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Barlow's disease
Medical Hypotheses (2002) 59(1), 52–56 ª 2002 Elsevier Science Ltd. All rights reserved. doi: 10.1016/S0306-9877(02)00114-7, available online at http://www.idealibrary.com
Barlow’s disease C. A. B. Clemetson Tulane University, New Orleans, Louisiana, USA
Summary The classical form of Barlow’s disease or infantile scurvy, with bruises, broken bones and sores that will not heal, is rarely seen today, but it seems to be reappearing under a different guise, when infants with borderline vitamin C depletion are assaulted with too many inoculations at one time. Moreover, it is now sometimes mistakenly diagnosed as child abuse. ª 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION When I wrote a review article entitled ‘Vaccinations, Inoculations and Ascorbic Acid’ (1), I was thinking of the benefits to be derived from the use of vitamin C to protect infants from the severe reactions which can occasionally occur following immunizations. I had no idea that failure to know or to understand the basic physiology involved in this subject could result in an innocent man being wrongly accused of child abuse and being sentenced to life in prison for ‘shaken baby syndrome.’ The basic facts would seem to be: • Vitamin C deficiency does still occur in the Western World. The plasma vitamin C status was found to be depleted, between 0.2 and 0.5 mg/100 ml (or 11– 28 lmol/L) in 30%, and to be deficient, below 0.2 mg/100 ml in 6% of people attending a Health Maintenance Organization (HM0 clinic) in Tempe, Arizona, as reported by Johnston and Thompson (2). The only reason that this is not more widely known, is that hospital laboratories do not as yet routinely conduct vitamin C analyses. • The blood leucocyte ascorbic acid concentration is further reduced by infection; even the common cold causes a 50% reduction of the leucocyte ascorbic acid concentration within 24 h (3). Moreover, Escherichia
•
•
•
•
•
•
• Received 3 July 2001 Accepted 1 November 2001 Correspondence to: Professor C. A. B. Clemetson, School of Medicine, Tulane University, 5844 Fontainblean Drive, New Orleans, LA 70125, USA. Phone: 504-866-1525.
52
coli endotoxin has been shown to inhibit the uptake of vitamin C by mouse fibroblasts in tissue culture (4). When the human plasma ascorbic acid level falls below 0.2 mg/100 ml, the whole blood histamine level is doubled or quadrupled (5) (see Fig. 3 on page 5 of vol. 52 of this journal, doi:mehy.1998.0775). Ascorbic acid is needed for the conversion of histamine to hydantoin-5-acetic acid and on to aspartic acid in vivo (6). The whole blood histamine level is also increased by vaccines or toxoids, by stresses such as heat or cold and by various drugs in guinea pigs (6); even sleeplack more than doubles the blood histamine levels of resident physicians (7). Ascorbic acid supplementation rapidly reduces the blood histamine levels of ascorbate-depleted subjects (5). Ascorbic acid supplementation reduces the morbidity and mortality following various inoculations in animals and in man. Even animals such as rabbits, rats and mice, which make their own ascorbic acid in the liver and do not need it as an essential nutrient, can be protected from bacterial toxins by supplemental ascorbic acid (see below). While increased tissue histamine levels declare themselves by causing asthma, hay fever or urticaria, an increased blood histamine concentration can be a silent killer. As physicians, we have learned that vitamin C deficiency impairs the hydroxylation of proline and lysine, which are essential building blocks for the synthesis of collagen and that fibroblasts and related chondroblast, osteoblast and odontoblast cells manufacture collagen as the foundation for fibrous tissue,
Barlow’s disease
53
Aborigine and other children in Australia demonstrated that ascorbic acid supplementation prevented deaths following the usual childhood inoculations in clinical practice. Even more remarkable have been the findings of € ller Souto and Lima (21) (Table 1), of Dey (22) (Table Bu 2) and of Fukada and Koyama (23), studying mice, rats and rabbits respectively; they observed remarkable protection, by ascorbic acid, against bacterial toxins in these animals, even though, like most mammals they make their own ascorbic acid from simple sugars in the liver. We, of course, are particularly vulnerable, as we, like apes, monkeys, guinea pigs and a mutant rat, lack the enzyme L -gulono-gamma-lactone oxidase, needed to synthesize this essential substance, so making us totally dependent on dietary vitamin C from fresh fruits and vegetables, or