- Email: [email protected]
Early Deficiency Diseases: Their Recognition and Treatment
The Medical Clinics of North America March, 1943
EARLY DEFICIENCY DISEASES: THEIR RECOGNITION AND TREATMENT JULIAN M. RUFFIN, M.D., F.A.C.P.-
IN past years the term "deficiency disease" has been used to designate such conditions as pellagra, beriberi, rickets and scurvy. We now know that these diseases represent advanced deficiencies of certain vitamins. They are clinical syndromes resulting from prolonged and profound vitamin depletion, and present characteristic features which, as a rule, can be recognized at a glance. The dermatitis, the appearance of the gums, mouth and tongue, the cheilosis, the keratitis, the mental confusion or delirium, the diarrhea and paresthesias of the extremities constitute a picture familiar to all and require no elaboration. Full-blown deficiency states are, however, becoming more and more infrequent. Today one rarely sees a true case of scurvy or beriberi in a general hospital, and even pellagra, which ten years ago was extremely common in certain sections of this country, is now encountered only occasionally. For example, in North Carolina, only 199 cases of pelllagra were reported in 1941, whereas in 1931 there were 2820. 1 It is reasonable to assume that all grades of deficiencies exist, ranging from those which are totally unrecognizable in the light of our present knowledge to those presenting the characteristic picture described above. Since such syndromes represent advanced stages of a vitamin deficiency, it follows that for every patient having pellagra or scurvy, for example, there must be many patients having a mild deficiency of . nicotinic acid or of vitamin C. It is with this group that our concern lies at the present time. • Associate Professor of Medicine and Director of the Medical Clinic, Duke University School of Medicine (Durham, North Carolina). 485
486
JULIAN M. RUFFIN
The Problem
The problem under discussion, then, is the recognition of those early phases of vitamin deficiency diseases whose vague general symptoms make the differential diagnosis extremely difficult. For example, one of the most unwanted and probably the most neglected patient of today is the so-called neurotic or neurasthenic-the person whose complaints are legion, such as weakness, nervousness, anorexia, indigestion, headache, backache, palpitation, and so on, whose "back draws and stomach quivers." Such patients constitute an all too familiar picture and are the bete noir of many clinics in this country. Do these patients really have organic disease or are they merely constitutional misfits, persons who have never been able to cope with the trials and vicissitudes of life? We know from experience that exhaustive studies, including blood and urine examinations, x-rays, electrocardiograms, basal metabolic rates, and blood chemistry will shed no light upon the diagnosis; and even operation or autopsy fails to give us the answer. Many physicians have adopted the attitude that they are essentially psychiatric problems. However, the question has been asked: "Is it possible that they represent an early or mild vitamin deficiency rather than a constitutional inferiority?" Vitamin Deficiencies Known to Occur in Man
It is now generally accepted that an· easily recognizable clinical picture results from an advanced deficiency of the following vit«mins: A, Bl (thiamine hydrochloride), nicotinic acid, riboflavin, C (ascorbic acid), D and K. While many other vitamins, especially those of the B complex, have been identified, there is still some doubt that their deficiency produces a characteristic syndrome in man. They may, and probably do, play an important part in intracellular metabolism. For example, it has been shown that certain patients having peripheral neuritis will not respond to the administration of thiamine until pantothenic acid is also given2; yet no characteristic syndrome in man resulting from pantothenic acid deficiency has been described. Such experiences lead us to the belief that single, isolated vitamin de-
EARLY DEFICIENCY DISEASES
487
ficiencies rarely if ever occur, a fact to be , borne constantly in mind when the question of treatment is being considered. DIAGNOSIS
While the diagnosis of advanced deficiency states is not difficult, the recognition of mild or early vitamin depletion presents a real problem. The diagnosis obviously must depend upon the correct evaluation of the symptoms, signs and accessory findings in any given case and also upon the response to specific therapy. I. History of an Inadequate Diet
Naturally, the history of subsistence upon a grossly inadequate diet would lead one to suspect the presence of an early deficiency. If there has been failure to include red meats, green vegetables and fruits, milk and eggs in the diet, some degree of nutritional deficiency may exist in the patient. However, failure to include these foods in the diet does not always lead to a vitamin deficiency, since it is possible to secure adequate vitamins from other sources. Likewise the history of an apparently adequate diet does not rule out a vitamin deficiency, for histories are frequently unreliable and the question of intestinal absorption has to be considered. Voluntary restriction of diet for any reason is a source of some of the deficiency states, and it should be borne in mind that the usual preoperative dietary restrictions are a potential source of trouble. In the South, most of the deficiencies are found in the tenant farmer class whose diet, in spite of an intensive educational program, still consists largely of white or corn bread, hominy grits, fatback, cow peas and molasses. 2. Symptoms
It has been pointed out that single deficiencies rarely, if ever, occur. It is difficult, therefore, to determine whether the symptoms described by the patient are due to a deficiency of one or more vitamins. It has been shown3 that vitamin C , deficiency as demonstrated by a low blood level of ascorbic acid is common and, as a rule, results in no recognizable symptoms. Vitamin A deficiencies are not often seen, and
488
JULIAN M. RUFFIN
