VITAMINS

1933 Blackfan KD, Wolbach SB. Vitamin A deficiency in infants. J Pediatr 1933; 3:679-706.
Kenneth Blackfan (1883-1941) (figure 1) was Associate Professor of Pediatrics at Johns Hopkins, then Professor of Pediatrics at Cincinnati and at Harvard from 1923 to 1941. He apparently ‘mentored’ both Louis Diamond and Sydney Farber. In 1941 he died of lung cancer at the age of 58 – at the height of his career. The Children's’ Hospital in Boston is on Blackfan Street - named after him.

Fig 1: Kenneth Blackfan

This is an interesting account primarily of early vitamin A deficiency, in which there was considerable interest at the time. In 13 infants and young children, 11 of whom were eventually autopsied, vitamin A deficiency was reported. Epithelial metaplasia due to vitamin A deficiency was considered an important predisposing factor to infection by causing – “loss of protective powers of the epithelium due to diminished or absent mucus secretion and loss of ciliary motion”. Six of the 11 infants autopsied had extensive pancreatic lesions (later recognised as typical of CF), that the authors correctly attributed to inspissation of secretion in the ducts.
The authors noted that “The pancreatic lesions were all identical and presumably representing a disease entity. At first we regarded the pancreatic changes as the result of vitamin A deficiency (as did Dorothy Andersen for some years). As the same condition has been found scores of times without other evidences of vitamin A deficiency and since it is not constant even in vitamin A deficiency, we must consider the two are not necessarily connected”. The photomicrograph of pancreas (figure 1b) is typical of the changes seen in CF for which Blackfan & May (1938 below) gave credit to Wolbach for the first clear description.

Figure 1b: Photomicrograph of pancreas. From the paper with permission.

The authors continue “The pancreatic lesion referred to is characterised by dilatation of acini and ducts, by inspissated secretion, atrophy of the acini, lymphoid and leukocyte infiltration of some degree and fibrosis. Our preliminary studies indicate that the pathogenesis of this striking pancreatic affection resides in the production of an abnormal secretion which inspissates and leads to distension and atrophy of ducts and acini. It is reasonable to assume that this pancreatic lesion, if extensive, may be responsible for failure to utilise fats and hence vitamin A in the presence of an adequate intake”.
The authors concluded that vitamin A deficiency was not infrequent and should be suspected without regard to the characteristic eye signs; histological evidence of vitamin A deficiency may appear in infants who appear to be receiving and adequate intake; they postulate that some factor or factors interfering with storage or utilisation of this vitamin lessens the availability of the supply essential for normal nutrition; certain diagnostic criteria to identify at an early stage are mentioned and vitamin A deficiency should be considered as a general systemic disease rather than as a local disease of the eye.

Simeon Burt Wolbach was born in 1880 in Grand Island, Nebraska, and grew up on the western plains. He attended Harvard Medical School (M.D., 1903), studying pathology under Councilman and Mallory. After medical school, he worked as director of the Bender Hygienic Laboratory in Albany, NY; pathologist at the Montreal General Hospital and teacher at McGill Medical School. In 1910, he returned to Harvard as an assistant professor of bacteriology. He was promoted to associate professor in 1914. In 1916, he was jointly appointed to the Departments of Bacteriology and Pathology. In 1917, he was pathologist to the Peter Bent Brigham Hospital and the Boston Lying-In Hospital. In 1922, he was appointed the Shattuck professor of pathology at Harvard. He held this position for 25 years. In 1947, he became the director of the Division of Nutritional Research at Children's Hospital in Boston. He held this position until his death in 1954. Wolbach's interests ranged from the effects of radiation to tropical medicine and infectious diseases. His work on radiation began with Porter in 1907. Later in life, he served as a consultant to the US Atomic Energy Commission (1951-1953). He did field research in Nigeria in 1911 related to the pathology of general paresis. Best known of his work on infectious diseases are his contributions to the understanding rickettsial illnesses, Rocky Mountain spotted fever (1919), and epidemic typhus in Poland (1920). Wolbach's most fundamental work was in the field of vitamin research, and the relationships of vitamins to tissue structure and the pathology of scurvy and other diseases.

