"The fallacy of administering mixtures of crystalline vitamins alone in nutritional deficiency" Stressing the word because these vitamins are not only extremely beneficial but quite often required for an effective therapy as long as the rest is covered. Book Series: Vitamins And Hormones ↪ Nutritional Therapy of Endocrine Disturbances - ScienceDirect By the ultra-pimp: Morton S. Biskind. Other relatives that often collaborate or research related subjects: Gerson (as GR Biskind), John (as JI Biskind) and Leonard (as LH Biskind). Believe it or not, these are some selected parts: "Although direct nutritional therapy of endocrine disturbances is of very recent origin, numerous clinical observations during the past half century, viewed in retrospect, reveal surprising correlations between nutritional and endocrine disturbances. And scattered animal investigations during the past thirty years have indicated a more direct relation between nutritional deficiency and changes in endocrine function. Among these older studies were the use of liver and liver extracts in diabetes (Gilbert, and Carnot, 1896). Stockton (1908) described the characteristic appearance of the tongue in diabetes as “large, red, ‘beefy,’ and bordered with a fissured margin...,” a description now accepted as classical of pellagra. Functional changes in the central nervous system in diabetes that we now recognize as characteristic of thiamine and niacinamide deficiency were described with great accuracy by Futcher in 1907. The occurrence of hyperglycemia in pigeons on a “vitamin-free” diet was reported by Funk and von Schoenborn in 1914; this observation was followed up by other workers but its clinical implications were long neglected." "Plaut (1923) first reported hypertrophy of the adrenals in avitaminosis in animals." "Testicular atrophy occurring secondary to “malnutrition” was mentioned by Reynolds and Macomber in 1921, and both testicular atrophy and gynccomastia have been known for some time to be associated vvith hepatic cirrhosis (cited by Glass et al., 1940)." "More direct evidence of a relation between nutrition and endocrine function was provided by Evans and Bishop (1922); they reported that rats on a vitamin B free diet became anestrous. This phenomenon was later shown to be due to the suppression of the anterior pituitary (Parkes, 1928; Marrian and Parkrs, 3929)." "On the basis of the latter investigations, and others implicating nutritional defects in alterations of hepatic morphology (Patek, 1937; Ando, 1938; Rhoads et al., 1938, 1940; Sebrell and Onstatt, 1938; Nakahara et al., 1939; Gyorgy and Goldblatt, 1939, 1940; Rich and Hamilton, 1940) (cf. also: Blumberg and McCollum, 1941; Daft et al., 1941; Earlet et al., 1941, 1942; Lillie et al., 1941, 1942; Lowry et aZ., 1941; Patek and Post, 1941 ; Broun and Muether, 1942), M. S. and G . R. Biskind (1941), utilizing the method of splenic implantation, found that, while castrate female rats with pellets of estrone in their spleens remained anestrous when on a normal diet, they went into continuous estrus when the diet was depleted in B complex vitamins, thus demonstrating that, in this type of nutritional deficiency, the liver loses its ability to inactivate estrogen. Addition of brewers yeast, or a mixture of crystalline thiamine, riboflavin, pyridoxine and calcium pantothenate, to the diet restored the anestrous state and subsequent depletion again led to continuous estrus (M. S. and G. R. Biskind, 1942; M. S. Biskind, 1943). Thus, the flow of estrogen through the liver could be controlled at will by witholding the B vitamins or restoring them to the diet. Impairment of the estrogen-inactivating mechanism of the liver occurred in the absence of detectable morphologic change in this organ (Fig. 1) (M. S. and G. R. Biskind, 1942); conversely, inactivation of estrogen can occur in livers which are the site of severe necrosis and fat infiltration, induced by a B complex-free diet supplemented with thiamine, riboflavin, pyridoxine and calcium pantothenate (Fig. 2) (M S. Biskind, 1944). The functional and morphologic changes in the liver thus bear no necessary relation to each other." "Subsequent investigation of the problem of estrogen inactivation in the liver has shown that, in the rat, thiamine and riboflavin alone among the B vitamins are adequate to permit hepatic destruction of estrogen (Singher, Taylor et al., 1944; Singher, Kensler et al., 1944; Segaloff and Segaloff, 1944: Shipley and Gyorgy, 1944) and that the presence of methionine is essential to this function (TJnna, Singher et al., 1944; Gyorgy and Goldblatt, 1945)." "Unna, Singher et al. (1944), György and Goldblatt (1945) and György (1945) have shown that, in the absence of an adequate amount of proteid, the B vitamins cannot maintain estrogen-inactivation in the liver. Hence, restriction of diet as performed in the paired feeding experiments of Drill and Pfeiffer could easily have reduced the protein intake below the critical level, and the