Mastering Manganese
InterClinical eNews February 2020, Issue 101
In this issue we examine one of the lesser known nutrients, Manganese. Although this is a trace element and is needed by the body in very small quantities, it is critical for good health.
What is manganese’s role in good health? How do we know when to prescribe it?
‘A well-known professional basketball player was a devout vegetarian. He felt he performed better if he kept to a strict vegetarian diet. However, while his shooting and concentration seemed improved, he kept breaking bones, which then healed very, very, slowly. His joints also became increasingly unstable. His basketball career seemed to be at a halt’.
‘Eventually, his physicians discovered he had no detectable manganese in his system. They immediately prescribed manganese supplements. Over a period of several months his bones began to mend, making him strong enough to return to the NBA court’. 1
What does manganese do?
Manganese (Mn) is the twelfth most abundant element on earth. It is a trace mineral, vital to human and animal life. In humans it appears to be required for the regulation of blood sugar levels and the growth and repair of connective tissues and cartilage. It is important for energy production, the breakdown of fats and the healthy function of the thyroid and adrenals. It is distributed throughout the human body’s tissue with most being found in the bone, kidneys, liver, pituitary, pancreas and brain. 2 Importantly, Mn activates enzymes associated with fatty acid metabolism and protein synthesis. 1
Mn is essential in bone metabolism along with cofactors, calcium, copper and zinc. Studies of post-menopausal women have demonstrated the effectiveness of supplementation with calcium, copper, Mn and zinc for bone mineral density. 3 A deficiency of Mn results in abnormal skeletal development because it is a preferred cofactor of enzymes called glycosyltransferases. These enzymes are required for the synthesis of proteoglycans needed for the formation of healthy cartilage and bone. 4
Mn functions as a cofactor for a variety of enzymes, including arginase, glutamine synthetase (GS), pyruvate carboxylase and manganese superoxide dismutase (MnSOD). Through these, Mn plays critically important roles in development, digestion, reproduction, antioxidant defense, energy production, immune response and regulation of neuronal activities. 5
- The Mn metalloezyme arginase has the homeostatic purpose of ridding the body of ammonia through urea synthesis, and to produce ornithine, the precursor for polyamines and prolines. Polyamines produced through ornithine decarboxylase are necessary for cell proliferation and regulation of several ion channels. 7
- Glutamine synthetase is an enzyme responsible for catalyzing the reaction that synthesizes glutamine from glutamate which is neurotoxic and ammonia which is toxic. 7
- Pyruvate carboxylase is a protein important in the conversion of carbon dioxide and pyruvate to oxaloacetate. It is involved in gluconeogenesis, lipogenesis and the krebs cycle. 13
- MnSOD is one of a family of enzymes that catalyses the disproportionation (the transformation of a substance into two or more dissimilar substances usually by simultaneous oxidation and reduction) of superoxide anion. This protects cells against oxidative damage. Aerobic life without MnSOD is not sustainable. It is a ubiquitous metalloenzyme essential for the survival of all aerobic organisms from bacteria, to humans. 6
Genetic Variation Affecting Homeostasis
Several genes affect Mn homeostasis. SLC39A8 deficiency (SLC39A8 – CDG) is an inborn error of metabolism affecting Mn transport via ZIP8. This results in Mn deficiency and neurological and motor dysfunction. Congenital glycosylation is another feature of this phenotype. In a small cohort, high doses of Mn sulfate (15-20 mg per kg) have been noted to resolve the enzyme dysfunction.8
The C allele of the SLC30A10 causes deficiency due to increased Mn efflux, which results in lower blood Mn. Conversely, the A allele of the same gene limits Mn efflux from cells and its transport to bile for excretion. This results in significantly higher blood levels and is associated with neurodevelopmental issues in children.9
Dietary Intake
In the diet Mn is mostly obtained from legumes, whole grains, nuts and rice. Studies have found that Mn intake has declined throughout the western world. At the turn of the century diets were based on wholegrains, cereals and other traditional foods. This meant that Mn intakes were much greater than the average intake today. As society has developed diets have become high in processed foods, fat and sugar. These foods contain almost no Mn due to the removal of the bran and germ of grains during processing. 10
The amount of Mn absorbed orally from food in humans ranges from 1% to 5% and is dependent on the amount and form of Mn and other dietary components such as fibre and phytates which can have a dramatic effect on absorption.
