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Thiamine Deficiency*
The Medical Clinics of North America March,1943
THIAMINE
DEFICIENCY·
RUSSELL M. WILDER, M.D., F.A.C.P.t BERIBERI
THE origin of the name "beriberi". is Singhalese, the native language· of Ceylon. The word means "I cannot" (Dorland). Great antiquity has been attributed to this disease. Descriptions of it are said to have appeared in Chinese litera-. ture of the third century before Christ, and a description is quoted by Vedder from the writings in 1642 A. D. of the Dutch physician JacobQj Bontius. However, a rereading of the classic treatises on beriberi by Braddon and Vedder, and of Vedder's translation of Bontius' description, leaves one with a strong suspicion that the disease called by this name by the ancients was something different from the beriberi of the late nineteenth and early twentieth centuries. The latter seems to have developed since the introduction of steampowered rice mills. Confusion always has existed in the differentiation of beriberi from hungeredema, scurvy and several tropical diseases, a fact which suggests that the disease described in antiquity and even by Bontius, although in some ways resembling the beriberi of more recent times, was not the same disease. Furthermore, long after beriberi became very prevalent in China, Burma, Java and Malaya, it was confined to persons whose diets consisted largely of highly milled or polished rice from commercial mills. At the same time it remained almost unknown, in the same regions, in the native populations subsisting on undermilled or unpolished rice from primitive mills. 1, 8 According to Vedder, it is possible to prepare a rice by primitive milling methods which is as highly polished as rice from the steam-powered mills. However, this involves much labor and such rice in all prob• From the Division of Medicine, Mayo Clinic, Rochester, Minnesota.
t Professor of Medicine, Mayo Foundation (Rochester, Minnesota);
Member, Food and Nutrition Board, National Research Council. 409
410
RUSSELL M. WILDER
ability was never prepared, in ancient times, in more than relatively small amounts . .Beriberi: a Deficiency Disease.-The recognition of beriberi as a deficiency disease resulted from Eijkman's4, 8 observations, begun in Java in 1890. Eijkman found that among fowls fed polished rice, weakness of the legs and other symptoms like those of human beriberi developed. Later, following other research, in cooperation with Grijns and V ordermann, he developed his conclusion that "there is present in rice polishings a substance . . . which is indispensable to health and lack of which causes nutritional polyneuritis." Incidence, Severity and Types of Beriberi.-A fifth of all disease in Malaya has been attributed to beriberi, with mortality rates in "epidemid" varying between recovery of all and death of all of those who developed the disease. 8 The average mortality rate, according to Vedder, has been 5 per cent. Three types of the disease have been described: (1) dry beriberi, in which multiple neuritis is the predominating feature; (2) wet beriberi, in which there are edema and serous effusion" without heart failure, and (3) a cardiac (acute) type with circulatory failure. Beriberi of infants, breast fed by women who themselves have latent or manifest beriberi, has been described by some writers. The common symptoms among these infants are vomiting, edema, aphonia, and in most cases loss of knee jerks. Beriberi in tbe Occident.-It is not to be supposed that beriberi is confined to the rice consumers of the Orient. 2 , 4, 9 .The disease has appeared in ships at sea, with or without accompanying scurvy, when rations were limited to ship biscuit and canned meat. It has been prevalent in Labrador and Newfoundland, where white bread, molasses and salt meat constituted the major part of the diets of many inhabitants. It developed among the British troops, restricted to white flour biscuits (hard tack) and horse meat, at the siege of Kut, and has been reported in "epidemic" form in several prisons or other institutions in the United States when white bread made up the major portion of a poor dietary.' More recently it has been recognized as a fairly common complication of alcoholism and pregnancy.
