Vitamin K Deficiency

Kale For Vitamin K.

What Is Vitamin K?

Vitamin K is a family of fat-soluble vitamins, called K vitamers, that exists in three forms:

• K1 is a natural form found in plants (phylloquinone);
• K2, found in some animal foods, is synthesized in the intestine (menaquinone); and
• K3, is a synthetic form that must be activated in the liver (menadione).

Vitamin K is essential for the formation of clotting factors in blood and bone proteins and serves as a cofactor in the production of  proteins that regulate blood clotting.

Q: What are the clotting factors that require vitamin K in the regulation of blood clotting?

A: The clotting factors that require vitamin K in the regulation of  blood clotting are factors II, VII, IX, and X.   Low coagulation factors on blood assay indicate an altered secondary coagulation disorder that is characterized by impaired clot formation.

Each coagulation factor must be present in sufficient quantity in order for normal clotting to occur.

What Is Vitamin K Deficiency In Celiac Disease and/or Gluten Sensitivity?

• Vitamin K deficiency is a classic symptom of celiac disease that is characterized by impaired clotting function and bone mineralization.1
• In addition to antibiotic therapy, treatment with other drugs that influence vitamin K resorption and metabolism may increase the risk of bleeding in patients with celiac disease with low prothrombin levels.2.
• Hypercoagulable autoimmune diseases like lupus erythematosus and antiphospholipid syndrome, associated with celiac disease just add risk to the patients.3
• Celiac disease induces malabsorption and deficiency of factors essential for fetal organogenesis, including vitamin K.4
• Deficiency may increase the risk of calcification of arterial walls, particularly in individuals on vitamin D supplementation (vitamin D promotes calcium absorption).
• Due to its critical role in bone formation, long-term vitamin K deficiency may impair bone integrity and growth, eventually predisposing to osteoporosis.
• A bone mineral density study investigating the behavior of K-dependent factors after vitamin K administration in untreated children with celiac disease demonstrated that all parameters return to normal in 15 days on a gluten free diet when intestinal absorption is regained. However, vitamin K administration determined a rapid increase in clotting activity of all K-dependent factors after 24 hours for severely compromised, newly diagnosed patients on a gluten free diet.5

How Prevalent Is Vitamin K Deficiency In Celiac Disease and/or Gluten Sensitivity?

Vitamin K deficiency is common in patients with untreated celiac disease.6

In a study of children at diagnosis and at one year follow-up, twenty-five percent (25%) had suboptimal vitamin K status at diagnosis and all resolved after 1 year.7

What Are The Symptoms?

Vitamin K deficiency is marked by these symptoms of abnormal bleeding, although mild deficiency may not affect clotting mechanisms:

• Easy bruising.
• Nosebleeds.
• Bleeding gums.
• Gastrointestinal bleeding.
• Excessive menstrual bleeding.
• Blood in the urine.
• In chronic deficiency, osteoporosis occurs.
• Increased risk of bone fractures.

How Does The Body Get Vitamin K?

• Most of the vitamers K from the diet are absorbed across the small intestine by micelle-dependent diffusion which requires a minimum of dietary fat, as well as, adequate biliary and pancreatic function.1
• Vitamin K1, found mainly in vegetables, is harder to absorb than vitamin K2, found mainly in animal foods, which is easily absorbed.

What Does Vitamin K Do in the Body:

1. Helps to form osteocalcin, a protein necessary for the mineralization of bone.
2. Protects against bone fracture in post-menopausal women.
3. Aids in the formation of glucose into glycogen for storage in the liver.
4. Promotes the prevention and reversal of arterial calcification, plaque progression and lipid peroxidation in atherosclerosis.

How Does Vitamin K Deficiency Develop In Celiac Disease and/or Gluten Sensitivity?

Vitamin K deficiency in celiac disease results from these mechanisms:

• Malabsorption due to gluten enteropathy.8
• Loss in diarrhea.
• Failure to produce it in the colon due to dysbiosis (unbalanced microbe population).

