Tired All the Time
Fatigue is a very common clinical presentation and can be due to a myriad of issues including stress, infection, inflammation, hormonal imbalance – the list goes on and on. That said, arguably one of the first things any clinician will think of when faced with a patient complaining of being “tired all the time” is iron, and whether enough oxygen is reaching the cells (or more accurately the mitochondria). However it’s not all about iron, but instead a team of nutrients and cellular transporters contribute to creating the energy we all need to enjoy our days.
Short and Sweet
Named for their bright colour, red blood cells (RBCs) are the most abundant cell in the blood, accounting for approximately 40-45% of blood volume.7 RBCs are produced during erythropoiesis, beginning as immature reticulocytes in the bone marrow, and then released into the bloodstream seven days later as matured RBCs (also referred to as erythrocytes).8 RBCs are abundant in haemoglobin (which, as the name alludes to, contains the iron-rich molecule haem, see Figure 1) and are responsible for binding and delivering vital oxygen to tissues for cellular respiration.9 With an average lifespan of only 120 days,10 ensuring healthy iron status is integral to supporting the ongoing production of healthy RBCs and, therefore, also maintaining cellular energy production.
It’s a Team Effort
That said, healthy RBC production requires more than just iron, with this process also relying on an adequate intake of vitamins B12 and folate.12 Various population groups including vegetarians and vegans,13 pregnant and lactating women,14 the elderly,15 and those with gastrointestinal dysfunction16 are at a greater risk of, in particular, inadequate B12 levels, meaning assessment and supplementation may be required. While dietary sources should lay the foundation for all nutrition, in some cases supplementation is required. For example, unlike B12 found in food, supplemental B12 (such as the activated form methylcobalamin), is not bound to a protein, therefore absorption is not impaired by low stomach acidity,17 which can reduce B12 uptake from dietary sources.
A deficiency of vitamin B12 (and/or insufficient folate intake) can result in large, immature and dysfunctional RBC formation. This is because B12 is a cofactor for the enzymatic conversion of homocysteine to methionine, to produce tetrahydrofolate; which is then converted to thymine monophosphate for incorporation into DNA.18 As such, a lack of either B12 or folate can result in impaired DNA synthesis and elevations in homocysteine, impacting healthy RBC development.19
Another team player in the iron and energy game is vitamin C, which enhances iron absorption and is particularly helpful if your aim is to also maximise iron uptake from dietary sources (e.g. green leafy vegetables). Vitamin C also potentiates the mobilisation of iron from inert tissue stores, which facilitates iron’s incorporation into protoporphyrin – part of the haem molecule.20 Supporting your patients with a highly bioavailable form of iron, activated B12, 5-MTHF (the activated form of folate) and vitamin C, such as with High Potency Vegetarian Iron with 5-MTHF, is a comprehensive way to promote the healthy production of RBCs.
Put a Spring in Your Step
It’s established that poor iron status is associated with symptoms of fatigue and lethargy,21 which is due to irons role in mitochondrial respiration as well as oxygen transfer.22 With RBCs responsible for delivering nutrients (as well as oxygen) to the tissues for cellular respiration,23 ensuring adequate intakes of iron along with vitamin B6 is a key strategy to help optimise energy production and therefore reduce fatigue. Vitamin B6 is required here as it is an essential catalyst for energy production within the Krebs cycle.24 In support of the clinical application of iron for fatigue, in particular, is a randomised, controlled trial of 144 non-anaemic women with unexplained fatigue who were prescribed iron, or placebo, daily for four weeks. At the conclusion of the trial, the women receiving iron had a 29% reduction in their fatigue scores,25 demonstrating patients don’t need to be at a low level of iron status to benefit. This is just one of many successful studies on iron which, along with the understanding of the role vitamin B6 plays in energy production, supports their use for fatigue cases.* In addition, for patients struggling to manage their energy levels there is the Metagenics Energy Program, which comprehensively tackles a range of drivers for what can be a frustrating situation for patients just wanting to go about their daily life with vitality.
