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The Safe Use of Nutritional Supplements April 2011

The Safe Use of Nutritional Supplements April 2011. Dr Alan Stewart MRCP www.stewartnutrition.co.uk. Are Nutritional Supplements always Safe?. Supplements of vitamins, minerals and other nutrients are taken by 40% of UK adults

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The Safe Use of Nutritional Supplements April 2011

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  1. The Safe Use of Nutritional SupplementsApril 2011 Dr Alan Stewart MRCP www.stewartnutrition.co.uk

  2. Are Nutritional Supplements always Safe? • Supplements of vitamins, minerals and other nutrients are taken by 40% of UK adults • Studies involving high dose supplements or their prolonged use have revealed adverse effects • The risks of supplement use need to be more well known • Practitioners and the supplement industry need to address the issue of supplement safety

  3. Nutritional Supplements: Responsibilities • Safety is central to FSA, DEFRA, EFSA & DoH policiesFood Standards Agency is responsible for food supplements • Professional and Authorizing Bodies Training of nutritionists is overseen by the National Occupation Standards, Nutritional Therapy Council and British Association for Applied Nutrition & Nutritional Therapy who set standards for training and practice • UK Supplement Industry – formulation, manufacture & marketing Health Food Manufacturers’ Associationwww.hfma.co.uk“ To promote high standards of product manufacture and presentation to ensure consumer safety..” Council for Responsible Nutrition UK www.crn.org.uk“members all agree to abide by voluntary quality standards to ensure consumer safety and confidence.” • Medicines Health Regulatory AuthorityAccepts reports of adverse reactions to nutritional supplements

  4. Nutritionists Training and Safety Standards • National Occupation Standards for Nutritional TherapyCNH8. Knowledge and Understanding “16. ways in which individual safety may be compromised by inappropriate treatment and how to minimise such risks “https://tools.skillsforhealth.org.uk/competence/show/html/id/2805/ • Nutritional Therapy CouncilCore Curriculum for accredited nutrition courses. 2.1.3 Micronutrients (L 3-7)“4. Explain the signs and symptoms associated with micronutrient/ orthomolecular compound deficiency, imbalance and toxicity.”2.2.2 Treatment and Scope of Methods of Nutritional Therapy“ 3. Discuss the purpose, range and limitations of different methods of nutritional therapy” • British Association for Applied Nutrition & Nutritional TherapyMission statement. “2. Promote high standards of education, training, practice and integrity in the nutrition profession”

  5. Distribution of Nutrient RequirementsAssumes a Gaussian (normal) distribution Dietary Reference Values: Dept of Health 1991 • LRNI “An amount enough for only the few people in a group who have low needs” • EAR “About half will usually need more than the EAR and half less” • RNI “An amount of the nutrient that is enough, or more than enough, for about 97% of people in a group”

  6. Nutrient Intake and Risk to HealthWHO Vitamin and Mineral Requirements in Human Nutrition 2004 • EAR Estimated Average Requirement • RNI Recommended Nutrient Intake • LRNI Lower Reference Nutrient Intake an amount enough for only a small % of population • UL Tolerable Upper Intake Level at which no evidence of toxicity is demonstrable

  7. Paracelsus: the Father of ToxicologyTheophrastus Phillipus Auroleus Bombastus von Hohenheim 1493-1541 • “All things are poison and nothing is without poison: only the dose makes a thing a poison.” • “Alle Dinge sind Gift und nichts ist ohne Gift: allein die Dosis macht, das ein Ding kein Gift ist.”

  8. Use of Nutritional Supplements in UKNational Diet and Nutrition Surveys • Supplement categories are reported with slight differences between surveys • Females are usually bigger consumers of supplements than males • Most iron and multivitamins with iron are consumed equally by females and males

  9. Proportion of Adult Males with low Intakes Intakes from Food, and Food + Supplements < LRNI

  10. Proportion of Adult Females with low Intakes Intakes from Food, and Food + Supplements < LRNI

  11. How Do Nutritional Deficiencies Develop?Adapted from Brin M. Journal of the American Medical Association 1964;187:762-766 • State of Adequacy • State of Negative Balance:1. Poor Intake 2. Reduced absorption 3. Increased losses 4. Increased requirement 5. Altered metabolism – illness, alcohol, drugs, toxins, genetics • Decline in Tissue Stores • Loss of Function:1. Symptoms 2. Physical Signs 3. Organ Failure • Death

