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Hot Topics in Nutrition for the Primary Care Physician

Hot Topics in Nutrition for the Primary Care Physician. Phillip Snider, RD, DO Bon Secours Medical Associates Virginia Beach, VA. Should Vitamins be Considered Drugs?.

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Hot Topics in Nutrition for the Primary Care Physician

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  1. Hot Topics in Nutrition for the Primary Care Physician Phillip Snider, RD, DO Bon Secours Medical Associates Virginia Beach, VA

  2. Should Vitamins be Considered Drugs? • Medline search of 4 online databases (Medline Plus, Drug Digest, Natural MedicineComprehensive Database, and the database of the University ofMaryland) 1966 through October 2009 • Vitamins are used by over 1/3 of North Americans • Vitamins have documented adverse effects and toxicities, andmost have documented interactions with drugs • Some vitamins(biotin, pantothenic acid, riboflavin, thiamine, vitamin B12,vitamin K) have minor and reversible adverse effects • Others,such as fat-soluble vitamins (A, E, D), can cause serious adverseevents • Two water-soluble vitamins, folic acid and niacin, canalso have significant toxicities and adverse events

  3. Should Vitamins be Considered Drugs? • Vitamins A, E, D, folic acid,and niacin should be categorized as over-the-counter medications • Labelingof vitamins, should include information on possible toxicities, dosing, recommendedupper intake limits, and concurrent use with other products • VitaminA should be excluded from multivitamin supplements and food fortificants • The Annals of Pharmacotherapy: Vol. 44, No. 2, pp. 311-324

  4. Folic Acid • Aka B9, Folacin or folate (natural form) • Name derived “folium” - Latin for leaf • Beans, peas, spinach, broccoli • Functions • Synthesize, repair and methylate DNA • Deficiency • Neural tube defects • Pernicious anemia • Accumulation of homocysteine • Theoretical increased risk of cancer

  5. Folate Metabolism • Intestinal Cells • Folate reduced to tetrahydrofolate • Folate reductase • inhibited by methotrexate • Methylated to N5-methyl-THF • primary blood form

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  7. Genetic polymorphism MTHFR C677T 7 out of 10 depressed patients 56% - C/T polymorphism 4 X more likely to have depression than general population 14% - T/T polymorphism Lifestyle ETOH Smoking Poor nutrition Medications anticonvulsants oral contraceptives lithium fenofibrates, niacin sulphasalazine methotrexate metformin Illness diabetes atrophic gastritis crohn’s disease hypothyroid renal failure Risk Factors Associated with Low Folate Alpert M, et al. Jrnl Clin Psychopharmacology. 2003;23(3):309-13. Arinami T, et al. Am J Genetics. 1997;74:526-28. Fava M, et al. Am J Psychiatry. 1997;154(3):426-28. Procopciuc L.M., Poster Pres. P86 presented at Biol Psych. 2005. Popakostas G, et al. Psychiatry Research, 2005;140(3):301-7. Bjelland I. et al. Arch Gen Psychiatry. 2003;60(6):618-26. Bottigleri T. Prog Neuro-Psychopharmacology & Biol Psychiatry. 2005; 29:1103-12. Kelly B J, et al. Psychopharmacol. 2004 ;18(4):567-71.

  8. Deplin as a Trimonoamine Modulator Stahl S.M. Novel Therapeutics for Depression: L-methylfolate as a Trimonoamine Modulator and Antidepressant Augmenting Agent. CNS Spectrums. 2007;12(10):739-744.

  9. L-methylfolate Bioavailability L-methylfolate Folic Acid Vs. DHF Reductase Enzyme Dihydrofolate (Dietary Folate) Tetrahydrofolate 5, 10 Methylene THF MTHFR C>T Polymorphism L-methylfolate • Folic acid requires a 4 step transformation process to be converted to the active form of folate, L-methylfolate (5-MTHF). • L-methylfolate is unaffected by the MTHFR CT polymorphism.

  10. Folic Acid (FA) Benefits • Nurse’s Health Study (JAMA 1998) • 80,000 nurses, 14 yr follow-up • Relative Risk - highest vs lowest quintile • RR = 0.69 for folate • RR = 0.67 for B-6 • RR = 0.55 for folate + B-6 • FA supplementation – vast majority of recent studies • Lowers homocysteine but this has not turned out to offer any clinical benefits

  11. Folic Acid (FA) Benefits • Depression • Deplin (L-methylfolatye) • Stroke • Limited evidence shows moderate benefit • Cancer • Complex relationship • High folate intake may protect against early carcinogenesis • High FA intake may promote advanced carcinogenesis • Dietary folate usually associated with lower risk • FA supplementation associated with higher risk

  12. FA and Cancer • A Finnish study • 29,133 older male smokers • Prostate CA risk - no relationship with serum folate levels • Recent RCT • FA 1 mg/day • Prostate CA increased • Dietary folate & plasma levels increased • Prostate CA decreased

