Vitamin K

from Wikipedia, the free encyclopedia
Structural formula of the most important K vitamins:
Vitamin K 1  =  phylloquinone .
Vitamin K 2  =  menaquinone -n.
Vitamin K 3  =  menadione

Vitamins K ( K for coagulation ) are in addition to vitamins A , D and E to the fat-soluble vitamins and are referred to collectively as vitamin K summarized. You are a co-factor in reactions of γ-Glutamylcarboxylase . This mechanism enables several coagulation factors to be activated (activation later proteolytic) and anticoagulant factors are activated and regulated.

Furthermore, K vitamins play an important role in cell growth for the activation of osteocalcin (a bone protein ), calbindin and the ligands for some receptor tyrosine kinases such as the growth-arrest-specific gene-6 .

Vitamin K 1 is indispensable for photosynthesis in plants .

history

The existence of a “vitamin K” was postulated by the Danish researcher Carl Peter Henrik Dam after he had noticed in 1929 during studies on the cholesterol synthesis of chicks that the special cholesterol-free diet given to them led to bleeding after more than two to three weeks came under the skin as well as muscles and other organs. With his work, he was able to rule out that these symptoms were caused by a deficiency in vitamins A , D , B1 , B2 or C , fats or cholesterol.

In 1931 Canadian researchers (McFarlane et al.) At the Ontario Agricultural College, while studying the vitamin A and D requirements of chickens, reported bleeding and delayed blood clotting when they marked them on the wings, but did not pursue this observation.

1933 found two US researchers (Holst and Halbrook) at the University of California found that these bleeding in chickens by feeding fresh cabbage could be prevented, but this led falsely to a lack of vitamin C back.

After pure vitamin C was soon available, Dam administered it parenterally to the chickens in order to rule out that impaired absorption from the digestive tract (as a result of a disrupted intestinal function due to the diet) could be responsible for the bleeding. And after the feeding of wheat germ oil offered no protection and, on the other hand, the administration of cereal grains and seeds prevented the coagulation disorder, he felt justified in 1934 to blame the lack of a certain, albeit still unknown substance in the diet for the problems observed.

Further feeding attempts followed and in 1935 this group of substances was finally recognized as an essential vitamin with lipophilic properties. The letter K was originally chosen for the sake of simplicity, because the lack of this substance hindered sufficient "co" -agulation ability ( clotting ) of the blood . The chemical structure of vitamin K was elucidated a short time later by Almquist and Stokstad at the University of California at Berkeley .

In 1943 Henrik Dam received the Nobel Prize for Medicine for the discovery and Edward Adelbert Doisy for the structure elucidation of this group of vitamins .

Representative

All substances with vitamin K activity are chemically derived from the naturally non-occurring 2-methyl-1,4-naphthoquinone ( menadione ). In addition to the unsubstituted, aromatic ring, the methyl group is a prerequisite for vitamin K activity ; the lipophilic side chain (which can vary in length depending on the K vitamin) determines fat solubility and other properties. Natural terpene chains with 20 carbon atoms are optimal . Side chains below 8 carbon atoms lead to inactivity, except for menadione. Up to 100 compounds with vitamin K activity are known.

Only vitamins K 1 and K 2 are of practical importance in (human) metabolism . Other 1,4-naphthoquinones have because of disadvantageous, e.g. T. toxic effects of no practical importance.

  • Vitamin K 1 or phylloquinone occurs in different concentrations in the chloroplasts of green plants as a normal component of the photosynthetic apparatus and partly in their fruits.
  • Vitamin K 2 or menaquinone is also produced in the human intestine by bacteria (e.g. some strains of Escherichia coli or Bacteroides fragilis ). According to recent studies, it can be synthesized from phylloquinone in limited quantities by humans and higher animals . The most common form is menaquinone-4 (n = 4 in the picture above). Compared to the other vitamin K analogues, menaquinone-4 has the most potent γ-carboxylation activity .
  • Vitamin K 3 or menadione is a synthetically produced substance without a side chain (this is supplemented by the human organism after ingestion). The water-insoluble vitamin K 3 was used earlier in the form of the water-soluble hydrogen sulfite adduct as an artificial "provitamin K".

Absorption and metabolism

Due to the heat stability of the vitamin K group, there is little loss of vitamins during preparation, especially during cooking. Vitamin K is also stable to oxygen . When exposed to light, vitamin K becomes inactive and quickly loses its bioavailability.

