iThyroid.com

Affect on Copper of Cortisol, Potassium, Disease

by Charles Weber

Copper nutrition is crucial for slipped discs, hemorrhoids, emphysema, aneurysms, and immunity.

CONTENTS of other chapters Back to INTRODUCTION chapter -- II. Arthritis Research -- III. Arthritis and Potassium -- IV. Roles of Potassium in the Body -- V. Electrolyte regulation (sodium and potassium) -- VI. Purpose of cortisol -- Back to; VII. Copper nutrition and physiology, page one -- Copper in Foods -- VIII. Nutritional Requirements -- IX. Potassium in Foods -- X. Processing Losses -- X,cont. Losses in the kitchen -- XI. Supplementation -- Side Effects and Heart Disease

INTRODUCTION

I have previously proposed that rheumatoid arthritis is accentuated by losses of potassium in our food supply and is largely a chronic potassium deficiency [Weber 1974] which causes alterations inside the cell of free amino acids [Iacobellis], interference by sodium with enzymes inside the cell as a result of the increased sodium there [Rubini], alterations of the potassium- sodium regulating hormone patterns which then affect other physiological processes, or some combination of these.

I have come to believe that a disturbance of copper metabolism is the most serious symptom of these other processes. The aspect of copper physiology which is most potentially dangerous is its role in activating lysyl oxidase, the enzyme which cross links collagen and elastin connecting tissue.[Sandberg, et al]. Copper's effect on elastin is especially important because elastin gains its strength primarily from cross linking [Carnes1971(discusses copper aminases)] and because elastin is the main material of several important organs, which include blood vessels, spinal discs, lungs, and skin [Carnes, 1977].

Overall Copper Physiology

Copper, largely tied up as protein, enters the stomach, and there and in the upper intestine [Sachs, et al] [Underwood p70], the proteins other than those entering from the bile [Owen] are degraded (bile proteins are degraded in infant rats when cortisol is low [Mistillis & Mearrick]), thus making the bile the means of excretion for adults [Sarkar p246]. Loss in sweat is usually negligible [Underwood p74} as is losses in urine [Evans 1973b p547]. The copper is moved across cell walls possibly associated with certain amino acids [Neumann PZ & Silverberg M] [Sarka p236]. It may be alpha aminoisobuteric acid which is involved since this amino acid behaves the opposite of other amino acids from cortisol [Chambers, et al]. The copper moves past a metallothionein barrier inside the cells [Cohen, et al] into the serum. Both copper and zinc increase the metallothionein barrier [Oestreicher & Cousins]. The serum carries it largely complexed to albumin and histidine [Frieden 1980 p104]., to the liver. The liver rapidly [Peisach, et al p482] removes it and stores it until such time as unknown hormones (which probably don't include cortisol in any direct way) cause the liver to release ceruloplasmin (which protein contains copper) to the target cells [Frieden] for general purposes, as well as unbound copper when under stress. Adrenaline (epinephrine) stimulates ceruloplasmin release 150% [Weiner and Cousins] as well as free copper and may be the stress hormone for copper [Evans 1973b p556, 557] . I suspect the immune peptide hormones may be used for immunity but I have no data. The ceruloplasmin transporter is destroyed by the target cells which includes those which make bile proteins for copper excretion. Ceruloplasmin has a half life of 130 hours [Sternlieb]. The target cells could include the cells which synthesize tropoelastin (elastin precursor). If these cells synthesize Lysyl oxidase (which cross links connective tissue), they probably must incorporate the copper into the enzyme inside the cell [Harris, et al, p175].

In case of infection, decline of the effect of cortisol and corticosterone (not necessarily concentration itself) shut down unnecessary copper enzymes. Probably this is in order to provide increased copper to the immune system. In case of a potassium wasting intestinal disease, both DOC (deoxycorticosterone, a steroid hormone) and cortisol are used for this purpose. If these hormones shut down copper enzymes permanently by an ongoing potassium deficiency, I suspect health is degraded. The most serious effects are weakening of the elastin tissue derived arteries by inhibition of the lysyl oxidase system, along with fatty buildup in the arteries. Increased excretion in the presence of marginal copper intake can lower liver stores of copper sufficiently that the immune system can not operate effectively. These two effects, along with heart failure account for most of the mortality of rheumatoid arthritis.[Matsuoka].

ELASTIN CONNECTING TISSUE

Elastin makes up the vertebrate disks above the sacroiliac, the blood vessels, much of the skin, the lungs, and the bronchial tubes of all vertebrates except the jawless fishes [Sage & Gray]. The blood vessels are the most important because an organism can not remain alive after a large blood vessel bursts. Ruptured blood vessels are second after heart failure in deaths among arthritic people [Matsuoka]. Tough disks are fairly important also, because of their role in guarding the main nerve trunk. Lungs and bronchial tubes are not subject to such extreme stress. However, emphysema can be produced in animals by a copper deficiency [Soskel, et al]. The emphysema seems to have an elastin defect greater than can be explained by cross linking alone [Soskel, et al]. and it is possible that an association will be uncovered in arthritic people, especially men, old women, or young women after a pregnancy. There is no current evidence that hemorrhoids are made worse by a copper deficiency, but limited experience leads me to believe that evidence will one day appear. I also suspect that a tendency to cut oneself while shaving will prove to be correlated also. If so, this would serve as a good early warning.

