Keywords

Introduction

Even 100 years after its discovery as an essential nutrient in rodents, research on vitamin E is still ongoing and many questions remain unanswered. Beyond the function as a lipophilic antioxidant, non-antioxidative mechanisms of vitamin E were observed, such as the modulation of signal transduction in cells and the modulation of gene transcription as well as inflammatory processes [1]. Structurally, vitamin E describes a group of fat-soluble compounds. Each of these molecules is composed of a chromanol ring and a phytyl-like side chain. The saturation of the side chain determines whether it is a tocopherol (TOH, saturated) or tocotrienol (T3, unsaturated). Depending on the methylation pattern of the chromanol ring, α-, β-, γ- or δ-derivatives are classified (α-form: C-5, C-7, C-8; β-form: C-5, C-8; γ-form: C-7, C-8; δ-form: C-8) [2]. These eight vitamin E congeners differ in their biological availability and antioxidant capacity; in terms of the abundance in human serum and efficacy, the most important member is α-TOH. Efficiency is defined by the following features: (i) most effective treatment of ataxia with vitamin E deficiency (AVED) disease [3], (ii) antioxidant capacity (prevention of oxidative hemolysis of erythrocytes in vitro) [4], and (iii) the ‘rat gestation-resorption test’ to examine the biological activity [1]. In addition, vitamin E-like structures such as tocomonoenol (T1) and marine-derived tocopherols (MDT) are often considered as members of the vitamin E family [5]. Figure 9.1 illustrates the structural differences of the side chain between the various vitamin E forms.

Fig. 9.1
The structures of the congeners of vitamin E. The congeners are tocopherol, tocomonoenol, tocotrienol, and M D T. The difference in structure is caused by the position of double bonds. The R 1 R 2 groups in alpha, beta, gamma, and delta are C H 3 C H 3, C H 3 H, H C H 3, and H H respectively.

Structural differences of the vitamin E side chain in different vitamin E congeners. Abbreviation: MDT marine-derived tocopherol

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The dietary sources of vitamin E are predominantly plants, more precisely vegetable oils (e.g., wheat germ, sunflower and olive) and nuts. In contrast, vegetables, fruits, dairy products, fish and meat are less efficient sources of vitamin E [6]. Table 9.1 shows the daily adequate intake (AI) and the upper intake level (UL) of α-TOH equivalents defined by the European Food Safety Authority (EFSA) in 2015 [7, 8]. However, it should be noted that vitamin E in amounts of the current ULs, has anti-coagulant and anti-platelet effects that may be responsible not only for ischemic events but also for bleeding complications. This is explained by the inhibition of the activation of vitamin K-dependent coagulation factors and platelet aggregation by vitamin E. Patients with the above-mentioned risk should refrain from supplementation with high doses of vitamin E [7, 9, 10].

Table 9.1 AI and UL for α-TOH equivalents defined by EFSA
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In a recent review, the controversial situation on the safety of the supplementation of vitamin E in human studies was discussed [11]. The different inclusion criteria and statistical analyses within the considered meta-analyses, leading to heterogeneity and misleading conclusions, have been criticized. Nevertheless, these meta-analyses are the basis for the risk classification of vitamin E supplementation. In addition, it is imperative to note whether vitamin E was administered alone or in combination with other nutrients [11]. In addition to the values for vitamin E intake published by the EFSA and the discussion about safety, it is striking that different European countries recommend different reference values for vitamin E. The proposed maximum daily doses are 30 mg/day in Germany [12], 39 mg/day in Belgium [13], 150 mg/day in France [14], 213 mg/day in Denmark [15], and 300 mg/day in Ireland [16]. The discrepancies are serious and show that an overall assessment of the safety of vitamin E and a critical re-evaluation of the available studies in the European area are imperative and urgently needed.

Metabolism of Vitamin E

Vitamin E follows the same uptake and metabolic pathways as other lipophilic molecules and is mainly absorbed in the proximal duodenum and transported to the liver via triglyceride-rich chylomicrons [18]. In contrast to other fat-soluble vitamins, no potentially toxic accumulation of vitamin E occurs in the liver, as increased vitamin E uptake results in intensified catabolism and in turn in increased excretion via urine and feces [2, 19, 20].

