Vitamin K and Cystic Fibrosis

C H A P T E R

23

Vitamin K and Cystic Fibrosis Mary Shannon Fracchia1, 2, Ronald E. Kleinman1, 2 1Department

of Pediatrics, Massachusetts General Hospital, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA

23.1 INTRODUCTION Vitamin K, a fat-soluble vitamin, takes its name from the German word koagulation, when it was discovered and reported in the German literature in 1929 to prevent hemorrhage in chickens. Vitamin K deficiency can be subclinical or present with symptoms that include full-blown coagulopathy. The typical presentation consists of easy bruising and mucosal bleeding. Newborn babies are at particular risk for vitamin K deficiency because vitamin K in maternal serum does not cross the placenta in amounts needed to support infant requirements in the perinatal period and human milk is a poor source for the nursing infant. Vitamin K prophylaxis is routinely given at birth to prevent hemorrhagic disease of the newborn. Less well known are more recent discoveries of the role of vitamin K in bone formation and the regulation of inflammation, particularly inhibition of arterial calcification. For patients with cystic fibrosis (CF), a chronic and progressive inflammatory disease, vitamin K may play several important roles that remain to be fully explored.

23.2  DIETARY SOURCES Naturally occurring vitamin K is present in several commonly consumed foods (Table 23.1). Specifically, vitamin K1 (phylloquinone, phytomenadione, phytonadione) is present in plants and is found in green leafy vegetables such as spinach, broccoli, and collard greens. Some vegetable oils, specifically soybean, canola, and cottonseed, also are sources of vitamin K1 [1]. Animal-based foods such as eggs, chicken, certain types of cheese, and butter contain vitamin K2 (menaquinones) [2]. Vitamin K2 is also synthesized by colonic bacteria. However, it is unclear how much intestinal bacteria contribute to total body vitamin K stores because bile salts are not present

Diet and Exercise in Cystic Fibrosis http://dx.doi.org/10.1016/B978-0-12-800051-9.00023-7

in the colon but they are needed to absorb vitamin K. Colonic bacteria can also convert vitamin K1 to vitamin K2. Most of the vitamin K directly measured in plasma is phylloquinone whereas more than 90% of the vitamin K stored in the liver consists of menaquinone [3].

23.3  VITAMIN K DIGESTION Vitamin K is a fat-soluble vitamin; thus, the presence of fat in the diet increases the intestinal absorption of dietary vitamin K. Plasma K1 levels highly correlate with serum triglyceride concentrations [1]. The pancreas secretes lipase, colipase, and phospholipases, enzymes required to hydrolyze triglycerides in advance of absorption. Therefore, those patients with pancreatic insufficiency are at particular risk for vitamin K deficiency. These include patients with CF and with other inherited disorders of pancreatic function such as Schwachman Diamond Syndrome as well as acquired conditions leading to pancreatitis and pancreatic exocrine failure. Newborn infants, patients with advanced liver disease, and those with significant small bowel resection are also at risk for fat malabsorption and fat-soluble vitamin deficiencies. Infants are born with a relatively sterile gut and do not get adequate quantities of vitamin K from placental transfer prepartum or from breast milk. Patients with liver disease have inadequate vitamin K stores and may have cholestasis and fat malabsorption, and those with significant small bowel resection have inadequate intestinal absorptive surface area.

23.4 BIOCHEMISTRY Biochemically, vitamin K is a group of 2-methyl1,4-naphthoquinone derivatives. Vitamin K is a cofactor for the enzyme γ-glutamyl carboxylase, which converts

187

Copyright © 2015 Elsevier Inc. All rights reserved.

188

23.  VITAMIN K AND CYSTIC FIBROSIS

TABLE 23.1  Dietary Sources of Vitamin K Vitamin K Content, μg/100 g

Vegetables and Herbs

Oils and Dairy

Vitamin K Content, μg/100 g

Parsley

900

Natto

Kale

817

Soybean

175

Collard greens

440

Canola

130

Spinach

360

Extra virgin olive

80

Brussel sprouts

275

Hard cheeses

76

Watercress

250

Soft cheeses

56

Green leaf lettuce

175

Mayonnaise

40

Cabbage

1000

90

Median values taken from Refs [1,3–5].