THIAMINE DEFICIENCY
411
Thiamine (Vitamin B1 ) Deficiency in Beriberi.-Few, if any, of the diseases attributed to malnutrition represent a deficiency of any single nutrient, and beriberi is no exception to the general rule. It does appear, however, that the pre.,. dominant deficiency in beriberi is that of thiamine (vitamin Bl ). A syndrome closely resembling beriberi can be produced in animals and man by limiting the intake of this vitamin. THIAMINE IN
FOODS
Thiamine occurs in almost every form of living thing and thus is present in every food as grown. However, fruits and several other foods, including the leafy green and yellow vegetables which are rich in other nutritive factors, are relatively poor in thiamine. The better sources are meat, peas and beans, nuts and grain. Furthermore, thiamine is destroyed by exposure to a temperature which is only a little higher than that of boiling water, so that canned meats subjected to autoclaving and all toasted cereals have lost much of their thiamine content. In the grains, and especially in rice and wheat, most of the thiamine is found in the layer of cells (the aleurone layer) which lies between the outer bran and the starch-filled cells of the endosperm. In modern commercial milling of both rice and wheat the aleurone layer is removed with the bran, whereas primitive methods of milling left this lay-er and with it most of the thiamine. The milling of wheat by modern methods, together with displacement by sugar of much of the wheat flour consumed in former times, has given the average Englishman of today a diet that contains less than half and little more than a third as much thiamine as was consumed by his forebears. The dietary situation in the United States is much the same as that in England, and the only reason that beriberi has been less common in these countries than in the Orient, where highly milled rice supplanted the rice of the primitive mills, is that decorticated wheat and sugar have together constituted a relatively smaller proportion of the total calories in most English and American diets than has rice in Oriental diets. The change nevertheless has been drastic, and the present low provision of thiamine is not
412
RUSSELL M. WILDER
without significance to the health of many persons in this and other countries where wheat is the staple food. * The basis for this assertion was revealed experimentally as follows: THIAMINE REQUIREMENTS
Thiamine deficiency was induced in human volunteers by Williams and associates 12 ,'14 by means of a diet of analyzed composition adequate in all other nutrients but limited in thiamine. In one of the experimentsl l the diet contained plain white flour and sugar in amounts comparable to the average daily per capita consumption of white flour and sugar in the United States. The balance of this diet was composed of foods which commonly appear on American tables. They did not, however, compensate adequately for the deficiencies of the flour and sugar. Beans, peas and nuts were omitted, but 3 ounces (85 gm.) of meat was provided as well as fruit, coffee cream, butter and leafy green and yellow vegetables. Supplements containing other vitamins and minerals insured an adequate supply of them. Although this diet contained by analysis as consumed only from 0.20 to 0.22 mg. of thiamine per 1000 calories, it could reasonably be regarded as not worse in this respect than the diets provided in many American and English families. Drummond and Wilbraham found the diet of working classes in England to contain 0.66 mg. of thiamine.a Symptoms of severe ill health and measurable abnormalities of metabolism developed among the subjects who ate the experimental diet described. This and other experiments similarly conducted10, 13 finally led to the conclusion that the minimal amount of thiamine required to prevent all evidence of thiamine deficiency, in persons whose diets contain carbohydrate, fat and protein in conventional proportions, is at least 0.45 mg. per 1000 calories. In the light of these studies the provision of 0.6 mg. per 1000 calories recommended by the Food and Nutrition Board in the Washington Nutrition Yardstick appears to be ·It was this situation that led to the recommendation of the Food and Nutrition Board of the National Research Council for restoration to white flour of an amount of thiamine approximating that removed in milling. The resulting enriched white flour and bread also should have added nicotinic acid (niacin) and iron in amounts related to those removed in milling.
THIAMINE DEFICIENCY
413
none too high. For a moderately active man consuming 3000 calories the recommended allowance of thiamine is 1.8 mg. or 600 international units. SYMPTOMS OF THIAMINE DEFICIENCY
The most conspicuous of the early abnormalities developing in all the experimental subjects of Williams and his associates, when the diet provided from 0.20 to 0.22 mg. of thiamine per 1000 calories, were changes in attitude and behavior and diminished inclination to perform accustomed tasks. All the subjects became depressed, uncooperative, apprehensive, irritable and quarrelsome. All became inefficient in their work and suffered minor accidents caused by clumsiness. In part this could be related to loss of ability to concentrate attention, in part to uncertainty of memory, in part to actual weakness. The Singhalese name "beriberi" ("I cannot") applies appropriately to the syndrome of athiaminosis. The abnormalities described and others to be related were not observable in a period of several weeks preliminary to the period of deprivation. They developed and increased~pro gressively in intensity during the many months of deprivation and disappeared after days or weeks when the intake of thiamine was increased. Thechartges of intake of thiamine were always made without knowledge of the subjects. Other complaints. in the periods of restricted thiamine were headache, backache, painful menses, sleeplessness, formication and sensitiveness to noise. Loss of appetite developed early in all cases and forced feeding later became necessary in many cases. There was little diarrhea; constipation was the rule. Slowing of the emptying time of the stomach and sluggish motility of the intestine could be demonstrated roentgenologically with barium meals. Epigastric burning after meals was a common complaint. Exertion aggravated all complaints. The weakness provoked by increasing exertion led to inactivity which in turn resulted in a relative remission. Thus all symptoms waxed and waned. 'Abnormalities of Metabolism.- The basal metabolic rate in most cases was lowered from 10 to 30 per cent. This was independent of any loss of body weight or limitation of the
414'
RUSSEL L M. WILDE R
total food ingested. The concentration of serum protein decreased moder ately in certain cases but not to less than the critical level of edema formation. Anemia of a macrocytic hyperchromi~ type developed in several instances. It was associated WIth achlorhydrIa. . The amoun t of thiamine in the twenty -four-h our collections of urine fell to levels that remained consistently much less than 0.1 mg. a day, and when test doses of 1 mg. of thiamine hydroc hlorid e were administered parenterally, 80 per cent or more was retained, in contrast to retention of only 60 per cent or less when the ti~sue stores of thiamine were adequate. Slightly elevated fastmg values for sugar in the blood and elevated blood sugar time curves occurred in some cases. They resembled those obtained in cases of mild diabetes. Abnormal elevations of the concentration in the blood of pyruvic acid and lactic acid were observed, especially after administration of glucose. 15 * Cardiovascular Distur bance s.-Low blood pressures (85 to 100 mm. of mercu ry systolic, 50 to 60 diastolic) developed in every case, together with symptoms of vasomotor instability, including pallor and giddiness on rising from recumbent positions. The pulse rates at rest were slow but abnormal acceleration always followed moderate exertion. There was marked sinus arrhythmia and complaints of precordial distress (pseudo-angina) were frequent. The T waves of the electrocardiogram were diminished, and in CR-2 leads became inverted. On the other hand, dilatation of the right side of the heart, such as is described in beriberi, was never detected, and the venous pressures remained normal. A moderate degree of pitting edema of the legs developed in only one subject; otherwise there was nothing to suggest the anasarca of the "wet" beriberi of the Orient. Possibly the edema so characteristic of Oriental beriberi depends less on deficiency of thiamine than on a deficiency of other nutrients or on the poor biologic quality of the protein obtained. Pos• Peters6 and his associates have shown that the signs of thiamine deficiency in p~geons ~nd rat~ result from a metabolic disorder of the nervous tissue, involvmg a bIOchemical defect of the process by which accumu lating pyruvic acid is normally removed.