The fat-soluble vitamin K ingested with food is absorbed to the extent of 20–70% by active transport into the mucosal cells of the upper small intestine ( jejunum ) with the help of bile acid and pancreatic lipase as emulsifiers . Vitamin K 2 , on the other hand, reaches the intestinal tissue by diffusion . Vitamin K, bound to chylomicrons and other lipoproteins , passes from the mucosal cells of the jejunum via the lymph into the thoracic duct , from there into the blood and via the blood finally into the tissues in which it is used (e.g. liver) . Storage can take place here for up to 14 days. There is no vitamin K in the umbilical cord blood ; it is hardly transmitted across the placenta. The fetal vitamin K supply in the liver is one-fifth that of an older child or adult.

Forms of transformation of vitamin K in the γ-carboxylation of the precursors of the coagulation factors

In the endoplasmic reticulum , vitamin K quinone is hydroxylated (reduced) to its biologically active form, vitamin K hydroquinone (also: vitamin KH 2 ). In the γ-carboxylation reaction, the activated vitamin KH 2 acts as a cofactor for γ-glutamyl carboxylase and is converted into a vitamin K-2,3- epoxide , while the glutamic acid of the protein is converted into γ-carboxy-glutamic acid by means of CO 2 and energy from ATP is carboxylated.

The epoxide of vitamin K is then converted back to the quinone of vitamin K by means of vitamin K epoxide reductase (VKOR for short) and the cycle can start again.

The biological activity of vitamin K is thus due to its ability to switch between its oxidized ( quinone ) and reduced ( hydroquinone ) forms in the vitamin K cycle. Epoxide reductase and vitamin K reductase can be inhibited by the anticoagulant drugs dicoumarol , marcumar and warfarin .

50% of the K vitamins are glucuronidated via the bile in the stool and 20% in water-soluble form via the kidneys via the urine.

The apolipoprotein E2 allele appears to be a risk factor for developing vitamin K deficiency.

Functions in humans

The essential importance of vitamin K lies in its contribution to the post-translational introduction of a carboxy group in the γ-position of glutamyl residues of certain proteins, whereby these are activated. So far fourteen proteins are known that have a γ-carboxy-glutamic acid and therefore vitamin K is necessary for their synthesis. Six of these proteins are linked to the blood coagulation system.

For vitamin K 2 , an essential function as an electron transporter in the mitochondria has been proven.

Blood clotting

Vitamin K is involved in converting the coagulation factors II (prothrombin), VII (proconvertin), IX (Christmas factor) and X (Stuart Prower factor) into their coagulant forms. These can then be bound to phospholipid membranes through their carboxyglutamate residues in the presence of calcium ions . This is where their biochemical activity lies in the coagulation system, in which they have essential functions in the process of plasmatic coagulation.

The anticoagulant proteins protein C and protein S are also synthesized as precursors in the liver and are also carboxylated with the help of vitamin K. Vitamin K thus has an essential function in regulating blood clotting. High doses of vitamin K (up to 40 mg daily) are not associated with pathologically altered coagulation values ​​(e.g. increased blood coagulation and a tendency to thrombosis ), since the increased tendency to coagulate and fibrinolysis remain in balance.

Anticoagulant drugs of the coumarin group such as phenprocoumon or warfarin can be neutralized by comparatively small amounts of vitamin K (1 mg); if they are in use, no vitamin K may be given in addition to normal food.

Bone metabolism

Vitamin K is a cofactor of the γ-Glutamylcarboxylase , the post-translationally in various proteins glutamic acid (Glu) to γ-carboxyglutamic acid (Gla) carboxylated . One of these proteins is osteocalcin , which can bind hydroxylapatite in carboxylated form and is therefore involved in bone mineralization . To achieve complete carboxylation of the osteocalcin, higher levels of vitamin K are necessary than to fully activate the coagulation system. An increased level of incompletely carboxylated osteocalcin is associated with lower bone density and an increased risk of bone fractures in older women.