DĂůŶƵƚƌŝƟŽŶ

ŝĂďĞƚĞƐ

ŽŶĞ ĚŝƐĞĂƐĞ ŝŶ&

sŝƚĂŵŝŶ ĂŶĚ< ĚĞĮĐŝĞŶĐLJ

^ƚĞƌŽŝĚƵƐĞ

FIGURE 23.1  Cystic fibrosis (CF) and bone disease.

glutamic acid (gla) residues to γ-carboxyglutamic residues (Figure 23.1). These gla residues are calcium binding moieties present on prothrombin (as well as clotting factors II, VII, IX, and X and proteins C, S, and Z), the bone proteins osteocalcin and periostin, gla-rich protein, and matrix gla protein. Undercarboxylated prothrombin leads to abnormal clotting and bleeding whereas undercarboxylated osteocalcin (ucOC or Glu-OC) has been associated with osteopenia and osteoporosis. Serum concentrations of ucOC and prothrombin (plasma prothrombin in vitamin K absence II (PIVKAII)) are released from the liver into the blood and are highly sensitive measures of vitamin K status [6]. On the other hand, prothrombin time (PT) is an insensitive marker of vitamin K deficiency

because it is only prolonged in advanced deficiency states.

23.5  VITAMIN K AND CF Vitamin K insufficiency or deficiency is highly prevalent in patients with CF. CF, the most common lethal genetic disease in Caucasians, often presents with pancreatic insufficiency. Over 90% of CF patients are pancreatic insufficient because of an absent or malfunctioning cystic fibrosis transmembrane regulator (CFTR). CFTR is a multifunctional protein located at the apical membrane of epithelia and is mainly involved in modulation of transepithelial ion transport, hydration of epithelial lining fluids, pH regulation, and inflammation [7]. The absence of CFTR in the epithelial lining of the pancreas leads to a protein-rich, viscous exocrine fluid that obstructs the pancreatic ducts as early as the second trimester of gestation. This obstruction leads to autodigestion of the pancreas and therefore pancreatic insufficiency. Patients with pancreatic insufficiency have decreased or absent levels of trypsin, chymotrypsin, amylase, lipase, colipase, and phospholipases, which results in significant maldigestion/malabsorption of dietary macro- and micronutrients. As a result of the lack of those enzymes needed for fatty acid liberation and absorption, patients are at risk for growth failure, fat-soluble vitamin deficiencies (vitamins A, D, E, and K), rectal prolapse, and steatorrhea. In addition, in patients with CF, vitamin K stores are depleted because of low dietary intake, short bowel syndrome in those who have undergone bowel resection as a result of meconium ileus, and the frequent use of antibiotics that diminishes the intraluminal production of vitamin K by gut microorganisms [8]. Although vitamin K ultimately may be shown to play a role in regulating the inflammation that occurs in patients with CF, apart from observations that the vitamin-K-dependent matrix gla protein is a potent inhibitor of arterial calcification [9], this remains a largely unexplored area. In observational studies, inverse associations have been reported between phylloquinone intake and circulating phylloquinone and bone loss at the hip among the elderly [2]. The decreased bone mass and increased risk of fractures in patients with CF because of inactivity, delayed puberty, increased use of corticosteroids, and persistent systemic inflammation may also be affected by vitamin K status [7]. The mechanism of action of vitamin K on bone mineral density (BMD) is still being explored. The rate of bone turnover is a major determinant of BMD [10]; increased bone turnover leads to decreased bone density. Vitamin K appears to increase osteoblastogenesis and

C.  VITAMIN DEFICIENCY, ANTIOXIDANTS, AND SUPPLEMENTATION IN CYSTIC FIBROSIS PATIENTS

189

23.8  Vitamin K Supplementation in CF

decrease osteoclastogenesis, perhaps through gamma carboxylation of bone-related proteins, including osteocalcin [1].

23.6  DIAGNOSIS OF VITAMIN K DEFICIENCY

of 20%. Intracranial hemorrhage occurs in 50% of these infants [3] (Table 23.3).

