Frequency and clinical progression of the vitamin E deficiency neurologic disorder in children with prolonged neonatal cholestasis

To determine the frequency of biochemical vitamin E deficiency and of the clinical signs of the vitamin E deficiency neurologic syndrome in children with prolonged neonatal cholestatic disorders, we studied 46 children (aged 1 month to 17.0 years) with chronic forms of intrahepatic neonatal cholestasis and 47 children (aged 4 months to 8.0 years) with extrahepatic biliary atresia. Based on serum vitamin E concentrations and the ratios of serum vitamin E concentration to total serum lipid concentration, 64% of the intrahepatic and 77% of the extrahepatic cholestasis groups were vitamin E deficient. Prior to age 1 year, neurologic function was normal in all children. Between ages 1 and 3 years, neurologic abnormalities were present in approximately 50% of the vitamin E-deficient children; after age 3 years, neurologic abnormalities were present in all vitamin E-deficient children. Areflexia was the first abnormality to develop between ages 1 and 4 years; truncal and limb ataxia, peripheral neuropathy, and ophthalmoplegia developed between ages 3 and 6 years. Neurologic dysfunction progressed to a disabling combination of findings by ages 8 to 10 years in the majority of vitamin E-deficient children. Neurologic function was normal in the vitamin E-sufficient children. We conclude that vitamin E status should be evaluated in infants in whom cholestasis is diagnosed, and effective therapy should be initiated to prevent or treat vitamin E deficiency at an early age.     

Vitamin E deficiency during chronic childhood cholestasis: presence of sural nerve lesion prior to 2 1/2 years of age

Vitamin E malabsorption and deficiency during chronic childhood cholestasis has been associated with a progressive ataxic neurologic syndrome. Hyporeflexia, the first sign of neurologic dysfunction, may begin prior to age 2 years, but severe symptoms do not develop until age 5 to 10 years. To establish the age of onset of neuropathologic lesions, we prospectively evaluated four young children with severe cholestasis. Malabsorption and deficiency of vitamin E were documented by low serum vitamin E concentrations, low serum vitamin E to total serum lipids ratios, elevated hydrogen peroxide hemolysis, and impaired absorption of a pharmacologic dose of alpha-tocopherol. Abnormal neurologic findings in two patients were limited to areflexia, ptosis, mild truncal ataxia, and hypotonia; two patients had minimal signs of neurologic dysfunction. Sural nerve histology at age 6 to 25 months revealed a degenerative axonopathy involving large-caliber myelinated fibers, but without quantitative axonal loss. Muscle histology and histochemistry tests yielded normal results. Our study suggests that neurologic injury may occur during the first two years of life in vitamin E-deficient children with cholestatic hepatobiliary disease, obligating aggressive attempts at correcting this deficiency state at a very young age.     

Deficiency of vitamins E and A in cystic fibrosis is independent of pancreatic function and current enzyme and vitamin supplementation

Abstract The aim of this study was to evaluate to what extent serum vitamins A and E in cystic fibrosis are affected by the underlying disease, pancreatic sufficiency or insufficiency, meconium ileus, nutritional status, age and treatment (enzyme and vitamin supplementation). Serum vitamin A and E levels were determined by high performance liquid chromatography in 210 cystic fibrosis patients, subdivided according to clinical condition into four subgroups (unsupplemented pancreatic insufficiency, supplemented meconium ileus, pancreatic sufficiency, supplemented pancreatic insufficiency) and compared with 42 control subjects. Vitamin A and E levels were generally lower in cystic fibrosis patients than in controls (P<0.002 andP<0.001 respectively). Subjects with pancreatic insufficiency regularly receiving enzyme and vitamin supplementation had significantly lower vitamin A (P<0.05) and vitamin E (P<0.01) levels than controls. In subjects with pancreatic sufficiency only vitamin A was significantly lower than in controls (P<0.01). Vitamin levels were not age-dependent in cystic fibrosis, and no significant correlation with standardized body weight (Z-score) was observed.Conclusion Cystic fibrosis patients show a clear tendency to vitamin A and E deficiency, irrespective of pancreatic function, body weight and standardized supplementation with pancreatic extract and liposoluble vitamins. Since the clinical significance of this deficiency is still not clear, longitudinal studies of cystic fibrosis patients with and without adequate vitamin supplementation are required.     

