Circulatory Manifestations of Vitamin Deficiency: Diagnosis, Treatment, and Prevention

Medical Clinics of North America May, 1939. New York Number

CLINIC OF DRS. NORMAN JOLLIFFE AND LOUIS A. ROSENBLUM FROM THE DEPARTMENT OF MEDICINE, NEW YORK UNIVERSITY COLLEGE OF MEDICINE, AND THE MEDICAL SERVICE OF HOSPITAL

THE

PSYCHIATRIC

DIVISION,

BELLEVUE

CIRCULATORY MANIFESTATIONS OF VITAMIN DEFICIENCY: DIAGNOSIS, TREATMENT, AND PREVENTION Introduction.~There is a considerable number of patients having circulatory disease for which a satisfactory etiologic diagnosis cannot be made. 1 Several observers have recently suggested that a vitamin deficiency may be the explanation of the circulatory failure in certain of these cases, and, in addition, may play a rOle in the development and aggravation of circulatory failure due to heart disease of conventional etiology. Circulatory disease is known to occur in vitamin deficiency syndromes. The heart is said to be enlarged at times in rickets,2 in scurvy/ and in edema and circulatory failure associated with severe and prolonged undernutrition in infants.4 It is in persons having beriberi, however, a disease due to a deficiency of vitamin B l , that circulatory disturbances are well known and described wherever the disease is observed. From the evidence presently available, excepting the possible role of vitamin C under saturation in conditioning the endocardium to infection,5 and the high incidence of vitamin C undersaturation in clinic patients having degenerative heart disease,6 it seems that beriberi is the only vitamin deficiency syndrome now known to be, in its more advanced states, regularly associated with circulatory failure. It is probable that most of the manifestations of circulatory failure noted in association with scurvy, pellagra, and epidemic dropsy are due to an associated vitamin Bl deficiency. Beriberi in the Orient.-To form a basis of reference with which to compare our patients, the circulatory manifestations of beriberi as seen in the Orient will be summarized. 759

760

NORMAN JOLLIFFE, LOUTS A. ROSENBLUM

Beriberi is best defined as "a complex clinical syndrome which follows failure to ingest, absorb or utilize sufficient amounts of vitamin Bl . It is as a rule associated with prolonged and too exclusive use of a diet rich in calories derived from refined carbohydrate or alcohol. It is characterized clinically by varying degrees of a peripheral symmetrical polyneuritis which may occur alone or in combination with edema, serous effusions, enlarged heart and circulatory failure."7 This definition indicates the clinical types, namely: (1) the neuritic or "dry" beriberi, in which the signs are predominantly limited to the nervous system; (2) the edematous or "wet" type, in which the polyneuritis, often minimal or mild (occasionally no signs can be detected) but sometimes severe, is associated with edema and serous effusions in the pericardial, pleural and peritoneal cavities; (3) the "cardiac" type, when the polyneuritis is associated with heart failure; and (4) the "mixed" type, a combination of polyneuritis, edema and congestive heart failure. These types of beriberi do not form a rigid clinical picture. In the "wet" type, the edema may be mild or severe, present only in the dependent parts, or there may be anasarca. In both the moderate and severe degrees of edema, serous effusions in the pericardial, pleural and peritoneal cavities are common. Pericardial effusions are more common than pleural and peritoneal, being noted at necropsy in SO per cent or more of the subjects. 8 Ascites is rarely extensive and is usually insufficient to cause pulmonary symptoms from upward pressure. The edema and serous effusions in this form of beriberi occur in the absence of an enlarged heart, dilated cervical veins, congested enlarged liver, basal pulmonary rales or other supporting evidence of congestive heart failure. They may occur without significant lowering of the total serum proteins or of its albumin fraction and without demonstrable kidney disease. Rest in bed without specific vitamin Bl therapy is followed, as a rule, by improvement or even disappearance of mild or moderate degrees of edema, and some improvement may be noted in the more severe grades of edema. When the weight is constant on rest in bed, adequate vitamin Bl therapy is effective. It is in this form of beriberi that the diagnosis of right heart failure is often incorrectly made if one does so without other definite evidence of congestive heart failure.