  12. State of Adequacy State of Negative Balance:1. Poor Intake 2. Reduced absorption3. Increased losses4. Increased requirement5. Altered metabolism illness, alcohol, drugs, genetics Decline in Tissue Stores Loss of Function:1. Symptoms 2. Physical Signs 3. Organ Failure Death State of Adequacy State of Positive Balance:1. Increased Intake 2. Increased absorption3. Reduced losses4. Reduced requirement5. Altered metabolism illness, alcohol, drugs, geneticsincreased sensitivity to nutrient Increase in Tissue Stores Loss of Function:1. Symptoms 2. Physical Signs 3. Organ Failure Death How the Two Forms of Malnutrition DevelopDeficiency Excess

  13. Risk Methodology and Supplement SafetyAdapted from FAO/WHO Environmental Health Criteria 240 (2009) and 1995/1997/1998 www.fao.org/docrep/008/ae922e/ae922e03.htm

  14. Risk Methodology and Supplement SafetyAdapted from FAO/WHO Environmental Health Criteria 240 (2009) and 1995/1997/1998 www.fao.org/docrep/008/ae922e/ae922e03.htm

  15. Methodology: 1. Risk Assessment • Possible Adverse EffectsExpert reports, data from trials, case reportsUS Supplements Label Database • Dose-Response EffectData mainly from trials and epidemiological data • Exposure AssessmentSources – food, supplements, water, industrial etc..UK National Diet and Nutrition Surveys, UK Committee on Toxicity – intakes from all sources • Modifying FactorsAge, smoking, asbestos, alcohol, disease of excretory organs – liver and kidney, drugs, genetic factors etc…

  16. Major Reports on Supplement Safety • Safe Upper Levels for Vitamins and Minerals May 2003Expert Group on Vitamins and Minerals, FSA Safe Upper Levels and Guidance Levelswww.food.gov.uk/multimedia/pdfs/vitmin2003.pdf • Review of Dietary Advice on Vitamin A Sept 2005Scientific Advisory Committee on Nutrition http://www.sacn.gov.uk/pdfs/sacn_vita_report.pdfhttp://www.sacn.gov.uk/pdfs/Vitamin_A_Report_and_Annexes.pdf • Tolerable Upper Intake Levels for Vitamins and Minerals Feb 2006Scientific Committee on Food, European Food Safety Authorityhttp://europa.eu.int/comm/food/fc/sc/scf/index_en.html • Mortality in Randomized Trials of AntioxidantSupplements for Primary and Secondary Prevention Mar 2007Bjelakovic G et al JAMA.2007;297:842-857www.cochrane.org/reviews/en/ab007176.html • Dietary Reference Intakes (and ULs) Book 2006(+ Tolerable Upper Intake Levels) Otten JJ et al Institute of Medicinehttp://www.nap.edu/catalog/11537.html

  17. UK Expert Group on Vitamins and Minerals 2003 • Safe Upper Levels, SULs 8derived from human data • Guidance Levels, GLs 22 derived from animal/incomplete human data • Based on a 60 kg female • “ ..are the doses of vitamins and minerals that susceptible individuals could take daily on a life-long basis, without medical supervision.” • Total Safe Intakes= food + water + supplementsfor retinol and some trace elements

  18. Defining a Toxic Intake Level • Levels usually derived from population intake, case reports or trial data • NOAEL/LOAEL: No/Lowest Observed Adverse Effect Level • Tolerable Upper Intake Level (UL) = NOAEL/LOAEL/Uncertainty Factor

  19. Setting Safe Upper LevelsHathcock J, Shao A. J. Nutr. 2008; 138:1992S-1995S Tolerable Upper = NOAEL/LOAEL Intake Level (UL) Uncertainty Factor, UF Uncertainty Factors selected by Institute of Medicine • Manganese = 1 • Vitamin D = 1.2 • Vitamin A and Zinc = 1.5 • Selenium and vitamin B6 = 2 • Folic acid = 5 • Vitamin E = 36

