Hypervitaminosis D

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Classification according to ICD-10
E67.3 Hypervitaminosis vitamin D.
ICD-10 online (WHO version 2019)

The hypervitaminosis D or vitamin D hypervitaminosis following an overdose of vitamin D -wirksamer substances such as calcitriol or a strong overdose of cholecalciferol .

Physiology, pharmacokinetics

Vitamin D 3 is a fat-soluble prohormone that is formed in the skin from 7-dehydrocholesterol with the help of UVB radiation or is ingested with food. It is quickly absorbed in the small intestine with food and released into the blood via the lymph past the liver. In the blood, like the other vitamin D metabolites, it is transported to> 90% bound to vitamin D-binding protein and has a half-life of 19-25 hours there. During this time it is either deposited in adipose tissue or hydroxylated to 25 (OH) vitamin D 3 in the liver . As 25 (OH) vitamin D 3 , it is bound to vitamin D-binding protein again in the blood and has a half-life in the blood of 19 days to 3–4 months. In its target tissues, especially in the kidneys, it is brought into its active form, the 1α, 25 (OH) 2 vitamin D 3 (calcitriol) (half-life three to five days). The last activation step is highly regulated, which is why the body has a high tolerance to the vitamin precursors, but not to the already activated form.

The formation of vitamin D 3 in the skin through sunlight containing UVB limits itself to a maximum of 250–500 µg daily in young adults. Little vitamin D is taken in with food , only fatty fish (and cod liver oil in particular ) contain significant amounts. A hypervitaminosis of vitamin D can therefore only occur due to improper handling of vitamin supplements in general.

The vitamin D metabolites and in particular the 1,25 (OH) 2 vitamin D 3 are broken down by 24-hydroxylases ; they are mainly excreted via the bile and stool. The 24-hydroxylase is encoded by the gene CYP24A1.

“Idiopathic infantile hypercalcemia” is caused by a mutation in the CYP24A1 gene , which inhibits the breakdown of vitamin D. Affected children have an increased sensitivity to vitamin D and, in the case of additional intake, an increased risk of hypercalcemia , which is characterized by growth retardation, vomiting, dehydration , fever attacks and nephrocalcemia . Subsequent research showed that the disorder persists into adulthood.

The toxic effects of vitamin D are mainly caused by its activated form, calcitriol , when its regulation is no longer guaranteed in the event of an overdose. However, with increased concentration, inactive precursors of calcitriol (100 times weaker) can activate the vitamin D receptor and thus mediate its effects and skip the regulations that otherwise strictly limit the effects of calcitriol.

dose

The toxic doses differ greatly between the precursor cholecalciferol and the activated hormone calcitriol . Ergocalciferol, which comes from the plant kingdom, has a somewhat weaker effect than cholecalciferol.

Cholecalciferol

Cholecalciferol (Vitamin D 3 )
RDA 10–20 µg (≙ 400–800  IU )
(40 IU ≙ 1 μg or 1 IU ≙ 0.025 μg)
UL > 10th year of life: 100 µg (≙ 4000 IU)
1st – 10th Year of life: 50 µg (≙ 2000 IU)
<1st year of life: 25 µg (≙ 1000 IU)
LD 50 Dog: 13 mg / kg (oral administration) Rat: 42 mg / kg (oral administration)
Different information depending on the source.
TD Lo Different information depending on the source.

There have been cases of oral overdose due to manufacturing defects and industrial accidents.

In the middle of the last century, rickets prophylaxis was often carried out as so-called shock therapy with excessive individual doses of vitamin D, with the idea that the vitamin D would be stored and that this procedure would therefore be safe. Temporary hypercalcemia and later nephrocalcinosis (for example, in 34% of one to two year old children who received 15 mg ergocalciferol orally every three to five months) did occur again and again .

The maximum dose that can be taken daily without serious side effects is unclear. The latest studies indicate that no side effects are to be expected for at least 10,000 IU (250 µg) daily over very long periods of time. The blood level of 25 (OH) vitamin D 3 does not rise into toxic ranges over a wide dose range up to the daily dose, which corresponds to the maximum synthesis capacity of the skin (10,000–20,000 IU). However, in some Israeli lifeguards with a very high endogenous vitamin D synthesis, beginning symptoms of hypercalciuria were found. Nevertheless, it is assumed that maximum daily doses in this range are associated with no serious side effects.

