It's another post by The Duck Dodgers, this in advance of a subsequent post that continues to explore the governmental policy of food enrichment or fortification in general, and iron in particular.
As we prepare to explore how mineral imbalances exacerbated by iron fortification and/or high meat intakes may promote chronic disease and inflammtion, we wanted to set the record straight about copper—a mineral that is absolutely essential for maintaining iron homeostasis.
Copper may be the most misunderstood mineral—it has recently gotten a bad rap in health circles. Chris Kresser explains the conventional wisdom of copper:
RHR: Could Copper-Zinc Imbalance Be Making You Sick?
One of the most common and important imbalances that we see in clinical practice with trace minerals is excess copper and deficient zinc. So, the ideal ratio between these two, if copper is in the numerator and zinc is in the denominator, would be 0.7 to 1, which means anywhere from 70% as much copper as zinc to even amounts of each. And one of the ways that you can recognize this or when you might suspect this, and this will tie into a future question that we're gonna talk about a little bit later in the show, is that copper and zinc are not only minerals, but they're also regarded as neurotransmitters in the brain. They have some of the functions of a neurotransmitter, so an imbalance in copper and zinc will lead to things like hyperactivity, ADHD, other kinds of behavioral disorders, and depression; and in fact, a lot of people who are labeled with autism and even paranoid schizophrenia, when they test their copper levels, they find out that they're elevated.
Then high copper can cause severe PMS. That's another red flag for me where I'll consider it. It can cause estrogen intolerance, and it can cause skin issues, so people with excess copper have a high incidence of acne or eczema, psoriasis, just sensitive skin in general, sunburn, people who are really apt to get sunburned even if they're only out for a short period of time, headaches, poor immune function…So, as you can see, most of the effects are nervous system related, nervous and endocrine system, I would say, with particular impact on the brain and behavioral health. So, those are the things to look for when you're considering copper-zinc imbalance as a potential issue.
Kresser recommends taking steps to reduce copper exposure if one's serum copper is high. Dr. Emily Deans, MD seems to agree. In July, Deans Tweeted:
Emily Deans, M.D. – @evolutionarypsy 4:57 PM – 3 Jul 2015
"I've started to test copper levels in a certain kind of patient…resistant depression with neurological complaints…and they are HIGH."
It has long been theorized that excess tissue copper can cause schizophrenia. However, this theory has neither been compellingly demonstrated nor convincingly refuted. Some have called copper a 'neurotoxin.' Yet, zinc is a 'neurotoxin' too. Of course, nobody calls zinc a neurotoxin—it's just copper they want to demonize.
If Deans' patients have high serum copper, and she thinks it means copper overload, she may want to look up depression inflammation and schizophrenia inflammation.
This fear of copper has gotten so bad that supplement manufacturers have begun removing copper from their mineral formulations. We contacted one of those manufacturers about this and were given the following response:
"We have removed the copper from our Trace Minerals at the request of several of our medical advisors. They have found that most individuals are testing with high levels of copper, and excess copper to be a problem for many health issues…While copper is an essential mineral important for several enzymatic reactions, many people are looking to avoid it due to the potential negative cognitive concerns."
There's just one problem…
The copper protein ceruloplasmin is an acute phase protein, which means it rises in the blood during inflammation. Here's a paper about what it does:
Ceruloplasmin: an acute phase reactant that scavenges oxygen-derived free radicals (1982)
Indeed, copper has well known anti-inflammatory properties. Your body needs it to fight inflammation.
More specifically, the main copper containing enzyme, ceruloplasmin, is significantly elevated in inflammatory conditions and has anti-inflammatory activity (Frieden 1986). And the copper content of serum is known to be elevated above normal values in various inflammatory diseases in man and laboratory animals. (Lewis 1984)
The body is intelligent. It lowers serum iron when inflammation is present (anemia of chronic disease)—to keep iron away from pathogens and cancers—and it raises copper to fight inflammation. This is not an accident. As you can see, serum tests at face value can be extremely misleading to health practitioners.
You might be surprised to learn that, according to the recent scientific literature, serum copper levels are now considered to be rather worthless for determining copper deficiency or copper overload.
Risks and benefits of copper in light of new insights of copper homeostasis (2011)
The most frequently used blood markers of copper metabolism are serum copper and Cp concentrations, which have proved useful to diagnose Menkes and Wilson disease and moderate to severe copper deficiency. However, these markers also act as acute phase proteins and as such increase during inflammation, pregnancy, aging and a number of diseases. Therefore, copper deficiency could be masked in these conditions. It is also clear that these markers are not sensitive enough to detect changes of a lesser magnitude…
…On the excess side, despite several efforts currently there are no candidate [diagnostic] markers. In the past several years, many proteins and enzymes present in blood have been measured in different conditions of copper exposure, but all of these studies have failed to identify a potential indicator of early effects of copper excess.
Yes, you read that correctly. Not only are serum copper tests unreliable, but it's possible to have elevated serum copper mask a copper deficiency.
