Micronutrients: Micro in Amount Macro Impact.

What are micronutrients?

As you know, vitamins and trace elements are the micronutrients and vitamins are essential for growth and health because of the involvement in specific metabolic functions and vitamins cannot be synthesized in the body.

Therefore, they must be provided by diet or as a supplement and there are 13 vitamins are essential.

9 of those are water soluble and 4 lipid soluble.

What are trace elements?

15 trace elements play important physiologic roles, 9 of these trace elements are associated with deficiency states in humans and trace elements cannot be synthesized in the body as well. If not supported, their deficit should lead to functional abnormalities.

Oral and parenteral trace elements requirements and dosage guidelines for adult

Stages leading to deficiency of micronutrients – infographic

Development of micronutrient deficiency

1. Because of an insufficient intake of trace elements, the body compensates it in order to improve itself. For example, by increasing the absorption or decreasing excretion and if inadequate intake persists, it results firstly in failure of biological functions.
2. This leads to metabolic changes and oxidative damage.
3. At a later stage, if the deficiency continues, not specific functional disruption appears, it leads to problems in immune function, cognitive function, weakness and tiredness.
4. Finally, micronutrient deficiencies cause clinical diseases, and death may occur at the final stage.

Clinical consequences of micronutrient imbalances in patients requiring parenteral nutrition

MICRONUTRIENT	STATUS	PATIENT/S	CLINICAL CONSEQUENCES
Selenium (Se)	Deficiency	Adults, long-term	Cardiomyopathy, skeletal myopathy, muscle weakness, loss of pigmentation1
			Fatal cardiomyopathy2
			Reversible cardiomyopathy, muscle weakness, nail changes2
		Adults, short-term	Reversible cardiomyopathy, muscle weakness, nail changes2
Zinc (Zn)	Deficiency	Adults, long-term	Skin lesions; other symptoms included alopecia, perioral ulcers, periungual lesions1
			Intractable vomiting1
			Severe skin lesions, diarrhea2
			Lymphopenia, decreased T cell responses3
Vitamin A	Deficiency	Adults, long-term	Visual disturbances4
Vitamin B1 (thiamine)	Deficiency	Adults, long-term	Lactic acidosis5
			Refractory lactic acidosis leading to death6
		Adults, post-operative	Confused state, mental sluggishness, horizontal nystagmus7
			Confusion, nystagmus8
Vitamin B7 (biotin)	Deficiency	Adults, long-term	Dry eyes, angular cheilitis, hair loss4
Vitamin E	Deficiency	Adults, long-term	Visual symptoms, signs of macular degeneration8
Vitamin K	Deficiency	Adults, long-term	Prolonged prothrombin time9
1. Fessler TA. Nutr Clin Pract. 2013;28.722-729; 2. Misra S, et al. Nutrition in Clinical Practice. 2000;15:120-126; 3. Leung FY. Clin Biochem. 1995;28:561-566; 4. Forbes GM, Et al. Nutrition. 1997;13:941-944; 5. Romanski SA, et al. Mayo Clin Proc. 1999;74:259-263; 6. CDC. Deaths associated with thiamine-deficient TPN. 1989; 7. Mirtallo JM. Nutr Clin Pract. 2015;30:86-91; 8. Biesalski HK. Gastroenterology. 2009;137:592-104; 9. Helphingstine CJ, et al. JPEN J Parenter Enteral Nutr. 2003;27:220-224.

The clinical consequences of micronutrient deficiency or toxicity in patients requiring parenteral nutrition therapy have been reported. In the literature, you can find about the trace elements or about vitamins in many guidelines or review articles (see the table footer above, and the references section at the end of the article).

Micronutrients status in short-term parenteral nutrition therapy

CLINICAL CONDITION FOR HOSPITALIZATION	MICRONUTRIENTS THAT MAY BE AFFECTED BY CONDITION
Critical illness, including intensive care unit stay1-8	Chromium, copper, iron, molybdenum, selenium, zinc, vitamin A, vitamin B, vitamin C, vitamin E
Major trauma, including major burns1-5,7	Selenium, zinc, vitamin C
Hemodialysis, severe gastrointestinal losses, renal failure4-5,7	Selenium, zinc, vitamin A, vitamin B9 (folic acid), vitamin C, vitamin E
Surgery4,7	Zinc, vitamin A, vitamin C, vitamin E
1. Fessler TA, Nutr Clin Pract. 2013;28:722-729; 2. Hardy G, et al. Nutrition. 2009;25:1073-1084; 3. Shenkin A, S, Gastroenterology. 2009;137:561-69; 4. Agarwal A, et al. J Endocrinol Metab. 2011;1:57-63; 5. Berger MM. Gastroenterology. 2009;137:570-78; 6. Mirtallo JM. Nutr Clin Pract. 2015;30:86-91; 7. Sriram K, Lonchyna VA. JPEN J Parenter Enteral Nutr. 2009;33:548-562; 8. Strachan S. Current Anaesthesia & Critical Care. 2010;21:44-48.

In the short term, some conditions, such as critical illness, major trauma, renal failure, or surgery, may affect micronutrients. And, for example, in intensive care unit patients, requirements of some micronutrients may increase, decrease or no change.