MANIFESTATIONS OF VITAMIN DEFICIENCY

76I

This diagnosis, in many studies in the Orient, was made in the past on the finding of right heart enlargement assumed only from percussion dullness to the right of the sternum, dullness which in many instances existed only in the mind of the observer. This incorrect interpretation of the picture of the "wet" type of the beriberi syndrome has caused many observers, particularly in the Western World, erroneously to exclude vitamin Bl deficiency as the cause of edema and serous effusions when no roentgenographic evidence of cardiac enlargement exists. The diagnosis of the cardiac form of beriberi should be made in the absence of definite heart enlargement only when there is evidence of congestive heart failure other than edema and serous effusions. If this rule is followed the cardiac form of beriberi will, as a rule, manifest signs of both right and left heart failure, though the signs attributed to failure of the right heart usually predominate. Consequently a patient with the cardiac form of beriberi usually shows, in addition to edema and serous effusions, dilated cervical veins, a palpable liver, dyspnea, and orthopnea; and will usually complain of palpitation, br~athlessness, particularly after exertion, and, often, of precordial pain. Pulmonary congestion is common, most patients developing pulmonary edema before exitus. The pulse is rapid, and bounding, and often there is a high pulse pressure with pistol shot sounds heard over the great arteries. Cyanosis is not frequent, but generalized arteriolar dilatation is common. If measured, the velocity of the blood flow is usually normal or increased, and there is a low arteriovenous oxygen difference. Teleoroentgenographic examination shows enlargement of the heart, attributed chiefly to enlargement of the right ventricle and auricle, and, frequently, increase in the size of the pulmonary conus and pulmonary artery is noted. The left auricle and ventricle often contribute to the enlargement of the cardiac shadow, but as a rule to a lesser extent than their mates on the right. Though few patients present normal electrocardiographic tracings, the alterations found are not usually characteristic or diagnostic. Circulatory collapse and sudden death are described as common in all studies of beriberi in the Orient. Some resemble shock, with rapid thready pulse and low or unobtainable blood pressure; others resemble the syndrome produced by a hyper-

762

NORMAN JOLLIFFE, LOUIS A. ROSENBLUM

active carotid sinus reflex of the vagotonic type. These manifestations may occur without previous warning, or only after other circulatory manifestations are well established. They occur most frequently in patients up and about, and particularly in those engaged in physical labor. Pathogenesis.-The pathogenesis of these circulatory disturbances, except that they are dependent upon a deficiency of vitamin Bl, is still largely conjectural. The most obvious explanation for the edema and serous effusions in the "wet" type of beriberi would be right heart failure, but edema and serous effusions alone, as pointed out by Keefer,9 are insuf·· ficient to justify the diagnosis of right heart failure. To what, then, should we attribute the edema and serous effusions when, in addition to lack of supporting evidence for right heart failure, there is no elevated capillary pressure, lowering of the plasma proteins, damage to the walls of the capillaries, lymphatic obstruction, high salt intake or sodium chloride retention, or a high fluid intake or warm environment? Weiss and Wilkins 10 call attention to the generalized arteriolar dilatation; Platt and Lull emphasize the high excretion of creatinine in the urine, muscle cramps, and accumulation of pyruvic acid in . the blood; and Thompson 12 points out that the kidney is the only organ other than the brain in which the oxygen uptake is lowered as a specific effect of the lack of vitamin Bl . Unless these observations contain the explanation, it seems that edema and serous effusions may be attributed to a specific action of vitamin Bl deficiency, the dynamics of which are not at present understood. The mechanism of the congestive heart failure, when it develops, has been variously explained. That the heart failure in these subjects is due to neuritis of the vagus nerve is untenable. Vagal paralysis does not cause enlargement of the heart; 13 there is no evidence that vagal neuritis can cause the picture of heart failure seen in beriberi, and many patients have beriberi without evidence of vagal involvement.9 That heart failure in beriberi is a result of respiratory paralysis is even more untenable. By this theory, dilatation of the right side of the heart and subsequent failure is due to the retraction of the lungs and elevation of the diaphragm that follow hydrothorax. This explanation fails to account for the presence of heart failure without hydrothorax or diaphragmatic paral-

