AJCN Tufts Nutrition Symposium, Boston & Online Sept 2009
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rashid, M.
Right arrow Articles by Pencharz, P. B
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rashid, M.
Right arrow Articles by Pencharz, P. B
Agricola
Right arrow Articles by Rashid, M.
Right arrow Articles by Pencharz, P. B
American Journal of Clinical Nutrition, Vol. 70, No. 3, 378-382, September 1999
© 1999 American Society for Clinical Nutrition

Original Research Communications

Prevalence of vitamin K deficiency in cystic fibrosis1,2,3

Mohsin Rashid, Peter Durie, Maureen Andrew, Daina Kalnins, Janey Shin, Mary Corey, Elizabeth Tullis and Paul B Pencharz

1 From the Divisions of Gastroenterology and Nutrition and Haematology, the Research Institute, The Hospital for Sick Children, Department of Medicine, St Michael's Hospital, Toronto, and the Departments of Paediatrics and Medicine, University of Toronto.

2 Supported by a grant from Scandipharm Inc, Birmingham, AL. MR was supported by the Duncan Gordon Fellowship by the Hospital for Sick Children Foundation and a grant from Janssen Pharmaceutica.

3 Address reprint requests to PB Pencharz, Division of Gastroenterology and Nutrition, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Canada M5G 1X8. E-mail: paul.pencharz{at}sickkids.on.ca.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Patients with cystic fibrosis (CF) are at risk of developing vitamin K deficiency because of pancreatic insufficiency, hepatobiliary disease, or both.

Objective: Our objective was to determine the prevalence of vitamin K deficiency in unsupplemented patients with CF and to identify risk factors that might be associated with the deficiency.

Design: Ninety-eight patients with CF—83 who were pancreatic insufficient (age: 15.2 ± 10.7 y; range: 0.6–45.8 y), 15 who were pancreatic sufficient (age: 26.2 ± 11.6 y; range: 6.5–45.3 y), and 62 healthy individuals (age: 16.2 ± 12.8 y; range: 1–45 y)—were studied prospectively. None had taken vitamin K supplements. Eight pancreatic-insufficient patients had advanced CF-associated liver disease. Plasma prothrombin in vitamin K absence (PIVKA-II) was measured by immunoassay. All control subjects had PIVKA-II concentrations <3 µg/L.

Results: Seventy-eight percent of pancreatic-insufficient patients had PIVKA-II concentrations >=3 µg/L (22.8 ± 35.7 µg/L). All patients with CF-associated liver disease had abnormal PIVKA-II concentrations. The mean PIVKA-II concentration of pancreatic-insufficient patients with liver disease was greater than that of those without liver disease (46.6 ± 65.3 compared with 15.3 ± 26.1 µg/L; P < 0.05). Five pancreatic-sufficient patients had mildly elevated PIVKA-II concentrations. Six (7%) pancreatic insufficient patients (3 with CF-associated liver disease) had mildly prolonged prothrombin time but no clinical bleeding. There was no correlation between PIVKA-II concentrations and severity of fat malabsorption or antibiotic use.

Conclusions: Vitamin K deficiency is common in unsupplemented patients with CF and pancreatic insufficiency and routine supplementation should be considered in all of these patients.

Key Words: Cystic fibrosis • vitamin K • PIVKA-II • cystic fibrosis–associated liver disease • prothrombin • {gamma}-glutamyl hydrolase


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients with cystic fibrosis (CF) are at risk of developing deficiencies of fat-soluble vitamins (A, D, E, and K) because of pancreatic insufficiency, hepatobiliary disease, or both (1, 2). Vitamin K is widely distributed in many foods (vitamin K1, or phylloquinone) and is also produced by intestinal bacteria (vitamin K2, or menaquinone). Factors in CF that predispose patients to vitamin K deficiency may include malabsorption, cholestatic or noncholestatic liver disease, and chronic antibiotic intake.

Vitamin K is a cofactor essential for posttranslational carboxylation of glutamic acid residues in many proteins in the body (3). These include proteins involved not only in coagulation (factors II, VII, IX, and X) but important proteins in bones (osteocalcin and matrix Gla protein) and other organs. In vita-min K deficiency, incompletely carboxylated proteins, which are functionally defective, appear in the plasma. These are called PIVKA (proteins induced by vitamin K absence). PIVKA-II is a measure of decarboxylated prothrombin and its presence is a sensitive marker for early vitamin K deficiency (4–7).

