Innovative study on vitamin E absorption

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A fresh look at how to best determine dietary guidelines for vitamin E has produced a surprising new finding: Though the vitamin is fat soluble, you don’t have to consume fat along with it for the body to absorb it.

“I think that’s remarkable,” said the study’s corresponding author, Maret Traber of Oregon State University, a leading authority on vitamin E who’s been researching the micronutrient for three decades.

“We used to think you had to eat vitamin E and fat simultaneously. What our study shows is that you can wait 12 hours without eating anything, then eat a fat-containing meal and vitamin E gets absorbed.”

The study was published today in The American Journal of Clinical Nutrition.

Vitamin E, known scientifically as alpha-tocopherol, has many biologic roles, one of which is to serve as an antioxidant, said Traber, a professor in the OSU College of Public Health and Human Sciences, and Ava Helen Pauling Professor at Oregon State’s Linus Pauling Institute.

Federal dietary guidelines call for 15 milligrams of vitamin E daily (by comparison, 65-90 milligrams of vitamin C are recommended). The new research could play a role in future vitamin E guidelines.

Vitamin E in human diets is most often provided by oils, such as olive oil. Many of the highest levels are in foods not routinely considered dietary staples, such as almonds, sunflower seeds and avocados.

“There’s increasingly clear evidence that vitamin E is associated with brain protection, and now we’re starting to better understand some of the underlying mechanisms,” Traber said.

In this latest study, Traber and collaborators used a novel technique involving deuterium-labeled vitamin E, administered both orally and intravenously, to study fractional vitamin E absorption in a group of non-obese, non-diabetic women ages 18-40 with normal blood pressure.

Fractional absorption means just what you would think—the fraction of the dose absorbed by the body rather than metabolized and excreted. Fractional absorption dictates how much of something, in this case vitamin E, a person needs to take to maintain the correct level in his or her body.

Deuterium, the vitamin E marker in this study, is an isotope of hydrogen with double the atomic mass of the regular version; deuterium has both a proton and a neutron, compared to just a proton for normal hydrogen, and is a common tracer in investigations of biochemical reactions.

Study subjects at the National Institutes of Health Clinical Center were given both oral and IV vitamin E and drank a liquid meal containing either 40% fat or no fat. Researchers then used a combination of tightly controlled dietary intakes to determine the roles fat and fasting played in vitamin E absorption.

“What this study says is, vitamin E gets taken up into the intestinal cell and sits there and waits for the next meal to come along,” Traber said. “It’s in a fat droplet, sitting there, waiting to be picked up, like a cargo container, and loaded onto a chylomicron truck.”

Chylomicrons are lipoprotein particles that transport dietary lipids—fats—around the body through the blood plasma.

The IV portion of the study, used in conjunction with the oral dosing to calculate fractional absorption, also yielded remarkable findings, Traber said.

“We injected the vitamin E in a lipid emulsion and expected it would take some time to disappear from the plasma and them come slowly back into circulation, but it was gone within 10 minutes,” Traber said. “High-density lipoproteins quickly acquired the vitamin E, and the chylomicrons quickly disappeared from circulation into the liver.

“The IV vitamin E we put into the body over three days, almost none of it came out again, like 2% of the dose,” she added. “No one had ever seen that before—normally you absorb about half of what you consume. That vitamin E that’s staying in the body, we don’t know where it goes, and finding that out is important for studying how much vitamin E you need to eat every day.”

Vitamin E is a group of eight compounds – four tocopherols and four tocotrienols, distinguished by their chemical structure.

Alpha-tocopherol is what vitamin E commonly refers to and is found in supplements and the European diet; gamma-tocopherol is the type of vitamin E most commonly found in the American diet.

“Plants make eight different forms of vitamin E and you absorb them all, but the liver only puts alpha-tocopherol back into the bloodstream,” Traber said.

“All of the other forms are metabolized and excreted.

That tells us the body is working very hard to get all the nutrients it can and will sort out what the toxins are later. That’s really exciting, because it explains why the liver needs an alpha-tocopherol transfer protein but the intestine does not.”


The term “Vitamin E” (VE) refers to a set of lipid-soluble compounds that includes both tocopherols and tocotrienols. Tocopherols represent the best part of VE consumed around the world, with γ-tocopherol being the most consumed by Americans [1], and α-tocopherol being the most represented in European diets [2].