apparent failure of methionine in their experiments, in contrast to the positive effect reported by Unna et al. and György, may have been due (assuming the possibility that other factors were equal) to differences in the basic proteid intake. From unpublished experiments of G. R. and M. S. Biskind (interrupted by vvartime exigencies) other factors in addition to thiamine, riboflavin and methionine appear to be involved in the estrogen-inactivating mechanism, and it appears that inanition can also disturb it, even though this has little practical significance. As discussed subsequently, in the clinical syndromes in which nutritional deficiency is associated with excess estrogen, the vast majority of subjects are extremely well fed; the latter respond dramatically to administration of the whole B complex." Mentioned: Vitamins B1 & B2 Are Required For Estrogen Inactivation By Liver "The observation by Plaut (1923), previously mentioned, that the adrenal cortex is hypertrophic in avitaminosis B in rats, is undoubtedly related to failure of inactivation of estrogen in the liver. Excess estrogen regularly produces this phenomenon (Korenchevskq and Dennison, 1935), and it was observed by the author in vitamin B deficient castrate animals with a pellet of estrogen or an ovary implanted in the spleen, showing protracted estrual reactions as a result of impaired inactivation in the liver." "A survey of necropsy records of female patients with cirrhosis of the liver (M. S. and L. H. Biskind, 1943) showed evidence of excess estrogen in every case in which data were available on the pelvic organs." "Bean (1942, 1943) has found that cutaneous vascular spiders and palmar erythema formerly associated mainly with cirrhosis of the liver, occur also in nutritional deficiency and at the period in pregnancy when estrogen increases significantly." "A considerable proportion of patients who have lesions of nutritional deficiency associated with functional uterine bleeding, cystic mastitis and premenstrual tension also have cutaneous vascular of the spiders and palmar erythema noted by Bean and by Perera. In addition, a tendency to develop petechial hemorrhages from relatively minor bruises and an increased tendency to bleed, are extremely common among these patients. This clears up rapidly on vitamin B complex therapy (M. S. Biskind, 1943; M. S., G. R. and L. H. Biskind, 1944; M. S. Biskind, unpublished), indicating that this phenomenon is related to dilatation of cutaneous vessels under the influence of estrogen and is not due to vitamin K deficiency, which has been thought to bear a relation to menorrhagia (Gubner and Ungerleider, 1944). However, in the patients who have prominent cutaneous vascular spiders, these rarely show more than slight or moderate regression under treatment[.] The palmar erythema, however, occasionally shows definite diminution after prolonged and intensive nutritional therapy (M. S. Biskind, unpublished)." "Deficiency of the vitamin B complex sets up a vicious cycle. For not only does vitamin B deprivation impair the inactivation of estrogen in the liver, but estrogen may cause vitamin B deficiency." "Heilig and Kantiengar (1942) found that in women in whom there is relatively low liver function (as measured by the ability to convert benzoic to hippuric acid) on the 13th or 14th day of the menstrual cycle, there is a further diminution in liver function on the first day of menstruation. This suggests that in women who have impaired liver function as a result of vitamin B complex deficiency, there is further impairment during the period of the cycle when the highest level of estrogen occurs." "[There is a need for greatly increase] intake of vitamin B complex during pregnancy and the puerperium." "[..]in diabetes, T. B. Futcher wrote in 1907, “Loss of sexual desire and power in men is common, and may be an early feature.” In intoxication with carbon disulfide, a liver poison, Edsall, writing the same year, pointed out that partial or complete impotence usually supervened. Cirrhosis of the liver has long been known to lead to testicular atrophy (cited by Glass et al., 1940). Reynolds and Macomber (1921) noted the occurrence of testicular atrophy in “malnutrition.”" "There was a striking correlation between the occurrence of indications of nutritional deficiency (atrophic glossitis, cheilosis, gingivitis, seborrhea alae nasae, keratosis of the lower eyelids, conjunctival injection, cutaneous vascular spiders, emotional instability, insomnia, rapid fatigability, peripheral neuritis, etc.) and the presence of testicular softening and atrophy. Gynecomastia occurred occasionally. Not infrequently in these cases, the liver was large and tender. Under intensive vitamin B complex therapy, not only did the lesions of nutritional deficiency clear up (with rapid diminution in the size of the liver when this was enlarged) but there was rapid and dramatic restoration of libido and potency. This was especially striking in cases of diabetes (Biskind