from raw meat. While some will point out that vitamin C deficiency is rare in infancy today, the evidence from experimental studies in rats, mice, rabbits and guinea pigs clearly shows that supplementary ascorbic acid can be life-saving, following the injection of toxoids, even in those animals which do not need it as a vitamin. So why is it not common practice to give ascorbic acid supplements before, with or after inoculations? Not only does vitamin C protect against diphtheria toxin, it also protects against tetanus toxin (22), typhoid endotoxin (23) and the toxins of four varieties of gasgangrene bacteria (21), as shown in Tables 1 and 2. Indeed ascorbic acid seems to have been protective against all toxins tested. Why then is this good news not more widely known? Public Health Authorities should arrange for the funding of studies of the plasma ascorbic acid (reduced
cartilage, bone and tooth dentin respectively (8). Moreover, we are aware that the larger blood vessels are encased by an outer sheath of fibrous tissue, but the bleeding of scurvy comes from the smallest capillaries and venules, which have very little in the way of a collagen sheath. • Moreover, there is no change in the blood coagulation time in scurvy (9,10). • It is the increased blood histamine, or histaminemia, that causes separation of the endothelial cells from one another in scurvy (11) (see Fig. 2 on page 5 of vol. 52 of this journal, doi:mehy.1998.0775): this causes the capillary fragility and the bleeding of scurvy. • Histaminemia from any other cause, such as that following vaccinations or inoculations, has an additive effect and further increases the capillary fragility. DISCUSSION All of these facts must be borne in mind when assessing the causes of capillary fragility; no one should be accused of child abuse just because an infant shows petechial hemorrhages in the retina at the back of the eye following a fall. There is no need to reiterate all of the evidence that ascorbic acid provides protection against diphtheria toxin, as originally shown by King and Menten (12) in 1935, not long after the isolation of ascorbic acid by € rgyi (13), and by King and Zvirbely and Szent-Gyo Waugh (14) in 1932. This protective effect of ascorbic acid against diphtheria toxin was confirmed by Harde (15), by Jungblut and Zwemer (16) and by Parrot and Richet (17) studying guinea pigs. Subsequent work by Kalokerinos (18,19) and by Dettman (20) working with
Table 1 Protective activity of L -ascorbic acid 10 mg daily, given intramuscularly to mice for 3 days preceding a single of a double LD50 dose of four different gas gangrene toxins AA treated
Controls
n
Dead at 48 h
n
Dead at 48 h
1 LD50 dose of toxin of: Clostridium welchii Clostridium septicum Clostridium oedematiens Clostridium histolyticum
55 30 22 18
14 7 3 3
26 10 11 15
2 LD50 dose C. welchii C. septicum C. oedematiens C. histolyticum
57 31 24 18
38 15 9 16
30 12 11 15
Percentage survival of controls
Percentage survival of AA treated mice
13 5 5 6
50 50 55 60
75 77 86 83
30 10 8 15
0 17 27 0
33 52 63 11
Note the surprisingly good protective activity by ascorbic acid, even in mice, which make their own ascorbic acid. €ller Souto and Lima (21), Translated and summarized by C. A. B. Clemetson. From Bu AA, L -ascorbic acid; n, number of animals. An LD 50 dose of toxin is that previously found to kill 50% of the animals. 2LD50 is twice that dose. Reproduced by permission of The Journal of Orthomolecular Medicine 1999;14:141.
ª 2002 Elsevier Science Ltd. All rights reserved.
Medical Hypotheses (2002) 59(1), 52–56
54 Clemetson
Table 2 Efficiency of vitamin C in counteracting the toxicity of tetanus antigen in adult rats Treatment
No. of rats
Symptoms
Survival
2MLD tetanus toxin i.m.
5
All convulsed and died within 47–65 h
None
2MLD tetanus toxin i.m. with 1 g AA/kg body weight i.p. and 1 g AA/kg b.i.d. for 3 days i.p.
5
Only very mild local tetanus after 48 h
All
l g AA/kg b.i.d. for 3 days then 2 MLD tetanus toxin + l g AA/kg b.i.d. for 3 days
5
No signs of toxicity
All
2 MLD tetanus toxin. 1 g AA/kg i.p. only when convulsions began after 16–26 h and continued b.i.d. for 3 days
5
Convulsions arrested
All
2 MLD tetanus toxin. Animals anesthetized after 40–47 h when general titanic convulsion occurred-then AA 300 mg. given i.v.
10
All
Data from Dey (22), summarized by C. A. B. Clemetson. AA, L -ascorbic acid; MLD, minimum lethal dose; 2 MLD, twice minimum lethal dose; i.m., intramuscular injection; i.p., intraperitoneal; i.v., intravenous; b.i.d., bis in die or twice daily. Reproduced with permission from The Journal of Orthomolecular Medicine 1999;14;141.
