Ocular signs and symptoms and vitamin A status in patients with cystic fibrosis treated with daily vitamin A supplements

BACKGROUND/AIMS: Patients with cystic fibrosis (CF) may have low plasma vitamin A levels from malabsorption, zinc deficiency, liver disease, or poor compliance with prescribed supplements. In view of the increasing number of adults with CF, many of whom drive cars, it is important to assess vitamin A status. In our centre an attempt has been made to achieve normal levels of fat soluble vitamins by annual estimation of plasma levels and appropriate oral supplementation. This study aimed to determine if this approach prevents vitamin A deficiency and the consequent problems with dark adaptation. METHODS: The study was conducted at the regional adult and paediatric cystic fibrosis unit and the patients were recruited from there. Dark adaptation studies were conducted at the department of ophthalmology, St James's University Hospital. All patients are regularly seen in the outpatient department by a CF specialist dietitian and have a comprehensive annual dietary assessment. 28 patients had the following investigations: serum retinol, plasma zinc, serum retinol binding protein, liver function tests, dark adaptation, contrast sensitivity, and anterior ocular surface status. 25 age and sex matched controls without CF or ocular pathology were also recruited for the dark adaptation study. RESULTS: None of the patients 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 cases 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. CONCLUSION: 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 but remains an unexplained phenomenon and deserves further study.     

Role of electroretinography in the assessment of retinal function as an indicator of vitamin A status

Hypovitaminosis A is associated with exocrine pancreatic insufficiency in cystic fibrosis. Peripheral retinal dysfunction is an early finding of vitamin A deficiency. We evaluated serum retinol and zinc as well as visual adaptation in 41 patients with cystic fibrosis, receiving generous pancreatic enzyme and micronutrient supplementation. Forty-one normal individuals matched for age and sex served as controls. Peripheral retinal function was measured by clinical electroretinography using an Electrophysiologic Personal Interfaced Computer and applying a standard protocol. Serum retinol in cystic fibrosis was significantly lower than that of the control group (0.30±0.01 versus 0.39±0.02 mg/l, p<0.001). Serum zinc concentrations were normal in the cystic fibrosis group (1.21±0.03 mg/l) and significantly higher than that of the control group (1.02±0.01 mg/l, p<0.001). The overall visual adaptation, however, was found to be normal and comparable in the two groups. It is concluded that, in cystic fibrosis, despite appropriate vitamin A supplementation, retinol serum concentration may be low. As serum retinol does not reflect vitamin A status, evaluation of visual adaptation may be a more appropriate way to monitor for vitamin A deficiency in cystic fibrosis.     

Rhodopsin levels and retinal function in cats during recovery from vitamin A deficiency

Extended vitamin A deficiency in the cat led to an abnormal appearance in the tapetal fundus with the formation of a dark brown streak centered on the area centralis. At this time rod sensitivity, as measured by the b-wave of the electroretinogram, was reduced by more than two log units; the level of rod visual pigment was reduced by about 90% throughout the paracentral retinal region and was essentially absent from the area centralis. Following oral supplementation with vitamin A there was a rapid partial recovery of both rhodopsin levels and rod sensitivity. Further recovery continued over more than 18 days to levels that were not substantially below normal. This recovery was absent from the area centralis, in which measured visual pigment levels remained very low. In supplemented cats, the brown color in the fundus faded but there remained a small hyper-reflective zone at the area centralis. Morphological examination of the central retina in a supplemented cat showed an outer nuclear layer reduced to one or two rows in the small zone with low rhodopsin levels. Cone but not rod photoreceptors were present in this zone and they appeared to lack outer segments. During recovery, the increase in rod sensitivity was approximately linearly related to the recovery of rhodopsin levels. Thus, in these conditions reduction in sensitivity resulting from previous vitamin A deficiency was limited by the ability of the photoreceptors to absorb incident quanta. The time course of the recovery of rhodopsin and sensitivity suggests that at least two processes were involved. The faster of these may be the regeneration of rhodopsin from existing opsin molecules in the outer segments, while the slower may depend on the renewal of the outer segments themselves.     