and Schreier, 1945), in which diminished gonadal function in the male has long been considered almost invariable (cf. Root and Bailey, 1945)." "Numerous studies already cited have established that cirrhosis of the liver can be produced by nutritional deficiency or nutritional imbalance and that the B vitamins (especially choline) and the protein content of the diet play a major role in this phenomenon. In addition to the lesion just mentioned, other disturbances have been produced in the liver, both functional and morphological, by vitamin B deficiency (Rhoads and Miller, 1938; Sebrell and Onstatt, 1938). Gyorgy and Goldblatt (1939, 1940, 1942) have shown that, in experimental cirrhosis of the liver in rats, the lesions may be prevented by the administration of brewer’s yeast, yeast extract or choline. Subsequently, Blumberg and McCollum (1941) also reported prevention of dietary cirrhosis with choline, and Lowry and his co-workers (1941) have reported successful treatment of this condition with choline and casein. Patek (1937) and Yatek and Post (1941), have noted amelioration of clinical hepatic cirrhosis with dietary therapy, mainly with sources of the vitamin B complex. Choline has also been found to be useful in clinical cirrhosis (Broun and Muether, 1941)." "Failure of the liver to inactivate estrogen in a deficiency of the vitamin B complex while this organ continues to inactivate androgen must seriously disturb the estrogen-androgen equilibrium. One possible consequence of such an alteration is indicated by the work of Lipschutz and his collaborators (1939-1944; cf. also Vargas, 1942; Marx et al., 1942; Dosne, 1944; Iglesias et al., 1944). Lipschutz et al. have shown that subserous fibroids can be produced by the continuous (but not by the intermittent) action of estrogen, not only in the uterus but also in other abdominal organs and in the abdominal wall. Fibroids thus produced can be prevented by the simultaneous administration of testosterone (or of progesterone or other steroids having the androstene nucleus)." "When viewed in the light of present knowledge on the relation of the B vitamins to inactivation of estrogen in the liver, a number of otherwise puzzling facts, especially in regard to tumors of the breast, become explicable. It is well known that the incidence of cancer of the breast is higher in obese women than in those of more nearly average proportions. This applies also to the occurrence of menorrhagia and other disturbances related to excess estrogen (M. S. Biskind, 1943). Loeb, Suntzeff et al. (1942) have shown that there is a definite direct correlation between body weight and the incidence of spontaneous mammary cancers in mice. The converse has been demonstrated by Tannenbaum (1940; 1942), who showed that caloric restriction diminished the incidence of mammary carcinomas." "As the need for thiamine and riboflavin is directly related to the caloric intake of carbohydrate, in a diet in which there is less than the minimal amount of these factors (and this is especially true of the present average American diet as well as that elsewhere) (Drummond and Wilbraham, 1939; Stiebeling, 1941, 1943; Jolliffe, 1943; Adamson et al., 1945), the greater the caloric intake, especially of carbohydrate, the greater the vitamin deficit. Clinically, obese patients virtually always show signs of avitaminosis unless they have had a nutritional supplement." "The fact that diabetics show an incidence of cancer six times that of the general population as a whole (Ellinger and Landsman, 1944) is quite in keeping with the etiologic relationship of nutritional deficiency to diabetes (see Section V)." "In the male, not only is spermatogenesis and spermic function affected directly by nutritional deficiency (vitamin A, vitamin E, [cf. Mason, 1939], riboflavin [MacLeod, 1942] and undoubtedly other factors) but the rise in body estrogen which results from failure of inactivation in the liver secondarily affects spermatogenesis. Biskind and Falk (1943) studied the effect of therapy with vitamin B complex (in some cases with addition of vitamin E) and found definite increases in sperm counts and in motility, and diminution in the percentage of abnormal forms, with apparent restoration of fertility in eight of thirteen cases." "The majority of the patients with syndromes related to excess estrogen studied by M. S., G. R and L. H. Biskind (1944) had a low basal metabolic rate. This was especially true of the patients with signs of severe or moderately severe nutritional deficiency. Administration of thyroid to these patients, in the absence of a vitamin B supplement, usually caused exacerbation of the signs and symptoms of the deficiency without significant change in the metabolic rate. The low metabolic rate in these patients may be the expression of a safety mechanism; the rise in body estrogen resulting from failure of inactivation in the liver depresses the pituitary with diminution in secretion of the thyrotropic principle." "In