look for the dramatic cases of DILI such as acetaminophen overdose, acute idiosyncratic reactions, and new onset of jaundice. The American College of Gastroenterology guidelines emphasize systematic evaluation and careful medication review when liver injury is suspected (2) but do not provide guidance for silent cumulative effects of multiple common medications. 

The National Institutes of Health LiverTox database reminds us that many widely prescribed medications can cause mild, often transient aminotransferase elevations that are typically asymptomatic and reversible (3). Alone, these laboratory changes may be inconsequential. In combination, especially in patients with metabolic risk factors, they may represent something more subtle: reduced hepatic reserve. 

We often mention renal and cardiac reserve, yet we rarely talk about hepatic reserve despite a significant number of our patients who exist in a gray zone where they have hepatic compensation susceptible to illness and damage. That clinic visit did not change my practice of prescribing common hepatically metabolized medications, but it did alter how I think about medication lists as a whole. I still start statins, and GLP-1 receptor agonists, but I now pause before reflexively continuing medications that have lingered on the list for years. I ask whether each drug is still providing meaningful benefits. I consider whether cumulative exposure matters more than any single agent. 

The review by Tran and colleagues (1) provides a high-value framework for evaluating abnormal liver test results. It also emphasizes that abnormal results are often downstream reflections of everyday decisions. Hepatology is not confined to consultation services or transplant centers; it is embedded in routine internal medicine. Every time we click “continue” on a medication list, we are participating in a metabolic negotiation between benefit and burden. The liver keeps score quietly. And sometimes, those mild elevations are not a mystery to solve, but a message to reconsider the list in front of us. 

References

1. Tran AN, Lim JK. Care of the patient with abnormal liver test results. Ann Intern Med. 2021;174:ITC129-ITC144. [PMID: 34516271] doi:10.7326/AITC202109210
2. Chalasani NP, Maddur H, Russo MW, et al; Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2021;116:878-898. [PMID: 33929376] doi:10.14309/ajg.0000000000001259
3. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. National Institute of Diabetes and Digestive and Kidney Diseases.

Daniel Bujnowski, MD

Daniel is a PGY-2 internal medicine resident at Duke University with an interest in medical education and metabolic disease. He is currently preparing for a fellowship in gastroenterology and hepatology.

Denise D. Pong, MD, MPH

Denise is a clinician-educator in Durham, North Carolina, where she practices as a primary care internist and serves as the Associate Program Director for Ambulatory Care for the Duke Internal Medicine Residency program.