Retinoids.

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In: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury, 2012–2018

Abstract

Retinoids are both natural and synthetic derivatives of vitamin A, several of which have been developed for medical uses, largely to replace vitamin A which in high, therapeutic doses is associated with considerable toxicity. Retinoids have multiple actions and play important roles in regulation of cell proliferation and differentiation, vision, bone growth, tumor suppression and immunity. The effects of retinoids are thought to be mediated by their binding to and activation of the retinoic acid and retinoid X receptors which regulate gene expression, important in normal growth and differentiation. Vitamin A in doses that have medical effects was found to be toxic, particularly when given long term. Modification of the vitamin A structure led to retinoid molecules that had many of its beneficial, but fewer of its adverse effects. Oral retinoids in use in the United States include acitretin for psoriasis and isotretinoin for severe nodular acne. Tretinoin is used topically and several other retinoids have been developed for therapy of uncommon forms of cancer (alitretinoin, bexarotene). The commonly used retinoids have many of the side effects of vitamin A including dry skin, cheilosis and nosebleeds and hair loss, but are not stored in the liver and do not cause the typical form of chronic liver disease associated with excessive vitamin A intake. Both acitretin and isotretinoin are teratogenic and embryotoxic and are contraindicated in women who are or intend to become pregnant. Retinoids have been implicated in causing mild-to-moderate elevations in routine liver tests, but these elevations are usually asymptomatic and transient, resolving spontaneously even with continued therapy. Marked elevations in serum aminotransferase levels during retinoid therapy are uncommon, and dose adjustment or drug discontinuation are rarely required for liver test abnormalities. Nevertheless, laboratory monitoring is recommended with routine liver tests at baseline and one month later, and testing thereafter only if abnormalities were found or symptoms arise. Several retinoids (acitretin, etretinate, retinal acetate) have been associated with a clinically apparent acute liver injury which typically arises during the first 3 months of therapy, has many features of hypersensitivity and can be severe and even fatal. Interestingly, isotretinoin often causes mild serum aminotransferase elevations and is commonly listed as having frequent adverse effects on the liver, but it has not been convincingly linked to instances of severe clinically apparent, acute liver injury with jaundice. Two retinoids used in dermatology, acitretin and isotretinoin, are discussed in this record and their combined references of retinoids are provided at the end of this introductory section. The hepatotoxicity of vitamin A is discussed separately in another record.

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