Drug-Induced Acute Autoimmune Hepatitis During Combination Therapy With Atorvastatin and Ezetimibe

By van Heyningen, Charles

Abstract

A case is presented of a patient who developed acute hepatitis during cholesterol-lowering treatment with atorvastatin and ezetimibe. Further investigations reveal a probable drug-induced autoimmune hepatitis, and ezetimibe is considered to be the most likely causal agent. This case is the first report of an autoimmune hepatitis associated with ezetimibe therapy.

Ann din Biochem 2005; 42: 402-404

Introduction

The statins have been used for many years for lowering LDL- cholesterol in the prevention of cardiovascular disease. Side- effects include altered liver function tests and (rarely) hepatitis. In addition, atorvastatin has been reported to induce a lupus-like syndrome and to trigger an autoimmune hepatitis.1

Ezetimibe inhibits the intestinal absorption of cholesterol and has recently been licensed as a therapy for hypercholesterolaemia, in combination with a statin or alone. Several studies on the efficacy and safety of ezetimibe co-administered with a statin have described small numbers of patients with elevated serum transaminase activity at or above three times the upper limit of the reference range.3″5 All such cases of raised hepatic enzyme activity have been asymptomatic and reversible. To date, there are no published cases of patients who have developed clinical signs of liver disease, including hepatitis and jaundice, while taking this combination.

We report the case of a woman who developed a drug-induced lupus- like autoimmune hepatitis while taking a combination of atorvastatin and ezetimibe, and discuss the possible mechanisms.

Case report

A 50-year-old woman was admitted to hospital after complaining of heartburn, nausea, vomiting and epigastric pain. She had a past medical history of thyroid disease (chronic Iymphocytic thyroiditis with multinodular goitre), osteoarthritis, ischaemic heart disease and hiatus hernia, and drank, on average, a bottle of wine (6 units of alcohol) per week. The patient had been taking 80 mg atorvastatin daily for 16 months, with no noted adverse effects and normal liver function tests without achieving target lipid levels. Ezetimibe 10 mg daily was added in 12 weeks prior to hospital admission. Other long-term drug therapies were frusemide, nitrate, diltiazem, diclofenac, paracetamol, atenolol, ibuprofen, clopidogrel, thyroxine and lactulose. She was not using over-the-counter medication or herbal remedies.

On examination, she was found to have epigastric tenderness. No abnormalities were found by electrocardiography, radiology of the chest and abdomen, upper gastrointestinal endoscopy or by ultrasound of the hepatobiliary system. Some fatty infiltration of the pancreas was seen on ultrasound imaging.

Serum liver function tests are shown in Table 1 and immunology test results in Table 2. Viral serology testing showed no evidence of a recent viral infection with hepatitis A, B or C, cytomegalovirus, or Epstein-Barr virus. Treatment with atorvastatin and ezetimibe was stopped three days after admission, and a liver biopsy was taken 10 days later.

The liver biopsy showed features of hepatocyte degeneration and apoptosis and infiltration by lymphocytes, eosinophils, plasma cells and neutrophil polymorphs. These findings are consistent with a druginduced hepatitis.

Liver function test results returned to normal levels over the subsequent eight weeks. She was started on rosuvastatin a month later and did not develop any further changes in liver enzyme activity or other sideeffects.

Table 1 Liver function tests

Discussion

This case report describes a patient with previous findings of autoimmune disease involving the thyroid. She was on long-term medication with numerous drugs, including atorvastatin. Three months after starting on ezetimibe, a new cholesterol absorption inhibitor, she developed acute hepatitis requiring admission to hospital.

The biochemical, immunological and histological findings following onset of this illness suggest a druginduced lupus-like autoimmune hepatitis. The time course suggests that ezetimibe alone or due to interaction with other drugs may have acted as a trigger for an autoimmune response acting on the liver. The contributory role of other drug exposures has to be considered in the aetiology.6 Based on temporal relationships and previous literature reports, ezetimibe, alone or in combination with atorvastatin, is considered to be the most likely causal agent. An autoimmune reaction to other drugs cannot be excluded, but is less likely, as the non-lipid- regulating therapy was continued without adverse events after the acute illness.

Ezetimibe is metabolized in the small intestine and liver via glucuronide conjugation.7 Both ezetimibe and its glucuronide arc slowly eliminated from plasma, with evidence of significant enterohepatic recycling.7 Ezetimibe is reported to inhibit cholesterol absorption from the gut8 by acting on a sterol transporter, Niemann-Pick Cl-like-1 protein. As the human liver expresses this transporter protein, ezetimibe may also act on the liver.9 Hence, ezetimibe or its glucuronide may be toxic to hepatocytes in a genetically predisposed patient when co- administered with or without other drug therapies.

Drug-induced hepatitis is often associated with antibodies directed against hepatic drug metabolizing enzymes.10 Ezetimibe induction of hepatic UDPglucuronosyltransferases may have stimulated autoantibody production against these target proteins.

In conclusion, this is the first known case report suggesting that ezetimibe may induce hepatitis, although the role of atorvastatin cannot be ruled out conclusively. The mechanism of injury is unknown, but may be a drug-induced autoimmune response or a direct toxic effect on the liver.

Acknowledgements

This case has been reported to the Committee on Safety of Medicines using the yellow card scheme. The CSM has received two other reports of hepatitis associated with the use of ezetimibe.

Dr P Johns (immunologist), Dr MT Haqqani (histopathologist), Mrs J Williams and Ms P Buffery (pharmacists) and Prof N Krasner (gastroenterologist) are thanked for their contributions to this report.

References

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8 Altmann SW, Davis HR, Zhu L, et al. Niemann-pick C-Like 1 protein is critical for intestinal cholesterol absorption. Science 2004; 303: 1201-4

9 Klett EL, Patel SB. Will the real cholesterol transporter please stand up. Science 2004; 303: 1149-50

10 Obermayer-Straub P, Strassburg CP, Manns MP. Target proteins in human autoimmunity: cytochromes P450 and UDP- glucuronosyltransferases. Can J Gastroenterol 2000; 14: 429-39

Accepted for publication 20 June 2005

Address

Clinical Laboratories, University Hospital Aintree, Lower Lane, Liverpool L9 7AL, UK

Correspondence

Charles van Heyningen

E-mail: charles.vanheyningen@aht. nwest.nhs.uk

Copyright Royal Society of Medicine Press Ltd. Sep 2005