The question of whether vitamin K supplements need to be taken by patients with CF and pancreatic insufficiency has been raised (8, 9). The previous studies examining the issue of vita-min K status in CF were limited by small sample sizes, lack of control subjects, and other methodologic problems (1, 10–14). The true prevalence of vitamin K deficiency in CF is not known and recommendations regarding routine supplementation are therefore controversial. The aim of the present study was to determine the prevalence of vitamin K deficiency in unsupplemented patients with CF and, if present, to identify risk factors that might be associated with the deficiency.


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
The study subjects were prospectively and randomly selected from patients attending a pediatric (The Hospital for Sick Children, Toronto) and adult (Wellesley Hospital, Toronto) CF clinic. Informed consent was obtained from all patients. The study was approved by the ethics review boards of the participating hospitals. On the basis of the characteristic clinical features and abnormal sweat test results, all 98 patients were known to have CF. Fecal fat balance studies (72 h) had been done routinely on these patients to assess the presence and degree of steatorrhea. Briefly, 72-h weighed dietary records were kept and fat intake was determined by using a computerized nutrient database. Feces were collected for 72 h and analyzed in the Clinical Chemistry Laboratory at The Hospital for Sick Children by using the method of Vandekamer et al (15). Eighty-three patients were pancreatic insufficient and 15 were pancreatic sufficient. Pancreatic insufficiency was defined as fecal fat excretion >=7% of fat intake (>=15% of fat intake in infants <6 mo old). Pancreatic sufficiency was defined as fecal fat excretion <7% of intake (or <15% in young infants; 16). Patients with pancreatic sufficiency did not receive pancreatic enzyme replacement therapy. A subgroup of 8 pancreatic-insufficient patients had advanced CF-associated liver disease characterized by multifocal biliary cirrhosis and portal hypertension.

Patients with pancreatic insufficiency were taking pancreatic enzyme supplements with meals and supplements of vitamins A, E, and D. None of the patients with CF had been taking any vitamin K supplements in the previous 6 mo. Clinical information derived from the patient's medical history and charts included the use of oral or parenteral antibiotics in the previous 4 wk and the degree of steatorrhea. Plasma from a group of 62 healthy subjects with a similar age and sex distribution was obtained for control data.

Plasma PIVKA-II concentrations were measured with a sensitive enzyme-linked immunosorbent assay (ELISA) by using a commercially available kit (Diagnostica Stago; Asnière, France) (17). The test was sensitive to PIVKA-II concentrations >2 µg/L. Prothrombin time was also measured.

Data are expressed as means ± SDs. For PIVKA-II values <=2 µg/L, a value of 2 µg/L was assigned. The Kruskal-Wallis test was used to test for differences between groups. Spearman rank correlation coefficients were used to evaluate the possible association of PIVKA-II concentration with age and degree of fat malabsorption. A value of P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The clinical features of the CF patients and control subjects are shown in Table 1Go. There were 61 (62% of subjects) children (aged <18 y) with CF, 4 of whom were pancreatic sufficient. PIVKA-II results are shown in Figure 1Go. All control subjects had PIVKA-II concentrations <3 µg/L: 89% had undetectable PIVKA-II concentrations (ie, <2 µg/L) and the remaining had concentrations between 2 and 3 µg/L. Furthermore, there were no significant differences with age. Therefore, a PIVKA-II >=3 µg/L was considered abnormal in further statistical analyses.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Ages of patients with cystic fibrosis and healthy control subjects1
 


View larger version (8K):
[in this window]
[in a new window]
  		FIGURE 1. Individual plasma concentrations of prothrombin induced in vitamin K absence (PIVKA-II) in control subjects (n = 62) and patients with cystic fibrosis: PI, pancreatic insufficient without liver disease (n = 75); PI-liver, pancreatic insufficient with liver disease (n = 8); and PS, pancreatic sufficient (n = 15). The values for the control subjects show the range of normal; a PIVKA-II concentration >=3 µg/L was considered abnormal (dotted line indicates 3 µg/L). PI-liver patients had PIVKA-II concentrations greater than those of PI patients (P < 0.05), which, in turn, were greater than those of PS patients (P < 0.05). Because most values are <50 µ/L, values >50 µ/L are collapsed to make the figure clearer.