likewise cause few if any symptoms in early cases. It seems probable that the symptoms which develop in early deficiency states are due to a depletion of one or more members of the B complex. By far the most constant and most important symptom in these early deficiencies is a sore mouth or tongue with or without cracks in the corners of the mouth. Ho,'Wever, preceding the development of the sore tongue the p'tients often complain of general lassitude, weakness, indigestion, nervousness, anorexia, insomnia or disturbance of bowel function, either constipation or Inild diarrhea. Occasionally, they may . complain of headache, palpitation, irritability or depression, nausea and paresthesias. They do not feel well but cannot describe clearly what is wrong. It must be realized that the symptoms described above are essentially those of the so-called "neurotic" or "neurasthenic" patient and it is frequently difficult if not impossible from the history alone to determine whether these are due to a vitamin deficiency, to a functional disturbance, or to some other unknown cause. The history of a sore mouth or tongue, cracks in the corners of the mouth, or paresthesia of the extremities should always be regarded as evidence of an early deficiency until it is proved to be otherwise. Patients having a true neu- . rosis or neurasthenia may develop an actual deficiency state and, indeed, the conditions frequently coexist. In such cases, the symptoms due to the deficiency can be alleviated by proper diet or vitamin therapy, whereas the underlying neurosis or neurasthenia will usually persist. 3. Physical Findings
Contrary to what might be expected, the apparent state of nutrition may be entirely normal in early deficiencies. At times, deficiency states are encountered in patients who are actually obese. As a rule the skin shows nothing unusual, . although one often sees scaling over the dorsum of the hands and a thickening and pigmentation over the bony prominences (Figs. 34 and 35). Occasionally one may observe small plugs in the follicles of the nasolabial folds (Fig. 36). These concretions are from 1 to 2 !Urn. in diameter and may
EARLY DEFICIENCY DISEASES
489
Fig. 34.-Thickening and pigmentation of the skin over hands. An inconstant finding and when present does not necessarily indicate a deficiency state.
Fig. 35.- Thickening. pigmentation and cracking of skin over bony prominences. May be due to trauma but often means a deficiency of the B complex.
490
JULIAN M. RUFFIN
be gray, light yellow, or brown in color. They are tightly adherent but after treatment will drop out, leaving a small depression. In more advanced cases they may occur over the nose or forehead.
Fig. 36.~Plugs in the sebaceous glands of nasolabial folds. Thought to indicate a riboflavin deficiency, but often clear up under nicotinic acid therapy alone. Most rapid recovery takes place after treattnent with crude liver extract or brewers' yeast.
By far the most important physical finding is that of a smooth, atrophic tongue (Figs. 37, 38, 39). The atrophy is observed first at the tip and on the margins. The whole tongue may be slick and shiny. In general, it is redder than normal and may have a beefy appearance. This marked red-
EARLY DEFICIENCY DISEASES
491
Fig. 37.-Normal tongue. Observe c?ating and papillae.
Fig. 38.-Atrophic tongue. Note papillary atrophy· on tip and at margins, also scars at the angles of the mouth. Earliest objective evidence of vitamin B deficiency.
492
JULIAN M. RUFFIN
ness may be present in spite of a severe anemia. The so-called "magenta tongue," said to occur in riboflavin deficiency,4 is rarely seen in this clinic. Accompanying the changes in the tongue, one frequently sees cracks or fissures at the angles of the mouth (Figs. 38,39). These are usually found on both sides, and vary from small cracks to deep fissures, which may bleed and are sometimes
Fig. 39.-Tongue showing marked atrophy of papillae. Note fissures at angles of mouth.
painful. At times they become encrusted. On healing, a thin white scar forms which may persist for months. These fissures are seen frequently in patients who have no teeth or poorly fitting dentures, but may occur in the presence of normal dentition. Spongy, bleeding gums, though known to occur especially in C deficiencies, are not often seen. The keratitis and vascularization of the cornea which have been described as early changes in riboflavin deficiency5 have been
EARLY DEFICIENCY DISEASES
493
an infrequent finding in this clinic, even though slit la,?p eXaInination has been employed in all cases. In genera~, the physical exmnination is otherwise negative except for the neurological findings. It is fairly common to demonstrate a diminution or loss of vibratory sense (to fork No. 256) and a stocking type of hypalgesia and of hypesthesia. The knee jerks are usually normal but occasionally the ankle jerks are diminished or absent. Calf tenderness is sometimes present but not common. Nutritional edema is rarely seen. Changes in the mental state of these patients have been mentioned. At times one observes a delayed reaction time, a mental sluggishness or retardation. Improvement in their mental state after proper therapy is often striking, and may be regarded as a therapeutic test of an existing deficiency. 4. Accessory Clinical Findings
The blood picture may be e~tirely normal but frequently a hypochromic anemia of varying severity is found. The urine and stool show nothing of significance. Occasionally one finds an achlorhydria but free hyw-ochloric acid may be present. Ileal studies are not particularly helpful since they usually are normal. In a few cases one will find pooling and segmentation of the barium suggesting from an x-ray standpoint an early deficiency stat~. This has been described7 as characteristic of sprue, but is common to many deficiency conditions. Gastroscopic findings likewise have proved disappointing. Atrophy of the gastric mucosa is found frequently in these conditions, but the mucosa may be normal. Total blood proteins and the albumin-globulin ratio are usually normal even in the presence of moderately severe deficiencies or anemias. Stool fat determination is within normal limits, except in patients having sprue or pancreatic disease. Basal metabolic rates, electrocardiograms and glucose tolerance tests are all normal. The proctoscopic. examination shows an entirely normal mucosa. Nerve biopsy, using the cutaneous nerve of the foot, shows evidence of degeneration in the majority of patients having early signs of a peripheral neuritis.
