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Home , B vitamins, Casimir Funk, Vitamin deficiency

of the B Complex

GRACE A. GOLDSMITH

iiN investigation of beriberi in the when he fed them natural . Birds Z\ late 19th century started the fed whole rice remained well. X A., chain of events that led to He noted that the disease that the discovery of vitamins. Beriberi had resulted from a. polished rice diet in long been a common and a serious birds resembled beriberi in man. disease in parts of the world where He believed that rice contained too polished rice was the staple . much starch, which poisoned nerve Ghristiaan Eijkman, a Dutch surgeon, cells, and that the outer layers, re- was carrying out studies on fowls in a moved from the grain in milling, were military hospital in Java in the 1890's. an antidote. His report was published To save money, he fed them scraps— in Dutch, and some time elapsed mostly polished rice—from the pa- before it was known generally. tients' meals. The fowls unexpectedly G. Grijns, another Dutch physician, developed a bad nerve ailment, which interpreted Dr. Eijkman's findings in a resulted in paralysis. different way. He concluded in 1901 Somewhat later the director of the that beriberi in birds or man was due hospital withheld permission to use to a deficiency or absence of an essen- the scraps, and Dr. Eijkman had to tial from the diet. buy natural or undermilled rice for From then on, chemists in many the he used in his experi- countries tried to concentrate the ments. The ailing birds improved substance in rice that prevented beri- after they began eating the natural rice. beri in order to obtain it in pure form. Dr. Eijkman then began a series of Among them was , of the experiments that led to the first clear Lister Institute, London, who coined concept of disease due to nutritional the term "vitamine" and applied it to deficiency. He fed polished the antiberiberi substance. to pigeons, chickens, and ducks. They B. G. P. Jansen and W, P. Donath developed the paralysis he had ob- in Holland in 1926 isolated the anti- served previously, and they recovered beriberi , and in the 1930's 139 140 TEARBOOK OF AGRICULTURE 1959 Robert R. Williams and his associates A LACK OF VITAMINS of the B complex determined its structure and synthe- is one of the forms of that sized it. often occur throughout the world. Be- Thus men discovered the cause and cause of the similar distribution of the cure of beriberi, which nevertheless in , a deficiency of remains a serious disease today in several factors is observed oftener than countries in which overpolished and a deficiency of a single substance. The overmilled rice is a staple in the diet. interrelationship of many of these vita- During the first stages of separating inins in life processes means that signs and identifying vitamins, the designa- of deficiency often are similar when tion 'Svater-soluble B" was given by the diet lacks any one of several factors. Dr. Elmer V. McCollum and Mar- Many physiologic and pathologic guerite Davis to the concentrates stresses influence the need for the B that cured beriberi. Vitamin B at that vitamins. Larger amounts are needed time was thought to be a single sub- during growth and in and stance. Later research showed that it lactation than in maintenance of consists of a number of substances that health in adult life. The requirement differ widely in chemical structure may be increased by diseases that but have much the same natural elevate and by conditions distribution in foods. associated with poor absorption, im- Of the 11 substances in the vitamin proper utilization, or increased excre- B complex that now are available in tion. Administration of antibiotics may pure form, five are components of one lead to in some or more coenzymes—, ribo- circumstances; in others, antibiotics flavin, , , and panto- spare vitamin requirements. thenic acid. Coenzymes are catalysts that have important and often related THIAMINE, or vitamin Bi, also known functions in the biochemical processes as the antineuritic or antiberiberi vita- by means of which are used min, is a water-soluble compound. It for energy and for building up or is readily broken down by heat in maintaining the cells and tissues of neutral or alkaline solutions. Its solu- the body. bility and the ease with which it is Two of the B vitamins, folie acid and destroyed are important, because over- , have antianemic proper- cooking food and discarding the v/ater ties and presumably exert their func- in which the food is cooked may cause tion in a similar way—that is, as large amounts of the vitamin to be lost. coenzymes. Thiamine is present in many natural These seven vitamins are essential foods but is abundant in few. Lean in and must be pork is one of the best sources. Dry included in the daily diet. beans and peas, certain of the organ Of the other four members of the B meats, and some nuts furnish sizable complex, is