form) and the whole blood histamine concentrations of adult (army, navy, air force or marine) volunteers before and at intervals after single or multiple inoculations. So many inoculants are given today, both to infants and to soldiers going overseas, that such studies are sorely needed. The toxicity of each inoculant has been tested before approval, but the toxicity of several inoculants given together can be additive, especially if the subject has borderline ascorbate depletion. Almost certainly the increase in the blood histamine level will be found to be much greater in people who are ascorbic acid depleted. The blood histamine concentration begins to rise when the plasma ascorbic acid level falls below the normal level of 1 mg/100 ml and rises exponentially when it falls below 0.7 mg/100 ml (5). Infant nutrition Barlow’s disease was a well recognized condition among bottle-fed infants, both in Europe and in the United States in the first half of the twentieth century. It occurred, not only among the poor who did not know or could not afford to buy orange juice as a supplement to the milk diet, but also among the infants of some affluent members of society, who boiled the milk to destroy any tuberculosis bacteria, so destroying all vitamin C. Other infants developed Barlow’s disease due to being fed a commercial ‘malt soap,’ whose alkalinity destroyed vitamin C. Today it is the fashion to give apple juice instead of orange juice, but apples are a poor substitute for oranges. One hundred grams of fresh orange juice (314 fluid ounces) contains 49 mg of vitamin C, but the same amount of apple juice contains only 1 mg of this vitamin. So unless the parent knows to buy apple juice with added vitamin C, there can still be a risk of vitamin C deMedical Hypotheses (2002) 59(1), 52–56
ficiency. Likewise we may suppose there could be a problem if the parent were to overdo any heating of the baby’s bottle in a microwave oven. Diagnostic difficulties One of the most characteristic signs of adult scurvy is swollen bleeding gums, but this is never seen in edentulous infants. It is bacteria in the crevice between the tooth and the gum that cause local infection; infection causes local vitamin C depletion and vitamin C depletion predisposes to infection, so a vicious cycle can develop, leading to the foul mouth and the bleeding gums of adult scurvy. Subdural hemorrhages, multiple bone fractures and sub-periosteal hemorrhages do occur in infantile scurvy (24,25) but all too often now the sub-periosteal hemorrhages lifting the growing sheath right off the bone, are thought to be the result of fractures, instead of being recognized as revealing their cause. Even this X-ray finding, formerly known as being characteristic of the healing phase of infantile scurvy, is now often said to be indicative of child abuse. Of course vitamin C deficiency is not the only cause of spontaneous bone fractures in infants; they can also occur in osteogenesis imperfecta or fragilitas osseum; moreover, capillary fragility and petechial hemorrhages occur in many other conditions ranging from infectious fevers to thrombocytopenic purpura or asphyxia. A family tragedy The pertinence of these observations can be readily appreciated when one considers the grave injustice suffered by Alan Yurko of Orlando, Florida, who was accused of ‘shaken baby syndrome,’ convicted and sentenced to life imprisonment for murder. ª 2002 Elsevier Science Ltd. All rights reserved.
Barlow’s disease
After becoming pregnant Francine Yurko became sick and remained so throughout her pregnancy, often to the point of dehydration, going from her original weight of 130 lb, down to 120 lb, at one point and finally coming back to her original weight of 130 lb, at the time of delivery. She said she was too sick to take her vitamins. When one considers that the currently recommended weight gain for pregnancy is 25–30 lb, it is clear that she was malnourished and so was her unborn child. The infant was a boy, born prematurely, weighing 5 lb 8 oz. He had several medical problems including respiratory distress syndrome, pneumonitis and jaundice. The jaundice was still evident 4 weeks after leaving hospital; his health was further impaired when he received six inoculations (diphtheria, whooping cough, tetanus, influenza B, oral polio vaccine, and hepatitis B) at 8 weeks of age. Eleven days later the infant developed a high-pitched cry and his skin became warm to touch. Having been warned at an earlier office visit that these things might ensue, Francine Yurko was not overly alarmed. Two days later when Alan Yurko was alone at home caring for the infant and his 4-year-old daughter, the infant wheezed, gagged and stopped breathing, so he picked him up by the heels and slapped him on the bottom to get him breathing again. He rushed the infant to hospital, but 3 days later it suffered another respiratory arrest in hospital and died at 10 weeks of age. Severe anemia, with a hemoglobin of 7.8 g and the jaundice were entirely consistent with Barlow’s disease. The only visible mark on his body when he was admitted to hospital was a small bruise on the right lower eyelid where his sister had dropped the feeding bottle. Post-mortem examination showed two more bruises on the temporal areas of his head and fresh bleeding into the right eye, but not the left. Cerebral edema and fresh subdural hemorrhages were present, especially on the right side of the brain, but also at the base of the brain, where pontine hemorrhage could well have accounted for his fever of 105 F. There were healing fractures at the costo-chondral junctions of the 5th, 6th, and 7th ribs on the left side. Fracture of the 10th rib may have occurred as a result of handling during the autopsy. Diffuse interstitial pneumonitis was observed. A diagnosis of ‘shaken baby syndrome’ was made by the pathologist, in concordance with the child abuse laws which require the reporting of child abuse whenever there is a suspicion of it. The prosecutors suspected both parents, but Francine Yurko refused to implicate her husband and Alan Yurko refused to plead guilty to a lesser charge, because he knew he was innocent. Clearly this infant’s death resulted from a concatenation of unfortunate circumstances causing vitamin C deficiency and capillary fragility. ª 2002 Elsevier Science Ltd. All rights reserved.