494
JULIAN M. RUFFIN
5. Vitamin Determinations
At the present time, in Duke Hospital, the following vitamin determinations* are being carried out: A, C, nicotinic acid, riboflavin, thiamine, pyridoxine, and K. Blood plasma is used for the determination of vitamins A and C. Nicotinic acid, thiamine, riboflavin and pyridoxine are determined by urinary excretion tests before and after test doses, and K is measured by the prothrombin time. Although too few cases have been studied to draw any final conclusions, the following generalizations can be made. The level of vitamin A is apt to be normal, except in cases of sprue or in patients having pancreatic disease. On the contrary, the level of C is well below the accepted normal value of 0.6 mg. per 10 cc. of plasma and is often zero, even though there is no clinical evidence of scurvy. The prothrombin time is usually normal, as is the pyridoxine determination. However, the excretion tests of nicotinic acid, thiamine and riboflavin are definitely lower than in normal controls. It should be pointed out that these tests are complicated procedures and lie strictly in the province of the special investigator. They are still in the experimental stage and their clinical usefulness at the present time is an unsettled question. 6. Response to Specific Therapy
Naturally, prompt or spectacular recovery after specific therapy is strong evidence of a vitamin deficiency. However, improvement in such symptoms as weakness, nervousness, indigestion and palpitation does not necessarily constitute proof of a deficiency state, as the same improvement is frequently encountered after treatment with such drugs as belladonna and phenobarbital. Improvement in such a vague clinical picture should be construed only as suggestive evidence of a deficiency. Summary
Since advanced deficiencies of vitamin A, thiamine, nicotinic acid, riboflavin, C, D and K result in easily recognizable .. This study is supported by a grant from the John and Mary R. Markle Foundation and the Anna H. Hanes Research Fund.
EARLY DEFICIENCY DISEASES
495
clinical pictures, and since the earliest symptoms of these deficiencies are so vague and indefinite as to render accurate classification impossible, it follows that at some stage in the development of the deficiency there must come a time when TABLE 1 SYMPTOMS, SIGNS AND LABORATORY FINDINGS NECESSARY FOR DIAGNOSIS OF MILD VITAMIN DEFICIENCIES*
Vitamin Deficiency A
Symptoms and Signs
Significant Laboratory Findings
Night blindness,t ch,anges in Decrease in blood level of viconjunctivae (?), scaly skin tamin A (?)
Thiamine (B I )
Paresthesia of extremities, Decrease in urinary excretion impairment of vibratory of thiamine. Nerve degeneration as shown by biopsy sense, decreased tendon reflexes, muscle tenderness
Nicotinic Acid
Sore mouth and tongue, red- Decrease in urinary excretion of nicotinic acid ness and papillary atrophy, roughening and scaling of skin over hands or bony prominences
Riboflavin
Photophobia and lacrimation, Vascularization of cornea, § decrease in urinary excretion of cheilosis,t "magenta tongue" (?) riboflavin
C
Spongy, bleeding gums, pe- Lowered vitamin C in blood techiae plasma
D K
Muscle weakness
Low blood phosphorus, elevation of serum phosphatase, x-ray changes
Bleeding
Increased prothrombin time
* Author's modification6 of table by Mackie.
t Occurs in conditions other than vitamin A deficiency. t Nonspecific. May occur in other deficiencies of the B complex and can be cured by vitamins other than riboflavin. § Nonspecific. Occurs in conditions other than riboflavin deficiency.
ce~ain findings are present which will justify the diagnosis. The significant symptoms, signs and laboratory findings which are necessary for the recognition of various mild vitamin deficiencies are shown in Table 1.