The importance of micronutrient support

The aggregated results of 15 trials in critically ill patients showed that antioxidant and trace elements supplementation was associated with a significant reduction in overall mortality.[4]

Drug therapy that decreases vitamin levels

And conditions also need to consider the decreased effect of drug therapy on micronutrient levels, especially on vitamins, for example, metformin and vitamin B12, methotrexate and folic acid. [5]

• Metformin – Vitamin B12
• Phenytoin – Folic acid, vitamin D
• Isoniazid – Vitamin B6
• Methotrexate – Folic acid Cholestyramine Vitamin A, D, E, K

All guidelines recommend that daily parenteral vitamins and trace elements supplies should be provided to patients receiving parenteral nutrition in order to improve nutrition status and to prevent complications of deficiencies.

Should we measure micronutrients levels during parenteral nutrition?

Short answer: not really!

Vitamins and trace elements

A standard dosage of vitamins and trace elements is recommended because individual requirements cannot be easily determined.

As previously mentioned, supplementation of micronutrients is recommended by guidelines. However, in university hospitals or in intensive care units, supplementation of micronutrients is not provided up to 50% of the patients.

Several parenteral multivitamin and trace element formulations are available, and micronutrients should be added to parenteral nutrition solutions. However, enteral nutrition products already included micronutrients.

So, additional micronutrients are unnecessary if patients are receiving enteral nutrition unless higher doses are needed. To maximize stability, macronutrients are not included in commercially the available parenteral nutrition solutions they need to be added prior to infusion.

Vitamin instability in parenteral nutrition

Vitamin stability is limited in the presence of air, light and some trace elements (TE)2	Vitamins and TE may be administered together5 assuming proper attention to: Light protection Air protection
Vitamin degradation may be caused by1: Light exposure  Chemical degradation Oxidation	Use of certain protections can help prevent vitamin degradation5 Light protection bags (work for ≤ 24 hours) Administration sets Short lines Multi-layered bags Removal of excess air after filling
1. Allwood MC and Kearney MC. Nutrition 1998;14:697-706; 2. Muhlebach S, et al. Basics in Clin Nutr ESPEN 2011;373-392; 3. Gibbons E, Allwood, MC Neal T and Hardy G. J Pharm.Biomed Anal 2001;25:605-611; 4. Biesalski HK, et al. Ger Med Sci 2009;7:Dec21; 5. Such Diaz A, et al. Nutr Hosp 2009;1-9.

Most vitamins, especially vitamin A and vitamin B2, are the most sensitive vitamins to light. Vitamin C is the least stable vitamin and may be associated with substantial loads of storing/administration.

How to protect vitamins and trace elements from degradation while administration?

Certain protections such as light protection, using light protection bags, multi-layer bags and removal of excess air after filling can help to maintain stability and according to recent ESPEN guidelines published in 2020, addition of vitamins to parenteral nutrition admixtures should be immediately prior to infusion and separating infusion of micronutrients is also an alternative recommendation.

What about monitoring micronutrient levels?

It’s usually unnecessary to routinely obtain certain levels of micronutrients. Levels of vitamin D, vitamin B, 12 and folate are the only ones easily available and of use in clinical practice, and obtaining serum levels of trace elements is even more difficult. Serum levels of trace elements may show recently administered trace elements and not tissue levels.

Parenteral nutrition may not contain expected levels of micronutrients

And parenteral nutrition may not contain expected levels of micronutrients due to contamination, instability, or compounding issues.

Since the deficiencies detected in the long term, guidelines generally recommended monitoring all signs and symptoms of the deficiencies.

Summary – take home message for micronutrients management

As a summary:

• Micronutrient requirements must be determined for each patient.
• Effect of some diseases or conditions on micronutrient requirements must be considered.
• Monitoring of micronutrients levels during parenteral nutrition therapy may be of limited value.
• Vitamins are generally not considered being stable enough for prolonged storage in parenteral nutrition preparations and in general, advice to be added to parenteral nutrition shortly before use.

References

1. Shenkin A. Micronutrients in health and disease. Postgrad Med J. 2006 Sep;82(971):559-67. doi: 10.1136/pgmj.2006.047670. PMID: 16954450; PMCID: PMC2585731.
2. Fessler TA. Trace elements in parenteral nutrition: a practical guide for dosage and monitoring for adult patients. Nutr Clin Pract. 2013 Dec;28(6):722-9. doi: 10.1177/0884533613506596. Epub 2013 Oct 25. PMID: 24163318.
3. Invited Review: Micronutrient and Trace Element Monitoring in Adult Nutrition Support
4. McClave SA, Taylor BE, Martindale RG, Warren MM, Johnson DR, Braunschweig C, McCarthy MS, Davanos E, Rice TW, Cresci GA, Gervasio JM, Sacks GS, Roberts PR, Compher C; Society of Critical Care Medicine; American Society for Parenteral and Enteral Nutrition. Guidelines for the Provision and Assessment of Nutrition Support Therapy in the Adult Critically Ill Patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.). JPEN J Parenter Enteral Nutr. 2016 Feb;40(2):159-211. doi: 10.1177/0148607115621863. Erratum in: JPEN J Parenter Enteral Nutr. 2016 Nov;40(8):1200. PMID: 26773077.
5. Yalçın N, Armut M, Kelleci Çakır B, Demirkan K. Drug-induced nutritional disorders. Clin Sci Nutr 2020; 1(3): 113-22.
6. Mehta NM, Duggan CP. Nutritional deficiencies during critical illness. Pediatr Clin North Am. 2009 Oct;56(5):1143-60. doi: 10.1016/j.pcl.2009.06.007. PMID: 19931068; PMCID: PMC4641569.