Nutritional Factors and Skin Diseases

Nutritional Factors and Skin Diseases WILLARD A. KREHL Department of Internal Medicine, Marquelte University School of Medicine, Milwaukee, Wisconsin I. Introduction. 11. Proteins and

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V. Vitamins-Facts and Fancy.. ... VI. Fat-soluble Vitamins 1. Vitamin A , . ...................

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3. Vitamin Bs (Pyridoxine, Pyri 4. Pantothenic Acid, Inositol, p-Aminohenzoic Acid, and Biotin

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X. Minerals and Trace Elements.. . ............................. 133 ............................. 134 1. Magnesium . . . . . . . . . . . . . . . . . . . 2. Calcium.. . . . ............................. . . . . . . . . . 134 4. Copper..

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1. Allergy.. ........................ 2. Xanthoma..

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I. INTRODUCTION From primitive times, man h a related the gloss and sheen of the hair coat and skin of his pets and herds with good dietary practices and good health. In experimental nutrition studies, a change in the hair coat and skin of animals has often been the first and most outstanding feature of a dietary deficiency disease. Unfortunately, these skin and hair changes are often nonspecific, and rarely permit the diagnosis of an isolated nutritional 121

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deficiency. Because these skin changes have appeared with poor diet, dermatologists have been much influenced by the use of special diets, vitamins, and minerals in nearly every conceivable dosage level and combination in an attempt to manage and treat skin diseases. Since accurate diagnosis is difficult under such conditions and since many skin diseases are of unknown etiology, much of this form of therapy has been doomed to failure and has tended to place the role of nutrition in the therapy of skin disease in disrepute. There is a place for nutrition in dermatology as in medicine generally; it should be kept, however, in proper perspective. Although dermatoses related to dietary deficiency states can appear 011 any part of the body, they tend to be located over areas of irritation or excessive stimulation. Lesions are most apt to appear on the backs of the hands, on the front and backs of the wrists, on the elbows, over the face, around the neck, under the breasts, over the knees and feet, and in the perianal region. These lesions are often bilaterally symmetrical and tend to be separated from healthier-appearing skin by a sharp line of demarcation. They are generally accompanied by burning, itching, and pain (Spies, 19554. The skin area in the average adult is about 1.75 square meters of a tough, yet resilient, douhle-layered structure which is the principle line of defense against the entrance of foreign substances and protects against almost evcry conceivable physical arid chemical stress. When damagcd, it has remarkable ability to repair it,self, thus reflecting its dynamic metabolic activity. Through its sweat glands and blood vessels, the skin provides the principal means by which the body heat is regulated, and through its nerve endings it permits sensation of contact with the external environment, perceiving heat, cold, pain, and other stimuli. The skin also reflects the emotions, such a~ embarrassment, fear, anger, and anxiety, and, unfortunately, a person’s age as well. We are even individualized by characteristic skin markings-our fingerprints and footprints. A brief review of the structure and physiology of the skin may be helpful in understanding the changes that take place in skin diseases (Pillsbury et al., 1956; Urback and Lewinn, 1946). The skin is composed of three principal layers: (1) epidermis, (2) corium (dermis or true skin), and (3) the subcutaneous tissue. The epidermis is a thin layer averaging about 0.2 mm. in thickness, in which the greatest metabolic activity of the skin is located. From the outside inward, the epidermis is composed of cell layers: (1) stratum corneum, (2) stratum granulosum, (3) prickle cell layer, and (4)the basal cell layer. Melanocyte cells, responsible for the production of skin pigment, are found in the basal cell layer. The epidermis overlies the corium or dermis in a wavelike pattern. The principal metabolic activity of the epidermis is the

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production of the protein keratin, which is the chief component of the layer stratum corneum. Keratin, by its toughness, elasticity, and resistance to chemical change, provides great protection. It is structurally integrated into the flat, shrunken, nonnucleated dead cells of the stratum corneum. The process of keratinization is, therefore, concerned with the production of keratin and the gradual elaboration and replacement of the stratum corneum from the basal cell layer of the epidermis. This response is continuous and may vary with the stimuli on the epidermis. There are two kinds of skin appendages derived from the epidermis: (1) glandular, i.e. apocrine and eccrine sweat glands, and sebaceous glands; and (2) keratinized structures, i.e. the hair follicles and hair and the nails. The corium or secondary protective layer supports the vascular bed and peripheral nerves of the skin and the epidermal appendages. The corium is also a large potential storehouse for water, blood, and electrolytes. This is well exemplified in the individual with edema. The subcutaneous tissue provides further support and is an excellent heat insulator, a good shock absorber, and a storehouse of calories in the form of fat.

