Carotenoderma--a review of the current literature.

Abstract

Carotenoderma is a phenomenon characterized by orange pigmentation of the skin, resulting from carotene deposition mainly in the stratum corneum. It is associated with a high blood β-carotene value, and is regarded as a significant physical finding, but a harmless condition. Various etiologies are responsible for this phenomenon: high β-carotene intake, including that from vegetables, fruits, eggs and nutrient supplements; several metabolic states such as hypothyroidism, diabetes mellitus, pregnancy and anorexia nervosa; and familial carotenemia. The scope of this article is to present an updated review of carotenemia, its causes and its metabolism. Von Noorden described carotenemia in 1907.1 While investigating diabetes mellitus and its treatment, he noticed a carroty pigmentation in patients whose treatment involved special diets. A year later, Moro noted the condition in infants.2 In 1919, Hess and Meyers3 gave the term “carotenemia” to the condition consisting of increased carotene blood levels and yellow skin pigmentation. During the last century, epidemics of carotenemia have occurred, usually as a result of rich carotene diets. Food rationing during the Second World War forced the public to consume large quantities of carrots and swedes, which were nutritious and inexpensive. It was than found to be transferred to infants by breast-feeding.4 During the 1970s carotenoderma was observed in many Japanese infants and in children who consumed high amounts of tangerines or tangerine juice.5 Carotenemia is endemic in West Africa, as a result of frequent use of red palm oil, which is rich in carotenoids.6 The stratum corneum has a high lipid content which has an affinity for carotene, and so the carotene pigment is concentrated in the stratum corneum. On direct immunofluorescence it can autofluorescence in a pemphigus-like intercellular pattern, and thus be mistaken for pemphigus vulgaris.7 Carotenoids are found in a complex with proteins or in crystalline carotenoid complexes in vegetables and fruits.8β-carotene is not synthesized in the human body. Its source is food. It gives some fruits and vegetables their orange-yellow hue. In green vegetables the yellow pigment is masked by chlorophyll. About one-third of ingested β-carotene is absorbed.9 Absorbance is affected by the fiber content of food, and by food processing. Mashing, cooking and pureeing of fruits and vegetables cause rupture of cells and enhance the availability of β-carotene.9 In the presence of bile acids it becomes incorporated into mixed micelles, from which it is absorbed by passive diffusion into the enterocytes in the small intestine mucosa. In the enterocyte, most of the β-carotene is converted into retinal by the enzyme 15-15′-dioxygenase.10 Retinal reductase converts retinal to retinol11 (vitamin A) which is than complexed with long-chain fatty acids to be transported to the liver as chylomicrons.12 It is not clear how much intact β-carotene is absorbed. In the literature, estimates vary between 10 and 80%. The amount of intact β-carotene absorbed is affected by β-carotene intake and vitamin A stores. β-carotene that is directly absorbed, however, is transported to the liver via the portal circulation.13, 14 Although β-carotene is fat-soluble, eating it with as little as 3–5 g fat per meal can still increase its plasma levels.15 Absorption is also enhanced by pancreatic lipase, bile acids and probably by the thyroid hormone. Disturbance of fat absorption, infection and intestinal disease may all impair β-carotene absorption.14 High gastric pH levels interfere with absorption, probably by inhibiting passive diffusion into the enterocyte.16 Certain constituents of food, such as sulfides and acids,17 can destroy β-carotene. Pectin interrupts micelle formation and hence interferes with β-carotene absorption.18 Lutein and canthaxantin inhibit the conversion of β-carotene to retinal.13 β-carotene is stored in the liver and adipose tissues, and can also be found in high concentrations in the testes and in the adrenals. In normal subjects there is a linear relationship between serum β-lipoprotein and serum β-carotene levels.19 Excretion of β-carotene occurs mainly through the colon and epidermis through sebaceous glands. A small amount is excreted through the urine.20 A number of mechanisms are presumed to be responsible for carotenemia (Table 1). The most common is excessive dietary consumption of β-carotene. Carotenemia may be observed 4–7 weeks after initiation of a diet rich in carotenoids.5 Foods with high β-carotene contents are listed in Table 2. In these cases of carotenemia, serum levels of vitamin A may be normal or elevated, although never high enough to cause hypervitaminosis A. The linear relationship between β-lipoprotein and β-carotene may cause carotenemia in hyperlipidemic-associated disorders, such as diabetes mellitus, nephrotic syndrome and hypothyroidism. In hypothyroidism, impaired conversion of β-carotene to vitamin A in addition to hyperlipidemia contributes to the development of carotenemia.21 In diabetes mellitus, in addition to hyperlipidemia, the conversion of β-carotene into vitamin A in