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.

The other side of vitamin D therapy: a case series of acute kidney injury due to malpractice-related vitamin D intoxication
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BACKGROUND: Vitamin D deficiency is highly prevalent in Indian Kashmir. Many people get injectable vitamin D (600,000 IU/injection). At times, the dose prescribed is far above the permissible limit. We report 62 patients with malpractice-related vitamin D intoxication, presenting with hypercalcemia and acute kidney injury (AKI). METHODS: The diagnosis was made on basis of (1) history of multiple intramuscular vitamin D injections (2) toxic serum levels of 25-OH vitamin D and (3) exclusion of common causes of hypercalcemia (malignancy and hyperparathyroidism). Their presentation was either de novo AKI in 51 (group 1) or acute on top of chronic kidney disease in 11 (group 2). RESULTS: The mean age was 60 ± 14 vs. 62 ± 13 years, approximate number of vitamin D injections received ranged from 4 to 28 (2.4 - 16.8 million units) vs. 3 to 24 (1.8 - 14.4 million units), mean creatinine at presentation was 3.2 ± 0.9 vs. 4.5 ± 1.1 mg/dL, which decreased to 1.2 ± 0.2 vs. 3.3 ± 1.0 mg/dL, mean serum calcium on admission was 13.7 ± 1.4 vs. 13.6 ± 2.0 mg/dL which decreased to 10.7 ± 1.2 vs. 11.0 ± 1.0 mg/dL on follow-up of 7.2 ± 0.6 months, mean vitamin D level was 313.3 ± 54.8 (range 235 - 375) vs. 303.7 ± 48.4 (range 210 - 375) nmol/L and mean PTH was 18.1 ± 9.6 (range 6.2 - 32) vs. 52.3 ± 12.6 (range 28 - 88) pg/mL in group 1 vs. group 2, respectively. The clinical presentation was weakness, constipation, abdominal pain, nausea, vomiting, anorexia, altered sensorium, and oliguria. The treatment received was intravenous fluids (normal saline) in all in group 1 and in 8/11 in group 2, short course of steroids (prednisolone) in 44, and bisphosphonate in 6. CONCLUSION: This is the largest case series of AKI secondary to vitamin D toxicity ever reported.
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Effect of vitamin D supplementation during pregnancy on the Th1/Th2 cell balance of rat offspring.

Vitamin D has important functions in the immune system, and it may suppress the proliferation of T helper (Th) cells and modulate their cytokine production. In this study, we aimed to investigate the effects of maternal supplementation with different doses of vitamin D on the allergy status of the offspring. We gave pregnant female rats a low dose (48000IU/kg, equal to 800IU/d in human) and a high dose (240000IU/kg,equal to 4000IU/d in human) of vitamin D3 intramuscular injection on gestation day (GD)17, and we used an enzyme-linked immunosorbent assay (ELISA) to determine the levels of immune responsive cytokines including IL-4, IgE, and interferon gamma (IFN-gamma) in the offspring. On postnatal day (PND) 21, plasma IL-4 levels were elevated by 10.43% (p < 0.01) in the offspring from the high dose vitamin D3 group compared with the control group. And offspring plasma IL-4 levels in the low dose group decreased by 7.27% (p < 0.05) compared with the control dose group. We found that the offspring of mothers given a low dose of vitamin D3 had a 6.17% (p < 0.01) decrease in their plasma IgE levels compared to control animals, but the high dose of vitamin D3 showed no effect. The serum 25(OH)D3 levels were negatively correlated with the IL-4 (r = -0.561, p < 0.01) and IgE (r = -0.421, p < 0.05) levels of the offspring from the low dose group. In the lung tissues of the offspring of the high dose group, we observed thickening of the alveolar septa and more inflammatory cells compared with the control group and low dose group. Thickened alveolar septa were also found in the lung tissues of the offspring from the control group. We conclude that high dose vitamin D3 maternal supplementation during pregnancy induced an imbalance of Th1 and Th2 cells in their offspring resulting allergic and inflammatory response.

Hypervitaminosis-D, an uncommon reality!

Vitamin D deficiency is highly prevalent in India. This has set off a trend among medical practitioners to prescribe vitamin D supplements empirically. Whilst this approach is generally safe, in predisposed individuals it may lead to hypervitaminosis D. Here we present a case where empirical use of high dose vitamin D supplementation had serious consequences highlighting the need to use vitamin D therapy judiciously and to remain vigilant for side-effects in high-risk individuals.

Status and trends in poisonings in Denmark 2007-2009.