several patients with enlarged thyroids who were treated nutritionally for syndromes related to excess estrogen (M. S., G. R. and L. H. Biskind, 1944; M. S. Biskind, unpublished), a definite diminution in the size of this gland was observed after several months of therapy with vitamin B complex; this was sufficiently striking to be noticed spontaneously by members of their families. In none of these cases, however, did the goiter completely regress during the period of observation. This is of interest in view of the well-known observation that patients with goiters show periodic further enlargement of the gland during the latter part of the intermenstruum, when the body estrogen rises, and that administration of estrogen to some patients with hyperthyroidism leads to diminution in the basal metabolic rate (Goldman et al., 1940). (Because the administered estrogen causes further exacerbation of an already tenuous nutritional equilibrium produced by the hyperthyroidism [see Fig. 71 it would seem inadvisable to use estrogen therapy for this purpose unless the nutritional defect were simultaneously corrected.)" "Williams and Kendall (1943) have reported that administered thyroid is “less effective in promoting metabolic activity... in a state of thiamine deficiency than it is when the intake of thiamine is adequate.”" "The observations described clarify numerous problems of thyroid therapy that have formerly been both confusing and frustrating. Thyroid is not only one of the most valuable of endocrine substances but it is also one of the most misused. Until the relation of thyroid function (and the physiologic activity of thyroxine) to nutritional status had been clarified, it was impossible to evaluate a number of clinical phenomena related to thyroid function and the metabolic effects of administered thyroid. Until the relation of thyroid function (and the physiologic activity of thyroxine) to nutritional status had been clarified, it was impossible to evaluate a number of clinical phenomena related to thyroid function and the metabolic effects of administered thyroid. Among these are: (1) the significance of the basal metabolic rate as an indication for thyroid therapy; (2) the frequent failure of administered thyroid to affect the basal metabolic rate, although side actions such as tachycardia and nervousness may be prominent; (3) the development of endocrine complications (e.g., menorrhagia, cystic mastitis) following the use of thyroid in the treatment of obesity." "It is notable that both the nutritional factors affecting thyroid function operate in the same direction. Failure of inactivation of estrogen in the liver leads to a consistently high blood estrogen which depresses the thyrogenic function of the anterior pituitary, and thiamine deficiency (the effect of other factors has not yet been reported) prevents the development of the normal metabolic effects of thyroxine, whether endogenous or administered. Thus, in the presence of nutritional deficiency, a low basal metabolic rate might be expected and little effect on the metabolic rate would be derived from ingestion of thyroid. Precisely this occurs. In such cases, both the usual assumption that a low basal metabolic rate is a necessary indication for thyroid, and that this can be remedied by giving thyroid, are fallacious. Actually the administration of thyroid in the presence of nutritional deficiency is sharply contraindicated; the sole effect of thyroid therapy in such cases is to cause an exacerbation of the nutritional deficiency, although, probably because of the protective mechanisms discussed, this exacerbation is often not as striking as that produced by estrogen." "The author makes it a practice always first to correct the avitaminosis and, when the lesions are healed, then, and then only, to administer thyroid if this is required, continuing the vitamin therapy at the same time." "The association of deficiencies in accessory dietary factors with certain defects in carbohydrate metabolism has been the subject of numerous studies. Among substances known to be necessary for utilization of carbohydrate are thiamine, riboflavin, niacin amide, pantothenic acid, ascorbic acid, vitamin A and vitamin D, although the role of the latter three is not as well understood as that of the B vitamins (the literature is cited by Itosenberg, 1932)." Volunteers are needed for Energin alone and Energin + pantethine in small amounts. "Soskin and his collaborators (Soskin et al., 1934, 1935, 1938, 1939, 1941, 1944), in a series of fundamental investigations, have demonstrated the basic role of the liver in maintaining normal carbohydrate balance." "As Waters and Rest (1942) have pointed out, “If one were obliged to name the organ in which insulin exerts the most potent influence, there would be little hesitation in selecting the liver.”" "It has become customary to think of diabetes mainly in terms of insulin deficiency (cf. Root and Bailey, 1945). On the basis of an investigation