Numerous animal experiments have shown that a copper deficiency can cause diseases affected by elastin tissue strength [Harris].. Aneurysms of the aorta are the chief cause of death of deficient chickens. Men who die of aneurysms have a liver content which can be as little as 26% of normal [Tilson}. This researcher speaks of low copper as a marker of aneurysms probably to avoid embarrassment with his colleagues in ascribing it as causal. The median layer of the blood vessel (where the elastin is) is thinner but its elastin copper content is the same as normal men. The overall thickness is not different [Senapati, et al]. The body must therefore have some way of preventing elastin tissue from growing if there is not enough lysyl oxidase for it. Men are more susceptible to aneurysms than young women, probably because estrogen increases the efficiency of absorption. However, women can be affected by some of these problems after pregnancy, probably because women must give the liver of their babies large copper stores in order to survive the low milk copper.

Dilated superficial veins (varicose veins) are observed in copper deficient organisms*. Elastin is about as flexible as a rubber band and can stretch to two times its length [Carnes 1977]. Collagen is about 1000 times stiffer. A healthy artery requires about 1000 mm of mercury or 10 times the normal mean blood pressure in order to rupture [Shadwick].

COPPER ENZYMES

Other enzymes than lysyl oxidase require copper to activate them. One is undoubtedly a mechanism behind anemia. [Underwood]. Tyrosinase incorporates tyrosine into melanin pigment and is the reason why copper deficient sheep fail to pigment*. It is conceivable that human gray hair is also arrives this way. Low white blood cell count (neutropenia) is the earliest symptom in copper deficient babies [Cordano, et al]. The immune system is very sensitive to adequate copper [Prohaska & Lukaseqycz ]. Copper deficient mice have lower number of antibody cells even though the spleen weight is greater [Prohaska & Lukasewicz]. The copper deficient spleens show little growth during an infection . The mechanism has not been elucidated. It is likely that several enzymes are involved, and white blood cells are rich in copper with four times as much as red cells [Mason p1993]. White cell count rises in affected babies within 2 or 3 days after supplement with 2 or 3 mg of copper per day and takes about a week to come to normal, which is a count of more than 1500 per ml for neutropenia and 5000 per ml for leukopenia [Holtzman, et al].

Supplements or copper rich foods should be used for babies with extreme care, as should be formula made from water out of copper plumbing (which can contribute 0.8 mg per day to adult intake [Delves HT]), or brass pots (which have harmed American Indian children [Bremner p45]), because babies can not excrete copper. Nursing babies would be even a little more at risk from supplements since mother's milk contains five times cow's milk [Delves p7]. Babies have 19 mg total copper at term, half in the liver [Klevay 1996 p2424]. New bornes have 230 ppm (parts per million) in the liver which compares to 35 ppm in an adult It must be obvious that 3 mg per day would overwhelm a baby in a short time if continued. Mason says that infants should get 0.05 mg/Kg per day and premature infants should get 0.09 mg/100 Kcal [Mason p1998]. I do not know at what age they can excrete copper. However they are said to have a an adult like liver in two years [Evans 1973b] and their serum levels increase to near adult levels in one month (4-6 months for preterm) [Lonnerdal].

Several brain neurotransmitters such as dopamine and norepinephrine are formed by copper enzymes. The brain other than the cerebellum and hypothalamus have these transmitters decreased 30% to 60% in various sectors by a copper deficiency [Feller 1983]. It is possible that this is part of the poor muscle tone and motor response sometimes observed in a deficiency*. Perhaps copper should be investigated for Parkinson's disease. Copper is thought to increase perception of red and green color [Isaacs, et al].

Diabetes

Copper depletion doubled glucose in blood of diabetic rats fed glucose, 50% higher for sucrose [Cohen, et al 1982]. There must be a copper catalyzed enzyme somewhere in the process, therefore. One investigator has suggested that buildup of copper in the kidneys of diabetics is responsible for the kidney damage which sometimes appears in diabetics (based on rats) [Failla & Kiser]. Diabetics probably absorb copper two times more readily than normals [Craft & Failla]. Diabetics may have a narrow safe range of intake. The pancreas can be irreversibly destroyed by a copper deficiency in rats inside a few months, but the isles of Langerhan are not affected [Smith, et al] [Fell]

Recurrent diarrhea is often observed in a copper deficit [Underwood]. This may be related to the known sensitivity of the immune system to copper. Copper deficient rats survive one third as long as normal which have been infected with Salmonella typhimeureum [Newberne & Gebhardt]. Scurvy like bone changes are a long term result [Underwood], probably caused by failure of bone collagen to cross link [Siegel & Martin (they named lysyl oxidase)]. It is very unlikely that this can be corrected by future intake because of low bone turnover, so adequate intake is crucial for older babies. Osteoportic bone with bone ends in children (similar to scurvy) should cause the first thought to be a copper deficiency [Delves p19]. The age at which human babies stop degrading bile copper protein is unknown to me, although it probably happens gradually. Collagen does turnover, but very slowly. Bone collagen is so slow that correct intake in childhood is essential. Elastin probably has a high turnover [Robert] and also may be porous to the enzyme. I feel that improvement in less than a week is reasonable to expect for elastin tissue {Author's experience]. This is fortunate in view of the extreme danger from elastin ruptures.

A copper deficiency has the characteristic of increasing cholesterol in the blood stream [Allen & Klevay]. A histidine induced cholesterol rise is abolished by copper supplements [Harvey, et al]. It has been suggested that a high zinc to copper intake ratio is an important part of this [Klevay 1978]. The rise in cholesterol and triglycerides has been attributed to a 40% or more reduction in lipoprotein lipase. I do not know whether this is a copper enzyme or not. This may be an adaptation to provide extra cholesterol for lining the arteries with deposits in order to help protect them against rupture by decreasing their internal diameter for the stress on the walls is directly proportional to the radius. Whatever the evolutionary stimulus, copper deficiency is a much more plausible explanation of high serum cholesterol than any difference in cholesterol intake, since the body can synthesize its own cholesterol and average cholesterol intake has not varied more than 5% in the last 100 years*. No enzyme system has been linked to this phenomenon yet with certainty to my knowledge. However the reduction of lipoprotein lipase during copper deficiency has been proposed [Lau & Klevay]. Non ceruloplasmin copper is said to signal the increase of cholesterol [Harvey, et al].

