Micronutrients B

Luisito O. Llido, MD, FPCS, DPBCNHead, Clinical Nutrition Services

St. Luke’s Medical Center, Philippines

Objectives

• To discuss classification of micronutrients

• To discuss rationale and mechanics of supplementation of micronutrients in parenteralnutrition

General functions/features

• Major role in fundamental metabolic reactions (e.g. energy production, signal transduction)

• Needed in biological processes like enzyme activities and cellular structure dynamics

• Work in combinations rather than individually

• Deficiencies result to organ dysfunction, poor wound healing, or altered immune function

Classification

• Vitamins: Fat or water soluble

• Trace elements → three groups:

– Cationic elements: Zn, Fe, Mn and Cu - absorbed from the gut with variable efficiency

– Anionic elements: Cr, Se, Mo and I which are absorbed efficiently by the gut and excreted mainly in the kidneys

– Organic compound combinations, (selenoamino acids, Cr in “glucose tolerance factor”, heme Fe and Co in cobalamin)

Dietary Reference Intake

• Dietary Reference Intake (DRI) is a better way of expressing requirements; subdivided to:

– Estimated Average Requirement (EAR)

– Recommended Daily Allowance (RDA)

– Tolerable Upper Limit (UL)

Dietary Reference Intakes: The Essential Guide to Nutrient Requirements. Washington DC, National Academies Press; 2006

Requirements

• The American Medical Association has established guidelines for the 13 essential vitamins and for trace elements (Se, Zn, Cu, Mn, Cr, Co, Fe, Fl, I, Mo,)1, 2

• Applicable to the general healthy population.

• Exact requirements in critically ill patients are unknown 3

1. Nutrition Advisory Group, JPEN J Parenter Enteral Nutr, 1975; 3:258 2. American Medical Association, Dept of Foods and Nutrition, JAMA, 1979;241:20513. Elia M. Lancet 1995; 5:1279-1284

Requirements in disease states

• Guidelines:

– Vitamins and trace elements (specifically selenium) should be provided to all patients receiving specialized nutrition therapy (especially critically ill patients)

– Level B recommendation

McClave SA. SCCM/ASPEN Guidelines. JPEN J Parenter Enteral Nutr 2009; 33:277

Definition of essential trace element*

• Universally present in tissues

• Concentration controlled

• Withdrawal causes clinical and biochemical effects

• Supplementation corrects clinical and biochemical effects

* Jeejeebhoy K. Micronutrients. 4th Asia Pacific Parenteral Nutrition Workshop June 2009; Kuala Lumpur, Malaysia

Absorption of micronutrients

Toxicity issues*

• Water soluble vitamins - toxicity is unlikely; x100 RDA is safe

• Fat soluble vitamins: x10 RDA is safe

• Trace elements: At recommended doses, toxicity due to nutritional support has not been reported

• Liver dysfunction: copper and manganese

* Sriram K. Micronutrients. Plenary Lecture, PENSA 2007, Manila, Philippines

Vitamin and trace elements monitoring

• Availability and affordability

– No practical way of measuring in most hospitals

– Special tests are available but very expensive

Anabolic minerals

• During intravenous nutrition:*

– N withdrawal → P, K, Na, Cl not retained

– K withdrawal → N and P not retained

– Na or P withdrawal → all elements not retained

• Weight gain without inclusion of N, P, K, Na → mainly due to fat, no protein build up

• Parenteral nutrition: anabolic minerals required* Rudman D et al. Elemental Balances during Intravenous Hyperalimentation

of Underweight Adult Subjects. J Clin Invest 1975; 55: 94-104.

VITAMINS

Vitamin K

• Key functions: – Coagulation (production of Factors II, VII, IX and X– Regulates osteocalcin in bone formation.

• Possible deficiency states: – No storage forms of vitamin K. – Deficiences (often subclinical) may occur rapidly– Antibiotics cause alterations in microbial flora reducing

bacterial synthesis

• Sources of vitamin K: – Diet, bacterial synthesis – Fat emulsions

• Lipid emulsions 1:

– 10% → 30.8 ug phylloquinone/ 100 ml

– 20% → 67.5 ug phylloquinone/ 100 ml

• Patients receiving 25-35% of calories as lipid did not require additional Vit K in over 4 weeks of infusion 2

1. Lennon C et al. The vitamin K content of intravenous lipid emulsions. JPEN 1993; 17: 142-4

2. Duerksen DR and Papineau N. The prevalence of coagulation abnormalities in hospitalized patients receiving lipid-based parenteralnutrition. JPEN 2004; 28: 30-3.