55
Many of us would say that it was unwise to give inoculations to a premature infant, especially when it was poorly, but it is easy to be wise after the event. No one should ever be accused of child abuse on such flimsy evidence, and certainly not without a blood analysis for vitamin C and for histamine. If there is any justice in this world Alan Yurko should be released from prison and so should all others falsely accused of child abuse. Critical addendum While it is readily appreciated that histaminemia due to inoculations, when added to the histaminemia of borderline ascorbic acid depletion, could cause endothelial damage leading to bleeding into the tissues, one would not expect bone fragility until and unless there were an almost complete deficiency of this vitamin. The explanation most likely is that the escape of blood into the tissues soon causes hemolysis and hemolysis rapidly destroys ascorbic acid (26), leading to frank scurvy. SUGGESTIONS Inoculations should not be given to premature infants or to other debilitated infants until they have fully recovered their health. Supplementary vitamin C (500 mg) should be given in orange juice to all infants before inoculation. Moreover, vitamin C should be given by injection whenever convulsions or other untoward events occur following inoculations. REFERENCES 1. Clemetson C. A. B. Vaccinations inoculations and ascorbic acid. J Orthomol Med 1999; 14: 137–142. 2. Johnston C. S., Thompson M. S. Vitamin C status of an out-patient population. J Am Coll Nutr 1998; 17: 366– 370. 3. Hume R., Weyers E. Changes in the leucocyte ascorbic acid concentration during the common cold. Scot Med J 1973; 18: 3. 4. Aleo J. J., Padh H. Inhibition of ascorbic acid uptake by endotoxin. Proc Soc Exp Biol Med 1985; 179: 128–131. 5. Clemetson C. A. B. Histamine and ascorbic acid in human blood. J Nutr 1980; 110: 662–668. 6. Chattejee I. B., Majumder A. K., Nandi B. K., Subramanian N. Synthesis and some major functions of vitamin C in animals. Ann N Y Acad Sci 1975; 258: 24–47. 7. Clemetson C. A. B. Lack of sleep, Chapter 17. In: Vitamin C; Vol. 1. Boca Raton: CRC Press, 1998: 215–221. 8. Stone N., Meister A. Function of ascorbic acid in the conversion of proline to collagen hydroxyproline. Nature (London) 1962; 194: 555. 9. Hess A. F. The involvement of the blood and blood vessels in infantile scurvy. Proc Soc Exp Biol Med 1913; 11: 130. 10. Cutforth R. H. Adult scurvy. Lancet 1958; 1: 454–456.
Medical Hypotheses (2002) 59(1), 52–56
56 Clemetson
11. Gore I., Tanaka Y., Fujinami T., Shirahama T. Endothelial changes produced by ascorbic acid deficiency in guinea pigs. Arch Pathol 1965; 80: 371–376. 12. King C. G., Menten M. L. The influence of vitamin C level upon resistance to diphtheria toxin. J Nutr 1935; 10: 129– 140. € rgyi A. The chemical nature of 13. Zvirbely J. L., Szent-Gyo vitamin C. Biochem J 1932; 27: 279–285. 14. King C. G., Waugh W. A. The chemical nature of vitamin C. J Sci 1932; 75: 357–358. 15. Harde E. Acide ascorbique (vitamin C) et intoxications. C R Acad Sci 1934; 119: 618–620. 16. Jungblut C. W., Zwemer R. L. Inactivation of diphtheria toxin in vivo and in vitro by crystalline vitamin C (ascorbic acid). Proc Soc Exp Biol Med 1935; 32: 1229–1234. a 17. Parrot J. L., Richet G. Accroissement de la sensabilite gime histamine chez le cobaye soumis a un re ne. C R Soc Biol 1945; 139: 1072–1075. scorbutoge 18. Kalokerinos A. Scurvy and the aboriginal infant mortality. Transactions 1969-70: 45. 19. Kalokerinos A. Every Second Child. Australia: Thomas Nelson, 1974.
Medical Hypotheses (2002) 59(1), 52–56
20. Dettman G. C. Aboriginal infant health and mortality rates. Letter to the editor. Med J Austral 1973; 1: 711–712. € ller Souto A., Lima C. Activity of L -Ascorbic Acid on 21. Bu the Toxins of Gas Gangrene; Vol. 12. Sao Paulo, Brasil: Memorias do instituto Butantan, 1939: 265–295 [in Portugese; 297–311 in French (same data)]. 22. Dey P. K. Efficiency of vitamin C in counteracting tetanus toxin toxicity. Naturwissenschaften 1966; 53: 310. 23. Fukada T., Koyama T. Prevention by ascorbic acid of liver glycogen depletion in endotoxin intoxication. Nature (London) 1963; 200: 1327. 24. Barlow T. On cases described as ‘acute rickets’, which are probably a combination of scurvy and rickets; the scurvy being an essential and the rickets being a variable element. Med Chir Trans 1883; 66: 159. € ller25. Hart C., Lessing O. Der Scorbut der Kleinen Kinder (Mo Barlowsche Krankheit). Stuttgart: Verlag von Ferdinand Enke, 1913. 26. Clemetson C. A. B. Hemolysis In: Vitamin C; Vol. 1. Boca Raton: CRC Press, 1989: 181–192 (Chapter 15).
