Snížení účinku vitamínu E

Ezetimibe

• NPC1 is the pharmacological target of ezetimibe
• Inhibitor of cholesterol endocytosis
• Widely used for treatment of this dyslipidemia [8]
• Inhibition of alpha-tocopherol absorption [8] suggests the involvement of NPC1 in dietary VE uptake
• Alpha-tocopherol is known to bind competitively with cholesterol at the N-terminal domain of NPC1
• Essential for the endocytosis of both compounds into the cell [8]

Secondary alpha-tocopherol deficiency

Obecně poruchy absorbce a metabolismu tuků všech příčin

Abetalipoproteinaemia (a digestive disorder characterized by fat malabsorption)

• Genetic defects in the microsomal TG transfer protein or in apoB (abeta- and hypobeta-lipoproteinemia)
• Results in progressive neuropathy and retinopathy in the first 2 decades of life [9]

Cholestatic liver diseases

• Chronic cholestatic hepatobiliary disease
• Including spinocerebellar ataxia with
• Loss of deep tendon reflexes,
• Truncal and limb ataxia,
• Loss of vibration and position senses,
• Ophthalmoplegia,
• Muscle weakness,
• Ptosis,
• Dysarthria [9]

Severe malnutrition

Fat malabsorption

Cystic fibrosis (Farrell et al., 1977; Jeffrey et al., 1987; Eggermont, 2006; Zamel et al., 2008)

• Plasma/serum alpha-tocopherol concentrations 2.5–12 µmol/L [2]
• Including spinocerebellar ataxia with
• Loss of deep tendon reflexes,
• Truncal and limb ataxia,
• Loss of vibration and position senses,
• Ophthalmoplegia,
• Muscle weakness,
• Ptosis,
• Dysarthria [9]

Liver disorders [6]

Disorders of fat metabolism [6]

Disorders of bile secretion [6]

Primary biliary cirrhosis [6]

Premature infants may have a low vitamin E reserve [6]

• May become deficient if fed a formula high in unsaturated fats and low in vitamin E [6]

Poor diet

• In rare cases by a [6]

Short bowel syndrome

• After decades of inadequate vitamin E absorption due to short bowel syndrome
• A 71-y-old man complained of neurologic abnormalities that were consistent with vitamin E deficiency
• And responded to vitamin E supplementation
• vitamin E is required throughout the life span [7]

Falciparum malaria

• Median: 7.33 µmol/L; range: 2.61–18.42 µmol/L found in children with falciparum malaria infections
• Compared with helathy control children median: 17.71 µmol/L; range: 6.48–28.08 µmol/L
• Both groups had similar ?-tocopherol:cholesterol ratios median (range):
• 4.61 (1.24–7.20)
• 5.15 (1.80–8.92) µmol/mmol
• Children with malaria had depressed cholesterol concentrations (mean ± SD: 1.89 ± 0.62 vs. 3.47 ± 0.59 mmol/L in controls)
• Both malnutrition and infectious diseases can lower circulating cholesterol and its lipoprotein carriers
• Correction of plasma alpha-tocopherol concentrations for lipids is not appropriate in cases in which circulating lipids are below normal concentrations [7]

TTPA knockout mice

• Resistant to cerebral malaria
• Resistance can be abrogated by supplementation with vitamin E [Herbas et al 2010a, Herbas et al 2010b]
• Confer protection against malaria [López et al 2010]
• Could explain the comparatively high prevalence of such pathogenic variants around the Mediterranean Sea [4]

TTPA pathogenic variants = mutace spojené se symptomy z deficitu

• Nearly complete penetrance in individuals who are homozygous or compound heterozygous for a TTPA pathogenic variant. [4]

Carrier (Heterozygote)