Cholesterol lowering drugs

have not prevented deaths. and the cholesterol level is nornal in the average heart attack victim

Potassium Deficiency

Some of these symptoms also appear in arthritic people. I believe I now see how potassium deficiency may be disturbing metabolism in order to produce them. Potassium wasting infectious disease is the most likely reason for a severe potassium deficiency in nature, not nutritional failure. I propose that the body uses the electrolyte hormone system to stimulate part of the immune system and to alter the basic physiology in order to mobilize the body's defenses against a lethal intestinal disease. Infections of the intestinal tract should be difficult to detect, and the diarrheas, including cholera, may be examples of the type of potassium wasting diseases which forced this system to evolve. Even in the modern world diarrhea is a major cause of death in children, especially in the tropics.

Resisting infection is an extremely important function of the body. It is even related to predation because a diseased animal has great difficulty escaping. It is therefore plausible, as I am about to propose, that numerous physiological processes are fundamentally altered in order to more effectively fight off infection, in the above case, diarrhea [Weber 1998]. The immune system is considerably weakened by inadequate copper as mentioned above. It is therefore logical for the body to attempt to increase the copper available to the white blood cells during disease. It would also be desirable to signal this increase using a hormone system which does it by declining effect. Otherwise a pathogen could evolve which could consistently overwhelm the immune system simply by making an enzyme which destroyed the hormones. Shutting down enzyme systems which were not immediately essential to immunity is one way to increase availability of copper.

11 Deoxycorticosterone (DOC) is a hormone probably used by the body to regulate sodium and potassium when intake of both of them is high. It declines during a deficiency of potassium and sodium. [Weber] It stimulates collagen synthesis [Popisilova] and would thus tend to cancel cortisol's [[Houck & Gladner] effect during diarrhea. Thus the collagen effect would not obtain during diarrhea when serum amino acids are of little consequence and collagen would not be compromised. Any compromises during diarrhea would not be important compared to the urgency of defeating or mitigating virulent diarrhea. However if there is an inappropriate potassium deficiency coupled with the high cortisol of emotional stress which goes on for years, connecting tissue may be weakened. The DOC effect is probably accentuated by low sodium.

The effects of muted cross linking by cortisol drop are especially serious for elastin tissue because the disordered rubbery organization of elastin depends entirely on the cross linking for strength [Sandberg, et al]. Lysyl oxidase oxidizes the amino group in lysine [Siegel & Martin] which amino acid is common in elastin. The aldehyde which forms spontaneously combines with adjacent amine and aldehyde groups to form strong covalent bonds and thus join together the fairly small protein precursor molecules. The same thing happens for collagen and bone also [Siegel & Martin], but collagen in tendons has many less cross links [Kelly & Harris, p227], probably made possible by collagen's greater length and more ordered structure which permits numerous weak hydrogen bonds to be effective. The strength of pig or chick tendon is little affected by copper deficiency, even though the animals are dying of ruptured aortas and even though the tendons have 70% the cross links of normal[O'Dell] [Chou]. The normal lesser number of cross links are desirable, for they permit the tendons to return to their original position after stress is relieved and not to cold flow as polymers held together only by hydrogen bonds do. The number of cross links are probably optimum, because too many would make the tendon brittle. Too few cross links would cause the tendon to become slack with time. Thus the body has a tough material which approaches steel in strength weight for weight and bones which are almost as strong as cast iron (I do not know how cross linked bone collagen is although both bone and tendon are type I collagen [O'Dell]). The lesser reliance by tendon collagen on cross linking for strength may be the reason why the body uses collagen to repair lesions in arteries during a deficiency instead of elastin [Waisman, et al]. Such a strategy may be a good immediate expedient for survival, but I suspect it results in an intractable hypertension eventually because collagen is less rubbery or elastic than elastin.

Superoxide

It has been proposed that the immune system generates superoxide in order to help kill bacteria*. Normally the copper catalyzed [Fridovich] superoxide dismutase enzyme destroys superoxide radicals, which are derived from white blood cells (neutrophils, eosinophils, and macrophages) [Smith & Bryant], as fast as the radicals form. This enzyme declines during infection [Flohe, et al] and is undoubtedly used by the body to help defeat serum infections [Smith] [Ghosh & Chatterjee]. Thus there would be a double advantage in diverting copper from this enzyme. I do not know yet whether decline of this enzyme is tied to the potassium hormone system or not. Superoxide degrades the joint fluids by de polymerizing hyaluronic acid [McCord] and possibly collagen [Sorrenson 1978 p252] as well as bacteria. I suspect that this is an unavoidable compromise, tolerated because of the extreme urgency of fighting disease. Decline of superoxide dismutase has been proposed as one of the mechanisms accounting for some of the symptoms of rheumatoid arthritis [Sorenson 1978], which is an indication that this enzyme is indeed tied to the potassium enzyme systems. Superoxide dismutase is low in children with rheumatoid arthritis. Injections are said to be beneficial in osteoarthritis [Rister, et al]

Glucocorticoids

I propose that the primary purpose of glucocorticoids (steroids oxygenated in the 17 carbon position) is to mobilize the body to resist infection. They do so by normally altering processes which increase pathogens' growth or adverse effects and then declining when under attack. As already mentioned this inverse style is much safer for resisting infection. I propose that cortisol is for intestinal disease and corticosterone for serum disease. Glucocorticoid mobilization for fight or flight is an adjunct made possible because most processes which resist infection are an antithesis for fight or flight [Weber 1998]. Release of ceruloplasmin copper transport protein from the liver is useful for both situations and is therefore controlled by a different hormone, epinephrine, for fight or flight [Evans 1973b p556, 557].