496
JULIAN M. RUFFIN TR EATM ENT6
Dietary Treament
Theoretically, the treatment of the mild vitamin deficiencies is simple and may be described in a few words: a well balanced diet supplemented with such vitamins as are indicated in each case. The patient should be urged to eat a variety of meats, green vegetables, milk, eggs and fruit juices. If such a diet is followed, and if there is no underlying disease which interferes with proper absorption and utilization, recovery is the rule. Unfortunately, it is one thing to prescribe a diet, but another to get the patient to eat it. There are few of us who are willing to change the habits of a lifetime. This is particularly true of tenant farmers, most of whom were raised on a deficient diet and show no inclination to change it even though they are warned that its continuance may prove detrimental to their health. The economic factor likewise plays a large part. The deficient diet to which these patients are accustomed is much cheaper than a well balanced one, and many of them simply cannot afford to buy the foods they need. Vitamin Therapy
When specific and recognizable deficiencies are found, vitamin therapy is definitely indicated but should always supplement dietary treatment, never replace it. In our experience, when one is reasonably sure that a specific deficiency is present, the best results are obtained only if the patient is given adequate doses of the vitamin or vitamins in which he is deficient. In deficiencies of the water-soluble vitamins, if no improvement is noted after ten to fourteen days of treatment, it is improbable that continued therapy will prove of value, and certainly there is little justification for continuing it longer than from three to four weeks. With the fat-soluble vitamin deficiencies, however, especially vitamin A, it may be necessary to continue treatment for a longer period of time. The most outstanding feature of the treatment of acute and severe vitamin deficiencies is the remarkable rapidity with
EARLY DEFICIENCY DISEASES
497
which symptoms subside when specific deficiencies are corrected by the administration of specific vitamins. It is justifiable to assume that in the mild deficiencies improvement should be noted just as rapidly as in the severe ones, and failure of the patient to improve after a reasonable length of time means either that there is a mistaken diagnosis or that irreyersible changes have taken place. In such cases further vitamin therapy is futile. In certain instances the parenteral administration of vitamins is not only justified but definitely indicated. In the preparation of the patient for an abdominal operation it is customary to administer large quantities of dextrose and saline solution by vein or subcutaneously. It has been emphasized by several writers that such a procedure may precipitate an TABLE 2 RECOMMENDED DOSAGE OF VITAMINS IN TREATMENT OF MILD DEFICIENCIES'
Vitamin A............................. Thiamine Hydrochloride. . . . . . . .. Nicotinic Acid. . . . . . . . . . . . . . . . .. Riboflavin. . . . . . . . . . . . . . . . . . . .. Ascorbic Acid .................. D .... '" ...................... K. . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Dosage (Oral) 15,000-20,000 U.S.P. units a day 5 mg. three times a day 50 mg. three times a day 1 mg. three times a day 0.1 gm. three times a day 2,000-2,500 U.S.P. units a day 1 mg. daily
acute deficiency state which might prove serious if not recognized and corrected. It is wise, therefore, whenever a subclinical deficiency is suspected, to give these patients, along with their dextrose, nicotinic acid, thiamine hydrochloride, riboflavin and ascorbic acid as a part of the preoperative care. In fact, the question of gastro-intestinal absorption of vita. mins is so poorly understood at the present time that one is justified in administering certain of the vitamins parenterally when specific deficiencies are suspected. This is particularly true in vitamin El and nicotinic acid deficiencies. It is customary to give 100 to 200 mg. of nicotinic acid and 20 to 30 mg. of thiamine hydrochloride intravenously for three to five days even though the deficiency is mild, continuing with the oral administration in much smaller doses for two to three weeks. The dosage recommended, after an initial three- to
498
JULIAN M. RUFFIN
five-day period in which larger doses are used either by mouth or parenterally, is shown in Table 2. The fact that single deficiencies are rarely, if ever, encountered is an excellent argument against the treatment of deficiency states with chemically pure substances. There are probably other vitamins as yet unknown which are essential to health. It is generally believed that yeast and whole liver contain most of the vitamins of the B complex, and it is a good practice when the patient can afford it to give whole liver, or an extract of liver, either by mouth or intramusculady. If liver extract cannot be obtained, brewers' yeaSt or autolyzed yeast (Vegex) is a satisfactory substitute. One must not lose sight of the fact that many maladjusted and neurasthenic persons have a coexisting mild vitamin deficiency. It is important, of course, to correct this deficiency by diet if possible, supplemented by vitamins if necessary. It is equally important to realize that vitamins are not the panacea of all ills; that they afford little relief in social, financial or domestic problems, that long-continued treatment with expensive vitamins is a serious and unnecessary drain on the patient's pocketbook and that, in the last analysis, a well balanced diet is the best treatment in most of the cases of mild vitamin deficiencies. The solution of the problem of the deficiency diseases lies not so much in the cure of the deficiency as in its prevention, not in the administration of pills but in an educational and social program which will not only teach the poorer classes what to eat but make it possible for them to secure the foods which are necessary for the maintenance of health. BIBLIOGRAPHY
1. Knox, J. C.: Personal communication, North Carolina State Board of Health, Raleigh, N. C. 2. Gordon, Edgar S.: Pantothenic Acid in Human Nutrition, The Biological Action of the Vitamins. Chicago, University of Chicago Press, July, 1942, pp. 136-142. 3. Milam, D. F.: A Nutrition Survey of a Small North Carolina Community. Am. J. Pub. Health, 32:406-412 (April) 1942. 4. Sydenstricker, V. P.: The Clinical Manifestations of Nicotinic Acid and Riboflavin Deficiency (Pellagra). Ann. Int. Med., 14:1499 (March) 1941.
EARLY DEFICIENCY DISEASES
499
5. Kruse, H. D., Sydenstricker, V. P., Sebrell, W. H. and Cleckley, H. M.: The Ocular Manifestations of Ariboflavinosis. Pub. Health Rep., 5): 157-169 (Jan. 26) 1940. 6. Ruffin, Julian M.: The Diagnosis and Treatment of Mild Vitamin Deficiencies: A Clinical Discussion. J.A.M.A., 117:1493-1496 (Nov. 1) 1941.