Low levels of pyridoxal 5'-phosphate in patients with cystic fibrosis

To determine the effect of cystic fibrosis on the regulation of plasma pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6, we measured this compound in plasma from 56 patients with cystic fibrosis. The concentration of PLP in plasma was assayed by a radioenzymatic technique. The results of this study showed that PLP concentration was decreased significantly (6.44 +/- 5.20 ng/mL, mean +/- SD; median 4.45 ng/mL) in patients with cystic fibrosis as compared with a group of hospitalized children with neither cystic fibrosis nor hepatic disease serving as a control group (13.2 +/- 5.04 ng/mL, mean +/- SD; median 12.5 ng/mL). Additionally, 25% of the population with cystic fibrosis exhibited exceedingly low plasma PLP level (less than 2.75 ng/mL). In patients with cystic fibrosis, significant inverse linear associations were found between plasma PLP and serum levels of SGOT and SGPT (PLP v SGOT: r = -.60, P less than .03; PLP v SGPT: r = -.50, P less than .03). This study demonstrated that a deficiency of plasma PLP is a common abnormality in cystic fibrosis and that the low PLP level may be a reflection of impaired vitamin B6 metabolism associated with this disorder.     

Selenium and vitamin E in mucoviscidosis

Selenium and vitamin E are two important components which protect membrane lipids from oxidative damage. Recently an abnormal fatty acid turnover in the membrane phospholipids was found in cystic fibrosis (CF). We studied vitamin E and selenium status in 26 CF children compared to a control group. we measured selenium concentration in plasma and erythrocytes using flameless atomic absorption. The measure of erythrocyte glutathione peroxidase activity allowed a functional assessment of selenium. Total plasma tocopherol concentrations (HPLC) were referred to total lipids. The vitamin E and selenium levels in not yet treated children (n = 6) were very low, with an important decrease in glutathione peroxydase activity. The antioxidative agents deficiency was mild in children with pancreatic enzyme replacement and vitamin E supplementation (n = 20). In the 2 groups, this deficiency was combined and may play a role in CF membrane abnormalities.     

Vitamin status in treated patients with cystic fibrosis.

The water-soluble (B1, B2, B6, C, folic acid) and fat-soluble vitamin (A, carotene, E, and D) status of 36 patients with cystic fibrosis was assessed and compared with a control group of 21 age-matched normal children. Twenty-seven of the patients were receiving vitamin supplements (except folic acid and vitamin E) at the time of investigation. Vitamin B1, B2, and B6 status was adequate in all patients, and there was little evidence of folic acid deficiency. Vitamin C stores might not have been adequate in some of these patients, despite daily supplements with 50 mg of the vitamin. Steatorrhoea, often severe, was present in most of them. Serum carotene and vitamin E concentrations were low in over 90% of patients and were related to the severity of steatorrhoea. Vitamin A was low in over 40% of the patients despite daily vitamin supplements of 4000 IU and correlated with the serum retinol-binding protein level. Serum 25-OH cholecalciferol was low in some patients whether or not they were receiving a daily supplement of 400 IU vitamin D. In a short-term supplementation trial with water-miscible preparations of vitamin A and E in 14 patients, the serum levels of both vitamins responded well to 2 weeks of treatment with 50 mg vitamin E and 4000 IU vitamin A. Except for serum vitamin A, which was lowest in patients with the poorest clinical grading, the other vitamins were not influenced by the clinical grade of the patients.     

Negative effects of oral fatty acid supplementation on sweat chloride in cystic fibrosis.