  13. FA and Cancer • Doubles the risk of prostate cancer • 2006 prospective study • 81,922 Swedish adults • High dietary folate • Associated with a reduced risk of pancreatic cancer

  14. FA and Cancer • 2007 RCT • Folic acid supplements • Did not reduce the risk of colorectal adenomas • Did significantly increase the presence of advanced adenomas by 67%

  15. A Randomized Trial on Folic Acid Supplementation and Risk of Recurrent Colorectal Adenoma • FA 1 mg/d (n = 338) vs placebo (n = 334) for 3-6.5 yr • Primary endpoint: Any new diagnosis of adenoma during the study period (May 1996-March 2004) • Secondary outcomes: Adenoma by site and stage and number of recurrent adenomas • Low plasma FA = sig decrease (RR: 0.61; P = 0.01) • Adequate plasma FA = no diff (RR: 1.28; P = 0.27) • Am J Clin Nutr. 2009 Dec;90(6):1623-31.

  16. Dietary Factors of One-carbon Metabolism & Prostate Cancer Risk • 27,111 Finnish male smokers aged 50-69 • End point = Diagnosis of prostate cancer between 1985 and 2002 • Vit B6 intake inversely associated with prostate cancer risk (RR for highest versus lowest quintile: 0.88; P = 0.045) • Vit B12 intake associated with sig incr risk (RR = 1.36; P = 0.01) • FA or alcohol intake no association with prostate cancer risk • FA or alcohol intake no association with risk according to stage of dz • Am J Clin Nutr. 2006 Oct;84(4):929-35

  17. FA and Cancer • European Journal of Gastroenterology & Hepatology University of Chile, in Santiago • Hospital-discharge data for two 4-year periods • before folic-acid fortification (1992–1996) • after (2001–2004) • Significant increase colon cancer • 162% in people 45 to 64 years • 190% in people 65 to 79 years

  18. FA and Cancer • Aspirin/Folate Polyp Prevention Study • J Natl Cancer Inst. 2009;101:432-435 • 3-fold increase in prostate cancer among men who took the folate supplement compared with men who took placebo

  19. AARP Diet and Health Study • Prospective study of 295,344 men 50 to 71 and free of cancer at enrollment in 1995 • Multivitamin use assessed at baseline. • 5% used multivitamins > 7 times a week • 36% took a multivitamin daily • 5 yr follow-up: 10,241 developed prostate cancer • 8,765 localized and • 1,476 advanced cancers • 179 cases of fatal prostate cancer

  20. AARP Diet and Health Study • No association: multivitamin use and risk of prostate cancer overall (relative risk 1.06) • No association: multivitamin use and risk of localized prostate cancer (RR 1.02) • Increased risk of advanced prostate cancer (RR 1.32) • Elevated risk of fatal prostate cancers (RR 1.98) • The associations were strongest in men with a family history of prostate cancer or those who took selenium, β-carotene, or zinc.

  21. FA and Cancer • Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele • Nested case-control study included 313 cases (age55–73 y at baseline) with invasive breast cancer and 626control subjects • Malmö Diet and Cancer – 17,000 women followed 10 yr, 10% had mutation in MTHFR 677T allele • Significant association of high plasma folateconcentration with increased risk of postmenopausal breast cancer in carriers of the 677T allele • Am J of Clin Nutr, Vol. 90, No. 5, 1380-1389, November 2009

  22. Vitamins & Cancer • Norwegian Vitamin Trial and Western Norway B Vitamin Intervention Trial • 6837 patients with ischemic heart disease • 1998 and 2005, and followed up through December 31, 2007 • FA 0.8 mg + B12 0.4 mg + Vitamin B6 40 mg (n = 1708) • FA 0.8 mg/d + B12 0.4 mg/d (n = 1703) • B6 alone 40 mg/d (n = 1705) • Placebo (n = 1721)

  23. Vitamins & Cancer • FA + B12 • 10.0% Dx cancer vs 8.4% HR 1.21; P = .02 • 4.0% Died-cancer vs 2.9% HR 1.38; P = .01 • 16.1% Died-all cause vs 13.8% HR 1.18; P = .01 • Most common cancer was lung cancer • Cancer Incidence and Mortality after Treatment with Folic Acid and Vitamin B12 • JAMA. 2009 Nov 18;302(19):2119-26.

