Antagonists: the interplay of opposing forces in the body

A pump in every cell, the sodium-potassium ATPase, keeps sodium mainly outside and potassium mainly inside the cells. The kidneys also regulate both together: when more sodium is excreted or retained, potassium excretion changes as well. In studies, the sodium-to-potassium ratio in 24-hour urine is more closely linked to blood pressure than either value alone. Because almost all potassium sits inside the cells, the blood value mainly reflects regulation, not intake.

1. Palmer BF. Regulation of Potassium Homeostasis. Clin J Am Soc Nephrol. 2015;10(6):1050–1060. doi.org/10.2215/CJN.08580813
2. Ndanuko RN et al. Association between the Urinary Sodium to Potassium Ratio and Blood Pressure in Adults. Adv Nutr. 2021;12(5):1751–1767. doi.org/10.1093/advances/nmab036

High amounts of zinc stimulate intestinal cells to form metallothionein, a protein that binds copper and reduces its absorption. This is why the upper intake level for zinc set by EFSA (25 mg per day) is based on copper status. During inflammation both blood values shift in opposite directions: copper rises, zinc falls, without the body stores necessarily having changed. We therefore look at both values together and take inflammation markers into account.

1. Linus Pauling Institute, Micronutrient Information Center: Zinc. lpi.oregonstate.edu/mic/minerals/zinc
2. Duncan A et al. The risk of copper deficiency in patients prescribed zinc supplements. J Clin Pathol. 2015;68(9):723–725. doi.org/10.1136/jclinpath-2014-202837

Calcium triggers muscle contraction, for example, while magnesium dampens calcium influx into the cell. The parathyroid gland also needs magnesium to regulate calcium balance. Because only about one percent of magnesium is found in blood serum, the serum value can look normal even when cellular stores are lower. An “ideal” calcium-to-magnesium ratio in blood has not been established; the range often quoted refers to diet and is a hypothesis.

1. Costello RB, Nielsen F. Interpreting magnesium status to enhance clinical care: key indicators. Curr Opin Clin Nutr Metab Care. 2017;20(6):504–511. doi.org/10.1097/MCO.0000000000000410
2. Costello RB et al. Perspective: Characterization of Dietary Supplements Containing Calcium and Magnesium and Their Respective Ratio. Adv Nutr. 2021;12(2):291–297. doi.org/10.1093/advances/nmaa160

Magnesium and potassium are not antagonists but partners: magnesium in kidney cells slows a channel (ROMK) through which potassium is excreted. When magnesium is low, the kidney can lose more potassium. This is why both values are often assessed together in laboratory medicine.

1. Huang CL, Kuo E. Mechanism of hypokalemia in magnesium deficiency. J Am Soc Nephrol. 2007;18(10):2649–2652. doi.org/10.1681/ASN.2007070792

Calcium and phosphate together form the mineral of bone and are kept in balance by three hormones: parathyroid hormone, active vitamin D and FGF23. When phosphate rises, the body responds, among other things, with increased excretion via the kidneys. Guidelines today recommend assessing both values together but individually; the calcium-phosphate product used in the past is considered of little value.

1. KDIGO 2017 Clinical Practice Guideline Update for CKD-MBD. Kidney Int Suppl. 2017;7(1):1–59. doi.org/10.1016/j.kisu.2017.04.001
2. Peacock M. Phosphate Metabolism in Health and Disease. Calcif Tissue Int. 2021;108(1):3–15. doi.org/10.1007/s00223-020-00686-3

Iron and copper show that antagonists can also depend on each other: copper-containing enzymes such as ceruloplasmin make sure iron can be released from stores and transported in the blood. At the same time, very high amounts of iron can affect copper balance. When iron metabolism looks unusual, it can therefore make sense to look at copper and ceruloplasmin as well.

1. Collins JF, Prohaska JR, Knutson MD. Metabolic crossroads of iron and copper. Nutr Rev. 2010;68(3):133–147. doi.org/10.1111/j.1753-4887.2010.00271.x

Iron and zinc partly use similar absorption routes in the gut. In studies, they influenced each other mainly when both were taken at the same time in higher doses without a meal; through a normal diet the effect is small. When we evaluate lab results, we therefore look at iron status (for example ferritin, transferrin saturation) and zinc together.