into the nutritional aspects of diabetes, Biskind and Schreier (1945) have suggested an alternative explanation, namely that, owing to impaired function of the liver, the latter organ is no longer able to respond to endogenous insulin, which need not be deficient. Carbohydrate balance could then be restored in two ways, by administration of additional insulin, which (if the functional defect is not too great) forces the recalcitrant liver to behave, or by restoring normal hepatic function so that the liver can respond to pancreatic insulin. Thus the concept of insulin resistance, now restricted to cases in which there is failure of response to exogenous insulin, might be extended to include many more (and perhaps most) cases of diabetes, which they believe are caused by the fact that the liver becomes resistant to the action of endogenous insulin." "Biskind and Schreier believe that impairment of the ability of the liver to maintain carbohydrate balance occurs as a result of nutritional deficiency, and they have shown that intensive nutritional therapy can partly or entirely restore this function." "In a group of 94 diabetics studied by Biskind and Schreier, every one showed signs and symptoms of deficiency of factors of the vitamin B complex. Glossitis occurred in almost all the patients (cf. Fig. 12). Cheilosis, nasolabial seborrhea, keratosis of the lower eyelids, splitting of the fingernails in layers, clouding of consciousness, nervousness, insomnia, impairment of memory for recent events, precordial pain or distress, gastrointestinal disturbances and polyneuritis were noted frequently. Syndromes related to excess estrogen occurred concomitantly." "For the most part, all these conditions showed a more or less prompt response to intensive nutritional therapy. Associated with the improvement in the avitaminotic lesions, marked improvement occurred in carbohydrate metabolism. In some cases the insulin requirement could be reduced; in others insulin could be eliminated altogether. Improvement in general health was usually striking." "In 1896, Gilbert a nd Carnot reported that liver had a beneficial but variable effect on diabetes. Following their initial publication, numerous French investigators studied the effects of various liver extracts with similar variable results. In 1922, Levine, in this country, reported improvement in 3 of 4 diabetics treated with a special liver extract. And several years later Blotner and Murphy (Murphy and Blotner, 1927; Blotner and Murphy, 1929, 1930) conducted an extremely well-controlled investigation which demonstrated conclusively in patients, that the feeding of raw liver (or of liver fractions other than those containing the antipernicious anemia factor) had a definite effect in lowering the blood sugar of diabetics." "Gaebler and Ciszewski (1945) found in 3 of 4 pancreatectomized dogs kept on a maintenance dosage of insulin, that withdrawal of the B vitamins from the diet caused exacerbation of the diabetic state and increased the insulin requirement by 50%. Using as a source of the B vitamins, either yeast (which has also been credited in the past with containing a blood sugar-reducing substance [cf. Dubin and Corbitt, 1923], and which has a history of use in diabetes almost as long as that of liver), or a mixture of thiamine, riboflavin, nicotinic acid, inositol, pyridoxine, pantothenic acid and p-aminobenzoid acid, they were able to produce prompt amelioration of the diabetic state and to reduce the insulin requirement to its former level. Richter et al. (1945) have shown that partially depancreatized rats, given free choice of various nutrients, consumed more proteid, more fat, much less carbohydrate and more of the components of the vitamin B complex--thiamine, riboflavin, pantothenic acid, pyridoxine and choline--than normal animals given a similar choice. So long as the depancreatized animals remained on the high proteid, high fat, high vitamin diet of their own selection, they showed no symptoms of diabetes; on a stock diet symptoms of diabetes appeared promptly." This is very interesting. They refrained from niacin and relied on tryptophan conversion instead, just like babyzords and dairy, to not boost oxidation and cause problems. Such diet is conserving and can prevent complications when there is not enough resources. "The use of single drugs has a strong modern tradition in medicine and, as a consequence, the tendency to administer thiamine or riboflavin or niacinamide alone, in an effort to correct lesions showing a predominant deficiency of one of these factors, is widespread. But clinically, single uncomplicated deficiency rarely, if ever, occur, and considering the difficulties involved in producing such deficiencies in animals under strict laboratory control, it would be extremely surprising to find a deficiency of a single vitamin in a human being even with the most esoteric dietary habits. The tendency to administer mixtures of the known crystalline B vitamins, while an