Due to its lipophilic structure, α-TOH is preferentially incorporated in the liver into very-low density lipoprotein (VLDL) and high-density lipoprotein (HDL) via the hepatic α-tocopherol transfer protein (α-TTP) and is systemically available to the body [21, 22]. All tocopherols and tocotrienols can be catabolized in the liver. For tocopherols, this is illustrated in Fig. 9.2. The metabolism for tocotrienols proceeds via the same steps, the side chain must be saturated in additional steps. However, the proportion of degraded and excreted non-α-TOH forms is higher than that of α-TOH [23].

Fig. 9.2
A flowchart of the tocopherol metabolism. T O H, the precursor molecule in the endoplasmic reticulum undergoes omega hydroxylation to form 13 O H in the peroxisome. Beta oxidations form 9 C O O H in the mitochondrion and finally produce C E H C or 3 C O O H molecules.

Hepatic metabolism of tocopherols. Abbreviations: CEHC (2′-carboxyethyl)-6-hydroxychroman, COOH carboxychromanol, ICM intermediate-chain metabolite, LCM long-chain metabolite, OH hydroxychromanol, SCM short-chain metabolite, TOH tocopherol

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The initial step of the catabolism of vitamin E is the formation of the alcohol derivative 13′-hydroxychromanol (13′-OH) [23]. This long-chain metabolite (LCM) is formed by CYP-dependent ω-hydroxylation and subsequent cleavage of the phytyl side chain in the endoplasmic reticulum (ER) [24, 25].

In 2012, Bardowell et al. [26] provided evidence that the cytochrome P450 (CYP) 4F2 is the major vitamin E ω-hydroxylase in the liver. These researchers showed in mice that a knockout of CYP4F14, the murine orthologue of CYP4F2, leads to a highly reduced excretion of vitamin E metabolites in urine and feces. Furthermore, an increased accumulation of γ-TOH and δ-TOH in tissues could be observed. It is therefore assumed that the oxidative metabolism initiated by CYP4F2 is responsible for the formation of 70–80% of the vitamin E metabolites in the body.

However, the knockout of CYP4F14 does not lead to the complete absence of the metabolites, which indicates the involvement of other enzymes in the catabolism of vitamin E; CYP3A4 is a proposed candidate [26]. In the following, ω-oxidation occurs by alcohol and aldehyde dehydrogenases in the peroxisome, resulting in the formation of the acid derivative 13′-hydroxycarboxychromanol (13′-COOH). Three steps of β-oxidation lead to the formation of intermediate-chain metabolites (ICMs) through the elimination of propionyl-CoA and acetyl-CoA. Another two rounds of β-oxidation follow in the mitochondria, leading to a stepwise shortening of the side chain and thus to the formation of shorter ICMs, and subsequently the terminal short-chain metabolites (SCMs) 3′-carboxychromanol (3′-COOH), also known as (2′-carboxyethyl)-6-hydroxychroman (CEHCs) [23, 27]. After conjugation via hepatic proteins such as sulfotransferases (SULT) and glutathione S-transferases (GST) in particular CEHC can be excreted in urine and feces [28]. The metabolites and modified metabolites are probably also excreted via bile. It is not known whether the metabolites enter the enterohepatic circulation [29]. How exactly the transition from the ER to and into the peroxisome as well as to and into the mitochondria takes place has not been conclusively clarified. So far, the expected CoA-bound intermediates have not been described. During the metabolism of tocotrienols, the double bonds in the side chain remain until β-oxidation. This suggests the involvement of other enzymes, such as the auxiliary enzymes 2,3-dienoyl-CoA reductase and 3,2-enoyl-CoA isomerase, which are known to be involved in the degradation of unsaturated fatty acids [27].