ª 2002 Elsevier Science Ltd. All rights reserved.
Barlow’s disease C. A. B. Clemetson Tulane University, New Orleans, Louisiana, USA
Summary The classical form of Barlow’s disease or infantile scurvy, with bruises, broken bones and sores that will not heal, is rarely seen today, but it seems to be reappearing under a different guise, when infants with borderline vitamin C depletion are assaulted with too many inoculations at one time. Moreover, it is now sometimes mistakenly diagnosed as child abuse. ª 2002 Elsevier Science Ltd. All rights reserved.
INTRODUCTION When I wrote a review article entitled ‘Vaccinations, Inoculations and Ascorbic Acid’ (1), I was thinking of the benefits to be derived from the use of vitamin C to protect infants from the severe reactions which can occasionally occur following immunizations. I had no idea that failure to know or to understand the basic physiology involved in this subject could result in an innocent man being wrongly accused of child abuse and being sentenced to life in prison for ‘shaken baby syndrome.’ The basic facts would seem to be: • Vitamin C deficiency does still occur in the Western World. The plasma vitamin C status was found to be depleted, between 0.2 and 0.5 mg/100 ml (or 11– 28 lmol/L) in 30%, and to be deficient, below 0.2 mg/100 ml in 6% of people attending a Health Maintenance Organization (HM0 clinic) in Tempe, Arizona, as reported by Johnston and Thompson (2). The only reason that this is not more widely known, is that hospital laboratories do not as yet routinely conduct vitamin C analyses. • The blood leucocyte ascorbic acid concentration is further reduced by infection; even the common cold causes a 50% reduction of the leucocyte ascorbic acid concentration within 24 h (3). Moreover, Escherichia
•
•
•
•
•
•
• Received 3 July 2001 Accepted 1 November 2001 Correspondence to: Professor C. A. B. Clemetson, School of Medicine, Tulane University, 5844 Fontainblean Drive, New Orleans, LA 70125, USA. Phone: 504-866-1525.
52
coli endotoxin has been shown to inhibit the uptake of vitamin C by mouse fibroblasts in tissue culture (4). When the human plasma ascorbic acid level falls below 0.2 mg/100 ml, the whole blood histamine level is doubled or quadrupled (5) (see Fig. 3 on page 5 of vol. 52 of this journal, doi:mehy.1998.0775). Ascorbic acid is needed for the conversion of histamine to hydantoin-5-acetic acid and on to aspartic acid in vivo (6). The whole blood histamine level is also increased by vaccines or toxoids, by stresses such as heat or cold and by various drugs in guinea pigs (6); even sleeplack more than doubles the blood histamine levels of resident physicians (7). Ascorbic acid supplementation rapidly reduces the blood histamine levels of ascorbate-depleted subjects (5). Ascorbic acid supplementation reduces the morbidity and mortality following various inoculations in animals and in man. Even animals such as rabbits, rats and mice, which make their own ascorbic acid in the liver and do not need it as an essential nutrient, can be protected from bacterial toxins by supplemental ascorbic acid (see below). While increased tissue histamine levels declare themselves by causing asthma, hay fever or urticaria, an increased blood histamine concentration can be a silent killer. As physicians, we have learned that vitamin C deficiency impairs the hydroxylation of proline and lysine, which are essential building blocks for the synthesis of collagen and that fibroblasts and related chondroblast, osteoblast and odontoblast cells manufacture collagen as the foundation for fibrous tissue,
Barlow’s disease
53
Aborigine and other children in Australia demonstrated that ascorbic acid supplementation prevented deaths following the usual childhood inoculations in clinical practice. Even more remarkable have been the findings of € ller Souto and Lima (21) (Table 1), of Dey (22) (Table Bu 2) and of Fukada and Koyama (23), studying mice, rats and rabbits respectively; they observed remarkable protection, by ascorbic acid, against bacterial toxins in these animals, even though, like most mammals they make their own ascorbic acid from simple sugars in the liver. We, of course, are particularly vulnerable, as we, like apes, monkeys, guinea pigs and a mutant rat, lack the enzyme L -gulono-gamma-lactone oxidase, needed to synthesize this essential substance, so making us totally dependent on dietary vitamin C from fresh fruits and vegetables, or from raw meat. While some will point out that vitamin C deficiency is rare in infancy today, the