Phillip Snider, RD, DO
Bon Secours Medical Associates
Virginia Beach, VA

 Medline search of 4 online databases (Medline Plus, Drug Digest,
Natural Medicine Comprehensive Database, and the database of the
University of Maryland) 1966 through October 2009





Vitamins are used by over 1/3 of North Americans
Vitamins have documented adverse effects and toxicities, and most have documented interactions with drugs
Some vitamins (biotin, pantothenic acid, riboflavin, thiamine, vitamin
B
12
, vitamin K) have minor and reversible adverse effects
Others, such as fat-soluble vitamins (A, E, D), can cause serious adverse events
Two water-soluble vitamins, folic acid and niacin, can also have significant toxicities and adverse events

 Vitamins A, E, D, folic acid, and niacin should be categorized as over-the-counter medications
 Labeling of vitamins, should include information on possible toxicities, dosing, recommended upper intake limits, and concurrent use with other products
 Vitamin A should be excluded from multivitamin supplements and food fortificants
 The Annals of Pharmacotherapy : Vol. 44, No. 2, pp. 311-324

 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

 Intestinal Cells
 Folate reduced to tetrahydrofolate
– Folate reductase
 inhibited by methotrexate
 Methylated to N
5
-methyl-THF
– primary blood form

Risk Factors Associated with Low Folate
 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
Alpert M, et al. Jrnl Clin Psychopharmacology. 2003;23(3):309-13.
Fava M, et al. Am J Psychiatry. 1997;154(3):426-28.
Arinami T, et al. Am J Genetics. 1997;74:526-28.
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.

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

Bioavailability
L-methylfolate
Vs.
Folic Acid
Dihydrofolate
(Dietary Folate)
Tetrahydrofolat e
DHF Reductase
Enzyme
5, 10 Methylene THF
L-methylfolate
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.

 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

 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

 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

 Doubles the risk of prostate cancer
 2006 prospective study
– 81,922 Swedish adults
– High dietary folate
 Associated with a reduced risk of pancreatic cancer

 2007 RCT
– Folic acid supplements

Did not reduce the risk of colorectal adenomas
 Did significantly increase the presence of advanced adenomas by 67%

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.

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

 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

 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


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

 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.

 Increased breast cancer risk at high plasma folate concentrations among women with the MTHFR 677T allele
 Nested case-control study included 313 cases (age 55 –
73 y at baseline) with invasive breast cancer and 626 control subjects
 Malmö Diet and Cancer – 17,000 women followed 10 yr,
10% had mutation in MTHFR 677T allele
 Significant association of high plasma folate concentration 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

 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)

 FA + B12
– 10.0% Dx cancer vs 8.4%
–
–
4.0% Died-cancer vs 2.9%
16.1% Died-all cause vs 13.8%
HR 1.21; P = .02
HR 1.38; P = .01
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.

 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

 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

RDA
UL
Women Pregnant
Women
Men
400 DFE 600 DFE 400 DFE
1,000 DFE 1,000 DFE 1,000 DFE
 Synthetic form ~2x bioavailable
– 1 DFE

1 mcg folate
 0.5 mcg folic acid (on empty stomach)

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

Vitamins and Cancer: Take Home Message

Hickey and Roberts’ microevolutionary model for cancer describes how cells undergoing carcinogenesis respond to redox
(antioxidant/oxidant) signaling and changes in redox state

It predicts that nutritional doses of antioxidant supplements, required daily for maintenance of normal health, inhibit carcinogenesis

Vitamins and Cancer: Take Home Message

Once a cancer is established, however, the model suggests that nutritional or pharmacologic doses of antioxidants may be contraindicated as they could accelerate tumor growth

Large pharmacologic doses of nutrients, which produce specific physiologic or biochemical effects, are indicated for the treatment of cancer or other diseases

Vitamins and Cancer: Take Home Message

In the oxidizing environment of a developing tumor, nutritional doses of antioxidants could lower oxidation levels and inhibit cancer cell death

By contrast, pharmacologic doses of redoxactive substances that alter the antioxidant– oxidant balance, such as vitamin C (acting as a pro-oxidant), have been shown to destroy cancer cells in vitro and in animal experiments

Vitamins and Cancer: Take Home Message

People in good health should select only highquality, natural, antioxidant supplements, or molecularly identical counterparts avoiding synthetic forms such as DL-alpha-tocopherol
(synthetic vitamin E)
 In metastatic cancer, only those supplements that have been shown to provoke a differential redox response in cancer cells, are appropriate
– Vitamin C, R-alpha-lipoic acid, and Vitamin K3

 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

 BMI = weight / height 2
 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

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

Relationship Between Weight Gain in
Adulthood and Risk of Type 2 Diabetes
6
5
Men
Women
4
3
2
1
0
-10 -5 0 5 10
Weight Change (kg)
Willett et al. N Engl J Med 1999;341:427.
15 20

Diagnosing the Metabolic Syndrome
Risk Factor
Abdominal obesity
Men
Women
Defining Level
>40 in
>35 in

150 mg/dL TG
HDL-C
Men
Women
Blood pressure
Fasting glucose
Diagnosis =  3
<40 mg/dL
<50 mg/dL