MANIFESTATIONS OF VITAMIN DEFICIENCY

763

ysis, or the lack of heart failure in the many subjects with tuberculosis treated by collapse therapy. Aalsmeer and Wenckebach14 attributed the heart failure to a disturbance of water metabolism, causing edema of the heart muscle with consequent loss in contractility. Without discussing the pros and cons of this theory, which has much to support it, the observations of Weiss and Wilkins 10 that the beriberi heart has an unaltered water content as compared with normal hearts, or hearts of patients dying of heart failure from other causes, is especially significant. To explain the loss of contractile power of the heart, several observations of different investigators must be correlated. The first of these is that vitamin Bl is a catalyst necessary in complete oxidation of carbohydrates,15 the lack of which decreases the contractile power of the heart muscle. The second is the observation of Harrison and Pilcher16 that edema per se increases the work of the heart and thus would secondarily contribute to the production of heart failure. The third is the frequent observation that subjects with beriberi who have polyneuritis of a degree still permitting physical effort are the most likely to develop heart failure. This is in agreement with Barr's17 study demonstrating the importance of physical exercise in the production of heart failure from any cause. These three factors are all present in most patients with beriberi who develop congestive heart failure. Pathology.-The cardiac pathology in vitamin Bl deficiency may be compared with the pathology of auricular fibrillation, in that one finds little that is specific. Aalsmeer and Wenckebach 14 studied the hearts of Javanese with beriberi and described interstitial edema and histological changes characterized by hydropic degeneration of the myocardial fibers and the conductive bundles. Most of these hearts also exhibited considerable dilatation of the right ventricle. In the group of hearts examined by Weiss and Wilkins lO the gross changes were not so marked or so frequent, but the histological features were identical with those described by Aalsmeer and Wenckebach. Weiss and Wilkins' data, however, indicated that the microscopic changes were neither specific nor characteristic and were present in other diseases. Their measurements of the water content of skeletal and cardiac muscles of patients with beriberi and with heart failure of known other

764

NORMAN JOLLIFFE, LOUIS A. ROSENBLUM

etiology, and of control groups without heart failure, disclosed no essential differences. Beriberi in the West.-The cardiovascular disturbances described in patients with beriberi in the Orient should be observed in the Western World if vitamin Bl deficiency is common. If vitamin Bl deficiency is rare, then these circulatory manifestations should be of still greater rarity. Opinion is widely divided as to the prevalence of vitamin Bl deficiency in this country. The feeling of many has recently been stated by Aykroyd: 18 "There is really little reason to believe that the average English or American dietary ... contains insuf~ ficient vitamin Bl for health." On the other hand, the clinical experience of a considerable group of physicians has recently been expressed by Strauss19 in the following language: "During the past decade it has been shown that beriberi is and has been endemic in the United States in characteristic form." In a recent paper we20 have presented in some detail a clinical evaluation of the evidence for these two statements showing that both may be correct and are not necessarily contradictory. The incidence of vitamin Bl deficiency in this country is difficult to estimate. Strauss19 states that beriberi is endemic. Weiss and Wilkins lo say that the cardiovascular manifestations alone occur in one out of every 160 admissions to two of the medical services of Boston City Hospital. The figures of Romano 2l and of our service22 indicate that from 20 to 30 per cent of alcohol addicts sufficiently ill to require hospitalization have evidence of vitamin Bl deficiency in the form of definite polyneuritis. In 1935 alcoholism accounted for over 11,000 first admissions to mental hospitals in the United States; 23 thus the frequency in this group alone provides a significant number of patients sufficient to warrant the serious attention of the profession in this country. Beriberi is a disease resulting from failure to ingest, absorb or utilize adequate amounts of vitamin B l . The average diet in the Orient is of borderline character in vitamin Bl, and because of the many factors increasing the requirement or preventing its absorption or utilization, beriberi is endemic. Most important of these factors in the Orient are hard physical labor, especially among the coolies, long-continued fevers of known and unknown etiology, and intestinal infestations leading to diarrhea.

MANIFESTATIONS OF VITAMIN DEFICIENCY

765

The average American diet, though it provides but one-third of the vitamin Bl contained in American 20 or English24 dietaries of a century ago, still provides us with a 20 to 80 per cent margin of safety 20 in this important vitamin. This margin of safety, however, applies to the average diet of all our people; it follows that a considerable number must consume either a superaverage or a subaverage amount of vitamin Bl. That this is true is evident from Williams and Spies'25 and from our20 calculations of the adequacy in vitamin Bl of the diets of wage earners and low salaried clerical workers. 26 These calculations show that a sufficient fraction of our population subsists on diets that are either borderline in character or provide such a small margin of safety that the presence of any of the factors increasing the vitamin Bl requirement, or conditions that prevent its absorption or utilization,2° is likely to be followed by clinical vitamin Bl deficiency. That the cardiovascular disturbances described as occurring in the Orient do occur in patients with vitamin Bl deficiency in this country has been pointed out by Weiss and Wilkins 10 and by this clinic.22 . 27 The subjects of our study27 were 83 alcohol addicts, between the ages of twenty-seven and fifty-one years, who did not have and never had chronic cardiovascular or acute or chronic kidney disease, and who had improved or recovered on discharge from the hospital. Eighteen showed none of the stigmata of alcohol addiction and were, therefore, labeled "uncomplicated." The remaining 65 showed nutritional complications of alcoholism; 61 had polyneuritis. The method of study was as follows: Upon admission to our service each patient was given the basal diet28 of borderline adequacy in vitamin Bl with an unrestricted intake of water and salt. During this preliminary period, lasting four to fourteen days, no specific medication was given, and the cardiovascular status of each subject was studied. On completion of the control studies, and after the patient had reached a constant weight level, the 65 patients who showed, in addition to their alcohol addiction, one or more of the diseases listed in Table 1 were given a weighed diet rich in vitamins, supplemented by 18 Gm. of vegex 29 daily. In addition to 3,100 calories, this regimen supplied 1,065 international units of vitamin Bl daily, approximately four times the estimated

766

NORMAN JOLLIFFE, LOUIS A. ROSENBLUM TABLE 1

DISTRIBUTION OF COMPLICATIONS IN THE ALcOHOL ADDICTS STlJDmD27

With peripheral neuritis.