1946 Palmer HD, Danielson WH, Lubchenco LO, Binkley EL. Absorption of vitamin A following enteral use of prostigmine in cystic fibrosis of pancreas. Am J Clin Path 1946; 16:535-549.
Prostigmine was apparently used by Flack to improve bowel motility, which was presumably the rationale for this study. However, oral or parenteral prostigmine did not improve vitamin A absorption in 3 children with CF but did induce active intestinal peristalsis. So the authors concluded that prostigmine did induce active peristalsis in patients with cystic fibrosis and seemed to promote regularity of bowel movements but the improvement was not greater than in children receiving their current supportive therapy.

1956 Nitowsky HM, Gordon HH, Tildon JT. Studies of tocopherol deficiency in infants and children IV. Effects of alpha tocopherol on creatinuria in patients with cystic fibrosis of the pancreas and biliary atresia. Bull Johns Hopkins Hosp 1956; 98:361-71. [PubMed]
There are numerous studies of vitamin E deficiency in CF as the vitamin is always very low in untreated and even in some treated, but inadequately supplemented, patients. Five children with CF and two with biliary atresia had abnormal haemolysis of erythrocytes in hydrogen peroxide decreased by relatively large doses of intravenous or oral vitamin E and decreased haemolysis. Creatinuria was decreased only in the CF children.

1958 Blanc WA, Reid JD, Andersen DH. Avitaminosis E in cystic fibrosis of the pancreas: a morphologic study of gastrointestinal and striated muscle. Pediatrics 1958; 22: 494-506. [PubMed]
Ceroid pigment was present in the smooth muscle fibres of the gastrointestinal tract of patients with cystic fibrosis. It was first seen in those dying during the second year of life and present in all after 5 years of age, the amount increasing with age. The only other condition where this pigment is found is biliary atresia and cirrhosis. It was considered as probably due to prolonged and severe vitamin E deficiency. However, alterations in striated muscle are rare and minimal in CF but common in severe vitamin E deficiency (Martin AJP, Moore T. Some effects of prolonged vitamin E deficiency. J Hyg 1939; 39:643; Human occurrence in one case of CF by Pappenheimer AM, Victor J. Am J Path 1946; 22:395).

1961 Levin S, Gordon MH, Nitowsky HM, Goldman C, di Sant’Agnese P, Gordon HH. Studies of tocopherol deficiency in infants and children. VI. Evaluation of muscle strength and effect of tocopherol administration in children with cystic fibrosis. Pediatr 1961; 27:578-588. [PubMed]
This is said to be the first randomized controlled trial in people with cystic fibrosis. A double blind placebo controlled parallel single centre randomised controlled trial in which the effect of tocopherol supplementation on muscle strength was evaluated, by means of a “hand bulb ergograph” which was squeezed to measure grip strength. There was no difference in strength noted with vitamin E supplementation – both the treated and placebo group improved.
Oppenheimer had been the first to report an infant with necrotic changes in muscle resembling those found in tocopherol deficiency (Oppenheimer. EH. Bull Johns Hopkins Hosp 1956; 98:353-358). The authors of the present studies concluded that “although the present study did not demonstrate a clinical functional effect of tocopherol therapy in patients with cystic fibrosis, its administration is recommended because of previously reported biochemical and pathological evidence of vitamin E deficiency in these subjects”.
This reasonable approach would be a lesson for some clinicians who would not use a treatment unless supported by a suitable randomised controlled trial - a view I have even heard expressed with regard to vitamin E supplements in CF! Here all the available reasonable information was considered before a policy was recommended that may well do good and was very unlikely to do harm to their patients.

1968 Petersen RA, Petersen VS, Robb RM. Vitamin A deficiency with xerophthalmia and night blindness in cystic fibrosis. Am J Dis Child 1968; 116:662-665. [PubMed]
The first report of night blindness in CF due to vitamin A deficiency in 16 year old girl who had been seriously under-treated and who had major social problems. Later reports showed abnormal nocturnal vision due to vitamin A deficiency (Rayner et al,1989 below) but not where vitamin levels had been monitored regularly and maintained in the normal range (Ansari et al, 1999 below).