Does Vitamin K Deficiency Respond To Gluten-Free Diet?

Yes. Celiac disease-related vitamin K deficiency responds quickly to gluten free diet.

6 Steps To Correct Vitamin K Deficiency:

• 1Meet, or Exceed the RDA (Recommended Dietary Allowances) for Vitamin K in micrograms (mcg) per day:

• 2Diet – Include Food Sources Richest in Vitamin K:

• 3 Diet – Avoid, Limit, or Eat Separately These Foods That Deplete or Interfere With Absorption:

• 4Monitor Medications That Deplete or Interfere With Absorption:

• 5Manage Nutritional Supplements to Obtain Vitamin K:

• 6Other Supplements That Deplete or Interfere With Absorption:

What Do Medical Research Tell About Vitamin K Deficiency In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“Vitamin D and K status influences bone mineral density and bone accrual in children and adolescents with celiac disease.” This study investigating the interrelationships between vitamin K/vitamin D status and lifestyle variables on bone mineral density (BMD) in children and adolescents with celiac disease at diagnosis and after 1 year on the gluten-free diet found that children and adolescents with celiac disease are at risk for suboptimal bone health at time of diagnosis and after 1 year on GFD likely due in part to suboptimal vitamin D/vitamin K status. “Therapeutic strategies aimed at optimizing these vitamin intakes may contribute to improved BMD in children with celiac disease.”

Children and adolescents aged 3-17 years with biopsy proven CD at diagnosis and after 1 year on the GFD were studied. BMD was measured using dual-energy X-ray absorptiometry. Relevant variables included: anthropometrics, vitamin D/K status, diet, physical activity and sunlight exposure.

Whole-body and lumbar-spine BMD-z scores were low (< or = -1) at diagnosis (10-20%) and after 1 year (30-32%) in the children, independent of symptoms. Whole-body BMD-z scores (-0.55±0.7 versus 0.72±1.5) and serum levels of 25(OH) vitamin D (90.3±24.8 versus 70.5±19.8 nmol/l) were significantly lower in older children (>10 years) when compared with younger children (< or =10 years) (P<0.001). Forty-three percent had suboptimal vitamin D status (25(OH)-vitamin D <75 nmol/l) at diagnosis; resolving in nearly half after 1 year on the GFD. Twenty-five percent had suboptimal vitamin K status at diagnosis; all resolved after 1 year.7

“Adult celiac disease with thrombosis: a case series of seven patients. Role of thrombophilic factors.” This retrospective study investigating clinical features and risk factors for thrombosis that may occur in adult celiac disease provides evidence that risk factors for thrombosis should be identified in patients in adult celiac disease in order to correct them and add a thromboembolic prophylaxis or prevention.

 Of 87 patients with adult celiac disease  seven cases of thrombosis were identified. Researchers looked to see if risk factors for thrombosis were identified and tested retrospectively antiphospholipid antibodies on the serum.

Results: The overall prevalence of thrombosis was 8 %, and 5.7 % for spontaneous thrombosis. Five patients had venous thrombosis, one had arterial thrombosis, and two had both. The seven patients consisted in six women and one man with a mean age of 44.8 years at time of thrombosis. Thrombotic events occurred before the diagnosis of celiac disease in four cases. In three cases, venous thrombosis was in unusual sites: 2 in the portal vein and one splenic vein thrombosis.

In six cases, risk factors for thrombosis were identified, which could be linked to celiac disease:one case of hyperhomocysteinemia, 3 cases of protein C and S deficiency due to vitamin K deficiency, and 2 cases of antiphospholipid antibodies.9

“Effect of the therapy with vitamin K on coagulation factors in celiac disease in children.” Study investigating the behavior of K-dependent factors after vitamin K administration in 37 untreated children with celiac-disease demonstrated that all parameters return to normal in 15 days on a gluten free diet when intestinal absorption is regained. However, Vitamin K administration determined a rapid increase in clotting activity of all K-dependent factors after 24 hours for severely compromised, newly diagnosed patients on a gluten free diet.

