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By: Susan Albert

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Vitamin K Fat soluble vitamin Stands between life and death Coenzyme Family of compounds Phylloquinone (K1) Menaquiones (K2) Menadione (K3) (Insel P., Turner, E., Ross, D., 2007)

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Functions of Vitamin K Blood clotting Factor II, Factor VIII, Factor IX Inactive clotting factor X Vitamin K (adds carbon dioxide to glutamic acid) Calcium Factor Xa Prothrombin Thrombin (Gropper et al., 2009)

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Bone Formation Inactive osteocalcin (substrate) Vitamin K Calcium Mechanism of action: carboxylation Active osteocalcin (product) (Insel et al., 2007)

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Recommendations Deficiencies are extremely rare No tolerable upper intake level Adequate Intake (AI) Men: 120 micrograms/day Women: about 90 micrograms/day Children: 30-55 micrograms/day (Insel et al., 2007)

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Sources of Vitamin K Other sources: vegetable oils (soybean, cottonseed, canola, and olive), animal products (egg yolks, butter, various cheeses, liver), soybean products (tofu) SourceGramsServingmcg Kale85~ cup694 Spinach85~ 3 cups410 Turnip greens85~3 cups213 Broccoli85~ cup120 Romaine lettuce85~ 1 cups87 Beef liver853 oz3.3 (Insel et al., 2007)

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Cancer Breast Colorectal Lung Liver (hepatocellular carcinoma) Pancreatic Prostate Factors that increase risk: tobacco, diet, exposure to carcinogens in environment/workplace (Insel et al., 2007)

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Mechanism of Action Vitamin K-dependent carboxylation reactions Potential Anticancer agent (Ohlsson et al., 2004) Specific link to cancer is still unclear Number proposed Focus on oxidative capacity of K3 Cell line research K exerts inhibitory effects (Alternative Medicine Review, 2009)

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Quick Review Sources of vitamin K? Functions? What are the three types?

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What is the relationship between vitamin K and cancer?

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Nimptsch, K., Rohrmann, S., Kaaks, R., & Linseisen, J. (2010). American Journal of Clinical Nutrition, 91(5), 1348-1358.

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Overview Study Design Prospective cohort study 24,340 participants 11, 438 men & 12,902 women Enrollment until 2008 Objective Location of study

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Method and Statistics Method Baseline Follow-up and outcome assessment Descriptive Mean Standard deviation Median Range Inferential Cox proportional hazards regression model with hazard ratios 95% confidence interval

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Results Q1Q2Q3Q4P value K1 Cases/non-cases129/5956104/5982111/5975115/5969 HR*10.880.890.93 95% CI(0.68,1.14)(0.69,1.16)(0.71,1.22)0.70 K2 Cases/non-cases156/5928114/597290/599698/5986 HR*10.770.640.72 95% CI(0.60, 0.99)(0.49, 0.85)(0.53, 0.98)0.03 Cancer Mortality Note: adapted from Nimptsch et al., 2010 * Age and sex stratified

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Results Q1Q2Q3Q4P value K1 HR*11.061.301.190.54 K2 HR*10.620.430.380.002 Lung Cancer Incidence Note: adapted from Nimptsch et al., 2010 * Age and sex stratified

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Results Q1Q2Q3Q4P Value K1 HR*10.891.00 0.84 K2 HR*10.790.670.650.03 Prostate Cancer Incidence Note: adapted from Nimptsch et al., 2010 * Age and sex stratified

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Other cancers Cancer typeP value for trend (K1) P value for trend (K2) Colorectal0.500.57 Premenopausal breast cancer 0.580.70 Postmenopausal breast cancer 0.510.57 Cancer Incidence Note: adapted from Nimptsch et al., 2010

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Strengths and Weaknesses Strengths Hypothesis Large sample size Statistics Planning and organization Validity Weaknesses Validity

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Conclusion No relationship between K1 and K2 Colorectal cancer incidence Pre & post menopausal breast cancer incidence No relationship between vitamin k1 Prostate cancer incidence Lung cancer incidence Cancer mortality Relationship between vitamin K2 Prostate cancer incidence Lung cancer incidence Cancer mortality

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What is the relationship between vitamin K and cancer?