Numerous researchers have examined the paradoxical role of copper in the process of inflammation, and they have determined that the increase in serum copper is a physiological response to inflammation, rather than a promoter of it (Sorenson 1977). Stephan Guyenet wrote about this in 2010.
Copper deficiency increases the severity of experimentally-induced inflammation. "…The elevation of plasma copper-containing components represents a physiologic response which may lead to remission. Promotion of this physiologic response would appear to be a valid approach to the treatment of…diseases with inflammatory components" (Sorenson 1984). Interestingly, this was not a recent discovery. Ancient cultures believed that foods high in copper and copper bracelets were beneficial in treating arthritic conditions (Whitehouse, 1976).
Furthermore, it has been shown that dietary copper must be increased to maintain adequate copper status of animals in an inflammatory state (Milanino, et al. 1985).
In recent posts, we've examined how iron intakes have skyrocketed over the past century, due to fortification and higher meat intakes. High iron intakes block the absorption of copper, promoting copper deficiency, While chelation of iron reverses copper deficiency, for those with true iron deficiencies, it's been known since at least the 1930s that iron deficiency anemia can be cured by increasing copper intakes.
In other words, the more iron you consume, the more copper you need. We need copper to get iron in and out of cells. Additionally copper (and manganese) is required for our most important and most powerful endogenous antioxidants (SOD).
Copper's role in managing iron is crucial for protecting our organs. In rats, modest fructose consumption can block copper absorption and promote hepatic iron overload, which in turn may lead to liver injury and fructose induced fatty liver.
In the United States, most people tend to eat a lot of iron-fortified refined grains and a lot of meat, yet Americans have low copper intakes from both diet and water. And when copper intakes are estimated from nutrition surveys using food-composition tables, the results usually overestimate copper.
Americans are fond of muscle meat, which is rich in zinc but realtively low in copper —zinc is well known to compete with copper for absorption. Therefore, it seems extremely unlikely that most Americans have too much dietary copper, particularly since dietary copper from food is not known to cause toxicity because of the potent and redundant mechanisms that effectively control copper absorption, storage and excretion over a wide range of dietary exposure levels.
Given all of the above, one has to wonder why practitioners and supplement manufacturers have become so confused about copper, particularly when researchers are raising concerns about Western diets being too low in copper. Unfortunately, few people have noticed that much of the confusion comes from just one individual, George Brewer.
Beyond all of the studies people cite that conflate inflammatory disorders and heart attacks with (physiologically normal) elevated serum copper levels, Brewer has published a number of papers hypothesizing that copper overload from water pipes (not from real food) is to blame for promoting Alzheimer's and neurological diseases. Unfortunately, Brewer's papers are full of errors and misconceptions. A dozen researchers have even rebuked Brewer's papers.
See: Reply To George Brewer Letter To JTEH Editor ("Toxicity Of Copper In Drinking Water")
The numerous researchers behind the letter wrote, "The current authors respectfully propose that Brewer's 'warnings' and recommendations could inadvertently result in a disservice and a potential danger to the public, for reasons outlined in the following."
Incidentally, many researchers now believe that Alzheimer's disease, ischemic heart disease and osteoporosis are the most likely human illnesses from low copper intakes.
Another antidote to Brewer can be found in an article titled, Copper: The Maligned Mineral. (Ignore the Illuminati reference at the top)
In upcoming posts, we will cover the mechanism of how copper deficiency promotes inflammation when fortified foods and/or high meat diets are consumed.
COMMENTS
Serum copper values are just a starting point, and should never be used in isolation to make a diagnosis. If serum copper is elevated or decreased, other markers like ceruloplasmin, 24-hour urine copper, AST/ALT, and less commonly, liver biopsy, [are needed] to further clarify the diagnostic picture.
In the same way, it's a mistake to assume that elevated ferritin is always caused by iron overload. Ferritin, like ceruloplasmin, is an acute-phase reactant which is increased in the inflammatory response. Unfortunately few practitioners understand this and will often diagnose iron overload solely on the basis of high ferritin.
This can all be avoided by running a comprehensive blood panel instead of testing isolated markers. That's exactly what we do for every patient that walks through our door. High serum copper masking iron deficiency? If there is iron deficiency, that will show up in UIBC, TIBC, serum iron, iron saturation, ferritin, and soluble transferrin receptor values, all of which we routinely test for.
So, while serum copper is unreliable as an isolated marker (as is the case for ferritin, and in fact just about any marker), that doesn't mean that it's "worthless", nor does it mean that high serum copper levels may indicate copper toxicity, nor does it mean that elevated copper in relation to zinc is not a clinical concern.
It is well-established that the toxic effects of certain metals can be either synergistic or additive, depending on the metals. For example, this study showed that >20 years of occupational exposure to copper, copper-lead, and copper-iron was associated with higher risk of Parkinson's disease (http://europepmc.org/abstract/med/10385887)—but the odds ratio was significantly higher for the combos than it was for copper alone.
