Semaglutide-Induced Liver Injury

ABSTRACT

Semaglutide, a glucagon-like peptide-1 receptor agonist widely used for managing type 2 diabetes mellitus and obesity. Reports of semaglutide-associated hepatotoxicity are exceedingly rare. We detail a case of a 44-year-old woman who developed liver injury with elevated liver enzymes after semaglutide initiation for weight management. Liver enzyme levels normalized after discontinuing the drug and worsened upon rechallenge, confirming semaglutide's potential to cause liver injury. In addition, our case study encompasses a literature review of all reported semaglutide-related drug-induced liver injury cases, highlighting the need for diligent liver function monitoring in patients on semaglutide and offering valuable insights into its hepatotoxic potential.

INTRODUCTION

Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) known for its effectiveness in managing type 2 diabetes mellitus and obesity.¹ GLP-1 RAs have also shown efficacy in metabolic dysfunction–associated steatotic liver disease, where they facilitate lipid oxidation and mitigate hepatic lipid accumulation, thus decreasing liver fat content.² Despite these therapeutic benefits, GLP-1 RAs are not without risks and are associated with gastrointestinal adverse effects ranging from mild abdominal discomfort and nausea to severe complications like pancreatitis and gastroparesis.¹

Although semaglutide has minimal hepatic metabolism suggesting a lower risk of hepatotoxicity.³ A meta-analysis by Yin et al highlighted an increased relative risk of 1.45 (0.29-7.19) for drug-induced liver injury (DILI) associated with GLP-1 rheumatoid arthritis.⁴ However, this association was not statistically significant. We present a rare case of semaglutide-induced liver injury in a 44-year-old woman, incorporating a review of literature.

CASE REPORT

A 44-year-old woman with no significant medical history was admitted because of a 2-week history of progressive jaundice, fatigue, and pruritus. Physical examination was only significant for scleral icterus and jaundice. There was no evidence of altered mentation or confusion. She denied using illicit drugs, antibiotic exposure, alcohol, or herbal medications. Her medications included semaglutide (1 mg per week) for weight loss, with the last dose 2 weeks ago.

The patient reported she experienced similar symptoms 6 months ago. She was found to have elevated liver enzymes aspartate aminotransferase (AST) at 229 U/L (Normal: 10–35 U/L), alanine aminotransferase (ALT) at 928 U/L (normal: 7–56 U/L), alkaline phosphatase (ALP) at 74 U/L (normal: 44–147 IU/L), and total bilirubin (T.B) at 4.7 mg/dL (normal: 0.3–1.2 mg/dL). An extensive diagnostic workup was negative for acute viral hepatitis, and autoimmune markers including antimitochondrial antibody, antismooth muscle antibody, and antinuclear antibody were unremarkable. In addition, alpha-1 antitrypsin deficiency, hemochromatosis gene analysis, and ceruloplasmin levels were also negative. Ferritin was significantly elevated at 1783 ng/mL (normal: 12–300 ng/mL). A right upper quadrant ultrasound was unremarkable and showed no signs of obstruction, steatosis, thrombosis, or cirrhosis. The patient had been using semaglutide for weight loss, which was discontinued because of suspected DILI. Upon cessation, her liver function tests normalized within 4 weeks.

Investigations

During this admission, ALT was 1459 U/L, AST was 760 U/L, ALP was 86 U/L, and gamma-glutamyl transferase was 90 U/L (normal: 5–55 U/L). T.B was 11.1 mg/dL, and direct bilirubin was 8.3 mg/dL (normal: 0–0.3 mg/dL). A urine drug screen, acetaminophen levels, and blood alcohol levels were negative. Acute viral hepatitis panel, antinuclear antibody, antismooth muscle antibody, and antimitochondrial antibody were negative. Blood copper levels at 130 μg/dL (normal: 70–175 μg/dL), ceruloplasmin levels at 30.3 mg/dL (normal: 15–60 mg/dL), and hemochromatosis gene panel were negative. Ferritin levels were elevated at 1,650 ng/mL. Serum protein electrophoresis revealed normal albumin and globulin levels. Although awaiting external records from the prior episode, the liver injury workup had already been initiated, resulting in duplication of laboratory tests within a 6-month short duration.

Diagnostic imaging and liver biopsy

Right upper quadrant ultrasound, a computed tomography scan of the abdomen and pelvis and a magnetic resonance cholangiopancreatography did not reveal any intrahepatic or extrahepatic biliary ductal dilation, mass, gallbladder, or pancreatic pathology.

A liver biopsy was performed, which revealed mild to moderate mononuclear cell infiltrate within the hepatic lobules and portal tracts, along with multiple large foci of hepatic necrosis exhibiting a mixed periportal and centrilobular pattern consistent with acute hepatitis.

Management and follow-up

The patient was managed conservatively. Her clinical condition and liver enzymes improved to ALT 1128 U/L, AST 445 U/L, ALP 87 U/L, T.B 9.6, and direct bilirubin 7.5 at the time of discharge. At 4-week follow-up, the patient was asymptomatic, her jaundice had resolved, and liver enzymes had normalized (Figure 1).

Figure 1.

The temporal relationship between semaglutide administration and liver enzymes alanine transaminase and aspartate transaminase patterns. ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury.

