Vitamin Deficiency Diseases: Their Diagnosis and Treatment

Medical Clinics of North America May, 1937. Mayo Clinic Number

VITAMIN DEFICIENCY DISEASES: THEIR DIAGNOSIS AND TREATMENT DWIGHT

L. WILBUR

IT is sometimes difficult to appreciate the fact that ill health and disease may result from deficiency or lack of some essential substance. It has been taught for many years that diseases result from an abnormal factor, such as bacterial or other toxins, growth of tumors or trauma, and only in the past forty years has the concept of deficiency disease arisen. Pellagra, beriberi, scurvy and rickets, which now are recognized as deficiency diseases, were at one time thought to be results of intoxications of various types. The later correct concept of deficiency diseases was based on the discovery of those things in foods which are essential for the health of the individual. Clinical and experimental evidence has indicated clearly that vitamins are not only essential for the preservation of health, but that a normal food supply furnishes them in adequate amounts. Although an insufficient intake of protein and certain minerals in the diet will produce states of deficiency, the term is generally used in relation to states of vitamin deficiency. Most people have become vitamin-conscious, and while physicians in general recognize that disease such as xerophthalmia, beriberi, and scurvy are rare, nevertheless they are constantly reminded, particularly by advertisements, that failure to maintain an adequate intake of this and that food containing vitamins will lead to a variety of diseases. Emphasis is persistently placed on the probability of occurrence of mild states of vitamin deficiency, difficult of recognition, and responding to specific vitamin therapy. Consequently, every wise clinician is continually on the lookout for states of vitamin deficiency among the patients he sees. There is considerable experimental evidence, substantiated in part by clinical experience that states of partial deficiency VOL. 2I-47

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are not uncommon, and that" the "optimal" requirement of a vitamin is much higher than the "minimal" or actual requirement. It is interesting to observe, in the United States at least, that the principal concern with regard to the production of deficiency diseases is not so much because of an insufficient quantity of food as it is because of the preparation of foods in highly concentrated and purified form, such as flour, prepared oils, foods "ready to serve," and so forth. Although such preparation of food has many benefits, it has limited the amount of food taken in the natural state, and it is in the natural state that foods are richest in vitamins. In the past few years the economic depression has, in some instances, reduced the ability of people to obtain foods in a natural state, because many such foods are perishable and therefore expensive. The importance of the gastro-intestinal tract in relation to the development and occurrence of deficiency diseases is continually being emphasized. It seems reasonable to believe that, in the United States, a considerable proportion of deficiency states will be found to arise as a result of abnormalities of digestion and alimentation. Changes in the gastro-intestinal tract which lead to failure of adequate absorption, no matter what the cause, may lead to deficiency diseases even though the diet contains an adequate supply of essential substances. VITAMIN A

The most readily appreciated clinical symptoms of vitamin A deficiency have to do with changes occurring in the eyes, and consequently in previous years this deficiency has been considered to be manifested chiefly if not entirely in this way, in fact, for years vitamin A was known as the anti-xerophthalmic vitamin since xerophthalmia occurred in vitamin A deficiency. It seems clear that vitamin A is closely related to the yellow pigment, carotene, which is widely distributed in nature and is found in carrots, squash, yellow corn, and other vegetables. Carotene is the chemical precursor of vitamin A, which is the primary alcoholic derivative produced by the symmetrical division into two parts of the beta-carotene molecule. Vitamin . A is probably a catalyst in its chemical action, and physio-