7. Hurst, Arthur: Pathogenesis of the Sprue Syndrome. Guy's Hospital Report, 91:1, 1942.
EARLY DEFICIENCY DISEASES: THEIR RECOGNITION AND TREATMENT JULIAN M. RUFFIN, M.D., F.A.C.P.-
IN past years the term "deficiency disease" has been used to designate such conditions as pellagra, beriberi, rickets and scurvy. We now know that these diseases represent advanced deficiencies of certain vitamins. They are clinical syndromes resulting from prolonged and profound vitamin depletion, and present characteristic features which, as a rule, can be recognized at a glance. The dermatitis, the appearance of the gums, mouth and tongue, the cheilosis, the keratitis, the mental confusion or delirium, the diarrhea and paresthesias of the extremities constitute a picture familiar to all and require no elaboration. Full-blown deficiency states are, however, becoming more and more infrequent. Today one rarely sees a true case of scurvy or beriberi in a general hospital, and even pellagra, which ten years ago was extremely common in certain sections of this country, is now encountered only occasionally. For example, in North Carolina, only 199 cases of pelllagra were reported in 1941, whereas in 1931 there were 2820. 1 It is reasonable to assume that all grades of deficiencies exist, ranging from those which are totally unrecognizable in the light of our present knowledge to those presenting the characteristic picture described above. Since such syndromes represent advanced stages of a vitamin deficiency, it follows that for every patient having pellagra or scurvy, for example, there must be many patients having a mild deficiency of . nicotinic acid or of vitamin C. It is with this group that our concern lies at the present time. • Associate Professor of Medicine and Director of the Medical Clinic, Duke University School of Medicine (Durham, North Carolina). 485
486
JULIAN M. RUFFIN
The Problem
The problem under discussion, then, is the recognition of those early phases of vitamin deficiency diseases whose vague general symptoms make the differential diagnosis extremely difficult. For example, one of the most unwanted and probably the most neglected patient of today is the so-called neurotic or neurasthenic-the person whose complaints are legion, such as weakness, nervousness, anorexia, indigestion, headache, backache, palpitation, and so on, whose "back draws and stomach quivers." Such patients constitute an all too familiar picture and are the bete noir of many clinics in this country. Do these patients really have organic disease or are they merely constitutional misfits, persons who have never been able to cope with the trials and vicissitudes of life? We know from experience that exhaustive studies, including blood and urine examinations, x-rays, electrocardiograms, basal metabolic rates, and blood chemistry will shed no light upon the diagnosis; and even operation or autopsy fails to give us the answer. Many physicians have adopted the attitude that they are essentially psychiatric problems. However, the question has been asked: "Is it possible that they represent an early or mild vitamin deficiency rather than a constitutional inferiority?" Vitamin Deficiencies Known to Occur in Man
It is now generally accepted that an· easily recognizable clinical picture results from an advanced deficiency of the following vit«mins: A, Bl (thiamine hydrochloride), nicotinic acid, riboflavin, C (ascorbic acid), D and K. While many other vitamins, especially those of the B complex, have been identified, there is still some doubt that their deficiency produces a characteristic syndrome in man. They may, and probably do, play an important part in intracellular metabolism. For example, it has been shown that certain patients having peripheral neuritis will not respond to the administration of thiamine until pantothenic acid is also given2; yet no characteristic syndrome in man resulting from pantothenic acid deficiency has been described. Such experiences lead us to the belief that single, isolated vitamin de-
EARLY DEFICIENCY DISEASES
487
ficiencies rarely if ever occur, a fact to be , borne constantly in mind when the question of treatment is being considered. DIAGNOSIS
While the diagnosis of advanced deficiency states is not difficult, the recognition of mild or early vitamin depletion presents a real problem. The diagnosis obviously must depend upon the correct evaluation of the symptoms, signs and accessory findings in any given case and also upon the response to specific therapy. I. History of an Inadequate Diet
Naturally, the history of subsistence upon a grossly inadequate diet would lead one to suspect the presence of an early deficiency. If there has been failure to include red meats, green vegetables and fruits, milk and eggs in the diet, some degree of nutritional deficiency may exist in the patient. However, failure to include these foods in the diet does not always lead to a vitamin deficiency, since it is possible to secure adequate vitamins from other sources. Likewise the history of an apparently adequate diet does not rule out a vitamin deficiency, for histories are frequently unreliable and the question of intestinal absorption has to be considered. Voluntary restriction of diet for any reason is a source of some of the deficiency states, and it should be borne in mind that the usual preoperative dietary restrictions are a potential source of trouble. In the South, most of the deficiencies are found in the tenant farmer class whose diet, in spite of an intensive educational program, still consists largely of white or corn bread, hominy grits, fatback, cow peas and molasses. 2. Symptoms
It has been pointed out that single deficiencies rarely, if ever, occur. It is difficult, therefore, to determine whether the symptoms described by the patient are due to a deficiency of one or more vitamins. It has been shown3 that vitamin C , deficiency as demonstrated by a low blood level of ascorbic acid is common and, as a rule, results in no recognizable symptoms. Vitamin A deficiencies are not often seen, and
488
JULIAN M. RUFFIN