There may be individual differences in the absorption and metabolism of vitamin E. Genetic factors, such as single nucleotide polymorphisms (SNPs) in genes encoding proteins for intestinal vitamin E absorption, may influence their efficiency [30]. Furthermore, genetic diseases that lead to impaired fat absorption can also affect the uptake of vitamin E; here, cystic fibrosis and abetalipoproteinemia are particularly relevant. The latter is caused by mutations in the microsomal triglyceride transfer protein (MTP), which is important for the formation of chylomicrons in the intestine and VLDL in the liver and is also involved in the intracellular metabolism of vitamin E in the intestine and liver [31]. Polymorphisms in MTP diminishing its function are expected to also affect the efficiency of vitamin E uptake [30]. Other individual factors also affect vitamin E uptake and thus the amount of vitamin E metabolites formed. Above all, gender, age and metabolic diseases are to be named. In an analysis of the Berlin Aging Study II, Weber et al. [32] observed a positive association between α- and γ-TOH plasma levels and age. This remained after adjustment for total plasma cholesterol. Different sex hormones also have an impact on vitamin E status. Serum androgen concentrations are negatively associated with serum vitamin E concentrations in men, while a positive association between serum estrogen concentrations and serum vitamin E concentrations has been found in women. Since the effect of sex hormones is more pronounced in younger individuals due to higher serum concentrations, the adverse effect of androgens and the enhancing effect of estrogens are stronger in younger men and women, respectively [33].

As outlined above, the catabolism of vitamin E comprises numerous steps. Of particular importance is the initial hydroxylation of the side chain by CYP3A4 and CYP4F2. SNPs have been identified that affect the activity of these enzymes. Patients with a common CYP4F2 variant (rs2108622), showed lower plasma α-TOH concentrations in the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) and Treatment of Nonalcoholic Fatty Liver Disease in Children (TONIC) studies [34]. Furthermore, the rs2108622-variant is associated with reduced metabolism of all tocopherols in vitro [35]. Mutations in the gene that encodes for the antioxidative protein haptoglobin (Hp) can also influence the function of vitamin E. Due to a dysfunctional polymorphism in the allele of Hp, affected individuals have particularly higher levels of oxidative stress [36]. There are two alleles at the Hp locus, namely 1 and 2, defined by the presence or absence of an intragenic duplication. As a result of the duplication, the biophysical properties of the Hp1 and Hp2 protein variants differ significantly. In particular, the Hp2 protein provides less antioxidant protection against hemoglobin compared to the Hp1 protein. The Hp2-2 genotype is with a prevalence of 36% in Caucasians [36]. Currently, there is only few data published that examined the relationship between Hp genotype and vitamin E. However, it has been suggested that patients with the Hp2-2 genotype benefit more from vitamin E supplementation, as they show less antioxidative benefit from Hp. There is a strong need for further studies to unravel the underlying mechanisms.

Diseases with Vitamin E Relevance

Even though there is still no common consensus for a maximum daily dose for supplementation, vitamin E is indicated to play an important role in various diseases (Fig. 9.3). In this section, a closer look at the relevance of vitamin E and its derivatives and metabolites for the prevention, progression and therapy of selected diseases is taken. The terminology of vitamin E or α-TOH used in the following sections relates to the respective references.

Fig. 9.3
A schematic of the role of vitamin E in different diseases. Alpha T O H is the only form that cures A V E D disease. Alpha T O H reduces the formation and progression of N A F L D and N A S H. Alpha T O H supplementation is not recommended for C V D prevention. Alpha T O H supports skin health.

Vitamin E and its role in AVED, CVD, NAFLD and atopic diseases (based on human studies). Abbreviations: α-TOH α-tocopherol, AVED ataxia with vitamin E deficiency, CVD cardiovascular diseases, NAFLD non-alcoholic fatty liver disease, NASH non-alcoholic steatohepatitis

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Ataxia with Vitamin E Deficiency

Ataxia with vitamin E deficiency (AVED, MIM #277460) is caused by rare autosomal recessive mutations of the gene encoding α-TTP (TTPA). There are more than 20 TTPA mutations known, which lead to different degrees of severity of AVED [22]. Two mutation variants occur frequently: (i) the variant p.His101Gln, which is associated with a late onset of the disease (> 30 years) and a rather mild disease course, and (ii) the variant c.744delA, which is associated with an early onset and a more severe disease course. Patients with the variant c.744delA also have an increased risk of cardiomyopathy [37]. Most often, the disease manifests in childhood and adolescence and is diagnosed from an extremely low plasma concentration of α-TOH as well as a severe intestinal fat malabsorption and abetalipoproteinemia [38]. If untreated, this severe deficiency brings considerable neurological complications to patients, such as gait ataxia, dysarthria and a progressive clumsiness resulting from prompt loss of proprioception [37, 39].