1970 Keating JP, Feigin RD. Increased intracranial pressure associated with probable vitamin A deficiency in cystic fibrosis. Pediatrics 1970; 46:41-46. [PubMed]
Two infants with CF aged four months had signs of raised intracranial pressure associated with vitamin A deficiency. One infant had xerophthalmia and keratomalacia; one had a cranial nerve injury with facial paralysis (also Abernathy 1976 below). Raised intracranial pressure has been described by a number of authors in young infants with CF and also in non-CF infants with vitamin A deficiency examples of which are reviewed in this paper.

1970 Torstenson OL, Humphrey GB, Edson JR, Warwick WJ. Cystic fibrosis presenting with severe hemorrhage due to vitamin K malabsorption: A report of 3 cases. Pediatrics 1970; 45:857-861. [PubMed]
Three infants with CF presented with severe bleeding secondary to vitamin K deficiency at one, three and four months of age . The authors mention that Shwachman had observed CF infants with prothrombin deficiency one of whom developed a subdural bleed (Shwachman et al. Pediatrics 1960; 25:155). Also di Sant’Agnese noted vitamin K deficiency leading to occasional bleeding (di Sant’Agnese & Vidaurreta JAMA 1960; 172:2065) and later four infants aged one to four months were reported by Walters TR & Koch F. (Am J Dis Child 1972; 124:641-642).

1973 Rucker RW. Harrison GM. Vitamin B 12 deficiency in cystic fibrosis. N Engl J Med 1973; 289:329. [PubMed]
Some malabsorption of vitamin B12 has been demonstrated in a number of later studies but absorption is much improved when pancreatic extract is added although not in all patients. However, in practice, a deficiency of the vitamin is very rare in CF even though supplements are not usually given (also Deren JJ et al. NEJM 1973; 288:949-950; Gueant JL et al. Pancreas 1990; 5: 559-567).

1976 Dolan TF. Hemolytic anemia and edema as the initial signs in infants with cystic fibrosis. Clin Pediatr 1976; 15:597-600.
Much of the interest in vitamin E up to this time had been in premature infants. Three of the 5 infants with CF in this report had low vitamin E levels, all had haemolytic anaemia and marked reticulocytosis. They note that although low levels of vitamin E had been described in CF (Blanc WA et al. Pediatrics 1958; 22:494) no clinical deficiency states had been described. (Review of “The occurrence and effects of human vitamin E deficiency” by Philip Farrell J Clin Invest 1977; 60:233-241).

1977 Farrell PM, Bieri JG, Fratantoni JF, Wood RE, di Sant’Agnese PA. The occurrence and effects of human vitamin E deficiency. J Clin Invest 1977; 60:233-241. [PubMed]
A detailed review of the subject by Phillip Farrell . All 52 CF patients with pancreatic insufficiency were deficient in vitamin E. Hydrogen peroxide induced haemolysis was increased and red cell survival of 15Cr-labelled erythrocytes was significantly decreased but was corrected by vitamin E. The authors concluded that “concomitant effects consistent with mild haemolysis but not anaemia occur and may be reversed with vitamin E therapy”. Daily doses of water soluble vitamin E were recommended for people with cystic fibrosis.
In a subsequent study from Leeds the haemoglobin was significantly increased with vitamin E treatment in the children with CF with longstanding low vitamin E levels from 13.14 g/100ml to 13.47g/100ml (Kelleher J et al. Internat J Vit Nutr Res 1987; 57:253-259). No change was seen in haemoglobin with treatment in this series of Phillip Farrell’s as, although the children had low vitamin E levels, they were not anaemic – Hb14.3g/100ml.