improvement over the use of single factors, produces clinical effects only slightly better. The addition to these mixtures of adequate quantities of yeast, yeast extracts, rice bran extract, suitable liver extracts or whole liver, produces dramatically superior results. For the purpose of supplying necessary nutritional factors that are as yet unidentified, liver is far superior to yeast or rice of the brans, the most suitable products being the 80% alcohol-insoluble fraction or whole desiccated liver (in doses supplying the equivalent of at least two or three ounces of liver a day)." @haidut - maybe you find something inspiring here. "The fallacy of administering mixtures of crystalline vitamins alone in nutritional deficiency is illustrated by the experiments of M. S. and G. R. Biskind (1942, 1944) illustrated in Figs. 1 and 2 (p. 152). In these experiments it was possible, by producing deficiency of all the factors of the B complex, to impair the estrogen-inactivating function of rat livers that appeared perfectly normal histologically. However, by administering a mixture of thiamine, riboflavin, pyridoxine and calcium pantothenate as the sole source of B vitamins, the estrogen-inactivating function could be restored but these rats all developed fatty livers containing focal areas of necrosis. This principle is further illustrated by a recent clinical report of T. and J. Gillman (1945) who studied liver biopsies in infantile pellagrins before and during nutritional therapy. The use of a mixture of thiamine, niacin and ascorbic acid or of riboflavin and niacin in these patients not only failed to effect histologic improvement in the fatty livers (which resembled morphologically the rat livers illustrated in Fig. 2 of this review) but caused actualy aggravation of the hepatic lesions. T. and J. Gillman demonstrated that "crude" parenteral antianemic liver extract was only moderately superior to the crystalline vitamins used. However, so compelling is the prevailing view that aqueous extracts of liver represent all the activity of whole liver that these workers turned, for an adequate source of essential nutritional factors, not to desiccated whole liver but to desiccated stomach, which they found to be superior to the parenteral liver extract previously used. It is unfortunate, from the standpoint of nutritional therapy, that liver extracts concentrated mainly with a view to increasing their antianemic potency, were for a long time virtually the only ones available; and only a small fraction of such extracts currently produced are used for the purpose for which they were originally intended--pernicious anemia. Most of them are employed for treatment of conditions for which they are ill-adapted--mainly nutritional deficiency. This is the more regrettable as the whole liver from which the extracts are derived would, if ingested as food, produce dramatically superior results. An investigation of the effectiveness of whole liver and various liver fractions in the treatment of avitaminosis was carried out by M. S. Biskind (1944), with a view to elucidating the factors involved in the refractoriness of certain lesions of avitaminosis B, especially certain types of atrophic glossitis. He found that although the great majority of patients had an excellent response to commercial preparations of the vitamin B complex, and the ameliorative effect persisted indefinitely as long as maintenance therapy was continued, in a few of them the atrophic glossitis showed only a temporary response to the B complex (even though other signs subsided), and this lesion the recurred in a more refractory form. Subsequent administration of aqueous liver extracts (together with the crystalline B factors) orally and parenterally, usually failed to have more than a slight effect on this type of glossitis. Addition to this regimen of the known liposuluble vitamins (A, D, E and K) was equally ineffective. However, the ingestion of cooked whole liver in an amount much less than that from which the ineffective extracts were derived, caused a rapid and complete healing of the tongue. If the ingestion of whole liver discontinued, the glossitis recurred in a few days. The lesion could again be healed on resuming this therapy and the tongue could be maintained in the normal state indefinitely as long as liver was ingested at lest several times a week. But whole liver alone could not control the associated signs and symptoms of nutritional deficiency; these responded to intensive therapy with the water-soluble B factors. Among the factors missing from the ineffective liver extracts is biotin, which is bound to the protein in liver. In view of the report by Sydenstricker et al. (1942) that atrophic glossitis may occur as a result of biotin deficiency in man, a biotin concentrate was administered parenterally in one patient, in a dose providing 50 y per day; no perceptible effect occurred. Accordingly, Biskind further investigated the effect of different liver extracts in