Potassium loss is the most serious aspect of intestinal diseases, so the electrolyte capabilities of cortisol, but not corticosterone, are oriented around conserving potassium by migration into the cells upon decline of cortisol [Knight, et al]. Cortisol, but not corticosterone, has its secretion from the adrenal cortex markedly reduced by low serum potassium (in vitro, that is test tube, experiments) [Mikosha, et al]. Sodium, water, glucose, amino acids, chloride, hydrogen ion, white blood cell activity, copper enzymes, and numerous other hormones and enzymes are controlled by cortisol such as to survive during virulent intestinal disease [Weber 1998

Cortisol works by declining effect, not necessarily declining concentration. Indeed, in most diseases glucocorticoids actually rise. However, at the same time T white blood cells secrete a protein, glucocorticosteroid- response modifying factor (GRMF), and the protein hormone interleukin-1 both of which inhibit the effect of cortisol on white blood cells other than the suppresser cells [Fairchild, et al]. The effect of GRMF on physiological processes is unknown at present. The husband and wife team working on GRMF were almost murdered and this disrupted current investigations. I suspect that most of cortisol's effects on copper enzymes will prove to be involved with GRMFs. These two protein factors thus raise the effective set point of cortisol. This system also uses interleukin-1 to stimulate the production of ACTH, and thereby also cortisol, instead of the brain's corticosteroid releasing factor (CRF) which last is used in the absence of infection. The immune cells thus take over their own regulation.

Cortisol

Cortisol, like DOC, also stimulates lysyl oxidase activity [Siegel], and undoubtedly for the same reason, that is to provide extra copper to white blood cells during infection upon decline. Its action on collagen is exactly the opposite of DOC's:[Popsilova & Popisil] for cortisol inhibits collagen formation [Manchester p273]. This is significant because collagen is the most bulk of protein, is inert, and makes relatively non vital structures, the skin being especially targeted by cortisol by ten times [Houck, et al][. This attribute of cortisol would be a desirable attribute if the pathogen were in the serum, because increased synthesis of collagen when cortisol declined would considerably lower free amino acids in the blood stream, and thus slow down bacterial growth. There would be little advantage from this during diarrhea, and this may be why DOC acts in the opposite direction and thus counteracts cortisol's effect when diarrhea is involved.

I submit that potassium would be a lot safer way of increasing cortisol than use of injections. Steroids are hormones, not pharmaceuticals. Their sole purpose is to keep important body functions and concentrations at values optimum for survival. There should be no reason why artificial additions should be necessary under normal conditions and adequate nutrition for anyone free of genetic defects (which is undoubtedly almost everyone). Quite often a steroid is injected with impunity and seemingly no immediate obvious adverse symptoms. But this is usually because other hormones alter in an attempt to adjust the imbalance and because many of the adverse symptoms such as, for instance, negative feedback which causes reduction in secretory cells of the hormone is a long time in materializing. One medical writer summed it up so: "it is remarkable how effective cortisol is in getting a seemingly hopeless patient on his feet again. Sometimes it is so effective, he can walk all the way to the autopsy table".

CERULOPLASMIN

Ceruloplasmin is higher than normal in the blood serum of arthritic people [Aiginger, et al]. The total serum copper concentrations are bimodal for the distribution of these people with the bottom mode about the same as normal people or people with osteoarthritis [Youssef, et al]. It could be that the bottom mode was from misdiagnoses.

Ceruloplasmin is almost certainly used as a transport protein to bring copper from the liver to the target cells [Frieden] in addition to its other transport uses. Ceruloplasmin is a blood protein which contains 6 [Frieden] or 8 [Sekiya, et al] atoms of copper inside the molecule which are not in equilibrium with the serum [Pelsach, et al]. Such a transport mechanism would be extremely useful in case of infection, because, since ceruloplasmin's copper is not in equilibrium with the serum, it is thus not available to pathogens. With that many copper atoms it is conceivable that it can give up its copper in more than one way. It must be destroyed in order to give up all its copper. Ceruloplasmin's half life is 130 hours [Sekiya} but has a higher turnover in rheumatoid arthritis [Sorrenson, 1978 p217]. One of its copper atoms may be exchangeable under reducing (anaerobic) conditions [Peisach], however. The hormone which causes rise of serum copper and ceruloplasmin from the liver because of stress may be epinephrine (adrenaline) [Evans 1973b p556] [Meyer, et al]. Cortisol is not directly part of it, although decline of ACTH which regulates cortisol may be for immunity [Evans 1973b p554]. Cortisol does stimulate the formation of metallothionein four or five fold, the copper storage protein [Piletz & Herschman]. Thus copper should become more available for ceruloplasmin synthesis inside the liver upon decline of cortisol. The main advantage of this last may be to help drain the intestinal contents of copper to deny copper to diarrhea bacteria, however. It may be cortisol decline which inhibits bile flow after adrenalectomy (amputation of adrenal glands) to conceivably further that same denial [Evans 1973b p556]. DOC decline inhibits liver copper uptake and increases free copper secretion from the liver [Gregoriadis & Sourkes]. This is logical since the serum copper can not nourish diarrhea bacteria.