important in amounts. Whole and enriched human nutrition but is probably not cereals and bread are dependable an essential dietary constituent be- sources. They can contribute valua- cause the body can form it from other ble amounts to the diet. The small compounds. amounts provided by other foods, such Very likely is required, by as , eggs, other meat, fruit, and man, but it is furnished by bacterial vegetables, add up and represent a synthesis in the intestinal tract as well worthwhile contribution to the diet. as by food. The thiamine requirement is related and p-aminobenzoic acid, to caloric intake. The minimum need other members of the B complex, have is approximately 0.20 to 0.23 milli- not been shown to be essential in gram per 1,000 Calories. This require- human nutrition. ment is based on experiments in which VITAMINS OF THE B COMPLEX 141 thiamine in the diet is restricted, on ministration of glucose and by exercise studies of diets of population groups, and form the basis of a diagnostic test and on estimates of the amounts ex- for . The concen- creted in the of people having tration of glucose, lactic acid, and known intakes of thiamine. pyruvic acid in blood is determined The requirement of infants in rela- after the administration of glucose and tion to Calories appears to be compa- a standard amount of exercise. Results rable to that of the adult. Human milk are expressed as a '' in- supplies an average of 0.21 milligram dex," which increases in thiamine de- per I, 000 Calories. We have evidence ficiency. that the ratio of carbohydrate to Thiamine deficiency has been pro- in the diet influences the requirement. duced experimentally in people. Ef- The recommended dietary allow- fects of a moderate shortage of thia- ance for thiamine is 0,5 milligram per mine include fatigability; ; loss 1,000 Calories. When an adult's diet of appetite; nausea; such psychic and furnishes fewer than 2,000 Calories a personality disturbances as moodiness, day, the thiamine allowance should irritability, and depression; a sensa- not be less than i milligram daily. tion of numbness in the legs; and ab- This allowance provides a large factor normalities of the electrocardiogram. of safety above the minimum, need and Advanced deficiency of thiamine, or seems desirable because requirements beriberi, is characterized by peripheral vary among individuals and because neuritis, heart disease, and . stores of thiamine in the body are not Peripheral neuritis is a disease of the large and may be exhausted readily in nerves of the extremities; usually both diseases associated with an increase in legs are afifected and sometimes the metabolism. arms as well. The symptoms include Bacteria in the intestines may syn- loss of sensation, muscle weakness, and thesize some thiamine, but the amount paralysis. available to the human body to sup- A deficiency of thiamine can also plement the dietary supply seems to be cause damage to the brain, which may small. be manifested by confusion, delirium, Thiamine is absorbed readily from and paralysis of the muscles that move the intestinal tract. It is excreted in the the eyeballs. This condition is called urine in amounts that reflect the Wernicke's syndrome. amount taken in and the amounts stored in tissues. Measurement of the , formerly known as vita- urinary excretion of thiamine after min B2 or G, is a water-soluble, yellow giving a small dose of thiamine is use- pigment. It is widely distributed in ful in determining whether body stores foods of plant and animal origin. It is are adequate or deficient. stable to heat, especially in acid solu- Thiamine functions in the body as a tions, but it is destroyed on exposure coenzyme, which is called cocarboxyl- to fight. ase. It acts as a catalyst in one of the Among the best sources of riboflavin chemical reactions by which glucose are milk and variety meats, like , () is broken down in the tissues to heart, and kidney. Other lean meat, supply energy. These reactions proceed cheese, eggs, and many of the leafy, stepwise, and cocarboxylase acts at an green vegetables also furnish valuable intermediate stage when a substance amounts. Whole-grain and enriched known as pyruvic acid has been formed. cereals and bread, in the amounts in In thiamine deficiency, pyruvic acid which they are eaten in this country, accumulates in the blood and tissues contribute important amounts of ribo- and there is a change in the ratio of flavin to the diet. this acid to lactic acid. These meta- Pasteurizing and drying milk do bolic changes are magnified by ad- not lower its riboflavin content very 142 YEARBOOK OF AGRICULTURE 1959 much, but exposure to sunlight de- of the mouth. In riboflavin deficiency, stroys large amounts of the vitamin. of the greasy type often The minimal daily requirement of involves the scrotum and may afí'ect riboflavin is about 0.6 to 0.7 milligram the face and ears. Another finding is for adults and 0.4 to 