 
Individual PIVKA-II values for patients with CF are shown in Figure 1Go according to pancreatic sufficiency. Overall, most (70 of 98) patients with CF had abnormal PIVKA-II concentrations. Those with pancreatic insufficiency had a wide range of PIVKA-II concentrations (2–200 µg/L), of which 65 (78%) had PIVKA-II concentrations >3 µg/L. The mean (±SD) PIVKA-II concentration of the pancreatic-insufficient group was 22.8 ± 35.7 µg/L (median: 7.5 µg/L). All 8 pancreatic-insufficient patients with CF-associated liver disease had abnormal PIVKA-II concentrations. The PIVKA-II concentration of pancreatic-insufficient patients with liver disease was greater than that of pancreatic-insufficient patients without liver disease (46.6 ± 65.3 compared with 15.3 ± 26.1 µg/L; P < 0.05).

Five pancreatic-sufficient patients (all adults) had mildly elevated PIVKA-II concentrations. The mean PIVKA-II concentration of pancreatic-sufficient patients was 3.4 ± 2.2 compared with 22.8 ± 35.7 µg/L for pancreatic-insufficient patients (P < 0.05). All patients at our clinics classified with pancreatic sufficiency are tested annually for serum trypsinogen concentrations (16) to confirm their status. Note that the pancreatic-sufficient patient with the highest PIVKA-II concentration (10 µg/L) had recently shown a decrease in his serum trypsinogen concentration, which prompted a repeat fecal fat balance study that showed abnormal fat absorption (84% of intake). It is likely that this patient was becoming pancreatic insufficient at the time of the PIVKA-II measurement. None of the remaining 4 pancreatic-sufficient patients had shown any change in their serum trypsinogen concentrations.

Fifty-nine (72%) of the pancreatic-insufficient patients were taking antibiotics or had taken antibiotics in the previous 4 wk. However, antibiotic use appeared not to have an effect on the proportion of pancreatic-insufficient patients with abnormal PIVKA-II concentrations (76% of those taking antibiotics compared with 83% of those not taking antibiotics; NS). In the pancreatic-sufficient group, 7 were taking antibiotics. Of the 5 pancreatic-sufficient patients with abnormal PIVKA-II concentrations, 2 were taking antibiotics. No significant difference in PIVKA-II concentrations was observed between patients taking antibiotics and those not taking antibiotics in either the pancreatic-insufficient or pancreatic-sufficient groups.

There were no significant differences in PIVKA-II concentrations between male and female patients. Age was not significantly correlated with PIVKA-II concentration, although we noted that greatly elevated PIVKA-II concentrations (>30 µg/L) were not seen in patients >22 y of age.

Six pancreatic-insufficient patients had mildly prolonged prothrombin time (>13.5 but <15.5 s), which included 3 patients with CF-associated liver disease. All of these patients had elevated PIVKA-II concentrations (range: 5–200 µg/L). None had clinical evidence of bleeding. None of the pancreatic-sufficient patients or control subjects had abnormal prothrombin times.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Previous studies of vitamin K status in CF patients have produced conflicting and inconclusive results (1, 10–14). Similarly, there are no consensus recommendations concerning the need for vitamin K supplementation in patients with CF. One of the drawbacks of these earlier studies was their small sample sizes (24–43 patients), which makes it difficult to assess the risk factors for vitamin K deficiency (severity of steatorrhea, antibiotic use, and presence of liver disease). Furthermore, in some studies, data from supplemented and unsupplemented patients were combined (12, 13). Moreover, the differences in results could also have been due to the variation in the laboratory tests used to assess vitamin K deficiency (9).

There are several laboratory methods of assessing vitamin K status (4–7, 18–23). Briefly, it is possible to measure phylloquinone directly by HPLC (23) and {gamma}-carboxylation of glutamate residues in clotting proteins (ie, PIVKA-II) or bone proteins (undercarboxylated osteocalcin) (21–23). Finally, measurement of urinary {gamma}-carboxyglutamic acid is a reflection of the release of {gamma}-glutamate derived from the breakdown of {gamma}-carboxylated proteins. A limitation of measuring phylloquinone concentrations is that they reflect primarily recent dietary intake. Conversely, measurement of the {gamma}-carboxylation of proteins is a measure of vitamin K function. The recent focus has been on finding improved functional endpoints with which to assess vitamin K status (4, 5, 21–23). Vitamin K is essential for the posttranslational carboxylation of glutamic acid residues in many proteins (3, 6), notably those involved with coagulation and the bone matrix. Both measurement of serum osteocalcin and urinary excretion of {gamma}-carboxyglutamic acid have been described (4, 7). Decreases in urinary {gamma}-carboxyglutamic acid excretion in vitamin K–deficient individuals appear to be age dependent until age 50 y, after which little change is seen (7, 22). In the present study, no age-dependent changes were detected.

