The Vitamin C Conspiracy Vitamin C
WE HAVE recently had an opportunity to review the clinical histories and pathologic findings in a group of children dying with varying degrees of scurvy. In three of these infants death came suddenly and quite unexpectedly. At autopsy all showed bone changes indicative of severe vitamin C deficiency; two had hypertrophy of the right ventricle of the heart. In each patient careful gross and microscopic examinations failed to reveal any other cause for death. It is to draw attention again to the role vitamin C deficiency may play in leading to cardiac insufficiency that the following cases are being recorded.
CASE 1 (A-7051).—A colored female infant was first brought to the Harriet Lane Dispensary at the age of 11 days with the complaint of "peculiar breathing and breath-holding spells." Although her delivery, which took place at home, was rather difficult, she breathed well immediately. Twelve hours later, however, she stopped breathing, went limp, and her lips turned blue. After this episode she seemed well enough until a few hours before coming to the dispensary when she was seen to stop breathing again several times. The examiner noted that the infant held her breath and then coughed up some white mucus. The examination otherwise was negative. She was sent to the Baltimore City Hospitals where calcium gluconate was administered. She had three similar attacks during the first five hours there but no recurrence during the following seven days of her stay. At 2 months of age she was brought again to the dispensary because of watery stools and vomiting of two days’ duration. Her formula was changed and she improved. Her next visit was at the age of 6 mouths when diarrhea and vomiting occurred again. At this time beading of the ribs was noted and a diagnosis of rickets was made. She was not seen again for four months and then was brought in dead by her mother who said she had gone to "dry her off" in the evening and found her lifeless. She had been perfectly well all that day. Post-mortem blood and spinal fluid cultures were sterile. There was no feeding history obtained other than the formula of 12 ounces of water, 6 ounces of Pet milk, and 1 tablespoon of sugar, advised at 3 months of age. There is no record as to whether orange juice or cod-liver oil had ever been given.
At autopsy (No. 16331) the following positive findings were noted. The body weighed 6 kg. The heart was obviously enlarged, weighing 65 Gm. This increase in size was due to hypertrophy of the right ventricle. All the valves were delicate and competent. The foramen ovale and ductus arteriosus were closed. The left ventricle did not seem enlarged. The myocardium of both ventricles was pale. The lungs contained fluid. The liver was yellowish. The line of ossification of the ribs was distinctly widened; the cartilage was movable on the shaft and the periosteum stripped from the cortex with a fair amount of ease. The meninges were delicate, and there was no evidence of hemorrhage.
Microscopically the myocardium of both ventricles was normal. The liver showed atrophy of the central cells and a good deal of fatty infiltration. The pulmonary alveoli contained fluid. The ribs showed characteristic changes of marked scurvy with virtually no healing. There was no microscopic evidence of rickets.
CASE 2 (H. L. H., 96642). —An 11-month-old colored male infant was brought to the Harriet Lane Dispensary with the following story. About 6 weeks before he had developed a nasal discharge, cough, and fever. He vomited also and was quite sick for two weeks and then seemed to improve, although soon thereafter he developed swollen knee joints. There was no fever and he did not seem very sick but he did not get any better either. At 1 A.M. the morning of admission he began to cry. His legs seemed more tender and even the covers on them made him scream. He was brought to the hospital shortly after. It was then learned that he had always been a feeding problem, having refused almost all solid foods. Cereal in milk had been given for the past six months. He spat up practically all the orange juice, cod-liver oil, and vegetables which were offered. On examination the child's legs were distorted, being large with wide shafts. He looked wan and pale. He did not seem in extremis and the mother was told the condition could be treated. Almost immediately, however, the baby's body stiffened, his back arched, and his eyes rolled up. By the time the clothes were removed and 64 mg. of caffeine were administered, he was gasping at very infrequent intervals; the pulse was impossible to feel and the heart sounds were faint. Artificial respiration was administered but without avail.
At autopsy (No. 15167) the following positive findings were noted. The body weighed 6.5 kg. and its nutrition was fairly good. The heart was dilated but not enlarged for the age, weighing 50 Gm. There were punctate hemorrhages beneath the epicardium and in one pulmonic valve cusp. There were hemorrhages in the gums, tongue, and lungs. The costochondral junctions were broadened and there was hemorrhage beneath the periosteum. The cranial cavity was not examined but the cerebrospinal fluid removed was clear. Blood culture was sterile.
Microscopically the heart was normal. The bones showed characteristic changes of extreme scurvy without rickets.
CASE 3 (A-15620). —A 7 ½ -month-old white male infant was brought to the Harriet Lane Dispensary gravely ill, and he died one-half an hour later. It was learned that six hours before the child had become blue and seemed to have difficulty in breathing. On examination the child appeared extremely cyanotic with slow and deep respirations. The costochondral junctions were sharply beaded. The child died suddenly just before a blood culture was to be taken. Post-mortem culture was sterile. The home was visited by a social service worker later who obtained the following information about the child's feeding. At birth he received a formula consisting of 2 ounces of milk powder, 2 ounces of water, and 1 teaspoon of sugar every four hours. He was said to have been given 1 to 2 ounces of orange juice three to four times a week, when the family could afford to buy oranges. At 4 months of age the diet was increased by the addition of chicken broth and canned vegetables. Cereal and cod-liver oil were never included. Recently the father had had work and 2 ounces of orange juice were given every day.
At autopsy (No. 16885) the following positive findings were noted. The body weighed 5 kg. The heart was enlarged, weighing 48 Gm. This was due to hypertrophy of the right ventricle. The myocardium was pale. The valves were delicate and competent; the foramen ovale and ductus arteriosus were closed. The lungs contained fluid. The line of ossification of the ribs was irregular; the cartilage was freely movable on the shaft, and the periosteum stripped from the cortex with extreme ease. The brain and meninges showed nothing. Post-mortem blood cultures were sterile.