  20. Definitions of Safe Levels • UK Safe Upper Levels (SULs) Guidance Levels (GLs) “are the doses of vitamins and minerals that susceptible individuals could take daily on a life-long basis, without medical supervision.”Single figure, applies to adults only, based on 60 kg femaleTotal Safe Intakes (TSIs) are set for retinol and some trace elements • US Tolerable Upper Intake Levels (ULs)Range of figures depending upon age and sex“is the highest average daily nutrient intake level likely to pose no risk of adverse effects for nearly all people in a particular group”Based on total intake from food, water and supplements • EU Tolerable Upper Intake Level (UL)“the maximum level of total chronic daily intake of a nutrient (from all sources) judged to be unlikely to pose a risk of adverse effects”.ULs vary with age and sex and exclude “those under medical supervision and certain disease states” but includes “sensitive individuals”

  21. Adverse Nutrient Reactions: Classification • Acute ToxicityMinor – gastrointestinal upset – Mg, Fe, Zn, Severe – large amounts of vitamins A, D, C • Chronic ToxicityOsteoporosis – vitamin ANervous system – vitamin B6, Mn, CuLiver disease – Fe, Cu, vitamin A, beta-caroteneMetabolic Effects – hypercalcaemia, renal stones, induced deficiency • Cancer Induction – antioxidants may act as pro-oxidant Growth Rate – zinc, vitamins A and B • Adverse Pregnancy EffectsFetal development/growth – Fe, vitamins A, C and E • Minor and Idiosyncratic Adverse EffectsDermatological – beta-carotene, vitamin B12, n-3 EFAs and others

  22. Sources of Nutrients • Food and BeveragesAll nutrients • Fortified FoodsVits A, D, E, C, B group, Ca, Fe and a few trace elements • SupplementsAll nutrients • WaterMains supply – Ca, Mg, Cu, Bottled – Mg, NaNon-mains supply – Ca, Mg, Cu, Fe and Mn • Air and Industrial ExposureMn (60,000 with exposure in UK – HSE estimate) Other trace elements • Drugs and OtherIodine (disinfectants, amiodarone, thyroxine) Ca/Mg (antacids), Cu (bracelet), Zn (dental fixative)Retinol (dermatological preparations), vit K (mouth wash)

  23. UK Population Exposure AssessmentThe National Diet and Nutrition Surveys • Four surveys covering ages 1.5 yrs to >85 yrs • Random samples of the British population with approximately 2,000 subjects in each. The very ill, pregnant women and those of no fixed abode were not included • Field-work conducted between 1990 and 2001 • Collected information on: - 4-7 day weighed dietary intakes- supplement and drug use- laboratory measures of nutrient status- alcohol intake and smoking- tests of liver and kidney function (elderly only)- BP and BMI • The surveys provide detailed information about the prevalence of nutritional deficiencies and excess and some of the associated risk factors

  24. Supplement Safety: Nutrients of Greatest ConcernPercentage Contribution to Total Intake from Supplements: NDNS data • The above are the nutrients most likely to be associated with a variety of adverse effects. No intake data on selenium

  25. Nutrients of Concern and Recommendations for Safe Daily Intakes

  26. Use of Nutritional Supplements in UKNational Diet and Nutrition Surveys • Supplement categories are reported with slight differences between surveys • Females are usually bigger consumers of supplements than males • Most iron and multivitamins with iron are consumed equally by females and males

  27. Safety of Vitamin A: SACN Sept 2005 • Total Safe Intake, TSI1500 ug/day • UK adult diet provides on average 700 ug/day • Supplements should usually be limited to 800 ug/daynone in pregnancy • % population intakes >TSI- adults (19-64yrs) M 9%, F 4%- elderly (65+ yrs) M 11%, F10% • High intakes can occur from: - food – liver, very high dairy - supplements multivitamins and cod liver oil

  28. Safety of Vitamin A: SACN Sept 2005 • Acute Toxicity: – rare >50,000ug/day- liver failure, death • Chronic Toxicity:- pregnancy (limb deformity)- osteoporosis- hair loss, dry skin- hypercalcaemia • Recommendations to:- Farming Industry- Food Supplement Industry • Supplement Industry:- overages of <30-65% according to CRN/HFMA- only 50% of cooperated in a subsequent survey