likewise cause few if any symptoms in early cases. It seems probable that the symptoms which develop in early deficiency states are due to a depletion of one or more members of the B complex. By far the most constant and most important symptom in these early deficiencies is a sore mouth or tongue with or without cracks in the corners of the mouth. Ho,'Wever, preceding the development of the sore tongue the p'tients often complain of general lassitude, weakness, indigestion, nervousness, anorexia, insomnia or disturbance of bowel function, either constipation or Inild diarrhea. Occasionally, they may . complain of headache, palpitation, irritability or depression, nausea and paresthesias. They do not feel well but cannot describe clearly what is wrong. It must be realized that the symptoms described above are essentially those of the so-called "neurotic" or "neurasthenic" patient and it is frequently difficult if not impossible from the history alone to determine whether these are due to a vitamin deficiency, to a functional disturbance, or to some other unknown cause. The history of a sore mouth or tongue, cracks in the corners of the mouth, or paresthesia of the extremities should always be regarded as evidence of an early deficiency until it is proved to be otherwise. Patients having a true neu- . rosis or neurasthenia may develop an actual deficiency state and, indeed, the conditions frequently coexist. In such cases, the symptoms due to the deficiency can be alleviated by proper diet or vitamin therapy, whereas the underlying neurosis or neurasthenia will usually persist. 3. Physical Findings
Contrary to what might be expected, the apparent state of nutrition may be entirely normal in early deficiencies. At times, deficiency states are encountered in patients who are actually obese. As a rule the skin shows nothing unusual, . although one often sees scaling over the dorsum of the hands and a thickening and pigmentation over the bony prominences (Figs. 34 and 35). Occasionally one may observe small plugs in the follicles of the nasolabial folds (Fig. 36). These concretions are from 1 to 2 !Urn. in diameter and may
EARLY DEFICIENCY DISEASES
489
Fig. 34.-Thickening and pigmentation of the skin over hands. An inconstant finding and when present does not necessarily indicate a deficiency state.
Fig. 35.- Thickening. pigmentation and cracking of skin over bony prominences. May be due to trauma but often means a deficiency of the B complex.
490
JULIAN M. RUFFIN
be gray, light yellow, or brown in color. They are tightly adherent but after treatment will drop out, leaving a small depression. In more advanced cases they may occur over the nose or forehead.
Fig. 36.~Plugs in the sebaceous glands of nasolabial folds. Thought to indicate a riboflavin deficiency, but often clear up under nicotinic acid therapy alone. Most rapid recovery takes place after treattnent with crude liver extract or brewers' yeast.
By far the most important physical finding is that of a smooth, atrophic tongue (Figs. 37, 38, 39). The atrophy is observed first at the tip and on the margins. The whole tongue may be slick and shiny. In general, it is redder than normal and may have a beefy appearance. This marked red-
EARLY DEFICIENCY DISEASES
491
Fig. 37.-Normal tongue. Observe c?ating and papillae.
Fig. 38.-Atrophic tongue. Note papillary atrophy· on tip and at margins, also scars at the angles of the mouth. Earliest objective evidence of vitamin B deficiency.
492
JULIAN M. RUFFIN
ness may be present in spite of a severe anemia. The so-called "magenta tongue," said to occur in riboflavin deficiency,4 is rarely seen in this clinic. Accompanying the changes in the tongue, one frequently sees cracks or fissures at the angles of the mouth (Figs. 38,39). These are usually found on both sides, and vary from small cracks to deep fissures, which may bleed and are sometimes
Fig. 39.-Tongue showing marked atrophy of papillae. Note fissures at angles of mouth.
painful. At times they become encrusted. On healing, a thin white scar forms which may persist for months. These fissures are seen frequently in patients who have no teeth or poorly fitting dentures, but may occur in the presence of normal dentition. Spongy, bleeding gums, though known to occur especially in C deficiencies, are not often seen. The keratitis and vascularization of the cornea which have been described as early changes in riboflavin deficiency5 have been
EARLY DEFICIENCY DISEASES
493
an infrequent finding in this clinic, even though slit la,?p eXaInination has been employed in all cases. In genera~, the physical exmnination is otherwise negative except for the neurological findings. It is fairly common to demonstrate a diminution or loss of vibratory sense (to fork No. 256) and a stocking type of hypalgesia and of hypesthesia. The knee jerks are usually normal but occasionally the ankle jerks are diminished or absent. Calf tenderness is sometimes present but not common. Nutritional edema is rarely seen. Changes in the mental state of these patients have been mentioned. At times one observes a delayed reaction time, a mental sluggishness or retardation. Improvement in their mental state after proper therapy is often striking, and may be regarded as a therapeutic test of an existing deficiency. 4. Accessory Clinical Findings
The blood picture may be e~tirely normal but frequently a hypochromic anemia of varying severity is found. The urine and stool show nothing of significance. Occasionally one finds an achlorhydria but free hyw-ochloric acid may be present. Ileal studies are not particularly helpful since they usually are normal. In a few cases one will find pooling and segmentation of the barium suggesting from an x-ray standpoint an early deficiency stat~. This has been described7 as characteristic of sprue, but is common to many deficiency conditions. Gastroscopic findings likewise have proved disappointing. Atrophy of the gastric mucosa is found frequently in these conditions, but the mucosa may be normal. Total blood proteins and the albumin-globulin ratio are usually normal even in the presence of moderately severe deficiencies or anemias. Stool fat determination is within normal limits, except in patients having sprue or pancreatic disease. Basal metabolic rates, electrocardiograms and glucose tolerance tests are all normal. The proctoscopic. examination shows an entirely normal mucosa. Nerve biopsy, using the cutaneous nerve of the foot, shows evidence of degeneration in the majority of patients having early signs of a peripheral neuritis.