130/

85 mm Hg

110 mg/dL

 What is Abdominal Obesity ?
 Can be defined by Waist Circumference
Male:
> 42 Inch
Male :
> 37 Inch
Female :
> 35 Inch
Female :
> 31.5 Inch
Better Method ?
Waist < ½ Height

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

 BMI > 35 plus >2 Comorbidities
– HTN, DM, Lipids, OSA, CAD, CVA, OA, SUI, GERD
 BMI > 40
 > 100 lb over Ideal weight

 5’0” person > 204 lb
 5’6” person > 247 lb
 6’0” person > 294 lb

 5’0” person > 170 lb
 5’6” person > 216 lb
 6’0” person > 258 lb




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…

 2/3 is overweight
– 50% are obese
 5% of the US population is morbidly obese
 BMI subgroups growing the fastest
– 35+ 40+

Surgery
Pharmacotherapy
Lifestyle Modification
Diet Physical Activity

BMI Category (kg/m
2
)
Treatment 25-26.9
27-29.9
30-34.9
35-39.9
>40
Diet,
Exercise,
Behavior Tx
+ + + + +
Pharmacotherapy
With comorbidities
+ + +
Surgery
With comorbidities
+
The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October
2000, NIH Pub. No.00-4084

 “Hey Doc, I am fat because my hormones are out of whack. I know I don’t eat too much. Can’t you check out what’s wrong with me and give me a pill to fix it?”



 NOT


 Psychotropic medications
– Tricyclic antidepressants
– Monoamine oxidase inhibitors
– Specific SSRIs
– Atypical antipsychotics
– Lithium

– Specific anticonvulsants
Older

-blockers
 Diabetes medications
–
–
Insulin
Sulfonylureas
– Thiazolidinediones
 Highly active antiretroviral therapy
 Tamoxifen
 Steroid hormones
–
–
Glucocorticoids
Progestational steroids

 “Yea, I know about balancing food and activity, but I don’t don’t eat that much.”
 “I don’t eat more than other people”
 “I only eat salads.”

Discrepancy Between Reported and Actual
Energy Intake and Expenditure
3000 Energy Intake
*
Energy Expenditure
2500
2000
1500
*
1000
500
0
Reported Actual
* P <0.05 vs reported.
Lichtman et al. N Engl J Med 1992;327:1893.
Reported Actual

“My problem is my metabolism is slow. Everything
I eat turns straight to fat.”

3000
Relationship Between Resting Energy
Expenditure and Fat-free Mass
Lean females
Obese females
Lean males
Obese males
2000
1000
0
0 30 40 50 60 70 80
REE = Resting energy expenditure
Owen. Mayo Clin Proc 1988;63:503.
Fat-Free Mass (kg)
90 100

 “Any time I try to lose weight, my metabolism slows down so much that I can’t lose weight.”

Energy Metabolism Before & After Weight Loss
Mean BMI Reduced from 31 to 23 kg/m 2
3500
3000
2500
2000
Resting Energy
Expenditure
1500
1000
* *
500
0
Before After Predicted
* P <0.05 vs before weight loss
Amatruda et al. J. Clin Invest 1993;92:1236.
Total Energy Expenditure
*
*
Before After Predicted

 “So obesity is all genetic.
There’s nothing I can do.”

50
40
Gene-Environment Interaction in the
Pathogenesis of Obesity
P <0.0001
Pima Indians
30
20
10
0
Maycoba, Mexico
Ravussin E et al. Diabetes Care 1994;17:1067-1074.
Arizona

Effect of Portion Size on Energy Intake
500
400
300
200
100
0
500 625 750 1000
Amount of Macaroni and Cheese Served (g)
Rolls et al. Am J Clin Nutr . 2000 Dec;76(6):1207-13.

Prevalence of Obesity by Hours of Daily TV
NHES Youth Aged 12-17 in 1967-70 and NLSY
Youth Aged 10-15 in 1990
Prevalence
(%)
20
15
10
5
0
40
35
30
25
NHES 1967-70
NLSY 1990
0-1 1-2 2-3 3-4 4-5
TV Hours Per Day (Youth Report)
>5

“I don’t think I need to change what I am eating.
I am going to work out and lose it that way.”

Physical Activity Alone Results in Minimal
Weight Loss
Control Group
Exercise Group
-3.0
-7.0
-5.0
* P <0.05 vs control group
Weight loss (kg)
Duration of each study ranged from 4 to 12 months.
Wing. Med Sci Sports Exerc 1999;31(suppl):S547.
-1.0
1.0
Stefanick 1998
Stefanick 1998a
Anderssen 1995
Hammer 1989
Verity 1989
R önnemaa 1988
Wood 1988
Wood 1983

Relationship Between Physical Activity and Maintenance of Weight Loss
P <0.001
100
80
60
40
20
0
Not Maintained Maintained
Weight Loss Pattern
Kayman et al. Am J Clin Nutr 1990;52:800.

 “Isn’t there some popular diet I can follow? One that makes it easy.”