0.5 milligram for injection of the blood vessels of the eye infants. Considerable evidence indi- and growth of the vessels into the cates that an intake of i. i to 1.6 milli- cornea, which normally does not con- grams daily will provide adequate tain these vessels. body stores. In animals, too little riboflavin dur- The need for riboflavin does not ing pregnancy may result in abnor- seem to be related to caloric consump- malities in the embryo or in abortion. tion but may be related to body We do not know whether any con- weight. Both riboflavin and genital defects in man may be due to requirements are increased by similar an inadequate supply of riboflavin in conditions, such as growth, pregnancy, the mother. and lactation. Riboflavin allowances Chemical tests arc available for es- accordingly are computed from the timating the adequacy of riboflavin protein allowances; a factor of 0.025 nutrition. The amount excreted in the is used. Recommendations for men urine can be measured and tends to and women are i .8 and i .5 milligrams reflect dietary supply and body stores. daily, respectively. One feature of riboflavin metabolism The recommended intake during can markedly influence the test, how- the second half of pregnancy is 2 milli- ever. Riboflavin is excreted when grams. During lactation it is 2.5 milli- protein of the body is being broken grams. The allowance for infants is down; it is retained when protein is 0.5 to 0.8 milligram daily. being accumulated. Thus, in acute Chemical research on riboflavin starvation, uncontrolled diabetes mel- started in 1879, but its function and litus, and other conditions associated importance in nutrition were not with negative nitrogen balance, ex- understood fully until the 1930's. Otto cretion in the urine does not reflect Warburg and W. Christian of Ger- body stores. many in 1932 studied a yellow enzyme The concentration of riboflavin in in and were able to split it into a red blood cells is under investigation protein and a pigment (flavin). as a measure of adequacy of riboflavin Later research disclosed riboflavin intake. This test may prove useful in to be an essential human nutrient, determining nutritional status. which is combined with protein in the body to form a number of important NiACiN, the -preventing vita- enzymes. These function min, was discovered after long search. in the respiration of tissue and act Its elusiveness may be explained closely with enzymes containing nia- partly by a recent finding that one of cin, another B vitamin. Some flavo- the amino acids, , is a prcr are known as oxidases since cursor of niacin. they catalyze the oxidation of various Pellagra was known to be associated chemical substances. with a poor, monotonous diet high in The functional association of ribo- corn, since the disease was first flavin and niacin-containing enzymes described in the i8th century by Gas-, helps to explain the similarity of cer- par Casal in Spain and Francesco. tain findings in deficiency of these two Frapoli in Italy. Theories regarding vitamins. the cause of pellagra w^ere many. For Deficiency of either may result in years, the disease was believed to be soreness and redness of the tongue and due to a toxic or infectious substance lips, atrophy of papillae on the surface in spoiled corn. Early in the present of the tongue, and cracks at the angles century, Casimir Funk suggested that VITAMINS OF THE B COMPLEX 143 pellagra was due to vitamin deficiency. Gelatin is an exception; it has almost Investigators in Egypt held that the no tryptophan. Lc^an meat and poultry disease was related to lack of an essen- are good somxes of both tryptophan tial a mino acid, probably tryptophan. and niacin. The investigations of Joseph Gold- Among plant sources, are bcrger, beginning about 1914, demon- outstanding in niacin and are also strated that pellagra is due to a among the i)cst sources of tryptophan. nutritional deficiency. Other plants that are good sources of and his associates both nutrients include beans, peas, at the University of Wisconsin in 1937 other , most nuts, and several discovered that nia ein (nicotinic acid) whole-grain or enriched cereal prod- cured blacktongue in dogs, a condi- ucts. Corn and rice are low in trypto- tion previously recognized as similar phan. Oatmeal is low in niacin. to pellagra in human beings. Shortly The requirement of niacin can be thereafter niacin was shown to be determined only in terms of both effective in the prevention and treat- niacin and tryptophan intake. Our ment of pellagra. studies and those of Dr. Horwitt The whole story was not yet com- indicate that the minimum amount plete, however. Diets in parts of the of niacin that will prevent pellagra world in which pellagra was rare con- in adults is about 9 milligrams daily. tained less niacin than did diets in This includes the niacin formed from areas in which pellagra was common. tryptophan, if we assume that 60 Furthermore, some