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logically it is essential for the maintenance of the integrity and normal state of all epithelial tissues. When vitamin A is present in insufficient quantities the epithelial tissues lose their normal appearance, and thickening or keratinization, followed by secondary infection, result. Night Blindness.-Deficiency of vitamin A .may lead to night blindness or inability to see clearly in dusky light; this is not an uncommon occurrence in the Orient but it is unusual in the United States. This condition may be defined as difficulty or inability to adapt vision to faint illumination, and it may result from intra-ocular lesions as well as from deficiency diseases. Jeans and Zentmire have studied the sensitivity to light following partial adaptation to darkness of school children in Iowa, and reported (1934) that about 20 per cent of the children who had subnormal vision in the dark were relieved promptly by partaking of cod liver oil; in a later report (1936) they found that with the same test, 20 per cent of a rural group, 53 per cent of a village group, and from 56 to 79 per cent of an urban group of school children presented evidence of vitamin A deficiency. Xerophthalmia.-This condition is manifested by dryness of the conjunctival tissues which, if it progresses, may lead to conjunctivitis, keratomalacia or softening of the cornea, and finally to blindness. Bitot's spots, triangUlar white spots appearing like dense foam of soap in the palpebral fissure, and subsequently light brown pigmentation of conjunctiva, may be present during this transition. Xerophthalmia is of exceedingly rare occurrence among infants in the United States. Cutaneous Lesions.-Since the principal influence of vitamin A is on epithelial tissues, it might be anticipated that cutaneous lesions would occur in vitamin A deficiency. The characteristic change, which is considered by some authorities to be the first manifestation of deficiency, consists of keratinization of a hard, dry papular type that resembles goose skin and is most marked on the extensor surfaces of the forearms, legs and thighs. Lesions of the Urinary Tract.-It has been recognized for several years that if an albino rat is given a diet deficient in vitamin A, keratinization of the epithelium of the renal pelvis develops and frequently urinary calculi of the calcium phos-

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phate type occur. Although there is evidence to substantiate the view that in some cases renal lithiasis of man may be related to deficiency of vitamin A, nevertheless the exact etiologic relationship cannot be stated until more information is available. Infections.-There has been much discussion of the relation of vitamin A to infections. In fact, this vitamin has been called the anti-infective vitamin, and much of it is prescribed for purposes of combating infections or for increasing resistance to them. The most important practical problem in this respect is not so much whether a person who is receiving an inadequate diet is less capable of resisting infection than is a normal person, but whether an amount of vitamin A in excess of that normally obtained by well-nourished persons will further increase resistance to infection. Since the only recognized anti-infective influence vitamin A possesses is in maintaining normal epithelium which will act as a barrier to infection, and since so far as is known the vitamin does not have any influence on immunologic processes, it seems obvious that vitamin A in reality is not an anti-infective vitamin. Miscellaneous.-Effects of deficiency of vitamin A on tissues other than those already considered have been described. Thickening of epithelial layers of the respiratory and gastrointestinal tracts have been reported, and cysts or acute and chronic inflammatory changes may develop. The relation of vitamin A to changes in the nervous system is questionable. In the experimental animal an insufficient intake of the vitamin may lead to failure of growth, but this apparently is not a significant clinical feature of deficiency of vitamin A in man. Diagnosis.-The clinical diagnosis of vitamin A deficiency is not easy. In the rare case in which xerophthalmia is present, and in which this deficiency is marked, with features noted in the foregoing, the diagnosis may not be difficult if it occurs to the mind of the examining physician. The principal interest at present is detection of states of mild or partial deficiency. When the physician is confronted by a patient whom he suspects may have vitamin A deficiency, he should inquire into the presence of night blindness, and on examining the patient he should look for dryness or pigmentation of the conjunctiva and a papular cutaneous eruption involving particularly the limBs, especially the extensor surfaces. Patients who have

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night blindness usually complain that it is impossible for them to see in the twilight, at night, or in a darkened room which they enter from the sunlight. They are likely to bump into objects when walking at night. If examination of the fundus of the eyes does not reveal retinitis pigmentosa or other intraocular cause for night blindness, the probability is great that the night blindness is of the essential type and is caused by nutritional abnormalities. If any of the symptoms noted are present, or if they are absent, and vitamin A deficiency is suspected, two other examinations may aid in determining the presence of this condition. The first is a study of the sensitivity to light following partial adaptation to darkness, as described by Jeans and Zentmire. Such an examination requires special equipment and experience, although if these are available, the test is simple. The second method consists of scraping the bulbar conjunctiva, making smears and examining them for keratinized epithelial cells. If either of these tests is positive or any of the previously noted symptoms are observed, it is reasonable to suspect that vitamin A deficiency is present. Confirmation is obtained if these signs disappear following administration of vitamin A or carotene. Until more satisfactory methods are available for determination of vitamin A in tissues, and until more is known of the physiology of the substance, physicians will have to depend on relatively indirect methods to determine the presence of vitamin A deficiency. If patients have renal calculi or suffer from repeated infections, and vitamin A deficiency is suspected, observations and examinations, as previously noted, may be of some value in suggesting, but not proving the presence of vitamin A deficiency. Treatment of Vitamin A Deficiency.-Deficiency of vitamin A usually may be prevented by the use of adequate amounts of the following foods rich in vitamin A or carotene: butter, cream, cod liver oil, carrots, eggs and spinach. Fish liver oils are rich in vitamin A, particularly those of the halibut, cod, burbot, and tuna. The daily requirement of vitamin A is not known, but is probably in the neighborhood of 6,000 to 10,000 U.S.P. units. In the treatment of vitamin A deficiency states the following measures are of value: (1) a diet high in content of foods