THIAMINE DEFICIENCY
415
sibly the periods of restriction of thiamine in the experiments were too short or the degree of the restriction insufficient tq produce edema. However, according to Vedder, it requires only ninety days "on a diet of highly milled rice to produce beriberi in man." A diet composed of white rice alone would provide 0.06 mg. of thiamine, and in one of the experiments of Williams and his associates14 four subjects were held for 150 days on a diet which provided only 0.075 mg. of thiamine per 1000 calories; yet no edema developed. Neurologic Manifestations.-Subjective disturbances of the sensory nervous system were encountered in all subjects receiving less than 0.45 mg. of thiamine per 1000 calories. They consisted of formication, paresthesia and increased sensitiveness to noise and to painful stimuli. Typical polyneuropathy, involving defects of sensory nervous pathways, loss of tendon reflexes, or paralysis of muscles, was observed in only four subjects and indisputably in only two. In these two the final picture closely resembled the descriptions of the dry beriberi of the Orient. Possibly inadequacy of nutrients other than thiamine contributes to the more frequent development of pronounced polyneuropathy in beriberi. Wernicke's syndrome has been observed by Jolliffe and Wortis 5 in twenty-seven patients, twenty-four of whom were alcoholics. In these patients the ophthalmoplegia and peripheral neuropathy characteristic of this condition responded to treatment with thiamine. In many of their cases a defect in the metabolism of pyruvic acid was demonstrated. Wernicke's syndrome was not observed in the cases of induced thiamine deficiency of Williams and his associates. DIAGNOSIS OF THIAMINE DEFICIENCY
An important conclusion to be drawn from the observations on induced athiaminosis is that the large majority of clinical cases of thiamine deficiency have in the past escaped detection because physicians have demanded the presence of edema or polyneuropathy before considering this diagnosis. The experiments described have revealed, however, that profound disability may develop before defects of sensory or motor pathways become apparent and that polyneuropathy is
416
RUSSELL M. WILDER
a manifestation of late rather than early, severe rather than mild deficiency of thiamine. The symptoms and signs of the earlier and more common manifestations of the disorder are multiple but unspecific. Therefore, badly needed for early diagnosis of this deficiency is a laboratory procedure that provides an indisputable diagnostic criterion. As yet none is available that is suitable for use in general practice. Lacking such a test a presumptive diagnosis can be reached as follows: 1. The presence of several of the symptoms and signs described in the preceding section, resulting in a syndrome of subhealth which resembles neurasthenia or chronic nervous exhaustion, should arouse the suspicion of thiamine deficiency. This should be considered carefully before assigning to such a case a diagnosis of neurasthenia or chronic nervous exhaustion. However, if the patient has been receiving thiamine recently as medication or has been on a satisfactory diet, the neurasthenic syndrome may have disappeared, leaving only the signs of multiple neuropathies. The following procedures, suggested by Ve-dder,8 reveal the presence of the neuropathies most frequently encountered: Squeeze the muscles of the calf to show muscular hyperesthesia; test the anterior surface of -the leg with a pin for anesthesia; test for diminished ankle and knee jerks and try the squatting test. Squatting on the heels is painful for the patient who has more severe deficiency, and because of muscular atrophy he is unable to rise from this position without using his hands or obtaining other assistance. The vibration sense is frequently diminished. 2. The existence of conditions which predispose to deficiencies should arouse suspicion. Such conditions are those which cause interference with intestinal absorption (gastrointestinal disturbance), or with utilization of thiamine (hepatic disease) or which increase the requirement of thiamine (pregnancy, febrile infections, or hard manual labor, especially at high temperatures). Thiamine is lost in perspiration. 3. The dietary history should be taken carefully. This is difficult to do and requires knowledge of food and nutrition on the part of the examiner. A diet high in polished rice, sugar, or unenriched white flour and relatively low in meat, beans, peas and nuts is almost certain to provide insufficient