Essential fatty acid supplementation with oral safflower oil (1 gm/kg/day) to 11 cystic fibrosis patients (aged 6 months to 14 years) for one year produced no significant change in sweat chloride concentration (mEq/liter) or sweat rate (gm/min/m2), Addition of vitamin E (10 mg/kg/day) to the safflower oil had no effect on sweat chloride concentration or rate compared to placebo. No clinical improvement could be detected compared to a control group. These results do not support previous reports of the effects of fatty acid supplementation on sweat electrolyte concentrations in cystic fibrosis.     

Intramuscular vitamin E repletion in children with chronic cholestasis

Progressive spinocerebellar degeneration was identified in six children with chronic cholestatic liver disease and attributed to severe vitamin E deficiency. In addition to areflexia, ataxia, dysmetria, and diminished vibratory and position sense, three patients had pigmentary retinopathy. Abnormalities were present on electromyography, nerve conduction studies, and electroretinography. Because the vitamin E deficiency was not corrected by oral administration of massive doses of vitamin E, vitamin E was administered by the intramuscular route. With doses of 50 to 100 mg of vitamin E every three to seven days, over a 32-month interval (range, 15 to 44 months), vitamin E deficiency and abnormal red blood cell peroxide hemolysis were corrected. Other than discomfort and occasional edema at the site of injection, there were no side effects of parenteral vitamin E therapy. In several other studies intramuscular vitamin E therapy has produced significant neurologic improvement in patients with similar characteristics. In this study clinical progression of spinocerebellar degeneration was arrested but improvement could not be demonstrated despite adequate vitamin E replacement.     

Night blindness and conjunctival xerosis caused by vitamin A deficiency in patients with cystic fibrosis.

Forty three patients with cystic fibrosis, aged 8-44 years (median 16 years), were examined for evidence of vitamin A deficiency. Eight patients 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.     

Retinol binding protein status in relation to ocular surface changes in patients with cystic fibrosis treated with daily vitamin A supplements

Cystic fibrosis (CF) is an autosomal recessive disease characterised by increased viscosity of mucus secretions and high chloride concentration in exocrine secretions. Clinically, the patients suffer from chronic pulmonary changes, chronic pancreatic deficiency, and an obstruction of the gastrointestinal tract. The disease affects all secretory epithelia including the eye. The influence of nutritional status on long-term survival and quality of life of CF patients is well documented. Steatorrhea, a consequence of decreased fat digestion and absorption may be associated with vitamin deficiences, including vitamin A. The aim of this study was to document plasma retinol binding protein (RBP) status, a specific plasma transport protein for vitamin A, and ocular surface changes in children and adolescents with CF. The patients were recruited at the 3rd Department of Paediatric Diseases, Medical University of Bialystok, Poland. All patients were regularly seen by a CF specialist dietitian. A group of 15 patients had the following investigations: plasma RBP, visual acuity, physical examination, tear film break-up time, fluorescein staining and Schirmer tear test. A group of 15 age- and sex-matched controls without CF or ocular pathology were also recruited. Plasma RBP concentrations were significantly lower in patients with CF than in the control group. CF patients showed a statistically significant increase in the incidence of clinical blepharitis. Five of the CF patients had clinical evidence of dry eyes. Conclusion:Low plasma retinol binding protein levels frequently occur in clinically stable and retinol supplemented cystic fibrosis patients, of whom five had dry eyes. We recommend monitoring of plasma retinol binding protein levels and evaluation of ocular surface changes, especially those with dry eye symptoms in all cystic fibrosis patients.     

Vitamin A in cystic fibrosis: case report and review of the literature

Much has been learned about vitamin A physiology in the last 50 years, yet few changes have been made in therapy. Unfamiliarity with vitamin A bioavailability and distribution may inadvertently result in toxicity. A literature search demonstrates that hypovitaminosis A has rarely been reported in patients with cystic fibrosis, and may manifest very differently in children of different ages. Furthermore, hypervitaminosis A may present with similar features, and can result from correction of deficiency. We report such a case in a 4.5-month-old infant, newly diagnosed with cystic fibrosis, who suffered first from vitamin A deficiency and then vitamin A toxicity. A brief review of vitamin A physiology, deficiency, and toxicity is presented.     