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rich in vitamin A; (2) supplements to the diet of vitamin A in cod or halibut liver oil or carotene in amounts of at least 10,000 U.S.P. units daily; (3) in rare instances by intramuscular injection of cod liver oil or other substances rich in vitamins. VITAMIN B,

Vitamin B 1 , the antiberiberi or antineuritic vitamin, also known as vitamin B, which has been prepared in crystalline form, is widely distributed in foods. While apparently a catalyst in its chemical activity, physiologically it is essential in the metabolism of carbohydrates, having some part to play, it is thought, in the oxidation of lactic and pyruvic acids. In vitamin Bl deficiency, there is an abnormality in the pyruvic acid metabolism of nerve tissue which in part is responsible for the disturbances of the nervous system and for degeneration of the peripheral nerves accompanying this condition. Multiple Neuritis.-Deficiency in vitamin Bl results in . multiple neuritis and although it is one of the characteristic features of beriberi, it may occur separately without other features of beriberi, or it may occur in association with other symptoms. There are no clinical features which distinguish the peripheral neuritis of alcoholism from that observed in pregnancy, or in beriberi, or in association with gastro-intestinal disturbances such as chronic diarrhea and vomiting. Recent evidence indicates that in many cases the neuritis which occurs in cases of chronic alcoholism and during pregnancy is the result not of alcohol or toxemia, but of a deficient intake or loss of vitamin Bl that accompanies these conditions. Efforts have been made to relate many other types of peripheral neuritis to a deficiency of vitamin B 1 , as yet with only partial success. Beriberi.-Beriberi, a disease common in the Orient, is rarely observed in the United States. The characteristic triad of symptoms is edema, peripheral neuritis, and cardiac failure. Although the presence of all 6f these symptoms would assure the diagnosis, they may not all be present. The cardiac symptoms usually occur as a result of failure of the right side of the heart, which is hypertrophied and dilated. Tachycardia is t;ommon, fever is often present, and a variety of the symptoms

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may occur, including anemia with macrocytosis of the erythrocytes. Ohanges in the Gastro-intestinal Tract.-A c;ieficiency of vitamin Bl has been reported to produce atrophy of the papillre of the tongue, achlorhydria, and hypotonicity and hypomotility of the musculature of the gastro-intestinal tract. An adequate explanation for these changes is difficult to obtain, although degeneration of Auerbach's plexus may be responsible for the abnormalities in motor function. Anorexia is the most commonly observed gastro-intestinal symptom, but constipation and vague abdominal complaints are not uncommon. Ohanges in the Oardiovascular System.-Evidence that the cardiovascular system is affected in deficiency of vitamin Bl is suggested by edema, tachycardia, or bradycardia, which occur in beriberi. Weiss and Wilkins reported that there are certain changes in function of the cardiovascular apparatus in vitamin Bl deficiency, consisting of simple tachycardia, vagus reflex irritability with bradycardia or with asystole and syncope and failure of the right or left side of the heart, peripheral arteriolar dilatation or vasomotor collapse with vascular constrictions in various combinations. Cardiovascular changes should not be considered as due to vitamin B 1 deficiency unless there is good evidence that the intake of this vitamin has been inadequate or there is associated evidence of the deficiency in other organs. Diagnosis.-The diagnosis of vitamin Bl deficiency is simple if well-developed beriberi is present. Our particular interest, however, is in states of partial deficiency, and in such conditions the diagnosis is difficult and requires considerable judgment and experience. There are no laboratory procedures which are helpful in determining the adequacy of the vitamin Bl metabolism of a patient. Recently, Hari"is and Leong have reported a method by which the vitamin Bl content of the urine can be estimated quantitatively, but as yet this is not practicable for ordinary clinical use. In some cases in which the diet of the patient is known, an estimation of the adequacy of the vitamin Bl content of the diet, as compared to the requirement of the patient, may be made by Cowgill's formula. He has shown that the requirement of Bl is proportional to both intake of calories and body weight.