In a statement published in 2020, the Federal Institute for Risk Assessment (BfR) pointed out that from a nutritional point of view it is not necessary to take products marketed as dietary supplements with a dosage of 50 and 100 μg cholecalciferol. The BfR currently regards the occurrence of health impairments as unlikely when such high-dose preparations are only consumed occasionally. With long-term and daily consumption, however, the current study situation indicates an increased health risk.

Calcitriol

Calcitriol is given, among other things, for the treatment and prophylaxis of bone metabolism disorders caused by chronic renal insufficiency . The dose can be given from 0.12 µg daily to about 1 µg under close medical supervision. The toxic threshold for adults is 250 µg ( Red List (Medicines) ). The half-life of externally given calcitriol in the blood is short at only three to six hours.

Calcitriol increases the absorption of calcium and phosphate ions in the small intestine (stimulates the synthesis of transport proteins). The increased calcium and phosphate content in the serum improves bone mineralization. In the case of calcium and phosphate deficiency, it also acts directly on osteoblasts. Their proliferation is increased, as is their synthesis of osteocalcin (whose gene is vitamin D-responsive), which inhibits mineralization. In high concentrations, calcitriol can also stimulate osteoclast differentiation. This increases the calcium and phosphate ion concentration in the blood.

Symptoms

A vitamin D overdose leads to an overstimulated calcium absorption in the intestine and calcium absorption from the bones and therefore to hypercalcemia (calcium in serum> 2.75 mmol / l) and hypercalciuria (calcium excretion> 10 mmol / l) /24 hours). This leads to the following effects:

  • The kidneys are damaged by calcium deposits, which leads to a decreased glomerular filtration rate . On the other hand, the renal tubules can no longer concentrate the urine as well, which can temporarily lead to polyuria and secondary polydipsia . Both lead to functional renal failure .
  • Long-term hypercalcaemia can also lead to calcium deposits in soft tissues such as blood vessels, heart, lungs, muscles and tendons.
  • Osteoporosis results in the bones .

Further symptoms, especially chronic overdose, are:

  • Loss of appetite , weight loss, vomiting, constipation, abdominal cramps, high blood pressure, psychosis
  • Muscle and tendon pain, headache
  • in children: persistent (persistent) increase in body temperature, irritability (irritability)
  • Hypoparathyroidism (underactive parathyroid glands)

Severe overdoses can lead to death.

diagnosis

The 25 (OH) vitamin D concentration in serum is a good biomarker for the vitamin D status. In hypervitaminosis, it is two to fifteen times higher than the normal range (see cholecalciferol ). Furthermore, hypercalcemia and reduced parathyroid hormone levels are often associated with this. An early symptom can be an increased excretion of calcium in the urine.

therapy

Cholecalciferol

As a rule, the poisoning is chronic: It is important to lower the calcium blood level by:

  • Low calcium diet
  • Forced diuresis (water tablets and increased fluid intake) with determination and substitution of urine electrolytes
  • Corticosteroids , calcitonin , colestyramine . Since vitamin D metabolites are stored, hypercalcaemia can persist for two months after a severely excessive dose.

Calcitriol

Usually acute overdoses: Due to the short half-life, usually only monitoring; in the case of very high overdoses, emergency hemodialysis may be necessary .

History

Synthetic vitamin D was available for the first time in 1928 and was used in high single doses ("shock therapy") in the 1940s to 1960s for rickets prophylaxis in infants (even longer in the GDR, until 1990). The single doses ranged from 3–15 mg (120,000–600,000 IU). The argument against continuous gifting at the time was that parents were not trusted to think about it every day. Among them there were regularly noticeable symptoms of hypervitaminosis (but no direct consequences of death), so that from 1964 a continuous rickets prophylaxis was officially recommended in the FRG, first with doses of 25–50 µg (1,000–2,000 IU) daily, then from 1970s with today's cans. Overdoses did not occur any more.

Hypervitaminosis D in grazing animals

Meadow golden oats ( Trisetum flavescens ) have a specialty in ruminants : they do not contain vitamin D as a precursor of the vitamin D hormone (calcitriol) that is actually active in the body, but rather calcitriol itself occurs especially in the alpine region, as this grass is more competitive here than higher quality grasses. Ruminants that have a good supply of grass select enough and therefore do not eat golden oats. The golden oats are only consumed in larger quantities when the supply is scarce, which leads to calcinosis : The animals become more immobile because more and more calcium is stored in the joints. It can also lead to hardening of the arteries and calcification of the lungs.