The mortality of chicks from salmonella infections rises significantly from zero if large amounts of copper as copper sulfate is fed, which supports the contention that this is the reason why their bodies increase ceruloplasmin four fold or even as much as six fold [Underwood p58] during infection but not equilibrium copper bound to albumin and histadine [Starcher & Hill]. This concept is reinforced by the fact that chicks in the absence of infection have a very low ceruloplasmin serum content [Starcher & Hill] unlike mammals. The fact that people with Wilson's disease are not susceptible to infection even though they cannot synthesize ceruloplasmin does not refute ceruloplasmin's role proposed above. This is because people with Wilson's disease can not excrete copper so that their cells are already loaded and even overloaded with copper. The high ceruloplasmin content of mammals in the absence of infection may originally have been an adaptation from their immune use to supply extra copper to the embryo by females. Even today human females have a higher ceruloplasmin content than males do [Frieden 1980 p110]. There may be a similar advantage keeping free copper from funguses as well as bacteria if a limited experiment I tried is an indication. Bacteria could not make use of the copper in ceruloplasmin unless they were to evolve an elaborate mechanism for preferentially binding the ceruloplasmin and then degrading it. This would be an unlikely occurrence. Ceruloplasmin declines in the serum greatly during a deficiency [Gomi]. This would not itself affect immunity except the ability to increase ceruloplasmin during infection is probably decreased also.

Something about ceruloplasmin may be related to Parkinson's disease [Frieden 1980, p108].

It is possible then, that the best way to relieve a copper deficiency which is concurrent with a bacterial infection would be by ceruloplasmin injections. Such a procedure would bear investigation since it is unlikely that people will change their diets and eat enough copper or delete copper physiology poisons which may include tobacco. White blood cell count is very sensitive to copper status and is the earliest and most consistent symptom of a deficiency [Cordano, et al]. Even a mild deficiency causes spleen derived immune cells to be significantly less competent as stimulators in general and also to be stimulated by endotoxin, pokeweed, and concavalin A [Lukasewicz & Prohaska]. Such animals took an average of one third as long a time to die as replete animals, and had four times the mortality [Newberne & Gebhardt]. I believe that the efficacy of adequate copper prior to an infection is established beyond any reasonable doubt. Dietary copper during an infection may be disadvantageous however, except during a deficiency, when it probably would be best to spread it out across the day complexed to protein. A depleted liver removes free copper from the blood with extreme rapidity, [Peisach, et al] however, so the danger is probably not acute.

Since ceruloplasmin is probably used to transport copper to the bile for excretion, excretion may inadvertently rise when ceruloplasmin rises during infection (I have no data to establish this). A similar mechanism may account for the higher ceruloplasmin content in the serum of arthritic people. Apparently decline of cortisol is not used for this purpose and the hormones which do are not known for sure. There could therefore be an increased excretion arising from the higher serum content of arthritic people. If this is so, arthritic people may need somewhat more copper than others until their potassium deficiency is relieved. This may be why their liver copper is low, why their whole blood copper does not rise even though the serum is high [Sorrenson 1978, p217] and part of the reason why they are much more likely to die from ruptured blood vessels (aneurysm) and infection than others [Matsuoka, et al]. Thus rheumatoid arthritis could be viewed as often a multiple deficiency, not all of the symptoms of which can be always removed by supplying only one of the missing nutrients.

Arthritic people also have a higher free copper content in their blood serum [May & Williams p294]. This would seem at first glance to be at variance with the concept that arthritis is an inappropriate immune response. However, intestinal diseases should not be affected much by free copper in the serum, so that immune copper responses accentuated by potassium deficiency may have some subtle differences from responses which are involved primarily with serum infections. Free copper may be more useful to an animal when muscle exertion is needed, because when sheep which have been subjected to a copper toxicity hear the bark of a dog, so much free copper can suddenly be released from the liver that it can kill them [Bremner p42]. Therefore this may be additional indication that people who have a serum infection should be guarded from fear. Free serum copper may be useful to someone with intestinal disease so that he can operate optimally. In addition, the vigor of copper's absorption may even be increased in babies in a diarrhea situation because of the decline in cortisol mentioned previously. Thus diarrhea bacteria would have the use of less copper. I have no assurance that this is the case in adults, and indeed corticosterone injections cause greater secretion of bile in baby rats but not in adults [Evans p234]. This may be an adjunct of coticosterone, used to get baby rats out of the non excretion mode. Rats are a poor experimental animal for this concept because they do not secrete cortisol. They probably were able to lose that secretion because they have a marked inhibition of cholera toxin by something in their intestinal fluid [Donowitz & Binder] and because their ascending colon absorbs water under c-AMP stimulation unlike their descending colon and other mammals [Hornyck, et al]. Rats should not be used for any experiments involving immunity, and perhaps better yet, for none.

Copper in the Diet

A copper deficiency is possible even without the inappropriate requirements of a potassium deficiency proposed. Processing food often lowers copper content. The standard hospital diet is less than 0.75 mg per day [Owen p13]. None of 40 ready to eat cereals had copper or manganese although 50% and 25% or more respectively for the MDR of iron and zinc was supplemented . 25% of supplements contained no copper[Johnson]. Zinc without copper is very dangerous. Diets of free choice are 1 mg per day [Holden, et al]. Western diets usually range between 2 and 4 mg per day and 20 USDA diets contained 1.05 per day [Mason p1998]. This compares to 4.5-5.8 mg per day in the Indies [Peisach p1998]. Intravenous is suggested to be one third the oral intake [Mason p2036]. The unpopularity of the rich source, liver, and the high cost of shellfish reinforce this situation for poor people not in the military (the military provides occasional shellfish). 2 mg per day is thought to be the minimum daily requirement (MDR) [Klevay 1982] and I suspect that 4 mg per day would be the safest intake (RDR) in order to cover everyone or perhaps the 6 mg. received in the Indies.