Prolonged prothrombin time is a late indicator of vitamin K deficiency. Conversely, PIVKA-II concentration has proven to be a sensitive indicator of early vitamin K deficiency (4, 7). The PIVKA-II concentration in plasma can be measured by numerous methods, including cross-immunoelectrophoresis, absorption of the physiologic prothrombin followed by measurement of PIVKA-II, the ratio of physiologically activated prothrombin to total prothrombin, and by an immunoassay using a specific antibody. The antibody test is the most sensitive (24). Plasma phylloquinone concentrations have also been measured, but do not correlate well with functional measures of vitamin K status (4, 25).

Phylloquinone concentrations were shown to fall dramatically and significantly in response to a vitamin K–deficient diet in healthy subjects, whereas PIVKA-II concentrations increased only slightly (7). Blood coagulation was not affected despite reductions in phylloquinone and small but significant increases in PIVKA-II concentrations (7). In another study, healthy subjects were given very low doses of the vitamin K antagonist warfarin. This treatment increased concentrations of under-{gamma}-carboxylated proteins, including PIVKA-II, but did not increase prothrombin time (5). The present evidence suggests that plasma phylloquinone concentrations are a marker of short-term vitamin K insufficiency, and they fall more dramatically and earlier than do functional measures of vitamin K status, such as PIVKA-II concentrations. Phylloquinone concentrations, which are measured by HPLC, are seldom clinically available. Therefore, functional assays such as prothrombin time have been relied on. The work summarized above (5, 7) showed that prothrombin time is a very insensitive assay of vitamin K status. Therefore, more sensitive functional assays, such as PIVKA-II concentration, are currently being used (4, 5, 7, 25).

Traditionally, vitamin K has been regarded as a vitamin necessary for hemostasis. However, there is emerging evidence that it has important roles in the production of many other proteins in the body (25). Osteocalcin and matrix {gamma}-carboxyglutamic acid protein are 2 of the vitamin K–dependent bone proteins (25–31). Although there is still uncertainty regarding the importance of vitamin K in bone growth and bone mineralization, a deficiency of vitamin K in CF patients may adversely affect skeletal growth. Clearly, this is an area that deserves careful future study.

This is the first large, prospective study of the prevalence of vitamin K deficiency in patients with CF; importantly, none of the patients had received supplemental vitamin K in the preceding 6 mo. Specific factors that are reported to increase the possibility of vitamin K deficiency are fat malabsorption (which is thought to worsen the absorption of dietary phylloquinone, a fat-soluble vitamin), chronic use of antibiotics (which may alter colonic flora and reduce the biosynthesis of menaquinones; 32–34), and liver disease (which may worsen fat absorption by further reducing the bile salt pool and may reduce the synthesis of clotting factors; 35).

Clearly, having normal fat absorption reduces the prevalence and degree of elevation of PIVKA-II concentrations. However, it is not clear why one-third of the CF patients with pancreatic sufficiency in our study had mildly elevated PIVKA-II concentrations. All of our patients have fecal fat absorption studies carried out at diagnosis (8). Those classified as pancreatic sufficient have had their serum trypsinogen concentrations monitored annually (16). Subsequent fecal fat studies were carried out if their trypsinogen concentrations fell, or if clinically indicated. As mentioned above, 1 of the 5 patients classified as being pancreatic sufficient (the pancreatic-sufficient patient with the highest PIVKA-II concentration) was noted some months after measurement of his PIVKA-II concentration to have a reduced trypsinogen concentration and a subsequent fecal fat study showed fat malabsorption. This patient was probably developing pancreatic insufficiency at the time that his PIVKA-II concentration was being measured. However the trypsinogen concentrations of the remaining 4 pancreatic-sufficient patients with elevated PIVKA-II concentrations have remained normal. It is possible that measurement of serum trypsinogen concentration is not sensitive enough to detect patients whose fat digestion is bordering on malabsorption.