Case reports on AVED have been known and documented since the 1980s [40, 41]. Patients suffering from AVED are treated with a high dosage of α-TOH (mostly 800 mg/day), so that normal plasma α-TOH concentrations are achieved. Kohlschütter et al. [42] described the long-term therapy (36 years) of an AVED patient. With a total dosage of 1.8 g oral α-TOH acetate per day obtained in three doses, plasma α-TOH concentrations were consistently maintained in a supernormal range of 20–40 mg/L. The patient had still no clinically apparent progression of the neurodegenerative process with this vitamin E therapy, but none of the neurological deficits improved [42]. In addition to the numerous case reports, an intervention study with 24 subjects has been published [3]. Only subjects with cerebellar ataxia, a serum vitamin E (α-TOH) concentration of less than 2 mg/L, and the presence of the c.744delA mutation in the TTPA gene were included. The study participants were treated with 800 mg RRR-α-TOH or DL-α-TOH daily in two separate doses, which resulted in normal plasma vitamin E status (7.14 ± 6.46 mg/L after 12 months) in almost all patients as well as a decreased Ataxia Rating Scale for cerebellar ataxia assessment [3].

Severe malnutrition or vitamin E-deficient diets for months lead to symptoms like AVED even in the absence of mutations in the TTPA gene. For example, patients with chronic diseases that impede the absorption of fat-soluble vitamins in the distal ileum may be affected. In this case, a low-dose therapy with vitamin E is sufficient and the symptoms are completely reversible [37].

Cardiovascular Diseases

The relationship between vitamin E and CVD has been extensively studied and analyzed [43,44,45,46]. Nevertheless, there is still interest in elucidating the effects of vitamin E on CVD. The reasons for this are obvious: first, CVD is still a leading cause of death worldwide. In European countries, almost four million people die from CVD each year; and the incidence continues to increase. It is currently estimated that more than 23.6 million deaths will be attributed to CVD worldwide by 2030 [44]. The group of CVD diseases includes disorders of the heart and blood vessels, such as myocardial infarction (MI), heart failure or atherosclerosis [47]. Second, the results of studies on vitamin E and CVD are ambiguous, making the evaluation of the effect of vitamin E challenging and multifaceted. Data from in vitro, ex vivo and in vivo studies indicate that vitamin E—or more precisely α-TOH—has protective and anti-atherogenic effects. Several reviews summarize these effects conscientiously and comprehensively [44, 45].

Despite the promising results of preclinical studies, randomized controlled trials (RCTs) in humans are inconclusive. This circumstance has been investigated in numerous meta-analyses, which led to different conclusions. Bjelakovic et al. [48] included 46 RCTs (171,224 patients) and found that the intake of vitamin E alone or in combination with other antioxidants significantly increased mortality; whereas Loffredo et al. [49] drew other conclusions: (i) Vitamin E administered alone reduces the incidence of MI, and (ii) vitamin E is ineffective in combination with other antioxidants. This meta-analysis included 16 RCTs involving 140,491 patients [49]. The most recent meta-analysis from 2021 included 18 RCTs (148,016 patients) and concluded that vitamin E can provide some benefits for the prevention of ischemic disease ([50], reviewed in [51]). Furthermore, Violi et al. [50] accomplished that the interventional studies with vitamin E should not be considered negative but inconclusive. Further studies with more appropriate design need to be conducted to evaluate the efficacy of vitamin E supplementation in patients with or at increased risk of CVD [50]. Several observational studies support the potential of vitamin E to reduce the risk of CVD (reviewed in [52]). However, the data situation is so controversial that according to the current state of research, the administration of vitamin E for the prevention or treatment of CVD is not recommended.