Without peripheral neuritis.

Total.

Peripheral neuritis only ..............

25

·.

25

Alcoholic encephalopathy or Korsakoff's syndrome ...................

16

2

18

Pellagra* ...........................

12

0

12

Laennec's cirrhosis ...................

7

2

9

Scurvy .............................

1

0

1

Total complicated ................. Uncomplicated .................... Total subjects .....................

61

4

65 18

.. ..

·. ·.

83

* Includes two cases of alcoholic stomatitis.

Tables 1, 2, and 3 by courtesy of the American Heart Journal.

average maintenance requirement of vitamin Bl for our patients. This therapy was maintained for periods varying from two weeks to two months. In 10 subjects the oral therapy was supplemented by 10 to 50 mg. of crystalline vitamin B 1 30 daily by parenteral administration. Observations were repeated at intervals throughout the period of hospitalization. The 18 alcohol addicts who showed none of the stigmata of alcohol addiction did not receive specific treatment, and the initial studies were not, as a rule, repeated. The data were analyzed by two methods: First, observations made during the control period on the group with complications were compared with those made on the group without complications. Second, a comparison was made in the group with complications before and after the period of vitamin therapy. The results by the first method of study are summarized in Table 2. The preponderance of signs and symptoms of cardiovascular dysfunction in the complicated cases, as compared with the uncomplicated cases, is obvious. Nineteen patients in the complicated group had dyspnea, palpitation, precordial pain, or peripheral cyanosis on admission; 20 had pitting edema; and 26 had enlarged, palpable livers; while no patient

767

MANIFESTATIONS OF VITAMIN DEFICIENCY TABLE 2

A COMPARISON OF THE CARDIOVASCULAR STATUS OF THE "UNCOMPLICATED" GROUP WITH· THE "COMPLICATED" GROUP DURING THE CONTROL PERIOD27 I

No. of cases: Male ............. Female ...........

Uncomplicated.

1~} 18

Complicated. 47} 65 18

Extremes in age ............... 28-49

27-51

Average age .....•............. 38

40

Previous heart disease ..........

0

Cardiovascular symptoms .......

0

19 (29%)

Edema .......................

0

20 (30.7%)

Palpable liver .................

0

26 (40%)

0

Average heart rate ............. 88

101

Cardiac murmurs ..............

0

Enlarged heart (x-ray) .........

o (out of 15)

9 (13.8%) 14 (out of 55

Average blood pressure ......... 134/84

136/87

Extremes of K: Male .......... 0.3745-0.4318 Female ........ 0.3946-0.4341

0.3500-0.6306 0.4041-0.5181

Average K: Male .............. 0.4021 Female ............ 0.4107

0.4323 0.4390

Low voltage of QRS in all 3 leads Low voltage of T-waves in all 3 leads ....................... Inverted T-waves in Lead 1. .................. in Lead Ill .......... ' .... ' . in Leads II and Ill .......... in all 3 leads ................

1 (5.5%)

1 (1.5%)

~ (55%»)

6 (9.2%)

3 0 0

(22%)

(47.7%)

2 3

J

i}

~} (5.5%)

Right axis deviation ............ Left axis deviation .............

0 1 (5.5%)

Average plasma protein .........

6.52

6.32

Albumin .................. : ... Globulin ......... , .......... , .

4.18 2.34

3.82 2.5

Anemia Mild ....................... Moderate ................... Severe ............ '" .......

