Terbinafine-induced liver injury with isolated serum alkaline phosphatase elevation: A case report and literature review

Abstract

In cholestatic drug-induced liver injury, serum liver function tests typically demonstrate concurrent elevations in alkaline phosphatase and γ-glutamyltransferase, with or without increases in alanine aminotransferase, aspartate aminotransferase, and total bilirubin. Isolated elevation of alkaline phosphatase is rare. Herein, we report a case of drug-induced liver injury characterized by isolated alkaline phosphatase elevation for clinicians. Following treatment with ursodeoxycholic acid, the patient achieved complete recovery. Clinicians should recognize that drug-induced liver injury may also present as an isolated elevation of alkaline phosphatase.

Introduction

Drug-induced liver injury (DILI) is defined as liver damage caused by prescription or over-the-counter (OTC) drugs, including chemicals, biologic agents, and Chinese patent medicines, as well as products such as herbal medicines (HMs), natural drugs, health products, and dietary supplements, along with their metabolites, excipients, contaminants, or impurities. ¹ In recent years, the incidence of DILI has increased worldwide and has become a major cause of acute liver failure (ALF). However, determining the true incidence of DILI in the general population remains challenging because of differences in research methodologies, study demographics, and diagnostic criteria. Available data estimate an annual incidence of at least 23.80/100,000 in China; ² 12/100,000 in South Korea; ³ and 13.9/100,000 to 19.1/100,000 in France and Iceland, respectively, based on prospective population-based studies.^4,5 In contrast, the reported annual incidence of DILI in the United States, Spain, and Sweden is less than 4.0/100,000.^6–8 The clinical phenotypes of DILI are classified as hepatocellular, cholestatic, and mixed. Hepatocellular injury accounts for approximately 42%–59% of cases and is characterized by marked elevation of alanine aminotransferase (ALT) or aspartate aminotransferase (AST), often resembling an “acute hepatitis” episode. It represents the most common clinical phenotype of DILI. Cholestatic injury comprises 20%–32% of cases and typically presents with concurrent elevations of alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) levels, with or without associated increases in ALT, AST, and total bilirubin (TBIL). Isolated elevation of ALP is uncommon. This report was prepared in accordance with the Case Report (CARE) guidelines. ⁹

Case report

A male patient in his early 60s presented to Hangzhou Red Cross Hospital because of abnormal liver function test results. He was started on 0.25 g oral terbinafine once daily for onychomycosis on 16 August 2023. Regular monitoring of liver function showed consistently normal results. However, repeat testing on 18 November revealed the following: TBIL, 12.3 μmol/L; ALT, 20 U/L; AST, 23 U/L; ALP, 1098 U/L; and GGT, 40 U/L. Notably, only ALP was markedly elevated. The patient reported no significant discomfort, and the physical examination was unremarkable.

Regarding past medical history, the patient had type 2 diabetes mellitus for more than 3 years and had been on long-term 0.5 g oral metformin twice daily. He denied the use of other medications, including health supplements and traditional Chinese herbal medicines. There was no recent history of fractures, blood transfusions, or hepatitis. Additionally, there was no history of alcohol consumption, heavy metal exposure, or long-term exposure to toxic substances. No hepatoprotective therapy had been administered prior to admission.

Comprehensive investigations were performed. Results were negative for hepatotropic viral hepatitis markers, ceruloplasmin, ferritin, transferrin saturation, antinuclear antibody spectrum, autoimmune liver disease panel, immunoglobulins, thyroid function, parathyroid hormone, serum calcium, serum phosphorus, tumor markers, and contrast-enhanced computed tomography (CT) of the liver.

The patient developed abnormal liver function 3 months after initiation of terbinafine. The Roussel Uclaf Causality Assessment Method (RUCAM) score was 8, indicating that DILI was highly probable.

Terbinafine was discontinued, and 250 mg oral ursodeoxycholic acid was initiated three times daily. ALP returned to normal after 80 days (Table 1). No adverse events occurred during the treatment period.

Table 1.

Changes in serum liver function during treatment.

Date	ALP (U/L)	GGT (U/L)	ALT (U/L)	AST (U/L)	TBIL (μmol/L)	Treatment plan
4 December 2023	732	43	20	21	11.2	250 mg ursodeoxycholic acid capsules three times daily.
4 January 2024	329	32	21	19	9.8	The existing treatment plan was continued.
5 February 2024	103	27	18	20	10.5	Ursodeoxycholic acid was discontinued.

ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: γ-glutamyltransferase; TBIL: total bilirubin.

Liver function tests normalized 4 weeks later (11 March 2024). The final diagnosis was established as acute cholestatic-type DILI with a RUCAM score of 8 points (high probability).

Discussion

ALP is distributed in the liver, bone, kidney, small intestine, and placenta, with the highest concentration in the liver followed by bone. Elevated ALP is commonly observed in the following conditions: (a) Hepatobiliary system diseases. Extrahepatic obstruction such as pancreatic head cancer and common bile duct stones; and intrahepatic cholestasis, including acute and chronic viral hepatitis, DILI, alcoholic hepatitis, and primary biliary cholangitis; (b) Bone diseases. Fibrous osteitis, rickets, osteomalacia, osteoblastoma, bone healing phase, and hyperparathyroidism; (c) Growing children and the second and third trimesters of pregnancy.