All 8 of the patients with CF-related liver disease had abnormally elevated PIVKA-II concentrations, suggesting that these patients should receive vitamin K supplements. Liver disease is known to adversely affect {gamma}-carboxylation of liver proteins, which can be corrected by giving more vitamin K (35). Furthermore, elevated PIVKA-II concentrations have been shown to be a marker of hepatocellular carcinoma (36). However, we have yet to diagnose liver cancer in any of our patients. Of the remaining 75 patients with pancreatic insufficiency but no clinically evident liver disease, 57 had abnormally elevated PIVKA-II concentrations. Because an elevated PIVKA-II concentration is regarded as a sensitive marker of vitamin K deficiency (4, 21), this would imply that the risk of subclinical vitamin K deficiency is high in patients with CF and pancreatic insufficiency, even in the absence of liver disease.

We also attempted to determine whether antibiotic use is a risk factor for developing vitamin K deficiency as measured by elevated PIVKA-II concentration. The importance of the endogenously synthesized menaquinones in meeting vitamin K needs is controversial (34). In our study, we found no effect of antibiotic use on vitamin K status. In future studies it would be desirable to examine PIVKA-II concentrations before and after a course of antibiotic therapy. Beker et al (14), in their randomized crossover study of weekly administration of phylloquinone supplements to patients with CF, were unable to show any effects of antibiotic administration.

In view of the high prevalence of vitamin K deficiency in patients with CF, our next step will be to investigate the effects of vitamin K supplementation on patients with pancreatic insufficiency. Sokol et al (1) studied 21 infants in whom CF was diagnosed within 6 wk of age and none had vitamin K deficiency on the basis of PIVKA-II concentrations. Sixteen of these infants were followed prospectively. After multivitamin supplementation (without vitamin K) and pancreatic enzyme replacement, their vitamin K status remained normal at 6 and 12 mo of age. PIVKA were identified by plasma immunoelectrophoresis. The investigators concluded that routine vitamin K supplementation is not required in infants diagnosed by newborn screening unless they are receiving antibiotics. All of these infants had received parenteral vitamin K at birth. Moreover, vitamin K deficiency in these infants could have been prevented by intake of vitamin K–enriched infant formulas. Because CF in these infants was diagnosed by newborn screening, they would be younger than children whose CF was diagnosed by symptoms and would not have suffered prolonged periods of malabsorption.

More recently, Beker et al (14) examined the effect of oral phylloquinone supplementation in a small number of mostly adult CF patients with pancreatic insufficiency but no CF-associated liver disease. Using serum osteocalcin, plasma PIVKA-II, and phylloquinone measurements, the investigators showed an improvement but not complete normalization of vitamin K status after oral supplementation with phylloquinone (5 mg given weekly). Most directly relevant to our study is that in only 5 of the 18 subjects studied did PIVKA-II concentrations become normal. Sokoll and Sadowski (22) suggested that 100–400 µg phylloquinone is required daily in adults (with normal fat absorption). It is not known whether weekly vitamin K supplements are as effective as daily supplements. Furthermore, what are the effects of fat malabsorption on the amount of supplemental vitamin K that needs to be given? These issues urgently need to be investigated.

In conclusion, vitamin K deficiency is very common in unsupplemented patients with CF and pancreatic insufficiency. Unsupplemented patients with CF-associated liver disease appear to be at greater risk. Therefore, routine supplementation should be considered in all CF patients with pancreatic insufficiency irrespective of the degree of steatorrhea or use of antibiotics.