6} (out of 17) (11.7%)

(15.4%)

3 (4.6%) 16 (24.6%)

~i

9

25.4%)

1

1~

Depressed S-T segments in Leads I and II ............ in Lead II .................. in Leads II and Ill. .........

o

=

}(out of 58) (72.4%)

768

NORMAN JOLLIFFE, LOUIS A. ROSENBLUM

in the uncomplicated group presented any of these signs. A comparison of the electrocardiograms shows a much greater incidence of inverted T-waves and depressed S-T segments in the complicated cases than in the uncomplicated ones. In 20 subjects in the complicated group the relation of ventricular systole to the entire cardiac cycle, as expressed by the constant K of Cheer and Dieuaide/ 1 was prolonged beyond normal limits. No patient without complications showed an abnormally large K. The patients in the complicated group revealed a higher incidence of tachycardia and a greater incidence and severity of anemia, but no significant difference in the plasma protein levels. The results by the second method of study are summarized in Table 3. Symptoms attributed to cardiovascular dysfuncTABLE 3 INCIDENCE AND TYPE OF CARDIOVASCULAR DISTURBANCES IN THE GROUP WITH COMPLICATIONS AND INCIDENCE OF CHANGES FOLLOWING THERAPy27

Number of cases in Number of column 1 in which Number cases on improved Per cent studies were improved. initial after repeated after therapy. study. therapy. Symptoms due to cardiovascular dysfunction .. Edema ....... ..... Palpable liver .... Cardiac murmurs .. Enlarged heart (x-ray) .. Systolic blood pressure above 150 .... . ... Diastolic blood pressure above 100 .......... Abnormally large value for K: Q-T = KvR=R. Low voltage of QRS in all 3 leads .............. Low voltage of T-waves in all 3 leads ......... Inverted T-waves in 1 or more leads ........... Depressed S-T segments. Right axis deviation .. Left axis deviation ...

19 20 26 9 14

19 20 26 9 8

19 20 14 8 4

100.0 100.0 53.9 88.9 50.0

15

15

14

93.3

9

9

8

88.9

20

10

5

50.0

1

1

1

100.0

6

4

3

75.0

25 10 3 16

15 10 3 7

11 10 3 4

73.3 100.0 100.0 57.1

tion, that is palpitation, dyspnea and precordial pain, which were present in 29 per cent of the subjects, disappeared in

MANIFESTATIONS OF VITAMIN DEFICIENCY

769

every instance within four days of admission, while the patients were maintained with the basal diet, and before therapy was instituted. Mild to severe edema was present in 20 patients, two of whom had anasarca. Eighteen (90 per cent) showed other signs of circulatory distress. In 12, the edema disappeared after the first day in the hospital; in 3 it disappeared gradually over a period of four days. In four subjects the edema did not disappear until after the institution of vitamin therapy. In one patient, who showed anasarca on admission, traces of edema of the lower extremities were still present when he was discharged fifty-one days later. Of the 26 subjects who had enlarged livers, 10 presented no other clinical evidences of cardiovascular disturbance. In 7 of these 10 the liver was no longer palpable at the completion of the study period. Of the nine patients with cardiac murmurs on admission, eight had only systolic murmurs. In one subject a systolic and diastolic murmur was present at the base. Persistence of a murmur throughout the period of hospitalization occurred in only one subject having a short rough systolic murmur over the aortic area which was not transmitted. Of the 14 patients with roentgenographic evidence of cardiac enlargement, seven had left axis deviation; one had right axis deviation; and six had no abnormal deviation of the electrical axis. Teleoroentgenograms were repeated before discharge in eight instances, in four of which the size and shape of the heart shadow were by then within normal limits. Of these four patients, one had shown right axis deviation, and three left axis deviation. All returned to normal before the final teleoroentgenogram. In only one of the four subjects whose cardiac enlargement persisted was there an associated deviation of the electrical axis (left) throughout the period of observation. Analysis of the blood pressure readings shows the rather high incidence of transient hypertension frequently noted in Oriental beriberi. Some abnormality in the electrocardiographic tracings occurred in over half of our subjects. Low voltage of the QRS in all three leads, depression of the S-T segments, and right axis deviation returned to normal in all subjects, while inversion of the T -waves returned to normal VOL. 23-49

