Pathogenesis

The term vitamin E denotes a group of 8 compounds with similar structures and antioxidant activity. The most potent member of these compounds is α-tocopherol, which is also the main form in humans. The best dietary sources of vitamin E are vegetable oils, seeds, nuts, green leafy vegetables, and margarine (see Table 48-1).

The majority of vitamin E is located within cell membranes, where it prevents lipid peroxidation and the formation of free radicals. Other antioxidants, such as ascorbic acid, enhance the antioxidant activity of vitamin E. The importance of other functions of vitamin E is still being delineated.

Premature infants are particularly susceptible to vitamin E deficiency, because there is significant transfer of vitamin E during the last trimester of pregnancy. Vitamin E deficiency in premature infants causes thrombocytosis, edema, and hemolysis potentially causing anemia. The risk of symptomatic vitamin E deficiency was increased by the use of formulas for premature infants that had a high content of polyunsaturated fatty acids (PUFAs). These formulas led to a high content of PUFAs in red blood cell membranes, making them more susceptible to oxidative stress, which could be ameliorated by vitamin E. Oxidative stress was augmented by aggressive use of iron supplementation; iron increases the production of oxygen radicals. The incidence of hemolysis due to vitamin E deficiency in premature infants decreased secondary to the use of formulas with a lower content of polyunsaturated fatty acids, less-aggressive use of iron, and provision of adequate vitamin E.

Because vitamin E is plentiful in common foods, primary dietary deficiency is rare except in premature infants and in severe, generalized malnutrition. Vitamin E deficiency does occur in children with fat malabsorption secondary to the need for bile acid for vitamin E absorption. Although symptomatic disease is most common in children with cholestatic liver disease, it can occur in patients with cystic fibrosis, celiac disease, short-bowel syndrome, or Crohn disease. The autosomal recessive disorder abetalipoproteinemia (Chapter 80) causes fat malabsorption, and vitamin E deficiency is a common complication.

In ataxia with isolated vitamin E deficiency (AVED), a rare autosomal recessive disorder, there are mutations in the gene for α-tocopherol transfer protein. Patients with this disorder are unable to incorporate vitamin E into lipoproteins before their release from the liver, leading to reduced serum levels of vitamin E. There is no associated fat malabsorption, and absorption of vitamin E from the intestine occurs normally.

Clinical Manifestations

A severe, progressive neurologic disorder occurs in patients with prolonged vitamin E deficiency. Clinical manifestations do not appear until after 1 yr of age, even in children with cholestasis since birth. Patients may have cerebellar disease, posterior column dysfunction, and retinal disease. Loss of deep tendon reflexes is usually the initial finding. Subsequent manifestations include limb ataxia (intention tremor, dysdiadochokinesia), truncal ataxia (wide-based, unsteady gait), dysarthria, ophthalmoplegia (limited upward gaze), nystagmus, decreased proprioception (positive Romberg test), decreased vibratory sensation, and dysarthria. Some patients have pigmentary retinopathy. Visual field constriction can progress to blindness. Cognition and behavior can also be affected. Myopathy and cardiac arrhythmias are less common findings.

In premature infants, hemolysis due to vitamin E deficiency typically develops during the 2nd month of life. Edema may also be present.

Laboratory Findings

Serum vitamin E levels increase in the presence of high serum lipid levels, even when vitamin E deficiency is present. Hence, vitamin E status is best determined by measuring the ratio of vitamin E to serum lipids; a ratio <0.8 mg/g is abnormal in older children and adults; <0.6 mg/g is abnormal in infants <1 yr. Premature infants with hemolysis due to vitamin E deficiency also often have elevated platelet counts.

Neurologic involvement can cause abnormal somatosensory evoked potentials and nerve conduction studies. Abnormalities on electroretinography can precede physical examination findings in patients with retinal involvement.

Diagnosis and Differential Diagnosis

Premature infants with unexplained hemolytic anemia after the 1st month of life, especially if thrombocytosis is present, either should be empirically treated with vitamin E or should have serum vitamin E and lipid levels measured. Children with neurologic findings and a disease that causes fat malabsorption should have their vitamin E status evaluated.

Because children with AVED do not have symptoms of malabsorption, a correct diagnosis requires a high index of suspicion. Friedreich ataxia has been misdiagnosed in some patients (Chapter 590.1). Children with unexplained ataxia should be screened for vitamin E deficiency.

Treatment

For correction of deficiency in neonates, the dose of vitamin E is 25-50 units/day for 1 wk, followed by adequate dietary intake. Children with deficiency due to malabsorption should receive 1 unit/kg/day, with the dose adjusted based on levels; ongoing treatment is necessary. Children with AVED normalize their serum vitamin E levels with high doses of vitamin E.

Prognosis

The hemolytic anemia in infants resolves with correction of the vitamin E deficiency. Some neurologic manifestations of vitamin E deficiency may be reversible with early treatment, but many patients have little or no improvement. Importantly, treatment prevents progression.

Prevention

Premature infants should receive sufficient vitamin E via formula or breast milk fortifier and formula without a high content of PUFAs. Children at risk for vitamin E deficiency due to malabsorption should be screened for deficiency and given adequate vitamin E supplementation. Vitamin preparations with high content of all of the fat-soluble vitamins are available.