1981 Congden PJ, Bruce G, Rothburn MM, Clarke PCN, Littlewood JM, Kelleher J, Losowsky MS. Vitamin status in treated patients with cystic fibrosis. Arch Dis Child 1981; 56:708-714. [PubMed]
This was our first nutritional research study from Seacroft and St James University Hospital, Leeds collaborating with the University Department of Medicine at St James's. The data was presented at the 1980 Toronto CF Conference. It was the first of many studies on the nutritional and gastrointestinal aspects of CF carried out in collaboration with Dr. Jerry Kelleher and members of Professor Monty Losowsky’s Department of Medicine. This study was coordinated by the late Dr. Peter Congden. Many of our patients, and those of some of our paediatric colleagues who were also included, had unexpectedly low fat-soluble vitamin levels and suboptimal control of intestinal absorption despite what we considered to be adequate enzyme and vitamin supplements; but the water soluble vitamin levels were satisfactory.

Figure 13: Vitamin A and E levels from paper. With permission of the BMJ Publishing Group.

These disappointing results, reflecting our suboptimal treatment in the late Seventies, prompted us to start annual Comprehensive CF Assessments in May 1980 along the lines suggested by Crozier in 1974; he stated that “success of treatment will depend on a complete assessment of the patient and then continuing attempts to obtain normal bodily function and maintain it”.
Our so-called “Comprehensive CF Assessments” proved so useful in identifying areas where we could improve treatment of our own patients, that in 1981 we offered the service to paediatric colleagues in the Yorkshire Region for their patients. It was through this offer, to accept patients for assessment and advice that the Leeds Regional CF Service developed.

1989 Rayner RJ, Tyrell JC, Hiller EJ, Marenah C, Neugebauer MA, Vernon SA, Brimlow G. Night blindness and conjunctival xerosis due to vitamin A deficiency in cystic fibrosis. Arch Dis Child 1989; 64:1151-1156. [PubMed]
Rosie Rayner, then the CF Research Fellow at Nottingham and now paediatrician in Wolverhampton, studied 43 patients with CF aged 8 to 44 years (median 16 years), for evidence of vitamin A deficiency. Eight had abnormal dark adaptation tests and three had conjunctival xerosis. Serum vitamin A and retinol binding protein concentrations were significantly lower in the affected patients who were also more likely to have abnormal liver function tests. Five patients were treated with 100,000-200,000 IU water miscible vitamin A orally and their daily vitamin supplements were increased to maintain normal concentrations. In four patients dark adaptation tests were repeated. Three were normal, but one patient required three further doses of water miscible vitamin A and a daily supplement of 12,000 IU vitamin A before her dark adaptation threshold returned to normal. Adolescents with cystic fibrosis are liable to develop night blindness and conjunctival xerosis, particularly if they have liver disease or fail to take daily vitamin supplements.
One of the papers reporting objective evidence of the clinical effects vitamin deficiency rather than merely reduced plasma levels. Obviously very important if adults with CF, of which there were increasing numbers, were driving at night. Histological evidence of vitamin A deficiency was evident in many of the early post-mortem studies – in fact, for some time it was regarded by Dorothy Andersen as a major factor in the pathogenesis of the condition.

1989 Choonara IA, Winn MJ, Park BK, Littlewood JM. Plasma vitamin K1 concentrations in cystic fibrosis. Arch Dis Child 1989; 64:732-734. [PubMed]
One of the first studies on vitamin K from the Leeds CF centre when Prof. Choonara worked there. Plasma concentrations in 37 patients mean age 10.6 years (2-23yrs) median 46ng/l and 16 controls 49ng/l. No relation found between an increase in prothrombin time and vitamin K plasma concentration.
However, subsequent studies using more efficient tests showed vitamin K was deficient in many patients and possibly related to later osteoporosis (Conway et al, 2005 below).