770

NORMAN ]OLLlFFE, LOUIS A. ROSENBLUM

in 11 of 15 subjects and left axis deviation disappeared in four of seven. The onset of symptoms referable to cardiovascular dysfunction was acute or subacute in every case, occurring from two days to two weeks before admission, and the symptoms were progressive. When palpitation, dyspnea, and precordial pain occurred, they were usually the first signs to be noted by the patient. In addition to one or more of the above, a typical patient presented the following: dependent edema, tachycardia, transient elevation of the systolic blood pressure, a palpable liver, a moderate degree of anemia, slight cardiac enlargement, a systolic murmur, and electrocardiographic abnormalities such as depression of the S-T segments, inverted T-waves, and prolongation of the constant K.31 The patients with signs and symptoms of cardiovascular dysfunction tended to improve when nothing was done except to keep them in bed on the basal diet, but improvement was hastened in every instance when the vitamin-rich diet was substituted for the vitamin-poor diet, and in four no improvement whatever was observed until after a vitamin-rich regimen had been instituted. As in Oriental beriberi, the clinical picture in our patients was varied. Had the clinical picture been uniform it would have been surprising in view of the differences in individual size, metabolism, degree of muscular activity, fluid intake and degree of vitamin Bl deficiency, and in the time element over which these various factors operate. Each of these factors is known to play a part in causing the type of clinical picture which develops. When several are operating at the same time, and in view of the possibilities for various combinations, one must expect a variable clinical picture. In a previous study 22 case reports illustrating this varied picture were presented. The circulatory manifestations, as occurring in our subjects, may be subdivided clinically as follows: 1. Edema and serous effusions occurring without enlargement of the heart or other signs of congestive heart failure. 2. Edema and serous effusions o"Ccurring with supporting signs and symptoms of congestive heart failure, usually with definite roentgenographic evidence of cardiac enlargement. 3. Sudden circulatory collapse. This complication may occur as the first manifestation of circulatory failure, or may

MANIFESTATIONS OF VITAMIN DEFICIENCY

77 I

complicate the manifestations classified in groups 1 and 2 or in subjects having only the "dry" type. DIAGNOSIS

The characteristic diagnostic features of the circulatory manifestations of beriberi are: 1. Dependence on vitamin Bl deficiency. 2. Mild degree, as a rule, of the polyneuritis. 3. Increased or normal velocity of the blood flow in the presence of congestive heart failure. 4. Rapid response to specific therapy with apparently complete and permanent reversibility of the circulatory manifestations. Before arriving at a presumptive diagnosis preceding therapy, a number of observations must be carefully evaluated. First, the more conventional etiological factors such as rheumatic fever, syphilis, hypertension, arteriosclerosis, and constrictive pericarditis must be eliminated.* Second, the nutritional history of the patient must be carefully appraised. There may be a history of an unbalanced or freak diet, regular consumption of extra-dietary supplements of vitamin-free calories as from alcohol, sugar, corn syrup or candy, or dietary restriction for any number of reasons. In hospital patients, maintenance with glucose infusions for more than a few days should be carefully evaluated. The presence· of gastro-intestinal disturbances, such as gastritis, enteritis, achlorhydria, colitis, malignancy, and liver disease suggests a lack of proper absorption or utilization of the vitamin in addition to a possible inadequate intake of food. Fevers, hyperthyroidism and other causes for increased total metabolism should be noted. Third, the presence of noncirculatory manifestations of deficiency disease should be carefully looked for. The most important is peripheral symmetrical polyneuritis, involving first and predominantly the lower extremities. It is not sufficient to test the knee jerks and observe for muscle atrophy, paraly;sis, and foot and wrist drop. These are the signs of advanced polyneuritis. Just as heart disease exists without paralysis, and foot and wrist drop. These are the signs of

* The role played by vitamin BI deficiency in the aggravation of congestive heart failure due to these etiologic factors is not considered in this paper.

772

NORMAN JOLLIFFE, LOUIS A. ROSENBLUM

nerve failure. It is therefore necessary to examine carefully for mild polyneuritis as evidenced by calf muscle tenderness, hyperesthesia of the plantar surface of the feet which may extend up the leg in a sock distribution, absent vibratory sensation in the toes, areas of anesthesia in the legs, particularly over the tibiae and in the dorsa of the feet. If these signs exist one may strongly suspect a polyneuritis, and if present with absent ankle jerks the diagnosis of polyneuritis is reasonably certain even if the knee jerks are preserved. Clinical evidence of deficiency in other vitamins, a stomatitis, glossitis, piling up of the gums, or a pellagrous dermatosis, should always make one look for signs of vitamin Bl deficiency. Finally, the response of the circulatory manifestations of vitamin Bl deficiency to adequate therapy is, as a rule, rapid. Without this response, as we lack a specific test for vitamin Bl deficiency, the diagnosis of circulatory failure on the basis of vitamin Bl deficiency can not be made with certainty. Treatment.-The treatment of the circulatory manifestations of vitamin Bl deficiency is a combination of rest in bed, diet, and vitamin Bl. Rest in bed should be absolute because of the danger of sudden death on exertion. Smith32 has recently pointed out the value of diet in treating any form of heart disease. The diet must be adequate in all essentials, with the elimination of all vitamin-free foods such as white bread, pastries, alcohol, corn syrup, candy, corn starch and soft drinks, yet one that the patient can eat, digest and absorb. When the patient is extremely ill, it must be largely restricted to milk, eggs, ground liver, pureed legumes, thin whole wheat cereals, and fruit juices, administered, if necessary, via nasal catheter. Following improvement, or in less severely ill patients, whole wheat bread should be added, the legumes need not be pureed, other vegetables and raw whole fruit added, and a wider variety of meats permitted, with substantial portions of either liver or pork muscle included in one of the meals daily. This diet should be supplemented by liberal amounts of a rich source of the entire vitamin B complex (such as brewer's yeast, vegex, wheat germ, or whole liver concentrates), a rich source of vitamins A and D (as halibut liver oil), and 400 to 500 mg. of cevitamic acid in