This study suggests that pro-oxidant copper ions affect glutathione in several ways, which in turn potentiates the effects of mercury toxicity. http://www.sciencedirect.com/science/article/pii/S0300483X00003310
This study reviewed the synergistic effects of multiple heavy metals and found that copper has a strongly synergistic toxic effect with other metals, especially cadmium. http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.466.9494&rep=rep1&type=pdf
There are many studies indicating that the zinc-copper ratio is altered in various disease states, including autism spectrum disorders (http://www.tandfonline.com/doi/abs/10.1080/13547500902783747), coronary heart disease (http://europepmc.org/abstract/med/19097489), rheumatoid arthritis (http://www.ncbi.nlm.nih.gov/pubmed/26450515), and colorectal cancer (http://www.ncbi.nlm.nih.gov/pubmed/26329996) to name a few.
Of course these are all inflammatory conditions, so it's difficult to know whether the observed copper elevations are cause, effect, or both. But this study found that copper was elevated *without concurrent iron deficiency or excess* in patients with Alzheimer's disease (http://www.ncbi.nlm.nih.gov/pubmed/26401693), and the authors speculated that alterations in zinc/copper levels may be implicated in the pathogenesis of AD.
For these reasons I maintain that serum copper levels, and serum copper zinc ratio, is still a useful indicator—provided that practitioners understand the limitations and do not make erroneous assumptions about causality.
The podcast of mine that you linked to was from 2012. I've learned a lot about metal toxicity since then, and if I could go back in time I would change the title to "Could copper-zinc imbalance be a sign that you're sick", or something along those lines, to make it clear that higher copper-zinc ratio is an indicator and doesn't always suggest that high serum copper is the cause of the problem.
Another potential indicator for Cu-Zn imbalance that I mentioned in my original comment is toxicity of other metals like mercury. Mercury compounds may replace Zn in the metalbinding
sites of metallothioneins, and there are other mechanisms by which Hg toxicity may lead to an altered Cu-Zn ratio. (http://www.ncbi.nlm.nih.gov/pubmed/23823984)
So in these children, a blood panel which shows high Cu-Zn ratio may lead to further testing that identifies Hg toxicity.
I would say that is a useful indicator. You just have to understand its limitations.
"Could I ask you please Chris, serum copper zinc ratio is a useful indicator of what?"
As I said in my original comment, it's an indicator of pathology of some kind that requires further testing and diagnosis.
That pathology may be inflammation, or it may be frank zinc deficiency caused be inadequate dietary intake (common in vegans and vegetarians), or it may be cause for further investigating conditions known to be associated with Cu-Zn imbalance, such as Alzheimer's (where Cu-Zn is thought to play a role in its pathogenesis), neurological problems like epilepsy (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135281/), iron deficiency, severe Wilson's disease (which usually presents with low serum copper, but in cases of liver damage can present with high serum copper), excess estrogens (either endogenously produced, or from birth control pills), and more.
For example, just yesterday I had a 23-year old female patient with copper levels above the reference range and zinc levels below the reference range. Upon further investigation, her total estrogens were high, and I discovered that she had been on birth control for 8 years. This was causing a variety of symptoms and related health problems for her—and it was the Cu-Zn imbalance that initially alerted me to the problem.
It is a marker that warrants further investigation, in the same way that high ferritin or high MCV or low Hemoglobin is.
Should also point out that inflammation, at least measured by CRP, does not always explain an increased Cu-Zn ratio.
http://www.ncbi.nlm.nih.gov/pubmed/26302926
Thanks Richard. I'm sure you know the old saying "Science proceeds one death at a time."
Or my version of that: "The history of science is characterized by most scientists being wrong about most things most of the time."
Always good to keep in mind!
See this article re: zinc and vegetarians: http://chriskresser.com/why-you-should-think-twice-about-vegetarian-and-vegan-diets/
"Overt zinc deficiency is not often seen in Western vegetarians, but their intake often falls below recommendations. This is another case where bioavailability is important; many plant foods that contain zinc also contain phytate, which inhibits zinc absorption. Vegetarian diets tend to reduce zinc absorption by about 35% compared with omniovorous diet. (8) Thus, even when the diet meets or exceeds the RDA for zinc, deficiency may still occur. One study suggested that vegetarians may require up to 50% more zinc than omnivores for this reason. (9)"
Keep in mind that suboptimal intake of nutrients (like zinc) that is not defined as frank deficiency has been shown to cause problems. In addition, the method of testing for deficiency or suboptimal intake makes all the difference in the world. I highlighted this in the discussion of B12 in that article. When total serum cobalamin is used as the defining marker of deficiency, B12 levels are not hugely different in omnivores, vegetarians, and vegans. However, when more sensitive markers like serum/urine MMA, homocysteine, and holo-TC are used, the difference in B12 levels in these populations is highly significant.
What about wearing copper bracelets – any thoughts on that?
And for a completely opposite opinion on copper (opposite to the "maligned mineral" article linked above), prepare to be completely confused by reading this one:
http://www.acu-cell.com/crcu.html
These opposing opinions, each stated so strongly as to appear to be the "only right answer" to copper, is why people throw up their ha
Check out this pro-copper article. (scroll down a bit and ignore the zany advertisements at the top).
http://skinbiology.com/copper-the-protective-antiaging-metal.html