11. PROTEINS AND AMINOACIDS The proteins of plasma, especially albumin, exert an effective osmotic influence in preventing the loss of water from the vascular system. Any clinical circumstance in which the plasma level of albumin falls below 2.5 gm. per 100 ml. often leads to the development of edema. Edema due to protein deficiency is frequently a by-product of war or famine, and terms like “war edema” and “hunger edema” have appeared. As protein deficiency develops, a decreased ability to make antibodies (Cannon et al., 1943) may occur. Long exposure to experimental diets low in protein results in extensive skin changes. These changes are characterized by dryness, scaliness, inelasticity, and a gray, pallid appearance suggestive of old age. Also noticed, is a blotchy, dirty, brownish pigmentation which may appear anywhere on the body, but most often on the face (Keys, 1948). While it is attractive to relate these skin alterations noted in protein deficiency to specific essential m n o acid deficiencies, this has been most difficult to establish. Certain metabolic blocks involving amino acid metabolism have been reported. In phenylpyruvic oligophrenia, marked skin changes occur characterized by eczematous eruptions and evidence of inadequate melanin formation (Jervis, 1937). In this condition, a genetically controlled metabolic block due to a nearly complete absence of phenylalanine hydroxylase limits the conversion of the amino acid phenyldanine to tyrosine, and is accompanied by an increased urinary excretion of phenyl-

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pyruvic acid (Moldave and Meister, 1957). Abnormal amounts of indole derivatives are also excreted in phenylketonuria (Armstrong et al., 1955). Since keratin, the chief protein of skin and hair, has substantial amounts of sulfur-containing amino acids, it is not surprising that methionine- and cystine-deficient rats show a retardation in hair growth. In this connection it has been reported that vanadium causes a toxicity in rats in which there is early evidence of poor hair growth, comparable to that noted in cystine and methionine deficiency. It has been suggested that vanadium may block the conversion of methionine to cystine (Mountain et al., 1953). Alkaptonuria is a disease in which a metabolic block interferes with the conversion of homogentisic acid to acetoacetic acid. Homogentisic acid in the urine turns to a black pigment on oxidation. In ochronosis a similar black pigment is deposited in the corium of the skin. If tyrosine or phenylalanine is fed to vitamin C-deficient infants or guinea pigs, alkaptonuria can be produced and then corrected by giving either vitamin C or folic acid (Levine et al., 1941;Morris et al., 1950;Sealock and Silberstein, 1940). Amino acids, especially tyrosine and phenylalanine, are important precursors of the skin pigment melanin. Melanin is derived from tyrosine by way of 3,4-dihydroxyphenylalanine (dopa) and its oxidation product, 3,4dioxyphenylalanine (dopaquinone), which is then converted to further melanin precursors. Lerner and Fitzpatrick (1950)postulated that a tyrosine deficiency may result in deficient melanin production. An individual unable to convert phenylalanine to tyrosine (absence of phenylalanine hydroxylase) would be dependent on dietary tyrosine for melanin formation; such is the cam in phenylpyruvic oligophrenia. The pituitary melanophore-stimulating hormone (MSH) exerts a powerful effect on melanin formation. Lerner et al. (1953)have shown that injections of huge amounts of purified MSH into man produced generalized melanosis and stimulated the appearance of flat, pigmented nevi. Widespread throughout the technically underdeveloped areas of the world, and especially in children between the ages of 1 and 4,is a protein deficiency manifested in the extreme by the disease known as kwashiorkor. This disease is characterized by faulty growth, marked liver enlargement with fatty infiltration, gastrointestinal disturbances including diarrhea, and extensive skin changes with hypopigmentahion and dryness of the hair and skin (Waterlow, 1955). That the United States is not immune from this disease is indicated by a report of four cases of kwashiorkor from Louisiana (Henington et al., 1958). Williams (1933)in the original description of kwashiorkor described the associated dermatosis and considered it non-pellagra in origin. The Food and Agriculture Organization (F.A.O.) report of kwashiorkor in Africa (Brock, 1952) concludes that “dermatosis is only an associated condition

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which probably may have several different origins and which is not an integral part of the syndrome.” The commonest form is described in the following terms: “This eruption occurs as sharply defined black varnished patches on the areas exposed to irritation (napkin area, buttocks, back and so forth) but none appears on the areas exposed to sunlight (the hands and face) on which classical pellagra should appear. These black islands rapidly enlarge, tend to coalesce and then peel to disclose a white or pink area underneath. They undergo spontaneous peeling quite independently of any specific treatment, but this usually occurs only if at the same time the case is improving.” A thickened “elephant-like skin” may be seen on the exterior surface of the knee. Another interesting feature associated with kwashiorkor is the so-called “flag sign.” If the hair is held up, one may see near the base a white band above and below which the hair is of normal color. This area of depigmentation represents the period during which the individual had the “fullblown” disease. The areas of normal hair color above and below the white band represent the periods before the onset of the disease and after the cure. Dyspigmentation may also affect the tips of the hair, with the development of a reddish hue. This in part may reflect the influence of exposure to sun and wind. Patchy or diffuse skin dyspigmentation that may be diflicult to differentiate from genetic hypopigmentation o c c w as a sign of nutritional deficiency in the kwashiorkor syndrome. Therapy for this disease is an adequate amount of protein, particularly of animal origin, although mixtures of selected vegetable proteins prove quite satisfactory. Mixtures of essential amino acids may also be used in therapy, indicating the specific role of protein in the etiology of kwashiorkor (Brock et al., 1956). The possibility of supplementing vegetable proteins with essential amino acids to improve their biological value may ultimately be practical, as the cost of manufacturing amino acids decreases.