 Succeed short term because restriction in food choice reduces calories
 Fail long term because restriction of food choices becomes unacceptable
 Promote a cycle of euphoria and despair that discourages belief in the possibility of success

 Used as an adjunct to diet/exercise
 Reserved for those with BMI>30 or those with BMI>27 and Comorbidities

Generic Name
Orlistat
Sibutramine
Diethylpropion
Phentermine
Phendimetrazine
Benzphetamine
Trade
Names
Xenical
Meridia
Tenulate
Adipex, lonamin
Bontril,
Prelu-2
Didrex
DEA
Schedule
None
IV
IV
IV
Approved
Use
Long-term
Long-term
Short-term
Year
Approved
1999
1997
1973
Short-term 1973
III
III
Short-term
Short-term
1961
1960

Additive Effects of Behavior and Diet Therapy with
Pharmacotherapy for Obesity
0
Medication alone
-5
Medication and behavior modification
-10
*
-15
-20
Medication, behavior modification and meal replacements
-25
0 2 4 6
Time (months)
* P <0.05 vs medication alone.
Wadden et al. Arch Intern Med 2001;161:218.
8 10 12
*





 80% excess weight loss in 18 months
 Roux-en-Y Gastric bypass the most widely accepted and best results
 Higher volume centers and surgeons have best results. Still risk and complications
 10 year weight loss maintenance best with surgery

Gastric Bypass

Lap Band

 BMI greater than 40
 BMI greater than 35 with obesity co-morbidity
 Attendance in a plausible structured program for some period of time, without sustained and significant degree of weight loss
 Not impaired psychiatrically?
 BMI greater than 60?





Diabetes
– 76.8% - Completely resolved
– 86.0% - Resolved or improved
Hyperlipidemia
– 70% - Improved
HTN
– 61.7% - Resolved
– 85.7% - Resolved or improved
Obstructive Sleep Apnea
–
–
83.6% - Resolved
85.7% - Resolved or improved
Buchwald H, et al. Bariatric Surgery:
A Systematic Review and Metaanalysis. JAMA, 14:1724-37, 2004


One study of 342 gastric bypass pts showed excellent long-term weight maintenance:
– % weight loss at:
 1 year (89%)
 2 years (87%)

5 years (70%)

10 years (75%)
 However, potential for pouch stretch, selfsabotage, etc. leading to weight regain over time.
 Surgery relatively new, will have to wait and reanalyze data in a few years.

 Flintstones “Complete”
 Women who still have menstrual periods need iron. All women need calcium!
 Common deficiencies: Iron, Folate, B
12
,
Calcium, Vitamin D

 Patient must commit to lifetime monitoring of height, weight, and nutritional status
 Women should not become pregnant up to
18 months after surgery
 Encourage patient to join a support group to celebrate and cope with weight loss

 Depression
–
–
Many expect things to get better post-op
Pre-existing depression exacerbated by stress of surgery
– Suicides increased post operatively in some series
– Ask about mood post-op
 Too much weight loss too fast
–
–
Look for signs of volume depletion
Puts at risk for infection

 First Year:
–
–
@3 months: CBC, Glu, Cr
@6 months: CMP, Ferritin, TIBC, B12, Folate, Ca


[PTH] (if Ca elevated or to ensure Ca stable)
[Vit D] (possibly to ensure adequate Ca)
 Every year thereafter:
– All of the above
 Postmenopausal women: BMD Screening
– Variable recommendations, probably worth screening and ensuring maximum calcium / vit D tx if low BMD

~5%
Weight Loss
5%-10%
Weight Loss
HbA1c
1 1
Blood Pressure
2 2
Total Cholesterol
3 3
HDL Cholesterol
3 3
Triglycerides
4
1. Wing RR et al. Arch Intern Med. 1987;147:1749-1753. 2. Mertens IL, Van Gaal LF. Obes Res. 2000;8:270-278. 3.
Blackburn G. Obes Res. 1995;3 (Suppl 2):211S-216S. 4. Ditschunheit HH et al. Eur J Clin Nutr. 2002;56:264-270.

 Obesity is a chronic disease
 Modest weight loss (5% -10% of body weight) can have considerable medical benefits
 Lifestyle change (diet and physical activity) is the cornerstone of therapy
 Pharmacotherapy can be useful in properly selected patients
 Bariatric surgery is the most effective therapy for obesity

•
Weight loss induced by diet and increased physical activity is the cornerstone of therapy
•
Weight loss induced by drug therapy can also improve specific features of the metabolic syndrome
•
Bariatric surgery is the most effective weight loss therapy for extremely obese subjects and improves all features of the metabolic syndrome

Obesity-Related Resources
Professional Associations
North American Association for the Study of
Obesity (NAASO)
American Academy of Family Physicians (AAFP)
American College of Sports Medicine (ACSM)
American Diabetes Association (ADA)
American Dietetic Association (ADA)
American Gastroenterological Association (AGA)
American Heart Association (AOA)
American Obesity Association (AOA)
American Society for Bariatric Surgery (ASBS) www.naaso.org
www.aafp.org
www.acsm.org
www.diabetes.org
www.eatright.org
www.gastro.org
www.americanheart.org
www.obesity.org
www.asbs.org