494
JULIAN M. RUFFIN
5. Vitamin Determinations
At the present time, in Duke Hospital, the following vitamin determinations* are being carried out: A, C, nicotinic acid, riboflavin, thiamine, pyridoxine, and K. Blood plasma is used for the determination of vitamins A and C. Nicotinic acid, thiamine, riboflavin and pyridoxine are determined by urinary excretion tests before and after test doses, and K is measured by the prothrombin time. Although too few cases have been studied to draw any final conclusions, the following generalizations can be made. The level of vitamin A is apt to be normal, except in cases of sprue or in patients having pancreatic disease. On the contrary, the level of C is well below the accepted normal value of 0.6 mg. per 10 cc. of plasma and is often zero, even though there is no clinical evidence of scurvy. The prothrombin time is usually normal, as is the pyridoxine determination. However, the excretion tests of nicotinic acid, thiamine and riboflavin are definitely lower than in normal controls. It should be pointed out that these tests are complicated procedures and lie strictly in the province of the special investigator. They are still in the experimental stage and their clinical usefulness at the present time is an unsettled question. 6. Response to Specific Therapy
Naturally, prompt or spectacular recovery after specific therapy is strong evidence of a vitamin deficiency. However, improvement in such symptoms as weakness, nervousness, indigestion and palpitation does not necessarily constitute proof of a deficiency state, as the same improvement is frequently encountered after treatment with such drugs as belladonna and phenobarbital. Improvement in such a vague clinical picture should be construed only as suggestive evidence of a deficiency. Summary
Since advanced deficiencies of vitamin A, thiamine, nicotinic acid, riboflavin, C, D and K result in easily recognizable .. This study is supported by a grant from the John and Mary R. Markle Foundation and the Anna H. Hanes Research Fund.
EARLY DEFICIENCY DISEASES
495
clinical pictures, and since the earliest symptoms of these deficiencies are so vague and indefinite as to render accurate classification impossible, it follows that at some stage in the development of the deficiency there must come a time when TABLE 1 SYMPTOMS, SIGNS AND LABORATORY FINDINGS NECESSARY FOR DIAGNOSIS OF MILD VITAMIN DEFICIENCIES*
Vitamin Deficiency A
Symptoms and Signs
Significant Laboratory Findings
Night blindness,t ch,anges in Decrease in blood level of viconjunctivae (?), scaly skin tamin A (?)
Thiamine (B I )
Paresthesia of extremities, Decrease in urinary excretion impairment of vibratory of thiamine. Nerve degeneration as shown by biopsy sense, decreased tendon reflexes, muscle tenderness
Nicotinic Acid
Sore mouth and tongue, red- Decrease in urinary excretion of nicotinic acid ness and papillary atrophy, roughening and scaling of skin over hands or bony prominences
Riboflavin
Photophobia and lacrimation, Vascularization of cornea, § decrease in urinary excretion of cheilosis,t "magenta tongue" (?) riboflavin
C
Spongy, bleeding gums, pe- Lowered vitamin C in blood techiae plasma
D K
Muscle weakness
Low blood phosphorus, elevation of serum phosphatase, x-ray changes
Bleeding
Increased prothrombin time
* Author's modification6 of table by Mackie.
t Occurs in conditions other than vitamin A deficiency. t Nonspecific. May occur in other deficiencies of the B complex and can be cured by vitamins other than riboflavin. § Nonspecific. Occurs in conditions other than riboflavin deficiency.
ce~ain findings are present which will justify the diagnosis. The significant symptoms, signs and laboratory findings which are necessary for the recognition of various mild vitamin deficiencies are shown in Table 1.