111. LIPIDS Several types of skin lesions, eczematous in character, have been associated with the long-term consumption of diets low in fat (Hansen and Burr, 1946). I t has also been noted that individuals who have excessive fat losses associated with idiopathic steatorrhea frequently have erythematosus eczematous lesions. Difficulties arise, however, in attempting to correlate these skin lesions with any specific biochemical abnormality. For example, while there is no significant difference between the level of total blood lipids in eczematous and noneczematous infants, it has been shown that the amount of unsaturated fatty acids is considerably lower in eczematous infants, particularly

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the levels of arachidonic and linoleic acids (Hansen, 1937). This observation has encouraged the use of fats and oils rich in these two substances in the treatment of eczema in infants-unfortunately, not with uniformly good results. Studies on the disease phrynoderma, or hyperkeratosis follicularis, have shown that the increased incidence of this disease is correlated with a lowered intake of essential fatty acids. Although vitamin A has often been proposed in the treatment of this disease, it has been effective in relatively few cases. However, recent studies in India, where this disease is common, have shown that the administration of raw linseed oil or linoleic acid produced marked clinical improvement in 2 4 weeks and cured many patients in 4-24 weeks (Rajagopal et al., 1952). Even better results were obtained when pyridoxine was combined with the essential fatty acid tkerapy of phrynoderma (Bagehi el al., 1959).

IV. OBESITYAND SKINDISEASE The obese patient seems to be plagued with skin disorders. With obesity, one has excessive fat folds with resultant intertrigo, caused primarily by friction between the skin surfaces and by the maceration of thc skin from accumulated moisture in these folds. These changes often lead to infection, particularly with staphylococcal organisms, or to fungus disease, e.g. dermatophytosis and moniliasis. Obese people, because of their thick subcutaneous layers of fat, tend to become overheated and to sweat profusely. This produces undesirable effects on normal skin, exaggerating areas of inflammation and producing skin raahes. Prickly heat, or miliaria rubra, is a commonly recognized evidence of sweat retention. Obviously, the therapy for this is correction of obesity by decreased caloric intake and increased exercise. This is more easily said than done, and the therapy and management of obesity still remain among the most difficult problems facing the physician. dietitian, and patient. V VITAMINS-FACTS AND FANCY

The search for vitamins has always captured the imagination of the research scientist, and because deficiencies of these substances are so often associated with skin and hair changes in experimental animals, it was an easy transition from animals to man by dermatologists and physicians eager to treat difficult dermatological problems. Hence, vitamins in every form, combination, and dosage level have been used in the treatment of skin diseases. As might be expected from this rather haphazard approach, a great variety of results have been reported. These are characterized mostly by their inconsistency. The question most often raised is the need for vitamins beyond that ordinarily present in a well-balanced diet. There

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is no simple answer to this question, but it should be remembered that in skin disease as with disease in general, there is tissue pathology, presumably accompanying abnormal metabolism. Certainly, adequate vitamin intake must be insured, and this is most easily done by appropriate vitamin supplementation. The danger lies, however, in overzealous specific claims for “skin cures” effected by vitamins, since many dermatological conditions improve without therapy and for no known reason. Claims for vitamin therapy must be made only after the closest control of experimental or clinical studies, and the most conservative judgment must be exercised.

VITAMINS VI. FAT-SOLUBLE 1. Vitamin A

Since vitamin A is intimately concerned in the maintenance of normal cell structure, one of the most characteristic changes seen in vitamin A deficiency is disintegration of epithelial surfaces followed by their replacement with a keratinized stratified epithelium. In man, lack of vitamin A (Wohl and Goodhart, 1960) may result in dryness, scaliness, furunculosis, and abscesses of the scalp and in bleaching, drying out, or loss of the hair. The follicular lesions, which are most helpful in establishing diagnosis, vary in size, the maximum diameter being 5 mm. They are hard, deeply pigmented, and surrounded by a zone of pigmentation. The center of the lesion, the papule, is a scaly, pointed plug of keratinized epithelium, which, if pressed out, leaves a crater. Though comedones are common on the face, the keratinized lesions do not occur there; hence the two are never associated, though both respond promptly to treatment with vitamin A. Histologic examination shows hyperplasia and hyperkeratinieation of the related epithelium around the hair follicles, together with metaplastic changes of the sweat ducts and degeneration of the glands, accounting for the dryness of the skin. Frazier and Hu (1931) have described a skin eruption occurring in Chinese soldiers which they consider typical of vitamin A deficiency. The skin first becomes dry and rough; then spinous papules appear at the sites of the hair follicles-first on the anterolateral surfaces of the thighs and the posterolateral aspects of the a m ; at last the eruptions occur over the entire integument. In debilitated patients and in those with poor habits of personal cleanliness, pustules may develop. Occasionally, atrophic ulcers appear. Microscopic study of the tissues shows hyperkeratinization of the epidermis and follicles together with metaplasia of the sweat duct epithelium into that of the squamous type. Proper diet causes a gradual improvement. As might be anticipated, those skin lesions which are.associated with a deficient intake of vitamin A respond to therapy with this vitamin.