Microscopically the heart showed no change. The bones showed characteristic lesions of severe scurvy in the process of healing. Early rickets was also present, as evidenced by defects in calcification of the cartilaginous matrix substance.
We have presented the clinical histories of three infants dying unexpectedly; all of them at autopsy were found to have severe scurvy. Two of them had right-sided cardiac hypertrophy. The usual causes of sudden death in infancy, such as congenital cardiac malformation, cerebral hemorrhage, and sepsis, were absent in these children. So, too, any severe antecedent illness which might have led to diarrhea and acidosis was also lacking. Unfortunately, we do not know how much anemia was present, since blood studies were not made. We are left, then, with the question as to what role vitamin C deficiency may play in producing cardiac failure.
In adult scurvy sudden death has been recognized from early times. Lind 1 cites a passage from Lord Anson’s A Voyage Around the World (1740-44) as follows: "Indeed the effects of this disease were, in almost every instance, wonderful. For many of our people, though confined to their hammocks, appeared to have no unconsiderable share of health; for they ate and drank heartily, were cheerful, and talked with much seeming vigour, and with a loud strong tone of voice; and yet on being the least moved, though it was only from one part of the ship to the other, and that in their hammocks, they have immediately expired. And others, who have confided in their seeming strength, and have resolved to get out of their hammocks, have died before they could well reach the deck. And it was no uncommon thing for these who could do some kind of duty, and walk the deck, to drop down dead in an instant on any endeavours to act with their utmost vigour." Again Lind says, "An uncommon degree of sloth and laziness which constantly accompanies this evil (scurvy) is often mistaken for the willful effect of the patient’s natural disposition. This has proved fatal to many, some of whom, when obliged by their officers to climb up the shrouds, have been seen to expire, and fall down from the top of the mast."
In 1914 Darling 2 called attention to the presence of right-sided cardiac hypertrophy in several fatal cases of adult scurvy. He pointed out the resemblance of these hearts to those found in beriberi. A few years later Hess 3 contributed a paper on "The Cardio-Respiratory Syndrome" in infantile scurvy. This consisted of increase in the rate of pulse and respiration, together with increase in size of the base of the heart. In some electrocardiographic tracings the T-waves were unusually tall. Another important report on the relationship of scurvy and the heart in children was made by Erdheim in 1918.4 He performed autopsies on thirty-one scorbutic children dying in Vienna, twenty-one of whom had hypertrophy of the right ventricle. The degree of right-sided enlargement varied with the severity of the scorbutic manifestations. Aschoff and Koch 5 reported that instances of death in adults from scurvy alone were rare. However, since no fatal cases were found in their series without pulmonary edema or cardiac enlargement, these authors state that death from heart failure in scorbutic patients must be kept in mind.
In a case of experimental scurvy in an adult, Crandon and co-workers 12 noted a fall in blood pressure (from 120/70 to 90/60) after the subject had been on a vitamin C-free diet for twenty-three weeks. The pressure returned to normal when ascorbic acid was restored to the diet. Electrocardiographic tracings were normal.
We may conclude then that in the literature there is indication that vitamin C deficiency does play a role in producing changes in cardiac function. However, that vitamin C deficiency alone may not be responsible for the anatomical cardiac changes seems likely in view of their absence in many cases of severe scurvy. We have recently reviewed 32 other autopsied cases of scurvy without rickets in infants, 19 of which were classified as moderate in degree while the rest were called severe. In only 2 of the former group was there definite cardiac hypertrophy; it was present in 3 of the severe cases. These 5 children had all been ill for varying intervals before death and the cause of death was not thought to be scurvy alone. Counting the case of scurvy unassociated with rickets which was reported in this paper, one obtained an incidence of cardiac hypertrophy in only 17 per cent of these children. The possibility of vitamin B1 deficiency in these children cannot be dismissed. Nor is the role which anemia might play at all clear.
Changes in the myocardium of scorbutic guinea pigs have been reported by numerous observers. Hojer 6 found atrophy of the muscle fibers with necrosis and calcification. Bessey and co-workers 7 noted irregular foci of fatty infiltration in the musculature. Recently attention has been drawn by Rinehart and Mettier 8 to the similarity between cardiac lesions in scorbutic guinea pigs injected with streptococci and the changes in rheumatic fever in man. Several observers 9, 10, 11 have repeated this work and in general the conclusions drawn indicate that definite changes do occur. These consist of focal hemorrhages and myocardial necroses with some proliferation of connective tissue elements. However, the lesions can be found in animals on a scorbutic diet with or without superimposed infection.
Little is known about physiologic changes in the myocardium in scurvy. As noted above, Hess saw tall T-waves in the electrocardiograms of children. However, in a case of experimental adult scurvy, Crandon and coworkers 12 noted no change in the tracings. In collaboration with Dr. Harry F. Klinefelter, Jr., we have recently begun electrocardiographic studies of scorbutic guinea pigs.
We are unable to put forward any satisfactory explanation as to why vitamin C deficiency may lead to cardiac insufficiency. It is hoped, however, that careful clinical studies in cases of severe scurvy before and after treatment may throw some light on the problem.
In three cases of severe scurvy in infancy death took place suddenly and unexpectedly. Two of the children had right-sided cardiac hypertrophy. Except for this, no other changes were found to account for death. The probable importance of vitamin C deficiency in producing myocardial hypertrophy and also in leading to cardiac insufficiency is discussed. It is pointed out that vitamin C deficiency may not be the only responsible factor.
From Journal of Pediatrics, Volume 20, Number 3, 1942, pp. 347-351.
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