By Andrea Bartels CNP NNCP RNT Registered Nutritional Therapist 25 Sep 2019

Copper: The Confounding Variable in Iron-Deficiency Anemia?

It's an accepted fact that the fastest way to increase iron status in an iron-deficient individual is through supplementation.

It's also accepted that the iron compounds most commonly used-such as ferrous sulfate and ferrous fumarate- carry with them unpleasant side effects in the gastrointestinal tract, let alone low bioavailability.

What's more, is that even when iron supplementation does only what is hoped for, the recipient may still complain of those hallmark indicators of iron deficiency. So what's going on? Could it be the case of one mineral deficiency replacing another?

Let's talk about copper.

Here is a micronutrient that still has not made it into every prenatal multivitamin-mineral supplement, let alone a daily multi for the general public. This is despite the Institute of Medicine's 1990 recommendation that 2 milligrams of copper be taken by pregnant women who use 25 milligrams of supplemental zinc to reduce the risk of copper deficiency in unborn fetuses.

Yes, copper is considered an essential nutrient that is vital for numerous vital functions, including nervous system function, energy production, collagen formation and hemoglobin synthesis, to name a few. It turns out that a copper-deficient state can actually mimic that of iron-deficiency.

Consider the symptoms of inadequate copper: fatigue, weakness, cognitive problems, cold sensitivity, and pallor. Sound familiar? That's because both iron and copper-deficient states can produce anemia resulting in poor oxygen-carrying capacity-not to mention thyroid impairment. What can be confusing is identifying whether the patient's symptoms are due to low iron or low copper.

So, how is copper important to iron and its function as hemoglobin-builder?

Copper is involved in numerous enzymes responsible for important metabolic processes, and at least 3 of these are key for iron metabolism:

1. Ceruloplasmin: This copper-containing protein functions mainly to unlock iron from tissue stores and release it into the bloodstream in times of need. Without adequate copper, ceruloplasmin drops, resulting in potentially toxic levels of iron build-up in the brain, liver, pancreas and eyes.
   
   
2. Hephaestin: This copper-containing enzyme ensures that iron gets bound to transferrin for delivery to tissues.
   
   
3. Hepcidin: This iron-regulating hormone inhibits iron release into the bloodstream. It's activated by copper.
   In these ways, copper is vital to iron metabolism and homeostasis.

Like iron, copper absorption is mediated by need. If levels of one of these minerals are low, then gastrointestinal uptake of consumed copper or iron is higher than average; meanwhile, when stores are high, absorption is reduced. This serves as a protective mechanism against toxicity (although factors like iron overdose, hemochromatosis or Wilson's disease will override this mechanism).

Let's return to our conundrum of similarities between iron and copper-deficiency anemias. When iron is low, copper stores in the liver, blood and gastrointestinal mucosa rise. Conversely, high iron intake by way of supplements results in copper deficiency. The bloodwork may be showing ferritin is fine after 3 months of use, however, the copper deficiency may be the reason for the continued fatigue, weakness, pallor and cold sensitivity.

While iron is the most common nutrient deficiency worldwide (according to the World Health Organization), true copper deficiency - outside of the genetically-inherited Menkes disease - is comparatively rare. However, there are a few exceptions to this rule that could be of interest to health practitioners of today. One of these is Celiac Disease.

With auto-immune diseases on the rise, Celiac is being diagnosed more often than ever before, with broader and clearer understanding of the clinical manifestations (and lack of classic textbook signs). While iron-deficiency anemia is well-known to be a clinical consequence of the intestinal damage caused by the mechanisms of Celiac and therefore routinely monitored, copper status is not.

In 2009, the American College of Gastroenterology noted in its clinical guidelines for Celiac Disease that copper deficiency is common among those with the disease. Yet, there have been no peer-reviewed studies nor recommendations where copper supplementation is given for this cohort. Perhaps this will change after yet another study, published in 2015, found that of the 200 Celiac patients measured, 15% of them had copper deficiency.

Another condition that can induce copper deficiency is high zinc intake.
For some reason, zinc grabbed and maintained the spotlight in the nutritional sciences world decades ago, provoking hair mineral analysis and taste tests that would ultimately see thousands, if not millions of individuals taking zinc supplements for a myriad of reasons (sore throats, immune health, stretch marks, wound healing, hair growth, et cetera). Indeed, this may have helped many, but as we health practitioners know, more is not always better. Individuals supplementing 60 milligrams or more of zinc daily for an extended period of time developed copper deficiency-which may explain copper's reputation as a zinc antagonist (and vice versa). (Realistically, the relationship between these two minerals is better described as synergistic.)

We talk about zinc and copper balance being important, with a proposed ratio of about 28:1 zinc to copper. But what about iron and copper? It's currently unknown what the best ratio is. Other questions that remain unanswered are: What is the mechanism by which copper deficiency causes anemia?
What causes the copper-loading in the livers of those with iron-deficiency anemia?
Further research will tell.

In the meantime, numerous studies have shown that copper is key for iron metabolism, with some of the mechanisms outlined here. There's still the issue of absorption. While it is not difficult to consume enough copper-rich foods-- like shellfish, liver, nuts, oats and seeds---animal studies suggest either absorption or bioavailability may be hindered by high consumption of fructose, histidine, cysteine, zinc, iron and ascorbic acid (For more on the effect of vitamin C on copper levels, read American physician and biochemist Carl Pfeiffer's work on schizophrenia).

Nutritional science is not an exact one, and outside the research labs few individuals have gone to the trouble of finding out the micronutrient composition of their daily meals. However, if we know that iron and copper have an important relationship-with the status of one influencing the other---we can begin to appreciate and take an active interest in patients with unresolved anemia symptoms.

PLV Copper Glycinate, in amino-acid chelated format of 1 mg per capsule, may be enough to prevent deficiency in anemic individuals whose symptoms persist

We recommend 1 capsule twice daily for the first 2-3 weeks, followed by just 1 capsule daily for maintenance.

References

Doguer, Caglar, Jung-Heun Ha and James F. Collins. Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver. Compr Physiol. 2018 Sep 14; 8(4): 1433-1461.

Freeman, Hugh James. Iron deficiency anemia in celiac disease. World J Gastroenterol. 2015 Aug 21; 21(31): 9233-9238.

Gulec, Sukru and James F. Collins. Molecular Mediators Governing Iron-Copper Interactions. Annu Rev Nutr. 2014; 34: 95-116.

Health Canada. Dietary Reference Intakes: Reference Values for Elements. https://www.canada.ca/en/health-canada/services/food-nutrition/healthy-eating/dietary-reference-intakes/tables/reference-values-elements-dietary-reference-intakes-tables-2005.html Accessed on Sept. 18th 2019.

Lonnerdal, B. Bioavailability of copper. Am J Clin Nutr. 1996 May;63(5):821S-9S.

Medical Biochemistry Page, The. "Iron and Copper Homeostasis".
https://themedicalbiochemistrypage.org/iron-copper.php#cu-proteins Accessed on Sept. 16th 2019.

National Institutes of Health, USA. Copper: Factsheet for Health Professionals. https://ods.od.nih.gov/factsheets/Copper-HealthProfessional/ Accessed Sept. 16th 2019.

National Research Council (US) Committee on Copper in Drinking Water. Copper in Drinking Water. Washington (DC): National Academies Press (US); 2000.

Pfeiffer, Carl. The Schizoprhenias: Ours to Conquer. Bio-Communications Press, 1988.