INTRODUCTION: The Danish Poison Information Centre (DPIC) provides information to the public and health care professionals on acute poisonings. The DPIC received 41,000 enquiries during the first three years of its existence as an open 24h telephone service. The aim of this data register study was to classify all substance exposures, to gain knowledge of the status and trends in poisonings (toxico-surveillance) and to evaluate the development in the number of contacts. MATERIAL AND METHODS: Information and inquiries were continuously entered into a poison-centre database. A new classification system was established during the study to ensure that all agents were properly classified. A total of 41,139 calls were divided into 18 substance categories, each consisting of 3-11 subgroups. RESULTS: The number of contacts per year increased by 70% from 2007 to 2009. Three contacts per thousand individuals in the Danish population were registered in 2009. For all groups, except drugs of abuse, the data showed an increase in the actual number of exposures from 2008 to 2009. Pharmaceuticals represent one third of substance exposures, and analgesics constitute a third of these poisonings. A relative increase in contacts concerning household substances, plants and vitamins was observed. CONCLUSION: The classification gave detailed knowledge of the current poisoning status. Evaluation of subgroups showed a need for a larger number of subgroups to ensure a sufficient level of toxico-surveillance. Compared to other national poison centres, we predict a doubling in enquiries during the next ten years, mainly from the public.

Hypercalcemia due to hypervitaminosis D: report of seven patients.

We retrospectively studied seven children (six girls, one boy) aged from 7.5 to 25 months who presented to our institution after taking large doses of vitamin D (900 000-4 000 000 U) prescribed by medical practitioners for wrong indications like failure to thrive, etc. The clinical manifestations were constipation, decreased appetite, lethargy, polyuria, dehydration and failure to thrive. All patients had hypercalcemia (serum calcium ranging from 12 to 16.8 mg/dl), high 25[OH]D levels (ranging from 96 to >150 ng/ml), suppressed intact parathyroid hormone (ranging from <3 to 8.1 pg/ml). Hypercalciuria (urinary calcium/creatinine ranging from 1 to 2.45) was found in all patients, while nephrocalcinosis was present in five patients. All were treated with intravenous fluids, oral prednisolone, restriction of calcium in diet, while four patients received pamidronate infusion for reducing hypercalcemia.

Universal versus selective iron supplementation for infants and the risk of unintentional poisoning in young children: a comparative study of two populations.

BACKGROUND: Iron continues to be a common cause of poisoning in young children, in part due to its widespread use and easy accessibility. OBJECTIVE: To determine differences in the epidemiology and outcome of unintentional iron ingestion by young children in populations practicing selective (eg, US) versus universal (eg, Israel) iron supplementation to infants. METHODS: All cases of unintentional iron ingestion in children younger than 7 years in a one year period were identified through the poison control center databases of 2 sites (Illinois and Israel). Parameters compared include patient sex and age; type, form, and dose of iron preparation; circumstances and clinical manifestations; management; and outcome. RESULTS: A total of 602 children were identified: 459 in Illinois and 143 in Israel. The majority of Illinois children ingested multivitamin preparations (94%), whereas Israeli children ingested single-ingredient iron preparations (78%) (p < 0.001). Iron doses ingested were higher in Israel (median 14.5 vs 6.6 mg/kg; p < 0.001) but remained within the nontoxic range for most children. No deaths or severe poisonings were reported, and 93% of children in both groups were asymptomatic. The majority of ingestions in both locations were due to unintentional self-ingestion. However, parental miscalculation occurred more frequently in Israel (16%) than in Illinois (1%). CONCLUSIONS: Universal iron supplementation to infants was not associated with a negative impact on the outcome of pediatric unintentional ingestions. Low-dose exposures were safely managed by on-site observation.

[Severe hypercalcemia due to vitamin D intoxication]. / Hypercalcémie majeure secondaire à une intoxication par la vitamine D.