• Requires prior identification of the TTPA pathogenic variants in the family.
• Moderately lowered plasma vitamin E concentration in heterozygotes is not a sensitive enough measure to distinguish between heterozygous carriers and non-carriers. [4]

c.744delA

• Mediterranean or North African ancestry [4]
• 132 Tunisian individuals with AVED, 91.7% were homozygous for the c.744delA pathogenic variant;
• 8.3% of individuals were homozygous for other pathogenic variants
• Most individuals are homozygous or compound heterozygous for one of the known pathogenic variants. [4]
• Associated with early onset
• A severe course
• Slightly increased risk for cardiomyopathy
• Mainly observed in individuals of Mediterranean or North African descent
• Severity may vary considerably even in persons from the same family
• Onset of symptoms may vary between ages 3 and 12 years [Cavalier et al 1998, Marzouki et al 2005]. [4]

c.552+2T>A

c.205-1G>T

c.400C>T

• [El Euch-Fayache et al 2014].

p.His101Gln

• Associated with late-onset disease (age >30 years)
• A mild course,
• Increased risk for pigmentary retinopathy
• Primarily reported in individuals of Japanese descent. [4]
• TTPA pathogenic variant in 21 of 801 randomly selected inhabitants of a Japanese island [4]
• One individual had previously been diagnosed with AVED [4]
• Calculated prevalence of one homozygous individual per 1500 inhabitants [4]
• Pathogenic variant was not detected in 150 unrelated individuals from Tokyo [4]

p.Arg59Trp

• Before age ten years, homozygoté [4]

p.Arg134Ter

• Before age ten years, homozygoté [4]

p.Glu141Lys

• Before age ten years, homozygoté [4]

c.486delT

• Before age ten years, homozygoté [4]

c.513_514insTT

• Before age ten years, homozygoté [4]

c.530-531AG>GTAAGT

• Before age ten years, homozygoté [4]

p.Arg221Trp

• After age ten years [4] [Cavalier et al 1998]

p.Ala120Thr

• After age ten years [4] [Cavalier et al 1998]

TTPA - alpha-tocopherol transfer protein

• Hepatic tocopherol transfer from chylomicrons to lipoproteins (i.e., TTPA) [5]
• The lack of functional alpha-TTP results in the rapid depletion of plasma alpha-tocopherol
• Alpha-TTP is needed to maintain plasma alpha-tocopherol concentrations.

rs6472073

• Was associated with a high level of significance [5]
• P = 2.1 × 10-5

rs1031551

• Was associated with a high level of significance [5]
• P = 2.9 × 10-5 in TTPA [5]

Anticonvulsant drugs

• Phenobarbital,
• Phenytoin (Dilantin),
• Carbamazepine (Tegretol)

• Lower plasma vitamin E concentrations in individuals with epilepsy [10]

Cholestyramine and colestipol, Orlistat, sucralfate, mineral oil, and the fat substitute, olestra

• Interfere with fat absorption
• May theoretically decrease the absorption of fat-soluble vitamins, including vitamin E [10]

Obezita

• VE is highly hydrophobic, and cannot adequately access inside cells to carry out its functions, including antioxidant activity
• obese people are especially vulnerable to suffering dyslipidemia and chronic low-grade inflammation [8]
• Presence of apolipoprotein risk variants would impair taking advantage of the properties of vitamin E, even when following current dietary recommendations [8]

(rs114375162

• Gly434Arg [8]
• Following NPC1 polymorphisms able to reveal diminished transport activity (21–63%)
• May influence bioavailability of VE [8]

rs139659653

• Arg417Trp [8]
• Following NPC1 polymorphisms able to reveal diminished transport activity (21–63%)
• May influence bioavailability of VE [8]

rs141973731

• Gly402Ser [8]
• Following NPC1 polymorphisms able to reveal diminished transport activity (21–63%)
• May influence bioavailability of VE [8]

rs62001882

• Ala395Val [8]
• Following NPC1 polymorphisms able to reveal diminished transport activity (21–63%)
• May influence bioavailability of VE [8]