Lending some support to this contention is the circumstance that underground Utah copper miners had 15.1 accidents per 200,000 man hours with no lost time Vs 10.9 accidents with lost time to give a ratio of 1.4. The figures for all underground Utah non copper miners were 4.4 and 8.4, giving a ratio of 0.5 [US Dept. Labor] as computed from bureau of mines statistics. There are figures for Arizona [Inzan & Hoyle]. Figures from other states trend in the same direction for underground mines, open pit mines, and processing plants. This would seem to indicate that copper miners are tougher than other miners, since each injury is less likely to cause lost time for copper miners. Also, the greater number of injuries to copper miners suggests that their greater toughness tends to make them more careless. The figures might have been even further apart if injuries not connected to strength such as eye injuries and burns had been removed from the data. New Jersey copper smelter workers Have 8% of injuries as back injuries vs. 20% for all other occupations. Two hundred and eighty patients having severe back pains were treated with copper salicylate. A majority were believed to have a slipped disc. Improvements were considerable and rapid [Sorrenson & Hangarter ]. Finnish copper miners are said to have much less arthritis and the women miners less anemia then other Finns [Sorrenson p223]. Finns have a lower copper intake than Americans, and as little as one half the intake of Africans and Asians, [Mason p1083] probably partly because of a high milk intake. Finns have the highest arthritis rate in the world, [Kellgren JH] possibly partly because of perspiration losses during saunas. Such figures suggest an environmental cause rather than genetic, and probably not climatic because Laplanders not much further north have a lower rate, while Masai people [Best & Taylor p768] join the Finns' low rate probably because of their milk intake also as well as low vegetation in the diet. Males who die from aneurysms have one fourth the tissue copper and two thirds the liver copper contents upon autopsy than normal [Tilson]. Since young women are not as affected by copper deficiency as men generally it must be because estrogen enhances absorption [Cohen, et al]. I suspect that this is an adaptation to furnish babies with sufficient copper to surmount the low intake while nursing milk. This is evidence that disruption of copper in arthritis is secondary because women have arthritis much more often than men.

A pervasive copper deficiency would be suggested from the beneficial effects of copper supplements on such diverse diseases as anemia, psoriasis, ulcers, ankylosing spondilitis (Ankylosing spondilitis probably heals slowly because the sacral and ileal joints are made of type I cartilage [Paquin, et al]. The lower ceruloplasmin in that disease may also be implicated in some way) [Sorrenson 1978, p223, 225, 253] , infection, cancer [Nriagu], impaired growth of the retina [Danks p211], seizures as discussed by Sorrenson, and deficiency creates atherosclerosis of the kidneys [Owen] since some of these diseases are common in our society. Copper supplement has healed slipped discs (in combination with pharmaceuticals). A copper deficiency may be the cause of arrhythmias associated with use of liquid protein diets [Klevay & Viestenz] (this reference has EKG data). If these diseases are related to copper there should be a correlation between them, but I have no information for this. Copper helps in removing abnormal EKGs caused by copper deficit but is not always on time, and did not prolong life indefinitely [Viestenz & Klevay]. In addition, any problem which is a function of strength of elastin tissue has a high probability of being accentuated by a copper deficiency. Several of these symptoms together would make the probability of a copper deficiency existing very high indeed and anything which would reduce or interfere with copper very dangerous.

If I am correct in this, there should be very little of these strength of elastin tissue diseases among people who eat a lot of shellfish, especially east coast oysters [Mason p1998]. Some of the advantage of east coast oysters may have disappeared now that the copper smelters have moved west to be near the mines. Shellfish use a copper pigment instead of iron to transport oxygen.
Squid and sour bugs are included for this circumstance. Squid has a fairly large fraction of the copper in the skin. It may be that they use the skin for excretion because the skin also contains much of the cadmium [Gajewska]. Cadmium causes changes similar to a copper deficiency [Lefevre, et al] [Festa , et al].. Copper tends to mute the toxic effects of cadmium [Costanzo, et al] and silver [Underwood p72]. Even so, it is probably best not to use the skin of squid.

The richest source of all is sheep liver, about two times cow liver and duck liver, and about ten times all other livers*. These other livers range from about 7 to 14 mg per pound. Dog and cat foods are also high in copper because copper is added. I do not know what the averages are for them. However, they are probably at the very least a fair source for poor people.

Vegetables high in starch have about 1 mg per pound. Legumes have a range the same as most livers, as do some oil seeds. Cereal grains are about half this. However do not be misled by figures based on weight for food which contains no water. Foods containing water have to be multiplied by the inverse of the water content to be comparable, or better yet, compared on a calorie content basis.. A dried apricot has exactly the same mineral content as it had directly from the field, for instance, per calorie or per weight. Leafy vegetables are probably higher than starchy vegetables, but I have no figures at present. Honey is very low, comparable to milk. [Lawler & Klevay]

Drinking water can contribute as much as 0.8 mg per day if it comes through copper pipes. Soft water and acid water contribute the largest amount [Sparrow, et al]. Copper bracelets are a rather ineffective source, but can have a small measurable effect on arthritis, especially in summer.[Walker & Keats]. It probably would be significant if a dozen or so wide bracelets were worn in summer, especially if they were corroded. I suppose for people who refuse to gain copper any other way it would be better than no way. I suspect that there will prove to be a strong negative correlation between acid water from copper pipes and aneurysms, slipped discs or hemorrhoids.

Milk

The poorest unprocessed source is milk. It contains less than 1/4 mg per pound. This may be an adaptation to protect the mammary glands or the baby against microorganism growth. Babies solve their copper problem with large stores in their liver. Adults who eat large amounts of milk would be at more risk if they had no other good source of copper. Milk is the food scientists use
when they wish to create a copper deficiency in animals. This low copper content may be part of the large increase in cardiovascular disease which has been statistically associated with milk. [Seely] [Klevay 1974]. Milk is said to be a greater risk factor than smoking cigarettes. All the cheeses are included in this category. If its copper content is the cause of its being a risk factor, correcting the problem should prove to be very easy.