foods such as milk milligrams of tryptophan are equiva- are low in niacin but they effectively lent to I milligram of niacin. The term prevent pellagra. These discrepancies ''niacin equivalent" is useful for ex- were cleared up after the discovery by pressing this total potential niacin value Willard Krehl and his associates in the of the diet. University of Wisconsin in 1945 that Calculation of the niacin equivalent either tryptophan or niacin could of the diets used by Dr. Goldberger, counteract a retarded growth in which resulted in pellagra, gives a produced by diets high in corn. figure of 12 milligrams. These diets Tryptophan has been shown since then were higher in Calories than those to be a precursor of niacin in many used by me and by Dr. Horwitt, and animal species, and the steps by which the niacin requirement appears to be this is converted to niacin related to caloric intake and to body have been determined. weight. We found that administration of Dr. Horwitt suggested a minimum tryptophan to people was followed need of 4.4 milligrams of niacin by an increased urinary excretion of equivalent for each 1,000 Calories niacin derivatives and that tryptophan furnished by the diet. was effective in the treatment of We found the minimum require- pellagra. Similar findings were re- ment in relation to body weight to ported by other investigators. The be slightly more than o.io milligram efficacy of tryptophan as a precursor of niacin per kilogram when the of niacin was studied in our labora- diet furnished 200 milligrams of tory in the Tulane University School tryptophan. of Medicine and by Max K. Horwitt Dr. Emmett Holt's studies and the and his associates. Approximately calculation of the niacin equivalent 60 milligrams of dietary tryptophan received by breast-fed infants suggest furnish i milligram of niacin, although that the requirement of infants is there is wide variation in this con- about 5 milligrams daily, if the con- version ratio among individuals. version of tryptophan to niacin is Most foods that are high in animal comparable to that in adults. protein are also high in tryptophan. Recommended dietary allowances 144 YEARBOOK OF AGRICULTURE 1959 for niacin expressed as niacin equiva- amounts. Few foods can be classed as lents are 17 to 21 milligrams for adults poor sources of this vitamin. and 6 to 7 milligrams for infants. These The exact requirement of vitamin amounts are 50 percent higher than B5 has not been determined. Probably the minimum need, calculated on the I to 2 milligrams daily should be basis of caloric intake or body weight, enough for an adult, an amount read- whichever is the greater amount. The ily provided by the average diet in the many uncertainties make this large . factor of safety seem desirable. The need of infants can be supplied Niacin functions in the body as a by milk, which contains 100 micro- component of two coenzymes, diphos- grams per liter. phopyridine nucleotide (DPN) and In animals, vitamin Bg requirement triphosphopyridine nucleotide (TPN), is increased by methionine (an amino in tissue respiration and glycolysis (the acid), protein, and sucrose (cane process by which sugar is broken down sugar) and apparently is reduced by to produce energy). Niacinamide was choline, essential fatty acids, biotin, found to be part of these coenzymes and . In the , vita- before its nutritional importance was min Bß is synthesized by intestinal or- discovered. They w^ork in close asso- ganisms, and some of this seems to be ciation with enzymes that contain available for metabolic needs. We do riboflavin. not know whether these findings apply Niacin deficiency is characterized to people. by dermatitis, particularly of areas of Vitamin Bg occurs in tissues predom- skin which are exposed to light or in- inantly as the phosphates of pyridoxal jury; inflammation of mucous mem- or . branes, including the entire gastro- functions as a intestinal tract, which results in a red, coenzyme in a number of chemical re- swollen, sore tongue and mouth, diar- actions involving amino acids. This rhea, and rectal irritation; and psychic explains the increased need of the vita- changes, such as irritability, anxiety, min when diets are high in protein. depression, and (in advanced pel- Enzymes containing vitamin Bo are lagra) delirium, hallucinations, con- important in many reactions that pro- fusion, disorientation, and stupor. vide material for the , In severe deficiency, hydrochloric a metabolic pathway that furnishes acid may be absent from the gastric energy for the body. juice. The excretion of niacin metabo- Vitamin Bg has a role in the conver- lites in the urine falls to low levels. An sion of tryptophan to niacin deriva- excretion of less than 2 milligrams in tives. This function forms the basis of a 24 hours is typical of pellagra. test for deficiency of vitamin Bg. When A deficiency of riboflavin often ac- a large amount of tryptophan is ad- companies