Vitamin K source in TPN

• Manifestations of deficiency:

– Estimation of prothrombin time (PT) may not detect subclinical vitamin K deficiency states, which may become pronounced after surgery or resuscitation

• Adverse reactions:

– Rapid IV administration may cause hypotension.

– Subsequent anticoagulation with warfarin becomes problematic

Vitamin K

Vitamin A

• Retinol, β-carotene• Key functions:

– Maintenance of mucosal integrity (bacterial translocation), – Growth and wound healing– Immune function– Vision

• Possible deficiency states: – GI losses – patients on steroids

• Vitamin A levels are increased in renal failure patients

Vitamin A

• Manifestations of deficiency: – Poor wound healing– Mucosa and skin changes – Diarrhea– Xerophthalmia– Low levels in acute pancreatitis

• Steroid and retinoids have antagonistic effects on wound healing:– Growth factors– Collagen deposition

• Dose: 10,000 to 15,000 IU/d for 7 days

Vitamin D

• Key functions:

– Calcium absorption, homeostasis, and metabolism

– Major role in immune competence/modulation

– Active metabolite: 1,25 dihydroxy Vitamin D or calcitriol

• Deficiency:– Osteomalacia and osteoporosis– Immune dysfunction

• Requirements:– 200 IU/day in adults

Vitamin D

• Metabolic bone disease in patients receiving long term PN

– Bone pain and fractures

– Hypercalcemia and hypercalciuria

– Negative calcium balance

– Low plasma PTH

– Osteomalacia

– Normal plasma 25-OH-Vitamin D

Jeejeebhoy K. Micronutrients. 4th Asia Pacific Parenteral Nutrition Workshop June 2009; Kuala Lumpur, Malaysia

Vitamin D

• Causes of metabolic bone disease:

– Toxins: aluminum, cadmium, strontium, silicon

– Drugs: furosemide, heparin, acetate

– Deficiency: calcium, phosphorus, magnesium, VitC, copper, boron

– Excess: Vitamin D, fluoride

– Note: long term PN may need withdrawal of:

• Vitamin D supplementation

• Calcium

Jeejeebhoy K. Micronutrients. 4th Asia Pacific Parenteral Nutrition Workshop June 2009; Kuala Lumpur, Malaysia

Vitamin E

• α-tocopherol commonly used

• Major role in antioxidant activity in cells

• Parenteral nutrition

– Dose in adults: 10-15 IU/day

Antioxidants

Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella F, Garcia I, Maier RV. Randomized, prospective trial of antioxidant supplementation in critically ill surgical

patients. Ann Surg. 2002; 236(6): 814-22.

1. α-tocopherol 1,000 IU (20 mL) q 8h per naso- or orogastric tube

2. ascorbic acid 1,000 mg given IV in 100 mL D5W q 8h for the shorter of the duration of admission to the ICU or 28 days.

Vitamin B1 (Thiamin)

• Major role: cofactor for oxidation of pyruvate, alpha ketoacids and branched chain amino acids

• Deficiency

– Alcoholics, high carbohydrate intake → as a component of “re-feeding syndrome”, iatrogenic → insufficient thiamine or loop diuretics

– Cardiac “wet” beri-beri (congestive heart failure)

– Gastrointestinal beri-beri (nausea, vomiting, abdominal pain (lactic acidosis) → responds to thiamin admin

• Parenteral nutrition: 5 mg/day

Vitamin B’s in parenteral nutrition*

• Deficiency of Riboflavin (Vit B2), Pyridoxine (Vit B6), Niacin, Biotin (Vit H), Folate, and B12 (Cobalamin) does not occur with FDA-AMA formula when added daily 1

• Low levels of Niacin, Pyridoxine, and Riboflavin noted with MVI-12 given 3x a week 2

1. Shils ME et al. Blood Vitamin Levels of Long-Term Adult Home Total ParenteralNutrition Patients: The Efficacy of the AMA-FDA Parenteral Multivitamin Formulation . JPEN 1985; 9: 179-88.