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In searching for clinical evidence of vitamin Bl deficiency, the physician should keep in mind the symptoms and signs noted in the foregoing, particularly those related to the nervous system and the gastro-intestinal tract. If patients reveal signs of peripheral neuritis, paresthesia of the extremities, tenderness of the muscles with weakness or paralysis, or a sore tongue which may have atrophied papillre, consideration should be given to the previous diet and to the presence of gastro-intestinal disease which might interfere with adequate nutrition. Great care must be exercised in a given case before attributing anorexia, or other gastro-intestinal symptoms to vitamin Bl deficiency. Prevention.-It has been estimated that the normal intake of vitamin Bl for an adult man is 1 mg. daily or 250 to 500 International Units. Since the vitamin is widely distributed in foods, it seems likely that only in cases in which the diet is exceptionally limited will deficiency of vitamin Bl occur. In cases of chronic alcoholism in which the diet is restricted markedly for a considerable time, deficiency of vitamin Bl is probably not infrequent. Although there is a suggestion in the work of Williams and his associates that vitamin Bl deficiency may be far more common than previously has been thought, proof is still lacking. The prevention of vitamin Bl deficiency lies in the intake of an ordinary well-balanced diet. Treatment of Deficiency.-In the treatment of vitamin Bl deficiency, a variety of therapeutic methods is available. Foods high in vitamin Bl content are yeast, fresh vegetables, whole cereals, and milk. Preparations of brewers' yeast in powdered or tablet form, and concentrates and crystals of vitamin Bl are available for therapeutic use. The crystals may be administered intramuscularly in solution or orally. Spies has emphasized, particularly, in the treatment of pellagra, the advisability of giving exceedingly large doses of vitamin preparations. This same principle probably holds in other vitamin deficiency states. It would be advisable, in a state of vitamin Bl deficiency, to give 25 gm. of powdered brewers' yeast (such as Harris') one or four times daily, depending on the degree of deficiency, along with a diet containing 4,000 calories and rich in vitamin-containing foods. The minimal therapeutic dose of vitamin Bl is probably about 10 to 20 mg. daily, and

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synthetically prepared crystals are now available at a reasonable cost. One advantage of giving yeast or a similar preparation in place of, or in addition to, the vitamin in crystalline or concentrated form is that, although marked relief is obtained in deficiency states from administration of vitamin Bl in this form, complete relief is generally not obtained until yeast or some substance containing all the factors of the old watersoluble vitamin B is given. Yeast contains apparently an essential substance which is not present in the crystalline and concentrated forms of vitamin B 1 or in B 2 (G). VITAMIN C

Vitamin C, which chemically is ascorbic acid, also known as cevitamic acid, is the antiscorbutic vitamin. More is known of the metabolism of this vitamin than of any other, and in recent years evidence has been accumulating that it is related not only to scurvy but also to dental caries, hemorrhagic diathesis, and anemia. Its relation to acute infections, particularly rheumatic fever, and its place in resistance to infection are uncertain. Vitamin C is a powerful reducing substance, and physiologically is essential in the formation and maintenance, in a normal state, of intercellular substance, particularly of the blood vessels, dental forming organs, and connective tissue. Scurvy.-Scurvy is uncommon in the United States, but it is observed occasionally among infants. The fundamental pathologic change is in the intercellular substance, particularly of the blood vessels and bones, with softening, which leads to hemorrhages into the subcutaneous, subperiosteal, gingival and other tissues. It has been observed that the intercellular substance, which ordinarily exists as a solid or gel, under circumstances of vitamin C deficiency may become a liquid. Early signs in the development of the disease are fleeting pains in the extremities, spongy and readily bleeding gums followed by evidence of hemorrhage into the skin and subperiosteal tissues, particularly of the long bones. Considerable interest lately has been given to "latent" or "preclinical" scurvy. The clinical features of this condition include dental caries in children, a hemorrhagic teIfdency which may express itself in hemorrhage from any organ, subcutaneous