a deficiency of niacin. ministered to deficient animals or man, Thiamine deficiency may also be pres- xanthurenic acid is excreted in the ent at times. urine in abnormal quantities. Vitamin Bg may also function in the metabo- VITAMIN BQ consists of a group of lism of essential fatty acids. three closely related substances, pyri- A deficiency of vitamin Bg due solely doxine, pyridoxal, and pyridoxamine. to dietary inadequacy has not been ob- They are widely distributed in foods served in adults. and are present in both free and bound Deficiency has been reported in in- form. fants who received a liquid milk for- The best sources of vitamin BQ are mula in which much of the vitamin Bg muscle meats, liver, vegetables, and was destroyed unknowingly in proc- whole-grain cereals. The bran from essing. The infants developed irrita- the cereal grains has especially large bility, muscular twitchings, and con- VITAMINS OF THE B COMPLEX 145 vulsive seizures. If vitamin Bß is not täte, is actually the acetylated coen- supplied in adequate amounts, infants zyme that reacts in numerous ways. cease gaining weight and may develop occupies a central posi- . tion in metabolism. It functions in the Experimental deficiency in adults has formation and breakdown of fatty acids been produced by the administration and in the entry of fat and carbohy- of a pyridoxine antagonist, desoxypy- drate into the citric acid cycle, a series ridoxine. Symptoms included irrita- of chemical reactions that provide en- bility, depression, and sleepiness. Other ergy for the organism. Coenzyme A findings were a seborrheic (greasy) functions in the synthesis of the por- type of dermatitis, skin lesions that re- phyrin part of the hemoglobin mole- sembled pellagra, soreness of the tongue cule and in the formation of sterols (such and lips, conjunctivitis, and peripheral as ) and steroid hormones neuritis. These abnormalities resemble (formed by the adrenal and sex glands). those seen in deficiency of ribofiavin, The symptoms of a deficiency of pan- niacin, and thiamine and attest the tothenic acid in animals are more di- close metabolic relationship of these verse than are observed for most other vitamins of the B complex. vitamins, perhaps because of the fun- Vitamin Bg metabolism may be al- damental importance of coenzyme A tered during pregnancy, and the re- in metabolism and the many reactions quirement may be increased. Pregnant in which it participates. women excrete abnormally large A deficiency disease due to lack of amounts of xanthurenic acid after the pantothenic acid has not been observed administration of tryptophan. There is in man. Diets may never be sufficiently also an abnormal response to adminis- low in this vitamin to produce defi- tration of alaninc, an amino acid. ciency. Blood urea nitrogen remains high for William Bean and his associates at more than 12 hours. Similar findings the State University of Iowa attempted have been observed in animals defi- to induce deficiency by administering cient in vitamin BQ. a pantothenic acid antagonist, omega- Pyridoxine has been shown to pre- methyl-pantothenic acid, to volunteer vent or alleviate the peripheral neuritis subjects who were receiving a diet that may develop when isoniazid, an devoid of pantothenic acid, antituberculosis medication, is ad- (A vitamin antagonist is a substance ministered. so similar in structure to the vitamin that the body accepts it in place of the PANTOTHENIG ACID is needed by man vitamin, but the antagonist is unable and many species of animals. to perform the functions of the true It is widely distributed in foods. Liver vitamin.) and eggs, particularly good sources, Numerous physical and biochemical contain 100-200 micrograms per gram. disturbances resulted. The subjects be- , , lean beef, skim came quarrelsome, sullen, and petu- milk, white potatoes and sweetpotatoes, lant. Some of them developed pains tomatoes, and are quite high and disturbances of sensation in the in pantothenic acid. arms and legs. Others noted loss of The human requirement is unknown appetite, indigestion, and nausea. but is probably not above 5 milligrams Fainting attacks were common. The daily. pulse tended to be unduly rapid. There Pantothenic acid has a vital role in seemed to be an increase in suscepti- metabolic processes as it is a constit- bility to infection. Laboratory tests uent of coenzyme A. This coenzyme showed many abnormal findings re- is required for acetylation, one of the lated to the numerous functions of essential chemical reactions of the body. pantothenic acid in the chemical re- An important compound, active ace- actions of the body. 477248°—59- -11 146 TEARBOOK OF AGRICULTURE 1950 A deficiency of pantothenic acid o.i to 0.2 milligram daily may suffice. may be responsible for the *'burning Much has been learned about the foot syndrome," which is encountered function of folacin and its derivatives, in places where other B complex