   ACKNOWLEDGMENTS
 
We thank Anna Tsang for her help with patient recruitment.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Sokol RJ, Reardon MC, Accurso FJ, et al. Fat-soluble-vitamin status during the first year of life in infants with cystic fibrosis identified by screening of newborns. Am J Clin Nutr 1989;50:1064–71.[Abstract/Free Full Text]
  2. Congden PJ, Bruce G, Rothburn MM, et al. Vitamin status in treated patients with cystic fibrosis. Arch Dis Child 1981;56:708–14.[Abstract/Free Full Text]
  3. Dowd P, Ham S, Naganathan S, Hershlin R. The mechanism of action of vitamin K. Annu Rev Nutr 1995;15:419–40.[Medline]
  4. Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. Am J Clin Nutr 1996;63:566–73.[Abstract/Free Full Text]
  5. Bach AU, Anderson SA, Foley AL, Williams EC, Suttie JW. Assessment of vitamin K status in human subjects administered "minidose" warfarin. Am J Clin Nutr 1996;64:894–902.[Abstract/Free Full Text]
  6. Shearer MJ. Vitamin K. Lancet 1995;345:229–34.[Medline]
  7. Ferland G, Sadowski JA, O'Brien ME. Dietary induced subclinical vitamin K deficiency in normal human subjects. J Clin Invest 1993;91:1761–8.
  8. Ramsey BW, Farrell PM, Pencharz PB. Nutritional support and management in cystic fibrosis: a consensus report. The Consensus Committee. Am J Clin Nutr 1992;55:108–16.[Abstract/Free Full Text]
  9. Durie PR. Vitamin K and the management of patients with cystic fibrosis. Can Med Assoc J 1994;151:933–6.[Abstract]
  10. Corrigan JJ Jr, Taussig LM, Beckerman R, Wagener JS. Factor II (prothrombin) coagulant activity and immunoreactive protein: detection of vitamin K deficiency and liver disease in patients with cystic fibrosis. J Pediatr 1981;99:254–7.[Medline]
  11. Choonara IA, Winn MJ, Park BK, Littlewood JM. Plasma vitamin K1 concentrations in cystic fibrosis. Arch Dis Child 1989;64:732–4.[Abstract/Free Full Text]
  12. Cornelissen EAM, van Lieburg AF, Motohara K, van Oostrom CG. Vitamin K status in cystic fibrosis. Acta Paediatr Scand 1992;81:658–61.
  13. De Montalembert M, Lenoir G, Saint-Raymond A, Rey J, Lefrere JJ. Increased PIVKA-II concentrations in patients with cystic fibrosis. J Clin Pathol 1992;45:180–1.[Abstract/Free Full Text]
  14. Beker LT, Ahrens RA, Fink RJ, et al. Effect of vitamin K supplementation on vitamin K status in cystic fibrosis patients. J Pediatr Gastroenterol Nutr 1997;24:512–7.[Medline]
  15. Vandekamer JH, Ten Bokkel Huinink H, Wyers HA. Rapid method for determination of fat in feces. J Biol Chem 1949;177:347–55.[Free Full Text]
  16. Durie PR, Forstner GG, Gaskin KJ, et al. Age-related alterations of immunoreactive pancreatic cationic trypsinogen in sera from cystic fibrosis patients with and without pancreatic insufficiency. Pediatr Res 1986;20:209–13.[Medline]
  17. Grosley BM, Hirchauer C, Chamnbrette B, Bezeaud A, Amiral J. Specific measurement of hypocarboxylated prothrombin in plasma or serum and application to the diagnosis of hepatocellular carcinoma. J Lab Clin Med 1996;127:553–64.[Medline]
  18. Rudiger VK, Greer FR, Suttie JW. Assessment of vitamin K status of the newborn infant. J Paediatr Gastroenterol Nutr 1993;16:231–8.[Medline]
  19. Blanchard RA, Furie BC, Kruger SF, Waneck G, Jorgensen MJ, Furie B. Immunoassays of human prothrombin species which correlate with functional coagulant activities. J Lab Clin Med 1983;101:242–55.[Medline]
  20. Motohara K, Kuroki Y, Kan H, Endo F, Matsuda I. Detection of vitamin K deficiency by use of an enzyme linked immunosorbent assay for circulating abnormal prothrombin. Paediatr Res 1985;19:354–7.[Medline]
  21. Rucker RB. Improved functional endpoints for use in vitamin K assessment: important implications for bone disease. Am J Clin Nutr 1997;65:883–4.[Free Full Text]
  22. Sokoll LJ, Sadowski JA. Comparison of biochemical indexes for assessing vitamin K nutritional status in a healthy adult population. Am J Clin Nutr 1996;63:566–76.
  23. Sokoll LJ, Booth SL, O'Brien ME, Davidson KW, Tsaioun KI, Sadowski JA. Changes in serum osteocalcin, plasma phylloquinone, and urinary {gamma}-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects. Am J Clin Nutr 1997;65:779–84.[Abstract/Free Full Text]
  24. Widdershoven J, van Munster P, De Abreu R, et al. Four methods compared for measuring des-carboxy prothrombin (PIVKA-II). Clin Chem 1987;33:2074–8.[Abstract/Free Full Text]
  25. Vermeer C, Jie KSG, Knapen MHJ. Role of vitamin K in bone metabolism. Annu Rev Nutr 1995;15:1–22.[Medline]
  26. Triffitt JT. The special proteins of bone tissue. Clin Sci 1987;72:399–408.[Medline]
  27. Knappen MHJ, Hamulyak K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med 1989;111:1001–5.
  28. Hauschka PV, Lian JB, Cole DEC, Gundberg CM. Osteocalcin and matrix Gla protein: vitamin K dependent proteins in bone. Physiol Rev 1989;69:990–1047.[Free Full Text]
  29. Maillard C, Berruyer M, Serre CM, Dechavanne M, Delmas PD. Protein-S, a vitamin K dependent protein, is a bone matrix component synthesized and secreted by osteoblasts. Endocrinology 1992;130:1599–604.[Abstract/Free Full Text]
  30. Rosen NH, Maitland LA, Suttie JW, Manning WJ, Glynn RJ, Greenspan SL. Vitamin K and maintenance of skeletal integrity in adults. Am J Med 1993;94:62–8.[Medline]
  31. Binkley NC, Suttie JW. Vitamin K nutrition and osteoporosis. J Nutr 1995;125:1812–21.
  32. Conly J, Stein K. Reduction of vitamin K2 concentrations in human liver associated with the use of broad spectrum antimicrobials. Clin Invest Med 1994;17:531–9.[Medline]
  33. Allison PM, Mummah-Schenedel LL, Kindberg CG, Harms CS, Bang NU, Suttie JW. Effects of a vitamin K-deficient diet and antibiotics in normal human volunteers. J Lab Clin Med 1987;110:180–8.[Medline]
  34. Suttie JW. The importance of menaquinones in human nutrition. Annu Rev Nutr 1995;15:399–417.[Medline]
  35. Blanchard RA, Furie BC, Jorgensen M, Kruger SF, Furie B. Acquired vitamin-dependent carboxylation dependent deficiency in liver disease. N Engl J Med 1981;305:242–8.[Abstract]
  36. Grazi GL, Mazziotti A, Legnani C, et al. The role of tumor markers in the diagnosis of hepatocellular carcinoma with special reference to the des-gamma-carboxy prothrombin. Liver Transpl Surg 1995;1:249–55.[Medline]
Received for publication May 21, 1998. Accepted for publication February 22, 1999.