evidence from experimental studies in rats, mice, rabbits and guinea pigs clearly shows that supplementary ascorbic acid can be life-saving, following the injection of toxoids, even in those animals which do not need it as a vitamin. So why is it not common practice to give ascorbic acid supplements before, with or after inoculations? Not only does vitamin C protect against diphtheria toxin, it also protects against tetanus toxin (22), typhoid endotoxin (23) and the toxins of four varieties of gasgangrene bacteria (21), as shown in Tables 1 and 2. Indeed ascorbic acid seems to have been protective against all toxins tested. Why then is this good news not more widely known? Public Health Authorities should arrange for the funding of studies of the plasma ascorbic acid (reduced
cartilage, bone and tooth dentin respectively (8). Moreover, we are aware that the larger blood vessels are encased by an outer sheath of fibrous tissue, but the bleeding of scurvy comes from the smallest capillaries and venules, which have very little in the way of a collagen sheath. • Moreover, there is no change in the blood coagulation time in scurvy (9,10). • It is the increased blood histamine, or histaminemia, that causes separation of the endothelial cells from one another in scurvy (11) (see Fig. 2 on page 5 of vol. 52 of this journal, doi:mehy.1998.0775): this causes the capillary fragility and the bleeding of scurvy. • Histaminemia from any other cause, such as that following vaccinations or inoculations, has an additive effect and further increases the capillary fragility. DISCUSSION All of these facts must be borne in mind when assessing the causes of capillary fragility; no one should be accused of child abuse just because an infant shows petechial hemorrhages in the retina at the back of the eye following a fall. There is no need to reiterate all of the evidence that ascorbic acid provides protection against diphtheria toxin, as originally shown by King and Menten (12) in 1935, not long after the isolation of ascorbic acid by € rgyi (13), and by King and Zvirbely and Szent-Gyo Waugh (14) in 1932. This protective effect of ascorbic acid against diphtheria toxin was confirmed by Harde (15), by Jungblut and Zwemer (16) and by Parrot and Richet (17) studying guinea pigs. Subsequent work by Kalokerinos (18,19) and by Dettman (20) working with
Table 1 Protective activity of L -ascorbic acid 10 mg daily, given intramuscularly to mice for 3 days preceding a single of a double LD50 dose of four different gas gangrene toxins AA treated
Controls
n
Dead at 48 h
n
Dead at 48 h
1 LD50 dose of toxin of: Clostridium welchii Clostridium septicum Clostridium oedematiens Clostridium histolyticum
55 30 22 18
14 7 3 3
26 10 11 15
2 LD50 dose C. welchii C. septicum C. oedematiens C. histolyticum
57 31 24 18
38 15 9 16
30 12 11 15
Percentage survival of controls
Percentage survival of AA treated mice
13 5 5 6
50 50 55 60
75 77 86 83
30 10 8 15
0 17 27 0
33 52 63 11
Note the surprisingly good protective activity by ascorbic acid, even in mice, which make their own ascorbic acid. €ller Souto and Lima (21), Translated and summarized by C. A. B. Clemetson. From Bu AA, L -ascorbic acid; n, number of animals. An LD 50 dose of toxin is that previously found to kill 50% of the animals. 2LD50 is twice that dose. Reproduced by permission of The Journal of Orthomolecular Medicine 1999;14:141.
ª 2002 Elsevier Science Ltd. All rights reserved.
Medical Hypotheses (2002) 59(1), 52–56
54 Clemetson
Table 2 Efficiency of vitamin C in counteracting the toxicity of tetanus antigen in adult rats Treatment
No. of rats
Symptoms
Survival
2MLD tetanus toxin i.m.
5
All convulsed and died within 47–65 h
None
2MLD tetanus toxin i.m. with 1 g AA/kg body weight i.p. and 1 g AA/kg b.i.d. for 3 days i.p.
5
Only very mild local tetanus after 48 h
All
l g AA/kg b.i.d. for 3 days then 2 MLD tetanus toxin + l g AA/kg b.i.d. for 3 days
5
No signs of toxicity
All
2 MLD tetanus toxin. 1 g AA/kg i.p. only when convulsions began after 16–26 h and continued b.i.d. for 3 days
5
Convulsions arrested
All
2 MLD tetanus toxin. Animals anesthetized after 40–47 h when general titanic convulsion occurred-then AA 300 mg. given i.v.
10
All
Data from Dey (22), summarized by C. A. B. Clemetson. AA, L -ascorbic acid; MLD, minimum lethal dose; 2 MLD, twice minimum lethal dose; i.m., intramuscular injection; i.p., intraperitoneal; i.v., intravenous; b.i.d., bis in die or twice daily. Reproduced with permission from The Journal of Orthomolecular Medicine 1999;14;141.