The children were randomized into two groups: 22 children receiving a single dose of 10 mg i.m. of Phytonadione (Konakion, Roche) on the initial day of GFD and 15 children who did not receive vitamin K administration. Prothrombin time (PT), PTT and clotting activity of Factors II, VII, IX, X were determined before the treatment and/or gluten free diet, and after 24 hours, 7 and 15 days. The results demonstrated that vitamin K administration determined a rapid increase in clotting activity of all K-dependent factors after 24 hours. These values remained normal after 7 and 15 days, except for Factor II, which slightly decreased on the 7th day.

On the contrary, the children not treated, had levels similar to those of acute stage. After 7 days these values showed a slight increase and reached normal limits on the 15th day. No significant changes were seen in either PT or PTT in the two groups. They were constantly prolonged, reaching normal limits on the 15th day. These results indicate that the vitamin K deficiency, not only seems constant in children with cleic disease, but also seems responsible for the hemocoagulative deficit of the K-dependent factors. After gluten free diet when intestinal absorption is regained, all parameters returned to normal. The Authors concluded that K-dependent factors can be used as short-term indexes of improved intestinal absorption and that the celiac children with severely compromised nutritional status can be treated with vitamin K (10 mg bolus).5

CASE REPORT SUMMARIES

“Celiac disease causing symptomatic hypocalcaemia, osteomalacia and coagulapathy.” This case report describes diagnosing celiac disease in a 36-year-old gentleman who presented with 6 months of poor energy, tingling in fingers and weight loss with a change in bowel habit. He appeared cachectic and had clubbing, demineralisation of teeth, pectus carinatus, kyphosis, spinal tenderness, proximal muscle weakness and generalised muscle atrophy. Chvostek’s and Trosseau’s signs were positive. His hemoglobin (Hb) was 8.7 g/dl, MCV 64.7 fl with low iron. Calcium corrected was 1.30 nmol/l, parathyroid hormone 440.4 ng/l, vitamin D <12.5 nmol/l; INR was 2.7 with coagulation inhibitor studies negative. Radiographs of spine and pelvis commented on osteopenia with thoracic kyphosis and mild anterior wedging of thoracic vertebrae. Antitissue transglutaminase was 145 U/ml, and antiendomysial antibodies were positive. An esophagogastroduodenoscopy was consistent with celiac disease. A diagnosis of osteomalacia and coagulopathy secondary to celiac disease was made.

The hypocalcaemia was treated with calcium gluconate infusions with symptomatic relief. Coagulopathy was treated with vitamin K intravenously with normalisation of INR (international normalised ratio), a lab measurement to determine coagulation.10

“Supplemental vitamin K improves the stability of anticoagulation in a patient with low tissue stores of vitamin K secondary to coeliac disease.” This case report describes the unstable course a 57-year-old with celiac disease requiring warfarin for a metallic mitral valve, who had poor INR stability (international normalised ratio is a lab study showing prothrombin time or the time it takes blood to clot) resulting in thrombotic and bleeding complications. Her vitamin K body stores were extremely low. Supplementation of vitamin K (100 μg daily) resulted in improvement in anticoagulation stability. The percentage time spent within target INR range doubled following vitamin K supplementation.

Serology revealed an anti-gliadin antibody level of >100 units and an anti-tissue transglutaminase level of >100 units, suggesting poor adherence to a gluten-free diet. Malabsorption was further supported by low levels of vitamin B12 (109 pmol/litre; normal range 148–443) and folate (1.9 ng/ml; normal range 3.5–16.1). “This case illustrates a relatively new approach to managing patients with highly unstable INR levels and provides extra understanding of factors influencing INR stability.”11

“Celiac disease with diffuse cutaneous vitamin K-deficiency bleeding.” This case report describes diagnosing celiac disease in a 4 year old girl with spontaneous, generalized bruising, abdominal distention, and signs of malnutrition. She had been treated previously with an antibiotic for diarrhea. Laboratory analyses showed the presence of iron-deficiency anemia, mild hypoalbuminemia, and considerably prolonged prothrombin time and activated thromboplastin time.

