This is a discussion of copper physiology and nutrition especially as pertaining to treatment of herniated discs, rheumatoid arthritis, hemorrhoids, emphysema, anemia, and maybe gray hair.
Page 1. - copper physiology, elastin tissue, copper enzymes, diabetes, potassium, superoxide, cortisol and corticosterone.
Page 2. - cortisol, ceruloplasmin, copper in the diet.
A site to obtain a book about potassium nutrition and physiology is shown at the end of this article.
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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, acidity in cell vacuoles, 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, upper spinal discs, lungs, and skin [Carnes, 1977]. 4 to 6 of 100 Americans autopsied died of a ruptured aneurysm and 40% of them had unruptured aneurysms [from a dead URL] (this is probably low since it is unlikely that all the aneurysms were found). Each year, approximately 16,000 Americans die due to a ruptured aortic aneurysm. Of the 200,000 strokes that occur each year, approximately 20% are cerebral hemorrhages (or aneurysms to the brain), and this kills another 40,000 Americans.An aortic aneurysm is considered serious if its diameter reaches more than 1.5 times the size of the normal aorta.. This makes copper deficiency a major bad health hazard. This relationship may be a large part of the reduction in aneurysms which increased potassium produces.
Another serious symptom is myeloneuropathy with spastic gait, distal parasthesias and sensory ataxia, which mimics the symptoms and radiographic findings in the degeneration associated with vitamin B12 deficiency [Spain].
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 glucocorticoids are low [Mistillis & Mearrick] ), thus making the bile the means of excretion for adults [Sarkar p246]. Loss in sweat is usually negligible [Underwood p74] as are 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 is probably carried to a metallothionein barrier and storage substance by glutathione [Steinebach] and then moves past the 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 do not include cortisol in any direct way) cause the liver to release ceruloplasmin (which protein contains copper) to bring copper to the target cells [Frieden] for general purposes, as well as unbound copper when under stress. The liver releases no copper to the plasma during a deficiency when the liver copper is below 2.7 milligrams per kilogram [Levenson 1998]. 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]. Cortisol does not directly mobilize copper in stress. I suspect the immune peptide hormones (one or more of the interleukins) may be used to stimulate copper for immunity but I have no data. The ceruloplasmin transporter is destroyed by the target cells, which includes those that make bile proteins for copper excretion. Ceruloplasmin has a half-life of 130 hours [Sternlieb]. The target cells could include the cells that synthesize tropoelastin (elastin precursor). If these cells synthesize Lysyl oxidase (which cross-links connective tissue), they probably must incorporate the copper into that enzyme inside the cell [Harris, et al, p175]. Copper chaperone proteins move the copper inside the cell cytoplasm into target enzymes, which may be a process to avoid copper toxicity. These chaperones have been identified in cells from bacteria on up to humans. These chaperones and cell membrane transport proteins have been elucidated considerably in recent years, and are very complicated. A defect in the gene that makes ATP7A chaperone protein is responsible for causing Menkes syndrome and a defect in the gene responsible for ATP7B chaperone protein causes Wilson’s syndrome.
In case of infection, decline of the effect of cortisol and corticosterone (not necessarily concentration itself, since glucocorticosteroid response modifying factor {GRMF} can inhibit those hormones) 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. Low potassium has been shown to be a risk factor for aneurysms [Koyanagi]. Increased excretion in the presence of marginal copper intake can lower liver stores of copper sufficiently that the immune system can not operate effectively. Infections are a major immediate cause of death in arthritis [Hollingsworth]. These two effects, along with heart failure account for most of the mortality of rheumatoid arthritis [Matsuoka], which itself has low cell potassium [LaCelle]. Linder and Hazegh-Azam have written a review of copper movement inside the body [Linder].
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]. Most of our country (America) must be afflicted with a marginal copper intake because almost half the people autopsied have an aneurysm. 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. Increased lung function is correlated in nonsmokers with drinking water out of copper pipes [Sparrow]. 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 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]. The lysyl oxidase is secreted normally, but its activity is reduced [Kosonen] due, no doubt, to some of the initial enzyme molecules (apo-enzyme) failing to contain copper [Rucker] [Smith-Mungo]. Aneurysms of the aorta are the chief cause of death of copper deficient chickens, and also depleting copper produces aneurysms in turkeys [Guenther]. 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 if he ascribed 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 of copper. 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 for them to survive the low milk copper. A baby’s liver has up to ten times as much copper as adult livers [Draper].
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]. Therefore keeping strength of arteries up would seem to be even more important than keeping blood pressure down so far as arteries are concerned, although not necessarily so far as kidney glomeruli are concerned. However a copper deficiency coupled with high sodium (or high chloride?) causes disruption of the glomeruli basement membrane resulting in acute kidney failure [Moore].
There is a serious defect with elastin connecting tissue in Marfan syndrome. Some of the same strength of connecting tissue problems seen in copper deficiency are seen Marfan syndrome. Sandra Simmons has proposed that copper nutrition should be explored in Marfan syndrome. This is a well-referenced article with comparisons to similar diseases. Marfan syndrome is probably a genetic defect, but there is a strong probability that it either operates through the copper physiology or is greatly affected by a deficiency. That some nutrient or other can affect this syndrome is plausible for if there were no ability at all to synthesize elastin these people would not be alive.
Other enzymes than lysyl oxidase require copper to activate them, Some of these are discussed below. They include; Tyrosinase, two forms of Superoxide dismutase or SOD1 (Breaks down the superoxide free radical), Cytochrome c oxidase (Electron transport involved in energy production), Dopamine –hydroxylase, (Converts dopamine to norepinephrine), Clotting Factor IV (Blood clotting), Thio oxidase (Disulfide-bond formation), Protein Kinase (Development of Nervous System), Dopamine mono-oxygenase (Catecholamine Synthesis from Tyrosine), diamine oxidase,histaminase,
Enzymes unknown to me are undoubtedly a mechanism behind anemia. [Underwood] Hephaestin, a multicopper ferroxidase involved in basolateral intestinal iron transport, is one enzyme that is involved, for decreased hephaestin activity in the intestine of copper-deficient mice causes systemic iron deficiency [Chen].
Tyrosinase incorporates tyrosine into melanin pigment and is the reason why copper deficient animals fail to pigment [McDowell] [Robbins] [Tear] [Zumpf] [Penrith] [Frank] [Scott] [Wu]. It is conceivable that human gray hair is also arrives this way but I know of no epidemiological studies. I suspect that the pigment loss is due to cell death, a mechanism possibly evolved to help put less strain on a deficiency. If so, relieving the deficiency will not necessarily bring back the pigment, although it has done so in one of my acquaintances.
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 ][Percival]. TETA poison reduced IL-2 (interleukin-2) production 50% but not in the presence of copper supplements [Hopkins 1996] and interleukin-2 is reduced by a copper deficiency [Percival p1065]. Neutrophils are reduced in numbers as well as function and superoxide anion production is 60% less. 2.5 milligrams total per day prevented further decline but was not enough to return to normal even though neutrophils turnover every 3-5 days [Percival p1067]. Thus this is a reasonable basis for setting 2.5 milligrams as the minimum daily requirement. 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] or more. New borne babies 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 might overwhelm a baby in a short time if continued. Copper absorption is proportional to intake from breast milk and formula (in rats), which formula is up to 10 times the amount in breast milk [Lonnerdal 1998 p1048s], although babies can tolerate a fairly high oversupply of copper beyond the above (Lonnerdal 1998 p1051s], so they must have a mechanism for retarding absorption through the intestines during excess. Mason says that infants should get 0.05 milligrams/kilogram of body weight per day and premature infants should get 0.09 milligrams/100 Kcal [Mason p1998]. I do not know at what age they can start to excrete copper. However they are said to have 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 1996]. All these problems of too much and too little are more arguments for using mother's milk if at all possible for normal babies.
The development of an embryo’s nervous system depends upon a copper-containing enzyme called protein kinase C (PKC). Researchers studied the PKC levels in the brains of rat babies whose mothers had been fed a copper deficient diet during and for a few weeks after pregnancy. Results showed that while PKC levels rose in all the rat groups during the three weeks after birth, the increase was only half as much in the group whose mothers got 1/6th the recommended copper and ¼ less in the rat that received only 1/3 the recommended intake. In addition, in this same group (1/3 recommended intake of 6 mcg./day), one form of PKC was off by 50% in the cerebellum. This is the area that is critical for motor function and coordination. Consistent with these results in baby animals, copper deficiency usually results in poor muscle coordination, presumably by the same deficits in PKC levels. A copper deficiency during pregnancy can result in numerous gross structural and biochemical abnormalities, which are thought to be from copper deficiency induced changes in free radical defense mechanisms, connective tissue metabolism and energy production by Lonnerdal and Uauy [Lonnerdal].
A copper deficiency produces a degeneration of the spinal cord involving the sheath around the nerve fibers, It is similar to the degeneration caused by a vitamin B-12 deficiency. Winston and Jaiser have proposed that the similarity is because of a dysfunction of the methylation cycle, which is dependant on vitamin B-12 catalyzed enzymes and may be dependant on copper catalyzed enzymes also [Winston]. Methionine synthase requires copper and they suggest that s-adenosylhomocysteine may be regulated by copper.
Cytochrome C oxidase is a fundamental enzyme in the body’s handling of oxygen. It contains 2 copper atoms and 2 iron atoms [Frieden 1974 p112]. Research with rats has shown that the cytochrome C oxidase activity in platelets correlates well with liver copper stores, the benchmark measure of copper status [Milne 1998]. So this would seem to be the best way to determine true copper status if the platelets can be isolated economically. However, owing to the reserve capacity of this enzyme, no dramatic changes in the overall rates of mitochondrial oxidative phosphorylation were detected in the brain of mice when cytochromeC oxidasewas was greatly reduced by a copper deficiency [from a dead URL]
Several recent reports suggest that the activity of the cuproenzyme peptidylglycine -amidating monooxygenase (PAM) in plasma merits special consideration as a potentially-useful indicator of Cu status. PAM is required for the post-translational modification of numerous neuroendocrine peptides to their bioactive forms which possess an amidated carboxyl terminus [Eipper et al. 1992]. Representative -amidated peptides include calcitonin, cholecystokinin, gastrin, neuropeptide Y, oxytocin and vasopressin. Two distinct catalytic activities are required for the covalent modification. The COOH-terminal glycyl residue of the peptide substrate is converted to peptidyl--hydroxyglycine by the Cu, ascorbate and molecular oxygen-dependent peptidylglycine -hydroxylating monooxygenase. The peptidyl--hydroxyglycine--amidating lyase cleaves the intermediate to produce the -amidated peptide and glyoxylate. Inhibition of PAM activity increases the concentration of glycine-extended peptides and decreases that of the -amidated peptides in tissues. The possibility that Cu availability affects PAM activity was suggested by several early studies. Treatment of murine pituitary cell cultures and rats with disulfiram, the disulfide dimer of the high-affinity Cu chelator diethyldithiocarbamate, inhibited PAM activity and increased the quantities of several glycine-extended peptides [Mains et al. 1986]. Also, serum activity of PAM was reduced in adult male rats after feeding a Cu-deficient diet for 9 weeks [Main et al. 1985]. The effects of marginal and moderate Cu deficiencies in young rats on the activities of several cuproenzymes in the heart and plasma. The results clearly showed that serum PAM activity, like that of Cp enzyme, was correlated with Cu intake. The activities of PAM, CCO and Cu,Zn-SOD in the heart also were modulated by Cu intake. The observation that in vitro addition of Cu2+ restored PAM activities in samples from Cu-restricted rats to those of the controls is particularly interesting. In contrast, exogenous Cu failed to increase the activities of Cp enzyme, CCO and Cu,Zn-SOD. Prohaska (1997) proposed that comparison of serum PAM activity in the presence and absence of Cu salt may be useful for assessing Cu status. Additional support for this possibility is available. First, several subjects with a mild variant of Menkes disease were found to have significantly lower levels of plasma Cu and Cp than control subjects [Prohaska et al. 1997]. Although plasma PAM activity was similar for the two groups, in vitro addition of Cu stimulated enzyme activity 3•0- and 1•6-fold in samples from subjects with Menkes disease and control subjects respectively (P ‹ 0•001). This finding suggests that the amount of plasma PAM protein increases in response to Cu deficiency. Second, the stimulatory influence of exogenous Cu on PAM activity in plasma from an adult female with acquired Cu deficiency [Smith et al. 1994] decreased in response to Cu supplementation in vivo (JR Prohaska, personal communication). Third, it is noteworthy that plasma PAM activity in adult male rats was not altered in response to a variety of changes in endocrine status and was similar in male and female animals [Mains et al. 1985]. Finally, quantification of PAM activity requires a small volume of plasma that can be obtained from a microhaematocrit tube, thereby eliminating the need for venipuncture [Prohaska, 1997] [Prohaska, et al 1997]. Further examination of the effects of nutritional, physiological and pathological stresses on plasma PAM activity is warranted in light of the observations concerning this cuproenzyme.
Coagulation factors V and VIII, which contain copper and have structural similarities to ceruloplasmin (the main copper- containing protein in plasma), are sensitive to changes in copper intake. Surprisingly, copper depletion caused factor VIII activity to significantly increase to almost twice the normal range. Factor VIII is a procoagulant, and an elevation of factor VIII activity is often seen in hypercoagulation and thrombotic disease, important risk factors for vascular disease [Milne 1996]’ So it appears that a copper deficiency might increase susceptibility to blood clots.
Several brain neurotransmitters such as dopamine and norepinephrine are formed and catabolized by copper enzymes such as tyrosine hydroxylase and dopamine-beta-hydroxylase [Tyrer]. 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 [*]. There is raised copper in the cerebrospinal fluid during Parkinson's disease [Beshgetoor]. Perhaps copper should be investigated for Parkinson's disease. Copper is thought to increase perception of red and green color [Isaacs, et al]. It has been suggested that epilepsy may be caused in babies by a copper deficiency [Elomaa]. A copper deficiency in rats causes the cerebrum to decrease in size and weight, the cortex to become thinner and the corpus striatum atrophy. Vacuolar degeneration and swelling of the mitochondria in the extrapyramidal system within the corpus striatum resulted in axon damage and disintegration of the myelin sheath. There is proliferation of endoplasmic reticulum in the dark neurons, swelling and rupture of mitochondria in the light neurons, which can result in necrosis of both types of neurons. The damage due to copper deficiency could not be reversed by copper supplements in diet. [Lu] A copper deficiency could be involved in sudden infant death syndrome by a similar mechanism [Reid]. Obviously it is very important that a deficiency not be permitted in older babies in view of the irreversibility of some of these effects.
It has been proposed that copper deficient embryos cause increased genetic defects [Jankowski, et al]. The authors suggest that the problem may arise because of oxidative damage to DNA produced by reduced superoxide dismutase (SOD) which is an enzyme which degrades superoxides. When the serum was supplemented with Superoxide dismutase and glutathione peroxidase the birth deformities were reduced, which led the researchers to suggest that oxidative damage was part of the cause [Hawk]. Copper deficiency in cattle causes chromosome abnormalities [Abba], which would seem to make adequate copper during a pregnancy very important. Velo, et al have proposed that control of free radicals by ceruloplasmin (but actually more likely by superoxide dismutase) is the protective role of copper against inflammation [Velo, et al]. More likely is that any role of copper deficiency in inflammation probably operates through the prostaglandin hormone system (possibly PG-f2) [Sorenson p252] [May & Williams p296].
A copper deficiency has been shown to increase the time it takes for cats to conceive [Fascetti].
Copper depletion doubled glucose in blood of diabetic rats fed glucose, 50% higher for sucrose [Cohen, et al 1982]. There must be a couple of copper catalyzed enzymes somewhere in the process, therefore. One investigator has suggested that buildup of copper in the kidneys of diabetics is responsible for the kidney damage that sometimes appears in diabetics (based on rats) [Failla & Kiser]. Diabetics probably absorb copper two times more readily than normal people [Craft & Failla]. Diabetics may have a narrow safe range of intake, therefore. It would be very desirable to find out for sure what this range is. 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]. Even so there is somewhat of negative correlation between copper in drinking water and onset of juvenile diabetes. [Zhao]. In cases of juvenile diabetes, there were lower than normal levels of reduced glutathione, ceruloplasmin oxidase activity, zinc, copper and sodium, while the other elements show no significant changes [Awadallah]. So it is possible that people with partial destruction of their beta cells could cut back on their medication with proper nutrition. It is possible that adequate copper could help prevent insulin dependant diabetes since it does so for ATZ poisoned mice [Sitasawad] and copper in drinking water has somewhat of a protective affect [Zhao]. This may be happening because of a synergism of copper deficiency with capsaicin poison in chili pepper [Weber 2008]. Once insulin dependant diabetes sets in, handling copper may be a problem and may be part of the difficulty with poor health afflicting diabetics.
Gastric lesions (ulcers?) were reduced 40% by several copper organic molecule complexes and lesions induced by indometacin almost 90% [Jimenez]. It would be desirable to know how much of this effect was due to altering a copper deficit. Dimethyl hydrazine produces much worse colon cancer in copper deficient rats [DiSilvestro]. This must be connected to the muting of the immune system by low copper.
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 rats that have been infected with Salmonella typhimeureum [Newberne & Gebhardt].
Scurvy like bone changes are a long-term result of a copper deficiency [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 of copper is crucial for older babies. However, copper supplements increased bone density in women [Klevay 1998] [Eaton-Evans] and patients with neck fractures had lower serum copper than controls [Conlan]. There was no indication mentioned in Klevay’s report that the connective cartilage was affected, however. Bone breaks heal with difficulty in the absence of copper [Dolwet]. Osteoportic bone with bone ends in children (similar to scurvy) should cause the first thought to be a copper deficiency [Delves p19]. Lowe et al have written a review of the affect of copper and zinc on bone loss [Lowe]. In one experiment the placebo group lost 2.23 % after two years. Those on calcium supplement lost 0.5%. Those on copper and zinc supplement lost 1.66%. Those on calcium , zinc, and copper gained 1.28%. Zinc stimulates formation of osteoblastic cells, the cells that form bone. If calcium or phytic acid is eaten at the same time as the zinc, an insoluble compound of zinc prevents its absorption. So obviously zinc and calcium should be taken at separate times. Elderly people have a much lower absorption of zinc [Lowe]. Manganese is also essential to prevent bone loss.
The age at which human babies stop degrading bile copper protein and thus start excreting copper is unknown to me, although it probably happens gradually. Collagen does turnover, but very slowly. Elastin probably has a high turnover [Robert] and also may be porous to the enzyme, lysyl oxidase. 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 of blood vessels.
A copper deficiency has the characteristic of increasing cholesterol in the blood stream [Allen & Klevay] [Reiser]. A histidine induced cholesterol rise is abolished by copper supplements [Harvey, et al]. It has been suggested that high zinc to copper intake ratio is an important part of this [Klevay 1978]. Too low a zinc status during a copper deficiency can be even more damaging to the heart. However adding copper without zinc can actually make the situation worse [Festa]. 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 [Brown]. 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] and it has been proposed that the high blood cholesterol is probably due to impaired conversion of cholesterol to bile acid [Mann p647]. Non ceruloplasmin copper is said to signal the increase of cholesterol [Harvey, et al].
Cholesterol lowering drugs have not prevented deaths (Golomb and Marcella have written a review of the affects of statin drugs on the body and have concluded the bad side effects of those drugs are because of inhibition of mitocondrial activity), the cholesterol level is normal in the average heart attack victim, and cholesterol in food is not correlated well with heart trouble,
The network of connective tissue in the heart fails after a copper deficiency [Borg] and this could contribute some to heart failure in those affected. In copper deficient rats the Q-T intervals are larger and the QRS amplitudes are increased [Shiry].
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 by the body’s immune system, and the diarrheas, including cholera, may be examples of the type of potassium wasting diseases that forced this system to evolve. Even in the modern world diarrhea is a major cause of death in children, especially in the tropics. When the diarrhea diseases first evolved it must have been devastating for terrestrial vertebrate organisms.
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 by cortisol 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 that 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 creation of enzyme systems which were not immediately essential to immunity such as cortisol does by declining is one way to increase availability of copper during infection. However this would probably increase copper excretion, so a potassium deficiency that goes on for a long time could indirectly create a copper deficiency at low copper intakes.
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 1983]. 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 effective 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 that goes on for years, connecting tissue may be weakened. The DOC effect is probably accentuated by low sodium. It would be interesting to know what affect 16 alpha 18 dihydroxydeoxycorticosterone has, which is the hormone I suspect used to regulate high sodium, low potassium intakes.
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 that 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 nevertheless, 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 is 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 copper 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 much less rubbery or elastic than elastin.
It has been proposed that the immune system generates superoxide in order to help kill bacteria [Battistoni]. 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 depolymerizing hyaluronic acid [McCord] and possibly collagen [Sorenson 1978 p252] as well as bacteria. I suspect that this is an unavoidable compromise, tolerated because of the extreme urgency of fighting disease. But, again, it could be ruinous if it were to go on for years. Decline of superoxide dismutase has been proposed as one of the mechanisms accounting for some of the symptoms of rheumatoid arthritis [Sorenson 1978], which, if so, 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]
AMIDATING ENZYME, ETC.
Aproximately 50% of all peptide hormones contain a terminal alpha-amide group (a nitrogen-carbon group similar to an amine but with an extra hyroxyl addition). It is synthesized there by an amidating enzyme containing two copper atoms [Freeman, 1993]. I do not know if any specific disease or diseases attend a deficiency of this enzyme, but it is highly probable that some aspect of health is degraded by a low performance of this enzyme.
Phenylalanin-4-monoxy-genase with both iron and copper as cofactors is responsible synthesis of tyrosine and degradation as well as hydroxylation of phenyl alanine. This enzyme makes tyrosine, an unessential amino acid, able to be synthesized in the body. This is important because tyrosine is necessary for synthesis of the catecholamines, norepinephrine, epinephrine, dopamine, and adrenaline. Low dopamine is involved in depression, hypertension, and scizophrenia. The above enzyme is also the only way to completely burn phenylalanine to carbon dioxide and water [Hufton, 1995].
For a lengthy discussion of copper enzymes see this site. Do not believe their too low a recommended intake though. 3 milligrams per day is necessary, and 4 or 5 is probably safer.
GLUCOCORTICOIDS
I propose that the primary purpose of glucocorticoids (steroids oxygenated in the 17-carbon position) is to mobilize the body to resist infection [Weber 1998]. They do so by normally altering processes that 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 that 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]. The kidneys have twice as much ceruloplasmin as liver [Linder] and, from messenger RNA evidence, the kidneys may synthesize ceruloplasmin [Linder], but I do not know if they are used as a source during infection or stress situations. 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 of potassium 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, in 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 in such a way as to survive during virulent intestinal disease [Weber 1998].
Continue to cortisol, ceruloplasmin, copper in diet,
Continue to copper sources, milk, interfering food, copper toxicity, affect on society. .
A table which gives copper and zinc per thousand Calories, is available at this site, as well as zinc/copper ratios.)
You may see here the way to acquire a very comprehensive book about potassium nutrition and physiology. It is called “POTASSIUM NUTRITION in Heart Disease, Rheumatoid Arthritis, Gout, Diabetes, Metabolic Shock, and High Blood Pressure”. The table of contents and the introduction are shown.
Strategies for Chronic fatigue syndrome (CFS) and fibromyalgia --------- When blood potassium is too high
The pioneering efforts about potassium for arthritis by Charles de Coti-Marsh enabled him to form a foundation currently active in England that promotes the use of potassium for arthritis and it has helped 3500 people.
There is an article discussing cashew nuts to cure a tooth abscess Which will prove useful
There is also an article which proposes some speculation about diabetes.
There is evidence that cell phones can produce tumors. Using remote ear phones would seem to be a good idea.
Fluoride in city water will cause fluorosis discoloration of teeth, weakened bones, damage to the kidneys, thyroid, and immune system, bone cancer, and, worst of all, damage to the nerves resembling Alzheimer’s disease. It will also cause damage to ligaments resembling arthritis. For a forum that discusses iodide (an antidote for fluoride) access this site.
See this site for some links to health articles.
For a procedure that discusses tetrathiomolybdate for removing copper and thus preventing further solid cancer growth and Hodgkin’s, see this site. This might buy some time until you can persuade a doctor to try tumor necrosis factor or interferon or an opioid antagonist drug called Naltrexone (Naltrexone in the large 50 mg size, originally manufactured by DuPont under the brand name ReVia, is now sold by Mallinckrodt as Depade and by Barr Laboratories under the generic name naltrexone) that blocks some endorphin receptors. Said blockage is thought to cause the body to temporarily secrete more endorphins, especially after midnight at night. These endorphins are thought to stimulate the immune system, and in particular to stimulate the TH-1 or type 1 antiviral response by decreased interleukin-4 and with increased gamma interferon and interleukin-2 and a simultaneous decrease of type 2 anti bacterial response [Sacerdote].
It appears to be especially effective for minimizing symptoms and retarding progression of multiple sclerosis (MS) There are drugs listed in this site that should not be taken with low dose Naltrexone, including cortisol. There is information in this site for mitigating side effects, including starting with one milligram doses. Advice how to proceed if you have been taking cortisol may be seen here. (also see these sites; this site and this site and this site and a trial) . A few doctors have had
encouraging results in Crohn's Disease, and even to some extent in cancer. Low doses of Naltrexone (LDN), 1.5 to 4.5 milligrams, at bedtime is used (timing is important, and it is important not to buy slow release forms). It is said to have no known bad side effects at those doses other than insomnia the first week or two in some. There is also reports from an extensive survey in this site. and an extensive discussion at this site.
I think some clinical studies on Naltrexone are in order, and it should not be a prescription drug (I have a petition to make Naltrexone an over the counter drug with the Center for Drug Evaluation and Research
FDA Rockville MD 20857, Re; Docket No. 2006P-0508-CPI. Perhaps if enough people wrote supporting the petition it could be enacted). Though side effects appear unlikely, it is not proven over longer periods. If you try it (it is a prescription medicine in the USA), it seems likely that you should discontinue if you get a bacterial infection in view of its inhibition of antibacterial response. Naltrexone is currently being used by Dr. Enlander, a New York City doctor, but with limited success using 3 to 4.5 milligram doses for CFS or CFIDS. Dr. Gale Guyer of Advanced Medical Center located in Zionsville, Indiana also is using it for cancer. Dr. Bihari has shown promising results for a large percentage of his cancer patients.
Olive leaf extract has shown clinical evidence of effectiveness against a wide range of viruses, including AIDS [Bihari], herpes, and cold viruses. It sometimes produces a Herxheimer or pathogen die off symptoms (from effectiveness against bacteria?). There is evidence that it is synergistic (reinforce each other) with Naltrexone. There have been a few case histories of improvement in what were probably arthritis patients and CFIDS patients. The active ingredient is said to be oleuropein or enolate. There has been very little follow up research done on it.
Also it has been found that curcumin in turmeric or curry powder will inhibit several forms of cancer, including melanoma. People who live in India where these spices are eaten, have one tenth the cancer elsewhere. It must be used with caution because it can sometimes aggravate the situation [Stix].
Here is an article with anecdotal evidence for pressurized oxygen, zinc, vitamin B6, and vitamin C after head injuries. They also claim a fair percentage of prison inmates from psychiatric disorders after head injuries.
See this site for evidence of a correlation between magnesium deficiency and cancer. The taurate has been proposed as the best magnesium supplement. Since taurine is physiologically active, this may prove to not be the case long term. Taurine or 2-aminoethanesulfonic acid is an acidic chemical substance sulfonated rather than carboxylated found in high abundance in the tissues of many animals (metazoa), especially sea animals. Taurine is also found in plants, fungi, and some bacterial species, but in far less abundance. It is an amine with a sulfonic acid functional group, but it is not an amino acid in the biological sense, not being one of the twenty protein-forming compounds encoded by the universal genetic code. Small polypeptides have been identified as containing taurine, but to date there has been no report of a transfer RNA that is specifically charged with taurine [from Wikipedia]. It is essential to babies and is the most abundant brain amino acid at birth. With maturation babies start to synthesize taurine and glutamate becomes the most abundant in the brain of adults. It is essential to adult cats.
It has been found that supplements of the amino acid, taurine, will restore the abnormal electrocardiogram present during a potassium deficiency by an unknown mechanism. This information has been used in several case histories by George Eby to control a long standing type of cardiac arrhythmia called pre atrial contractions (PACs), a benign but irritating and nerve racking heart problem, with 2.5 grams of taurine with each meal.
Taurine is said to be low in the diets of vegetarians. The 2.5 grams recommended by the American Heart Association causes diarrhea in some people and should probably be reduced in those people.
There is strong evidence that taurine could have beneficial affects on type I diabetes, and could reduce organ peroxidation and plasma lipids. The retina, lens, and nerves respond better to taurine than other organs [Franconi]. Taurine has been used for high blood pressure [Fujita], migraine headache (I suspect that less than 1000 milligrams can remove the headache caused by allergy to peanuts), high cholesterol, epilepsy, macular degeneration, Alzheimer’s disease, liver disorders, alcoholism, and cystic fibrosis, and depression. Keep in mind that some people may have a genetic defect that limits the amount of taurine tolerated and that adequate molybdenum may desirable. Taurine may make a copper deficiency worse, based on a single case history [Brien Quirk, private communication]. This may be because taurine may be mobilizing copper and zinc into the plasma [Li]. So if you should decide to take taurine, make sure your copper intake is more than adequate, as well as your zinc. Taurine may be obtaind from health food stores as capsules.
A site is available which shows. foods which are high in one nutrient and low in another (including calories). This last site should be especially useful for a quick list of foods to consider first, or for those who must restrict another nutrient because of a genetic difficulty with absorption or utilization
You may find useful for definitions and easy to use a search for abstracts of journal references, "Gateway". You must click on “ MEDLINE/PubMed” or for definitions click on "find terms". or a list of medical search engines
You may find useful a search for abstracts of journal references, "Gateway”. Google’s scholar feature is also an excellent source of literature articles in all fields.
There is a free browser called Firefox, which is said to be less susceptible to viruses or crashes, has many interesting features, imports information from Iexplore while leaving Iexplore intact. You can also install their emailer. A feature that lists all the URLs on a viewed site can be useful when working on your own site.
The author has a degree in chemistry and a master of science degree in soil science. He has researched this copper subject for 45 years, primarily library research. He has cured his own early onset of arthritis and has cured his slipped disc and hemorrhoids with copper supplements. He has published articles on allied subjects in; The Journal of Theoretical Biology (1970, 1983), The Journal of Applied Nutrition (1974), which gained the best article of the year award, Clinical and Experimental Rheumatology (1983), and Medical Hypotheses (1984, 1999, 2007, 2008)
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Email to Charles Weber = isoptera at att.net
This article updated in March 2014
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