Ocular findings in cystic fibrosis patients receiving vitamin A supplementation

Background: Vitamin A deficiency with eye symptoms has been reported in patients with cystic fibrosis who received the recommended daily intake of vitamin A. Methods: We measured serum retinol, dark adaptation, contrast sensitivity, and dry eye status in 35 adult cystic fibrosis patients to ascertain whether they had ocular signs or symptons. Results: Median serum retinol concentration was 1.95 mol/l, range 1.08–4.01 mol/l, with no values indicating vitamin A deficiency. Retinal light sensitivity was normal. Nineteen patients had reduced contrast sensitivity. Conjunctival imprints all showed plenty of goblet cells, but were characteristic of dry eye in 42% of patients (n=14). Decreased tear film stability was found in 49% (n=17), tear production was low in 31% (n=11), and 23% (n=8) showed an increased amount of dying epithelial cells. Nine patients (26%) had keratocon-junctivitis sicca according to the Copenhagen criteria. Conclusion: Our patients had no biochemical or clinical signs of vitamin A deficiency. We speculate that the high incidence of dry eye could be a primary manifestation of cystic fibrosis.     

Attempts to define the minimal serum level of vitamin A required for normal visual function in a patient with severe fat malabsorption

A case with severe malabsorption of fat soluble vitamins is described. The malabsorption developed after an intestinal bypass operation due to morbid obesity. Night blindness occurred as the first symptom of vitamin A deficiency. The cone visual sensory threshold was elevated about one log unit and the rod threshold abot two and a half log units. No changes of the a- and b-waves of the electroretinogram (ERG) was observed. However, during the initial phase of very low serum reninol level (0.21 mumol/l) the summed amplitudes of the oscillatory potentials (OPs) were lower. After parenteral therapy with vitamin A the night blindness disappeared and the dark-adapted rod and cone threshold sensitivity recovered to normal. However, the time-course of rod adaptation first reached normal levels after 5 months. The amplitudes of the OPs of the ERG response returned to normal when the serum retinol level had increased close to normal. Serum retinol levels of 0.7 mumol/l or higher were always associated with normal or close to normal dark-adapted rod sensitivity. However, a normal serum retinol level (> 0.95 mumol/l) and a normal dark-adapted rod threshold sensitivity were not always associated with a normal time-course of the rod adaptation. It is concluded, that the maintenance dosage of vitamin A must be individualized and that patients who have undergone jejuno-ilea bypass surgery must be carefully monitored for vitamin A deficiency by both serum levels and dark adaptation measurements.     

Xerophthalmia and acquired night blindness in a patient with a history of gastrointestinal neoplasia and normal serum vitamin A levels

A 69-year-old male patient presented to our department with a 3-month history of nyctalopia. Reviewing of his general health revealed a history of gastrointestinal tumor treated with a modified WHIPPLE operation. Ocular findings at presentation included mild xerophthalmic features and nonspecific pigmentary retinal changes. A standard full-field electroretinogram (ERG) was obtained that showed normal photopic function and extinguished scotopic function. The ocular symptoms, the history and the ERG findings suggested vitamin A deficiency as a possible cause for his complaints. Serum vitamin A levels were subsequently requested, but the results were within normal limits. Despite the normal serum vitamin A levels, the patient was instructed to commence treatment with high doses of oral vitamin A supplements. One month after the onset of the treatment, the patient reported that his visual function has significantly improved, while repeat ERG testing revealed that scotopic function has improved to normal levels. This case highlights that in patients with acquired night blindness due to vitamin A deficiency, the ERG responses possibly represent a more sensitive marker compared to the serum levels of vitamin A.     