Levy et al. [53] discovered that the genotype Hp2-2 is relevant for the cardioprotective effects of vitamin E. This finding is a possible explanation for the observed inconclusive results. In their study, high-dose vitamin E supplementation decreased the risk of cardiovascular events in patients with type 2 diabetic mellitus (T2DM) holding the Hp2-2 genotype. Therefore, a recent trial in diabetic patients from Singapore could not confirm these results; here, the Hp genotype had no relevance in patients with T2DM [54]. However, this hypothesis was proven in a selected cohort analysis of the Heart Outcome Prevention Evaluation (HOPE), Women’s Health Study (WHS), and Israel Cardiovascular Vitamin E (ICARE) studies [55]. In all three studies, fewer cardiovascular events (i.e., stroke, MI and cardiovascular deaths) were observed in diabetic subjects with an Hp2-2 genotype after vitamin E intervention than in diabetic patients with Hp1-1 or Hp2-1 genotype.

Non-alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of liver diseases that range from isolated fatty deposits in the liver (NAFL) to inflammatory steatohepatitis (NASH) to connective tissue proliferation and loss of function of the liver, namely cirrhosis [56]. The disease development is strongly linked with the metabolic syndrome such as T2DM and dyslipidemias [57]. NAFLD is associated with an increased risk of hepatocellular carcinoma and other cancers, as well as increased overall mortality [58]. It is estimated that the prevalence of NAFLD will increase to 48.7% in Europe and 45.4% in North America by 2025 [59]. The multifactorial pathogenesis is not yet fully understood. As described in Rinella et al. [60], insulin resistance is a central factor in the development of NAFLD. The resulting impaired regulation of lipolysis and triglyceride storage leads to increased formation of free fatty acids. Further, the interaction of free fatty acids and dietary sugars promote the formation of intrahepatic fat via de novo lipogenesis. Fat accumulates in the liver mainly as triglycerides which in turn leads to the formation of lipid droplets and the clinical pattern of lipotoxicity-caused liver steatosis. Consequently, oxidative stress, stress in the endoplasmic reticulum and activation of the inflammasome lead to a cycle of inflammation and hepatocyte damage, which result in the development of NASH, liver cirrhosis and hepatocellular carcinoma [60].

Currently, there is no approved drug for the treatment of NAFLD. Recommended interventions are weight loss and lifestyles changes including a balanced diet. However, anti-diabetic therapies have shown improvements of NASH [61]. Another promising treatment strategy is the use of high doses of vitamin E. Patients with NAFLD suffer from increased oxidative stress, which suggests that antioxidants are increasingly depleted. Indeed, in patients with NAFLD, α-TOH plasma concentrations are reduced. Presumably also due to an accumulation in hepatic lipid droplets [62]. Consequently, vitamin E needs to be restored to counterbalance oxidative processes. In RCTs, supplementation of high doses of vitamin E of 800 IU daily has been shown to reduce oxidative stress in NAFLD. The PIVENS study, published in 2010, is the largest RCT investigating the role of vitamin E in NASH, including 247 non-diabetic patients. Treatment with 800 IU of vitamin E daily for 96 weeks significantly improved histological characteristics of NASH compared to placebo and the insulin sensitizer pioglitazone (30 mg/day). However, the level of fibrosis did not improve [63]. Similar results were shown in a study of 86 subjects with T2DM. Again, 800 IU vitamin E per day improved NAFLD histologically but showed no effects on fibrosis [64]. A multi-year study including 236 T2DM and non-diabetic patients with NASH showed that the daily intake of 800 IU vitamin E increased transplant-free survival and reduced hepatic decompensation [65].

The most recent guidelines of the European Association for the Study of the Liver (EASL) recommend vitamin E treatment for selected patients with NASH and markers of fibrosis, while the American Association for the Study of Liver Diseases (AASLD) states that vitamin E (800 IU/day) “may be considered” for the treatment of non-diabetic patients with NASH [60]. Most importantly, due to the lack of reliable studies, vitamin E is currently not recommended for the treatment of NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis and cryptogenic cirrhosis [57, 60]. One reason for these cautious recommendations could be the side effects of high-dose vitamin E treatment. These include increased risk of bleeding, prostate cancer, heart failure and hemorrhagic stroke [66, 67]. However, the PIVENS study found no significant differences in adverse events between the vitamin E and the pioglitazone or the placebo groups [60, 63, 68].