Tests revealed that blood clotting improved after the patient received fresh frozen plasma. A coagulation profile showed a decrease in clotting factors II, VII, IX, and X. The patient was given intravenous vitamin K therapy (5 mg/d) for 3 days. All coagulation tests were normalized, and bruising started to disappear. Positive serology (immunoglobulin A antitissue transglutaminase and immunoglobulin A antiendomysial antibodies) and small bowel mucosal histopathology confirmed the presence of celiac disease. The girl recovered completely after she was put on a gluten-free diet. “Vitamin K-deficiency bleeding is a rare complication that occurs almost exclusively in patients with typical celiac disease manifestations. In addition to antibiotic therapy, treatment with other drugs that influence vitamin K resorption and metabolism may increase the risk of bleeding in patients with celiac disease with low prothrombin levels.”12.

1. Kathleen Mahan and Sylvia Escott-Stump, ed. Krause’s Food, Nutrition & Diet Therapy, 10th Edition. Philadelphia, PA. USA: W.B. Saunders Company, 2000. [↩] [↩] [↩]
2. Djuric Z, Zivic S, Katic V. Celiac disease with diffuse cutaneous vitamin K-deficiency bleeding. Adv Ther. 2007 Nov-Dec;24(6):1286-9 [↩]
3. Lerner A, Blank M. Hypercoagulability in celiac disease – An update. Autoimmun Rev. 2014 Aug 20. pii: S1568-9972(14)00146-3. doi:10.1016/j.autrev.2014.07.004. [↩]
4. Stazi AV, Mantovani A. A risk factor for female fertility and pregnancy: celiac disease. Gynocological and Endocrinology. Dec 2000;14(6):454-463. [↩]
5. Bottaro G, Fichera A, Ricca O, Praticò G, Ciulla U, Trifiletti A, Iudica ML, Failla P, Patanè R. Effect of the therapy with vitamin K on coagulation factors in celiac disease in children. Pediatr Med Chir. 1986 Jul-Aug;8(4):551-4. [↩] [↩]
6. Murray JA, the widening spectrum of celiac disease. American Journal of Clinical Nutrition. Mar 1999; 69(3):354-365. [↩]
7. Mager DR1, Qiao J, Turner J. Vitamin D and K status influences bone mineral density and bone accrual in children and adolescents with celiac disease. Eur J Clin Nutr. 2012 Apr;66(4):488-95. doi: 10.1038/ejcn.2011.176. [↩] [↩]
8. Lerner A, Blank M. Hypercoagulability in celiac disease – An update. Autoimmun Rev. 2014 Aug 20. pii: S1568-9972(14)00146-3. doi:10.1016/j.autrev.2014.07.004. [↩]
9. Berthoux E1, Fabien N, Chayvialle JA, Ninet J, Durieu I. Adult celiac disease with thrombosis: a case series of seven patients. Role of thrombophilic factors. Rev Med Interne. 2011 Oct;32(10):600-4. doi: 10.1016/j.revmed.2011.02.025. [↩]
10. McNicholas BA, Bell M. Coeliac disease causing symptomatic hypocalcaemia, osteomalacia and coagulapathy. BMJ Case Rep. 2010 Dec 1;2010. pii: bcr0920092262. doi: 10.1136/bcr.09.2009.2262. [↩]
11. Janeczko CE, Sweeney K, Connaghan G. Supplemental vitamin K improves the stability of anticoagulation in a patient with low tissue stores of vitamin K secondary to coeliac disease. BMJ Case Rep. 2009;2009. pii: bcr10.2008.1067. doi: 10.1136/bcr.10.2008.1067. [↩]
12. Djuric Z, Zivic S, Katic V. Celiac disease with diffuse cutaneous vitamin K-deficiency bleeding. Adv Ther. 2007 Nov-Dec;24(6):1286-9 [↩]