1. Fischer Walker C et al. Interactive effects of iron and zinc on biochemical and functional outcomes in supplementation trials. Am J Clin Nutr. 2005;82(1):5–12. doi.org/10.1093/ajcn.82.1.5
2. Kondaiah P et al. Iron and Zinc Homeostasis and Interactions. Nutrients. 2019;11(8):1885. doi.org/10.3390/nu11081885

In studies, calcium reduces the absorption of iron from the same meal; even amounts like those in a glass of milk had a measurable effect. In long-term studies, however, iron status hardly changed with more calcium, because the body adapts. When interpreting iron values, the time gap between calcium-rich foods or supplements and iron-containing meals can still play a role.

1. Hallberg L et al. Calcium: effect of different amounts on nonheme- and heme-iron absorption in humans. Am J Clin Nutr. 1991;53(1):112–119. doi.org/10.1093/ajcn/53.1.112
2. Lönnerdal B. Calcium and iron absorption – mechanisms and public health relevance. Int J Vitam Nutr Res. 2010;80(4–5):293–299. doi.org/10.1024/0300-9831/a000036

Manganese and iron are absorbed in the gut via the same transport routes. When iron stores are low, the body provides more of these transporters and absorbs more manganese as well. A manganese value in the blood is therefore best interpreted together with iron status, especially ferritin.

1. Finley JW. Manganese absorption and retention by young women is associated with serum ferritin concentration. Am J Clin Nutr. 1999;70(1):37–43. doi.org/10.1093/ajcn/70.1.37

Selenium is a building block of important protective enzymes. Mercury binds selenium unusually tightly and can thereby withdraw it from these enzymes. Researchers therefore discuss looking at the ratio of mercury to selenium, for example in fish, rather than only at mercury content. What this ratio means for an individual person has not yet been conclusively clarified.

1. Ralston NV, Raymond LJ. Dietary selenium’s protective effects against methylmercury toxicity. Toxicology. 2010;278(1):112–123. doi.org/10.1016/j.tox.2010.06.004
2. Tinggi U, Perkins AV. Selenium Status: Its Interactions with Dietary Mercury Exposure and Implications in Human Health. Nutrients. 2022;14(24):5308. doi.org/10.3390/nu14245308

The heavy metal cadmium is chemically so similar to zinc that it can use zinc’s transport routes and binding sites in the body. In research, mainly in animal studies, zinc status influenced the uptake and storage of cadmium. Cadmium exposure is measured in the lab in blood or urine; the main source is usually tobacco smoke.

1. Brzóska MM, Moniuszko-Jakoniuk J. Interactions between cadmium and zinc in the organism. Food Chem Toxicol. 2001;39(10):967–980. doi.org/10.1016/s0278-6915(01)00048-5

Molybdenum can bind copper chemically. In grazing animals, a lot of molybdenum in feed leads to copper deficiency, and a molybdenum compound is used in medicine specifically to bind copper. In humans, controlled studies showed no measurable effect on copper status even with clearly increased dietary intake. We list this pair mainly for completeness.

1. Turnlund JR et al. Molybdenum absorption, excretion, and retention studied with stable isotopes in young men at five intakes of dietary molybdenum. Am J Clin Nutr. 1995;62(4):790–796. doi.org/10.1093/ajcn/62.4.790

Vitamin D ensures that calcium is absorbed from food and stimulates the formation of certain proteins that bind calcium. These proteins, such as osteocalcin in bone and matrix Gla protein in the vessel wall, only become functional with the help of vitamin K. How important this interplay is for an individual person is still being researched.

1. van Ballegooijen AJ et al. The Synergistic Interplay between Vitamins D and K for Bone and Cardiovascular Health: A Narrative Review. Int J Endocrinol. 2017;2017:7454376. doi.org/10.1155/2017/7454376

Folate and vitamin B12 work closely together in blood formation. A high folic acid intake can mask the typical blood-count changes of vitamin B12 deficiency, while the deficiency persists elsewhere, for example in the nervous system. For a meaningful assessment, B12 markers such as holotranscobalamin or methylmalonic acid are therefore measured independently of the blood count.

1. Mills JL, Molloy AM, Reynolds EH. Do the benefits of folic acid fortification outweigh the risk of masking vitamin B12 deficiency? BMJ. 2018;360:k724. doi.org/10.1136/bmj.k724