maintaining or restoring the estrogen-inactivating function of the liver in rats (utilizing the technic of G. R. Biskind and Mark, 1939), when these extracts were added to a vitamin B complex-free diet. The first preparation was an antianemic extract soluble in 70% alcohol; the second was a nonsaponifiable liposoluble extract originally described by Wiles and Maurer (1939), obtained from the portion of liver remaining after the antianemic fraction is separated. The nonsaponifiable lipoid extract of liver had a definite, but quite limited, effect in preventing impairment of the estrogen-inactivating function of the liver in animals on a vitamin B complex-free diet and in restoring this function in animals not previously depleted. Another aqueous antianemic liver extract, more highly purified by additional alcohol precipitation, was even less effective. The lipoid extract could neither restore the body weight of animals depleted in the B complex nor maintain it in nondepleted animals. The antianemic fraction likewise could not restore the body weight in depleted animals but could maintain it (and actually permit a further gain) in rats not previously depleted. In contrast to the limited effects of either extract alone, a mixture of the water-soluble and liposoluble fractions, in proportions representing equal amounts of fresh liver, had a striking effect in restoring the estrogen-inactivating function of the liver and in maintaining it. In addition this mixture caused rapid gainz in body weight in animals previously depleted. This evidence provides experimental confirmation for the existence of factors essential to nutrition in the lipoid fraction of liver and suggests the advisability of combining these liver factors with those now employed in manufacturing commercial preparations for nutritional therapy. Turner and Miller (1943) have obtained from liver lipoids two substances that stimulate the production of white blood cells. The simplest method of administering a combination of aqueous and lipoid fractions of liver is to use the whole desiccated unfractionated liver substance. This, as already indicated, has been found to be extremely effective as a source of accessory nutritional factors in the nutritional therapy of syndromes related to excess estrogen by M. S. Biskind (1944) and of diabetes by Biskind and Schreier (1945). Cooperman et al. (1945) have found whole desiccated liver to contain a factor or factors (not present in aqueous liver extracts tested) which are essential to nutrition of the monkey. Failure of absorption is common in severe deficiencies, as changes take place in the gastro-intestinal of the tracts rather early. Many patients therefore require parenteral therapy. However, as the available parenteral liver extracts lack essential nutritional factors, it is not as yet possible to administer complete B complex therapy by the parenteral route. Therefore, mixtures of crystalline B vitamins are thus used along with oral administration of the more nearly complete preparations. The following is the therapeutic regime employed by Biskind et Schreier (1945) in the nutritional therapy of diabetes. The nutritional factors given orally are usually administered in the following daily amounts, in divided doses after meals: 36-45 mg. thiamine 21-36 mg. riboflavin ..200 mg. niacinamide (occasionally increased to 500 mg.) 12-27 mg. calcium pantothenate ......3 mg. pyridoxine ...210 mg. choline 27-150 mg. inositol 60-280 y L. casei factor (folic acid) These vitamins were derived in part from crystalline material and in part from brewers' yest extract, 80% alcohol-insoluble liver extract, desiccated whole liver or combinations of these (the inositol and folic acid were derived solely from the natural sources); 300 mg. ascorbic acid was often included." "Although many patients respond rapidly and dramatically to therapy with the vitamin B factors, not a few have severe lesions of nutritional deficiency which respond slowly despite intensive therapy (cf. Kruse, 1942, 1943). Sometimes rather sudden improvement occurs following protracted intensive therapy, as in some of the cases of diabetes observed by Biskind and Schreier (1945). Perseverance is therefore important. And, as already indicated, the importance of including in the nutritional regime adequate amounts of accessory B complex factors (preferably in the form of suitable liver fractions or desiccated liver or combinations of these) cannot be too strongly stressed. Few patients respond satisfactorily to mixture of crystalline B factors alone or to those containing, as sources of accessory factors, a few grains of brewers' of the yeasts." "As in other conditions related to nutritional deficiency, large doses of B complex factors must be administered indefinitely even after all morphological defects have healed, the minimum maintenance dosage at this stage being at least five to ten times the maintenance amounts for normal persons (cf. Martin and Koop, 1942) and often much more."