EYES

1923 Wilson JR, DuBois RO. Report of a fatal case of keratomalacia in an infant with postmortem examination. Am J Dis Child 1923; 26:431-446.
A female infant aged five months died 18 days after admission. She had been fed almost entirely on diluted condensed milk and was severely wasted. There was severe keratomalacia and eventually perforation of the left cornea. At autopsy microscopic examination showed extensive changes in many organs including the lungs, salivary glands and pancreas. There were inflammatory lesions in the lachrymal and salivary glands.
The pancreas (figure 12) showed keratinisation in certain ducts, many epithelial lined cyst like cavities, a marked inflammatory processes and extensive fibrosis. The lungs also showed keratinisation of the epithelium a marked peribronchitis, bronchiectatic cavities and abscesses. The authors observed - “To the mechanical effect of desquamated keratinized epithelium we are inclined to attribute the pancreatic cysts and bronchiectasis”.
This is an interesting paper as Dorothy Andersen, who described CF in 1938 (below), for many years considered the pancreatic lesions and intestinal malabsorption to be primary and the other systemic effects to be the result of the vitamin A deficiency which, for example, caused secondary squamous conversion of the lining respiratory epithelium. It seems almost certain that the present infant had CF with severe secondary vitamin A deficiency.

1931 Daffinee RW, Higgins HL, Mallory TB. Corneal ulcers and roughened conjunctivae associated with fat intolerance. N Engl J Med 1931; 204:1264-1267.
A white male infant aged six months had spots on his eyes noted by the mother also weight loss. He died of bronchopneumonia one month later and at one stage was excreting 40% of his dietary fat intake (70% of which was neutral fat). Autopsy showed almost complete atresia of the cystic duct and histologically “extremely marked disease of the pancreas” - practically all the acinar tissue had disappeared. The lungs showed multiple abscesses. Mallory, the author who was the pathologist, writes “in the later stages of the disease he had a definite pancreatic lack whatever the original cause may have been”.
There can be little doubt that this infant had CF although there are a number of reports suggesting that severe stenosis or even atresia of the pancreatic duct may the the primary cause of the clinical syndrome

1933 Blackfan KD, Wolbach SB. Vitamin A deficiency in infants. J Pediatr 1933; 3:679-706.
Kenneth Blackfan (1883-1941) 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.
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 1) is typical of the changes seen in CF for which Blackfan & May (1938 below) gave credit to Wolbach for the first clear description.

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.

1960 Bruce GM, Denning CR, Spalter HF. Ocular findings in cystic fibrosis of the pancreas: a preliminary report. Arch Ophthalmol 1960; 63:391-401. [PubMed]
The authors became aware of complaints referable to impaired vision and abnormal fundal appearances in their patients in the summer of 1958 and they report the eye findings in 27 patients. Definite impairment of vision was noted in 4 of 10 patients. Characteristic findings were “varying degrees of engorgement and edema of the disc marked in some instances by haemorrhages and in others by cystic changes in the macula”. All those affected had severe pulmonary involvement and raised gammaglobulin levels in the serum and spinal fluid. A later report failed to provide an explanation for the eye changes including chronic hypoxia, hypercapnia, right heart failure, increased intracranial pressure, a bleeding tendency or some disturbance of serum globulins (Soc Pediatr Res 1960; abstract 127). In 1963 the effects of chloramphenicol were reported (Denning et al, 1963 below).

Dr Carolyn Denning was one of the leading CF paediatricians at that time working first in New York with Dorothy Andersen and later at St Vincent’s Hospital in New York. In the figure 5 she is examining the hand print of a person with CF on a “Shwachman plate” (see N Eng J Med 1956:255:999-1001 above). I had the pleasure of visiting her unit in the late Eighties, having been encouraged to do so by Ron Tucker the then Director of the UK CF Trust; he was very keen that I should visit her. Carolyn Denning was the first woman to chair the National Cystic Fibrosis Foundation’s Medical Advisory Council and was one of the first to organize and initiate a multidisciplinary team approach to management of the disease – this was very apparent when visiting her and her team at St Vincent’s. A quote from the website “A Changing Face of Medicine” typifies her general approach - "My office visits," she says, "are conducted in a private setting with no interruptions by telephone or office personnel with a one-hour minimum allotted to each patient. I am realistic yet optimistic, stressing the importance of hope. I am current on research activities in the field as well as other important relevant events. I follow through on all matters pertaining to the patient and his office visit and I am available by telephone at all times. I put great stress on personal integrity, ethics and moral beliefs. As director of a large, multi-disciplinary group of health professionals, I have worked hard to choose people who share the same philosophy." It was good to see such an excellent team in action.

1963 Rubin LS, Barbero GJ, Chernick WS, Sibinga MS. Pupillary reactivity as a measure of autonomic balance in cystic fibrosis. J Pediatr 1963; 63:1120-1129. [PubMed]
There was considerable interest in possible abnormalities of the autonomic nervous system considered to be in some way related to the basic defect. The authors found significant differences in the pupillary reactivity between people with CF and controls. Holzel in Manchester had found normal levels of acetyl cholinesterase in various tissues and concluded any cholinergic over-stimulation was not due to absence of the hydrolysing enzyme (Holzel A et al. Lancet 1962; i: 822-823 above). Autonomic abnormalities were later confirmed by Davies et al, (N Eng J Med 1980; 302:1453-1456 below) and more recently were reviewed by Mirakhur A et al. (J R Soc Med 2003; 96 Suppl 43:11-17).
Although there was considerable interest in autonomic abnormalities this knowledge does not appear to have made any contribution to either the treatment or the understanding of the basic defect. There was a later report of excessive finger wrinkling in people with CF when their fingers were immersed in warm water and this phenomenon has been related to autonomic function (Elliott, 1974 below).

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.

2008 Mrugacz M. Kasacka I. Bakunowicz-Lazarczyk A. Kaczmarski M. Kulak W. Impression cytology of the conjunctival epithelial cells in patients with cystic fibrosis. Eye 2008; 22:1137-1140. [PubMed]
Cystic fibrosis affects all secretory epithelia, including the eye, and belongs to the group of ocular surface epithelial diseases, termed keratoconjunctivitis sicca or dry eye syndrome. The aim of this study was to evaluate goblet cell population and conjunctival epithelial morphology in patients with CF. A total of 20 CF patients and 20 controls underwent conjunctival impression cytology. Impression cytology showed conjunctival squamous metaplasia and goblet cell loss in patients with CF. The reduced goblet cell numbers and squamous metaplasia may be indicative of a higher degree of epithelial damage of conjunctival epithelial cells in CF patients, and the presence of neutrophils is a strong sign for an inflammatory background of this disease.In view of the simple, noninvasive nature of impression cytology, this technique may prove to be an important tool for the diagnosis and monitoring of dry eye changes in CF patients.

These changes are reported in a number of reports dealing with vitamin A status and still appear to be present even when the vitamin levels are normal. (Ansari EA et al. 1999[PubMed]).