In mammals, VE plays an important role as an antioxidant due to its capacity to bind free radicals.

Mechanistically, this takes place if the hydroxyl group of the chromanol ring is not esterified, for example to a phosphoric acid, or is hidden by protein binding. In addition, tocopherols have a lipophilic tail that is able to interact with cellular lipids and other molecules, including DNA, protecting them from oxidation or peroxidation damage.

In addition, severe α-tocopherol deficiency causes important neuronal disorders, such as ataxia, and oxidative-based disorders, such as cardiovascular disease, cancer, or cataracts [3].

In fact, European food products that are considered important sources of VE are able to bear the claim “Vitamin E contributes to the protection of cell constituents from oxidative damage”, as this role has been recognized by the European Food Safety Authority (EFSA) [4].

However, VE benefits to health go beyond its lipophilic antioxidant potential in cellular structures.

Different forms of VE and its derivatives may act as modulators of enzymes mainly involved in signal transduction, affect gene expression (e.g., redox-regulated), have immunomodulatory properties, and play a relevant role in degenerative diseases [5].

Recently, several reviews have addressed a number of new potential roles of VE, which is still not totally understood or characterized [5,6,7,8,9,10,11].

Furthermore, some studies have outlined the relevance that VE and derivatives may have in obesity, cardiovascular disease (CAD), and metabolic-related diseases.

Critical pathways involved in metabolic syndrome are under the influence of VE, and evidence suggests that in specific cases, adequate supplementation would be an appropriate strategy to help in treatment of the prevention of obesity and its associated comorbidities [12,13].

However, dietary reference values for VE in obese populations have not yet been defined, and clinical trials show contradictory results with VE supplementation [5].

In fact, insufficient data on biomarkers and methodological uncertainties to estimate VE intake, together with inconsistent effects on health, have led to the proposal of adequate intakes (AI) of α-tocopherol, which have been based on observed intakes in a general and apparently non-VE deficient population [14].

The causes can be multiple and interconnected: serum concentrations of VE are increasing in an age-dependent manner, and are highly influenced by different blood lipids.

No good methods to control for this confounding effect have been effective. Furthermore, very heterogeneous α-tocopherol plasma levels are found in the general population (range 19.9–34.2 µmol/L); even within one country, values may range from 5 µmol/L to 35 µmol/L, and this is accompanied by a significant percentage of the population (79%) not reaching the proposed desirable concentration of 30 µmol/L, at which beneficial effects may occur [15], making it even more difficult to address the impact of VE homeostasis when suboptimal levels are the ‘standard’ situation in the population.

In addition, there is no clear evidence that obese individuals have different VE levels in plasma than healthy people, which is contrary to the association of low vitamin D levels with obese individuals [16].

In fact, obese individuals may show either low [17] or high [18] levels of plasma VE in comparison with normal weight subjects in different studies.

People with metabolic syndrome (MetS) may show half of the plasma VE found in the reference group (i.e., 12.5 µmol/L versus 25.5 µmol/L), despite a similar intake of VE (8.85 mg versus 9.33 mg of α-tocopherol [18].

Regardless of the expected benefits from VE consumption regarding CAD and even cancer, some supplementation trials did not succeed in showing them [19].

Indeed, the beneficial effects of VE have been recently revised, highlighting some important controversy regarding CAD and the mortality effects of VE supplementation [5].

A meta-analysis concluded that VE supplementation (400–800 IU) decreased the risk of suffering both non-fatal and fatal myocardial infarction, while this preventive effect did not appear using other antioxidants [20].

However, concerning stroke relative risk, supplementation with VE (50–800 IU) did not seem to affect the total stroke risk, but did increase the risk of hemorrhagic stroke by 22% [21].

In addition, the uptake of supplemented VE varies widely among individuals but, after only one year of treatment, the response seems to be homogenized [22]. Therefore, polymorphisms in the key genes dealing with the physiological management of VE, or in genes coding for proteins that execute its bioactive properties, emerge as a feasible explanation for the VE variability observed in these trials.

In fact, genetic variants associated with circulating VE levels [23], bioavailability, absorption, and metabolism [24,25,26] have been identified during the last few years [27]. Recently, a set of 28 single nucleotide proteins (SNPs), concentrated on 11 genes, has been considered a useful tool in explaining a significant part (82%) of the interindividual variability of VE bioavailability in healthy humans [26].