23.8  VITAMIN K SUPPLEMENTATION IN CF

In Europe and North America the only pharmaceutical vitamin K preparation currently available is phylloquinone. Menaquinone-4 is available as a pharmaceutical preparation in Japan [2] and is approved for the prevention and treatment of osteoporosis there. Phylloquinone is available as oral, subcutaneous, intramuscular, and intravenous preparations. The American Academy of Pediatrics recommends a single intramuscular injection of 0.05–1.0 mg of vitamin K for all term infants within an hour of birth [12]. In contrast to repeated oral doses, intramuscular injection does not require parental compliance and protects against early- and late-onset deficiency. Late-onset vitamin K deficiency, seen in those infants that do not receive prophylactic supplemental vitamin K after birth and are exclusively breastfed from birth, occurs between 2 and 12 weeks of age. These infants present with a severe coagulopathy, with a mortality rate

There is extensive debate on how much supplemental vitamin K should be provided on a daily basis to patients with CF to achieve sufficiency. Table 23.3 presents the adequate intake of the daily reference intake of vitamin K by age. The 2002 Cystic Fibrosis Foundation guidelines [14] recommend a daily supplemental dose of vitamin K of 300–500 μg in patients with CF. A recent review by Jaganath [15] supports this recommendation. Vitamin K preparations are extremely safe and well tolerated [16]. However, Dougherty et al. [17] examined those factors that might predict vitamin K insufficiency in patients with CF and the daily dose of supplemental vitamin K needed to produce sufficiency in the study population. Subjects between the ages of 8 and 25 years with CF and pancreatic insufficiency and mild-to-moderate lung disease were recruited. Very importantly, a contemporary comparison group of healthy subjects aged 8–21 years was also recruited for this study. Anthropometric measures, body composition, sexual maturation, pulmonary function, and CFTR genotype were obtained. Total osteocalcin and ucOC (%ucOC) were determined in healthy and CF subjects with pancreatic insufficiency. PIVKAII and serum 25-hydroxyvitamin D were also obtained in the CF patients only. Dietary intake was assessed by using 3-day weighed food records. CF patients were divided into three groups according to vitamin K supplementation: <150  μg/day (low), 150–900 μg/day (mid), and >1000 μg/day (high). Overall, subjects with CF had a higher prevalence of vitamin K deficiency (on the basis of %ucOC) compared with healthy subjects. Of note, most healthy subjects

TABLE 23.2  Biomarkers of Vitamin K Deficiency

TABLE 23.3  The Adequate Intake (AI) of the Daily Reference Intake of Vitamin K by Age

As mentioned previously, ucOC (or Glu-OC) and prothrombin (PIVKAII) are serum markers of vitamin K deficiency. It is possible to directly measure serum phylloquinone concentration [8]. Measurements of serum levels of osteocalcin and prothrombin reflect vitamin K function. In healthy, well-nourished individuals, less than 20% of osteocalcin is undercarboxylated. Levels of 20–50% indicate insufficiency, and more than 50% undercarboxylation indicates vitamin K deficiency (Table 23.2).

23.7  VITAMIN K PREPARATIONS

Biomarkers

Normal Values

Values in Vitamin K Deficiency

Vitamin K1 (phylloquinone), μg/L

1.1

<1.1

PIVKAII, μg/L

<3

Undercarboxylated osteocalcin, μg/L

Group

AI

Babies 1–6 months

2 μg/day

Babies 7–12 months

2.5 μg/day

>3

Children 1–3 years

30 μg/day

<0.6

2.7 ± 1.00

Children 4–8 years

55 μg/day

Children 9–13 years

60 μg/day

Percentage undercarboxylated osteocalcin, %

<10

24 ± 1

Children 14–18 years

75 μg/day

Women

90 μg/day

Prothrombin time, s

11–13.5

Men

120 μg/day

Data taken from Refs [8,11].

>13.5

Data taken from Refs [3,4,13].

C.  VITAMIN DEFICIENCY, ANTIOXIDANTS, AND SUPPLEMENTATION IN CYSTIC FIBROSIS PATIENTS

190

23.  VITAMIN K AND CYSTIC FIBROSIS

(63%) were classified as insufficient, although none were deficient. The subjects with CF had median daily dietary intakes of vitamin K below the recommended adequate intake for age and sex of healthy children. Fifty-nine percent of CF subjects also did not meet their recommended daily energy intake. Only those children with CF and pancreatic insufficiency who received >1000 μg/day of vitamin K achieved a status similar to healthy subjects. The dose of supplemental vitamin K predicted vitamin K status for CF patients with pancreatic insufficiency.