Give so They May Grow
The incidence of low iron stores can be high amongst pregnant women, with low iron status reported to be as high as 23% in this population.26 Insufficient iron in pregnancy is of concern as this can increase the risk of premature labour, intrauterine growth retardation, perinatal and maternal mortality, and postpartum depression.27 The World Health Organisation recommends the screening of iron status in all pregnant women and advocates that inadequate iron levels should be treated with iron supplementation.28 One of the challenges with this recommendation is that many iron supplements can create undesirable gastrointestinal effects such as constipation, putting patients off their use. A study in pregnant women found 15 mg/day of iron bisglycinate was more effective at preventing pregnancy-related iron depletion than 40 mg/day from iron sulphate,29 making this a viable option for this population group, particularly as iron bisglycinate has been shown to have fewer undesirable effects.30
Enhancing the Uptake
If iron supplementation is required, its clinical effectiveness (and its likelihood to not create gastrointestinal distress) is dependent on its bioavailability. Iron bound to cations, such as sulphur (iron sulphate), may disassociate in the gut releasing free iron. The absorption of free iron is a difficult and inefficient process and can cause symptoms of constipation and nausea.31, 32, 33In contrast, iron bisglycinate (such as Meta Fe®) is a more bioavailable form of iron (see Figure 2),34 clinically proven to improve and maintain iron status, and associated with fewer undesirable gastrointestinal effects.35 The covalent bonding of two glycine molecules to iron is what creates iron bisglycinate.36 Being bound to glycine, the iron is readily absorbed via peptide channels in the gut, rather than competing for ionic channels with other minerals. It is this strong covalent bonding that makes Meta Fe® resist disassociation in the gut, making it more tolerable to patients. Meta Fe® iron bisglycinate is found in High Potency Vegetarian Iron with 5-MTHF.
Energy From Within
By supporting your patients RBC production with a team of nutrients including highly bioavailable iron, activated B12 and 5-MTHF, vitamins C and B6, cellular energy production can be enhanced; leading to more optimal energy levels and reduced sensations of fatigue. High Potency Vegetarian Iron with 5-MTHF may assist people with increased demands for these nutrients such as pregnant and lactating women, the elderly, and patients with gastrointestinal dysfunction, as well as some vegetarians and vegans. For patients wanting to kick-start their energy, also look ‘bigger picture’ with the Metagenics Energy Program solutions to get your patients back on track and raring to go.
*Iron excess can also manifest with symptoms of fatigue and lethargy. As inappropriately prescribed supplemental iron can be harmful it is recommended to always obtain iron studies to assess baseline iron and ferritin levels first, and routinely afterwards to monitor changes.
References
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Keshav S, Stevens R. New concepts in iron deficiency anaemia. BJGP. 2018 Jan;67(654):10-11. doi: 10.3399/bjgp17X688465
Malczewska-Lenczowska J, Sitkowski D, Surała O, Orysiak J, Szczepańska B, Witek K. The association between iron and vitamin D status in female elite athletes. Nutrients. 2018 Jan 31;10(2):167.
Malczewska-Lenczowska J, Sitkowski D, Surała O, Orysiak J, Szczepańska B, Witek K. The association between iron and vitamin D status in female elite athletes. Nutrients. 2018 Jan 31;10(2):167.
Roy A, Fuentes-Afflick E, Fernald LC, Young SL. Pica is prevalent and strongly associated with iron deficiency among Hispanic pregnant women living in the United States. Appetite. 2018 Jan 1;120:163-70.
Roy A, Fuentes-Afflick E, Fernald LC, Young SL. Pica is prevalent and strongly associated with iron deficiency among Hispanic pregnant women living in the United States. Appetite. 2018 Jan 1;120:163-70.
American Society of Hematology. Blood Basics [internet]. Washington DC: American Society of Hematology USA; 2018 [cited 2018 Feb 28]. Available from http://www.hematology.org/Patients/Basics/.
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Gropper S, Smith J. Advanced nutrition and human metabolism. 6th ed. Australia: Wadsworth Cengage Learning; 2013. p.491.
American Society of Hematology. Blood Basics [internet]. Washington DC: American Society of Hematology USA; 2018 [cited 2018 Feb 28]. Available from http://www.hematology.org/Patients/Basics/.
The Protein Data Bank, Protoporphyrin IX containing Fe heme (Synonym). 1999. [cited 2016 Sept 21]. Available from: http://www.rcsb.org/pdb/explore/jmol.do?structureId=4HHB&bionumber=1
Braunstein EM. Merck Manual. Red blood cell production. [internet]. Kenilworth: Merck Sharp & Dohme Corp. 2018 [cited 2018 Feb 28]. Available from: https://www.merckmanuals.com/professional/hematology-and-oncology/approach-to-the-patient-with-anemia/red-blood-cell-production.