The necessity of dealing with this circumstance is no doubt the reason for the different handling of copper by women vs. men and the strong effect of female hormones on copper physiology. The lesser effects of copper supplements on women with arthritis*, the much less rate of aneurysms among women, and the tendency for these differences to recede as women get older is probably
related to that necessity. What little copper is in milk must be part of its cellular components. Copper must be virtually unavailable to most bacteria attempting to live in milk, and this may be the reason why women evolved the ability to give their babies copper through liver storage rather than by milk content.

Interfering Food Elements

Eating large amounts of zinc interferes with absorption of copper [Fischer, et al] [[Cheek, et al]. Using "all purpose" vitamin supplements devoid of copper such as used to be prevalent is thus rather dangerous. Eating large amounts of vitamin C (ascorbic acid) is thought to interfere with utilization of copper within the body [Underwood p71] although Evans thinks absorption is decreased [Evans 1973b]. Vitamin C causes ruptures of the aorta in deficient animals [Owen]. I do not know what the mechanisms are. Gaining carbohydrate in the form of sucrose or fructose will more than triple the mortality from ruptures in the top of the heart in copper deficient rats
[Reiser]. So far as I know the mechanism is unknown. Phytates which are found in wheat tend to decrease absorption somewhat [Underwood p71]. A copper metabolism poison has been found in one of the wild nightshade plants Childers & Russo, so that it is conceivable that the tame nightshades, tomatoes, potatoes, egg plants, peppers, and tobacco have vestiges of something similar. Sulfide acts to inhibit absorption [Sarkar] p238], which might be of interest to those who still take sulfur and molasses. Molybdenum causes symptoms of a copper deficiency even though the liver copper stays high [Evans 1973b]. The minimum daily requirement must then be partly a
function of the status of one's other nutrition. I feel that it should be possible to receive enough copper even if all the above interferences are present, although I know of no research which establishes this. Someone who is receiving marginal amounts of copper, however, appears to me to be in grave danger if even a few of the above interferences are present. It may be prudent to cut back on most if not all of them.

Copper Toxicity

Too much copper is toxic. The amounts showing acute toxicity are large. A man sized pig must receive over 200 mg one time to show obvious acute signs [Higgins]. About ten times this amount is a favorite way to commit suicide in Bombay, India*. I suspect that a chronic toxicity for years can cause loss of weight, high blood pressure (salt intolerant), impotence, loss of ability to excrete potassium resulting in nighttime muscle spasms, and lymph edema. I suspect that most of these symptoms probably arise from a concurrent zinc deficiency because of interference with zinc absorption. The edema could conceivably be connected with disruption of potassium channels. In a study, Choe and his colleagues used X-ray crystallography to resolve the structures of four potassium channels from the sea slug Aplysia. The channels, called Shaw, Shab, Shal and Shaker, represent the four classes of potassium channels found in all higher organisms, including humans. With the exception of Shaker, all of the channels contained four zinc atoms in analogous positions. "Each channel resembles a funnel," said Choe, "and the zinc elements ring the end that empties into the cell's interior." Neuroscientists have known for decades that dyes that bind to zinc stain brain cells in unique patterns, indicating that zinc should have a role in brain function. And studies have shown that zinc can enhance learning in undernourished children. The nature of zinc's organization in the brain, however, had been unclear.

Copper does not interfere with zinc as badly as zinc interferes with copper [Cheek, et al] but it does interfere. I suspect that swelling of prostrate tissue via a zinc deficiency accounts for some of the above symptoms by interfering with bladder emptying.. A zinc deficiency may be connected to swollen prostate tissue, since zinc inhibits prostate growth*.

Toxicity

Some members of society are or may be at great risk from copper toxicity. People who have Wilson's disease (a genetic inability to synthesize ceruloplasmin), one of the three most common forms of schizophrenia*. and babies head the list. For some reason schizophrenia and rheumatoid arthritis seldom occur in the same person while a group of ankylosing spondilitis patients almost all had schizophrenia or an atypical psychosis [Osterberg 1978]. Diabetics are more efficient at absorbing copper, and may have a narrow safe range as already mentioned. For a discussion of copper toxicity see http://www.merck.com/pubs/mmanual/section1/chapter4/4j.htm .

Two mg per day has been recommended for copper deficient babies, but I suspect this is much too high if maintained. Premature babies are usually born with too small a liver reserve to get safely past the nursing period, but one must use care with supplements. 0.09 mg per 100 Kcal has been recommended [Mason p2028]. I suspect that a seat of the pants criteria for such babies would be little more totally than the amount in the liver of normal babies above and beyond theamount they otherwise would receive in their milk. Normal should probably be two or three times as much per body weight as adults require or about 0.08 mg/Kg. and 0.04 for toddlers Perhaps that ratio should be less for very fat babies. A full term baby has 230 parts per million of copper in its liver*, or 105 mg per pound of liver. I know of no way to determine clinically how much it actually contains although modern ultra sound devices should be able to determine liver size. Red blood cell superoxide dismutase has been proposed as a good criteria of copper status in rats
[Feller, et al]. Serum contents are not a reliable indicator since infections, emotional stress, and possibly potassium deficiency have an overriding effect. Liver biopsies are impractical but would be the best way if they were available [Klevay & Madeiros, 196, p2423S]. Hair analysis is ambiguous, does not change much [Danks p222], and subject to contamination. Marginal copper
deficits do not change serum copper, or tissue copper-zinc superoxide dismutase enzyme even though ultra structural alterations in the heart, reduced copper in the brain, markedly decreased IL-2 production, and reduced immune function appear [Hopkins & Failla].