During the Nurses' Health Study , a study with over 72,000 subjects, it was shown that vitamin K 1 has a significant influence on the risk of osteoporosis. The group that consumed the least amount of vitamin K 1 had a 42% increased risk of hip fractures (caused by osteoporosis). Interestingly, it was also shown that subjects who took a higher amount of vitamin D and took less vitamin K at the same time had an increased risk of bone fractures. On the basis of these and other studies, the European Food Safety Authority (EFSA) issued a positive opinion - thus a health-related statement ("Vitamin K contributes to the maintenance of normal bones") is permitted. In the opinion of the EFSA, adequate vitamin K intake is guaranteed through a balanced diet.

Vitamin K also inhibits osteoclast activity : the 1,25 (OH) 2 D 3 - VDR complex in the osteoblasts increases the formation of RANKL and thus promotes it (viewed in isolation in osteoblasts and especially under conditions of significant vitamin D overdoses) bone loss. Under conditions of the (more frequent) vitamin D deficiency, this effect is not relevant, as 1,25 (OH) 2 D 3 also suppresses the parathyroid hormone and ensures a good supply of calcium and phosphate to the body, i.e. indirectly in this way acts to strengthen bones. This bone-degrading effect of the 1,25 (OH) 2 D 3 - VDR complex can be suppressed by vitamin K 2 , so that osteoporosis therapy with vitamin D can be supported by vitamin K 2 .

Vitamin K 2 inhibits cyclooxygenase-2 in a dose-dependent manner , and above it the synthesis of PGE 2 (which is induced by 1,25 (OH) 2 VitD 3 ) and which increases bone resorption.

In animal experiments with rats it could be shown that high doses (around 30 mg / kg daily) of vitamin K 2 inhibited bone loss caused by conditions such as inactivity osteoporosis , administration of prednisolone , overexpression of G-CSF or bone loss due to phenytoin .

Vitamin K 1 and vitamin K 2 were tested in several clinical trials for efficacy in osteoporosis prevention and therapy: women after menopause are considered important risk group for osteoporosis. According to various studies, vitamin K supplementation has no effect on reducing the risk of vertebral fractures. With regard to fractures in other bones, there was at most a small benefit, but this is no longer evident in studies with good quality.

Cell growth regulation

A number of vitamin K-dependent receptor-ligand systems exist that are involved in cell metabolism, cell survival, their transformations and their replications. These include Gas6 , a vitamin K-dependent protein which, as a ligand, binds to various receptor tyrosine kinases and activates them. Vitamin K is linked to cell growth regulation and the formation of tumors.

In vitro and in vivo experiments with vitamin K 1 , vitamin K 2 and vitamin K 3 were carried out on various tumors and in various cancers , which often showed promising results, while the relevant mechanisms of action are still the subject of various researches.

On the other hand, two epidemiological studies at the beginning of the 1990s had shown an increased cancer rate in children who received vitamin K intramuscularly as newborns as a prophylaxis of vitamin K deficiency bleeding . Although these results could not be confirmed, in many countries they led to oral vitamin K prophylaxis being preferred in healthy newborns.

Vascular calcification

It is assumed that the process of vascular calcification is also controlled by proteins with γ-carboxylated glutamic acid residues ("Gla proteins"). Calcification of large arteries is particularly common in older people with osteoporosis who have a poorly saturated vitamin K status. It is therefore speculated that vitamin K protects against "hardening of the arteries".

Vitamin K 2 is important for a healthy cardiovascular system : The Rotterdam Heart Study clearly showed that people who ate foods with a high proportion of natural vitamin K 2 (at least 32 µg daily) over a ten-year observation period clearly had fewer calcium deposits in their arteries and far better cardiovascular health than others. The result of the study is that vitamin K 2 reduces the risk of developing vascular calcification or dying of cardiovascular disease by 50%. Another study showed that vitamin K 2 can not only prevent calcification, but can even reverse it: In the study, rats were given the vitamin K antagonist warfarin to induce calcification of the arteries. Some of the rats then received food containing vitamin K 2 , while the others were fed normal food. Vitamin K 2 led to a 50% reduction in the calcium content in the arteries of the animals.

