An improved understanding of its physiology has led to better therapeutic use of
vitamin E in recent years. It is a physiological membrane bound antioxidant,
protecting cell membrane lipids from oxidant damage by free redicals.
Cholestatic liver disease, abetalipoproteinemia and ataxia with vitamin E
deficiency are the common deficiency states where vitamin E is of definite
therapeutic value, while reports of unproven benefits abound in literature.
Vitamin E status of the body can be assessed by serum levels and various
functional studies. The new water soluble form, tocopherol polyethylene glycol
succinate (TPGS), is therapeutically superior to the standard oral forms
available. Details of physiology and therapeutic application of the vitamin are
discussed.

BAKCGROUND: A predictable consequence of cholestasis is malabsorption of
fat-soluble factors, (vitamins A, D, E, K) and other free radical scavengers,
such as carotenoids. It has been suggested that oxygen-derived free radicals may be involved in the pathogenesis of chronic liver damage. AIMS: (i) To evaluate retinol, alpha-tocopherol and carotenoid plasma levels in two groups of patients with chronic cholestatic liver disease (primary biliary cirrhosis and primary sclerosing cholangitis); (ii) to compare the respective plasma levels with those of the general population; (iii) to correlate the plasma levels with disease
severity. METHODS: A total of 105 patients with chronic cholestasis were
included in the study: 86 with primary biliary cirrhosis (81 female, five male,
mean age 55.5 11 years), 19 with primary sclerosing cholangitis (seven
female, 12 male, mean age 35 11 years; six patients had associated
inflammatory bowel disease); 105 sex- and age-matched subjects from the general population in the same geographical area (88 female, 17 male, mean age 51.3.5 10 years) served as controls. Carotenoids (lutein zeaxanthin, lycopene, beta-carotene, alpha-carotene, beta-cryptoxanthin), retinol and alpha-tocopherol were assayed by high-pressure liquid chromatography. A food frequency questionnaire was administered to each subject to evaluate the quality and the quantity of dietary compounds. Data were processed by analysis of variance and linear regression analysis, as appropriate. RESULTS: Both primary biliary cirrhosis and primary sclerosing cholangitis patients had significantly lower levels of retinol, alpha-tocopherol, total carotenoids, lutein, zeaxanthin, lycopene, alpha- and beta-carotene than controls (P < 0.0001). Among the cholestatic patients, no significant difference in the concentration of
antioxidants was observed between primary biliary cirrhosis and primary
sclerosing cholangitis subjects. Anti-oxidant plasma levels were not affected by
the severity of the histological stage in primary biliary cirrhosis, but a
negative correlation was found between total carotenoids and both alkaline
phosphatase (ALP) and gammaglutamyl transpeptidase (GGT) (P < 0.013 and P < 0.018, respectively). Within the primary sclerosing cholangitis group, no
correlation was found between total carotenoids and cholestatic enzymes.
Nutritional intake in cholestatic patients was comparable to controls, including
fruit and vegetable intake. CONCLUSIONS: Although no clinical sign of deficiency is evident, plasma levels of antioxidants are low in cholestatic patients even in early stages of the disease. This is probably due to malabsorption of fat-soluble vitamins, as well as other mechanisms of hepatic release, suggesting the need for dietary supplementation.

BACKGROUND: The symptoms of the chronic cholestatic liver disease primary
biliary cirrhosis (PBC), in particular fatigue and chronic pruritus, adversely
affect quality of life and respond only poorly to treatment. Recent studies have
suggested that oxidative stress may play a role in tissue damage in cholestatic
liver disease and may contribute to symptoms, such as fatigue. We have,
therefore, examined, in an open-label pilot study, the therapeutic effects of
antioxidant medication on the biochemistry and symptomatology of PBC. METHODS: Patients were randomized to 3 months treatment with a compound antioxidant vitamin preparation (Bio-Antox), four tablets daily (n = 11, group 1), or the combination of Bio-Quinone Q10 (100 mg) with Bio-Antox (n = 13, group 2). Biochemical and symptomatic responses were assessed at 3 months. RESULTS: Significant improvement in both pruritus and fatigue was seen in the patients in group 2. Mean itch visual analogue score improved from 2.4 3.0 to 0.4 0.7 post therapy (P < 0.05) while mean night itch severity score improved from 2.6 1.9 to 1.3 0.7 (P < 0.05). Nine of 13 of these patients reported
less fatigue, while 10/13 showed an improvement in at least one domain of their
Fisk Fatigue Severity Score. No significant improvement in itch and only limited
improvement in fatigue were seen in the patients in group 1. No change in
biochemical parameters was seen in either group. CONCLUSIONS: Antioxidant
therapy, as a combination of Bio-Antox and Bio-Quinone Q10, may improve the
pruritus and fatigue of PBC. This combination of therapy should be investigated
further in a double-blind, placebo-controlled trial.