DWIGHT L. WILBUR

petechire, a positive capillary resistance test, and a variety of indefinite symptoms, such as fatigue, pallor, underweight, frequent infections, anemia, and fleeting pains in the extremities, which usually are mistaken for rheumatism. Dental Caries.-Dental caries is frequently observed in experimentally produced scurvy, and clinically it has been considered by some observers to be one of the earliest signs of latent scurvy. Vitamin C is essential for the functional activity of certain cells necessary for formation of teeth, especially odontoblasts and cementoblasts, and it prevents their premature degeneration. When insufficient quantities of vitamin C are present, caries may occur. Although it has been suggested by Hanke and others that dental caries is caused mainly by lack of vitamin C in the diet, this opinion is not widely held. The actual incidence of caries from this cause is still not clear, and there are no gross signs characteristic of this type of caries. If the vitamin C deficiency is marked, the adjacent gums may be swollen, red, spongy, and bleed easily. Hemorrhagic Diathesis.-Great interest has been shown in the relation which may possibly exist between vitamin C deficiency and a tendency to hemorrhages.Itis well recognized that there is a hemorrhagic tendency in scurvy which is caused, as noted previously, by abnormalities of the intercellular substances of the capillaries and perhaps also by changes in the blood. Whether one can relate, to vitamin C deficiency, isolated or repeated so-called idiopathic hemorrhages from the nose, gastro-intestinal tract, urinary tract, uterus or other tissues, when signs of vitamin C deficiency other than the hemorrh ages are lacking is a question much discussed at present, but still unanswered. In this connection there has been much discussion of the capillary resistance test. It still remains to be proved that this measure is accurate in its portrayal of vitamin C deficiency, and it undoubtedly will be superseded soon by estimations of the vitamin C content of the blood and urine and vitamin C tolerance tests. Anemia.-Presnell has noted a reduced number of platelets and anemia, and Minot has emphasized the occurrence of normocytic or slightly macrocytic anemia in states of deficiency of vitamin C. Reticulocytosis of patients with infections following administration of large quantities of vitamin C has been reported by Faulkner.

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Miscellaneous.-The relation of vitamin C to the endocrine glands and particularly to the suprarenal glands, is still uncertain. Vitamin C is abundant in the suprarenal cortex and medulla, but its direct or indirect relation to the hormones of the suprarenal gland is still not clear. There has been considerable interest in the possible relation between vitamin C . and infections, particularly rheumatic fever and perhaps chronic infectious arthritis. Although changes in the joints similar to those observed in these conditions have been observed in animals which receive diets deficient in vitamin C, there is much evidence against a direct etiologic relationship between deficiency of vitamin C and rheumatic diseases. The clinical value of vitamin C in combating it1fections of any type is still uncertain, although laboratory evidence suggests that the vitamin may have certain detoxifying properties. Diagnosis.-The diagnosis of scurvy is relatively simple in a well-developed case. The spongy, bleeding gums, painful extremities, and evidence of subperiosteal, subcutaneous, and other hemorrhages are diagnostic signs. The diagnosis of latent or preclinical scurvy is difficult, but suspicion should be aroused if patients reveal considerable dental caries, have unexplained hemorrhages of any type or in any situation, or have long-continued infections. Persons who have used little citrous fruit, tomatoes, milk, and fresh fruits and vegetables may have, or may develop, latent scurvy. It is exceedingly important to emphasize that such conditions do not establish the diagnosis, but only suggest the possibility of it. Fortunately, physicians possess better methods of determining the presence or absence of partial deficiency of vitamin C than of any other vitamin. The use of capillary resistance tests, estimations of the content of vitamin C in the blood and urine, the use of vitamin C tolerance tests, and estimations of vitamin C saturation are all valuable in this connection. In addition, a therapeutic test in which ascorbic acid is given may produce presumptive evidence of previous deficiency of this vitamin. If the physician will bear in mind the symptoms previously enumerated as occurring in vitamin C deficiency, the first step to a diagnosis will have been made. The next step perhaps is performance of the capillary resistance test. This is rela-