THIAMINE DEFICIENCY
417
thiamine. If a history of alcoholism is given one should always suspect thiamine deficiency. The diet of alcoholic patients is usually deficient, digestion and absorption are impaired, and the total metabolism often is increased, particularly in delirium tremens, creating an increased demand for thiamine and other vitamins. 5 It is well to remember that intravenous administration of dextrose may exhaust the body stores of several vitamins. The stores of thiamine are depleted rapidly by this means and in a previously malnourished person acuteathiaminosis characterized by anorexia, vomiting and paralytic ileus can be precipitated by such injections. They should be fortified with thiamine in an amount of not less than 1 mg. of thiamine for every 50 mg. of sugar. 4. A therapeutic test should be performed in all suspected cases. All therapeutic tests are full of diagnostic pitfalls. They should always be performed without the knowledge of the patient. The response when thiamine is given may be prompt or delayed, depending on the duration of the deficiency. A true neuropathy, if one exists, represents an anatomic defect which at best is very slowly reversible. Such a condition may take weeks to improve and recovery may never be complete. TREATMENT OF THIAMINE DEFICIENCY
As in all deficiency states and diseases, thiamine deficiency, when encountered clinically, is almost invariably accompanied by other deficiencies. Therefore, plans for treatment should include multiple restorations. The basis of good treatment is a diet carefully planned to meet fully the recommended daily allowances of the Food and Nutrition Board. Likewise additional vitamin B complex as a whole should be provided. When parenteral administration is necessary, the vitamin B complex can be given by injecting a liver extract of the less concentrated type in 3-cc. doses daily. Otherwise give dried brewers' yeast by mouth in doses of from 45 to 60 gm. a day. With this give thiamine hydrochloride, by mouth if possible, otherwise subcutaneously, in doses of from 3.3 to 10 mg. three or four times daily. Persistence will be rewarded. Although prompt effects may be observed in severe as well as
418
RUSSELL M. WILDER
in mild deficiencies of short duration, more chronic cases may require months of such intensive treatment. BIBLIOGRAPHY
1. Braddon, W. L.: The Cause and Prevention and Beri-beri. New York, Rebman Co., .1907.
2. Cowgill, G. R.: The Vitamin B Requirement of Man. New Haven, . Yale University Press, 1934. 3. Drummond, J. C. and Wilbraham, Anne: The Englishman's Food. A History of Five Centuries of English Diet. London, Jonathan Cape, 1940.
4. Harris, L. J.: Vitamins and Vitamin Deficiencies. Philadelphia, P. Blakiston's Son & Co., 1938. 5. Jolliffe, Norman and Wortis, Herman: Encephalopathia Alcoholica: an Evaluation of Vitamin Therapy. Am. J. Psychiat., 98:34(}-346' (Nov.) 1941. 6. Peters, R. A.: The Biochemical Lesion in Vitamin Bl Deficiency: Applicatipn of Modern Biochemical Analysis in Its Diagnosis. Lancet, 1:1161-1165 (May 23) 1936. 7. Spies, T. D. and Butt, H. R.: Vitamins and Avitaminosis. In: Duncan, G. G.: Diseases of Metabolism; Detailed Method of Diagnosis and Treatment. A Text for the Practitioner. Philadelphia, W. B. Saunders Co., 1942, chap. 8, pp. 366-502. 8. Vedder, E. B.: Beriberi. New York, Wm. Wood & Co., 1913. 9. Williams, R. R. and Spies, T. D.: Vitamin Bl (Thiamin) and Its Use in Medicine. New York, The Macmillan Co., 1938. 10. Williams, R. D., Mason, H. L. and Wilder, R. M.: The Minimum Daily Requirement of Thiamine of Man. J. Nutrition. (In press.} 11. William, R. D., Mason, H. L. and Wilder, R. M.: Unpublished data. 12. ·Williams, R. D., Mason, H. L., Power, M. H. and Wilder, R. M.: Induced Thiamine (Vitamin BI ) Deficiency in Man: Relation of Depletion of Thiamine to Development of Biochemical Defect and of Polyneuropathy. Arch. Int. Med. (In press.) 13. Williams, R. D., Mason, H. L., Smith, B. F. and Wilder, R. M.: Induced Thiamine (Vitamin BI) Deficiency and the Thiamine R~ quirement of Man; Further Observations. Arch. Int. Med., 69: . 721-738 (May) 1942. 14. Williams, R. D., Mason, H. L., Wilder, R. M. and Smith, B. F.: Observations on Induced Thiamine (Vitamin BI) Deficiency in Man. Arch. Int. Med., 66:785-799 (Oct.) 1940. 15. Wortis, Herman, Bueding, Ernest, Stein, M. H. and Jolliffe, Norman: Pyruvic Acid Studies in the Wernicke Syndrome. Arch. Neurol. & Psychiat., 47:215-222 (Feb.) 1942.