UNLABELLED: We report on a case of severe hypercalcemia due to vitamin D intoxication in a 4-month-old infant, CASE REPORT: A 4-month-old boy was admitted for anorexia, weakness, hypotonia, constipation and lethargy. Initial physical examination evidenced a severe axial hypotonia, signs of moderate intracellular dehydration, polyuria and leucocyturia. Hemodynamic parameters were normal. The infant's origin was Turkish. Basic blood chemistry showed a high serum calcium concentration of 4.28 and 4.55 mmol/l on a second control. The EKG showed a short QTc interval calculated at 0.34 s. Due to worsening neurological condition, the infant was referred to the pediatric intensive care unit. Because of the association of neurological impairment, EKG abnormality and high serum calcium level, haemodialysis was performed. Treatment included hyperhydration, high doses of intravenous of loop diuretics and sodium pamidronate infusion. Hormonal, radiological, abdominal and cardiac investigations combined with a new parental interview led to the diagnosis of vitamin D intoxication due to excessive daily administration. We were unable to determine the exact total amount because of the language barrier. Clinical outcome was marked by nephrocalcinosis without renal function impairment, iliac venous thrombosis secondary to the dialysis catheter and a full neurological recovery without sequelae after 3 months. DISCUSSION: Fear of rickets, especially in Turkish families residing in France, can lead some parents to administer massive daily quantities of vitamin D. This practice is facilitated by the possibility of purchasing high dosage forms of vitamin D via the Internet. When faced with an infant presenting with digestive disorders such as vomiting and constipation, associated with neurological troubles (lethargy, hypotonia) and hypercalcemia, vitamin D intoxication should be considered after tumoral, hormonal or malformative (Williams-Beuren syndrome) causes have been eliminated. Combined with hyperhydration and loop diuretics, biphosphonate infusion often allows to control hypercalcemia. Nephrocalcinosis seems correlated to chronic administration while cardiovascular disorders are more likely associated with massive acute vitamin D administration, severe dysrhythmia being rare in children in this context.

[Neonatal intoxication to vitamin D in premature babies: A series of 16 cases]. / Intoxication néonatale à la vitamine D chez des anciens prématurés : une série de 16 cas.

INTRODUCTION: Preterm neonates are particularly at risk of vitamin D (25-D) deficiency. To prevent rickets and osteopenia in this population, international guidelines vary between 800 and 1000IU per day of vitamin D in Europe and recommend 400IU per day in the USA. Target levels of circulating 25-D are not well identified, with the lower target level 50-75nmol/L and the upper target level probably 120nmol/L. METHODS: Between 2013 and 2015, 16 premature infants (born<35WG) were referred to pediatric nephrology clinics because of symptoms secondary to 25-D overdose during the neonatal period. Clinical and biological data were retrospectively reviewed to better define this population. The results are presented as the median (range). RESULTS: Gestational age was 27 (24-35)WG with a birth weight of 810 (560-2120)g. Nephrocalcinosis was the initial symptom in 37% of cases, hypercalcemia in 44%, and hypercalciuria in 19%. Daily vitamin D doses were 333 (35-676)IU. Age and body weight at initial symptom were 36.6 (27.6-47.6)WG and 2300 (640-3760)g, respectively. The 25-D level at the time of the first dosage was 210 (119-350)nmol/L and the 1-25 vitamin D level was 370 (245-718)pmol/L (local normal values for age<240). During follow-up, 12 patients displayed nephrocalcinosis, ten hypercalciuria, and three hypercalcemia. The 25-D level normalized in ten patients within 10 (3-32)months after vitamin D withdrawal. Nephrocalcinosis improved in ten of 12 patients, within 12 (3-30)months. Vitamin D could be readministered in ten patients. When searched (n=3), no CYP24A1 mutation was identified in two patients, but was identified in the heterozygous state in one. CONCLUSION: A 25-D overdose should be systematically ruled out in the presence of nephrocalcinosis, hypercalcemia, and/or hypercalciuria during infancy in children born preterm. Studies are required to assess the exact frequency of 25-D deficiency and overdose in this population, as well as to evaluate the potential deleterious effects of this imbalance on bone, kidney, and brain development.

A fatal case of systemic fat embolism resulting from gluteal injections of vitamin e for cosmetic enhancement.

Recently in Mexico the number of cosmetic surgeries has increased. These procedures are often carried out by unqualified people using obsolete and contraindicated products such as injectable oil, which cause uncorrectable disfigurement or more serious complications, even death, after reaching the systemic circulation. We report the case of a fat embolism syndrome (FES) caused by injections of vitamin E (tocopherol) in order to increase the volume of the buttocks. This case of a FES caused by injections of vitamin E was confirmed by gas chromatography coupled to mass spectrometry.

Hypercalcemia and renal function impairment associated with vitamin D toxicity: case report.

Nowadays vitamin D (25-OHD) deficiency is supposed to be a global epidemic condition. Expectedly, vitamin D measurement and intake exponentially increased in Brazil in this decade. Although the benefit of vitamin D to general health is still in debate, its indiscriminate use potentially may lead to enhance the incidence of vitamin D intoxication, which is considered a rare disorder. We report a case of a 70 year old diabetic male with chronic renal disease (blood creatinine of 1.6 mg/dL) who progressed suddenly to acute kidney injury (blood creatinine of 5.7 mg/dL) associated with hypercalcemia and high blood levels of vitamin D. Vitamin D and calcitriol were discontinued and hypercalcemia was managed by hydration followed by furosemide. Thereafter, disodium pamidronate was administered and the patient did not undergo on dialysis. It took approximately 14 months to normalize 25-OHD levels and blood creatinine returned to basal levels only after 24 months. The indicated labeling dosage was 2000 IU, but most likely the vitamin D manipulated preparation was higher as the vitamin D blood levels were very high. Although rare, vitamin D intoxication is becoming more frequent as the patients use frequently manipulated preparations that could be subject to errors in the manufacturing and labeling of the tablets or capsules. The present report alerts to the potential increase in the incidence of severe vitamin D intoxication due to the frequent use of this secosteroid as a nutritional supplement. At the same time, it is necessary to improve regulation on the nutrient supplement market.