DISCUSSION

This is a rare case of semaglutide-induced liver injury, as demonstrated by the timing of semaglutide initiation relative to the onset of symptoms, the complete normalization of liver enzymes after the drug's discontinuation, and the recurrence of symptoms upon reexposure to the drug. The exact pathophysiological mechanism of semaglutide-associated DILI remains elusive. Unlike intrinsic DILI, which is predictable and dose-dependent, semaglutide-related liver injury appears to be idiosyncratic, which is unpredictable, affecting only a susceptible subset of individuals, and not clearly related to the dosage administered.^5,6 A recent study on tirzepatide-related DILI proposed that elevated liver enzyme levels might result from the rapid mobilization of fat from the liver, a possible mechanism of liver injury.⁷ Jiayi Ma et al described a case of concurrent renal and liver injuries and identified heterozygous ABCC2 and DHCR7 gene variants in a patient with semaglutide-associated liver injury but did not establish a definitive link between the variants and hepatotoxicity.³

The diagnosis of DILI necessitates a high index of suspicion and a methodical approach, particularly when symptoms emerge shortly after the initiation of a new medication.^5,6 In this case, the use of the Roussel Uclaf causality assessment method scale resulted in a score of 8, indicating that semaglutide is a probable cause of DILI⁵ (Table 1).

Table 1.

RUCAM score⁵

Factors	Points
Time to onset from beginning of the drug	2
Course of ALT after drug withdrawal	2
Risk factors (age >55, alcohol, pregnancy)	0
Concomitant drug use	0
Exclusion of other causes	1
Previous information on drug hepatotoxicity	0
Response to reexposure	3
RUCAM score	8

ALT, alanine aminotransferase; RUCAM, Roussel Uclaf causality assessment method.

We compared this case with 4 other reports of semaglutide-induced liver injury in Table 2.^3,8–10 Our case is the only 1 with a documented rechallenge, providing stronger evidence of causality. Despite medical advice, the patient independently resumed semaglutide using leftover medication because of absence of Food and Drug Administration (FDA) safety warnings or publicly available data linking semaglutide to liver injury. A FDA Adverse Event Reporting System database study reported hepatobiliary events, including cholelithiasis and cholecystitis with oral semaglutide. However, cases of liver injury remain absent from these reports.¹¹

Table 2.

Literature review and comparison of semaglutide-induced liver injury cases^3,8–10

Author (yr of publication)	Enslin et al (2021)	Jiayi Ma et al (2022)	Santiago et al (2023)	Alghamdi et al (2024)	This case report
Type of study	Abstract	Case report	Abstract	Case report	Not yet published
Gender	Male	Male	Female	Female	Female
Age	79	51	67	29	44
Symptoms	Fatigue	Abdominal pain, fatigue, nausea, vomiting	Abdominal pain, nausea, vomiting	Abdominal pain, nausea, vomiting	Fatigue, abdominal pain, nausea, vomiting, and pruritus
Jaundice +/−	Absent	Present	Absent	Present	Present
Latency period	6 wk	6 mo	2 wk	4 wk	4 wk
Diagnosis	AI-DILI	DILI	DILI	AI-DILI	DILI
R value	3.6	0.6	16.5	1.75	37
Type	Mixed	Cholestatic	Hepatocellular	Cholestatic	Hepatocellular
RUCAM	6 (probable)	3 (possible)	7 (probable)	3 (possible)	8 (probable)
Liver biopsy	NA	Marked diffuse bile duct injury with patchy ductular reaction and mild cholestasis, portal tract edema marked ductular reaction, and chronic inflammatory infiltrate	NA	Moderate inflammation of portal tract and mild interface hepatitis with mixed inflammation with lymphocytes and neutrophil	Mild-moderate mononuclear cells infiltrate within hepatic lobules and portal tract. Multiple large foci of hepatic necrosis within hepatic lobules, mixed periportal and centrilobular pattern
Rechallenge Test	No	No	No	No	Positive Rechallenge Test
Treatment	Conservative/drug discontinuation	Failed steroid therapy	Conservative/drug discontinuation	Steroid therapy	Conservative/drug discontinuation
Prognosis	Resolution	Biliary cirrhosis, liver transplant	Resolution	Resolution	Resolution

DILI, drug-induced liver injury; AI-DILI, autoimmune like drug induced liver injury, RUCAM, Roussel Uclaf causality assessment method; NA, not applicable

In conclusion, this case underscores the complexity of diagnosing and managing DILI associated with semaglutide use. The evidence from the patient's medical history, the normalization of liver enzymes upon drug discontinuation, and the reexposure to the drug strongly suggest a causal relationship between semaglutide and liver injury. Although the exact pathophysiological mechanism remains elusive, this case contributes to the growing body of literature suggesting that semaglutide might induce liver injury.

DISCLOSURES

Author contributions: H. Kalsi: Conceptualized and designed the study, collected and managed patient data, drafted the initial manuscript, and critically revised the manuscript. SS Arora: Conducted the literature search, summarized findings, and assisted in drafting the literature review section and tables. K. Essilfie-Quaye: Assisted in clinical assessment and follow-up, reviewed the manuscript for clinical accuracy. R. Bassi: Prepared figures and tables, and reviewed the manuscript for clinical accuracy. N. Akhavan: Oversaw clinical management, provided critical revisions, and ensured clinical accuracy. Y. Perbtani: Developed methodology for systematic data collection, reviewed and edited the manuscript for gastroenterological insights. TS Brar: Provided overall leadership, supervised the study and manuscript preparation, acted as article guarantor, and performed the final manuscript review.

Acknowledgments: This work was supported by HCA Healthcare and/or an HCA Healthcare affiliated entity. The views expressed in this publication represent those of the author(s) and do not necessarily represent the official views of HCA Healthcare or any of its affiliated entities.

Financial disclosure: None to report.

Previous presentation: ACG Annual Scientific Meeting, October 25–29, 2024, Philadelphia, PA.

Informed consent was obtained for this case report.

ABBREVIATIONS:

ED

emergency department

EGD

esophagogastroduodenoscopy

EUS

endoscopic ultarsound

IR

interventional radiology

LAMS

lumen-apposing metal stent

PCD

percutaneous catheter drainage