THIAMINE
DEFICIENCY·
RUSSELL M. WILDER, M.D., F.A.C.P.t BERIBERI
THE origin of the name "beriberi". is Singhalese, the native language· of Ceylon. The word means "I cannot" (Dorland). Great antiquity has been attributed to this disease. Descriptions of it are said to have appeared in Chinese litera-. ture of the third century before Christ, and a description is quoted by Vedder from the writings in 1642 A. D. of the Dutch physician JacobQj Bontius. However, a rereading of the classic treatises on beriberi by Braddon and Vedder, and of Vedder's translation of Bontius' description, leaves one with a strong suspicion that the disease called by this name by the ancients was something different from the beriberi of the late nineteenth and early twentieth centuries. The latter seems to have developed since the introduction of steampowered rice mills. Confusion always has existed in the differentiation of beriberi from hungeredema, scurvy and several tropical diseases, a fact which suggests that the disease described in antiquity and even by Bontius, although in some ways resembling the beriberi of more recent times, was not the same disease. Furthermore, long after beriberi became very prevalent in China, Burma, Java and Malaya, it was confined to persons whose diets consisted largely of highly milled or polished rice from commercial mills. At the same time it remained almost unknown, in the same regions, in the native populations subsisting on undermilled or unpolished rice from primitive mills. 1, 8 According to Vedder, it is possible to prepare a rice by primitive milling methods which is as highly polished as rice from the steam-powered mills. However, this involves much labor and such rice in all prob• From the Division of Medicine, Mayo Clinic, Rochester, Minnesota.
t Professor of Medicine, Mayo Foundation (Rochester, Minnesota);
Member, Food and Nutrition Board, National Research Council. 409
410
RUSSELL M. WILDER
ability was never prepared, in ancient times, in more than relatively small amounts . .Beriberi: a Deficiency Disease.-The recognition of beriberi as a deficiency disease resulted from Eijkman's4, 8 observations, begun in Java in 1890. Eijkman found that among fowls fed polished rice, weakness of the legs and other symptoms like those of human beriberi developed. Later, following other research, in cooperation with Grijns and V ordermann, he developed his conclusion that "there is present in rice polishings a substance . . . which is indispensable to health and lack of which causes nutritional polyneuritis." Incidence, Severity and Types of Beriberi.-A fifth of all disease in Malaya has been attributed to beriberi, with mortality rates in "epidemid" varying between recovery of all and death of all of those who developed the disease. 8 The average mortality rate, according to Vedder, has been 5 per cent. Three types of the disease have been described: (1) dry beriberi, in which multiple neuritis is the predominating feature; (2) wet beriberi, in which there are edema and serous effusion" without heart failure, and (3) a cardiac (acute) type with circulatory failure. Beriberi of infants, breast fed by women who themselves have latent or manifest beriberi, has been described by some writers. The common symptoms among these infants are vomiting, edema, aphonia, and in most cases loss of knee jerks. Beriberi in tbe Occident.-It is not to be supposed that beriberi is confined to the rice consumers of the Orient. 2 , 4, 9 .The disease has appeared in ships at sea, with or without accompanying scurvy, when rations were limited to ship biscuit and canned meat. It has been prevalent in Labrador and Newfoundland, where white bread, molasses and salt meat constituted the major part of the diets of many inhabitants. It developed among the British troops, restricted to white flour biscuits (hard tack) and horse meat, at the siege of Kut, and has been reported in "epidemic" form in several prisons or other institutions in the United States when white bread made up the major portion of a poor dietary.' More recently it has been recognized as a fairly common complication of alcoholism and pregnancy.