DWIGHT L. WILBUR

tively simple and can be performed in the office by marking an area on the skin, 60 mm. in diameter, in the antecubital fossa of one forearm. Following this, venous stasis is produced for fifteen minutes with a sphygmomanometer cuff at a pressure of SO mm. of mercury. If more than eight petechire develop on the marked area, the test is positive; if less than five develop, it is negative. Although this test is not specific, it is suggestive, and, if positive in a case in which vitamin C deficiency is suspected, it should lead to studies either of vitamin C saturation or a therapeutic trial with vitamin C. The quantitative estimation of vitamin C in the urine is relatively simple and can be performed after the method of Harris and Ray with the indicator, dichlorophenolindophenol.· At present data are insufficient to permit evaluation of the estimation of vitamin C in the urine excreted during twenty-four hours. The amount excreted depends on the intake and on the saturation of the tissues. Youmans and others reported that an excretion of 20 mg. of vitamin C per day is the lower limit of normal in adults. Estimation of the vitamin C content of the blood is still of uncertain value. Although Abt and his associates expressed the belief that the values they obtained for the reduced cevitamic acid content of the blood plasma will prove a convenient, rapid and accurate method for the detection of subclinical scurvy, this opinion remains to be confirmed. Probably in the future the use of tolerance tests, or of methods of determining the saturation of the tissues with vitamin C will prove most valuable in determining latent scurvy. For example, Youmans has estimated that if a test dose of 600 mg. of vitamin C is given, at least 30 per cent should be excreted in the urine of a normal individual in twenty-four hours. Further observations are necessary before standards are established in this rapidly developed field. Prevention.-Scurvy or vitamin C deficiency may be avoided by intake of a diet adequate in fresh fruits, particularly of the citrous variety, and vegetables. In infants, this. is readily accomplished by the almost universal use of orange juice or a substitute. The minimal intake of vitamin C necessary to prevent si/ins of deficiency is not certain, but probably approximates 20 mg. daily. Occasionally much larger quantities' apparently are necessary; it was necessary to give one patient 200 mg:daily to prevent hemorrhagic tendencies.

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Treatment of Deficiency.-;-The diet should be high in its content of fresh vegetables and fruits, particularly citrous fruits. This may be supplemented by the administration of vitamin C, in synthetic crystalline form, by mouth or intravenously; from 50 to 200 mg. or more daily should be sufficient in therapy. When given intravenously, solutions of the sodium salt of cevitamic acid approaching approximate isotonicity can be used; that is, 1 per cent of the salt dissolved in physiologic salt solution or 3 per cent dissolved in distilled water. If only the acid is available, it should be neutralized with half its weight of sodium bicarbonate in physiologic salt solution or water before it is injected. VITAMIN D

Vitamin D, which is the antirachitic vitamin, is probably the one best known by the layman because it is widely advertised. Rickets is such a widespread disease of infants in the northern hemisphere that it could be classified as probably the most common deficiency disease. Seven chemical substances have been shown to possess vitamin D activity, and consequently the vitamin is not a single chemical substance. Physiologically, the vitamin plays an essential part in the metabolism of calcium and phosphorus, having to do with the retention of calcium and phosphorus in the body as a whole, in the deposition of calcium and phosphorus in the bones, and perhaps in the concentration of these elements in the blood. Calcium, phosphorus, vitamin D and parathyroid hormone are essential for mineralization of normal bone, and the individual part played by each in this metabolic process is still not clear. Rickets.-Deficiency of vitamin D results in rickets, and' it has been stated that from 50 to 90 per cent of infants have signs of rickets. The fundamental fault in this disease is failure of adequate mineralization of the bones. The earliest symptoms are usually restlessness, irritability, and head sweating, which are followed by enlargement of the costochondral junctions and formation of the "rachitic rosary." The head may become enlarged and square, the fontanels may remain large, and softening of the parietal bones often results. The epiphyses of the wrists are often enlarged. Weakness of the