  29. Reported Retinol content of Liver in UK PublicationsMon Manual of Nutrition HMSO, CoF Composition of Foods HMSO/RSC

  30. Retinol Content of SupplementsSafe Upper Level 800 ug/day • Cod Liver Oil 10 mls 1,800ug • Holford Multivitamin 1,200ug • HealthSpan Multi 50+ 1,000 ug • H and B ABC Plus Senior 1,050 ug • Solgar Solovit 750 ug • Biocare Adult Multi Vit+Mins 600 ug • Continental Multivitamins None • Solgar Multivitamins – many None • Seven Seas Premium CLO None • CLO in Norway reduced by 70%

  31. Retinol Status of the British Population (estimates)Plasma Retinol Levels NDNS Data Collected 1990-2001

  32. Serum Retinol and the Risk of Fracture[Swedish men aged 49-51 yrs, 30 year cohort study]Michaelsson K et al NEJM 2003:348:287-294Dark line = mean and 95% CIs

  33. Retinol Intake and FractureFeskanich D et al. JAMA 2002;287:47-54 • Nurses’ Health Study in the USA • 72,337 predominantly white post-menopausal women 18 yr follow-up • High intakes of retinol >2000 ug/day vs <500 ug/day; fracture RR 1.89; 95% CI 1.33 to 2.68

  34. Serum Vitamin A and Hip Fracture. NHANES I prospective analysis of follow-up dataOpotowsky et al Am J Med 2004;117(3):169-74 • 2799 women age 50 -74 years in the US • No linear relationship between serum retinol and risk of hip fracture • Fracture risk was increased in the:lowest quintile – HR 1.9 (95% CI:1.1-3.3)highest quintile – HR 2.1 (95% CI:1.2-3.6) • Both low and high serum retinol may be associated with an increased risk

  35. Serum Retinoids and Beta-Carotene as Predictors of Hip and Other Fractures in Elderly WomenBarker et al J Bone Miner Res 2005;20:913-920 • Prospective study of 2606 British women median age 75 years followed up for a median duration of 3.7 years • Subjects were part of a bisphosphonate trial • 312 incident osteoporotic fractures and 92 incident hip fractures • The risk of osteoporotic fracture was slightly less in the highest quartile of serum retinol • Multivitamin or cod liver oil use was associated with a significantly lower risk of any fracture • “We suggest that there is not sufficient evidence to support the elimination of retinol supplements or restriction of dietary intake of pre-formed retinol or beta-carotene on the basis of skeletal risk” • However, this was not a representative survey ……

  36. Barker et al study comparison with NDNS populationBarker et al J Bone Miner Res 2005;20:913-920 • Subject exclusion criteria:hypocalcaemianeutropeniaabnormal LFTsrenal impairment • Serum retinol and 25(OH)D correlated r = 0.12, p <0.001 • * Weight difference cases vs controls (p <0.01) • Conclusion:CLO/Multivitamins are safe in elderly women if – none of the above and not overweight/obese i.e. non-normal population • However many will have an increased risk as they age

  37. Renal Function and Plasma Retinol: NDNS 65+Correlation between deteriorating renal function and plasma retinol

  38. How Common are Abnormal Liver Function Tests? NDNS 65+ Prevalence: Plasma Alkaline Phosphatase >110 IU/L Plasma Gamma-Glutamyl Transferase >50/32 IU/L • Abnormal LFTs may occur in 10% - 30% of UK adults • Common causes:- Alcohol excess- Obesity - NAFLD- Hepatitis B and C- Drug-induced - Auto-immune liver disease • Elevated Alkaline Phosphatase - cholestatic liver disease - increased mortality • Elevated Gamma GT- usually alcohol excess • Abnormal LFTS- potential accumulation Mn, Cu - altered vitamin A status- reduced 25(OH) vit.D

  39. Retinol: Liver Disease • Reduced Hepatic Content in Liver DiseaseLeo and Lieber. NEJM 1982;307:597-601 • Elevated Plasma Retinol with high Alcohol Intake20% increase in plasma DNSBA 1989 • Supplements Increase Plasma (Liver) Alkaline PhosphataseUse of 7,576 ug/day for 3.8 yrs was associated with a 7% increaseCartmel B et al AJCN 1999;69:937-43 • Liver Damage with High Doses >15,000 ug/daySheth A et al J Am Diet Assoc 2008;108(9) 1536-7 • Hepatitis C - Poorer Response to Interferon in those with high total intake of retinolLoguerico C et al Am J Gastro. 2008;103(12) 3159-3166

