Suspected Pyridostigmine-Related Hepatotoxicity

ABSTRACT

Drug-induced liver injury describes the result of toxicity to the liver from offending drugs and/or their metabolites. Most cases are acute and resolve quickly after the medication is discontinued. It is a diagnosis of exclusion after ruling out other causes of liver injury, such as infectious and autoimmune etiologies. When drug-induced liver injury is suspected, the culprit can be determined by establishing a temporal relationship between drug exposure and the development of signs and symptoms of liver injury. In this case presentation, we discuss a patient who developed liver injury from pyridostigmine in the management of acute colonic pseudo-obstruction (Ogilvie syndrome).

INTRODUCTION

Drug-induced liver injury (DILI) can occur from a variety of medications and is identified after excluding alternative causes using laboratory, imaging, and biopsy findings. The R factor is a commonly utilized scoring system to describe the pattern of liver injury; a value above 5 signifies hepatocellular liver injury, a value below 2 represents cholestatic liver injury, and a value in between is considered mixed type.¹ It can then be further characterized into 2 subgroups, intrinsic where it is dose-dependent, has a short onset, and more common, or idiosyncratic where it is not dose dependent and occurs in a smaller population of patients with a longer onset.² Although there are many common offending drugs that can cause an intrinsic pattern including acetaminophen, amiodarone, valproic acid, and statins, there is a paucity of literature describing pyridostigmine as a cause of DILI.²

CASE REPORT

A 72-year-old man with medical history of left femoral deep vein thrombosis and pulmonary embolism on apixaban, chronic kidney disease, dysphagia, and hypertension presented for evaluation of achalasia. On outpatient endoscopy, he was found to have a distensibility index of 0.38 via endoluminal functional lumen imaging probe. He was hospitalized to rule out pseudo-achalasia and was planned for Per-Oral esophageal myotomy. He underwent Per-Oral esophageal myotomy successfully and was placed on a full liquid diet for 1 week. Unfortunately, he developed frequent episodes of diarrhea, found to have Clostridium difficile colitis, and was started on oral vancomycin. Shortly after, the patient developed significant abdominal distension and tenderness. As part of his workup, an abdominal x-ray was performed showing moderate stool burden in the sigmoid colon, splenic flexure, and hepatic flexure (Figure 1). Computed tomography scan of the abdomen revealed proctocolitis with colonic distension, concerning for Ogilvie syndrome (Figure 2). The patient was made nil per os, and rectal and nasogastric tubes were placed for decompression. Multiple promotility agents were trialed, including neostigmine and misoprostol with no improvement. He was ultimately initiated on pyridostigmine 60 mg 3 times daily, and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were noted to be elevated 20 days after pyridostigmine initiation. The calculated R score was 2.2, reflecting a mixed etiology of liver injury, prompting further serologies and imaging. Magnetic resonance cholangiopancreatography and computed tomography abdomen were nonrevealing. Viral, genetic, and autoimmune workup also did not show significant findings (Figure 3). Acetaminophen and alcohol levels were negative although the patient was an occasional social drinker.

Figure 1.

Abdominal X-Ray revealing distended loops of bowel.

Figure 2.

Computed tomography abdomen revealing proctocolitis with colonic distension.

Figure 3.

Serological/infectious workup.

Within 2 days, AST improved from 776 IU/L to 148 IU/L (normal 5–34 IU/L), and ALT from 637 IU/L to 297 IU/L (normal 0–50 IU/L). Pyridostigmine was restarted at 30 mg 3 times daily. However, within 24 hours, AST increased from 148 to 1258 IU/L, ALT from 297 to 1235 IU/L, with alkaline phosphatase at 741 IU/L (normal 40–150 IU/L). Total bilirubin was normal, international normalized ratio was elevated to 2.19, and worsening mental status was noted, which was concerning for acute liver failure. Pyridostigmine was discontinued, with immediate improvement of liver function tests and clinical status. Within a day, ALT improved from 1235 IU/L to 729, AST from 1,258 to 298, and alkaline phosphatase to 596. Within 2 weeks, the liver function tests were within normal limits (Figure 4). A liver biopsy was not indicated since our patient had no prior hepatic medical history, a negative workup, and made a full recovery after discontinuation of pyridostigmine.

Figure 4.

Serum transaminases after pyridostigmine initiation. ALT, alanine aminotransferase; AST, aspartate aminotransferase.

