High Risk for Hyperlipidemia and the Metabolic Syndrome after an Episode of Hypertriglyceridemia during 13-cis Retinoic Acid Therapy for Acne: A Pharmacogenetic Study

16 April 2002 | Volume 136 Issue 8 | Pages 582-589

Background: Administration of 13-cis retinoic acid (isotretinoin) for acne is occasionally accompanied by hyperlipidemia. It is not known why some persons develop this side effect.

Objective: To determine whether isotretinoin triggers a familial susceptibility to hyperlipidemia and the metabolic syndrome.

Design: Cross-sectional comparison.

Setting: University hospital in Lausanne, Switzerland.

Participants: 102 persons in whom triglyceride levels increased at least 1.0 mmol/L ( 89 mg/dL) (hyperresponders) and 100 persons in whom triglyceride levels changed 0.1 mmol/L ( 9 mg/dL) or less (nonresponders) during isotretinoin therapy for acne. Parents of 71 hyperresponders and 60 nonresponders were also evaluated.

Measurements: Waist-to-hip ratio; fasting glucose, insulin, and lipid levels; and apoE genotype.

Results: Hyperresponders and nonresponders had similar pretreatment body weight and plasma lipid levels. When reevaluated approximately 4 years after completion of isotretinoin therapy, hyperresponders were more likely to have hypertriglyceridemia (triglyceride level > 2.0 mmol/L [>177 mg/dL]; odds ratio [OR], 4.8 [95% CI, 1.6 to 13.8]), hypercholesterolemia (cholesterol level > 6.5 mmol/L [>252 mg/dL]; OR, 9.1 [CI, 1.9 to 43]), truncal obesity (waist-to-hip ratio > 0.90 [OR, 11.0 (CI, 2.0 to 59)], and hyperinsulinemia (insulin–glucose ratio > 7.2; OR, 3.0 [CI, 1.6 to 5.7]). In addition, more hyperresponders had at least one parent with hypertriglyceridemia (OR, 2.6 [CI, 1.2 to 5.7]) or a ratio of total to high-density lipoprotein cholesterol that exceeded 4.0 (OR, 3.5 [CI, 1.5 to 8.0]). Lipid response to isotretinoin was closely associated with the apoE gene.

Conclusion: Persons who develop hypertriglyceridemia during isotretinoin therapy for acne, as well as their parents, are at increased risk for future hyperlipidemia and the metabolic syndrome.

Editors' Notes Context Isotretinoin (Accutane, Roche, Basel, Switzerland) is the treatment of choice for severe acne that is resistant to topical treatment. Approximately 20% of patients develop marked elevations in triglyceride levels. The mechanism responsible for isotretinoin-induced hyperlipidemia is unknown. Contribution This study showed that isotretinoin-induced hypertriglyceridemia identifies patients at high risk for chronic hyperlipidemia, truncal obesity, and hyperinsulinemia. The apoE gene and 2 and 4 alleles were more common in patients with isotretinoin-induced hypertriglyceridemia than in patients who had no lipid abnormalities while taking the drug. Implications People with isotretinoin-induced hypertriglyceridemia have increased risks for chronic hyperlipidemia and the metabolic syndrome that are possibly related to the apoE gene. –The Editors

 

Author and Article Information

From CHUV University Hospital, University Medical Policlinic, and University of Lausanne, Lausanne; and Kantonsspital, St-Gallen, Switzerland.

Acknowledgments: The authors thank the study participants and dermatologists Drs. P. Morier, B. Vion, and A. Zurn for identifying patients with acne. They also thank Letizia Accordino, Yacine Ali-Yahia, Einard Castillo, Gilda Crespell, Marianne Darioli, and Monique Devaud for technical help; Juan Ruiz for providing the methods to examine the PPAR- Pro12Ala polymorphism; and Françoise Grange, Jacques-Antoine Haefliger, Claude Pichard, Philippe Sudre, Gérard Waeber, and Walter Wahli for helpful discussions.

Grant Support: By Swiss National Foundation for Scientific Research, (32-44471.95 [Dr. Mooser] and 31-5113.98 [Dr. Desvergne]); the Octave Botnar and Placide Nicod Foundation; the Michel Tossizza Foundation; and Multidisciplinary Priority Project, Lausanne University.

Requests for Single Reprints: Vincent Mooser, MD, Department of Medicine, CHUV University Hospital, CH-1011 Lausanne, Switzerland; e-mail, vincent.mooser{at}chuv.hospvd.ch.

Current Author Addresses: Drs. Rodondi, Lenain, Medinger, Nicod, and Mooser: Department of Internal Medicine, CHUV University Hospital, CH-1011 Lausanne, Switzerland.

Drs. Darioli and Perdrix: University Medical Policlinic, Rue César-Roux 9, CH-1005 Lausanne, Switzerland.

Dr. Ramelet: Place Benjamin-Constant 2, CH-1003 Lausanne, Switzerland.

Dr. Hohl: Division of Dermatology, Beaumont 13, CHUV University Hospital, CH-1011 Lausanne, Switzerland.

Dr. Riesen: Clinical Chemistry Laboratory, Kantonsspital, CH-9007 St-Gallen, Switzerland.

Drs. Walther, Medinger, and Desvergne: Institute of Animal Biology, University of Lausanne/Dorigny, CH-1015 Lausanne, Switzerland.

Dr. Wietlisbach: Institute for Social and Preventive Medicine, University of Lausanne, Rue du Bugnon 13, CH-1011 Lausanne, Switzerland.

Author Contributions: Conception and design: N. Rodondi, R. Darioli, A-A. Ramelet, D. Hohl, B. Desvergne, V. Mooser.

Analysis and interpretation of the data: N. Rodondi, R. Darioli, V. Wietlisbach, B. Desvergne, V. Mooser.

Drafting of the article: N. Rodondi, V. Mooser.

Critical revision of the article for important intellectual content: N. Rodondi, R. Darioli, V. Wietlisbach, P. Nicod, B. Desvergne, V. Mooser.

Final approval of the article: N. Rodondi, R. Darioli, A-A. Ramelet, D. Hohl, V. Lenain, J. Perdrix, V. Wietlisbach, W.F. Riesen, T. Walther, L. Medinger, P. Nicod, B. Desvergne, V. Mooser.

Provision of study material or patients: N. Rodondi, R. Darioli, A-A. Ramelet, D. Hohl, V. Mooser.

Statistical expertise: N. Rodondi, R. Darioli, J. Perdrix, V. Wietlisbach, V. Mooser.

Obtaining of funding: R. Darioli, A-A. Ramelet, D. Hohl, P. Nicod, B. Desvergne, V. Mooser.

Administrative, technical, or logistic support: N. Rodondi, R. Darioli, A-A. Ramelet, D. Hohl, V. Lenain, W.F. Riesen, T. Walther, L. Medinger, P. Nicod, B. Desvergne, V. Mooser.

Collection and assembly of data: N. Rodondi, V. Mooser.