MANIFESTATIONS OF VITAMIN DEFICIENCY

77 3

divided doses daily. Restriction of salt or fluids is not necessary. In addition to the adequate diet and its supplements, specific therapy, that is, thiamin chloride (synthetic vitamin B 1 ) should be administered parenterally, erring on the side of wasting the vitamin rather than giving an insufficient amount. If the patient is in marked circulatory collapse or severe congestive failure, large amounts of thiamin chloride should be given, up to 1000 mg. in divided doses, within the first twentyfour hours. The first dose may consist of 100 mg. intravenously and 300 mg. intramuscularly, with subsequent administration of 200 mg. intramuscularly every three to six hours. Thereafter the dosage of thiamin chloride should be reduced to amounts recommended for the less severely ill patients. This latter group can be safely treated, depending on severity, by parenteral administration of 20 to 200 mg. of thiamin chloride daily, preferably given in two doses, intramuscularly. After the patient is saturated with thiamin chloride, which may be recognized when a distinct odor of burnt rubber is detected in the urine, the amount of thiamin may be reduced to 10 mg. daily till convalescence is well established. Following convalescence, the balanced diet supplemented by rich sources of the vitamin B complex is sufficient, unless a complication exists indicating an unusual requirement of vitamin Bl, in which case thiamin chloride should be continued in amounts of 5 to 10 mg. daily. No mention has been made of correcting the underlying defects primarily responsible for the deficiency, which may be simply an inadequate diet or, more frequently, an underlying alcoholism. Occasionally, some disease preventing the ingestion, absorption or utilization of the vitamin will be discovered. During the convalescence these must be found and eradicated to effect a complete and permanent cure. Prevention.-The prevention of these circulatory manifestations is, of course, the prevention of vitamin Bl deficiency not only in the general, presumably normal, population, but alsb in those under the care of the medical profession. In the general population, the first and best solution would be the substitution of whole wheat bread and whole grain cereals for white bread and refined cereals, plus a reduction

774

NORMAN JOLLIFFE, LOUIS A. ROSENBLUM

in our annual per capita consumption of 100 pounds of vitamin-free sugar and of vitamin-free alcohol. The second solution would be the addition by the manufacturers to these vitamin-free foods, such as white bread, refined cereals, sugar, candy and alcohol, of sufficient amounts of thiamin chloride to bring the vitamin : calory ratio of these foods above borderline levels. Approximately 0.5 mg. of thiamin chloride for each 1000 calories of foodstuff would provide a margin of safety. This, of course, would not replace other nutritional factors· removed in the milling and refining processes, but because of the preference of the American public for highly milled products this may be the only practical solution. The third way would be for each individual consuming a borderline diet to take a daily supplement of either 2 mg. of thiamin chloride or, preferably, of a preparation of the entire vitamin B complex in an amount which would contain an equivalent of 2 mg. of thiamin chloride (666 I. U. of vitamin Bl). The latter method, because of the expense of these preparations, would be impractical for a large portion of our people. The prevention of vitamin B 1 deficiency in persons in ill health consists of the recognition of those factors, previously mentioned, that alter the vitamin Bl requirement, followed by the administration of sufficient amounts of vitamin B 1. In these conditions, the administration of vitamin Bl alone is not usually sufficient, and we therefore recommend the use of the entire vitamin B complex plus 5 to 10 mg. of thiamin chloride daily. In diseases interfering with absorption, the parenteral route should be utilized. A danger exists in hospital patients who are' maintained for any length of time with parenteral feedings of glucose, as in postoperative conditions. This danger can be obviated either by separate administration of thiamin chloride, or by including it in the infusion. BmLIOGRAPHY La ChapelIe, C. E.: A Study of Myocardial Hypert~'ophy of Uncertain Etiology Associated with Congestive Heart Failure, Am. Heart J., 15: 582, 1938. 2. Abt, 1. A.: The Child's Heart in Avitaminosis, Am. J. Dis. Child., 50: 455, 1935. 3. Wolbach, S. B.: Pathologic Changes Resulting from Vitamin Deficiency, Jour. Amer. Med. Assoc., 108: 7, 1937. 1. Kaplan, B. I., Clark, E., and De