DISCUSSION

The annual incidence of DILI worldwide is estimated to be 14 to 19.1 per 100,000 persons.³ It is one of the most common causes for withdrawal of medications in the marketplace; risk factors include adult age, female sex, and comorbidities such as obesity, diabetes, and chronic viral hepatitis.^4–6

In this case, our patient developed a mixed liver injury after initiation of pyridostigmine. Rechallenge with a lower dose caused a recurrence of liver enzyme elevation, suggesting an idiosyncratic type of liver injury that we suspect to be caused by the drug. The patient had a prolonged hospital course, with medication reconciliation revealing use of potentially hepatotoxic agents including acetaminophen, atorvastatin, hydralazine, metronidazole, ampicillin, and piperacillin-sulbactam. However, acetaminophen was limited to under 4 g daily and held during most of the time of his hospital stay, making it an unlikely culprit. Atorvastatin and hydralazine were held once liver enzymes were elevated and not resumed until after they normalized. The aforementioned antibiotics were completed 1 to 2 months prior and typically cause cholestatic liver injury. Causality was assessed using the Roussel Uclaf Causality Assessment Method, which yielded a score of 9 and the Naranjo score was 8, consistent with highly probable, and probable DILI, respectively. Although he was briefly in the intensive care unit when receiving neostigmine therapy, he remained normotensive and did not require any vasopressors, making ischemic hepatopathy very low on the differential. Liver biopsy is an important tool in distinguishing DILI from autoimmune hepatitis, although this was not performed due to improvement of his liver enzymes.²

Pyridostigmine is an acetylcholinesterase inhibitor that increases extracellular acetylcholine levels in the neuromuscular junction by impairing its breakdown. It is commonly used in the management of myasthenia gravis, and constipation from colonic pseudo-obstruction, thought to exert its effects by increasing gastrointestinal motility.⁷ It is hydrolyzed by hepatocellular cholinesterases and excreted in the urine as an unchanged drug and metabolites. Despite hepatic metabolism being a substantial part of its elimination pathway, no specific information is available on the pharmacokinetics of pyridostigmine in hepatic impairment.⁸

The mechanism of pyridostigmine-induced liver injury is unclear, but a hypothesis can be extrapolated from studies performed in mice models and on similar compounds. Cholinergic receptors are expressed on hepatocytes and Kupffer cells, and animal studies have shown that parasympathetic stimulation can attenuate liver injury.^9,10 Conversely, cholinergic overstimulation, such as in organophosphate poisoning, has been linked to oxidative stress in the liver, likely due to ischemic or metabolic changes from cholinergic toxidrome, although hepatotoxicity is typically mild.¹¹ Tacrine, an older cholinesterase inhibitor, is known to cause reversible hepatotoxicity greater than 3 times the upper limit of normal through 2 known mechanisms. Metabolism of the compound through Cytochrome p450 can generate toxic intermediates.¹¹ Tacrine can also deplete adenosine triphosphate at the hepatocellular level by acting as a mitochondrial membrane uncoupler.¹² We postulate that pyridostigmine may cause liver injury through similar direct and indirect effects on the cellular level.

Other common anticholinergics such as donepezil and rivastigmine do not have a well-established mechanism of hepatotoxicity. However, pyridostigmine has been documented to rarely cause hepatotoxicity since it is metabolized largely by plasma cholinesterases without forming hepatotoxic intermediates.^13,14 FDA's Adverse Event Reporting System Database contains no hepatic safety signal, and Livertox has no mention of pyridostigmine.^15,16 In WHO VigiAccess, hepatobiliary disorders represent 1% of adverse reports, with only 6 total DILI incidents.¹⁷ In 2021, the FDA's DILIrank dataset, changed pyridostigmine from “no DILI concern” to “very low DILI concern” to support the link mentioned in these rare, idiosyncratic reports.¹⁸

This case illustrates the possible association of pyridostigmine and DILI, which to our knowledge is the first report of this phenomenon. Although a useful medication for pseudo-obstruction, it may be prudent for clinicians to be aware of this risk and conduct an appropriate risk-benefit analysis before initiation.

DISCLOSURES

Author contributions: L. DiBenedetto wrote the first draft of the manuscript, acquisition of data, created the graph and table, and revised the work. V. Wong and U. Nasir contributed to the conception of the work, reviewed and revised the graph and table, and contributed to interpretation of data as well as critically reviewed the manuscript. B. Asif provided expertise in hepatology, contributed to design of report and table, and critically reviewed the manuscript ensuring accuracy of the work. All authors have read and approved the final manuscript and agree to be accountable for aspects of the work. L. DiBenedetto is the article guarantor.

Financial disclosure: None to report.

Previous presentation: ACG Conference, Pennsylvania, October 2024.

All attempts have been exhausted in trying to contact the patient, next of kin for informed consent to publish their information, but consent could not be obtained.

ABBREVIATIONS:

AST

aspartate aminotransferase

ALT

alanine aminotransferase

ALP

alkaline phosphatase

DILI

drug induced liver injury

XR

X-Ray