Moll R, Davis B. Iron, vitamin B12 and folate. Medicine. 2017 Apr 1;45(4):198-203.
Khuu G, Dika C. Iron deficiency anemia in pregnant women. The Nurse Practitioner. 2017 Oct 18;42(10):42-7.
Flood VM, Smith WT, Webb KL, Rochtchina E, Anderson VE, Mitchell P. Prevalence of low serum folate and vitamin B12 in an older Australian population. Aust NZ J Public Health. 2006 Feb;30(1):38-41.
Keshav S, Stevens R. New concepts in iron deficiency anaemia. BJGP. 2018 Jan;67(654):10-11. doi:10.3399/bjgp17X688465
Paul C, Brady DM. Comparative bioavailabilty and utilization of particular forms of B12 supplements with Potential to Mitigate B12-related genetic polymorphisms. Intergrative Medicine. 2017;16(1):42-49.
Gropper S, Smith. 2013. Advanced Nutrition and Human Metabolism. 6th ed. Australia: Wadsworth, Cengage Learning; p. 354-60.
Colledge N, Walker B, Ralston S, editors. 2010. Davidson’s principles and practice of medicine. 21st ed. Edinburgh, Churchill Livingstone/Elsevier; p.1020-22.
Braun L, Cohen M. Herbs and natural substances: an evidence-based guide. Vol 2. 4th ed. Sydney: Churchill Livingstone; 2015. p.1101-24.
Young I, Parker HM, Rangan A, Prvan T, Cook RL, Donges CE, et al. Association between haem and non-haem iron intake and serum ferritin in healthy young women. Nutrients. 2018 Jan 12;10(1):81.
Buratti P, Gammella E, Rybinska I, Cairo G, Recalcati S. Recent advances in iron metabolism: relevance for health, exercise, and performance. Med. Sci. Sports Exerc. 2015 Aug 1;47(8):1596-604.
Gropper S, Smith J. Advanced nutrition and human metabolism. 6th ed. Australia: Wadsworth Cengage Learning; 2013. p.491.
Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ. Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways. Chem Biol Interact. 2006 Oct 27;163(1-2):113-32.
Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, et al. Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial. BMJ. 2003 May 24;326(7399):1124.
Khuu G, Dika C. Iron deficiency anemia in pregnant women. The Nurse Practitioner. 2017 Oct 18;42(10):42-7.
Khuu G, Dika C. Iron deficiency anemia in pregnant women. The Nurse Practitioner. 2017 Oct 18;42(10):42-7.
Khuu G, Dika C. Iron deficiency anemia in pregnant women. The Nurse Practitioner. 2017 Oct 18;42(10):42-7.
Szarfarc SC, de Cassana LM, Fujimori E, Guerra-Shinohara EM, de Oliveira IM. Relative effectiveness of iron bis-glycinate chelate (Ferrochel) and ferrous sulfate in the control of iron deficiency in pregnant women. Arch Latinoam Nutr. 2001 Mar;51(1 Suppl 1):42-47.
Pineda O, Ashmead HD. Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bisglycinate chelate. Nutrition. 2001 May;17(5):381-384.
Ashmead SD. The chemistry of ferrous bis-glycinate chelate. Arch Latinoam Nutr. 2001 Mar;51(1 Suppl 1):7-12.
García-Casal MN, Layrisse M. The effect of change in pH on the solubility of iron bis-glycinate chelate and other iron compounds. Arch Latinoam Nutr. 2001 Mar;51(1 Suppl 1):35-36.
Pineda O, Ashmead HD. Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bisglycinate chelate. Nutrition. 2001 May;17(5):381-384.
Pineda O, Ashmead HD. Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bisglycinate chelate. Nutrition. 2001 May;17(5):381-4.
Pineda O, Ashmead HD. Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bisglycinate chelate. Nutrition. 2001 May;17(5):381-4.
Ashmead SD. The chemistry of ferrous bis-glycinate chelate. Arch Latinoam Nutr. 2001 Mar;51(1 Suppl 1):7-12.
Pineda O, Ashmead HD. Effectiveness of treatment of iron-deficiency anemia in infants and young children with ferrous bisglycinate chelate. Nutrition. 2001 May;17(5):381-4.
Original image courtesy of Toa Heftiba
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