Visual function and rhodopsin levels in humans with vitamin A deficiency

Details of rod and cone dysfunction in vitamin A deficiency have been studied in two subjects with primary biliary cirrhosis and one with Crohn's disease, all of whom presented with symptoms of night blindness. Visual function in the mid-peripheral retina was monitored with two-color adaptometry and rhodopsin levels were measured by fundus reflectometry. Initially all three subjects had no measurable rod function and delayed cone adaptation. In one case the dark-adapted cone threshold was also elevated. Oral supplementation with vitamin A restored visual function to normal within 8 days in all subjects. During supplementation, cone function was restored more rapidly than that of rods, though the pattern of recovery was similar for each receptor type. Final thresholds improved first, though the rates at which they were reached were abnormally slow. As recovery continued, adaptation kinetics returned to normal. When rod adaptation was delayed, the regeneration of rhodopsin was also abnormally slow. When rod final threshold was 2 log units higher than normal, rhodopsin regeneration was incomplete, reaching about 70% of the normal level. The initial stages of visual dysfunction during onset of vitamin A deficiency were studied in one subject, and were found to mirror the pattern seen during recovery: rod adaptation was initially slower than normal, but reached completion. Cone adaptation remained normal until rod function was almost absent.     

ERGs in children with pancreatic enzyme insufficient and pancreatic enzyme sufficient cystic fibrosis

Objectives We recorded scotopic and photopic flash electroretinograms (ERGs) in pediatric subjects with cystic fibrosis, aged 4 to 18 years, who were either pancreatic insufficient (PI) or pancreatic sufficient (PS). The aim of the study was to determine whether vitamin supplementation in the PI group allowed comparable retinal function in these two groups. Methods ERGs were recorded from a mixed-gender group of 41 children and adolescents (4 to 17 years of age) with cystic fibrosis. The subjects were grouped according to pancreatic function into PI (n = 29) and PS (n = 12). Full-field flash ERGs were recorded from one eye using a DTL fiber. The pupil was dilated prior to recording using two drops of 0.5% tropicamide. ISCEV photopic and scotopic stimuli and recording conditions were used. Serum levels of vitamin A, β carotene and retinol binding protein (RBP) were measured on the day of ERG recording. Results There was no significant difference in ERG amplitudes or implicit times between PI and PS groups. Vitamin A, β carotene, and RBP levels were not significantly different across the two groups and were not correlated with implicit times or amplitudes of any of the ERG types recorded here. Conclusion Similarity of ERGs across the PI and PS cystic fibrosis patient populations tested here suggests that the supplementation protocol applied to these populations allows similar levels of retinal function (as indicated by flash ERG parameters) in the two groups.     

Vitamin A deficiency in treated cystic fibrosis: case report.

We describe a patient with cystic fibrosis and hepatic involvement who, although on pancreatic extract, developed vitamin A deficiency, night blindness, and a characteristic fundus picture. All of these abnormalities were reversed by oral vitamin A supplementation.     

Improvement of Scotopic Electroretinograms and Night Blindness with Recovery of Serum Zinc Levels

Background We sought to determine the cause of reduced scotopic and photopic electroretinograms (ERGs) and night blindness in a 46-year-old man with liver dysfunction but no history of alcoholism. Case A 46-year-old Japanese man with a complaint of visual difficulties in dim light for 1 month. Observations By electrophysiological investigation, the patient was found to have low levels of serum zinc and vitamin A on admission. The rod b wave was unrecordable, and the bright-flash ERGs were reduced, with the a wave > b wave. The amplitudes of the cone and 30-Hz flicker responses were also reduced, and their implicit times were prolonged. Three weeks after admission, the patient's serum zinc level recovered to normal levels, but his serum vitamin A level was still low. The symptoms of night blindness were gone, and the rod ERGs and single bright-flash responses were within normal limits. However, the cone ERGs and 30-Hz flicker responses were still depressed. Conclusions The recovery of scotopic function together with the recovery of zinc but not vitamin A levels suggests that the ERG changes were most likely related to low zinc levels.     