The emerging concept of “precision nutrition” is based on new knowledge, which is mainly derived from –omic biomarkers describing specific characteristics of individuals, and aims to define more effective, personalized nutritional guidelines [28].

This type of approach takes into account genetic variants that modulate the effective benefits of VE. Thus, specific requirements can be achieved by means of more accurate intake, adjusted to the individual’s bioavailability. However, only a few studies have carried out research on the influence of relevant genetic variants on the effects of VE and its metabolism, and so far, a holistic perspective is still missing.

Thus, the objective of this review is to gain a better understanding of the nutrigenetic influence of VE, by specifically analyzing those that could be particularly relevant in the prevention or treatment of obesity and its associated complications.

Etiology

In developed countries, it is unlikely that vitamin E deficiency occurs due to diet intake insufficiency and the more common causes are below.

  • Premature low birth weight infants with a weight less than 1500 grams (3.3 pounds)
  • Mutations in the tocopherol transfer protein causing impaired fat metabolism
  • Disrupted fat malabsorption as the small intestine requires fat to absorb vitamin E
  • Patients with cystic fibrosis patients fail to secrete pancreatic enzymes to absorb vitamins A, D, E, and K
  • Short-bowel syndrome patients may take years to develop symptoms. Surgical resection, mesenteric vascular thrombosis, and pseudo-obstruction are a few examples of this issue
  • Chronic cholestatic hepatobiliary disease leads to a decrease in bile flow and micelle formation that is needed for vitamin E absorption
  • Crohn’s disease, exocrine pancreatic insufficiency, and liver disease may all not absorb fat
  • Abetalipoproteinemia an autosomal-recessive disease causes an error in lipoprotein production and transportation
  • Isolated vitamin E deficiency syndrome an autosomal recessive disorder of chromosome arm 8q

In developing countries, the most common cause is inadequate intake of vitamin E.

Epidemiology

Serum levels of alpha-tocopherol in 0.1% of United States adults over the age of 20 have been found to be deficient. Surveys of the same data set have shown that 89.8% of men and 96.3% of women 19 years of age or older have insufficient intake of alpha-tocopherol. Some studies have shown alpha-tocopherol to be lower in pediatric populations and higher in pregnancy.[5]

Pathophysiology

Vitamin E works as an antioxidant, immunomodulation and antiplatelet effects.

Antioxidant Effect

Vitamin E prevents propagated oxidation of saturated fatty acids within membranes. Also, vitamin E may prevent oxidative changes to LDLs, reducing coronary heart diseases.

Immunomodulation

Vitamin E decreases the production of prostaglandin E2 and serum lipid peroxides while enhancing lymphocyte proliferation.

Antiplatelet Effect

Vitamin E inhibits platelet adhesion by preventing oxidative changes to LDLs and inhibition of platelet aggregation by reducing prostaglandin E2. Another effect is inhibiting protein kinase C causing smooth-muscle proliferation.

Even though research has shown that vitamin E assists with the prevention of heart disease and atherosclerosis it has not been approved for this use by the United States Food and Drug Administration (FDA).

History and Physical

Patients may present with one of the causative histories listed along with symptoms of ataxia, difficulty with upward gaze, and hyporeflexia.

Not as common symptoms include muscle weakness and visual-field constriction.

The most severe symptoms are blindness, dementia, and cardiac arrhythmias.

If vitamin E deficiency is expected, a full neurological exam is recommended as well as a standard physical exam.

Patients presenting early may show hyporeflexia, decreased night vision, loss/decreased vibratory sense, however, have normal cognition.

A more moderate stage of this deficiency may show limb and truncal ataxia, profuse muscle weakness, and limited upward gaze.

Late presentations may show cardiac arrhythmias and possible blindness with reduced cognition. Ataxia is the most common exam finding.

Patients that have abetalipoproteinemia have eye problems often including pigmented retinopathy and visual field issues. However, patients suffering from cholestatic liver disease often have personality and behavioral disorders.

Evaluation

A low alpha-tocopherol level or low ratio serum alpha-tocopherol to serum lipids measurement is the mainstay of diagnosis.