2. Mikalunas V et al. Abnormal vitamin levels in patients receiving home total parenteral nutrition. J Clin Gastroenterol 2001; 33: 393-6

* Jeejeebhoy K. Micronutrients. 4th Asia Pacific Parenteral Nutrition Workshop June 2009; Kuala Lumpur, Malaysia

Vitamin C

• Main role: – Antioxidant

– Collagen synthesis and wound healing

– Synthesis of carnitine

– Synthesis of neurotransmitters

• Deficiency:– Previous high intake with abrupt cessation (“rebound

scurvy”), burns, all critically ill patients

• Excreted in urine as oxalate– 35%-50% of urine oxalate may be from ascorbic acid

metabolism

Vitamin C

• Plasma Vitamin C in critical illness:

Long CL et al. Ascorbic acid dynamics in the seriously ill and injured. J Surg Res 2003; 109(2): 144-8

TRACE ELEMENTS

Trace elements

• Chromium 1

– Chromium infusion reverses extreme insulin resistance in a cardiothoracic ICU patient 2

– Distribution in all tissues

• Bound to peptide chromomodulin

• Chromomodulin activates tyrosine kinase of insulin receptor

– Cellular level falls with age

• Directly related to age related glucose tolerance

1. Jeejeebhoy K. Micronutrients. 4th Asia Pacific Parenteral Nutrition Workshop June 2009; Kuala Lumpur, Malaysia

2. Via M et al. Nutr Clin Pract 2008; 23: 325-8

Trace elements

• Chromium:

– Exact requirements not known

– Excretion in urine:

• normal = 6-10 ug/day)

• enhanced by rise in insulin levels (in diabetics/NIDDM = 20 ug/day)

– Parenteral nutrition: due to glucose infusion requirements may be around 20 ug/day

Trace elements

• Selenium

– Present in cells as selenocysteine

– Integral part of glutathione peroxidase: major role in antioxidant activity of all cells

– High concentrations in liver, kidney, pancreas, and heart

– Excreted in urine (14%-20%) and feces (33%-58%)

Trace elements

• Selenium

– Requirements:

• minimal intake of 20-54 ug/day

• Increased requirements in severe burns

• May also be increased in sepsis

– Deficiency manifestations:

• Muscle pain

• Cardiomyopathy

Trace elements

• Zinc

– Major Role:

• Protein and carbohydrate metabolism

• Immune system – cell mediated immunity

• Anti-inflammatory, anti-oxidant 1

• Wound healing

• Acute phase response

– The Zn content of the human body is the highest for any trace element, except for Fe

Trace elements

• Zinc

– Deficiencies:

• Excessive GI losses (protracted diarrhea, emesis, high-output fistulas), short bowel syndrome, pancreatic insufficiency, Trauma, burns, Alcoholism, Renal insufficiency, High dose steroids probably secondary to proteolysis, HIV infection, malignancies

• increases mortality

– Zn supplementation at high doses decreased mortality *

* Knoell DL et al. Zinc deficiency increases organ damage and mortality in a murinemodel of polymicrobial sepsis. Crit Care Med, 2009: 37:1380-1388

Trace elements

• Copper– Major role:

• Iron oxidase → iron transport

• Lysine metabolism → collagen/wound healing

– Excretion: bile

– Deficiency: • Nephrotic syndrome, GI protein loss

• Neutropenia

– Increased levels in: cancer, sepsis, contraceptive use

Trace elements

• Iron

– Major role:

• Hemoglobin

• Myoglobin

– Losses:

• Normal: 0.6-1 mg/day

• Menstruation: 1.1-1.8 mg/day

– Parenteral nutrition: 2 mg/day

• Safe to use iron in the post-operative period *

* Torres S et al. Intravenous iron following cardiac surgery does not increase the infection rate. Surg Infect. 2006; 7:361.

Vitamin requirements in ICU*Vitamin Dose Effect of critical illness ICU dose

Vit A 3300 IU/day Low levels Unknown

Vit D 250 IU/day Pancreatitis Nil

Vit E 10-50 mg/day Increased peroxidation

100 mg/day burns

Vit K 10 mg/wk Increased pro-time w/ antibiotics

Thiamin 3 mg/day Low levels 5 mg/day

Riboflavin 3.6 mg/day

Niacin 40 mg/day

Pyridoxin 4 mgday

Vit C 100 mg/day Low levels 500 mg/day

* Jeejeebhoy K. Micronutrients. 4th Asia Pacific Parenteral Nutrition Workshop June 2009; Kuala Lumpur, Malaysia

Conclusion

• Daily supplementation of micronutrients in parenteral nutrition based on DRI is acceptable

• Higher levels may benefit critically ill patients

• Long term parenteral nutrition has different requirements

• There is a need to understand the mechanism of micronutrient activity in different conditions in order to provide correct supplementation dosages