form) and the whole blood histamine concentrations of adult (army, navy, air force or marine) volunteers before and at intervals after single or multiple inoculations. So many inoculants are given today, both to infants and to soldiers going overseas, that such studies are sorely needed. The toxicity of each inoculant has been tested before approval, but the toxicity of several inoculants given together can be additive, especially if the subject has borderline ascorbate depletion. Almost certainly the increase in the blood histamine level will be found to be much greater in people who are ascorbic acid depleted. The blood histamine concentration begins to rise when the plasma ascorbic acid level falls below the normal level of 1 mg/100 ml and rises exponentially when it falls below 0.7 mg/100 ml (5). Infant nutrition Barlow’s disease was a well recognized condition among bottle-fed infants, both in Europe and in the United States in the first half of the twentieth century. It occurred, not only among the poor who did not know or could not afford to buy orange juice as a supplement to the milk diet, but also among the infants of some affluent members of society, who boiled the milk to destroy any tuberculosis bacteria, so destroying all vitamin C. Other infants developed Barlow’s disease due to being fed a commercial ‘malt soap,’ whose alkalinity destroyed vitamin C. Today it is the fashion to give apple juice instead of orange juice, but apples are a poor substitute for oranges. One hundred grams of fresh orange juice (314 fluid ounces) contains 49 mg of vitamin C, but the same amount of apple juice contains only 1 mg of this vitamin. So unless the parent knows to buy apple juice with added vitamin C, there can still be a risk of vitamin C deMedical Hypotheses (2002) 59(1), 52–56
ficiency. Likewise we may suppose there could be a problem if the parent were to overdo any heating of the baby’s bottle in a microwave oven. Diagnostic difficulties One of the most characteristic signs of adult scurvy is swollen bleeding gums, but this is never seen in edentulous infants. It is bacteria in the crevice between the tooth and the gum that cause local infection; infection causes local vitamin C depletion and vitamin C depletion predisposes to infection, so a vicious cycle can develop, leading to the foul mouth and the bleeding gums of adult scurvy. Subdural hemorrhages, multiple bone fractures and sub-periosteal hemorrhages do occur in infantile scurvy (24,25) but all too often now the sub-periosteal hemorrhages lifting the growing sheath right off the bone, are thought to be the result of fractures, instead of being recognized as revealing their cause. Even this X-ray finding, formerly known as being characteristic of the healing phase of infantile scurvy, is now often said to be indicative of child abuse. Of course vitamin C deficiency is not the only cause of spontaneous bone fractures in infants; they can also occur in osteogenesis imperfecta or fragilitas osseum; moreover, capillary fragility and petechial hemorrhages occur in many other conditions ranging from infectious fevers to thrombocytopenic purpura or asphyxia. A family tragedy The pertinence of these observations can be readily appreciated when one considers the grave injustice suffered by Alan Yurko of Orlando, Florida, who was accused of ‘shaken baby syndrome,’ convicted and sentenced to life imprisonment for murder. ª 2002 Elsevier Science Ltd. All rights reserved.
Barlow’s disease
After becoming pregnant Francine Yurko became sick and remained so throughout her pregnancy, often to the point of dehydration, going from her original weight of 130 lb, down to 120 lb, at one point and finally coming back to her original weight of 130 lb, at the time of delivery. She said she was too sick to take her vitamins. When one considers that the currently recommended weight gain for pregnancy is 25–30 lb, it is clear that she was malnourished and so was her unborn child. The infant was a boy, born prematurely, weighing 5 lb 8 oz. He had several medical problems including respiratory distress syndrome, pneumonitis and jaundice. The jaundice was still evident 4 weeks after leaving hospital; his health was further impaired when he received six inoculations (diphtheria, whooping cough, tetanus, influenza B, oral polio vaccine, and hepatitis B) at 8 weeks of age. Eleven days later the infant developed a high-pitched cry and his skin became warm to touch. Having been warned at an earlier office visit that these things might ensue, Francine Yurko was not overly alarmed. Two days later when Alan Yurko was alone at home caring for the infant and his 4-year-old daughter, the infant wheezed, gagged and stopped breathing, so he picked him up by the heels and slapped him on the bottom to get him breathing again. He rushed the infant to hospital, but 3 days later it suffered another respiratory arrest in hospital and died at 10 weeks of age. Severe anemia, with a hemoglobin of 7.8 g and the jaundice were entirely consistent with Barlow’s disease. The only visible mark on his body when he was admitted to hospital was a small bruise on the right lower eyelid where his sister had dropped the feeding bottle. Post-mortem examination showed two more bruises on the temporal areas of his head and fresh bleeding into the right eye, but not the left. Cerebral edema and fresh subdural hemorrhages were present, especially on the right side of the brain, but also at the base of the brain, where pontine hemorrhage could well have accounted for his fever of 105 F. There were healing fractures at the costo-chondral junctions of the 5th, 6th, and 7th ribs on the left side. Fracture of the 10th rib may have occurred as a result of handling during the autopsy. Diffuse interstitial pneumonitis was observed. A diagnosis of ‘shaken baby syndrome’ was made by the pathologist, in concordance with the child abuse laws which require the reporting of child abuse whenever there is a suspicion of it. The prosecutors suspected both parents, but Francine Yurko refused to implicate her husband and Alan Yurko refused to plead guilty to a lesser charge, because he knew he was innocent. Clearly this infant’s death resulted from a concatenation of unfortunate circumstances causing vitamin C deficiency and capillary fragility. ª 2002 Elsevier Science Ltd. All rights reserved.