THIAMINE DEFICIENCY
411
Thiamine (Vitamin B1 ) Deficiency in Beriberi.-Few, if any, of the diseases attributed to malnutrition represent a deficiency of any single nutrient, and beriberi is no exception to the general rule. It does appear, however, that the pre.,. dominant deficiency in beriberi is that of thiamine (vitamin Bl ). A syndrome closely resembling beriberi can be produced in animals and man by limiting the intake of this vitamin. THIAMINE IN
FOODS
Thiamine occurs in almost every form of living thing and thus is present in every food as grown. However, fruits and several other foods, including the leafy green and yellow vegetables which are rich in other nutritive factors, are relatively poor in thiamine. The better sources are meat, peas and beans, nuts and grain. Furthermore, thiamine is destroyed by exposure to a temperature which is only a little higher than that of boiling water, so that canned meats subjected to autoclaving and all toasted cereals have lost much of their thiamine content. In the grains, and especially in rice and wheat, most of the thiamine is found in the layer of cells (the aleurone layer) which lies between the outer bran and the starch-filled cells of the endosperm. In modern commercial milling of both rice and wheat the aleurone layer is removed with the bran, whereas primitive methods of milling left this lay-er and with it most of the thiamine. The milling of wheat by modern methods, together with displacement by sugar of much of the wheat flour consumed in former times, has given the average Englishman of today a diet that contains less than half and little more than a third as much thiamine as was consumed by his forebears. The dietary situation in the United States is much the same as that in England, and the only reason that beriberi has been less common in these countries than in the Orient, where highly milled rice supplanted the rice of the primitive mills, is that decorticated wheat and sugar have together constituted a relatively smaller proportion of the total calories in most English and American diets than has rice in Oriental diets. The change nevertheless has been drastic, and the present low provision of thiamine is not
412
RUSSELL M. WILDER
without significance to the health of many persons in this and other countries where wheat is the staple food. * The basis for this assertion was revealed experimentally as follows: THIAMINE REQUIREMENTS
Thiamine deficiency was induced in human volunteers by Williams and associates 12 ,'14 by means of a diet of analyzed composition adequate in all other nutrients but limited in thiamine. In one of the experimentsl l the diet contained plain white flour and sugar in amounts comparable to the average daily per capita consumption of white flour and sugar in the United States. The balance of this diet was composed of foods which commonly appear on American tables. They did not, however, compensate adequately for the deficiencies of the flour and sugar. Beans, peas and nuts were omitted, but 3 ounces (85 gm.) of meat was provided as well as fruit, coffee cream, butter and leafy green and yellow vegetables. Supplements containing other vitamins and minerals insured an adequate supply of them. Although this diet contained by analysis as consumed only from 0.20 to 0.22 mg. of thiamine per 1000 calories, it could reasonably be regarded as not worse in this respect than the diets provided in many American and English families. Drummond and Wilbraham found the diet of working classes in England to contain 0.66 mg. of thiamine.a Symptoms of severe ill health and measurable abnormalities of metabolism developed among the subjects who ate the experimental diet described. This and other experiments similarly conducted10, 13 finally led to the conclusion that the minimal amount of thiamine required to prevent all evidence of thiamine deficiency, in persons whose diets contain carbohydrate, fat and protein in conventional proportions, is at least 0.45 mg. per 1000 calories. In the light of these studies the provision of 0.6 mg. per 1000 calories recommended by the Food and Nutrition Board in the Washington Nutrition Yardstick appears to be ·It was this situation that led to the recommendation of the Food and Nutrition Board of the National Research Council for restoration to white flour of an amount of thiamine approximating that removed in milling. The resulting enriched white flour and bread also should have added nicotinic acid (niacin) and iron in amounts related to those removed in milling.
THIAMINE DEFICIENCY
413
none too high. For a moderately active man consuming 3000 calories the recommended allowance of thiamine is 1.8 mg. or 600 international units. SYMPTOMS OF THIAMINE DEFICIENCY
The most conspicuous of the early abnormalities developing in all the experimental subjects of Williams and his associates, when the diet provided from 0.20 to 0.22 mg. of thiamine per 1000 calories, were changes in attitude and behavior and diminished inclination to perform accustomed tasks. All the subjects became depressed, uncooperative, apprehensive, irritable and quarrelsome. All became inefficient in their work and suffered minor accidents caused by clumsiness. In part this could be related to loss of ability to concentrate attention, in part to uncertainty of memory, in part to actual weakness. The Singhalese name "beriberi" ("I cannot") applies appropriately to the syndrome of athiaminosis. The abnormalities described and others to be related were not observable in a period of several weeks preliminary to the period of deprivation. They developed and increased~pro gressively in intensity during the many months of deprivation and disappeared after days or weeks when the intake of thiamine was increased. Thechartges of intake of thiamine were always made without knowledge of the subjects. Other complaints. in the periods of restricted thiamine were headache, backache, painful menses, sleeplessness, formication and sensitiveness to noise. Loss of appetite developed early in all cases and forced feeding later became necessary in many cases. There was little diarrhea; constipation was the rule. Slowing of the emptying time of the stomach and sluggish motility of the intestine could be demonstrated roentgenologically with barium meals. Epigastric burning after meals was a common complaint. Exertion aggravated all complaints. The weakness provoked by increasing exertion led to inactivity which in turn resulted in a relative remission. Thus all symptoms waxed and waned. 'Abnormalities of Metabolism.- The basal metabolic rate in most cases was lowered from 10 to 30 per cent. This was independent of any loss of body weight or limitation of the
414'
RUSSEL L M. WILDE R
total food ingested. The concentration of serum protein decreased moder ately in certain cases but not to less than the critical level of edema formation. Anemia of a macrocytic hyperchromi~ type developed in several instances. It was associated WIth achlorhydrIa. . The amoun t of thiamine in the twenty -four-h our collections of urine fell to levels that remained consistently much less than 0.1 mg. a day, and when test doses of 1 mg. of thiamine hydroc hlorid e were administered parenterally, 80 per cent or more was retained, in contrast to retention of only 60 per cent or less when the ti~sue stores of thiamine were adequate. Slightly elevated fastmg values for sugar in the blood and elevated blood sugar time curves occurred in some cases. They resembled those obtained in cases of mild diabetes. Abnormal elevations of the concentration in the blood of pyruvic acid and lactic acid were observed, especially after administration of glucose. 15 * Cardiovascular Distur bance s.-Low blood pressures (85 to 100 mm. of mercu ry systolic, 50 to 60 diastolic) developed in every case, together with symptoms of vasomotor instability, including pallor and giddiness on rising from recumbent positions. The pulse rates at rest were slow but abnormal acceleration always followed moderate exertion. There was marked sinus arrhythmia and complaints of precordial distress (pseudo-angina) were frequent. The T waves of the electrocardiogram were diminished, and in CR-2 leads became inverted. On the other hand, dilatation of the right side of the heart, such as is described in beriberi, was never detected, and the venous pressures remained normal. A moderate degree of pitting edema of the legs developed in only one subject; otherwise there was nothing to suggest the anasarca of the "wet" beriberi of the Orient. Possibly the edema so characteristic of Oriental beriberi depends less on deficiency of thiamine than on a deficiency of other nutrients or on the poor biologic quality of the protein obtained. Pos• Peters6 and his associates have shown that the signs of thiamine deficiency in p~geons ~nd rat~ result from a metabolic disorder of the nervous tissue, involvmg a bIOchemical defect of the process by which accumu lating pyruvic acid is normally removed.