Approach to the Child with Hypercalcaemia.

Hypercalcaemia is rare in children. In adulthood, the causes are most frequently malignancy and primary hyperparathyroidism. In children, however, the aetiologies are diverse and age specific, and many have an underlying genetic basis. Hypercalcaemia is a serious condition that frequently leads to end-organ damage. In order to provide the most appropriate treatment, a key part of the management pathway is to establish the correct diagnosis promptly. When considering a practical approach to hypercalcaemia in children, it is helpful to consider the causes of hypercalcaemia according to the accompanying levels of parathyroid hormone (PTH), indicating whether the causes are PTH dependent or PTH independent. This chapter reviews the recent advances in this area and presents a practical approach to the investigation and subsequent management of this condition.

Seasonality of reported poison exposures.

Review of 3,381 records from New Hampshire Poison Center for July through September 1981 and January through March 1982 revealed no seasonal difference in the total number of calls. A significant predominance in the summer reports was noted for plants, pesticides, envenomations, and acetaminophen exposures. During the winter a predominance was noted for aspirin, vitamins, cold and cough remedies, liniments, foods, and calls with no specific agent identified.

Toxicological problems resulting from exposure to traditional remedies and food supplements.

The National Poisons Unit, London, carried out a pilot survey to investigate the frequency and severity of adverse effects/toxicity from exposure to traditional medicines and food supplements reported to the Unit. Enquiries related to suspected poisoning events were reviewed retrospectively from January 1983 to March 1989, and prospectively in 1991. Further information about cases identified by the prospective review was obtained, when appropriate, by follow-up questionnaire, clinical consultation by a consultant toxicologist, toxicological analyses of samples from patients and from products, and botanical identification of dried plant material. In total, 5536 enquiries were identified. Symptoms were reported in 657 (12%) of these. There was a large number of reports of accidental ingestion of vitamin preparations by children under 5 years. Appropriate assessment was possible in only relatively few cases, due to insufficient documentation, and poor labelling of certain products. A probable link between exposure and adverse effects was identified in 42 cases, and was highly probable in two. Heavy metal poisoning resulting from use of contaminated traditional remedies was confirmed in 5 cases. There was evidence that some patients took excessive doses of food supplements, without realising that this might result in toxic effects. The results of this pilot study suggest that there is a need for further surveillance to provide an appropriate risk assessment of food supplements and herbal remedies, improved quality control and labelling of these products, and increased awareness of their potential hazard.

Food, supplements, and fortified foods: scientific evaluations in regard to toxicology and nutrient bioavailability.

Food, supplements, and fortified foods can all be appropriate sources of nutrients. It is the responsibility of nutrition educators to help consumers use those nutrient sources appropriately. Consumers should consider at least six factors when they select foods, supplements, and fortified foods: flavor, convenience, cost, nutrient content, toxic factors, and bioavailability of nutrients. Consumers are often less concerned about the latter two factors than they should be. For example, many case histories have been published on the symptoms caused by overconsumption of vitamins A, B-6, C, and D and nicotinic acid. Generally those toxic symptoms were caused by the ingestion of supplements, not foods. Current widespread use of supplements containing one or two nutrients may not only cause overt toxicity symptoms but also adversely affect the bioavailability of other nutrients. For example, ingestion of excessive amounts of vitamin C appears to interfere with copper metabolism in human subjects; ingestion of high levels of zinc impairs immune function, depresses copper absorption, and induces anemia; consumption of supplemental calcium as calcium phosphate dibasic is associated with renal calcification in rats; and ingestion of supplemental magnesium depresses the apparent absorption of calcium and retention of calcium in bone by rats.

Hazards of nonprescription medications.

There are hundreds of nonprescription medications available to the consumer. Among these are a number that have potential for toxicity when taken in overdoses or in combination with other medications. This article addresses the pathophysiology, diagnosis, and treatment of selected over-the-counter medication intoxications including antihistamines, dextromethorphan, sympathomimetics, nutritional supplements, and herbal preparations.