Cryptogenic Intracranial Hemorrhagic Strokes Associated with Hypervitaminosis E and Acutely Elevated α-Tocopherol Levels.

OBJECTIVES: Up to 41% of intracerebral hemorrhages (ICH) are considered cryptogenic despite a thorough investigation to determine etiology. Certain over-the-counter supplements may increase proclivity to bleeding, and we hypothesize that specifically vitamin E may have an association with ICH and acutely elevated serum levels of α-tocopherol. Our aim is to report 3 cases of recently admitted patients with hypervitaminosis E and otherwise cryptogenic ICH. METHODS: At our institution between January and December 2018, 179 patients were admitted with ICH with 73 imputed to be "cryptogenic" (without clear etiology as per Structural vascular lesions, Medication, Amyloid angiopathy, Systemic disease, Hypertension, or Undetermined and Hypertension, Amyloid angiopathy, Tumor, Oral anticoagulants, vascular Malformation, Infrequent causes, and Cryptogenic criteria). Of these, we found 3 (4.1%) clearly admitted to consistent use of vitamin E supplementation for which α-tocopherol levels were checked. We describe the clinical presentation and course of these patients and their etiologic and diagnostic evaluations including neuroimaging and α-tocopherol laboratory data. RESULTS: All patients in this series were consistently consuming higher than recommended doses of vitamin E and developed acute ICH. The first 2 patients both had subcortical (thalamic) intraparenchymal hemorrhages while the third had an intraventricular hemorrhage. Serum α-tocopherol levels in patient A, B, and C were elevated at 30.8, 46.7, and 23.3 mg/L, respectively (normal range 5.7-19.9 mg/L) with a mean of 33.6 mg/L. No clear alternate etiologies to their ICH could be conclusively determined despite thorough workups. CONCLUSIONS: In patients with cryptogenic ICH, clinicians should consider hypervitaminosis E and check serum α-tocopherol level during admission. Reviewing the patient's pharmacologic history, including over-the-counter supplements such as vitamin E, may help identify its association, and its avoidance in the future may mitigate risk. With its known vitamin K antagonism, hypo-prothrombinemic effect, cytochrome p-450 interaction, and antiplatelet activity, vitamin E may not be as benign as presumed. Its consumption in nonrecommended doses may increase ICH risk, which may be underestimated and under-reported.

α-Tocopherol Intake Decreases Phylloquinone Concentration in Bone but Does Not Affect Bone Metabolism in Rats.

Previous studies have shown that α-tocopherol intake lowers phylloquinone (PK) concentration in some extrahepatic tissues in rats. The study's aim was to clarify the effect of α-tocopherol intake on vitamin K concentration in bone, as well as the physiological action of vitamin K. Male Wistar rats were divided into 4 groups. Over a 3-mo period, the K-free group was fed a vitamin K-free diet with 50 mg RRR-α-tocopherol/kg, the E-free group was fed a diet containing 0.75 mg PK/kg without vitamin E, the control group was fed a diet containing 0.75 mg PK/kg with 50 mg RRR-α-tocopherol/kg, and the E-excess group was fed a diet containing 0.75 mg PK/kg with 500 mg RRR-α-tocopherol/kg. PK concentration in the liver was higher in E-excess rats than in E-free rats, was lower in the tibias of control rats than in those of E-free rats, and was lower in E-excess rats than in control rats. Menaquinone-4 (MK-4) concentration in the liver was higher in E-excess rats than in E-free and control rats. However, MK-4 concentrations in the tibias of E-free, control, and E-excess rats were almost the same. Blood coagulation activity was lower in K-free rats than in the other rats but was not affected by the level of α-tocopherol intake. Additionally, dietary intake of PK and α-tocopherol did not affect uncarboxylated-osteocalcin concentration in the serum, femur density, or expression of the genes related to bone resorption and formation in the femur. These results suggest that α-tocopherol intake decreases PK concentration in bone but does not affect bone metabolism in rats.

Excess α-tocopherol decreases extrahepatic phylloquinone in phylloquinone-fed rats but not menaquinone-4 in menaquinone-4-fed rats.

SCOPE: The effects of vitamin E on vitamin K metabolism were elucidated by comparing the effect of tocopherol intake on vitamin K concentrations in rats fed phylloquinone (PK) or menaquinone (MK)-4. METHODS AND RESULTS: Initially, the dietary effect of RRR-α-tocopherol, but not RRR-γ-tocopherol, in decreasing extrahepatic PK concentrations was confirmed. Subsequently, rats were fed a PK or MK-4-containing diet (0.75 mg/kg) with RRR-α-tocopherol (0, 10, 50, or 500 mg/kg) for 6 weeks. In rats fed PK, α-tocopherol consumption decreased PK in kidney, lung, heart, muscle, testis, and brain but not in serum and liver. However, in rats fed MK-4, α-tocopherol consumption did not decrease MK-4 in serum and tissues. Finally, vitamin K- and E-depleted rats were administered PK or MK-4 (0.2 mg) with RRR-α-tocopherol (0, 1, or 10 mg) by gavage. After PK administration, α-tocopherol was observed to decrease PK in kidney, adrenal gland, lung, testis, and brain but not in serum and liver, whereas, after MK-4 administration, α-tocopherol did not affect MK-4 in serum and tissues. CONCLUSION: Excess α-tocopherol decreased extrahepatic PK in rats fed PK but not MK-4 in rats fed MK-4.