Intrahepatic Cholestasis Induced by Leflunomide: An Unusual Presentation of DILI

Introduction and Objectives

Leflunomide is a drug used to treat autoimmune diseases. However, despite its therapeutic benefits, adverse effects have been reported after six months of treatment, including liver damage.

Materials and Patients

A 19-year-old female from Acayucan, Veracruz, without significant hereditary or family history, drug addiction denied, with a pathological history of hypothyroidism for 2 years and rheumatoid arthritis since the age of 15, treated with leflunomide 20 mg, chloroquine 150 mg, levothyroxine 100 mcg. She presented in October 2022 with nausea, vomiting, postprandial abdominal pain, jaundice. Abdominal ultrasound revealed chronic calculous cholecystitis. Laparoscopic cholecystectomy was performed in December 2022 without complications. After surgical treatment, he persisted with jaundice, alteration of liver function tests of mixed pattern that evolves to cholestatic pattern (R factor 0.2, see Table 1). Non-reactive to viral hepatitis A, B and C, HIV, negative antibodies ANA, AML, AMA, anti-DNAds, anti-Smith, anti-Rho, complement C3 145 and C4 33. Cholangiography, with hepatomegaly, diffuse hepatic steatosis without evidence of biliary lesions. Liver biopsy showed features of portal and lobular hepatitis, intracytoplasmic and intracanalicular cholestasis, macrovesicular steatosis, and F2 fibrosis according to METAVIR (Fig. 1), which were not consistent with autoimmune or viral disease. RUCAM score with possible relation to hepatoxicity (4 points), so it is considered drug-induced liver injury (leflunomide).

Results

Leflunomide was discontinued and treatment was adjusted to chloroquine 150 mg and prednisone 50 mg. Clinical and biochemical improvement was observed.

Conclusions

This case highlights the importance of suspecting DILI in patients treated with potentially hepatotoxic drugs and with alterations in liver biochemistry. It is a rare disease for which there are no specific markers. Therefore, liver biopsy is a useful tool for early diagnosis.

Ethical statement

The identity of the patients is protected. Consentment was obtained.

Declaration of interests

None

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Figure 1. Liver tissue with widened portal spaces, mild inflammatory portal infiltrate, thick droplet steatosis, intracytoplasmic and ductal cholestasis.

Table 1.

Control of laboratory studies

PARAMETER	11-Feb	23-Feb	23-Mar	21-Apr	24-May	5-Jul
Total bilirubin (mg/dL)	3.8	4.1	8.61	14.5	8.15	0.76
Direct bilirubin (mg/dL)	2.47	3.3	6.64	7.81	-	0.34
Indirect bilirubin (mg/dL)	1.33	0.8	1.97	6.77	-	0.42
AST (U/L)	65	95	277	236	168	48
ALT (U/L)	18	29	41	64	101	50
Alkaline phosphatase (U/L)	253	142	569	217	146	132
GGT (U/L)	245	413	322	702	607	154
TG (mg/dL)	-	-	803	411	225	155
Cholesterol (mg/dL)	-	-	324	289	296	194