1989 Sokol RJ. Reardon MC. Accurso FJ. Stall C. Narkewicz M. Abman SH. Hammond KB. Fat-soluble-vitamin status during the first year of life in infants with cystic fibrosis identified by screening of newborns. Am J Clin Nutr 1989; 50:1064-1071. [PubMed]
Another report on infants diagnosed in the Colorado neonatal screening programme. Fat-soluble vitamin status during the first year of life in 36 infants with CF was examined; biochemical evidence of fat-soluble-vitamin deficiency is common before the age 3 months in CF infants.
A further report on these 36 infants (Sokol RJ, et al. Pediatr Pulmonol 1991; Suppl 7:52-55) after treatment with pancreatic enzymes, a multiple vitamin preparation, and additional vitamin E was associated with normalization of serum albumin, retinol, and 25-hydroxyvitamin D and negative PIVKA testing (for vitamin K) at six and 12 months of age. Several patients remained vitamin E deficient, but this was felt to be due to poor adherence to the treatment.
These studies from Denver of some of the earlier screened CF infants were important as they drew attention to the very early onset of nutritional deficiencies in the infants. Biochemical evidence of fat-soluble vitamin deficiency is common before three months of age and responds to adequate supplementation in the first year of life. Also the initial fall off in weight gain may take many months to recover.

1994 Wilfond BS, Farrell PM, Laxova A, Mischler E. Severe hemolytic anemia associated with vitamin E deficiency in infants with cystic fibrosis. Implications for neonatal screening. Clin Pediatr 1994; 33:2-7. [PubMed]
Three infants with CF and malnutrition leading to severe anemia beginning as early as six weeks of age. They had high reticulocyte counts, negative Coombs' tests, abnormal peroxide haemolysis test results, and biochemical evidence of vitamin E deficiency. Oral administration of alpha-tocopherol resulted in rapid correction of the laboratory abnormalities.
Phillip Farrell has published extensively on vitamin E deficiency both in premature infants and those with CF (see Farrell et al, J Clin Invest 1977; 60:233-241 above). This report emphasises the early onset of fat soluble vitamin deficiencies in infants with CF as also found in the Colorado screened infants (Sokol et al, 1991 above)

1995 Morkeberg JC, Edmund C, Prause JU, Lanng S, Koch C, Michaelsen KF. Ocular findings in cystic fibrosis patients receiving vitamin A supplementation. Graefe’s Arch Clin Exp Ophthalmol 1995; 233:709-713. [PubMed]
Only 26% of 35 patients examined in the Copenhagen clinic had normal vitamin A status as measured by serum retinol and light sensitivity but reduced contrast sensitivity. Conjunctival imprints showed dry eye in 42%; decreased tear stability in 49% and other abnormalities of low tear production (31%) and increased numbers of dying cells (23%). In fact 26% were considered to have the criteria for “keratoconjunctivitis sica”. The authors even suggested that the high incidence of dry eye could be a primary manifestation of CF.
These findings are more likely the result of suboptimal vitamin A status particularly as only 26% had normal vitamin A levels. In studies where vitamin A status is regularly monitored to maintain normal serum levels, only reduced contrast sensitivity is found (Ansari et al. 1999 below) and the cause of this is unexplained.

1999 Ansari EA, Sahni K, Etherington C, Morton A, Conway SP, Moya E, Littlewood JM. Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treated with daily vitamin A supplements. Br J Ophthalmol 1999; 83:688-691. [PubMed]
Since the first Leeds studies on vitamin levels in 1978 (Congden et al, 1981 above), oral supplementation has been guided by annual monitoring of vitamin levels; also all patients are seen regularly by a CF specialist dietitian and most have a comprehensive annual dietary assessment. None of the 28 patients in this study had vitamin A deficiency, the median value of serum retinol being 48 microg/dl, range 31-80 microg/dl (normal range 30-80 microg/dl). Dark adaptation was normal in all patients compared with the control group where the mean value was 3.4 log units of threshold luminance (95% confidence interval 2.4-4.0). None of the test group had a value of threshold luminance 2 SD above the mean value for the control group. Eight patients had reduced contrast sensitivity. The median value for serum zinc was 14.2 micromol/ l, range 13-81 micromol/l (normal range 8-23 micromol/l) and the median value for retinol binding protein was 36 mg/l, range 13-81 mg/l (normal range 35-58 mg/l). There was no correlation between dark adaptation and serum retinol, zinc, or retinol binding protein. Two patients had clinical evidence of dry eye.
So regular estimates of plasma vitamin A, together with appropriate supplementation and expert dietetic review, can maintain normal dark adaptation in patients with cystic fibrosis. The occurrence of reduced contrast sensitivity function is well documented in CF and confirmed in this study but remains an unexplained phenomenon (also Morkeberg et al, 1995 above).