  24. Food Fortification • FDA started FA fortification in 1996 • All flour in US fortified with FA at a level of 140 μg/100 gr • Estimated to supply an extra 100 μg daily to the average diet

  25. Food Fortification • Study of 1480 subjects • FA intake actually increased by 190 µg/d • Total folate intake increased by 323 DFE/d • Folic acid intake above the UL seen only among those taking FA supplements as well as folic acid found in fortified grain products • Some researchers have advocated that this be increased to double and even four times this amount

  26. Folic Acid • Synthetic form ~2x bioavailable • 1 DFE • 1 mcg folate • 0.5 mcg folic acid (on empty stomach)

  27. Folic acid fortification and public health: Report on threshold doses above which unmetabolized folic acid appear in serum • BMC Public Health 2007, 7:41doi:10.1186/1471-2458-7-41 • Electronic version of this article http://www.biomedcentral.com/1471-2458/7/41

  28. Vitamins and Cancer: Take Home Message • Hickey andRoberts’ microevolutionary model for cancer describeshow cells undergoing carcinogenesis respond to redox (antioxidant/oxidant)signaling and changes in redox state • It predicts thatnutritional doses of antioxidant supplements, required dailyfor maintenance of normal health, inhibit carcinogenesis

  29. Vitamins and Cancer: Take Home Message • Once a canceris established, however, the model suggests that nutritional or pharmacologic doses of antioxidants may be contraindicated as they could acceleratetumor growth • Large pharmacologic doses of nutrients, which produce specificphysiologic or biochemical effects, are indicated for the treatmentof cancer or other diseases

  30. Vitamins and Cancer: Take Home Message • In the oxidizingenvironment of a developing tumor, nutritional doses of antioxidantscould lower oxidation levels and inhibit cancer cell death • By contrast, pharmacologic doses of redox-active substancesthat alter the antioxidant–oxidant balance, such as vitaminC (acting as a pro-oxidant), have been shown to destroy cancercells in vitro and in animal experiments

  31. Vitamins and Cancer: Take Home Message • People in goodhealth should select only high-quality, natural, antioxidantsupplements, or molecularly identical counterparts avoidingsynthetic forms such as DL-alpha-tocopherol (synthetic vitaminE) • In metastatic cancer, only thosesupplements that have been shown to provoke a differential redoxresponse in cancer cells, are appropriate • Vitamin C, R-alpha-lipoicacid, and Vitamin K3

  32. Interaction b/w FA and B12 • FA can correct pernicious anemia from B12 deficiency • FA does not correct the neurological impact • 3 carbon to 2 carbon conversion affected • MMA accumulates • Mixed neuropathy • FA over the UL (1 mg/day) can mask B12 deficiency

  33. Obesity and Overweight

  34. Establish diagnosis:BMI • BMI = weight / height2 • Correlates well with direct measures of adiposity • Overweight child: BMI >85th and <95th percentile • Obese child: BMI > 95th percentile • If child < 3 years old, use weight for height

  35. Medical Complications of Obesity Idiopathic intracranial hypertension Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Stroke Cataracts Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis Coronary heart disease Diabetes Dyslipidemia Hypertension Severe pancreatitis Gall bladder disease Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome Osteoarthritis Phlebitis venous stasis Skin Gout

  36. Complications of Childhood Obesity

  37. -10 -5 0 5 10 15 20 Relationship Between Weight Gain in Adulthood and Risk of Type 2 Diabetes Men Women Relative Risk Weight Change (kg) Willett et al. N Engl J Med 1999;341:427.

  38. Diagnosing the Metabolic Syndrome Diagnosis = 3

  39. Defining Cardiometaboilc Risk What is Abdominal Obesity ? Can be defined by Waist Circumference Better Method ? Waist < ½ Height

  40. BMI Categories • A BMI of: Classifies one as: • <18.5 Underweight • 18.5-24.9 Normal weight • 25-29.9 Overweight • 30-34.9 Obesity Class I • 35-39.9 Obesity Class II • 40-49.9 Obesity Class III • 50 and above Super Obesity

  41. Morbid Obesity • BMI > 35 plus >2 Comorbidities • HTN, DM, Lipids, OSA, CAD, CVA, OA, SUI, GERD • BMI > 40 • > 100 lb over Ideal weight

  42. Morbid Obesity Examples: BMI > 40 • 5’0” person > 204 lb • 5’6” person > 247 lb • 6’0” person > 294 lb

  43. Morbid Obesity Examples: BMI > 35 • 5’0” person > 170 lb • 5’6” person > 216 lb • 6’0” person > 258 lb

  44. Obesity is a BIG problem… • 1.7 billion worldwide are overweight or obese • The US has a higher percentage of overweight and obese people than any country in the world • And the numbers are growing…

  45. US Incidence of Obesity • 2/3 is overweight • 50% are obese • 5% of the US population is morbidly obese • BMI subgroups growing the fastest • 35+ 40+

  46. Why Are We So Fat&What Can We Do About It?

  47. Surgery Pharmacotherapy Lifestyle Modification Diet Physical Activity Obesity Treatment Pyramid

  48. Guide for Selecting Obesity Treatment BMI Category (kg/m2) The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084

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