Vitamin E (alpha-tocopherol) is an essential nutrient and an important
antioxidant. Its plasma levels are dependent upon oral intake, absorption and
transfer of the vitamin to a circulating lipoprotein. The latter step is
controlled by alpha-tocopherol transfer protein (alpha-TTP), which is a 278
amino acid protein encoded on chromosome 8, known to be synthesized in the
liver. Mutations in alpha-TTP are associated with a neurological syndrome of
spinocerebellar ataxia, called ataxia with vitamin E deficiency (AVED). Earlier
studies suggested that alpha-TTP is found only in the liver. In order to
establish whether alpha-TTP is expressed in the human brain, and what
relationship this has to AVED, we studied immunohistochemically the presence of alpha-TTP in the brains of a patient with AVED, normal subjects, and patients
with Alzheimer's disease (AD), Down's syndrome (DS), cholestatic liver disease
(CLD) and abetalipoproteinemia (ABL). The neuropathology of both AD and DS is thought to be related in part to oxidative stress. The diseases of AVED, of
cholestatic liver disease, and of abetalipoproteinemia are thought to be due to
lack of circulating tocopherol, leading to inadequate protection against
oxidative damage. We demonstrate the presence of alpha-TTP in cerebellar
Purkinje cells in patients having vitamin E deficiency states or diseases
associated with oxidative stress. Copyright 1999 Elsevier Science B.V.

Vitamin E is one of the most important lipid-soluble antioxidant nutrients.
Severe vitamin E deficiency can have a profound effect on the central nervous
system. Cystic fibrosis, chronic cholestatic liver disease,
abetalipoproteinemia, short bowel syndrome, isolated vitamin E deficiency
syndrome and other malabsorption syndromes all may cause varying degrees of
neurologic deficits due to related vitamin deficiencies. The classic
abnormalities in vitamin E deficiency progress from hyporeflexia, ataxia,
limitations in upward gaze and strabismus to long-tract defects, profound muscle
weakness and visual field constriction. Patients with severe, prolonged
deficiency may develop complete blindness, dementia and cardiac arrhythmias.
Treatment must be tailored to the underlying cause of vitamin E deficiency and
may include oral or parenteral vitamin supplementation. The more advanced the
deficits, the more limited the response to therapy. Therefore, a good neurologic
examination and periodic serum vitamin E levels are essential in patients at
risk of vitamin E deficiency.

The purpose of this study was to determine the prevalence of vitamin E
deficiency in adults with chronic cholestatic liver disease and to quantify the
association between their psychomotor performance and vitamin E status. In 42
female patients with primary biliary cirrhosis, 43.5% met two standard criteria
for vitamin E deficiency. Vitamin E-deficient patients performed less well than
did healthy control subjects on six of eight neuropsychologic tests of
psychomotor capacity (p less than 0.01). Vitamin E-sufficient patients did not
differ significantly from normal control subjects. Serum vitamin E
concentrations were significantly lower in the group classified as significantly
psychomotor-impaired by two independent neuropsychologists (blind to vitamin E status) whereas liver-injury measures failed to distinguish between these two
groups. Patients with low serum vitamin E exhibited clinically evident
neurologic abnormalities. These data suggest that vitamin E deficiency may, in
part, underlie psychomotor and neurologic disturbance found in adult patients
with chronic cholestatic liver disease.