although their exact metabolic role deficiencies are common. This condi- has not been delineated. It seems tion has been reported to respond to likely that a derivative of doses of pantothenic acid. is the functioning form of the vitamin Other studies indicate that panto- and that this derivative combines thenic acid may influence the reaction with a protein and functions as a of human subjects to stress. coenzyme. Folacin participates in the formation by the body of complex THE FOLIG ACID group of vitamins chemical compounds known as pu- are essential for many animal species. rines and pyrimidines that are utilized They are necessary for the formation in the building up of nucleoproteins— of blood cells in man. that is, proteins that arc found in the Members of this group include nucleus of every . folacin (or pteroylglutamic acid), The essentiality of folacin for hema- pteroyltriglutamic acid, pteroylhepta- topoiesis (the manufacture of blood glutamic acid, and folinic acid or cells) in man presumably resides in its citrovorum factor, a derivative of folie function in the formation of purines acid that occurs in natural materials and pyrimidines. in both free and combined form. Folie acid stimulates the formation Information is meager concerning of blood cells in certain , the amounts of folacin and folinic which are characterized by oversized acid compounds in foods and their red cells and the accumulation in the biological availability. Enzymes that bone marrow of immature red blood can break down conjugated pteroyl- cells, called megaloblasts. The bone glutamates (combined forms of folie marrow is the organ that manufactures acid) to folacin occur in many animal blood cells. It cannot complete the tissues. In several natural products, process in the absence of folie acid. these enzymes or conjugases are ac- Vitamin B12 also is needed for the companied by an inhibitor. This formation of blood cells and is efl'ec- inhibitor appears to influence the tive in the treatment of many anemias. availability of the combined forms of The exact biochemical interrela- folacin to human subjects. These tionships of these two vitamins in findings illustrate the difficulties in- metabolism have not been clarified. volved in estimating the folacin that Vitamin B12, like folacin, seems neces- is available from foods and in deter- sary for the formation of nucleoproteins. mining the human need for it. Two human anemias appear to be The best sources include liver, dry due primarily to folacin deficiency— beans, lentils, cowpeas, asparagus, macrocytic anemia of pregnancy and broccoli, , and collards. Other of infancy. good sources include kidney, peanuts, These anemias occasionally respond filberts, , immature or young to treatment with vitamin B12. lima beans, cabbage, , Sprue and nutritional macrocytic chard, turnip greens, lettuce, beet anemia often improve when either greens, and whole-wheat products. folacin or vitamin B12 is administered. Intestinal bacteria synthesize folacin. Sprue is a disease in which absorption This source may be important in man, of food from the intestinal tract is because experimental deficiency has seriously impaired, and the stools con- not been induced by diets low in tain large amounts of fat. Folacin may folacin. The dietary requirement of improve absorption in this condition. folacin is not known, but available In pernicious anemia, treatment evidence suggests that approximately with folacin may bring the blood status VITAMINS OF THE B COMPLEX 147 to normal, but relapse occurs. Damage The search for vitamin B125 which is to the spinal cord and peripheral the antipernicious anemia factor of nerves, which, is a common finding in liver, forms an interesting chapter in pernicious anemia, is neither pre- medical investigation. Pertiicious ane- vented nor alleviated. mia was an incurable disease until The mechanism by which deficiency 1926, when George R. Miaot and of folacin develops is not clear. The William P. Murphy, of Boston, showed deficiency may be of dietary origin that feeding whole liver was effective in some instances but not in others. therapy. WiUiam Castle and his as- Defective absorption may explain sociates at Harvard demonstrated that deficiency at times. mixtures of beef muscle and normal Macrocytic anemia of pregnancy gastric juice would also induce remis- may be related to an increased folacin sion in pernicious anemia. Beef muscle requirement that is not met by the alone and beef muscle and the gastric diet. Folacin has a role in the repro- juice of a patient with pernicious ductive process in animals. anemia were ineffectual. The syndrome of folacin deficiency Castle postulated that a substance in man is exemplified best by the in gastric juice (intrinsic factor) com- symptoms that develop when large bined with a substance in food (ex- amounts of a folie acid antagonist such trinsic factor) to form the antiperni- as aminopterin arc administered. cious