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"Are There Problems with Current Doses of Micronutrients?"
Gil Hardy PhD FRSCProfessor of Pharmaceutical and
Clinical Nutrition
New ZealandNew Zealand
Parenteral Nutrition
“No you can’t be a Beatle with that tie”
Liverpool
• Prof Sherwood Jones• Dr Mike Peaston
Whiston HospitalLiverpool
“The Practitioner 1966”
“intravenous feeding is routinely instituted if either oral or tube feeding is contraindicated”
Early HPN Patient – Dr Stan Dudrick1970s
5050+ + componentscomponentsinto a singleinto a single bagbag
All-In-One (AIO) PN Admixtures
First UK HPN patient
at St MarksLondon
1977
Fat Friends?
Thin Friends 1980
Fat Friends 2005
Support GroupSupport Group:
Patients On Intravenous and Naso Gastric Nutrition Therapy
‘Supporting all patients on enteral and parenteral nutrition’
Contact and mutual support for people receiving artificial nutrition in the
community
www.pinnt.co.uk
email: [email protected]
Registered Charity 327878
The ‘Champagne Effect’
Are we Flogging a Dead Horse?
Multilayer Bags Oxygen Impermeable
Minimise Vitamin Degradation
Eliminate Air Bubbles
No Champagne Effect
Micronutrients
Vit D Vit C Vit E Biotin
9 Trace Elements
13 Vitamins
Vitamins in Parenteral Nutrition
* FNB – Food and Nutrition Board oral RDA
*
Fat Soluble
Water Soluble
Cernevit®
Identical to
MVI-12®
Not your ordinary nutrients!Vitamins are catalysts for metabolic processes driven by enzymesMany enzymes contain Trace Elements as key componentsMany micronutrients are powerful AntioxidantsMicronutrients are critical and life-saving
“Micro in content: Mega in importance”
Micronutrient - Synergisms
ROOH, ROH Tocopheryl Ascorbate GSSG NADPHFree radicals
Vit E Vit C
ROO-, RO- Tocopherol Dehydro- GSH NADP Ascorbate
GPx (Se) Vit B12
Free Radicals Antioxidants Energy
Too Little:problems of inadequate micronutrients
Impaired Function• ↓Wound Healing • ↓Immunity • ↑Free Radicals
↓Antioxidant Activity
Too Little:problems of inadequate micronutrients
Clinical DeficiencyScurvy, osteomalacia, retinal problems
Thiamine in PN
B1 participates as co-enzyme in oxidative decarboxylation reactions
essential in PN for glucose metabolism body stores very limited
paediatric fatalities due tothiamine deficiency
death due to lactic acidosis,subsequent heart failure
Water-soluble Vitamins B group, Biotin, C, K, Folic acid Not stored by the bodyMust be taken on a regular basis, just as in a regular oral dietExcess excreted in the urine (“renal threshold”)If given too rapidly, renal threshold is exceeded and vitamins lost in urine Unstable in air and sunlight
Vitamins A, D, E
Soluble in body fatStored by the bodyCan overdose (hypervitaminosis A)Overdoses can be toxicCare with storage and administrationVitamin A lost on bag and set surfacesLosses if exposed to sunlight
Vitamin DNature Clinical Practice Gastroenterology & Hepatology (2006) 3, 689-699
• 80 nmol/liter of 25(OH)D
• 3-100 ng/ml of 25(OH)D
• 400 IU/day (DeLuca ASPEN 2009)
• 1600-1800 IU/day (Jacobs 2009)
Vitamin D: Optimal Concentrations
Time in sunshine to achieve dietary equivalent of 1000 IU of vitamin D per day (Jacobs 2009)
25% exposure Webb et al. skin types (1-6):
2 hours, 25 min3 hours, 45 min1 hour, 8 minSkin Type 52 hours, 5 min1 hour, 19 min28 minutesSkin Type 2
January 20
25 minutes17 minutes15 minutesSkin Type 511 minutes7 minutes7 minutesSkin Type 2
July 20
NYC: Partly cloudy at
noon
NYC: Full sunshine at
noon
Tucson: Full sunshine at
noon
Date, Skin Type
Skin type 2: Caucasian, blond or red hair, freckles, fair skin, blue or green eyesVery sensitive to UV; usually burns easily; tans with difficulty, fair skin toneSkin type 5: Middle Eastern, Latin, Light African American, IndianMinimally sensitive to UV; rarely burns, tans easily, olive or dark skin tone
The Answer?