23.9  TREATMENT OF VITAMIN K DEFICIENCY The treatment of patients with vitamin K deficiency is based on the International Normalized Ratio (INR). According to the guidelines put forth by the American College of Chest Physicians [18], patients with a normal INR and vitamin K deficiency should receive a single daily oral dose of 2.5 mg of vitamin K. Those patients with an INR between 1.5 and 1.8 should receive an initial intramuscular dose of 2.5 mg followed by an oral dose of 2.5 mg daily. Patients with an INR greater than 1.8 should receive 2–5 mg intramuscularly once followed by 5 mg orally once daily. Those patients with major bleeding from vitamin K antagonists should receive vitamin K intravenously. With severe obstructive liver disease, intramuscular or intravenous administration should be considered because intraluminal bile salts are needed for optimal absorption of oral vitamin K [19].

23.10 SUMMARY Patients with CF are at risk of vitamin K deficiency because of an inability to absorb fat because of pancreatic insufficiency. These patients are at risk for clotting disorders and decreased BMD. The most sensitive diagnostic test for vitamin K deficiency is ucOC. PIVKAII is also a sensitive marker of vitamin K deficiency. Supplementation with 0.3–0.5 mg/day of vitamin K is recommended for patients with CF, although larger doses may be more effective in preventing insufficiency.

References [1] Pearson D. Bone health and osteoporosis. The role of vitamin K and potential antagonism by anticoagulants. Nutr Clin Prac 2007;22:517. [2] Shea MK, Booth SL. Update on the role of vitamin K on skeletal health. Nutr Rev 2008;66(10):549–57. [3] Van Winckel M, De Bruyne R, Van De Velde S, Van Biervliet S. Vitamin K, an update for the paediatrician. Eur J Pediatr 2009;168:127–34. [4] Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K1. J Nutr 1998;128:785–8. [5] Shearer MJ. Vitamin K. Lancet 1995;345:229–34. [6] Conway S, Wolfe S, Brownlee K, White H, Holroyd B, Truscott J, et al. Vitamin K status among children with cystic fibrosis and its relationship to bone mineral density and bone turnover. Pediatrics 2005;115:1325–31. [7] Sermet-Gaudelus I, Castanet M, Retsch-Bogart, Aris RM. Update on cystic fibrosis-related bone disease: a special focus on children. Paediatr Respir Rev 2009;10:134–42. [8] Rashid M, Durie P, Andrew M, Kalnins D, Shin J, Corey M, et al. Prevalence of vitamin K deficiency in cystic fibrosis. Am J Clin Nutr 1999;70:378–82. [9] Fodor D, Albu A, Poanta L, Porojan M. Vitamin K and vascular calcifications. Acta Physiol Hug September 2010; 97(3):256–66. [10] Cashman K. Vitamin K status may be an important determinant of childhood bone health. Nutr Rev 2005;63:284–9. [11] Mummah-Schnedel LL, Suttie JW. Serum phylloquinone concentration in the adult population. Am J Clin Nutr November 1986;44(5):686–9. [12] American Academy of Pediatrics, Committee on Nutrition. Controversies concerning vitamin K and the newborn. Pediatrics 2003;112:191–2. [13] Wilson DC, Rashid M, Durie PR, Tsang A, Kalnins D, Andrew M, et al. Treatment of vitamin K deficiency in cystic fibrosis: effectiveness of a daily fat-soluble vitamin combination. J Pediatr 2001;138:851–5. [14] Borowitz D, Baker RD, Stallings V. Consensus report on nutrition for paediatric patients with cystic fibrosis. J Pediatr Gastroenterol Nutr 2002;35:246–59. [15] Jagannath VA, Fedorowicz Z, Thaker V, Chang AB. Vitamin K supplementation for cystic fibrosis. Cochrane Database Syst Rev 2013;4. [16] Conway SP. Vitamin K in cystic fibrosis. J R Soc Med 2004;97 (Suppl. 44):48–61. [17] Dougherty KA, Schall JI, Stallings VA. Suboptimal vitamin K status despite supplementation in children and young adults with cystic fibrosis. Am J Clin Nutr 2010;92:660–7. [18] Hirsh J, Guyatt G, Albers GW, Harrington R, Schünemann HJ. et al. Executive summary: ­American College of Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133(Suppl. 6):71–109. [19] Weber P. Vitamin K and bone health. Nutrition 2001;17:880–7.

C.  VITAMIN DEFICIENCY, ANTIOXIDANTS, AND SUPPLEMENTATION IN CYSTIC FIBROSIS PATIENTS