anemia factor of liver. Intrinsic Manifestations include (a sore, factor was absent from the gastric red, smooth tongue), , gastro- juice of patients who had pernicious intestinal lesions, and anemia. Similar anemia. findings occur in sprue and nutritional As each new B vitamin was dis- macrocytic anemia; they often revert covered, it was tested for antiperni- to normal with folacin therapy. cious anemia activity. Folie acid at Folacin is functionally related to first was thought to be the active ascorbic acid. Mcgaloblasiic anemia principle of liver, as it caused improve- of infancy occurs in infants receiving ment in the blood picture in pernicious diets deficient in ascorbic acid. It can anemia. be prevented by ascorbic acid but Later study indicated that folie acid responds to treatment only with folacin would not maintain normal blood or folinic acid. status and failed to influence the Folacin is related to the metabolism neurologic changes that occur in this of the amino acid tyrosine, and so is disease. A serious handicap in the ascorbic acid. An abnormal excretion search for the antipernicious anemia of tyrosine metabolites in the urine factor was the need to test all materials occurs in infants who lack ascorbic in human subjects who had pernicious acid. Administration of ascorbic acid anemia in relapse. No animal devel- or large doses of folacin relieve the oped a comparable disease. abnormality. Mary Shorb, of the University of Maryland, in 1947 found that liver VITAMIN B125 like many other mem- extract contained a growth factor that bers of the B complex, is not a single was required by a micro-organism, substance but consists of several closely Lactobacillus lactis Dorner. Using this related compounds with similar ac- microbiological assay, Edward L. tivity. The term "cobalamin" is ap- Rickes and his associates, at Rah way, plied to this group of substances be- N.J., isolated B12 in 1948. cause they contain cobalt. Vitamin B12 Lester Smith, in England, at about is , named for the the same time isolated the vitamin by cyanide ion in the molecule. Other procedures designed to obtain in pure compounds are hydroxycobalamin and form the red pigment that gave color nltritocobalamin. to active preparations of liver. 148 TEARBOOK OF AGRICULTURE 1959 Vitamin Bio was shown to be effec- of intrinsic factor from the gastric juice. tive in the treatment of pernicious Pernicious anemia is characterized anemia by Randolph West, of Colum- by degenerative lesions in the spinal bia University, and others. cord and peripheral nerves as well as Subsequently it was discovered that by macrocytic (large cell) anemia. vitamin B12 is not only the antiper- The concentration of vitamin B12 in nicious anemia factor of liver but also blood is extremely low. Failure of ab- the extrinsic factor of food. sorption of vitamin B12 can be demon- Intrinsic factor of gastric juice ap- strated by administration of Co^^ vita- pears to be necessary for the absorp- min B12—that is, vitamin B12 containing tion of vitamin B12, but the mechanism radioactive cobalt. If intrinsic factor of action has not been determined. is given with Co^^ vitamin B12, absorp- Intrinsic factor may have other tion is increased to normal. functions as well. We have found that Macrocytic anemia that follows sur- intrinsic factor will increase the bind- gical removal of the stomach is due to ing of vitamin B12 by proteins in failure of absorption of vitamin B12, as tissues and in human serum. in pernicious anemia. Sprue may be Vitamin B12 is found in animal pro- associated with a deficiency of vitamin tein foods. The best sources are liver B12, as are some other syndromes due and kidney. Other sources are muscle to intestinal mal absorption. In these meats, milk, cheese, fish, and eggs. As situations, there is failure of absorption far as we know, fruit and vegetables do of vitamin B12, even when intrinsic not furnish any vitamin B12. factor is administered with the vitamin. The dietary requirement for the vita- A deficiency of vitamin B12 due to min is unknown. A normal diet is dietary inadequacy is rare. Only two estimated to contain 8 to 15 micro- cases of severe macrocytic anemia on grams. The daily administration by this basis have been reported. A small injection of i microgram will induce percentage of persons who subsist for remission in pernicious anemia. The years on a strict vegetarian diet, how- normal adult presumably needs to ab- ever, have been found to develop other sorb an amount no larger than this. signs of . Sore- The biological availability of vitamin ness of the mouth and tongue, numb- B12 in the diet has not been determined. ness and tingling of the hands, pains in Much remains to be learned about the back, and (in one instance) com- the specific functions of vitamin B12 in bined degeneration of the spinal cord bodily processes. It appears to be in- have been observed. Levels of vitamin volved in the synthesis