Copper combined with a wide range of chelating agents have been recommended for rheumatoid arthritis [Sorrenson & Hangarter]. I have no evidence that such a strategy is unusually dangerous. However, I think some caution is in order because when lysyl oxidase activity increases, blood pressure does also [Iwatsuki et al]. It is not possible that inhibition of this enzyme operates through artery wall thickness because the effect takes place in a week. I suspect that this is an adaptation to help protect arteries weakened by copper deprivation from rupturing. If massive doses are given it is conceivable that this protection could be defeated before arteries have a
chance to strengthen. Elastin has a fairly high turnover rate [Robert] and lysyl oxidase has a half life of only 16 hours [Siegel]. However strengthening is hardly instantaneous. I suspect one must allow at least a week for sure significant strengthening. A normal body contains only 150 mg of
copper*, so even someone containing only half of normal should be able to correct a deficiency in a reasonable time with a total intake no more than ten mg per day (8 mg supplement), but cutting intake back to 6 mg total or so total [Osterberg 1980 pp. 135, 142] upon repletion and making sure that seven times as much zinc is taken with the supplement dose. Completely safe
supplementation for people with weakened elastin tissue may yet prove to be a little less than this or should be this but coupled with blood pressure medicines. In animal experiments adequate intake may be 5 to 10 times as high as intakes which cause deficiencies [Klevay & Madeiros 1996 p2422S]

It is possible that growth of funguses is enhanced by free copper. Growth is enhanced by externally applied copper. That large amounts of copper can be toxic should definitely not make one reluctant to use reasonable copper supplements if you are not in one of the copper abnormal groups mentioned above. For normal people on a marginal diet I suspect that a supplement of 4
mg per day would be adequate and very desirable. I suspect that amounts 2 or 3 times this would have little adverse affect, but I know of no experiments. People eating unprocessed food devoid of milk and in an active life probably usually need no supplements or extra liver. However if you have a slow healing spinal disk, varicose veins, shaving cuts, hemorrhoids, or emphysema I would
warmly recommend at the very least considering eating shellfish. Elastin diseases are extremely dangerous.

Effect on Society

The degenerative diseases mentioned above (aneurysms, slipped disc, hemorrhoids, emphysema, arthritis) are among the most destructive, painful, and numerous in our society. If copper status is an important parameter affecting them as I suspect, increasing copper intake should have a dramatic effect on our collective health. That copper is below optimum in a large number of people is virtually certain from current evidence. People vary considerably in their genetic makeup, and there are several dozen enzymes and hormones containing or affecting copper, so it should not be surprising that the symptoms of rheumatoid arthritis and the other diseases above
should vary greatly or that "spontaneous" remissions are possible. When you further consider that other nutrients and circumstances also vary enormously, especially for those eating processed food, it is not safe to assume that copper is not deficient because all the symptoms are not present. Any symptom should trigger consideration of increased intake from some source.

Clinical Strategies

It seems to me that injections of GRMF and interleukin-1 along with other hormones secreted by T-cells would be of considerable value in fighting AIDS if done right. Small amounts injected every ten minutes or so would be the only efficacious way since the half life of the protein peptide hormones is usually low, as little as 6 minutes in the case of cachectin. [Hall & Goldstein]. If T-cells prove to be responsible for mobilizing copper but the hormone can not be isolated, I would suspect that ceruloplasmin should be injected also but its long half life would seem to make unnecessary frequent injections. If secretion of immune hormones responsible for removing cancer in the body such as the synergism which has been demonstrated between interferon and cachectin
(tumor necrosis factor) for breast cancer* prove to be dependent on copper for maximum production, ceruloplasmin injections may be in order for people who refuse to eat copper in addition to injections of those hormones. If injections of these peptide hormones are the only way to resolve the situation many small injections are the way it should be done. Massive injections once a day such as are currently used are both ineffective and dangerous. Frequent injections may seem irritating to the patient and unprofitable to the medical profession, but the main consideration is to get rid of the disease. When the hormone massively injected is insulin, wild swings in other hormones are also created, notably 18 hydroxy deoxycorticosterone (the potassium retaining
hormone) and probably cortisol also. It is possible that diabetics subjected to such drastic swings have the disadvantages of some of the worst effects of both the high and low states, especially in the case of cortisol. It may be the source of some of the health problems that diabetics are afflicted with.

I would also suspect that if strains of bacterial diarrheas could be developed genetically devoid of their ability to synthesize the c-AMP stimulating enterotoxin and encapsulated in an enteric tablet in overwhelming numbers in order to avoid destruction by stomach acids, it might be possible to
prevent most of the potassium loss implied in those diseases by competition of the mutant strain with wild cholera and thus not be hung solely on the cortisol system to survive. It might also prove to prevent the disease during an epidemic. When the patient goes back to eating food again, it might be a good idea to start with foods low in copper such as milk and honey, and of course oral rehydration (ORT) salts right from the start, which include potassium, which last is now done. If copper is low ceruloplasmin injections would probably solve the problem of using low copper foods.

There is no excuse for humans to have a copper deficiency. Shellfish are excellent sources and have already been part of successful farming procedures (oysters) or have a high probability of being able to be farmed without too much environmental damage (shrimp). In addition there are
vast tonnages in Antarctic krill. Furthermore some species of terrestrial snails are considered pests and actually exterminated and discarded. For those who have religious or quasi-religious convictions, or taste instincts against eating shellfish or liver, supplements are inexpensive. There is enough copper in one small electric motor to keep a whole town supplied for quite a while. Better
the copper into supplements than into a motorized wheel chair, but always in moderation and with seven times as much zinc.