Elements
Mn, Zn, Cu, Fe, Se
Co-enzymes, structural, metabolic
Traces usually obtained from food
HPNers rely almost entirely on
PN regimen
Trace
Too Little or Too Much• Diarrhoea
– Zinc↓ Copper↓• Cholestasis
– Manganese↑• Renal insufficiency
– Aluminium↑• Blood loss
– Iron↓
Hair LossIron↓ Zinc↓ Selenium↕ Biotin↓
• role: Mn S.O.D, pyruvate carboxylaseAntioxidant protection Energy metabolismNo PN deficiency (unless induced)
• dosageAdults: [150-800 μg/d (3-15 μmol/d) AMA][275μg/d AuSPEN 1999 ] 60 - 100 μg/d ASPEN 2004
Recommend: 55μg/day (1 μmol/d) ESPEN 2006Infants : 1 μg/kg/d -1.5 μg/kg/d (max 50μg/d)
Manganese (Mn)
Hardy, Manzanares, Menendez Nutrition 2009Hardy ASPEN Workshop 2009
WARNING: brain accumulation - cholestasis
Manganese in Long Term HPN Patients (Case Reports)
• 25y male HPN 5yrs and 57y male HPN 10yrs• MTE additive: Zn, Cu, Cr, Se, Mn (500mcg/day)
• Plasma Mn: 59.9 and 42.0 nmol/l (normal :5.5-18.2 nmol/l)
• MRI showed Mn deposition in globus pallidus• 9 mo after withdrawal of Mn = MRI normal
• 54 Peds (760g- 65.2kg)• Received 20mcg/kg Cu and 5mcg/kg Mn per day• 15 Cu: 21 Mn: 7 Cu & Mn: 20 had cholestasis• Determine Cu and Mn levels monthly
Mcmillan et al NCP 2008:23;161
Stevens et al NCP 2008:23;197
“opinion is now weighted in favour of excluding opinion is now weighted in favour of excluding MnMn from routine PN regimensfrom routine PN regimens””
• Numerous incidents of PN-associated Mn toxicity and/or hypermanganesemia
• Over 50% of HPN patients may have elevated Mn levels leading to hypermanganesemia– Cerebral, hepatic complications
• No reports of Mn Deficiency
• Mn contamination in additives
• Post mortem data confirm accumulation of Mn(Howard and Shenkin 2007)
COCNMC 2008
Hypermanganesemia
Selenium
Incorporated into Selenoproteins (25+)
• Glutathione Peroxidase (GPx) contains 4 atoms Selenium
• important Antioxidant - removes lipid peroxides
• anti-inflammatory – down regulates NFkB
• Essential for Male Fertility (XY) and Reproduction
• GPx protects developing sperm
Only trace element specified in Genetic Codei.e. Selenocysteine (21st Amino Acid)
“The Se-XY Nutraceutical”
Factors affecting micro-nutrient stability in PN
• Amino Acid buffering• Fat Emulsion source• Electrolytes and
Antioxidants• Concentrations of
nutrients and pH• Sequence of Mixing
*Oxygen * Light * Heat 0
20
40
60
80
100
0 7 14 21 28 60 90 120 150 180
-2 C 4 C 25 C
Time/Days
% T
hiam
ine
% V
itam
in C
Allwood & Hardy Clin Nutr 1992
Trace Elements vs Vitamins in PN
Vitamin C oxidation is catalysedby copper ions or seleniteVitamin C losses 48 hours after mixing
Selenite interacts with Vitamin C at low pHFerric iron may destabilise lipid-PNAdditives must be kept apart until
immediately before administrationAdverse influences of air and light
Protect all PN from Light!
DosageRecommendations
• Zinc: 1-3mg/d adults• 12mg/L g.i losses, diarrhea
• Copper: 0.3mg/d adults• 0.4-0.5mg/d diarrhea• 20mcg/kg/d peds
• Chromium: 10-15mcg/d adults• 0.14-0.2mcg/kg/d peds
• Selenium: 60-100mcg/d adults• 2-2.5mcg/kg/d peds
• Iron: 1mg/d adult males• 1.5mg/d adult females• 500mcg/d peds
• Iodine: 70-150mcg/d adults• 1mcg/kg/d peds
Gastroenterology 2009
DosageRecommendations
• Vitamin C: 100-200mg/d adults• 20-100mg/d peds
• Vitamin D: 30-100 ng/ml 25OH D• 400 IU/d
• Vitamin K: 150mcg/d adults• 2.5-5mg/week• 10mcg/d peds
• Choline: 1-2g/d adults• Carnitine 2-5mg/d adults
• Biotin: 60-69mcg/d adults
• Vitamin B12: 6-50mcg/d adults
Gastroenterology 2009
Daniells & Hardy COCNMC 2010
Manzanares & Hardy COCNMC 2010
More is not always better !
More is not always better !
Chromium >3mg ↑ joint degeneration, immune problemsCopper > 5mg ↑ behavioural problems, infections, anemiaIron ↑ vomiting, diarrhoea, hyperglycemiaManganese ↑ neuro symptomsSelenium > 750 mcg/d ↓ Deiodination, ↑ hair + nail discolorationZinc > 50 mcg/d ↓ immunity Vitamin C > 1 g/d ↑ oxalosis, acute RFVitamin E > 150 mg/d ↑ mortality Some Tocopherols ↑ toxic (tocotrienols)
Conclusion• Long Term HPNers may have increased
micronutrient requirements.
• Micro supplements can:– improve antioxidant capacity– enhance the immune response – reduce infection rates
• CARE:– A Trace is Good. More is not always Better– Make All Additions Aseptically: Protect from Light– Monitor regularly
• RESEARCH
Micronutrients: Future Research
• Better data on deficiency syndromes• Optimum requirements in IF• Synergy between micronutrients• Efficacy of supra-physiological doses• Better Analytical methods• Stability and compatibility issues
Do you have other problems/questions?
Do you have other problems/questions?
Here’s to the Next 25 Years !!!