2005 Koscik RL, Lai HJ, Laxova A, Zaremba KM, Kosorok MR, Douglas JA, Rock MJ, Splaingard ML, Farrell PM. Preventing early, prolonged vitamin E deficiency: an opportunity for better cognitive outcomes via early diagnosis through neonatal screening. J Pediatr 2005; 147:S51-6. [PubMed]
The objective of this study was to evaluate cognitive function in children with CF and the influence of both early diagnosis through neonatal screening and the potential effect of early malnutrition. Significantly lower cognitive scores correlated with indicators of malnutrition and un favourable family factors such as single parents, lower socioeconomic status, and less parental education. Results suggest that prevention of prolonged malnutrition by early diagnosis and nutritional therapy, following neonatal screening, particularly minimizing the duration of vitamin E deficiency, is associated with better cognitive functioning in children with CF.

Thus important evidence that diagnosis via newborn screening may benefit the cognitive development of children with CF, particularly in those prone to vitamin E deficiency during infancy – which is the majority. Another important positive in favour of newborn screening for CF from the Wisconsin study.

2005 Conway SP, Wolfe SP, Brownlee KG, White H, Oldroyd B, Truscott JG, Harvey JM, Shearer MJ. Vitamin K status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover. Pediatrics 2005; 115:1325-1331. [PubMed]
The aim of this study was to assess vitamin K status in an unselected population of children with CF and to investigate any vitamin K effect on bone turnover and bone mineral status. One hundred and six children entered the study. Vitamin K1 deficiency was common (70%) and the authors suggested that routine supplements should be considered.
Through its role in the carboxylation of osteocalcin, vitamin K deficiency may be associated with an uncoupling of the balance between bone resorption and bone formation. However, a cause-effect relationship between vitamin K deficiency and low bone mass has not been proved.

2006 Aird FK. Greene SA. Ogston SA. Macdonald TM. Mukhopadhyay S. Vitamin A and lung function in CF. J Cyst Fibros 2006; 5:129-131. [PubMed]
Laboratory evidence suggests that vitamin A could have a protective effect on respiratory status in patients with cystic fibrosis (CF). This study shows a significant correlation between serum vitamin A concentrations and every aspect of lung function tested in 38 patients with stable CF. Serum vitamin D and vitamin E concentrations were also measured but did not show any significant correlations with lung function.

This is interesting as Dorothy Andersen intial likened the changes in the bronchial epithelium to the epithelial metaplasia found in vitamin A deficiency and for some years considered that the pulmonary problems were related to the changes in the bronchial epithelium leading to a infection - i.e. the condition was primarily the result of intestinal malabsorption resulting in vitamin deficiency. The authors of the present paper note this is the first study showing a definite relationship between vitamin A levels and respiratory function tests in CF. Earlier Bines et al 2005 had found no relationship between lung inflammation and vitamin A or vitamin E (Bines JE et al. J Paediatr Child Health 2005; 41:663-668. [PubMed]).

2007 Basu AP. Kumar P. Devlin AM. O'Brien CJ. Cystic fibrosis presenting with bilateral facial palsy. Eur J Paediatr Neurol 2007; 11:240-242. [PubMed]
A 15-week old male infant presented with bilateral lower motor neuron facial palsy of unknown cause. Subsequently his growth deteriorated and he developed progressively worsening cough and wheeze. A diagnosis of cystic fibrosis was confirmed and hypovitaminosis A detected. Improvement of the facial palsy was noted following standard management of cystic fibrosis including vitamin A supplementation.

Presentations due to the manifestations of vitamin deficiency, particularly of vitamin A, are well documented. A similar case in a 10 week old infant was reported with low vitamin A levels and bilateral facial nerve paralysis (Cameron C et al. J Cyst Fibros 2007; 6:241-243. [PubMed]

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