Occurrence

Vitamin K content in plant foods
Food Vitamin K content
per 100 g of food
Kale 0817 µg
Purslane 0381 µg
chives 0380 µg
spinach 0305 µg
Grapeseed oil 0280 µg
Chickpeas 0264 µg
Watercress 0250 µg
fennel 0240 µg
Brussels sprouts 0236 µg
Soy flour 0200 µg
Mung beans 0170 µg
Broccoli 0155 µg
Rapeseed oil 0150 µg
Soybean oil 0138 µg
Wheat germ 0131 µg
lenses 0123 µg
sauerkraut 0 7.7 µg
Souci / specialist / herb: The composition of food - nutritional tables. 7th edition. 2008

For the often incorrect information on sauerkraut, see also:

Phylloquinone is mainly found in food , which is why more details can be found there. To what extent bacterial menaquinones from the intestinal flora contribute to the vitamin K supply is controversial. In the body, phylloquinone seems to be able to be converted to the more active menaquinone-4, as it is found in increased numbers in extrahepatic tissues. The mechanism is still unknown. Vitamin K is u. a. contained in green leafy vegetables (spinach, lettuce), cabbage, parsley, avocado (see table opposite). It can also be found in some animal products such as whole milk or fat dairy products, egg yolks and meat (offal, muscle meat).

It is important that the vitamin K is hardly transmitted diaplacentally and that the newborn receives little vitamin K with the breast milk. Contrary to the widespread opinion that colostrum contains a lot of vitamin K compared to breast milk, a study showed that there are practically no differences in the vitamin K content of breast milk and colostrum. The vitamin K content of breast milk depends on the mother's food intake and is around 3 µg / 100 ml.

requirement

The German Nutrition Society recommends a daily intake of 4–10 µg for infants, 15–50 µg - increasing with age - for children up to 14 years of age, 60–65 µg for women and 70–80 µg for men. Since breastfed infants are exposed to the (rare) risk of clinically relevant vitamin K deficiency with the risk of dangerous cerebral hemorrhage, vitamin K prophylaxis is recommended in most countries around the world. In Germany, it is usually dosed orally at 3 × 2 mg at birth, after about 1 week and after about 4–6 weeks. There are different dosage regimens in other countries.

Detection methods and status determination

The plasma concentration of vitamin K 1 is given as 0.3–1 ng / ml blood, depending on the detection method.

The Koller test (change in the Quick value after a single intravenous administration of vitamin K) can be used to determine whether a carboxylation disorder of the vitamin K-dependent coagulation proteins is due to a deficient absorption of vitamin K (vitamin K deficiency in the liver e.g. . in cholestasis) or liver cell damage with a protein synthesis disorder and therefore a metabolic disorder for vitamin K. The detection of insufficiently carboxylated vitamin K-dependent proteins is more sensitive.

Deficiency symptoms (hypovitaminoses)

Overall, with a normal diet, more serious hypovitaminoses and avitaminoses are rare (if the need is not measured according to the requirements of osteoporosis prophylaxis, etc., which require significantly higher doses). However, there are a few situations in which they may very well arise:

Drug anticoagulation

Coumarin derivatives, which are used for oral anticoagulation are opponent (antagonists) of the vitamin K and can in overdose lead to life-threatening bleeding due to a relative vitamin K deficiency. The coumarin derivatives are enzyme inhibitors v. a. vitamin K epoxide reductase (VKOR) and thus lead, despite sufficient presence of vitamin K epoxide, to a deficiency of vitamin K hydroquinone, which is necessary for the carboxylase step in the protein formation of the vitamin K-dependent Proteins is necessary.

Since there are polymorphisms in the VKORC1 gene, which codes for the VKOR enzyme, which are inhibited to varying degrees by coumarin derivatives, there are sometimes difficulties in finding the correct coumarin dosage and considerations to detect VKOR polymorphisms in advance using a genetic test . However, despite three large studies, it is unclear whether this actually leads to better dosages and fewer complications.

Vitamin K deficient bleeding in the newborn (neonatorum haemorrhagic disease)

Initially, the newborn has little contact with vitamin K. Vitamin K hardly crosses the placenta and only appears in very small amounts in colostrum and in normal breast milk. Therefore, breastfed newborns without additional vitamin K prophylaxis have a risk of approximately 1: 10,000 of vitamin K deficiency bleeding, which in severe cases can lead to death (e.g. from sudden cerebral haemorrhage). Newborns with liver or biliary disease, premature babies or malnourished infants in particular are at high risk because they cannot properly absorb and utilize the little vitamin K that is offered. The bleeding usually occurs in the first twelve weeks. All healthy newborns can therefore receive vitamin K prophylaxis. This is typically given either as 1 mg vitamin K intramuscularly (e.g. Australia, USA), 3 × 2 mg vitamin K 1 , orally at the age of 0, 1 and 4 weeks (e.g. in Germany (U1-U3) , Switzerland) or 1 mg orally after birth and then dosed 150 µg daily up to the 12th week (Netherlands). The risk of late bleeding from vitamin K deficiency can thus be reduced to 0: 100,000 or 0.44: 100,000. It should be noted, however, that a connection between the intramuscularly administered vitamin K dose for newborns and later leukemia diseases has been reported, which, based on recent studies, can be classified as very low, but cannot be clearly ruled out.