496
JULIAN M. RUFFIN TR EATM ENT6
Dietary Treament
Theoretically, the treatment of the mild vitamin deficiencies is simple and may be described in a few words: a well balanced diet supplemented with such vitamins as are indicated in each case. The patient should be urged to eat a variety of meats, green vegetables, milk, eggs and fruit juices. If such a diet is followed, and if there is no underlying disease which interferes with proper absorption and utilization, recovery is the rule. Unfortunately, it is one thing to prescribe a diet, but another to get the patient to eat it. There are few of us who are willing to change the habits of a lifetime. This is particularly true of tenant farmers, most of whom were raised on a deficient diet and show no inclination to change it even though they are warned that its continuance may prove detrimental to their health. The economic factor likewise plays a large part. The deficient diet to which these patients are accustomed is much cheaper than a well balanced one, and many of them simply cannot afford to buy the foods they need. Vitamin Therapy
When specific and recognizable deficiencies are found, vitamin therapy is definitely indicated but should always supplement dietary treatment, never replace it. In our experience, when one is reasonably sure that a specific deficiency is present, the best results are obtained only if the patient is given adequate doses of the vitamin or vitamins in which he is deficient. In deficiencies of the water-soluble vitamins, if no improvement is noted after ten to fourteen days of treatment, it is improbable that continued therapy will prove of value, and certainly there is little justification for continuing it longer than from three to four weeks. With the fat-soluble vitamin deficiencies, however, especially vitamin A, it may be necessary to continue treatment for a longer period of time. The most outstanding feature of the treatment of acute and severe vitamin deficiencies is the remarkable rapidity with
EARLY DEFICIENCY DISEASES
497
which symptoms subside when specific deficiencies are corrected by the administration of specific vitamins. It is justifiable to assume that in the mild deficiencies improvement should be noted just as rapidly as in the severe ones, and failure of the patient to improve after a reasonable length of time means either that there is a mistaken diagnosis or that irreyersible changes have taken place. In such cases further vitamin therapy is futile. In certain instances the parenteral administration of vitamins is not only justified but definitely indicated. In the preparation of the patient for an abdominal operation it is customary to administer large quantities of dextrose and saline solution by vein or subcutaneously. It has been emphasized by several writers that such a procedure may precipitate an TABLE 2 RECOMMENDED DOSAGE OF VITAMINS IN TREATMENT OF MILD DEFICIENCIES'
Vitamin A............................. Thiamine Hydrochloride. . . . . . . .. Nicotinic Acid. . . . . . . . . . . . . . . . .. Riboflavin. . . . . . . . . . . . . . . . . . . .. Ascorbic Acid .................. D .... '" ...................... K. . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Dosage (Oral) 15,000-20,000 U.S.P. units a day 5 mg. three times a day 50 mg. three times a day 1 mg. three times a day 0.1 gm. three times a day 2,000-2,500 U.S.P. units a day 1 mg. daily
acute deficiency state which might prove serious if not recognized and corrected. It is wise, therefore, whenever a subclinical deficiency is suspected, to give these patients, along with their dextrose, nicotinic acid, thiamine hydrochloride, riboflavin and ascorbic acid as a part of the preoperative care. In fact, the question of gastro-intestinal absorption of vita. mins is so poorly understood at the present time that one is justified in administering certain of the vitamins parenterally when specific deficiencies are suspected. This is particularly true in vitamin El and nicotinic acid deficiencies. It is customary to give 100 to 200 mg. of nicotinic acid and 20 to 30 mg. of thiamine hydrochloride intravenously for three to five days even though the deficiency is mild, continuing with the oral administration in much smaller doses for two to three weeks. The dosage recommended, after an initial three- to
498
JULIAN M. RUFFIN
five-day period in which larger doses are used either by mouth or parenterally, is shown in Table 2. The fact that single deficiencies are rarely, if ever, encountered is an excellent argument against the treatment of deficiency states with chemically pure substances. There are probably other vitamins as yet unknown which are essential to health. It is generally believed that yeast and whole liver contain most of the vitamins of the B complex, and it is a good practice when the patient can afford it to give whole liver, or an extract of liver, either by mouth or intramusculady. If liver extract cannot be obtained, brewers' yeaSt or autolyzed yeast (Vegex) is a satisfactory substitute. One must not lose sight of the fact that many maladjusted and neurasthenic persons have a coexisting mild vitamin deficiency. It is important, of course, to correct this deficiency by diet if possible, supplemented by vitamins if necessary. It is equally important to realize that vitamins are not the panacea of all ills; that they afford little relief in social, financial or domestic problems, that long-continued treatment with expensive vitamins is a serious and unnecessary drain on the patient's pocketbook and that, in the last analysis, a well balanced diet is the best treatment in most of the cases of mild vitamin deficiencies. The solution of the problem of the deficiency diseases lies not so much in the cure of the deficiency as in its prevention, not in the administration of pills but in an educational and social program which will not only teach the poorer classes what to eat but make it possible for them to secure the foods which are necessary for the maintenance of health. BIBLIOGRAPHY
1. Knox, J. C.: Personal communication, North Carolina State Board of Health, Raleigh, N. C. 2. Gordon, Edgar S.: Pantothenic Acid in Human Nutrition, The Biological Action of the Vitamins. Chicago, University of Chicago Press, July, 1942, pp. 136-142. 3. Milam, D. F.: A Nutrition Survey of a Small North Carolina Community. Am. J. Pub. Health, 32:406-412 (April) 1942. 4. Sydenstricker, V. P.: The Clinical Manifestations of Nicotinic Acid and Riboflavin Deficiency (Pellagra). Ann. Int. Med., 14:1499 (March) 1941.
EARLY DEFICIENCY DISEASES
499
5. Kruse, H. D., Sydenstricker, V. P., Sebrell, W. H. and Cleckley, H. M.: The Ocular Manifestations of Ariboflavinosis. Pub. Health Rep., 5): 157-169 (Jan. 26) 1940. 6. Ruffin, Julian M.: The Diagnosis and Treatment of Mild Vitamin Deficiencies: A Clinical Discussion. J.A.M.A., 117:1493-1496 (Nov. 1) 1941.
7. Hurst, Arthur: Pathogenesis of the Sprue Syndrome. Guy's Hospital Report, 91:1, 1942.