In liver diseases, ALP elevation is usually accompanied by an increase in GGT. According to the 2021 Guidelines for the Management of Cholestatic Liver Disease, cholestatic liver disease can be diagnosed when ALP levels are ≥1.5 × the upper limit of normal (ULN) and GGT levels are ≥3 × ULN. When ALP is elevated but GGT does not increase, hepatogenic diseases can often be excluded. However, some special cholestasis liver diseases, including familial intrahepatic cholestasis (FIC) types 1, 2, 4, 5, and 6; benign recurrent intrahepatic cholestasis (BRIC); and USP53 deficiency disease are characterized by an increase in conjugated bilirubin or bile acid levels without an increase in GGT levels.^10,11 When ALP is elevated in isolation, measurement of GGT can help determine whether the elevation is of hepatic or nonhepatic origin. ¹² GGT is highly expressed in the liver and is also present in the kidney, intestine, prostate, and pancreas, but not in bone. Therefore, it is useful in confirming that an elevated ALP level originates from the liver rather than bone. ¹³

The 2021 Asia-Pacific ¹⁴ and European ¹⁵ DILI guidelines and the 2023 Chinese DILI guidelines all recommend using the diagnostic criteria proposed by the International Serious Adverse Events Consortium in 2011. ¹⁶ The liver biochemical thresholds for acute DILI should meet at least one of the following criteria: (a) ALT ≥5 × ULN; (b) ALP ≥2 × ULN (particularly accompanied by an increased GGT level after exclusion of bone disease); (c)ALT ≥3 × ULN and TBIL ≥2 × ULN. ¹ GGT elevation is not mandatory; however, in clinical practice, DILI-related ALP elevation is usually accompanied by an increase in GGT, with or without elevations in ALT, AST, and TBIL. Isolated ALP elevation is rare, and no relevant literature has reported such cases.^17–20 In addition, a major diagnostic challenge in DILI is the absence of a gold standard, as the diagnosis is primarily based on exclusion of other etiologies.

Terbinafine-induced hepatotoxicity is a recognized adverse effect and is clearly stated in the drug package inserts. However, it is uncommon in clinical practice, with fewer than 1% of treated patients developing liver injury. ²¹ The estimated global annual incidence of terbinafine-associated liver injury is approximately 2.5 cases per 100,000. ²² The initial pattern of injury may be hepatocellular or cholestatic; however, it typically progresses to a cholestatic pattern. ²³ Most cases of terbinafine-induced liver damage resolve within 3–6 months after drug withdrawal, whereas severe outcomes such as bile duct disappearance syndrome or ALF are rare. ²⁴ Current reports of terbinafine-induced liver injury typically describe abnormalities in multiple biomarkers, including TBIL, ALT, AST, ALP, and GGT. Isolated elevation of ALP has not been reported.^25–30 Therefore, the mechanism by which terbinafine induces liver injury characterized by isolated ALP elevation remains unclear. It is uncertain whether this presentation represents an early stage of DILI, with potential subsequent increases in ALT, GGT, or other liver enzymes. However, due to the occurrence of liver injury, drug discontinuation is generally adopted in clinical practice, making it difficult to observe the changes in liver function with continued terbinafine administration. Additionally, the patient had a long-term history of oral metformin use, and it is difficult to determine whether a drug–drug interaction between terbinafine and metformin contributed to the liver injury. Although no such interaction is mentioned in the package inserts of either medication, the liver injury is most likely associated with terbinafine. Enterogenic and familial ALP elevations have been reported;^31–33 however, this case clearly does not belong to such categories. The authors have previously reported a case of DILI presenting with isolated serum ALP elevation; however, given the patient’s concurrent use of multiple medications, the causative agent could not be definitively identified. ³⁴ Therefore, two key points merit consideration: (a) the underlying mechanism of DILI presenting with isolated ALP elevation and the potential involvement of specific molecular targets; (b) classification of cholestatic DILI as a distinct subtype of cholestasis, given its diagnostic differences from cholestasis associated with other common liver diseases according to relevant guidelines.

The final diagnosis was established based on the medical history, RUCAM score, exclusion of alternative causes of liver injury, and follow-up after treatment. This case highlights that terbinafine-induced liver injury may present with isolated elevation of serum ALP rather than the typical pattern of combined transaminase and bilirubin elevation. Clinicians should be aware of this atypical presentation when evaluating patients receiving terbinafine therapy.

Patient perspective

I was prescribed oral terbinafine for tinea pedis and underwent regular normal liver function testing as advised. Approximately 12 weeks after starting treatment, follow-up testing revealed an isolated elevation in serum ALP, without any symptoms. My doctor suspected DILI, arranged additional examinations, discontinued terbinafine, and prescribed oral ursodeoxycholic acid (UDCA). I experienced no discomfort during UDCA treatment, and subsequent tests showed that my ALP levels gradually returned to normal. This experience increased my awareness of potential medication-related adverse effects and highlighted the importance of regular monitoring and timely communication with clinicians. I am grateful to my healthcare team for their prompt management, which prevented further progression of liver injury.

Conclusion

It is important to recognize that DILI can manifest as an isolated elevation of serum ALP. When isolated serum ALP elevation occurs with a high suspicion of DILI, the recommended approach is to first discontinue the suspected drug, initiate appropriate liver-protective therapy, and institute close clinical follow-up. If the response is suboptimal, relevant investigations should be performed to exclude other etiologies and avoid unnecessary testing. Although terbinafine is widely used as an antifungal agent and hepatotoxicity is a recognized adverse effect, it is not severe enough to warrant a contraindication, and close monitoring remains a practical approach in clinical practice.