Malnutrition

A deficiency with blood clotting disorders can also occur through a diet that is poor in vitamin K. However, this is very rare and usually occurs as a mixed form with deficiencies in other nutrients or vitamins.

Fat absorption disorder

A vitamin K deficiency can be caused by a reduced intake of fat-soluble vitamins, e.g. B. be the result of exocrine pancreatic insufficiency .

Overdoses (hypervitaminoses)

Vitamin K 1 and vitamin K 2 are non-toxic even in high doses. There is no such thing as vitamin K hypervitaminosis , if you disregard the substitution treatment in newborns: Here, high doses of vitamin K can trigger hemolysis because the as yet undeveloped glucuronidation mechanism by vitamin K is so used in newborns that bilirubin is not glucuronidation can be increased sufficiently and an elimination disorder for bilirubin occurs ( neonatal icterus ), which can spread pathologically. This mainly concerned the use of menadione in vitamin K prophylaxis, which was used temporarily because it was supposed to be more safely absorbed as a water-soluble provitamin. Intramuscular administration of 1 mg vitamin K 1 after birth leads to a 100-fold increase in blood levels after 4 days.

literature

  • CG Victora, P. van Haecke: Vitamin K prophylaxis in less developed countries: policy issues and relevance to breastfeeding promotion. In: Am. J. Public. Health. 88: 203-209 (1998); PMID 9491008 ; PMC 1508196 (free full text, PDF).