Functional observations in vitamin A deficiency: diagnosis and time course of recovery

AIMS: To describe the effects of vitamin A deficiency (VAD) on retinal function and the subsequent recovery following treatment in three patients with systemic conditions (two with Crohn disease; one secondary to IgE syndrome). METHODS: Electrophysiological testing (including pattern electroretinogram, PERG; electroretinogram, ERG; visual-evoked potential) established the diagnosis of VAD. Repeat testing was carried out in two patients to monitor the time course of recovery following intramuscular vitamin A injection. The third patient had repeat recordings following 13 months of oral supplementation. RESULTS: All three patients initially displayed a characteristic absence of rod function associated with VAD. In addition, delayed and reduced amplitude cone ERGs, loss of short wavelength cone (S-cone) function and subnormal macular function were observed in two patients. Restoration of rod and generalised cone function was rapid in the two patients who received intramuscular injection, with normalisation of some electrophysiological responses after only 3 days. Normal S-cone amplitudes and cone latencies were reached within 12 days of vitamin A injection. Macular function returned to within normal limits by 12 days postinjection in one patient, but remained mildly subnormal in the second patient. Full recovery was present after 13 months oral supplementation in the third patient. CONCLUSIONS: Novel observations regarding dark-adapted cone function, S-cone function, and PERG are presented. The differences between the effects of VAD on rod and cone function, and their rate of recovery, may reflect differences in the visual cycle between the two photoreceptor classes. The importance of rapidly and accurately diagnosing VAD, a treatable condition, is noted.     

Abetalipoproteinemia. Report of an unusual patient

Abetalipoproteinemia (Bassen-Kornzweig syndrome, acanthocytosis) was diagnosed at age 13 months in a black male. At age 13 months, the electroretinogram was nonrecordable and a pigmentary retinopathy was obvious with ophthalmoscopy. Following dietary modification and vitamin supplementation, the scotopic electroretinogram improved to about 30% of normal.     

Ocular findings in cystic fibrosis

We examined 32 patients with cystic fibrosis, paying special attention to optic nerve performance and pupillary function. Decreased visual acuity occurred in nine of 64 eyes. Three of 17 patients (18%) who used chloramphenicol had bilaterally delayed P100 waves of the visual-evoked response of greater than 3 standard deviations. This was not found in patients who did not use chloramphenicol. Contrast sensitivity in patients with cystic fibrosis was decreased at every spatial frequency when compared to healthy controls. This decrease was noted in patients who did and did not use chloramphenicol, suggesting that chloramphenicol is not the only cause of decreased contrast sensitivity in cystic fibrosis. With pharmacologic pupil testing we determined that patients with cystic fibrosis display a preganglionic oculosympathetic paresis that corresponded to the disease severity, as measured by the Shwachman score.     

Advanced xerophthalmia as a presenting sign in cystic fibrosis

Xerophthalmia is a common complication of vitamin A deficiency in communities where malnutrition is found. We report on a 16-month-old infant with severe photophobia and failure to thrive. On examination, her major presenting sign was corneal xerosis, with corneal and conjunctival keratinization, and corneal stromal edema with opacification. Based on these findings, vitamin A deficiency secondary to fat malabsorption was suspected, and a workup confirmed the diagnosis of cystic fibrosis. With parenteral vitamin A supplementation, she had complete resolution of her ocular signs and symptoms. This case illustrates the value of a complete ophthalmic examination in the diagnosis of fat malabsorption syndromes.     

Vitamin A Deficiency Presenting with ‘Itchy Eyes’

We present the case of an 88-year-old female living in metropolitan Melbourne, Australia who developed vitamin A deficiency manifesting as ‘itchy eyes’ due to a bizarre dietary habit. Slit lamp examination revealed Bitot''s spots and a subsequent vitamin A serum level test revealed severe deficiency. An electroretinogram showed grossly reduced a- and b-wave amplitudes consistent with generalised rod and cone dysfunction - these parameters showed marked improvement 5 months post supplementation. This case highlights the presence of vitamin A deficiency in the developed world and that a careful dietary history should be taken when assessing a patient complaining of ‘itchy eyes’. Timely diagnosis and treatment may result in dramatic resolution of symptoms and signs as well as prevention of serious morbidity.Key Words: Nyctalopia, Bitot''s spots, Xerophthalmia, Hypovitaminosis A, Electroretinogram     

Dark adaptation compared with electrooculography in primary biliary cirrhosis

In a series of asymptomatic patients with primary biliary cirrhosis there was a significant impairment of dark adaptation thresholds as compared with a control group. Vitamin A levels were abnormally low in only two of the patients and these two both showed high dark adaptation thresholds. The electrooculogram was reduced in only the most severely affected case. It is suggested that visual function tests should be performed alongside vitamin A level measurements before deciding on treatment.     