the liver may be impaired22 and thus an elevation of serum β-carotene levels may occur. Carotenemia in anorexia nervosa is chiefly related to a diet that is rich in β-carotene sources, mainly carrots and other low-energy yellow vegetables. Some consider the cause to be an acquired defect in the metabolism or utilization of vitamin A. It may also be related to abnormalities of lipid metabolism, such as the decreased catabolism of β-lipoprotein23 and hypothyroidism which are observed in this disease.24 Liver disease may cause carotenemia due to impaired conversion of β-carotene into vitamin A. In these cases carotenenoderma may be masked by jaundice.14 Kidney diseases, particularly nephrotic syndrome and chronic glomerulonephritis, may be associated with elevated serum levels of β-carotene. In nephrotic syndrome it is attributed to hyperlipidemia. An interesting finding is the absence of carotenoderma in patients who suffer from renal disease in spite of elevated serum β-carotene.14 Metabolic (idiopathic) carotenemia is thought to result from a relative or absolute deficiency of 15-15′-dioxygenase, which leads to accumulation of β-carotene and to low to normal vitamin A levels. This enzyme defect may be familial.19 High β-carotene levels in Alzheimer's disease are also suggested to arise from an abnormality in the conversion of β-carotene to vitamin A.25 Hypopituitarism and male castrates are conditions that have also been reported to be associated with carotenemia.9 There is an anecdotal report of carotenemia and Simmond's disease.14 The yellow pigmentation of β-carotene appears when its concentrations in the serum exceed 250 µg/dL. It is deposited mainly in the stratum corneum, in sweat and in sebum, and hence pigmentation is noted in areas where sweating is marked, such as the nasolabial folds, palms and soles. It can extend to the entire body. The sclerae are not affected and this helps to distinguish carotenoderma from jaundice. Another typical sign of carotenoderma is its enhanced appearance under artificial light.26 Jaundice is caused by hyperbilirubinemia manifested by a yellow pigmentation that is most prominent in the sclerae, and is usually diffuse. Typical findings are constitutional symptoms, which only seldom appear in carotenemia. Lycopen is a physiologically inert isomer of carotenoid that is not converted into vitamin A. It is found in tomatoes, rose hips and bittersweet berries. Its metabolism is similar to that of β-carotene. Skin pigmentation in lycopenemia has a deeper tinge than that in carotenemia and occurs on the palms and soles but also on the palate. The sclerae are also unaffected in this condition. It can be differentiated from carotenemia on the basis of spectrophotometeria.27 Riboflavinemia has also been reported to cause yellow skin.28 Some drugs and chemicals may cause yellow pigmentation of the skin – e.g. quinacrine, mepacrine, saffron, santonin, fluorescein, dinitrophenol, canthaxanthine, tetryl and picric acids and acriflavine.10 There is a debate as to whether carotenemia is a harmless condition. Some authors report that long-standing carotenemia has been associated with weakness, weight loss, hepatomegaly, hypotension, neutropenia29 and amenorrhea.30 Others report no abnormality with high serum β-carotene.31 There is, however, an agreement that carotenemia is not associated with vitamin A toxicity. Dietary carotenemia is easily manageable within weeks to months on a low β-carotene diet.10 Carotenemia associated with hyper-β-lipoproteinemia is reversible by treatment of the underlying cause or with a lipid-lowering diet. There is not yet a satisfactory treatment for metabolic carotenemia.12 Carotenoderma is a well-known physical finding which is considered to be harmless. The importance of recognizing this condition is chiefly in calming the patient and in avoidance of unnecessary examinations, which can be unpleasant to the patient and may have economic implications. Recognizing the different etiologies is important, although only rarely is carotenoderma the first sign of an underlying disease. Usually, the primary physician can reveal the correct etiology by performing simple blood tests and taking a short history and thus help to resolve the condition. The properties of β-carotene as an antioxidant and free radical scavenger, and the results of some epidemiological studies that have shown an inverse relation between its intake and various cancers and cardiovascular diseases, have led to a vast amount of research on β-carotene and its derivatives. Nevertheless, a few large studies, such as The Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study32 and The Beta-Carotene and Retinol Efficacy Trial (CARET),33 found no benefit and possible adverse reactions when it was given in pharmacological doses. Apart from anecdotal complications of carotenemia, we did not find any evidence of long-term complications or benefits resulting from carotenemia. It may be worthwhile to conduct a long-term prospective study in patients with carotenemia for the prevalence of malignancy and cardiovascular diseases and thus to determine whether this condition is truly a harmless one when its sole cause is high β-carotene intake.