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sibly the periods of restriction of thiamine in the experiments were too short or the degree of the restriction insufficient tq produce edema. However, according to Vedder, it requires only ninety days "on a diet of highly milled rice to produce beriberi in man." A diet composed of white rice alone would provide 0.06 mg. of thiamine, and in one of the experiments of Williams and his associates14 four subjects were held for 150 days on a diet which provided only 0.075 mg. of thiamine per 1000 calories; yet no edema developed. Neurologic Manifestations.-Subjective disturbances of the sensory nervous system were encountered in all subjects receiving less than 0.45 mg. of thiamine per 1000 calories. They consisted of formication, paresthesia and increased sensitiveness to noise and to painful stimuli. Typical polyneuropathy, involving defects of sensory nervous pathways, loss of tendon reflexes, or paralysis of muscles, was observed in only four subjects and indisputably in only two. In these two the final picture closely resembled the descriptions of the dry beriberi of the Orient. Possibly inadequacy of nutrients other than thiamine contributes to the more frequent development of pronounced polyneuropathy in beriberi. Wernicke's syndrome has been observed by Jolliffe and Wortis 5 in twenty-seven patients, twenty-four of whom were alcoholics. In these patients the ophthalmoplegia and peripheral neuropathy characteristic of this condition responded to treatment with thiamine. In many of their cases a defect in the metabolism of pyruvic acid was demonstrated. Wernicke's syndrome was not observed in the cases of induced thiamine deficiency of Williams and his associates. DIAGNOSIS OF THIAMINE DEFICIENCY
An important conclusion to be drawn from the observations on induced athiaminosis is that the large majority of clinical cases of thiamine deficiency have in the past escaped detection because physicians have demanded the presence of edema or polyneuropathy before considering this diagnosis. The experiments described have revealed, however, that profound disability may develop before defects of sensory or motor pathways become apparent and that polyneuropathy is
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a manifestation of late rather than early, severe rather than mild deficiency of thiamine. The symptoms and signs of the earlier and more common manifestations of the disorder are multiple but unspecific. Therefore, badly needed for early diagnosis of this deficiency is a laboratory procedure that provides an indisputable diagnostic criterion. As yet none is available that is suitable for use in general practice. Lacking such a test a presumptive diagnosis can be reached as follows: 1. The presence of several of the symptoms and signs described in the preceding section, resulting in a syndrome of subhealth which resembles neurasthenia or chronic nervous exhaustion, should arouse the suspicion of thiamine deficiency. This should be considered carefully before assigning to such a case a diagnosis of neurasthenia or chronic nervous exhaustion. However, if the patient has been receiving thiamine recently as medication or has been on a satisfactory diet, the neurasthenic syndrome may have disappeared, leaving only the signs of multiple neuropathies. The following procedures, suggested by Ve-dder,8 reveal the presence of the neuropathies most frequently encountered: Squeeze the muscles of the calf to show muscular hyperesthesia; test the anterior surface of -the leg with a pin for anesthesia; test for diminished ankle and knee jerks and try the squatting test. Squatting on the heels is painful for the patient who has more severe deficiency, and because of muscular atrophy he is unable to rise from this position without using his hands or obtaining other assistance. The vibration sense is frequently diminished. 2. The existence of conditions which predispose to deficiencies should arouse suspicion. Such conditions are those which cause interference with intestinal absorption (gastrointestinal disturbance), or with utilization of thiamine (hepatic disease) or which increase the requirement of thiamine (pregnancy, febrile infections, or hard manual labor, especially at high temperatures). Thiamine is lost in perspiration. 3. The dietary history should be taken carefully. This is difficult to do and requires knowledge of food and nutrition on the part of the examiner. A diet high in polished rice, sugar, or unenriched white flour and relatively low in meat, beans, peas and nuts is almost certain to provide insufficient