Web links

Individual evidence

  1. ↑ Katja Wiemann: Contribution to the history of nutritional research in domestic chickens (until 1950) (PDF; 8.4 MB), University of Veterinary Medicine Hannover
  2. ^ Lecture by Henrik Dam on the Nobel Prize ceremony on December 12, 1945
  3. ↑ Information from the Nobel Foundation on the award ceremony in 1943 to Henrik Dam and Edward A. Doisy (English)
  4. ↑ a b c d e f H.K. Biesalsky (ed.): Nutritional medicine. 2nd Edition. Georg Thieme Verlag, Stuttgart 1999, ISBN 3-13-100292-1 .
  5. ↑ a b c d e f S. M. Plaza, DW Lamson: Vitamin K2 in bone metabolism and osteoporosis. In: Alternative medicine review: a journal of clinical therapeutic. Volume 10, Number 1, March 2005, pp. 24-35, PMID 15771560 (review).
  6. ↑ AM Craciun, C. Vermeer: Apolipoprotein E genotype may influence urinary gammacarboxyglutamate (Gla) concentrations in young individuals. In: General physiology and biophysics. ahead of print, July 2, 2013, PMID 23817635 , doi : 10.4149 / gpb_2013030
  7. ↑ M. Vos, G. Esposito et al. a .: Vitamin K2 Is a Mitochondrial Electron Carrier That Rescues Pink1 Deficiency. In: Science . 336, 2012, pp. 1306-1310, doi : 10.1126 / science.1218632 .
  8. ↑ D. Feskanich, P. Weber, WC Willett, H. Rockett, SL Booth, GA Colditz: Vitamin K intake and hip fractures in women: a prospective study. In: The American journal of clinical nutrition. Volume 69, Number 1, January 1999, pp. 74-79, PMID 9925126 .
  9. ↑ EFSA Journal 2009; 7 (9): 1228. Scientific Opinion on the substantiation of health claims related to vitamin K and maintenance of bone doi: 10.2903 / j.efsa.2009.1228
  10. ↑ a b c Iris Hinneburg: Osteoporosis: Does vitamin K protect against brittle bones? In: Medicine transparent . June 9, 2020, accessed August 27, 2020 .
  11. ↑ AS Dusso, AJ Brown, E. Slatopolsky: Vitamin D. In: American Journal of Physiology - Renal physiology. Volume 289, Number 1, July 2005, pp. F8-28, doi: 10.1152 / ajprenal.00336.2004 , PMID 15951480 (review).
  12. ^ DW Lamson, SM Plaza: The anticancer effects of vitamin K. In: Alternative medicine review: a journal of clinical therapeutic. Volume 8, Number 3, August 2003, pp. 303-318, PMID 12946240 (review).
  13. ↑ U. Göbel, R. von Kries: Vitamin K prophylaxis: protection against bleeding without cancer risk possible . In: Deutsches Ärzteblatt. Vol. 94 (1997), No. 46, pp. A-3109-3113.
  14. ↑ LJ Schurgers u. a .: Role of vitamin K and vitamin-K-dependent proteins in vascular calcification. In: Zeitschrift für Kardiologie Vol. 90 (2001), No. 3, pp. 57-63. PMID 11374034
  15. ↑ Geleijnse u. a .: Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study In: J Nutr. (2004) Nov; 134 (11), pp. 3100-3105, PMID 15514282
  16. ↑ Schurgers et al. a .: Regression of warfarin-induced medial elastocalcinosis by high intake of vitamin K in rats In: Blood . (2007) Apr 1; ​​109 (7), pp. 2823-2831, PMID 17138823
  17. ↑ Vitamin K in foods (PDF; 52 kB). From: Souci / Expert / Kraut: The Composition of Food - Nutritional Tables. 7th edition. 2008, ISBN 978-3-8047-5038-8 .
  18. ↑ Measurement errors with sauerkraut (PDF; 32 kB).
  19. ↑ a b "Canfield LM et al .: Vitamin K in colostrum and mature human milk over the lactation period - a cross-sectional study." Am J Clin Nutr. 1991 Mar; 53 (3): 730-5
  20. ↑ Vitamin K: Estimates for an adequate intake. German Nutrition Society , accessed February 2, 2017.
  21. ↑ Bruce Furie: Do Pharmacogenetics Have a Role in the Dosing of Vitamin K Antagonists ?. In: New England Journal of Medicine. 369, 2013, pp. 2345-2346, doi : 10.1056 / NEJMe1313682
  22. ↑ AH Sutor: Vitamin K deficiency bleeding in infants and children. A status report . In: Seminars in Thrombosis and Hemostasis , Vol. 21 (1995), pp. 317-329.
  23. ↑ See also Ludwig Weissbecker: Vitamin K avitaminosis (hypoprothrombinemia). In: Ludwig Heilmeyer (ed.): Textbook of internal medicine. Springer-Verlag, Berlin / Göttingen / Heidelberg 1955; 2nd edition ibid. 1961, p. 1089 f.
  24. ↑ AH Sutor et al. a .: Vitamin K Deficiency Bleeding (VKDB) in Infancy. In: Thrombosis and Haemostasis . Vol. 81 (1999), p. 457.
  25. ^ J. Peter de Winter, Koen FM Joosten, Marloes M. Ijland, Henkjan J. Verkade, Martin Offringa: [New Dutch practice guideline for administration of vitamin K to full-term newborns] . In: Nederlands Tijdschrift Voor Geneeskunde . tape 155 , no. 18 , January 1, 2011, p. A936 , PMID 21672291 .
  26. ↑ M. Cornelissen u. a .: "Prevention of vitamin K deficiency bleeding: efficacy of different multiple oral dose schedules of vitamin K", Eur J Pediatr, Vol. 156 (1997), p. 126.
  27. ^ R. von Kries, A. Hachmeister, U. Göbel: Can 3 oral 2 mg doses of vitamin K effectively prevent late vitamin K deficiency bleeding? In: Eur J Pediatr. Vol. 158 Suppl. 3 (1999), p. 183.
  28. ↑ J. Golding et al. a .: Childhood cancer, intramuscular vitamin K, and pethidine given during labor. In: BMJ . Vol. 305 (1992), pp. 341-346.
  29. ^ S. Passmore et al. a .: Case-control studies of relation between childhood cancer and neonatal vitamin K administration. In: BMJ. Vol. 316 (1998), p. 178.
  30. ↑ Silke Klapdor, Eva Richter, Rainer Klapdor: Fat-soluble vitamins in diseases of the pancreas. In: Ernahrung -Umschau , issue 08/12, pages 436–441.