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muscles, tardy dentition, and spinal curvature may be accompanying signs. The roentgenologic features of the long bones are characteristic; they are first observable at the lower epiphysis of the ulna and femur, and consist of broadening and concavity with irregularity of the epiphysis. There is less density or calcification of the bone than in the normal. Characteristic changes in the chemical constituents of the blood may occur, with decrease in the percentage of inorganic phosphate. Osteomalacia and Osteoporosis.-Osteomalacia or adult rickets has frequently been reported in China but is not observed in the United States. Osteoporosis, however, is not of infrequent occurrence, but it is difficult to judge in the isolated case if it results from abnormality of calcium, phosphorus, parathyroid, or vitamin D metabolism. Not infrequently, in association with celiac disease, there may be osteoporosis, secondary probably to interference with absorption from the bowel of calcium or vitamin D. The recognition of osteoporosis depends entirely on roentgenologic examination. It frequently is associated with pain in the spinal column and shortening of the body height. Tetany.-Tetany may accompany rickets, or it may be associated with celiac disease or sprue which interferes with absorption of calcium~ phosphorus, and vitamin D. Tetany, however, is not the result of vitamin D deficiency exclusively. When osteoporosis and low serum calcium accompany tetany, the diagnosis is most likely tetany caused by insufficiency of calcium or of intake or absorption of vitamin D. Dental Caries.-There is little doubt that vitamin D is essential to normal dentition. An inadequate intake of vitamin D is considered by some workers as the most frequent cause of dental caries. An insufficient intake of vitamin D is not the only mechanism by which dental caries is produced, since caries may occur when intake -of vitamin D is adequate. Diagnosis of Vitamin D Deficiency.-The diagnosis of rickets is usually simple. When the classical symptoms are present, the diagnosis is obvious clinically. In cases in which the symptoms are less clear cut, the diagnosis may be suspected clinically and confirmed by roentgenologic studies of the long bones:,

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States of partial deficiency of vitamin D may be suspected if persons have dental caries, tetany, frequently occurring fractures, and osteoporosis of the bones. Patients who have abnormalities of intestinal absorption, such as occur in celiac disease, sprue, and so forth, may present such a deficiency. Whether it is the result of deficiency of calcium or phosphorus or of abnormalities in function of the parathyroid glands may be difficult to determine. The administration of vitamin D may be helpful in distinguishing osteoporosis which is on a basis of deficiency from other types, but it does not necessarily prove that it is attributable to deficiency of vitamin D alone. It is probable that states of vitamin D deficiency are extremely uncommon among adults. Prevention.-Vitamin D is specific in the prevention of rickets. It may be administered as cod liver oil, viosterol, irradiated milk, or cereals, or by irradiation of the skin by ultraviolet light. Shelling and Hopper reached the conclusion that five drops of viosterol containing about 1,125 U.S.P. units of vitamin D is efficacious in preventing rickets. Jeans reported that an animal source vitamin D in the amount present in one standard teaspoonful of average high-grade cod liver oil or in milk containing 400 U.S.P. units to the quart (1,000 c.c.) is adequate for the infant from the standpoint of retention of calcium and growth. Treatment.-Vitamin D can be administered in a variety of ways. It may be given in fish oils, such as cod liver oil (viosterol), and in a variety of foods, milk, cereals, and so forth. Irradiation of the skin with ultraviolet light will produce vitamin D in the skin, and is useful for the prevention and treatment of rickets. Foods which contain ergosterol, such as milk and cereals, can be irradiated before ingestion, and vitamin D activity may be obtained. Application of vitamin D to the skin results in absorption and utilization. of the vitamin. Therapeutic doses of vitamin D in treating rickets may be in the neighborhood of 20 drops of viosterol (4,500 U.S.P. units), or a similar number of units in other form. In adults with senile osteoporosis, 10 drops of viosterol three times daily in conjunction with 4 gm. of calcium lactate or tribasic calcium phosphate three times daily often will relieve symptoms.

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Since the demonstration that the original water-soluhle vitamin B is composed of several separate fractions, there has been much interest in the character and physiologic properties of the heat stable or antidermatitic factor, B2 or vitamin G. For years this vitamin has been mentioned as of etiologic significance in pellagra. Within the last year it has been demonstrated that vitamin G is in fact two substances: one a flavine and the other a supplementary substance contained in yeast extracts and identical with Gyorgy's vitamin B G • The physiologic functions of these two fractions are still not clear; apparently neither alone possesses the growth-promoting action which together they manifest. Recent evidence suggests that the pellagra-preventing factor is the supplementary substance of vitamin B G• Singly or together, the two factors are essential for normal functioning of the skin, nervous system, and gastro-intestinal tract. Pellagra.-The etiology of pellagra is still not clear. That a dietary fault exists in most cases seems certain, but whether or not such a faulty diet is the exclusiveetiologic agent has not been proved. While it has been generally accepted that pellagra associated with chronic alcoholism, or so-called alcoholic pellagra, is due to inadequate diet, eminent clinicians have previously failed to accept the likelihood that so-called endemic pellagra in the South was exclusively a deficiency disease. However, recent observations of McLester, Spies and their associates indicate that probably most if not all cases of endemic pellagra may be controlled or cured by dietary measures. Although pellagra is common in the South it is not often observed in the North, and when it occurs is often in association with chronic alcoholism and organic disease of the gastro-intestinal tract. This type of pellagra, secondary pellagra, has been noted by Eusterman and O'Leary and other workers, and is of serious prognostic importance, particularly if surgical treatment of a gastro-intestinal lesion is contemplated. The diagnosis of pellagra still rests on the triad of three d's -dermatitis, diarrhea, and dementia, but these occur simultaneously in severe cases only. Perhaps the most characteristic