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4. Waring, J. I.: Nutritional Heart Disease in Children, Am. J. Dis. Child., 55: 750, 1938. 5. Rhinehart, J. F., and Mettier, S. R.: The Heart Valves in Experimental Scurvy and in Scurvy with Superimposed Infection, Scientific Proceedings, Am. Assoc. Path. and Bact., Am. J. Path., 9: 932, 1933. 6. RaIli, E. P.: Personal communication. 7. Spies, T. D.: Personal communication. 8. Vedder, E. B.: The Pathology of Beriberi, Jour. Amer. Med. Assoc., 110: 893, 1938. 9. Keefer, C. S.: The Beriberi Heart, Arch. Int. Med., 45: 1 (Jan.), 1930. 10. Weiss, S., and Willdns, R. W.: The Nature of the Cardiovascular Disturbances in Vitamin Deficiency States, Trans. Assoc. Am. Phys., 5i: 341, 1936 .• Idem: The Nature of the Cardiovascular Disturbances in Nutritional Deficiency States (Beriberi), Ann. Int. Med., 11: 104 (July), 1937. 11. Platt, B. S., and Lu, G. D.: Chemical and Clinical Findings in Beriberi with Special Reference to Vitamin BI Deficiency, Quart. J. Med., 5: 355, 1936. 12. Thompson, R. H. S.: The Action of Crystalline Vitamin BI on the Respiration of Polyneuritic Tissues in Vitro, Biochem. J., 28: 909, 1934. 13. Hodges, P. C., and Eyster, J. A. E.: Estimation of the Cardiac Area in Man, Am. J. Roent., 12: 252, 1924. 14. Aalsmeer, W. C., and Wenckebach, K. F.: Herz und Kreislauf bei der Beriberi Krankheit, Wien. Arch. f. inn. Med., 16: 193, 1929. 15. Peters, R. A.: The Biochemical Lesion in Vitamin BI Deficiency, Lancet, 1: 1161, 1936. 16. Harrison, T. R., and Pilcher, C.: Studies in Congestive Heart Failure. 1. The Effect of Edema on Oxygen Utilization, J. CIin. Invest., 8: 259, 1930. 17. Barr, D. P.: Exercise in Cardiac Disease, Jour. Amer. Med. Assoc., 91: 1354, 1928. 18. Aykroyd, W. R.: Vitamins and Other Dietary Essentials, London, Heinemann, 1936. 19. Strauss, M. B.: The Therapeutic Use of Vitamin Bl in Polyneuritis

and Cardiovascular Conditions: Clinical Indications, Jour. Amer. Med. Assoc., 110: 953, 1938. 20. Jolliffe, N.: A Clinical Evaluation of the Adequacy of Vitamin BI in the American Diet, Int. Clinics, 4: 46 (Dec.), 1938. 21. Romano, J ..: Deficiency Syndromes Associated with Chronic Alcoholism, Am. J. Med. Sci., 194: 645 (Nov.), 1937. 22. Goodhart, R., and Jolliffe, N.: Beriberi in Alcohol Addicts, Jour. Amer. Med. Assoc., 111: 380 (July 30), 1938. 23. Miles, W. R.: Psychological Factors in Alcoholism, Ment. Hyg., 21: 529 (Oct.), 1937. 24. Baker, A. Z., Wright, M. D., and Drummond, J. C.: The Nutritive Value of Bread, J. Soc. Chem. Ind., 55: 191, 1937. 25. Williams, R. R., and Spies, T. D.: Vitamin BI and Its Use in Medicine, New York, The MacmilIan Co., 1938. 26. U. S. Dept. of Agric., Bureau of Home Economics, Diets of Families of Wage Earners and Low Salaried Clerical Workers Living in Industrial Communities in Three Regions of the United States, 1934-36. 27. Goodhart, R., and JoIliffe, N.: The Role of Nutritional Deficiencies in the Production of Cardiovascular Disturbances in the Alcohol Addict, Am. Heart J., 15: 569 (May), 1938. 28. JolIiffe, N., and Colbert, C. N.: The Etiology of Polyneuritis in the Alcohol Addict, Jour. Amer. Med. Assoc., 107: 642 (Aug. 29), 1936.

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29. Supplied by Vegex, Inc., New York. 30. "Betabion," supplied by Merck & Co., Rahway, N. J. 31. Cheer, S. N., and Dieuaide, F. R.: Studies of the Electrical Systole (Q-T Interval) of the Heart: Its Duration in Cardiac Failure, J. Clin. Invest., 10: 889, 1931. 32. Smith, F. M.: Diet and Theophylline in Treatment of Cardiac Failure. Jour. Amer. Med. Assoc., 91: 1274, 1928.