In adults, alpha-tocopherol levels should be less than 5 mcg/mL. In an adult with hyperlipidemia, the abnormal lipids may affect the vitamin E levels and a serum alpha-tocopherol to lipids level, needing to be less than 0.8 mg/g) is more accurate. A pediatric patient with abetalipoproteinemia will have serum alpha-tocopherol levels that are not detectable.

Treatment / Management

Treatment addresses the underlying cause of the deficiency (fat malabsorption, fat metabolism disorders, among others) and then provide oral vitamin E supplementation.

Also, a modification in diet can assist in the supplementation, increase intake of leafy vegetables, whole grains, nuts, seeds, vegetable oils and fortified cereals is highly recommended.

Though normally presented in our diets, adults need 15mg of vitamin E per day. A supplement of 15 to 25 mg/kg once per day or mixed tocopherols 200 IU can both be used. If a patient has issues with the small intestine and/or oral ingestion intramuscular injection is necessary.[6][7][8][9] 

The recommended daily allowance of alpha-tocopherol is as follows.

  • Age 0 to 6 months: 3 mg
  • Age 6 to 12 months: 4 mg
  • Age 1 to 3 years: 6 mg
  • Age 4 to 10 years: 7 mg
  • Adults and elderly patients: 10 mg

Differential Diagnosis

While developing a differential diagnosis, clinicians must consider other possible vitamin deficiencies as well as the following: 

  • Friedreich ataxia
  • Ataxia with vitamin E deficiency (AVED)
  • Stroke
  • Cerebral palsy
  • Paraneoplastic syndrome
  • Biliary disease
  • Short-Bowl syndrome
  • Mutations in the tocopherol transfer protein causing impaired fat metabolism 
  • Cystic fibrosis 
  • Chronic cholestatic hepatobiliary disease 
  • Crohn’s disease
  • Exocrine pancreatic insufficiency
  • Liver disease 
  • Abetalipoproteinemia
  • Isolated vitamin E deficiency

Prognosis

If left untreated, symptoms may worsen. However, once diagnosed, the outcome is very good as most symptoms will resolve quickly. However, as the deficiency becomes more pronounced, the therapy will be more restricted. Patients who are at risk for vitamin E deficiency should be tested and evaluated regularly.

Complications

Vitamin E has a few interactions with medications that are listed below:

  • Anticoagulation and antiplatelet medications: due to vitamin E inhibiting platelet aggregation and disrupting vitamin K clotting factors there is a protentional increase risk of bleeding combining these two.
  • Simvastatin and niacin: Vitamin E can reduce the amount of high-density lipoprotein (HDL) which is the opposite desired effect of taking simvastatin and/or niacin.

Consultations

Depending on the cause many consultations may be required. However, if the biliary problem is discovered a gastroenterologist should be consulted. 

Deterrence and Patient Education

Replacement recommendations vary by causing disease and are as follows:

  • Abetalipoproteinemia: 100 to 200 IU/kg per day
  • Chronic cholestasis: 15 to 25 IU/kg per day
  • Cystic fibrosis: 5 to 10 IU/kg per day
  • Short-bowel syndrome: 200 to 3600 IU per day
  • Isolated vitamin E deficiency: 800 to 3600 IU per day

Vitamin E is safe for pregnancy and breastfeeding. Both vitamin K and omega-6 fatty acids requirements may increase with high doses of vitamin E.

Enhancing Healthcare Team Outcomes

Vitamin E deficiency is not common in North America but when it occurs, healthcare workers including the nurse practitioner should work the patient up for additional mineral deficiencies.

The goal is to address the underlying cause of the deficiency (fat malabsorption, fat metabolism disorders, among others) and then provide oral vitamin E supplementation.

A dietary consult should be sought and the patient educated about the foods that contain vitamin E. The outlook for patients treated for vitamin E deficiency is good provided the patient is compliant with the dietary changes and/or supplements. (Level V)


More information: Maret G Traber et al, Vitamin E absorption and kinetics in healthy women, as modulated by food and by fat, studied using 2 deuterium-labeled α-tocopherols in a 3-phase crossover design, The American Journal of Clinical Nutrition (2019). DOI: 10.1093/ajcn/nqz172

Journal information: American Journal of Clinical Nutrition
Provided by Oregon State University

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