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feature is the dermatitis, without which the diagnosis is difficult and questionable. The cutaneous lesions consist of dermatitis suggesting sunburn, a reddened, dirty-brown skin, parchmentlike, rough and scaly, affecting principally the exposed surfaces, especially the backs of the hands, wrists and forearms, usually in a symmetrical fashion. The face, neck, genitalia and legs may be similarly involved. Gastro-intestinal symptoms which accompany pellagra are variable; diarrhea is the most common in advanced cases and it may be intractable. In less severe cases there may be flatulence, anorexia, vague abdominal distress and at times constipation. Achlorhydria is a frequent finding. Nervous symptoms are not at all uncommon and while dementia is characteristic of severe pellagra in the less severe forms, symptoms characteristic of neurasthenia, such as exhaustion, lassitude, and insomnia, may be present. Loss of weight is characteristic. The development of any of these symptoms, when accompanied by dermatitis of the type mentioned, should suggest the possibility of pellagra. It is wise to examine the stomach and colon of patients for evidence of organic disease if they have pellagra and apparently have been on an adequate diet, or who because of gastro-intestinal symptoms are unable to eat normally. Not infrequently obstructing lesions, particularly malignant ones, or evidence of ulcerative colitis will be found. Treatment.-Despite variability in opinion as to its etiology, the treatment of pellagra is chiefly dietary. The rapid strides which have been made in this respect are well illustrated . by Spies, who reported that in the Lakeside Hospital, Cleveland, from 1926 to 1930, 54 per cent of seventy-three patients with pellagra died, despite good care in the hospital. During the past five years Spies and his associates have been able to reduce the mortality to 5 per cent or less among persons who have severe pellagra. The diet should be adequate, the patient should rest, and symptomatic measures should be instituted. In the dietary treatment, Spies has emphasized the importance of very large amounts of foods and preparations high in content of vitamins. Foods particularly rich in vitamin G are fresh vegetables, especially leafy ones, milk, cream and eggs. Beef, potatoes, and citrous juices are good sources of the vitamin. Yeast and VOL. 21-48

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DWIGHT L. WILBUR

yeast extracts are especially rich sources of vitamin G, which is also found in liver extract for parenteral use. In some cases in which vomiting is not present, Spies suggested the use of a well-balanced diet containing 4,000 calories or more, and in addition good brewers' yeast, wheat germ, or liver extract. Good brewers' yeast or wheat germ may be given in doses of 10 to 20 gm. in iced drinks at intervals of three to four hours to make a total of 75 to 100 gm. daily. Liver extract given parenterally in from three to five doses of 20 c.c. each daily is specific, and although expensive is of especial value for patients who, because of a sore mouth or vomiting, cannot tolerate an adequate diet. Adequate rest with hospital and nursing care is essential in the treatment of severe pellagra. Symptomatic treatment consists of the use of sedatives, antiseptic solutions, such as potassium permanganate, 1: 5,000, applied to the skin and tincture of· opium in large doses to control diarrhea. In milder cases in which the diagnosis is uncertain or questionable, the diet should be high in vitamin content and supplemented by 1 ounce (30 c.c.) or more of brewers' yeast or wheat germ, or liver extract given parenterally in doses of 10 c.c. daily. For patients with organic disease of the digestive tract and pellagra, and for whom surgical treatment is contemplated, the pellagra should be treated before any operative procedures are carried out. Such patients do not stand operations well. The use of liver extract parenterally is of particular value to these patients, since it permits administration of vitamin G without disturbing the gastro-intestinal tract and since the action is rapid.