Mn is absorbed by the intestinal cells as Mn+3 by binding to transferrin. Through endocytosis it is brought into the cell and dissociated into Mn+3 and Mn+2. Mn+2 is then transported into the cytosol. The protein ferroportin, exports iron from the cell and has been implicated in Mn efflux. Mn is then released into the circulation where it is bound to albumin and β-albumin for transport to the peripheral tissues. Due to the shared use of the transporter transferrin, Mn absorption can be adversely affected by the presence of iron in the diet. Other minerals that may compete for Mn absorption are calcium, zinc and cadmium. 10
A deficiency in trace elements that are synergistic can also lead to poor Mn status. Nutrients considered synergistic to Mn include the minerals iron, magnesium, phosphorus, potassium and zinc; and vitamins A, B1, B3, B5, B6 and E. 1
Deficiency and Excess
A deficiency of Mn has been associated with numerous diseases and poor health outcomes and is due mostly to inadequate intake or interaction with competing minerals. Mn deficiency symptoms can be non-specific ranging from poor bone growth, skeletal defects and impaired growth, to poor glucose tolerance and abnormal metabolism of carbohydrates and fats.
It has been suggested that Mn intake could serve as a protective antioxidant against chronic diseases associated with low Mn levels such as diabetes, metabolic syndrome, asthma, osteoporosis and dyslipidemia. 10
On the other hand Mn excess symptoms tend to target those organs that are primary storage sites, especially the brain. Symptoms can include irritability, aggressiveness, cognitive and behavioural deficits and reduction in motor function. A susceptibility to manganese toxicity can be caused by chronic liver disease and iron deficiency. 4
How to determine Manganese status
In the United States, Hair Tissue Mineral Analysis (HTMA) results appear to show Mn deficiency to be as prevalent as iron deficiency. 1 Since many of the symptoms of Mn deficiency are non-specific and permanent, finding a quick, non-invasive way to screen for deficiency is imperative. A study has shown that ‘mineral balance and excretion data are not useful biomarkers of manganese exposure’, therefore it is essential to find another way to obtain Mn status. 11
Hair Tissue Mineral Analysis (HTMA) has a long history. For many years researchers have used it to study minerals excesses and deficiencies in human nutrition. HTMA is not a diagnostic tool but provided the sample is properly obtained; it can reveal nutritional and toxic element levels. With a proper understanding of nutrition, and the complex interrelationships between minerals, an individual metabolic profile of the body can be understood. (See www.interclinical.com.au for a list of studies using HTMA). From the results of an HTMA, a practitioner can then choose other focused testing to confirm the best treatment.
Conclusion
Manganese is essential for life, but because of the decline in the quality of the average diet, dietary intake has decreased. Conducting a test for nutrient levels can establish if a deficiency is present. However, obtaining mineral content from blood samples is complex. HTMA can measure essential trace elements with appropriate specificity, sensitivity, speed, simplicity and cost. 12 With careful supplementation and a healthy eating plan deficiency can be addressed.
REFERENCES
1 Watts, D. Trace elements and other essential nutrients, 1995 Ch. 10, p 117-123
2 Frontiers in Bioscience, Landmark 23 (2018) pp. 1655-1679
3 Saltman PD, Strause LG. The role of trace minerals in osteoporosis. J Am Coll Nutr. 1993 Aug; 12(4):384-9
4 Linus Pauling Institute: Manganese
5 Chen.P, Bornhorst.J, Maschner.J. Manganese metabolism in humans. Front Biosci (Landmark Ed.). 2018 1;23:1655-1679
6 Miriyala. S, et al Manganese superoxide dismutase, MnSOD and its mimics. Biochimica et Biophysica Acta 1822 (2012) 794-814
7 Caldwell, R.B, Toque, H.A, Narayanan, S.P, Caldwell R.W. Arginase: an old enzyme with new tricks. Trends Pharmacol Sci, 2015 Jun; 36(6): 395-405
8 Park, J.H et al, SLC39A8 deficiency: biochemical correction and major clinical improvement by manganese therapy. Genetics in Medicine. Feb 2018, vol. 20, No. 2.
9 Whalberg K.E et al. Polymorphisms in Manganese Transporters SLC30A10 and SLC39A8 are associated with children’s neurodevelopment by influencing manganese homeostasis. Frontiers in Genetics, Dec. 2018 Vol 9, Article 664.
10 Freeland-Graves JH, Mousa TY, Kim S. International variability in diet and requirements of manganese: causes and consequences. Journal of Trace Elements in Medicine and Biology 2016;38(supplement C):24-32.
11 Greger JL. Nutrition versus toxicology of manganese in humans: evaluation of potential biomarkers. Neurotoxicology. 1999 Apr-Jun;20(2-3):205-12.
12 Park, SB, Choi SW, Nam AY. Hair Tissue Mineral Analysis and Metabolic Syndrome. Biol Tace Elem Res 2009 130:218-228.
13 Smith LD, Garg U. Biomarkers in Inborn Errors of Metabolism. 2017 1st Ed. Elsevier Ch 5.
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