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]
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
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]