Vitamin K status in cystic fibrosis

Appearance of PIVKA-II (protein induced by vitamin K absence-II) in serum is a biochemical sign of insufficient vitamin K-dependent carboxylation of prothrombin. Plasma concentrations of PIVKA-II and vitamin K1 were determined in 24 children with cystic fibrosis. Eight were supplemented with vitamin K1. The purpose of the study was to determine the occurrence of vitamin K deficiency in cystic fibrosis and to evaluate the effect of vitamin K supplementation. PIVKA-II was detectable in only one unsupplemented child. In this patient, the concentration of vitamin K1 was below the limit of detection of 60 ng/l. Vitamin K1 levels in the other unsupplemented children were normal (mean 476 ng/l = 1 mmol/l). The supplemented patients showed extremely high levels of vitamin K1 (mean 22445 ng/l = 50 nmol/l). In conclusion, vitamin K deficiency occurs infrequently in cystic fibrosis. Checking the coagulation system is advised, but routine vitamin K supplementation is not recommended. If additional vitamin K is needed, the starting dose should not exceed 1 mg daily.     

Lipid peroxidation and vitamin E levels during pregnancy in rats

The present study examined pregnancy-related changes in the level of lipoperoxides and antioxidative substances such as superoxide dismutase (SOD), catalase, glutathione peroxidase (GSH-Px) and vitamin E in the maternal and fetal serum, liver, lungs, and placenta using Wistar rats. Pregnant rats fed a standard diet (control animals) showed an increase of lipoperoxides in the blood to a level 3 times greater than the non-pregnant level. When the rats were fed a vitamin E-deficient diet, lipoperoxides were produced in much greater amounts. Fetal blood also contained greater concentrations of lipoperoxides by the use of a vitamin E-deficient diet. However, liver and lung tissues contained lipoperoxides in essentially constant concentrations throughout non-pregnancy and pregnancy. Fetal liver and lung tissues showed higher concentrations than the maternal concentrations. Fetal blood and tissue concentrations of vitamin E reflected the maternal concentrations, and the values in vitamin E-deficient animals were as small as 0.1-0.2 of the values in normally fed animals. As a protective factor against lipid peroxidation, SOD was slightly increased in the liver tissues of pregnant control animals, but catalase and GSH-Px were significantly decreased in the organ. A similar tendency was observed in vitamin E-deficient animals.     

Isolated hypoglossal nerve paralysis following influenza vaccination.

Isolated right hypoglossal (12th) nerve paralysis occurred after bivalent killed influenza vaccine (types A and B) immunization of a 7-month-old girl with cystic fibrosis. Two days after the third immunizing dose, fever and right hypoglossal paralysis developed. There were no other neurologic signs, and she recovered completely over the following three months.     

Prevalence of giardiasis in patients with cystic fibrosis

A group of 107 patients with cystic fibrosis and a control group of 64 normal members of households of patients with cystic fibrosis were surveyed for Giardia lamblia cysts and trophozoites by counterimmunoelectrophoresis of fecal samples. The patient group had a significantly higher rate of infestation than the control group (28.0% vs 6.3%, P = 0.0006), and the disparity between the two groups increased with age (P = 0.005). Aside from cystic fibrosis, all risk factors examined were without influence, except for the presence of household members less than or equal to 5 years of age. We conclude that our patients with cystic fibrosis have a previously unrecognized increased prevalence of giardiasis compared with that in a control population.     

Vitamin E status in children with cystic fibrosis and pancreatic insufficiency

Vitamin E status was compared in 69 children (7.0-10.0 years) with cystic fibrosis and pancreatic with the National Health and Nutrition Examination Survey III sample (6.0-11.9 years). With median vitamin E intakes of 6 mg/day (dietary) and 224 mg/day (supplemental), children with cystic fibrosis had higher serum alpha-tocopherol:cholesterol ratios, higher alpha-tocopherol, and lower cholesterol levels than in the National Health and Nutrition Examination Survey.     