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The use of vitamin A in the treatment of other diseases associated with excessive keratinization, particularly those involving the hair follicle, have not always yielded consistently beneficial results. This therapy has been shown to be of some therapeutic value, however, in the treatment of pityriasis rubra pilaris and Darier’s disease. While such treatment may provide symptomatic improvement, it is rarely curative. In view of the fact that vitamin A in huge doses has been used in the treatment of certain dermatological lesions, a word of caution is in order. Doses of 100,OOO to 300,000 units per day may produce signs and symptoms of vitamin A intoxication, which resemble the lesions of vitamin A deficiency as far as the skin is concerned (Jeghers and Marraro, 1958). In addition, bone changes take place, which reduce the density of the bones and make them brittle. Of interest also, is the fact that an excessive intake of provitamin A, carotene, produces a yellowish discoloration of the skin and carotenemia. This, at first glance, may be confused with jaundice. It represents an inability of the body to convert carotene to vitamin A rapidly enough in the face of a large carotene intake. 8. Vitamin K , Vitamin E, and Vitamin D A deficiency of vitamin K resulting in impaired synthesis of prothrombin may result in a cutaneous purpura reflecting impairment of the coagulation mechanism. No clear-cut cutaneous manifestations have been reported associated with vitamin E deficiency. In fact, to this time, there is little evidence of substantial nature to show that vitamin E is required by man, except that when unsaturated fatty acid intake is increased in subjects on vitamin Edeficient diets, their red blood cells show increased hemolysis on exposure to hydrogen peroxide (Horwitt et al., 1956). Studies now in progress may yet reveal an important role for vitamin E in human nutrition. Vitamin D is of interest to the dermatologist since sunlight converts vitamin D precursors in the skin to the active form of the vitamin. Vitamin D wa8 at one time used successfully in the treatment of lupus vulgaris, but this therapy has been abandoned in favor of the more specific antituberculosis drugs. As with vitamin A, vitamin D given in continued large doses may cause toxic manifestations with extensive soft tissue calcification. It must, therefore, be used with caution.

ACID VII. ASCORBIC In ascorbic acid deficiency there is impairment of the structure of the ground substance of the connective tissue, and in scurvy the skin may show secondary changes, such aa petechial hemorrhage and inelasticity. As mentioned before, ascorbic acid is also concerned with the metabolism of the

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amino acids tyrosine and phenylalanine, which are precursor substances for the formation of the melanin pigments of the skin. Hyperkeratotic follicular papules on the calves and buttocks have been reported in ascorbic acid deficiency. These resemble comparable cutaneous lesions seen in vitamin A deficiency. Frazier and Marmelszadt (1948) offered the suggestion that ascorbic acid may play a role in the utilization of vitamin A. Further indications for an interrelationship between vitamin A and ascorbic acid is the report by Mayer and Krehl (1948) that one of the first symptoms of the vitamin A deficiency syndrome is a depletion of the animal’s ascorbic acid reserves. This was evidenced by symptoms resembling scurvy and curable with ascorbic acid. In addition, there were decreases in the ascorbic acid content of liver, blood, and adrenals. Since this was observed in the rat, it might be considered that vitamin A deficiency in some way interfered with the animal’s normal mechanism for synthesizing ascorbic acid. Therapy with ascorbic acid has been proposed for a variety of skin diseases, such as allergic contact dermatitis, atopic dermatitis, psoriasis, and acne vulgaris. Unless there is associated ascorbic acid deficiency, no benefit is derived from the use of this vitamin in the specific treatment of the above conditions.

VIII. VITAMIN B COMPLEX DEFICIENCIES Experimental animal studies in which deficiencies of the B complex vitamins have been establishedare all associated with some skin or hair changes, ranging from mild to severe. The correlation between these changes noted in animals and various dermatological lesions seen in man, remains unclear. Riboflavin, niacin, pyridoxine, p-aminobenzoic acid, and possibly pantothenic acid are the members of the B complex group of vitarnine that have some known clinical dermatological significance for man. 1. RiboJEavin Aside from causing growth failure, riboflavin deficiency results in changes in the skin, mucous membrane, and eyes. These have been divided into three groups : oral, cutaneous, and ocular. Riboflavin-deficient rats exhibit alopecia over the abdomen, the hair is unkempt and often crusted with a dark brown material, and the skin of denuded areaa may become dry, scaly, and erythematous. Histological sections through the skin on microscopic examination show atrophy of the epidermis, follicles, sweat glands, and sebaceous glands. Increased vascularization of the cornea is the primary ocular manifestation of riboflavin deficiency. Unfortunately, this is not specific for riboflavin and may be seen also in certain amino acid deficiencies. A syndrome of riboflavin deficiency has been described in man (Sebrell