Individual evidence

  1. ↑ a b c d e Entry on Cholecalciferol in the Hazardous Substances Data Bank , accessed July 29, 2012.
  2. ↑ a b c d e f Opinion of the Scientific Committee on Food on the Tolerable Upper Intake Level of Vitamin D . (PDF; 394 kB) Scientific Committee on Food of the European Commission , December 4, 2002.
  3. ↑ Cytochrome P450, Family 24, Subfamily A, Polypeptide 1; CYP24A1.  In: Online Mendelian Inheritance in Man . (English)
  4. ↑ KP Schlingmann, M. Kaufmann, S. Weber, A. Irwin, C. Goos, U. John, J. Misselwitz, G. Klaus, E. Kuwertz-Bröking, H. Fehrenbach, AM Wingen, T. Güran, JG Hoenderop, RJ Bindels, DE Prosser, G. Jones, M. Konrad: Mutations in CYP24A1 and idiopathic infantile hypercalcemia. In: The New England Journal of Medicine . Volume 365, number 5, August 2011, pp. 410-421, doi: 10.1056 / NEJMoa1103864 . PMID 21675912 (free full text).
  5. ↑ E. De Paolis, GL Scaglione, M. De Bonis, A. Minucci, E. Capoluongo: CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype. In: Clinical chemistry and laboratory medicine. [electronic publication before printing] June 2019, doi: 10.1515 / cclm-2018-1208 . PMID 31188746 (Review).
  6. ↑ T. Jobst-Schwan, A. Pannes, KP Schlingmann, KU Eckardt, BB Beck, MS Wiesener: Discordant Clinical Course of Vitamin D Hydroxylase (CYP24A1) Associated Hypercalcemia in Two Adult Brothers With Nephrocalcinosis. In: Kidney & blood pressure research. Volume 40, number 5, 2015, pp. 443-451, doi: 10.1159 / 000368520 . PMID 26304832 (Review) (free full text).
  7. ↑ AS Dusso u. A .: Vitamin D . ( Memento of the original from May 15, 2007 in the Internet Archive ) Info: The archive link was inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. In: Am J Physiol Renal Physiol. Volume 289, 2005, pp. F8-F28. @1@ 2Template: Webachiv / IABot / ajprenal.physiology.org
  8. ↑ DGE estimates for vitamin D accessed on November 19, 2016.
  9. ↑ Scientific Opinion on the tolerable upper intake level of vitamin D . Scientific Committee on Food of the European Commission , July 27, 2012.
  10. ↑ National Academies Press: Dietary Reference Intakes for Calcium and Vitamin D: Tolerable Upper Intake Levels: Calcium and Vitamin D
  11. ↑ National Academies Press: Dietary Reference Intakes for Calcium and Vitamin D: Tolerable Upper Intake Levels: Calcium and Vitamin D:
    Table 6-3: Case Reports of Vitamin D Intoxication: Intake and Plasma Measures
  12. ↑ National Academies Press: Dietary Reference Intakes for Calcium and Vitamin D: Tolerable Upper Intake Levels: Calcium and Vitamin D:
    Table 6-4: Vitamin D Tolerable Upper Intake Levels (UL) by Life Stage
  13. ↑ National Institutes of Health [NIH (Office of Dietary Supplements)]: Vitamin D (Fact Sheet for Health Professionals)
  14. ↑ Edward F. Marshall: cholecalciferol: A UNIQUE toxicant FOR RODENT CONTROL . In: Proceedings of the Eleventh Vertebrate Pest Conference (1984) . March 1, 1984 ( unl.edu [accessed May 10, 2020]).
  15. ↑ Patrick J. McCullough, Douglas S. Lehrer, Jeffrey Amend: Daily oral dosing of vitamin D3 using 5000 TO 50,000 international units a day in long-term hospitalized patients: Insights from a seven year experience . In: The Journal of Steroid Biochemistry and Molecular Biology . tape 189 , May 1, 2019, ISSN  0960-0760 , p. 228–239 , doi : 10.1016 / j.jsbmb.2018.12.010 ( sciencedirect.com [accessed November 11, 2019]).
  16. ↑ Federal Institute for Risk Assessment (BfR): Vitamin D: Ingestion of high-dose food supplements unnecessary. In: Federal Institute for Risk Assessment (BfR). Federal Institute for Risk Assessment (BfR), July 31, 2020, accessed on August 4, 2020 .
  17. ↑ D. Drenkhahn (Ed.): Anatomie. Volume 1. 16th edition. Urban & Fischer, Munich 2003, pp. 147–148.
  18. ^ MF Holick .: Vitamin D. In: Clinical Reviews in Bone and Mineral Metabolism. 1 3-4, 2002, pp. 181-207. doi: 10.1385 / BMM: 1: 3-4: 181 .