This article has been cited by other articles:


Home page
 PediatricsHome page
S. P. Conway, S. P. Wolfe, K. G. Brownlee, H. White, B. Oldroyd, J. G. Truscott, J. M. Harvey, and M. J. Shearer
Vitamin K Status Among Children With Cystic Fibrosis and Its Relationship to Bone Mineral Density and Bone Turnover
Pediatrics, May 1, 2005; 115(5): 1325 - 1331.
[Abstract] [Full Text] [PDF]

Home page
 Arch. Dis. Child.Home page
J H L van Hoorn, J J E Hendriks, C Vermeer, and P Ph Forget
Vitamin K supplementation in cystic fibrosis
Arch. Dis. Child., November 1, 2003; 88(11): 974 - 975.
[Abstract] [Full Text] [PDF]

Home page
 Arch. Dis. Child.Home page
T Verghese and D Beverley
Vitamin K deficient bleeding in cystic fibrosis
Arch. Dis. Child., June 1, 2003; 88(6): 553 - 553.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. L. Elkin, S. Vedi, S. Bord, N. J. Garrahan, M. E. Hodson, and J. E. Compston
Histomorphometric Analysis of Bone Biopsies from the Iliac Crest of Adults with Cystic Fibrosis
Am. J. Respir. Crit. Care Med., December 1, 2002; 166(11): 1470 - 1474.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Rashid, M.
Right arrow Articles by Pencharz, P. B
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Rashid, M.
Right arrow Articles by Pencharz, P. B
Agricola
Right arrow Articles by Rashid, M.
Right arrow Articles by Pencharz, P. B

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS