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Copper response to rheumatoid arthritis
Medical Hypotheses15: 333-348,1984
COPPER RESPONSE TO RHEUMATOID ARTHRITIS C. E. Weber, 141 Mt. Horeb Road, Warren, N. J. 07060 ABSTRACT Rheumatoid arthritis can be divided into two syndromes, one a potassium deficiency, the other an inappropriate copper requirement seriously affecting the elastin tissues through reduced lysyl oxidase cross linking. The malfunction in copper may arise from the steroids which regulate potassium, which reduces those steroids, and through that, increases the copper response to the needs It is a mechanism which may have of the immune system. evolved to help fight potassium wasting infections. INTRODUCTION I have previously proposed that a considerable part of the degeneration of mesenchyme tissue in our society is due to losses of potassium in our food supply, and that in particular rheumatoid arthritis may be a chronic potassium deficiency (1) which causes alterations inside the cell of free amino acid (2), interference by sodium with enzymes inside the cell as a result of the increased sodium there (3), alterations of the potassium-sodium regulating hormone patterns which then have indirect effects on other physiological processes, by other consequences of the deficiency, or some combination of these. I would now like to propose, given that the above view is accepted as possible, that rheumatoid arthritis may be split up into two syndromes, one primarily a potassium deficiency, and the other, while triggered by a potassium deficiency, perpetuated by a concomitant disruption of the copper metabolism of the body, and most seriously affecting tissue composed of elastin. Tissues high in elastin are the spinal discs, the blood vessels, the lungs, and the skin (4) of vertebrate animals higher than jawless fish (5). Thus people subjected to a potassium deficiency are suggested to have an inappropriately high requirement for copper. 333
DISCUSSION Effects of Copper Deficiency An actual copper deficiency is already known to drastically decrease the strength of arteries (6) and to cause emphysema in the absence of smoking (7) in experimental animals. It will also cause a large drop in numbers of leukocytes (leukopenia and neutropenia) along with much lower resistance to infection (8). It produces anemia and failure of pigmentation (9). A copper deficiency causes cholesterol to be synthesized in much larger quantities (10). There is a chance that this is an adaptation for supplying cholesterol to line arteries in order to reduce their internal diameter and thus the hydrostatic pressure on their walls. Thus they would -be less liable to rupture when elastin is not cross linked enough. Apparently nonceruloplasmin copper in serum signals the increase (11). Lysyl Oxidase Cross Linking It is widely accepted that the reason for loss of elastin strength is that there is insufficient copper available for incorporation into the extracellular enzyme, lysyl oxidase (121, whidh cross links tropoelastin protein to form the rubbery elastin polymer. It does so by oxidizing the amine group on the lysine in the protein chain to aldehyde which spontaneously condenses with adjacent lysyl amines and aldehydes to make covalent bonds. The covalent bonds create the rubbery elasticity of elastin (13). Lysyl oxidase probably requires pyridoxal phosphate as well as copper (6). This same enzyme catalyzes cross linking of bone and ligament collagen also (141, but the failure to do so does not have the same disastrous effect on strength of tendons. Tendons have their strength preserved intact during copper deprivation (15). This may be because the collagen is more ordered and can thus make more effective use of its hydrogen bond cross links in tissue strong in one direction. This may be why tendons are seldom.ruptured in arthritis. Tendons have much fewer covalent cross links than elastin tissue (16 on p. 227). However, it can be perceived that these few cross links would be very useful, enabling the tendon to return to its original position after being stressed to a reasonable extent, and not to cold flow, as polymers held together only by hydrogen bonds do. This lesser loss of strength by collagen may be the evolutionary reason why copper deficient pigs make use of collagen to heal lesions in their arteries (17). The effect of low copper on collagen would be more obvious, perhaps, if figures were used which measured the permanent
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deformation under large steady stresses; copper deficient chick tendons have 70% the cross links as normal tendon (18). Transport
and Utilization
of Copper
Ceruloplasmin is an oxidation enzyme. It is very probably utilized as a transport protein as one of its functions. It probably transports copper from the liver where ceruloplasmin is synthesized to the target cells (19). The bile is used for excretion and it is virtually certain that bile cells obtain their copper from ceruloplasmin. Since it contains six (19 on p. 118) or eight (20) copper atoms it could conceivably transport copper in more than one way. The ceruloplasmin may have to be destroyed in order to give up all its copper. Ceruloplasmin half life is 130 hours (20). However, some of the copper is exchangeable under reducing conditions (21). It is likely that the liver is used as a storage and coordinating organ for copper. The target cells could include the cells which synthesize tropoelastin. If these cells synthesize lysyl oxidase, they probably must incorporate the copper inside the cell (22, on p. 175). Animals which are subjected to a copper deficiency have a low liver copper content (8). Their serum ceruloplasmin content is much lower than normal also (23). This would seem to indicate that the liver normally only synthesizes ceruloplasmin to the full extent when copper is adequate. Hypothesis to Explain Alteration of Copper Metabolism Rheumatoid arthritis is associated with a high ceruloplasmin and non-ceruloplasmin copper content in the serum compared to normal people (24). At the same time the liver copper content of arthritis is low (25, on p. 222). Liver absorbs injested copper very rapidly (21 on p. 4821, so this low content suggests that intake is not keeping pace with excretion, since liver is the only storage organ. The inappropriate copper requirement which I proposed in the introduction could be caused by an abnormally high ~,ysyl oxidase normally destruction of connecting tissue, has a half life of about 16 hours (26). The increased level of ceruloplasmin may be a response designed to bring more copper to cells synthesizing lysyl oxidase, which somehow send a signal indicating their need. Sorenson
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visualizes some such physiologically adaptive response, leading to the induction or synthesis of needed copper dependent enzymes (25 on p. 216). If ceruloplasmin is used to transport copper to lysyl oxidase generating cells, it cannot be the only way, or people who have Wilson's disease with its absence of ceruloplasmin could not survive (27). Hypothesis Linking Copper to the Immune System I feel that the most likely hypothesis is that a hormone system is utilized, which increases copper uptake by leukocytes (white cells) because some malfunction causes the body to falsely perceive an infectious attack. At the same time more ceruloplasmih is synthesized in response to the same hormone system in order to help implement the need for an increased copper supply. Less immediately urgent copper enzymes such as those incorporating iron into hemoglobin and lysyl oxidase are suppressed. Suppression of superoxide dismutase is probably especially important, since the superoxide which it removes is thought to be pa.?t of the immune system's defense. Lending support to this hypothesis is the circumstance that viral and bacterial diseases cause marked elevations of ceruloplasmin (9 on p. 66). Erythrocyte (red cell) copper is reduced, sufficiently so that whole blood shows no net rise in rheumatoid arthritis (25 on p. 217). Lower leukocyte count is one of the earliest and most consistent symptoms of a copper deficiency (28). It would seem that leukocytes are sensitive to copper (8) and that an enhanced copper supply would be extremely desirable during infection. It would be least dangerous for an immune hormone system to have an inhibitory effect on the immune system It a hormone system evolved which and its copper supply. worked by enhancing the immune system when under attack, a bacterial species could evolve which could consistently overwhelm the immune system simply by developing an enzyme which degrades steroids. Hypothesis Relating Copper to Potassium It could be that potassium exerts part of its protective effect (29) against rheumatoid arthritis by virtue of preventing potassium regulating hormones from acting as For the part of the signalling system postulated above. reason noted above, it would be safest to use a hormone It would be even more which declined during a deficiency.
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precise, ii the disease in question were a diarrhea, that the hormone declined under sodium deprivation as well. Such a hormone probably is deoxycorticosterone (DOC) (30). DOC is known to enhance activity of lysyl oxidase (31). Therefore DOC may be utilized as part of the perception that the body was under attack. The value of such a mechanism would possibly be reinforced by the desirability of strong blood vessels when high sodium intake tended to increase blood pressure. Microorganisms which poison the body's potassium metabolism rank among the most lethal of pathological organisms. If a disease exists which could be as lethal as cholera, for instance, and cannot be reliably or quickly detected by the body's immune system (if not now, then in the past), the mechanism suggested above would be of priceless value. Immune Hormone Control of Copper It would be highly desirable if hormones which normally inhibited the immune system such as cortisol and corticosterone were tied into such a system. If the excretory mechanism was not under the control of these postulated immune inhibiting hormones, the higher serum copper when they declined should cause enhanced excretions. If copper intake were marginal, as is the consistently less than 2 mg per day in free choice diets containing no liver (32), the decline in liver copper would be explained. This decline could make elastin repairs weak after potassium returned to normal until copper could also be built up. The characteristics that an immune inhibiting hormone should have in order to match the above hypothesis are: (1) inhibition by the hormone of copper utilization by leukocytes or ceruloplasmin production, (2) enhancement by it of other copper enzymes unessential to immunity, (3) reduced serum concentration during potassium deficiency, and (4) no effect on or inhibition of copper excretion. Corticosterone and cortisol are hormones which partly match such characteristics. They enhance lysyl oxidase activity (26). The synthesis of cortisol from 11 deoxycortisol precursor is inhibited by potassium restriction (33A) so that potassium does have an effect on this hormone. I have no information at present of how the above two hormones alter in the serum at low potassium intake, but it is possible that there is a direct effect of potassium intake. They have inhibitory effects on the immune system, but I have no information on copper utilization
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by leukocytes. The bile is utilized for copper excretion, since bile copper is not reabsorbed (33 on p. 245). In newly born rats, corticosterone increases excretion (33 on One would suspect this would be desirP. 234) of copper. able for avoiding loss during infection. Why it is not retained in adults is mysterious, but it is not in rats (33B, on p. 234). Therefore this excretory pattern is consistent with this hypothesis for adult rats. Perhaps the young rats can not tolerate extra copper excretion during infection because of their milk diet with its extremely low copper content, and gain their immunity to potassium wasting disease through something in the milk, and to some extent perhaps, through the low copper content itself. An increase of serum potassium content by one of the hormones of such a system would be very useful in dealing with a potassium wasting disease. The well-known movement of potassium out of the cells by cortisol (29) is therefore supportive of this hypothesis, and would assist survival during a severe potassium loss when the movement reversed if cortisol declines. Thus, during a potassium deficiency, lysyl oxidase and other copper enzymes would decline, the immune system would become more active, the nervous system would become more sensitive to pain, leukocyte copper enzyme activity should increase, and superoxide dismutase should decline. Collagen formation would not necessarily change much, since cortisol (33C) and DOC (33D) have opposite effects The other on degradation and synthesis of collagen. effects of DOC and cortisol on physiology should interfere with warding off a potassium wasting disease, but I cannot tie them in with certainty at this time. The chief disadvantage which I perceive to such a system, is that a pathogen could evolve which interferes with potassium excretion or causes a false potassium perception, in which case presumedly the immune system would be muted and mortality increased by this pathogen. Such a system would also be somewhat disadvantageous in case of a potassium deficiency from causes other than disease such as is the case in many modern diets,in dehydration, and as resulting from shock. The possibility also exists of compromise at other times when potassium is disrupted such as during shock, when movement of potassium into the blood by However, potassium cortisol can be life threatening. wasting diseases are both universal and common, and if the diarrheas are the diseases in question, would presumedly be the overriding consideration even to the present day.
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Consequences
of Copper Disruption
Whatever triggers an inappropriate requirement, if copper becomes insufficient to cross link the connecting tissue, these tissues will remain too weak even after the arthritis is relieved. Therefore, people who are on a marginal copper intake (as most people are) may be at considerable risk even after potassium has been brought to normal and most symptoms have disappeared. If copper is increased as well, the elastin tissue should heal faster than other connecting tissue, since it is probably degraded and regenerated fairly rapidly and constantly throughout life (34). Copper mechanisms other than inhibition of lysyl oxidase have been proposed to account for the effects of rheumatoid arthritis. A lack of superoxide dismutase has been proposed as permitting tissue damage by the superoxide (25 on p. 252). Superoxide is also believed to destroy synovial fluid viscosity !35). Changes in histamine activity, prostaglaudin synthesis, and lysosomal membrane stability have also been suggested as mechanisms (25 on p. 252). It is quite feasible, in fact likely, that more than one copper mechanism is involved in accounting for some of the symptoms of rheumatoid arthritis. It is also possible that the primary initiating regulation is the steroid system, and the effects that some corticosteroids have on this disease is suggestive that steroids do trigger some of the symptoms. In ankylosing spondilitis the ceruloplasmin is even higher than it is in rheumatoid arthritis although non-ceruloplasmin copper is lower than normal (24). However, copper supplements are only effective in ameliorating the disease in prolonged therapy (25 on p. 225). Ankylosinq spondilitis affects the sacral and ileal joints which are made of type I cartilage, not elastin (36). Lower turnover of collagen may explain why copper therapy seems ineffective. The lower serum nonceruloplasmin copper (24) may also be implicated in some way. Syndromes Proposed to be Associated with Arthritis Aneurisms and emphysema in the absence of smoking have already been certainly related to a copper deficiency in numerous animal experiments. The emphysema seems to have an elastin defect greater than can be explained by inadequate cross linking alone (7). In addition, it is possible that varicose veins, hemorrhoids, strokes caused by ruptured blood vessels, susceptibility to shaving cuts and bleeding gums, and slow healing back injuries may be involved in real and inappropriate copper deficiencies, since these all involve strength of elastin tissue. 339
Corroborative
Evidence
It should be possible to gain some circumstantial support for these proposals by determining the prevalence of the above diseases among copper miners or smelters. Men who work in Finnish copper mines are said to have very little rheumatism or susceptibility to infections (37 on p. 29). Women who start to work in copper mines have been noted to lose their anemia (25 on p. 223). People who use copper water pipes in soft water districts should also show a variation, since these pipes can impart as much as 0.8 mg per day in a society which receives only 1 or 2 milligrams per day. A weak correlation has been found with lung capacity (38). The incidence of injuries which result in no lost days among Utah underground copper miners is 15.1 per 200;OO0 man hours. The incidence of injuries which result in lostdays is 10.9, or a ratio of 1.4. The figures for all Utah noncopper metallic underground miners are 4.4 and 8.2 respectively, giving a ratio of 0.5 (39). These figures suggest that copper miners are noticeably tougher than other miners, since each injury less often results in lost days. Other copper states trend in the same direction for underground mines, open pit mines, and processing plants, whenever there are enough injuries to give meaningful data. If injuries like burns, electric shock, and eye injuries unrelated to toughness were removed from the figures, it is likely that the ratios would be even further apart. 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 (37 on p. 236).
CONCLUSIONS There should also be a strong negative correlation with the above syndromes for people who eat a lot of shellfish which are the richest sources of copper (9 on p. 92). People who eat a lot of liver, dog, and cat food should be in a similar position. Copper bracelets should be marginal because only small amounts are absorbed through the skin (40). If any reader has any formal or informal statistics relating ingestion of shellfish to any of the above diseases, the author would very much desire to hear of them. Milk is the poorest source (9 on p. 92). There may prove to be a small positive association with use of milk. This association may be enhanced in people who take zinc (41) or ascorbic acid supplements, for it has been found these substances retard copper absorption (42) or
340
exaggerate the effect of a deficiency (9 on p. 711, Eating sucrose or fructose instead of glurespectively. cose may also enhance elastin strength loss since rupture of the heart is 3.5 times more likely in copper deficient rats (43). It is possible that this is part (41) of the correlation of milk with cardiovascular disease as determined by Seely (44). Rheumatoid arthritis is commonly considered a benign disease and people often live a long time with it. However, they die eventually, and when they do, one of the most prevalent terminal events is ruptured blood vessels (45) * Males dying of aneurisms have one-fourth the normal tissue copper and two-thirds the liver copper (46) of normal. This would seem to indicate that, if an inappropriate copper requirement is one symptomatic aspect of rheumatoid arthritis, it is the most serious aspect, especially for men. If the residual reduction of total copper from the acute stages of the disease is having an adverse effect on immune cells as well as lysyl oxidase, there should be a greater susceptability to infection. Arthritics are more prone to infection than normal people (45). It is possible that a statistical association between rheumatoid arthritis and the diseases involving loss of strength of elastin in addition to aneurisms such as hemorrhoids, slow healing back injury, and susceptability to shaving cuts will be found. If this hypothesis can be validated, it may be that rheumatoid arthritis would become an example of a disease which can be produced by marginal amounts of one element, but only completely healed by adequate or more than adequate amounts of both it and another element, at least It is likely that with regard to some of the symptoms. the additional requirement can be easily met by diet. The current status of investigation makes it clear that potassium directly or indirectly affects or is affected by several steroid hormones which are also deeply involved with The effects of potassium the immune system or copper. regulating hormones on copper should be further investigated, for it is possible that copper requirements could be reduced for people who drink milk but won't eat shellfish. It would also be desirable that all arthritis I susresearch carefully monitor potassium and copper. pect that a search for steroid hormone regulators of copFurthermore, the per homeostatis would also be fruitful. search should not end upon discovery of an internal hormone regulator, since there is a good chance that there is more than one. The varied spectrum of symptoms ia the copper genetic diseases and ordinary deficiency would lend There also may be peripheral support to such a suspicion. hormones involved, and of course estrogen and cortisol are already clearly implicated, the first possibly to increase
341
copper in the liver of the fetus (32 on p. 239) to circumvent low milk copper and the second possibly to make copper more available to the immune system upon cortisol withdrawal. Every known hormone should be tested for its affect on copper, and the reverse. If the important symptoms of rheumatoid arthritis are materializing through the effects of low potassium on copper metabolism and are doing so as mediated by a spectrum of several hormones which control sodium, potassium, amino acids, proteins, energy pathways, pain, copper enzymes, and immune reactions of extraordinary complexity ramifying through the whole body, it is not surprising that, except for whole body potassium and status of copper, the symptoms are so varied and undefinitive. It should be possible to gain additional. evidence for the concept that mammals may really be organized around survival from potassium wasting infections by testing the cure time when each of the pertinent steroids are injected during such infections. Clues may also be apparent when free amino acids, glucose, or ceruloplasmin are artificiaily placed in the serum during There also should, one would suspect, be no infection. control over copper enzymes by electrolyte regulating hormones in salt water fish and perhaps in fresh water fish, but may be in some brackish water fish. A hormone which increased blood pressure with rising copper body content would have clear life saving advanIf it ever evolved, it would be sure to remain in tages. the genetic stream for the purpose of protecting the body It is against aneurisms and strokes during a deficiency. not likely that such an effect could be obtained by an inherent mechanism involving copper catalized neurotransmitters in the absence of a hormone, because production of dopamine and norepinephrine varies very much in different areas of the brain during a deficiency (47) as does receptor density (48) and so these neurotransmitters cannot be varying solely because of their dependence on the activity of the copper catalyzed enzyme utilized in their synthesis as related to serum copper contents (21). There is a hint of such a hormone in an experiment using a lysyl oxidase inhibitor, in which deoxycorticosterone hypertension was prevented by the inhibitor (49). It is not possible that the inhibitor is acting by changing only the thickness of the blood vessels, because the drop in pressure was too rapid, about one week. Until research throws light on the matter, it might be well to avoid massive doses of copper to relieve the low body content of arthritics as is sometimes done, Since
342
blood pressure may be permitted to rise before the elastin It is true that there are some has a chance to strengthen. built-in controls in the absorption process which protect The metallothionein in the the body against copper toxicity. intestinal cells is probably the regulator of absorption by inhibiting absorption (50). The absorption of copper with intake is only linear up to about 0.04 mg per 1000 grams of body weight in the rat (51) which would be about 3 mg total in humans. Also the activity of dopamine, B-monoxyqenase is only increased 25 % by free copper (52) in a body in which there are plenty of chelating molecules to tie up copper. Even so, it would be best to err on the side of caution,.and 6 or 7 mg per day of copper should prove to be enough to eventually relieve any low liver content (53 on PP. 135, 142). We don't know what hormones are involved and it is almost impossible to assess the implications of the inherent enzyme properties in the presence of a very complicated array of chelating agents outside the cell and a virtually unknown situation inside. These massive doses are only safely possible with the copper chelated to pharmaceutical and protein chelating agents, and the effects of the former on the body are virtually unknown. It is possible that diabetics have a narrow safe range (54). A statistical study of the relation of arthritis to blood pressure, of copper intake to blood pressure, and a search for the hormone which varies norepinephrine in the brain by copper might prove valuable. A search for steroids affecting copper or copper enzyme and pump poisons in foods and as emanating from pathological bacteria might also prove useful. Solenaceous vegetables, because some are known to cause a copper deficiency (55), and organisms which cause rheumatic heart disease may be good candidates for a start. Evolution of steroid synthesis by bacteria must be very difficult. I feel that recombinent experiments with copper, potassium, and immune controlling hormones should be banned, because if such immune inhibiting steroids could ever be produced by pathological organisms, the results could be very disadvantageous. That people are not getting optimum copper for whatever reason, low intake, interference, or inappropriateness, is likely, in view of the significantly beneficial results which are obtained with supplements and pharmaceuticals in such diverse areas as anemia, rheumatoid arthritis, ulcers, infection, cancer, and seizures (56). The prevalence of diseases in our society known to be caused in animals by copper deficits such as aneurisms, emphysema, and anemia is suggestive, and epidemiological studies are likely to be informative.
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47. Feller, D. J., & O'Dell, B. L. Dopamine and norepinephrine in discrete areas of copper deficient rat J. Neurochem. 34: 1259, 1980. brain. 48. Feller, D. J., O'Dell, B. L., & Bylund, D. B. Alterations in neurotransmitter receptor binding in discrete areas of the copper deficient rat brain. J. Neurochem. 38: 519, 1982. 49. Iwatsuki, K., Cardinale, G., Spector, S., & Udenfriend, S. Reduction of blood pressure and vascular collagen Proc. in hypertensive rats by 6-aminopropionitrile. Natl. Acad. Sci. USA 74: 360, 1977. 50. Cohen, D. I., Illowsky, B., & Linder, M. C. Altered copper absorption in tumor bearing and estrogen treated rats. Am. J. Physiol. 236: E 309, 1979. 51. Marceau, N., Aspin, N., 6 Sass-Kortsak, tion of copper-64 from gastrointestinal rat. Am. J. Physiol. 218: 377, 1970.
A. The absorptract of the
52. Skotland, T., & Jones, T. Enzyme-bound copper of dopemine beta monooxygenase activation of the holoenzyme by added copper and uncoupling of electron transfer. J. Inorg. Biochem. 18: 11, 1983. 53. Osterberg, Pharmacol.
R. Physiology and pharmacology Ther. 9: 121, 1980.
of copper.
54. Failla, M. L., & Kiser, R. A. Hepatic and renal metabolism of copper and zinc in the diabetic rat. Am. J. Physiol. 244: E 115. 55. Childers, N. F., & Russo, G. M. Nightshades and health (in Chapter 6, p. 127). Somerset Press, Somerville, N. J. 56. Sorrenson, J. R. V. The anti-inflammatory activities of copper complexes, p. 77. In Metal ions in biological systems, Vol. 14 (M. Sigel, Ed.). Marcel Dekker, Inc., New York, 1982.
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COPPER RESPONSE TO RHEUMATOID ARTHRITIS C. E. Weber, 141 Mt. Horeb Road, Warren, N. J. 07060 ABSTRACT Rheumatoid arthritis can be divided into two syndromes, one a potassium deficiency, the other an inappropriate copper requirement seriously affecting the elastin tissues through reduced lysyl oxidase cross linking. The malfunction in copper may arise from the steroids which regulate potassium, which reduces those steroids, and through that, increases the copper response to the needs It is a mechanism which may have of the immune system. evolved to help fight potassium wasting infections. INTRODUCTION I have previously proposed that a considerable part of the degeneration of mesenchyme tissue in our society is due to losses of potassium in our food supply, and that in particular rheumatoid arthritis may be a chronic potassium deficiency (1) which causes alterations inside the cell of free amino acid (2), interference by sodium with enzymes inside the cell as a result of the increased sodium there (3), alterations of the potassium-sodium regulating hormone patterns which then have indirect effects on other physiological processes, by other consequences of the deficiency, or some combination of these. I would now like to propose, given that the above view is accepted as possible, that rheumatoid arthritis may be split up into two syndromes, one primarily a potassium deficiency, and the other, while triggered by a potassium deficiency, perpetuated by a concomitant disruption of the copper metabolism of the body, and most seriously affecting tissue composed of elastin. Tissues high in elastin are the spinal discs, the blood vessels, the lungs, and the skin (4) of vertebrate animals higher than jawless fish (5). Thus people subjected to a potassium deficiency are suggested to have an inappropriately high requirement for copper. 333
DISCUSSION Effects of Copper Deficiency An actual copper deficiency is already known to drastically decrease the strength of arteries (6) and to cause emphysema in the absence of smoking (7) in experimental animals. It will also cause a large drop in numbers of leukocytes (leukopenia and neutropenia) along with much lower resistance to infection (8). It produces anemia and failure of pigmentation (9). A copper deficiency causes cholesterol to be synthesized in much larger quantities (10). There is a chance that this is an adaptation for supplying cholesterol to line arteries in order to reduce their internal diameter and thus the hydrostatic pressure on their walls. Thus they would -be less liable to rupture when elastin is not cross linked enough. Apparently nonceruloplasmin copper in serum signals the increase (11). Lysyl Oxidase Cross Linking It is widely accepted that the reason for loss of elastin strength is that there is insufficient copper available for incorporation into the extracellular enzyme, lysyl oxidase (121, whidh cross links tropoelastin protein to form the rubbery elastin polymer. It does so by oxidizing the amine group on the lysine in the protein chain to aldehyde which spontaneously condenses with adjacent lysyl amines and aldehydes to make covalent bonds. The covalent bonds create the rubbery elasticity of elastin (13). Lysyl oxidase probably requires pyridoxal phosphate as well as copper (6). This same enzyme catalyzes cross linking of bone and ligament collagen also (141, but the failure to do so does not have the same disastrous effect on strength of tendons. Tendons have their strength preserved intact during copper deprivation (15). This may be because the collagen is more ordered and can thus make more effective use of its hydrogen bond cross links in tissue strong in one direction. This may be why tendons are seldom.ruptured in arthritis. Tendons have much fewer covalent cross links than elastin tissue (16 on p. 227). However, it can be perceived that these few cross links would be very useful, enabling the tendon to return to its original position after being stressed to a reasonable extent, and not to cold flow, as polymers held together only by hydrogen bonds do. This lesser loss of strength by collagen may be the evolutionary reason why copper deficient pigs make use of collagen to heal lesions in their arteries (17). The effect of low copper on collagen would be more obvious, perhaps, if figures were used which measured the permanent
334
deformation under large steady stresses; copper deficient chick tendons have 70% the cross links as normal tendon (18). Transport
and Utilization
of Copper
Ceruloplasmin is an oxidation enzyme. It is very probably utilized as a transport protein as one of its functions. It probably transports copper from the liver where ceruloplasmin is synthesized to the target cells (19). The bile is used for excretion and it is virtually certain that bile cells obtain their copper from ceruloplasmin. Since it contains six (19 on p. 118) or eight (20) copper atoms it could conceivably transport copper in more than one way. The ceruloplasmin may have to be destroyed in order to give up all its copper. Ceruloplasmin half life is 130 hours (20). However, some of the copper is exchangeable under reducing conditions (21). It is likely that the liver is used as a storage and coordinating organ for copper. The target cells could include the cells which synthesize tropoelastin. If these cells synthesize lysyl oxidase, they probably must incorporate the copper inside the cell (22, on p. 175). Animals which are subjected to a copper deficiency have a low liver copper content (8). Their serum ceruloplasmin content is much lower than normal also (23). This would seem to indicate that the liver normally only synthesizes ceruloplasmin to the full extent when copper is adequate. Hypothesis to Explain Alteration of Copper Metabolism Rheumatoid arthritis is associated with a high ceruloplasmin and non-ceruloplasmin copper content in the serum compared to normal people (24). At the same time the liver copper content of arthritis is low (25, on p. 222). Liver absorbs injested copper very rapidly (21 on p. 4821, so this low content suggests that intake is not keeping pace with excretion, since liver is the only storage organ. The inappropriate copper requirement which I proposed in the introduction could be caused by an abnormally high ~,ysyl oxidase normally destruction of connecting tissue, has a half life of about 16 hours (26). The increased level of ceruloplasmin may be a response designed to bring more copper to cells synthesizing lysyl oxidase, which somehow send a signal indicating their need. Sorenson
335
visualizes some such physiologically adaptive response, leading to the induction or synthesis of needed copper dependent enzymes (25 on p. 216). If ceruloplasmin is used to transport copper to lysyl oxidase generating cells, it cannot be the only way, or people who have Wilson's disease with its absence of ceruloplasmin could not survive (27). Hypothesis Linking Copper to the Immune System I feel that the most likely hypothesis is that a hormone system is utilized, which increases copper uptake by leukocytes (white cells) because some malfunction causes the body to falsely perceive an infectious attack. At the same time more ceruloplasmih is synthesized in response to the same hormone system in order to help implement the need for an increased copper supply. Less immediately urgent copper enzymes such as those incorporating iron into hemoglobin and lysyl oxidase are suppressed. Suppression of superoxide dismutase is probably especially important, since the superoxide which it removes is thought to be pa.?t of the immune system's defense. Lending support to this hypothesis is the circumstance that viral and bacterial diseases cause marked elevations of ceruloplasmin (9 on p. 66). Erythrocyte (red cell) copper is reduced, sufficiently so that whole blood shows no net rise in rheumatoid arthritis (25 on p. 217). Lower leukocyte count is one of the earliest and most consistent symptoms of a copper deficiency (28). It would seem that leukocytes are sensitive to copper (8) and that an enhanced copper supply would be extremely desirable during infection. It would be least dangerous for an immune hormone system to have an inhibitory effect on the immune system It a hormone system evolved which and its copper supply. worked by enhancing the immune system when under attack, a bacterial species could evolve which could consistently overwhelm the immune system simply by developing an enzyme which degrades steroids. Hypothesis Relating Copper to Potassium It could be that potassium exerts part of its protective effect (29) against rheumatoid arthritis by virtue of preventing potassium regulating hormones from acting as For the part of the signalling system postulated above. reason noted above, it would be safest to use a hormone It would be even more which declined during a deficiency.
336
precise, ii the disease in question were a diarrhea, that the hormone declined under sodium deprivation as well. Such a hormone probably is deoxycorticosterone (DOC) (30). DOC is known to enhance activity of lysyl oxidase (31). Therefore DOC may be utilized as part of the perception that the body was under attack. The value of such a mechanism would possibly be reinforced by the desirability of strong blood vessels when high sodium intake tended to increase blood pressure. Microorganisms which poison the body's potassium metabolism rank among the most lethal of pathological organisms. If a disease exists which could be as lethal as cholera, for instance, and cannot be reliably or quickly detected by the body's immune system (if not now, then in the past), the mechanism suggested above would be of priceless value. Immune Hormone Control of Copper It would be highly desirable if hormones which normally inhibited the immune system such as cortisol and corticosterone were tied into such a system. If the excretory mechanism was not under the control of these postulated immune inhibiting hormones, the higher serum copper when they declined should cause enhanced excretions. If copper intake were marginal, as is the consistently less than 2 mg per day in free choice diets containing no liver (32), the decline in liver copper would be explained. This decline could make elastin repairs weak after potassium returned to normal until copper could also be built up. The characteristics that an immune inhibiting hormone should have in order to match the above hypothesis are: (1) inhibition by the hormone of copper utilization by leukocytes or ceruloplasmin production, (2) enhancement by it of other copper enzymes unessential to immunity, (3) reduced serum concentration during potassium deficiency, and (4) no effect on or inhibition of copper excretion. Corticosterone and cortisol are hormones which partly match such characteristics. They enhance lysyl oxidase activity (26). The synthesis of cortisol from 11 deoxycortisol precursor is inhibited by potassium restriction (33A) so that potassium does have an effect on this hormone. I have no information at present of how the above two hormones alter in the serum at low potassium intake, but it is possible that there is a direct effect of potassium intake. They have inhibitory effects on the immune system, but I have no information on copper utilization
337
by leukocytes. The bile is utilized for copper excretion, since bile copper is not reabsorbed (33 on p. 245). In newly born rats, corticosterone increases excretion (33 on One would suspect this would be desirP. 234) of copper. able for avoiding loss during infection. Why it is not retained in adults is mysterious, but it is not in rats (33B, on p. 234). Therefore this excretory pattern is consistent with this hypothesis for adult rats. Perhaps the young rats can not tolerate extra copper excretion during infection because of their milk diet with its extremely low copper content, and gain their immunity to potassium wasting disease through something in the milk, and to some extent perhaps, through the low copper content itself. An increase of serum potassium content by one of the hormones of such a system would be very useful in dealing with a potassium wasting disease. The well-known movement of potassium out of the cells by cortisol (29) is therefore supportive of this hypothesis, and would assist survival during a severe potassium loss when the movement reversed if cortisol declines. Thus, during a potassium deficiency, lysyl oxidase and other copper enzymes would decline, the immune system would become more active, the nervous system would become more sensitive to pain, leukocyte copper enzyme activity should increase, and superoxide dismutase should decline. Collagen formation would not necessarily change much, since cortisol (33C) and DOC (33D) have opposite effects The other on degradation and synthesis of collagen. effects of DOC and cortisol on physiology should interfere with warding off a potassium wasting disease, but I cannot tie them in with certainty at this time. The chief disadvantage which I perceive to such a system, is that a pathogen could evolve which interferes with potassium excretion or causes a false potassium perception, in which case presumedly the immune system would be muted and mortality increased by this pathogen. Such a system would also be somewhat disadvantageous in case of a potassium deficiency from causes other than disease such as is the case in many modern diets,in dehydration, and as resulting from shock. The possibility also exists of compromise at other times when potassium is disrupted such as during shock, when movement of potassium into the blood by However, potassium cortisol can be life threatening. wasting diseases are both universal and common, and if the diarrheas are the diseases in question, would presumedly be the overriding consideration even to the present day.
338
Consequences
of Copper Disruption
Whatever triggers an inappropriate requirement, if copper becomes insufficient to cross link the connecting tissue, these tissues will remain too weak even after the arthritis is relieved. Therefore, people who are on a marginal copper intake (as most people are) may be at considerable risk even after potassium has been brought to normal and most symptoms have disappeared. If copper is increased as well, the elastin tissue should heal faster than other connecting tissue, since it is probably degraded and regenerated fairly rapidly and constantly throughout life (34). Copper mechanisms other than inhibition of lysyl oxidase have been proposed to account for the effects of rheumatoid arthritis. A lack of superoxide dismutase has been proposed as permitting tissue damage by the superoxide (25 on p. 252). Superoxide is also believed to destroy synovial fluid viscosity !35). Changes in histamine activity, prostaglaudin synthesis, and lysosomal membrane stability have also been suggested as mechanisms (25 on p. 252). It is quite feasible, in fact likely, that more than one copper mechanism is involved in accounting for some of the symptoms of rheumatoid arthritis. It is also possible that the primary initiating regulation is the steroid system, and the effects that some corticosteroids have on this disease is suggestive that steroids do trigger some of the symptoms. In ankylosing spondilitis the ceruloplasmin is even higher than it is in rheumatoid arthritis although non-ceruloplasmin copper is lower than normal (24). However, copper supplements are only effective in ameliorating the disease in prolonged therapy (25 on p. 225). Ankylosinq spondilitis affects the sacral and ileal joints which are made of type I cartilage, not elastin (36). Lower turnover of collagen may explain why copper therapy seems ineffective. The lower serum nonceruloplasmin copper (24) may also be implicated in some way. Syndromes Proposed to be Associated with Arthritis Aneurisms and emphysema in the absence of smoking have already been certainly related to a copper deficiency in numerous animal experiments. The emphysema seems to have an elastin defect greater than can be explained by inadequate cross linking alone (7). In addition, it is possible that varicose veins, hemorrhoids, strokes caused by ruptured blood vessels, susceptibility to shaving cuts and bleeding gums, and slow healing back injuries may be involved in real and inappropriate copper deficiencies, since these all involve strength of elastin tissue. 339
Corroborative
Evidence
It should be possible to gain some circumstantial support for these proposals by determining the prevalence of the above diseases among copper miners or smelters. Men who work in Finnish copper mines are said to have very little rheumatism or susceptibility to infections (37 on p. 29). Women who start to work in copper mines have been noted to lose their anemia (25 on p. 223). People who use copper water pipes in soft water districts should also show a variation, since these pipes can impart as much as 0.8 mg per day in a society which receives only 1 or 2 milligrams per day. A weak correlation has been found with lung capacity (38). The incidence of injuries which result in no lost days among Utah underground copper miners is 15.1 per 200;OO0 man hours. The incidence of injuries which result in lostdays is 10.9, or a ratio of 1.4. The figures for all Utah noncopper metallic underground miners are 4.4 and 8.2 respectively, giving a ratio of 0.5 (39). These figures suggest that copper miners are noticeably tougher than other miners, since each injury less often results in lost days. Other copper states trend in the same direction for underground mines, open pit mines, and processing plants, whenever there are enough injuries to give meaningful data. If injuries like burns, electric shock, and eye injuries unrelated to toughness were removed from the figures, it is likely that the ratios would be even further apart. 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 (37 on p. 236).
CONCLUSIONS There should also be a strong negative correlation with the above syndromes for people who eat a lot of shellfish which are the richest sources of copper (9 on p. 92). People who eat a lot of liver, dog, and cat food should be in a similar position. Copper bracelets should be marginal because only small amounts are absorbed through the skin (40). If any reader has any formal or informal statistics relating ingestion of shellfish to any of the above diseases, the author would very much desire to hear of them. Milk is the poorest source (9 on p. 92). There may prove to be a small positive association with use of milk. This association may be enhanced in people who take zinc (41) or ascorbic acid supplements, for it has been found these substances retard copper absorption (42) or
340
exaggerate the effect of a deficiency (9 on p. 711, Eating sucrose or fructose instead of glurespectively. cose may also enhance elastin strength loss since rupture of the heart is 3.5 times more likely in copper deficient rats (43). It is possible that this is part (41) of the correlation of milk with cardiovascular disease as determined by Seely (44). Rheumatoid arthritis is commonly considered a benign disease and people often live a long time with it. However, they die eventually, and when they do, one of the most prevalent terminal events is ruptured blood vessels (45) * Males dying of aneurisms have one-fourth the normal tissue copper and two-thirds the liver copper (46) of normal. This would seem to indicate that, if an inappropriate copper requirement is one symptomatic aspect of rheumatoid arthritis, it is the most serious aspect, especially for men. If the residual reduction of total copper from the acute stages of the disease is having an adverse effect on immune cells as well as lysyl oxidase, there should be a greater susceptability to infection. Arthritics are more prone to infection than normal people (45). It is possible that a statistical association between rheumatoid arthritis and the diseases involving loss of strength of elastin in addition to aneurisms such as hemorrhoids, slow healing back injury, and susceptability to shaving cuts will be found. If this hypothesis can be validated, it may be that rheumatoid arthritis would become an example of a disease which can be produced by marginal amounts of one element, but only completely healed by adequate or more than adequate amounts of both it and another element, at least It is likely that with regard to some of the symptoms. the additional requirement can be easily met by diet. The current status of investigation makes it clear that potassium directly or indirectly affects or is affected by several steroid hormones which are also deeply involved with The effects of potassium the immune system or copper. regulating hormones on copper should be further investigated, for it is possible that copper requirements could be reduced for people who drink milk but won't eat shellfish. It would also be desirable that all arthritis I susresearch carefully monitor potassium and copper. pect that a search for steroid hormone regulators of copFurthermore, the per homeostatis would also be fruitful. search should not end upon discovery of an internal hormone regulator, since there is a good chance that there is more than one. The varied spectrum of symptoms ia the copper genetic diseases and ordinary deficiency would lend There also may be peripheral support to such a suspicion. hormones involved, and of course estrogen and cortisol are already clearly implicated, the first possibly to increase
341
copper in the liver of the fetus (32 on p. 239) to circumvent low milk copper and the second possibly to make copper more available to the immune system upon cortisol withdrawal. Every known hormone should be tested for its affect on copper, and the reverse. If the important symptoms of rheumatoid arthritis are materializing through the effects of low potassium on copper metabolism and are doing so as mediated by a spectrum of several hormones which control sodium, potassium, amino acids, proteins, energy pathways, pain, copper enzymes, and immune reactions of extraordinary complexity ramifying through the whole body, it is not surprising that, except for whole body potassium and status of copper, the symptoms are so varied and undefinitive. It should be possible to gain additional. evidence for the concept that mammals may really be organized around survival from potassium wasting infections by testing the cure time when each of the pertinent steroids are injected during such infections. Clues may also be apparent when free amino acids, glucose, or ceruloplasmin are artificiaily placed in the serum during There also should, one would suspect, be no infection. control over copper enzymes by electrolyte regulating hormones in salt water fish and perhaps in fresh water fish, but may be in some brackish water fish. A hormone which increased blood pressure with rising copper body content would have clear life saving advanIf it ever evolved, it would be sure to remain in tages. the genetic stream for the purpose of protecting the body It is against aneurisms and strokes during a deficiency. not likely that such an effect could be obtained by an inherent mechanism involving copper catalized neurotransmitters in the absence of a hormone, because production of dopamine and norepinephrine varies very much in different areas of the brain during a deficiency (47) as does receptor density (48) and so these neurotransmitters cannot be varying solely because of their dependence on the activity of the copper catalyzed enzyme utilized in their synthesis as related to serum copper contents (21). There is a hint of such a hormone in an experiment using a lysyl oxidase inhibitor, in which deoxycorticosterone hypertension was prevented by the inhibitor (49). It is not possible that the inhibitor is acting by changing only the thickness of the blood vessels, because the drop in pressure was too rapid, about one week. Until research throws light on the matter, it might be well to avoid massive doses of copper to relieve the low body content of arthritics as is sometimes done, Since
342
blood pressure may be permitted to rise before the elastin It is true that there are some has a chance to strengthen. built-in controls in the absorption process which protect The metallothionein in the the body against copper toxicity. intestinal cells is probably the regulator of absorption by inhibiting absorption (50). The absorption of copper with intake is only linear up to about 0.04 mg per 1000 grams of body weight in the rat (51) which would be about 3 mg total in humans. Also the activity of dopamine, B-monoxyqenase is only increased 25 % by free copper (52) in a body in which there are plenty of chelating molecules to tie up copper. Even so, it would be best to err on the side of caution,.and 6 or 7 mg per day of copper should prove to be enough to eventually relieve any low liver content (53 on PP. 135, 142). We don't know what hormones are involved and it is almost impossible to assess the implications of the inherent enzyme properties in the presence of a very complicated array of chelating agents outside the cell and a virtually unknown situation inside. These massive doses are only safely possible with the copper chelated to pharmaceutical and protein chelating agents, and the effects of the former on the body are virtually unknown. It is possible that diabetics have a narrow safe range (54). A statistical study of the relation of arthritis to blood pressure, of copper intake to blood pressure, and a search for the hormone which varies norepinephrine in the brain by copper might prove valuable. A search for steroids affecting copper or copper enzyme and pump poisons in foods and as emanating from pathological bacteria might also prove useful. Solenaceous vegetables, because some are known to cause a copper deficiency (55), and organisms which cause rheumatic heart disease may be good candidates for a start. Evolution of steroid synthesis by bacteria must be very difficult. I feel that recombinent experiments with copper, potassium, and immune controlling hormones should be banned, because if such immune inhibiting steroids could ever be produced by pathological organisms, the results could be very disadvantageous. That people are not getting optimum copper for whatever reason, low intake, interference, or inappropriateness, is likely, in view of the significantly beneficial results which are obtained with supplements and pharmaceuticals in such diverse areas as anemia, rheumatoid arthritis, ulcers, infection, cancer, and seizures (56). The prevalence of diseases in our society known to be caused in animals by copper deficits such as aneurisms, emphysema, and anemia is suggestive, and epidemiological studies are likely to be informative.
343
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