Several studies show that vitamin E supplementation is not effective in all NAFLD patients [63, 64, 69]. In the PIVENS study, for example, an improvement in histological parameters through vitamin E supplementation could only be shown in 50% of the patients. This could again be due to the individual metabolism of vitamin E (Hp2-2, SNPs, etc.; see Sect. 9.2). Further broad-scale studies are therefore needed, as there is currently a huge heterogeneity in the study results. Genotypic studies should also be considered to ensure that patients who benefit from vitamin E treatment are included.

We would like to point out that the terminology of liver diseases has recently changed by an international group of experts. This results in the following change in nomenclature: “metabolic dysfunction associated fatty liver disease” (MAFLD) instead of NAFLD and “metabolic dysfunction associated steatohepatitis” (MASH) instead of NASH [70,71,72]. However, adapting the terminology does not change the characteristics of the disease. In addition, the former terminology appears to be more familiar to the reader and makes it easier to classify existing literature. Therefore, we use the terminology NAFLD and NASH here.

Skin Health and Atopic Diseases

The skin is the largest organ in the human body and acts as a protective barrier against the outside world. The human skin is composed of three distinct layers: epidermis, dermis and hypodermis [73]. Each layer has a unique specialization: due to its keratinization, the epidermis serves as the actual protective barrier, while its basal layer is constantly renewed. The lipid content and the numerous structural proteins ensure firmness of the epidermis and adhesion to the dermis, respectively, and comprise a mechanical barrier against pathogens. The dermis provides mechanical strength to the skin and the hypodermis consists primarily of loose connective tissue with embedded adipose tissue that insulate and protect the skin [73].

Vitamin E, more precisely α-TOH, is the most prominent antioxidant in human skin [74]. The primary role of α-TOH in the skin is the maintenance of the membrane integrity [75], which is constantly challenged by endogenous or exogenous stressors such as ultraviolet (UV) radiation, drugs and xenobiotics, air pollutants and endogenous generation of reactive oxygen species (ROS) and other free radicals produced during physiological cellular metabolism [76]. Vitamin E (tocopherols) dampens oxidative processes by forming a tocopheryl radical, which consequently needs to be recycled by vitamin C and glutathione to be constantly available as an antioxidant [77].

In the stratum corneum, the vitamin E recycling process is inefficient since vitamin E is the only antioxidant present in this outer layer of the epidermis. Consequently, oxidative challenges deplete α-TOH in stratum corneum without replacement [78]. Topical application of natural and synthesized forms of vitamin E protects against UVA and UVB light exposure [76]. Next to reported advantages of vitamin E against oxidative damage, a few cases of allergic contact dermatitis were observed since the 1960 [79, 80]. The stability of vitamin E applied as cosmeceutical is still under discussion [81]. Synthetic forms of vitamin E and degraded forms of vitamin E, such as α‐tocopheryl quinine and tocopheryl acetate, are more pronounced to cause allergic contact dermatitis rather than natural forms of vitamin E. Furthermore, the amount of vitamin E used in the cosmetic products is crucial [82, 83]. Despite this discussion, current concern is only for topical, rather than oral, vitamin E, and the incidence of vitamin E-associated allergic contact dermatitis is low [84]. Therefore, topical application of vitamin E is considered to be safe [76]. In addition, orally administered vitamin E seems to be a useful agent for the therapy of acute (wound healing [85] etc.) and chronic (epidermolysis bullosa [85,86,87], acne vulgaris [88, 89] etc.) skin diseases, and is discussed for some rare diseases with symptoms such as the yellow nail syndrome [90,91,92,93,94], or Hailey-Hailey disease [95].

Wound Healing

During healing of severe wounds, systemic concentrations of free radical scavengers, such as vitamin E, drop, likely due to the increased oxidative stress. In the process of healing these free radical scavengers recover [96]. Recent work demonstrated promising antioxidant activity, collagen synthesis, and wound closure properties of vitamin E encapsulated in different forms of nanoparticles, nanoemulsions and wound dressings etc. in vitro [97,98,99,100,101] and in rodents [102,103,104]. Studies in diabetic mice showed that orally applied γ-TOH (35 mg/kg body weight daily) for 2 weeks supports early cutaneous wound healing by the regulation of inflammation, apoptosis and the antioxidant defense system [102]. The combination of selenium nanoparticles with vitamin E revealed improved wound healing in rats after 2 weeks of topical application [103], and copper-doped borate bioactive glass/poly(lactic-co-glycolic acid) coating loaded with 3% vitamin E stimulated angiogenesis and significantly improved wound closure in rats [104]. In diabetic patients delayed wound healing due to elevated oxidative stress level is a severe complication [105]. In line with this, diabetic patients with foot ulcer show significantly lower concentrations of circulating vitamin E [106], and wound healing under diabetic conditions can be improved by vitamin E applied topically [107] and orally [108] in rodents as well as in patients with diabetic foot ulcer in which co-supplementation of vitamin E (400 IU/d) and magnesium (250 mg/d) for 12 weeks reduced ulcer length and depth [109]. Despite the promising effects of vitamin E on wound healing observed in in vitro studies, preclinical studies, and pilot studies in humans, there is a significant lack of robust studies justifying vitamin E as a first-line treatment strategy for wound healing [110]. Recent research focusses on LCMs of vitamin E, which are reported as highly potent anti-inflammatory molecules [111,112,113]. Therefore, an impact of the LCMs in skin health and wound healing can be assumed. Indeed, application of the LCM α-13′-COOH attenuated T-helper cell (Th) 2-response in a three-dimensional human skin model of atopic dermatitis [114] and improved wound healing in diabetic mice [115]. Thus, α-13′-COOH is a promising natural compound for the treatment of inflammatory skin diseases and wound healing [114].

Atopic Dermatitis

Worldwide, about 20% of children and about 10% of adults are affected by atopic dermatitis, which accounts for the most common chronic inflammatory skin disease [116]. The disease is characterized by a defective skin barrier. Consequently, allergens and bacteria penetrate to the bloodstream and cause or enhance inflammation, and thus weaken the immune system [117]. Depending on the severity of the disease, patients suffer from itching, dry skin, burning and skin tension. The current gold-standard in the therapy of atopic dermatitis are fast-acting anti-inflammatory drugs such as glucocorticoids. Since these agents also weaken the immune system if used over a long time [118], alternative treatment methods are needed. As an inflammatory disease, an excessive use of antioxidants occurs in atopic dermatitis. Consequently, plasma concentrations of vitamin E were found to be decreased in dogs [119] and humans suffering from atopic dermatitis [120] and correlate with diseases severity [120]. Interestingly, vitamin E concentrations in skin are higher in atopic dermatitis in canine [119] and humans [121] than in healthy controls. α-TOH is present in the sebum in high concentrations, assuming the sebaceous gland secretion route as possible delivery pathway of α-TOH in human skin [122]. This is most likely to offset the increased oxidative stress seen in atopic dermatitis skin. The antioxidant vitamin E has additional anti-inflammatory properties [120]. Thus, vitamin E is gaining attention as a potential adjuvant therapy. In dogs, the daily oral application of 8.1 IU vitamin E/kg body weight for 8 weeks decreased the extent and severity of atopic dermatitis [123]. Both, oral supplementation of natural vitamin E (400 IU/day) for eight months [124] and synthetic all-rac-α-TOH (600 IU) for 60 days [125] lead to remission of the disease in affected individuals. Combined therapy of oral supplementation of vitamin E with topical application of vitamin E may improve symptoms of atopic dermatitis and other skin diseases even more. This combined approach has to be tested in respective trials.

However, the promising effects of vitamin E application are based on case reports and randomized trials with small numbers of participants. Therefore, large scaled controlled clinical studies are needed to confirm the promising therapeutic effects of vitamin E therapy in skin diseases [85].

Conclusions and Outlook

100 years of vitamin E research have revealed a wide spectrum of effects of this vitamin. Vitamin E plays an important role in the prevention and therapy of various diseases, but often the study outcomes from human trials are insufficient to clearly recommend its supplementation. In addition, a revised and standardized risk assessment and intake recommendation for vitamin E is urgently needed. Recently, a discussion to change the nomenclature has also been initiated in the field of vitamin E research. Thus, α-TOH is the only effective form of vitamin E in the treatment of AVED, α-TOH only is proposed as ‘the vitamin E’ [126]. Furthermore, the detection of LCMs in human serum has provided the first indications of their possible role as systemic signaling molecules. Consideration of LCMs in vitamin E research could contribute to a better understanding of the complex mode of action of vitamin E [127].