Acquired temporary night blindness in vitamin A and zinc deficiency in anorexia nervosa nine years after kidney transplantation

BACKGROUND: Vitamin and trace element deficiencies may cause visual disturbances. Before starting a substitutional therapy, specific investigations should be performed. HISTORY AND SIGNS: We present a kidney-transplanted patient who suffered for 6 months from night blindness. The electroretinography showed a severe decrease of the rod activity. Except for an irregular pigmentation in the far periphery, the fundus appeared normal. These findings were indicative of a vitamin A and zinc deficiency. The laboratory tests showed decreased vitamin A and zinc serum levels. THERAPY AND OUTCOME: After three months of substitutional therapy the electroretinogram had normalized and the patient was free of symptoms. CONCLUSIONS: Visual disturbances due to vitamin and trace element deficiencies are rare in Europe. If suspected, since the diagnosis and the treatment of nutritional deficiencies are simple, specific investigations and a substitutional therapy should be initiated.     

The relationship between serum trace element changes and visual function in heavy smokers

PURPOSE: The aim of this prospective study was to evaluate serum manganese (Mn), zinc (Zn) and copper (Cu) levels and visual functions including visual acuity, colour vision, pattern visual evoked potentials (PVEPs), and contrast sensitivity in heavy smokers and to compare these with the equivalent levels and functions in non-smokers. METHODS: Data were recorded in 24 healthy, chronic and heavy cigarette smokers and 16 healthy, non-smoking control subjects. Serum Zn, Cu and Mn concentrations in all subjects were measured by atomic absorption spectrophotometry. RESULTS: Both study and control subjects had normal visual acuity and colour vision. Pattern visual evoked potentials were normal in all study and control subjects. Contrast sensitivity was significantly reduced in heavy smokers compared to non-smokers (p < 0.023), despite the fact that central vision and PVEP responses were not affected. Mean serum Mn and Zn levels were significantly lower in smokers than in non-smokers (p < 0.0001 and p < 0.005, respectively). CONCLUSIONS: Reduced contrast sensitivity values associated with low levels of serum Mn and Zn, which function as cofactors of superoxide dismutase in erythrocyte and other nucleated cells, suggest a possible role of trace elements in smoking-induced early retinal toxicity.     

Through a shade darkly

A 43-year-old man complained of difficulty seeing in dim light (nyctalopia). A prolonged photostress test and abnormal electroretinogram confirmed retinal rather than optic nerve dysfunction. Vitamin A deficiency secondary to remote ileal-jejunal bypass was diagnosed, and his visual symptoms and signs reversed with oral vitamin A supplementation.     

Vitamin A in Stargardt disease—an evidence-based update

Background: High intake of vitamin A is suspected to be a risk factor for the progression of Stargardt disease (STGD1) and many health authorities recommend Stargardt patients not to use oral vitamin A supplements outside that provided naturally in the food. The present study provides the first systematic review of the current level of evidence regarding the role of supplementary vitamin A in STGD1.

Materials and methods: We conducted a systematic scientific literature search in the Pubmed database on studies reporting on the effect of oral vitamin A or serum retinol on visual function.

Results: In animal studies neither high nor low serum retinol in an Abca4 knockout mouse model of Stargardt showed any effect on electroretinography (ERG). In humans, significantly better visual function was reported in a cross-sectional study of patients with a low dietary intake of vitamin A, whereas a prospective study did not find any correlation between vitamin A supplementation and visual acuity. A newly introduced vitamin A substitute (C20-D(3)-vitamin A) has shown promising effects on ERG in a Stargardt mouse model.

Conclusions: There are few studies on the effect of vitamin A in STGD1. The scarcity and inconclusiveness of evidence available impel further research efforts to reach a more confident conclusion. Currently, recommendations to avoid vitamin A dietary supplementation rely mainly on a theoretical background. Animal studies on vitamin A substitute as a possible therapeutic approach in preventing or slowing vision loss in STGD1 seems promising but further clinical trials are needed to verify the results.