55
Many of us would say that it was unwise to give inoculations to a premature infant, especially when it was poorly, but it is easy to be wise after the event. No one should ever be accused of child abuse on such flimsy evidence, and certainly not without a blood analysis for vitamin C and for histamine. If there is any justice in this world Alan Yurko should be released from prison and so should all others falsely accused of child abuse. Critical addendum While it is readily appreciated that histaminemia due to inoculations, when added to the histaminemia of borderline ascorbic acid depletion, could cause endothelial damage leading to bleeding into the tissues, one would not expect bone fragility until and unless there were an almost complete deficiency of this vitamin. The explanation most likely is that the escape of blood into the tissues soon causes hemolysis and hemolysis rapidly destroys ascorbic acid (26), leading to frank scurvy. SUGGESTIONS Inoculations should not be given to premature infants or to other debilitated infants until they have fully recovered their health. Supplementary vitamin C (500 mg) should be given in orange juice to all infants before inoculation. Moreover, vitamin C should be given by injection whenever convulsions or other untoward events occur following inoculations. REFERENCES 1. Clemetson C. A. B. Vaccinations inoculations and ascorbic acid. J Orthomol Med 1999; 14: 137–142. 2. Johnston C. S., Thompson M. S. Vitamin C status of an out-patient population. J Am Coll Nutr 1998; 17: 366– 370. 3. Hume R., Weyers E. Changes in the leucocyte ascorbic acid concentration during the common cold. Scot Med J 1973; 18: 3. 4. Aleo J. J., Padh H. Inhibition of ascorbic acid uptake by endotoxin. Proc Soc Exp Biol Med 1985; 179: 128–131. 5. Clemetson C. A. B. Histamine and ascorbic acid in human blood. J Nutr 1980; 110: 662–668. 6. Chattejee I. B., Majumder A. K., Nandi B. K., Subramanian N. Synthesis and some major functions of vitamin C in animals. Ann N Y Acad Sci 1975; 258: 24–47. 7. Clemetson C. A. B. Lack of sleep, Chapter 17. In: Vitamin C; Vol. 1. Boca Raton: CRC Press, 1998: 215–221. 8. Stone N., Meister A. Function of ascorbic acid in the conversion of proline to collagen hydroxyproline. Nature (London) 1962; 194: 555. 9. Hess A. F. The involvement of the blood and blood vessels in infantile scurvy. Proc Soc Exp Biol Med 1913; 11: 130. 10. Cutforth R. H. Adult scurvy. Lancet 1958; 1: 454–456.
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11. Gore I., Tanaka Y., Fujinami T., Shirahama T. Endothelial changes produced by ascorbic acid deficiency in guinea pigs. Arch Pathol 1965; 80: 371–376. 12. King C. G., Menten M. L. The influence of vitamin C level upon resistance to diphtheria toxin. J Nutr 1935; 10: 129– 140. € rgyi A. The chemical nature of 13. Zvirbely J. L., Szent-Gyo vitamin C. Biochem J 1932; 27: 279–285. 14. King C. G., Waugh W. A. The chemical nature of vitamin C. J Sci 1932; 75: 357–358. 15. Harde E. Acide ascorbique (vitamin C) et intoxications. C R Acad Sci 1934; 119: 618–620. 16. Jungblut C. W., Zwemer R. L. Inactivation of diphtheria toxin in vivo and in vitro by crystalline vitamin C (ascorbic acid). Proc Soc Exp Biol Med 1935; 32: 1229–1234. a 17. Parrot J. L., Richet G. Accroissement de la sensabilite gime histamine chez le cobaye soumis a un re ne. C R Soc Biol 1945; 139: 1072–1075. scorbutoge 18. Kalokerinos A. Scurvy and the aboriginal infant mortality. Transactions 1969-70: 45. 19. Kalokerinos A. Every Second Child. Australia: Thomas Nelson, 1974.
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20. Dettman G. C. Aboriginal infant health and mortality rates. Letter to the editor. Med J Austral 1973; 1: 711–712. € ller Souto A., Lima C. Activity of L -Ascorbic Acid on 21. Bu the Toxins of Gas Gangrene; Vol. 12. Sao Paulo, Brasil: Memorias do instituto Butantan, 1939: 265–295 [in Portugese; 297–311 in French (same data)]. 22. Dey P. K. Efficiency of vitamin C in counteracting tetanus toxin toxicity. Naturwissenschaften 1966; 53: 310. 23. Fukada T., Koyama T. Prevention by ascorbic acid of liver glycogen depletion in endotoxin intoxication. Nature (London) 1963; 200: 1327. 24. Barlow T. On cases described as ‘acute rickets’, which are probably a combination of scurvy and rickets; the scurvy being an essential and the rickets being a variable element. Med Chir Trans 1883; 66: 159. € ller25. Hart C., Lessing O. Der Scorbut der Kleinen Kinder (Mo Barlowsche Krankheit). Stuttgart: Verlag von Ferdinand Enke, 1913. 26. Clemetson C. A. B. Hemolysis In: Vitamin C; Vol. 1. Boca Raton: CRC Press, 1989: 181–192 (Chapter 15).
ª 2002 Elsevier Science Ltd. All rights reserved.