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thiamine. If a history of alcoholism is given one should always suspect thiamine deficiency. The diet of alcoholic patients is usually deficient, digestion and absorption are impaired, and the total metabolism often is increased, particularly in delirium tremens, creating an increased demand for thiamine and other vitamins. 5 It is well to remember that intravenous administration of dextrose may exhaust the body stores of several vitamins. The stores of thiamine are depleted rapidly by this means and in a previously malnourished person acuteathiaminosis characterized by anorexia, vomiting and paralytic ileus can be precipitated by such injections. They should be fortified with thiamine in an amount of not less than 1 mg. of thiamine for every 50 mg. of sugar. 4. A therapeutic test should be performed in all suspected cases. All therapeutic tests are full of diagnostic pitfalls. They should always be performed without the knowledge of the patient. The response when thiamine is given may be prompt or delayed, depending on the duration of the deficiency. A true neuropathy, if one exists, represents an anatomic defect which at best is very slowly reversible. Such a condition may take weeks to improve and recovery may never be complete. TREATMENT OF THIAMINE DEFICIENCY
As in all deficiency states and diseases, thiamine deficiency, when encountered clinically, is almost invariably accompanied by other deficiencies. Therefore, plans for treatment should include multiple restorations. The basis of good treatment is a diet carefully planned to meet fully the recommended daily allowances of the Food and Nutrition Board. Likewise additional vitamin B complex as a whole should be provided. When parenteral administration is necessary, the vitamin B complex can be given by injecting a liver extract of the less concentrated type in 3-cc. doses daily. Otherwise give dried brewers' yeast by mouth in doses of from 45 to 60 gm. a day. With this give thiamine hydrochloride, by mouth if possible, otherwise subcutaneously, in doses of from 3.3 to 10 mg. three or four times daily. Persistence will be rewarded. Although prompt effects may be observed in severe as well as
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in mild deficiencies of short duration, more chronic cases may require months of such intensive treatment. BIBLIOGRAPHY
1. Braddon, W. L.: The Cause and Prevention and Beri-beri. New York, Rebman Co., .1907.
2. Cowgill, G. R.: The Vitamin B Requirement of Man. New Haven, . Yale University Press, 1934. 3. Drummond, J. C. and Wilbraham, Anne: The Englishman's Food. A History of Five Centuries of English Diet. London, Jonathan Cape, 1940.
4. Harris, L. J.: Vitamins and Vitamin Deficiencies. Philadelphia, P. Blakiston's Son & Co., 1938. 5. Jolliffe, Norman and Wortis, Herman: Encephalopathia Alcoholica: an Evaluation of Vitamin Therapy. Am. J. Psychiat., 98:34(}-346' (Nov.) 1941. 6. Peters, R. A.: The Biochemical Lesion in Vitamin Bl Deficiency: Applicatipn of Modern Biochemical Analysis in Its Diagnosis. Lancet, 1:1161-1165 (May 23) 1936. 7. Spies, T. D. and Butt, H. R.: Vitamins and Avitaminosis. In: Duncan, G. G.: Diseases of Metabolism; Detailed Method of Diagnosis and Treatment. A Text for the Practitioner. Philadelphia, W. B. Saunders Co., 1942, chap. 8, pp. 366-502. 8. Vedder, E. B.: Beriberi. New York, Wm. Wood & Co., 1913. 9. Williams, R. R. and Spies, T. D.: Vitamin Bl (Thiamin) and Its Use in Medicine. New York, The Macmillan Co., 1938. 10. Williams, R. D., Mason, H. L. and Wilder, R. M.: The Minimum Daily Requirement of Thiamine of Man. J. Nutrition. (In press.} 11. William, R. D., Mason, H. L. and Wilder, R. M.: Unpublished data. 12. ·Williams, R. D., Mason, H. L., Power, M. H. and Wilder, R. M.: Induced Thiamine (Vitamin BI ) Deficiency in Man: Relation of Depletion of Thiamine to Development of Biochemical Defect and of Polyneuropathy. Arch. Int. Med. (In press.) 13. Williams, R. D., Mason, H. L., Smith, B. F. and Wilder, R. M.: Induced Thiamine (Vitamin BI) Deficiency and the Thiamine R~ quirement of Man; Further Observations. Arch. Int. Med., 69: . 721-738 (May) 1942. 14. Williams, R. D., Mason, H. L., Wilder, R. M. and Smith, B. F.: Observations on Induced Thiamine (Vitamin BI) Deficiency in Man. Arch. Int. Med., 66:785-799 (Oct.) 1940. 15. Wortis, Herman, Bueding, Ernest, Stein, M. H. and Jolliffe, Norman: Pyruvic Acid Studies in the Wernicke Syndrome. Arch. Neurol. & Psychiat., 47:215-222 (Feb.) 1942.