  40. Hepatic Vitamin A content and Liver DiseaseLeo and Lieber 1982

  41. Vitamin A: Liver Disease and AlcoholDNSBA 1989 alcohol consumption and plasma retinol in British Adults

  42. Effect of 21 day Alcohol Abstinence and Supplement Programme on Vitamin A and Carotenoids (serum levels umol/l)Geugeun S et al JACN 2003, 22(4): 303-310. 106 Alcoholic French subjects. Supplement: beta-carotene 6mg, Vitamin C 120mg, Vitamin E 30mg, Zinc 20 mg, Selenium 100ug

  43. Elevated Serum Vitamin A and Metabolic SyndromeGraham T et al NEJM 2006;354:2552-2563 • Retinol Binding Protein transports retinol and thyroxine • Produced by the liver, choroid plexus and adipose tissue • RBP4 is produced by adipocytes and is the main carrier protein for retinol in serum • Elevated RBP4 is associated with abdominal obesity, raised TG levels, decreased HDL levels and systolic hypertension • Serum RBP4 correlates with insulin resistance in obese and pre-diabetic subjects • Serum RBP4 and serum retinol levels are moderately correlated

  44. Diet and Response of Hepatitis C to InterferonLoguerico C et al Am J Gastro 2008;103:3159-3166 • The response of patients with HCV-hepatitis to standard treatment is ~60% • The response is significantly better in younger people, with early disease, who are not obese, drink less alcohol and differs with the viral genotype • The patient’s diet may also be a factor • Intake of some micronutrients may increase and others reduce the chance of successful outcome to therapy • Because multiple statistical analyses were made no firm conclusions about micronutrient intake and disease progression can (yet) be made

  45. Diet and Response of Hepatitis C to InterferonLoguerico C et al Am J Gastro 2008;103:3159-3166 • 1084 with HCV-related chronic hepatitis in Southern Italy 24-48 wk trial • Patients with HIV, HBV-hepatitis or other major illness were excluded • 432 Treated with interferon + ribavarin. 246 responded; 186 didn’t respond • Non-responders were likely to be >50 yrs, BMI >25 kg/m2 and alcohol ++ • 7-day diet diaries were used to calculate nutrient intake • Intakes were also compared with 2,326 healthy blood-donor controls

  46. Vitamin A Excess: Case Histories

  47. Retinol: OC Pill, HRT and Pregnancy • The OC Pill and HRT These cause a small, probably insignificant, rise in serum retinol • Pregnancy and Lactation Requirement IncreasesThe Reference Nutrient Intake, rises from 600 ug/day to 700 ug and in lactation to 950 ug/day. A diet rich in dairy foods and vegetables should be emphasised • Retinol is needed for growth and particularly in utero and infancy for full lung and kidney development. The full consequences of deficiency in the infant might only be observed later in adult life • Pregnancy SafetyCMO (1990) and SACN advise pregnant women to avoid liver and retinol supplements as an excess (3, 000 ug/day) can cause limb deformity. Beta-carotene supplements are considered to be safe. • However the pattern of vitamin A intake has changed dramatically

  48. Vitamin A Intakes in Younger Women: Mean values ug/dayFood-sourced Pre-formed Retinol All Sources - Retinol Equiv. • All Sources = retinol + carotene from diet + supplements • The fall in liver and full-fat dairy consumption over the last two decades has greatly reduced the intake of pre-formed retinol especially in young women • The impact of this on pregnancy and infant health is not known • The rise in obesity and alcohol intake in women might influence vitamin A metabolism, requirements and the suitability and safety of supplements

  49. Clinical Picture of Chronic Retinol Excess

  50. Treatment of Retinol Excess/ Elevated Plasma Retinol • Stop high intake –supplements, foods (liver & fortified foods) • Reduce weight if obese or abdominal obesity • Assess liver and renal function and plasma calcium • Limit alcohol if excessive or abnormal liver function tests • Reduce weight if overweight especially if T2D or liver disease • Assess osteoporosis risk and vitamin D status and treat • Assess other nutrients excess or deficiency (zinc) and treat • Review drug treatment (oc pill, tetracycline, sodium valproate) • Advise against pregnancy • Reassess after 2-3 months

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