The use of vitamin E in childhood

The essential effects of Tocopherol are based on its antioxidative capacity. Tocopherol, however, is just one in a group of antioxidants, which are important for the organism. Established indication for therapeutical application of vitamin E in infancy is only vitamin-E-malabsorption in connection with chronic cholestasis, pancreatic insufficiency (cystic fibrosis) and short bowel syndrome. In emergency therapy vitamin E is suggested with high dosage in case of shock lung and haemolytic-uraemic syndrome. Positive effects of daily vitamin E application in connection with prophylaxis of retinopathy prematurity, bronchopulmonary dysplasia and intraventricular encephalorrhagia of premature infants of severe underweight are not established. Very questionable therapeutic or prophylactic efficiency is opposed to the risk of higher incidence of severe complications in caring for premature infants of severe underweight, such as enterocolitis necroticans and neonatal septicaemia.     

Antioxidant effect of beta-carotene in cystic fibrosis and bronchiectasis: clinical and laboratory parameters of a pilot study

The carotenoids are potent antioxidants with the ability to quench singlet oxygen and other toxic oxygen species. The aim of this pilot study was to investigate the protective effect of β-carotene on oxidant system in patients with cystic fibrosis (CF) and in patients with bronchiectasis (BE) caused by a reason other than CF. Eighteen children with CF and 15 children with BE followed in the Pediatric Chest Disease Unit of Hacettepe University, and 15 healthy children participated in the study. Compared with the controls, significantly lower plasma levels of β-carotene were found in the CF group and significantly lower plasma levels of vitamin E in the CF and BE groups. The standardization of carotenoid levels for total cholesterol did not significantly attenuate these differences. In addition, there were significantly higher levels of malondialdehyde (a marker of lipid peroxidation) and tumour necrosis factor-α (TNF-α) in children with CF and in children with BE than in normal subjects. After 6 mo of β-carotene supplementation, the plasma levels of β-carotene and vitamin E increased and the plasma levels of TNF-α and malondialdehyde decreased in both groups.
Conclusion : Potent antioxidants, β-carotene and vitamin E are deficient in patients with CF and in patients with BE, and they are more susceptible to oxidative damage. These patients may benefit from β-carotene supplementation.     

Assessment of selected bone metabolism marker concentrations in children with cystic fibrosis

Aim: The aim of this study was to assess bone formation and resorption processes and bone metabolism regulators, such as osteoprotegerin and fetuin-A in children with cystic fibrosis. Material and methods: We examined 45 children with cystic fibrosis aged 5-13 years treated at the Institute of Mother and Child in Warsaw. The control group consisted of 35 healthy children in the same synage range without any diseases which may influence bone metabolism. We determined serum calcium and phosphate levels by colorimetric methods, vitamin D3 by the chemiluminiscence method and bone metabolism markers (osteocalcin, 5b isoenzyme of tartrate-resistant acid phosphatase, osteoprotegerin, fetuin-A) by immunoenzymatic methods. Results: Mean serum concentrations of calcium and phosphate in the studied children were within the reference ranges. However, the level of 25-hydroxyvitamin D3 was significantly lower in patients with cystic fibrosis compared to the controls (19.3±7.6 vs 25.2±8.9 ng/ml, p<0.01). In cystic fibrosis children we observed a statistically significant lower concentration of osteocalcin (81.9±28.9 vs 97.9±28.6 ng/ ml, p<0.01) and similar activity of 5b isoenzyme of tartrate-resistant acid phosphatase (12.5±2.9 vs 13.4±3.5 U/L) as compared to healthy peers. Mean serum concentration of osteoprotegerin in patients with CF was significantly lower than in the control children (4.1±0.98 vs 4.59±0.86 pmol/l, p<0.05). Serum concentration of fetuin-A was comparable in both groups of children. Conclusions: In children with cystic fibrosis changes in the profile of bone metabolism markers were observed. Even patients with CF who are clinically stable and supplemented with vitamins are at risk of osteopenia and osteoporosis in their later life. Therefore, they should be under a comprehensive medical and nutritional care in order to achieve their optimal peak bone mass.