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Sarin, S.K., Kumar, M., Hissar, S., Pandey, C., & Sharma, B.C. (2006). Journal of Gastroenterology & Hematology, 21(9), 1478-1482.

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Overview Study Design: randomized controlled clinical trial Total participants: 42 Placebo group (n=19) High dose of vitamin K3 (n=23) Objective Location of study

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Method & Statistics Method Baseline characteristics Criteria to be included (4) Treatment Descriptive statistics Median Range Mean Standard deviation Inferential statistics Student t-test Chi squared test Kaplan-Meier survival curves

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Baseline Characteristics CharacteristicsVitamin K( n=23)Placebo (n=19)P-Value Age (years) Mean +/- SD50.7 +/- 11.951.7 +/- 8.40.859 Median4854 Range27-7241-69 Sex n (%) Male 18 (78.3) 15(78.9) 1.000 Female 5(21.7) 4(21.1) Etiology n (%) Hepatitis B 17(73.9) 15(78.9) 0.895 Hepatitis C 4 (17.4) 3(15.8) Other 2 (8.7) 1 (5.3) Note: adapted from Sarin et al., 2006

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Results Groupn (%)Survival (months) median (range) 1-year survival n (%) High dose K3 Complete response1 (4.3)371/1 (100) Partial response3 (13)14 (11-28)2/3 (66.7) Objective response4 (17.4)21 (11-37)3/4 (75) Non-responsive19 (82.6)5 (1-16)4/19 (21.1) Stable disease4 (17.4)12.5 (3-16)3/4 (75) Progressive disease15 (65.2)3.5(1-13)1/14 (6.7) Placebo19 (100)5(1.5-21)3/19(15.8) Note: adapted from Sarin et al., 2006 Survival of patients with advanced heptacellular carcinoma treated with high dose K3 or placebo

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Causes of death in patients with advanced hepatocellular carcinoma treated with high dose K3 or placebo TreatmentCancer related n (%) Hepatic failure n (%) Hemorrhage n (%) High dose K313 (56.5)6 (26.1)4 (17.4) Placebo14 (73.7)4 (21.1)1 (5.3) Note: adapted from Sarin et al., 2006

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Kaplan-Meier survival curves

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Strengths and Weaknesses Strengths Purpose Evidence of planning and organization Statistics clearly stated Population Weaknesses First trial for those with advanced liver cancer Demographics Population Small sample size

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Conclusion More research is needed High doses do not affect overall survival Vitamin K3 does not cure cancer 1 patient achieved complete response 13% partial response 17.4% objective response All patients died

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Final Conclusions The relationship between vitamin K and cancer

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Vitamins A and D but not E and K decreased the cell number in human pancreatic cell lines B. Ohlsson, E. Albrechtsson & J. Axelson

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Overview Study design Experimental Seven pancreatic cancer cell lines Objective Location

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Method and Statistics Method Descriptive statistics Mean Standard deviation Inferential Statistics Kruskal-Wallis test Mann-Whitney U test

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Results

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Strengths and Weaknesses Strengths Purpose Evidence of planning and organization Statistics clearly stated Weaknesses Weaknesses Controlled environment Statistics Future research

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Verdict Vitamin K1 No relationship Vitamin K2 Lung cancer incidence Prostate cancer incidence Overall cancer mortality Vitamin K3 More research needed

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Future Direction American Cancer Society Vitamin K1 and K2 (Nimptsch et al., 2010) Biomarkers More studies in humans Vitamin K3 (Sarin et al., 2006). Larger studies Different dosages

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Any questions?