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and Butler, 1938) which is manifested by a sore, magenta-colored tongue, cheilosis, angular stomatitis, and seborrheic dermatitis about the nose and scrotum. Horwitt (1955a) reported on experimental riboflavin deficiency in human subjects and emphasized that all features of the riboflavin syndrome do not necessarily appear in all subjects. Local trauma, irritation, or infection may serve as a trigger mechanism to make manifest the signs of deficiency. Of interest are the results of studies on nutrition in the Far East by Pollack (1956). This work, carried out on Chinese Nationalist Army troops on Formosa, indicates a high incidence of riboflavin deficiency, and an interesting associated syndrome called the oral-genital syndrome has been described. Scrota1 dermatitis was observed very often in those individuals who also had angular stomatitis, cheilosis, magenta tongue, and nasolabial seborrhea. When the biochemical findings in blood and urine were correlated with the clinical findings in the oral-genital syndrome, it was evident that a riboflavin deficiency was involved. Niacin deficiency was also noted in significant numbers in this study. Enrichment of the rice in the diet with riboflavin and niacin rapidly eliminated the signs attributable to the deficiency of these vitamins. It is now becoming evident from nutrition surveys conducted in many areas of the world that riboflavin deficiency is one of the most common.

2. Niacin DPficiency-Pehyra The earliest symptoms of pellagra may involve either the skin or the gastrointestinal tract. Premonitory evidence of skin involvement may appear as a temporary redness like that of sunburn; it clears up without a trace only to return later in severer degree. Earliest lesions are usually macular, of a light or dark red color, but these coalesce and form a dark red or purplish eruption followed by desquamation (Spies, 1955b). The areas involved are those of friction and exposure. The face, neck, hands, forearms, and feet are the usual sites. This early eruption may be accompanied by considerable swelling of the involved parts. In severe cases, bullae may be present, but usually these dry up, leaving crusts, though they may of course become infected. Ulceration has been known to occur. A highly characteristic feature of the erythema and subsequent pigmentation is the occurrence of sharp margination of the wrist or forearm producing the so-called “pellagrous glove.” The skin manifestations are usually present in three stages: (1) congestion; (2) thickening and pigmentation; (3) atrophic thinning. Subjective symptoms are usually slight; and they consist chiefly of a burning sensation rather than an itching. The mucous membranes are also involved. The tongue becomes swollen and denuded and is often brilliant red in color. The buccal mucous mem-

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hrane may, in severe cases, have a similar appearance; the redness may at times extend to the lips, too. Sometimes the oral commissures become fissured. Thousands of pellagrous patients have now been treated with niacinamide. Doses up to 3 or 4 gm. daily may be administered safely, although the average dose is 100 mg. three times daily. In a day or two, the redness of the oral, pharyngeal, and vaginal mucous membranes is reduced; nausea, vomiting, and excessive salivation decrease; and bowel movements become normal. Unless the continuity of the skin is broken, the acute red lesions fade rapidly. The acute mental symptoms, varying from confusion to delirium and mania, usually disappear quickly. The addition of thiamine is often necessary to improve symptoms due to involvement of the peripheral nervous system. Riboflavin may be required if there is clinical evidence of an associated riboflavin deficiency. This is indicative of the multiple nature of deficiency diseases. Diets in which corn predominates are prone to lead to niacin deficiency and pellagra, especially if these diets are inadequate in proteins that contain tryptophan (Krehl et al., 1946). The niacin requirement is significantly affected by the amount of tryptophan in the diet, aa this amino acid is metabolically converted by the body to niacin. The approximate dietary replacement ratio is 50 or 60 mg. of tryptophan to 1 mg. of niacin (Horwitt, 1955h). Another interesting aspect of niacin therapy is the dermatological effect of producing a marked cutaneous vasodilatation with extensive flushing of the skin. This characteristic is not shared by niacinamide. Many of the phenomena observed in pellagra, such aa abdominal distress, diarrhea, pigmentation of the skin, and photosensitivity are often found in patients exhibiting acute toxic porphyria. Rosenblum and Jolliffe (1940) found porphyrinuria present in six of nine inebriates who had pellagra. In only three of these could the porphyrinuria be correlated with the severity of the disease. It was concluded that the symptoms of pellagra were in no way dependent on impaired porphyrin metabolism as manifested by increased porphyrinuria. The presence of liver dysfunction in the patients studied may well have accounted for the excessive production of coproporphyrin 111. 3. Vihmin Ba (Pyridoxim,Pyridoxal,Pyridoxamine)

Animals, especially the rat, develop severe skin lesions in vitamin Be deficiency (Gyorgy and Eckhardt, 1939). Vasodilatation with erythema over the skin of the paws, followed by hyperkeratosis, scaling, and edema, occurs. Essential fatty acid deficiency results in a dermatitis in the rat similar to that seen in pyridoxine deficiency. This is indicative of an inter-

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relationship between pyridoxine and fatty acid metabolism. High-fat diets, rich in the essential fatty acids, will delay the onset of pyridoxine deficiency dermatitis, and the reverse of this situation also holds true (Gross, 1940). Vitamin Ba is important particularly for the conversion of linoleic acid to arachidonic acid. Vitamin Ba is essential also in the metabolism of tryptophan, and this fact is used as a test for the adequacy of pyridoxine nutrition. After a test load of tryptophan, the urinary excretion of xanthurenic acid, an abnormal metabolite of tryptophan, is greatly increased if the individual has had a previous low intake of vitamin Ba (Lepkovsky et al., 1943). Pyridoxine deficiency has been produced in human subjects (Schreiner et al., 1952) by the use of a pyridoxine antagonist 4-deoxypyridoxine, and in association with this deficiency there is seen a seborrhea-like lesion about the eyes, nasal labial fold, and mouth, with extension to the eyebrow and skin behind the ears. The scrota1and perineal regions were occasionally involved. Inbertrigo developed under the breasts and in other moist areas. Hyperpigmented and scaly pellagra-like dermatitis also developed in some instances in the regions of the collar, forearms, elbows, and thighs. There was a significant increase in xanthurenic acid excretion after a test load of tryptophan. There was noted a rapid regression of all lesions, including a reduction in xanthurenic acid excretion, after the administration of pyridoxine, pyridoxal, or pyridoxamine in doses as low as 5 mg. daily (Vilter, 1956). Variable success has been claimed in the treatment of ordinary seborrheic dermatitis using a pyridoxine ointment in topical application, suggesting the possibility of a local vitamin Be metabolic defect in the skin.

4. Pantothenic Acid, Inositol, p-Aminobenzoic Acid, and Biotin Experiments reported by Woolley (1940a) have shown that pantothenic acid has an influence on the growth of hair. It has also been shown that a deficiency of pantothenic acid is a factor in the graying of hair and that pantothenic acid improves the skin and decreases graying of the fur of experimental animals (Dimik and Lepp, 1940; Morgan and Simms. 1940). Unna et al. (1941) found that black rats fed a synthetic diet deficient in pantothenic acid become gray in from 4 to 6 weeks. Pantothenic acid at a level of 100 mg. a day will prevent or cure this condition. On the other hand, Williams and Major (1940) found pantothenic acid to be without effect on the graying of hair. There is no evidence that pantothenic acid acts in human beings as it seems to act in various animals. Spies et al. (1940) believe, however, that pantothenic acid and riboflavin are intimately associated in their behavior; and it is true that patients with cheilosis and other manifestations of riboflavin deficiency have shown marked improvement when given pantothenic acid. Though the human requirements and possible

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therapeutic doses are unknown, it is known that as much as 100 mg. of pantothenic acid daily is well tolerated. Little is known about inositol; its relation to human nutrition is still a subject for investigation. Considerable interest has been aroused by the investigations of Woolley (1940b), who has shown that inositol will cure alopecia in mice (Woolley, 1941). Thirty-three patients with lupus erythematosus were given 1 4 gm. of p-aminobenzoic acid (PABA) at 2-3-hour intervals by Zarofonetis (1949). Two of ten with chronic discoid lupus showed no improvement; one patient had a poor response, and seven had good to excellent responses. Improvement occurred in the seven patients with scleroderma, the sclerodermatous areas gradually softening and becoming thinner and more pliable. PABA produced improvement in five patients with dermat,itis herpetiformis. Toxic hepatitis, drug fever, and nausea and vpniting may occasionally result from PABA, and much more careful work must be done before any serious recommendations can be made for its use in dermatological conditions. Biotin-deficient rats develop marked loss of hair with erythema of the underlying skin. Marked periorbital hair loss is also noted, which may represent in part a complication from inositol deficiency. No counterpart deficiency has been demonstrated in man. IX. SIDE EFFECTS OF VITAMIN THERAPY Certain undesirable cutaneous side effects may be associated with the use of vitamins. These are for the most part allergic in character. Thiamine may cause urticaria, angioneurotic edema, pruritis, and contact dermatitis. Niacin produces marked erythema, peripheral vasodilation, and pruritis. This is a common reaction in patients who are given niacin in an attempt to lower the blood cholesterol. This cutaneous reaction to niacin, interestingly, is not seen with niacinamide, which, incidentally, does not lower blood cholesterol levels. Vitamin BIZ, which contains cobalt, may cause reactions in cobalt-sensitive patients, especially when given by the parenteral route. Vitamins, like other chemical substances, might be expected to cause allergic reactions with dermatological manifestations in a certain number of individuals. Fortunately, the incidence is insignificant.

X. MINERALSAND TRACE ELEMENTS A large number of mineral elements have been shown to be essential nutrients, either in macro or micro amounts. Animals fed a diet deficient in any one of four of these elements, i.e., calcium, magnesium, zinc, and copper, develop skin lesions.

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1. Magnesium

Magnesium deficiency in the rat (McCollum and Orent, 1931) produces very dramatic changes not only in greatly increased nerve and muscle irritability, but also in the skin (Sullivan and Evans, 1944a). After about 7-12 days on a magnesium-deficient diet, marked erythema of the skin develops. This is a transitory phenomenon, and in a matter of a few minutes the animal’s skin may change from a flushed, erythematous condition to a pale, white, bloodless appearance. As the deficiency proceeds, the erythema is more persistent; at the same time irritability increases to the point where convulsive seizures may develop on the slightest stimulation. The skin changes continue with the development of edema, scaling, and hyperkeratosis. Although serum magnesium levels are reduced, the magnesium content of the skin remains normal (Sullivan and Evans, 194413). Curiously, in magnesiumdeficient rats, nucleated red blood cells are seen in abnormally large numbers in the peripheral blood (Krehl, 1957). The fact that magnesium is an essential factor in the functioning of a number of important enzymes is indicative of its importance in normal metabolism.

W. Calcium I t has been suggested that calcium hau an important function in capillary permeability through its effect on the calcium proteinate of the intercellular cement substance (Chambers and Zweiflack, 1940). Calcium-deficient animals develop extensive hemorrhages supposedly because of the weakness of capillary walls lacking in extracellular cement substance. 3. zinc Todd et al. (1934) produced zinc deficiency in the rat, observing growth retardation, alopecia, dryness and scaling of the skin, all of which could be corrected by the addition of 0.1 mg. of zinc to the daily diet. Follis et al. (1941) demonstrated histologically the presence in the skin of acanthosis and heavy parakeratotic scales. Also noted was a marked atrophy of the hair follicles while the sebaceous glands showed a distinct hyperplasia.

4. Copper Copper-deficient animals exhibit a severe anemia, not correctable with iron, with poor growth and skin and hair changes (Hart et al., 1928). Copper has an unusual effect on the formation of disulfide cross linkages (Marston, 1952). The wool fibers from copper-deficient sheep are weak because of artificial rupture of disulfide linkages. Also, the total sulfur content of wool fibers is 10-15 % below normal in copper deficiency. It is thought that the oxidative closure of the sulfhydryl residues to disulfide linkages is catalyzed by copper. Copper is also essential for tyrosinase activity and hence is of importance in melanin formation (Lerner et al., 1949).

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XI. DIETAND DERMATOLOGICAL PROBLEMS 1. Allerg9

Food allergy may be the cause of many skin lesions, including atopic dermatis, urticaria, infantile dermatitis, and eczema (McGovern and Zuckerman, 1956. The allergenic properties of a food depend on the nature of the food, the quantity and concentration of the food in the diet, and the duration of exposure to the allergenic substance. In addition, one must consider the problem of host susceptibility. A family with an allergic background should alert one to exert special care in the feeding of its infants and small children, particularly during the period of “physiologic, immunologic immaturity.” Food allergens may enter the body by way of the gastrointestinal tract, and derangements of the gastrointestinal system are among the prime factors leading to food allergy. Almost all foods and beverages have at one time or another been incriminated as being allergenic, but those that are most common are: unaltered egg protein, milk protein, fish and eeafood, wheat, corn, tomatoes, spinach, cabbage, asparagus, rhubarb, celery, onion, garlic, and citrus fruits and juices. When the allergenic role of a food has been established, it may be corrected by elimination of the food in question or by specific desensitization. Unfortunately, food elimination as a means of therapy may lead to rather bizarre and unusual dietary patterns. There must be careful supervision of the diet under these circumstances in order to insure adequate and balanced nutrition. To indicate the really great difficulties and complexities of dermatology, two important dermatological problems with unknown etiology and for which there is no specific proved therapy deserve mention. These are psoriasis and acne vulgaris. These are selected also because diet has been so extensively involved in their management. d . Xanthoma

Xanthoma of the skin, characterized by round or oval, solid firm, reddishbrown papules, are often distributed over the buttocks, elbows, and knees and may be seen in patients with diabetes or hypercholesterolemia from almost any cause; a familial form of xanthomatoses is also known. Analyses of these xanthomatous lesions show an excess of fatty acids, cholesterol, and other lipid substances. Their deposition probably reflects the high cholesterol content of blood and other lipids in patients with disordered fat metabolism, such as may be seen in poorly controlled diabetics and in patients with other abnormalities of lipid metabolism, some of which may be familial in origin. Some observers have reported marked improvement