of nucleopro- B12 in the blood are lower than normal teins through participation in the me- in vegetarians. tabolism of purines and pyrimidines. The close relationship to folie acid . CHOLINE is not a vitamin in the in stimulating blood regeneration has strict sense. It is classified usually as a been discussed. The specific role of member of the vitamin B complex. It this vitamin in the metabolism of nerve is an essential nutrient in that methyl tissue has not been determined. groups (part of the choline molecule) Vitamin B12 is essential for the growth must be included in the diet. The of animals. It may have a growth-pro- amino acid methionine (in protein) moting effect in man in certain condi- and betaine are other dietary sources tions of diet and nutrition. of methyl groups. It seems likely that Pernicious anemia is the most im- choline and methionine are not com- portant human disease that is due to pletely interchangeable as sources of too little vitamin B12. The deficiency methyl in all species. is not due to dietary inadequacy but to A dietary requirement for choline failure of absorption of the vitamin cannot be given, since the compound from the intestinal tract in the absence can be manufactured in the body and VITAMINS OP THE B COMPLEX 149 the need for choline depends also on It seems unlikely that a dietary de- other sources of methyl groups. The ficiency of biotin occurs in human be- average diet contains 250 to 600 milli- ings. The requirement has not been grams of choline. determined. Foods that supply large amounts of Biotin seems to be an essential com- choline are liver, kidney, brain, muscle ponent of a coenzyme in carbon di- meats, nuts, beans, peas, and skim oxide fixation, an important reaction milk. Moderate amounts exist in ce- in intermediary metabolism. Consid- reals and a number of vegetables. erable data suggest that one manifesta- Choline functions in the body as a tion of this role of biotin is a require- source of labile methyl groups and in ment for purine synthesis. Biotin is the the formation of phospholipicls, a class of anti-egg-white injury factor. Raw ftgg fatty substancesfoundin all body tissues. white contains the protein, avidin, The most important phospholipids which combines with biotin to prevent are , cephalin, and sphingö- its absorption. myclin. These compounds are found Virgil Sydenstricker and associates especially in nerve tissue. Lecithin and at the University of Georgia produced cephalin are present in egg yolks. Cho- experimental deficiency of biotin in line is a component of the compound people by feeding large amounts of raw acetylcholinc, which functions in the Qgg white. Manifestations included a transmission of nerve impulses across dry, scaly dermatitis and changes in neuromuscular junctions. the color of the skin. Nervous symp- Labile methyl groups are used in the toms, tongue lesions, and aJDnormali- synthesis of , N^-methylnico- ties in the electrocardiogram were tinamide (an excretion product of nia- noted—findings similar to those pro- cin) and probably other vital sub- duced by deficiency of other vitamins stances, such as epinephrine, the hor- of the B complex. mone of the adrenal medulla. Methyl groups have a lipotropic function— GRACE A. GOLDSMITH, M.D., is pro- that is, they prevent the accumulation fessor oj medicine in the Tulane University of fat in the liver. School of Medicine^ New Orleans. She also Choline deficiency leads to many ab- is consultant physician^ Charity Hospital of normal findings in various animal spe- Louisiana^ New Orleans; chairman^ Food cies, among them hemorrhagic lesions and Nutrition Boards National Academy of in the kidney. Sciences-National Research Council; and Incomplete evidence suggests that member of the Council on Foods and Nutri- choline may have an influence on fatty tion of the American Medical Association. infiltration of the liver in man. Cho- line, mcthionine, vitamin B12, and folie acid are interrelated in the prevention If all that we k?iow about ?iiitrition of fatty livers in animals under certain were applied to modern society, the result dietary conditions. would be an enormous improvement in pub- lic health, at least equal to that which BiOTiN is needed in animal nutrition resulted when the germ theory of infectious and presumably is essential for man. disease was made the basis of It is present in many foods and is syn- and medical work.—FRANK G. BOUD- thesized by the intestinal bacteria. The REAU, M.D. urinary excretion of biotin in humans at times is greater than the intake. We know that a lot of people who are Liver, milk, meat, nuts, egg yolk, regarded as poor prospects for jobs need most vegetables, and a number of food. They are set down in personnel fruits (bananas, grapefruit, tomatoes, records as lazy and dumb. What is really watermelon, and strawberries) contain wrong with them is that they are hungry.— significant amounts of biotin. PAUL V. MCNUTT.