Apoprotein, lipoprotein and lipid parameters of 36 normolipidemic subjects (23 males, mean age 22.7 ± 7.6 years; 13 females, mean age 26.2 ± 9.8 years) receiving oral isotretinoin (mean daily dose 0.73 ± 0.26 mg/kg body weight) for nodulocystic acne (n = 18), severe acne papulopustulosa (n = 15), gram-negative folliculitis (n = 2) and papulopustular rosacea (n = l) were monitored before and during isotretinoin therapy at biweekly intervals over a period of 14.6 ± 5.6 weeks. Pretreatment values of mean plasma triglycerides increased significantly (p < 0.001) from 81.8 ± 31.9 mg/dl to 112.4 ± 38.7 mg/dl (47.4%) during isotretinoin treatment. With respect to the mean percent increase of plasma triglycerides from pretreatment levels, patients were classified as nonresponders ( < 10% triglyceride increase), responders ( > 10% < 50% triglyceride increase) and hyperresponders ( > 50% triglyceride increase), revealing a distribution of 25.0, 36.1 and 38.9%, respectively. Isotretinoin treatment had no influence on the isoelectric focusing pattern of apoprotein E isoforms and C apoproteins. In particular, apoprotein C-II, the cofactor of lipoprotein lipase, was not affected. No correlation between apoprotein E phenotypes (2/3, 3/3, 3/4) and the mean plasma triglyceride increase could be demonstrated. Apoprotein B-48, a marker of chylomicrons and atherogenic chylomicron remnants, could not be detected by SDS-PAGE. On the other hand in 21.0% of patients with preexisting mean lipoprotein Lp(a) levels of 18.1 ± 12.9 mg/dl a moderate increase of atherogenic Lp(a) to mean levels of 37.0 ± 22.0 mg/dl was observed. Pretreatment values of very-low-density lipoprotein (VLDL) apoprotein (apo) B (7.5 ± 2.0 mg/dl), low-density lipoprotein apo B (67.3 ± 17.5 mg/dl) and total plasma apo B (76.6 ± 19.0 mg/dl) increased significantly to levels of 10.3 ± 2.4 mg/dl (p < 0.001), 75.7 ± 15.8 mg/dl (p < 0.10) and 85.9 ± 17.7 mg/dl (p < 0.05), respectively. As lipoprotein lipase and hepatic lipase activities have been shown to be unaffected by isotretinoin treatment, our data support the hypothesis that isotretinoin induces hepatic oversecretion of VLDL, a condition resembling type IV hyperlipidemia in diabetics, familial hypertriglyceridemia or familial combined hyperlipidemia.

Inverse alterations in plasma levels of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are recognized side effects of systemic treatment with the synthetic retinoids isotretinoin and etretinate. The mass quotients of total plasma cholesterol and high-density lipoprotein cholesterol as well as low-density lipoprotein cholesterol and high-density lipoprotein cholesterol are well-established predictive risk factors of cardiovascular disease. We evaluated and compared these lipoprotein cholesterol ratios of 80 patients treated systemically with isotretinoin (13-cis-retinoic acid) and 81 patients treated with etretinate (aromatic retinoid). Lipoprotein cholesterol data were derived from 5 lipid studies on isotretinoin, including our own results, and 4 published lipid studies on etretinate. For all isotretinoin and etretinate lipid studies, significant increases in the mean plasma levels of total cholesterol and low-density lipoprotein cholesterol and significant decreases in the mean concentration of high-density lipoprotein cholesterol were demonstrated. In comparison with etretinate, oral isotretinoin gave rise to a nearly twofold percent increase of both lipoprotein cholesterol ratios from pretreatment levels. Furthermore, for isotretinoin, an approximately linear dose-related increase of the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol could be observed. If sustained over long periods, the mean differential rise of the ratio of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol of 0.92 +/- 0.51 for isotretinoin and 0.56 +/- 0.10 for etretinate indicates an increased risk of cardiovascular disease for both retinoids. Etretinate could be identified as the less harmful retinoid for prolonged oral therapy.

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