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and even disappearance of these xanthoma when the patient waa placed on a low-fat diet for a long period of time (Wile et al., 1929). Unfortunately, this is often very difficult to achieve and the results are discouraging. 3.Psol-iasis Psoriasis is a chronic, inflammatory skin disease characterized by the development of reddish, erythematous patches covered with raised, silverywhite, dried scales. Cracking and fissuring of the skin in the extensive psoriatic area is quite common. The disease affects primarily the extensor surfaces of the body and the scalp, although it may be very widely disseminated. Although such patients have failed to show any clear-cut metabolic distubance as the underlying cause of this dermatitis, some interesting studies have been conducted. It has been demonstrated that a diet free from fat or very low in protein is moderately effective in the treatment of psoriasis (Buckley, 1912). Schamberg (1932) has been the outstanding proponent of the low-protein diet, and he has indicated that psoriatic individuals give definite signs of abnormal nitrogen retention. Patients with psoriasis, placed on diets containing no more than 4 or 5 gm. of nitrogen per day, with an adequate caloric intake, were able to maintain their weight and experienced a gradual disappearance of the lesions of this disease. Unfortunately, when this very restricted dietary regimen is discontinued, the disease returns. Psoriatic scales containing keratin-like protein have an unusually high content of sulfur amino acids. In this connection, it is worth noting that the standard therapy of psoriasis with coal tar and ultraviolet light are both known to disrupt the metabolism of the sulfhydryl group and may provide a clue to understanding and therapy of this disease. It has also been reported that there is an interesting relationship between decreased urinary secretion of sulfur and of ascorbic acid in patients with psoriasis. Experiments with diets containing a maximum of 250 mg. of sulfur per day in patients for periods of several months have yielded inconsistent results. It would be of considerable interest to feed psoriatic patients for extended periods of time on purely synthetic diets with known intakes of all nutrients. In this way, the role of the sulfur amino acids metabolism in psoriasis might be clarified.

4. Acne vulgaris Acne vulgaris is a chronic inflammatory disease of the sebaceous glands and the pylosebaceous structures of the skin and is almost always associated with seborrhea. This is predominantly a dermatological diseme of youth, particularly teenage youth, and associated with it are all the emotional and psychological factors so prevalent in this age group. It is a

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rather common clinical experience that gross dietary indiscretion, particularly by taking too much cake, candy, ice cream and chocolates, aggravates an existing acne. This strongly suggests that the skin condition may be associated with a disturbance of carbohydrate metabolism (Lemon and Hermann, 1940). Not all agree on this, and improvement has been reported in patients taking a high carbohydrate diet (Crawford and Swartz, 1936). It is also thought that acne is made worse by diets high in fat. Unfortunately, low-fat diets have not been particularly effective in the management of this problem. It may well be that the principal effect of high-fat diets is to permit excessive weight gain in individuals with acne, who are often withdrawn, quiet, and relatively inactive because of the emotional trauma that is associated with this disease. It has been pointed out that the diet of the Eskimo is mostly fat and protein, but Eskimos have relatively little or no acne. One cannot doubt that psychoneurogenous factors play a significant role in producing exacerbation of this disease. In addition, fatigue and exhaustion are often predisposing factors. In view of the fact that we have no specific knowledge aa to the cause or treatment of acne, it seems most reasonable to place people with this disease on a well-balanced diet that does not contribute an excessive amount of calories, so that weight gain is not excessive. Such a diet should contribute all the food nutrients in the recommended daily allowances. Perhaps most important of all, the child or individual with this disease, as with all difficult dermatological diseases, must have the necessary psychological lift from the physician and from his friends and family to permit him to learn to live with his disease and function as much like a normal individual as possible. Again, often easier said than done.

XII. SUMMARY There is little doubt that dietary deficiency, whether primary or conditioned, may be associated with dermatological lesions that can respond to specific therapy with vitamins or unusual diets. Dermatoses are certainly associated with obesity, and since this is such a common disease, therapy directed at weight reduction will probably provide the best management in related dermatological problems. The general dermatological changes aasociated with undernutrition, rather rare in this country, are extremely common in technically underdeveloped areas, and here improvement of the protein intake seems to be the most rational way of correcting these difliculties. Along with increased protein intake would come more vitamins. Certainly, allergies to foods may produce dermatoses, and such allergies should be ruled out if suspected either on the basis of family history or by history of the patient’s food intake. It is extremely important that careful nutritional history should be taken

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on every patient presenting a dermatological problem and that physical examination and, if necessary, biochemical studies should be made in order to rule out nutritional abnormality. For example, phenylpyruvic oligophrenia may be diagnosed simply and early by testing the urine with ferric chloride. Early diagnosis and therapy by restricting phenylalanine will produce most gratifying results. It must be remembered that the underlying defects reIated to dermatoses of unknown etiology may be the result of improper nutrition or metabolic errors endured over very long periods of time. Hence, their correction by diet or improved metabolism may require long and intensive therapy. REFERENCES Armstrong, M.D., Shaw, K. N. F., and Robinson, K. 8.1955.J. Biol. Chem. 213,797804.

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