Polyunsaturated fatty acids of biomembranes are a major target of lipid
peroxidation. In vitamin E deficiency an efficient delivery of a high oral
loading dose of all-rac-alpha-tocopheryl acetate to erythrocyte membranes could provide an early onset antioxidative effect. We investigated short-term changes in erythrocyte alpha-tocopherol after a single oral dose of 100 mg
all-rac-alpha-tocopheryl acetate/kg in 10 vitamin E-deficient cystic fibrosis
(CF) patients. Over 24 h, erythrocyte alpha-tocopherol increased 68% to 420% of preloading concentrations. With two exceptions, peak values were achieved 12 or 24 h after administration, which was 3-18 h later than peak plasma
concentrations. Separate median-based curve estimates for the changes in
erythrocyte alpha-tocopherol for five patients with and five without associated
cholestatic liver disease were obtained. Cross-sectional test results revealed
significantly lower erythrocyte alpha-tocopherol for the 9- and 24-h
observations for patients with cholestatic liver disease compared with those
without. Oral all-rac-alpha-tocopheryl acetate can be rapidly incorporated into
erythrocyte membranes in vitamin E-deficient CF patients.

Prevention of vascular disease and acute pancreatitis is the goal of
hyperlipidemia treatment. The risk of coronary heart disease (CHD) increases
with increasing plasma cholesterol levels because low-density lipoprotein (LDL),
the major carrier of cholesterol in the plasma, is atherogenic. High-density
lipoprotein (HDL), especially the HDL2 subfraction, protects against CHD.
Hypertriglyceridemia, although not an independent risk factor for CHD, is
generally accompanied by low HDL cholesterol (HDLch), which may predispose to CHD. Reducing plasma LDL and raising HDL levels are thus goals in preventing CHD. Serum LDL levels may be lowered by reducing saturated fat and cholesterol intake; weight loss may decrease LDL but is more effective in lowering plasma triglycerides and raising HDLch. The percent of total calories from polyunsaturated, monounsaturated, and saturated fats should be less than 10%, up to 10-15%, and less than 10%, respectively. High cholesterol intake increases the flux of cholesterol, which may be harmful to arterial walls, but beyond a certain point does not increase plasma cholesterol levels. Some diets change the composition rather than the level of LDL and apoproteins. Weight reduction and maintenance are the most effective dietary measures to lower plasma triglycerides; omega-3 fatty acids (fish oils) have shown promise in reducing triglyceride but not cholesterol levels. Substitution of starch for sugar
lowered triglyceride levels toward normal in hypertriglyceridemia patients.
Fasting triglyceride levels rise in all individuals fed high-carbohydrate diets,
but the high levels persist in hypertriglyceridemia patients. Weight loss,
cessation of cigarette smoking, increased physical activity, good control of
diabetes, and moderate alcohol use all raise HDLch levels. Vitamin E deficiency
causes neurological sequelae in children with severe malabsorption problems due to abetalipoproteinemia or cholestatic liver disease.

The vitamin E status of 146 adults with chronic liver disease was assessed by
estimating both their serum vitamin E concentration and the ratio of serum
vitamin E to serum cholesterol concentration. Low levels of vitamin E occurred
most frequently in patients with primary biliary cirrhosis and other forms of
chronic cholestatic liver disease. When a serum vitamin E concentration of 12.3
mumol/l (mean-2 SD of a control population) was taken as the lower limit of
normal, 44% of patients with primary biliary cirrhosis and 32% with other
chronic cholestatic liver disease had a reduced concentration, indicating a
biochemical deficiency of vitamin E. If a vitamin E/total cholesterol ratio of
2.35 mumol/mmol was taken as the lower limit of normal, then 64% and 43% of
patients with primary biliary cirrhosis and other chronic cholestatic liver
disease, respectively, had a biochemical deficiency of vitamin E. Of the
patients with chronic cholestasis and a serum bilirubin concentration greater
than 100 mumol/l, 91% had a reduced vitamin E/cholesterol ratio. Twelve patients with primary biliary cirrhosis and severe vitamin E deficiency (serum vitamin E less than 5.0 mumol/l and a vitamin E/cholesterol ratio less than 1.0
mumol/mmol) underwent extensive neurological investigation. Five had a mild
mixed sensorimotor peripheral neuropathy, which was not, however, typical of the neurological syndrome associated with vitamin E deficiency. In patients with
severe biochemical deficiency of vitamin E (less than 5 mumol/l and less than 1
mumol/mmol total cholesterol), administration of large oral doses of vitamin E
only increased serum concentrations to within the normal range in one patient;
in the others even weekly parenteral administration over a 3-month period did
not correct deficiency. In patients with less severe biochemical deficiency, the
serum vitamin E concentration and vitamin E/total cholesterol ratio were
restored to normal by oral or intramuscular supplements of the vitamin.

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.