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The Nutritional Relationships of Copper David L

The Nutritional Relationships of Copper David L

The Nutritional Relationships of David L. Watts, D.C., Ph.D., F.A.C.E.P.1

Introduction milligrams percent. When sampled properly, The copper was shown to be an TMA can provide a good index of nutritional essential nutrient for hemoglobin synthesis in copper status13 14 and relationship to other animals in 1928.1 The therapeutic use of copper synergistic and antagonistic trace elements. and its requirements in humans was later reported by Mills and others.2 3 Copper has since been Conditions Associated with Copper Imbalance found to be a constituent of many important One of the earliest conditions found to be including , associated with is iron (cytoplasm), deficiency , which could only be corrected , B-hydroxylase, lysyl with copper supplementation. Copper deficiency oxidase, , and monoamine oxidase. impairs iron absorption, reduces synthesis, The copper content of a healthy adult has been and increases iron accumulation in storage reported to be approximately eighty milligrams.4 tissues. These processes are dependent upon The highest level of copper is found in the copper through the effects of the copper 15 and , followed by the heart, , Ceruloplasmin. A chronic copper deficiency pancreas, spleen, lungs, , and muscle. can result in , a condition characterized by an increase in iron accumulation Copper Evaluation Through Tissue Mineral in body tissues due to an impairment in the Analysis (TMA) of Human reutilization of hemoglobin iron. Hemosiderosis TMA of hair has proven to be a good method is known to occur in malignancies, inflammatory for assessing nutritional copper status. Recently disorders, and rheumatoid arthritis.16 Medeiros5 reported positive correlations of TMA copper levels in animals based upon three levels Arthritis and Copper of dietary copper intake. This study supports the Iron accumulation in the joints due to copper feasibility for the use of TMA in detecting deficiency can be a major contributor to changes in the diet of copper and other . rheumatoid arthritis.17 Studies reported by Medeiros' study also confirms the findings of Kishore et al illustrated the relationship of copper earlier investigators, which also support the deficiency and arthritis in animal studies. validity of using TMA in assessing copper Adjuvant arthritis was more severe in animals on status.6 7 8 9 Ikeda, et al10 found that the hair a copper deficient diet, and the tissue iron levels concentration of copper correlates with blood were found to be over four hundred percent of hemoglobin levels in children. Hair copper normal.18 It has been stated that rheumatoid concentrations have been found to reflect liver arthritis has become prevalent within the past copper concentration.11 A study reporting the century due to industrialization, i.e. the increased mineral content of maternal and neonate hair production and use of copper antagonists such as revealed an excellent correlation of metals cadmium, , lead, etc. Rainsford hypothesized including copper and establishes a basis for the that the low incidence of rheumatoid arthritis in use of TMA in monitoring the nutritional mineral Europe during pre-industrial times may have status of both the mother and fetus.12 been due to the protection by copper commonly The ideal TMA level of copper established by used in cooking and eating utensils of the Trace Elements, Inc. is 2.5 period.19TMA studies of patients with rheuma- Trace Elements, Inc., P.O. Box 514, Addison, Texas 75001. 99 Journal of Orthomolecular Medicine Vol. 4, No. 2, 1989 toid arthritis almost always reveal a low tissue while elevated tissue copper is found with copper level. The more chronic cases show high chronic viral infections. Presently it is not clear iron/copper ratios. An elevated tissue iron/copper whether infectious conditions cause the TMA ratio can also indicate a chronic bacterial copper abnormalities, but it is strongly suspected infection. Rheumatoid arthritis can be secondary that copper status can predispose an individual to to and sometimes caused by an infectious agent either a viral or bacterial infection. The indication resulting in copper depletion or a disturbance in that copper can be a causative factor in the copper balance. It is also well known that incidence of viral or bacterial infections is spontaneous remission of rheumatoid arthritis reflected in studies by Luster and co-workers. occurs in conditions associated with increased They report that estrogen has an enhancing or copper retention such as pregnancy and biliary suppressing effect upon the immune system.28 obstruction.20 An Australian study (Walker, et al) Thus the relationship between copper and demonstrated improvement of symptoms of estrogen cannot be overlooked. It has also been rheumatoid arthritis by absorption of copper reported that women have an increased through the from the wearing of copper susceptibility to viral infections prior to bracelets. menstruation (at which time estrogen and copper TMA studies clearly show that individuals levels are high) and an increased tendency toward with some forms of rheumatoid arthritis, have bacterial infections directly following increased copper requirements. However, TMA menstruation (at which time estrogen and copper studies have revealed that tissue copper levels are levels fall). Generally speaking, we find that above normal in patients with osteoarthritis. This copper deficiency causes a disturbance in cellular can be explained by the calcium-copper- immunity, while copper excess causes a D relationship discussed later. disturbance in humoral immunity. This information indicates that any factor that Infections — Bacterial antagonizes copper retention can be considered as Infections are known to affect mineral having anti-viral properties. Those that are 21 metabolism and requirements. During a synergistic such as vitamin D, B1, B12, and B10, bacterial infection iron is sequestered into storage which enhance copper retention, can be consi- tissue (reticuloendothelial-bone-spleen-liver). dered as having anti-bacterial properties (see This is a normal response since bacteria require figure 1 and 2). As an example, vitamin A, which iron in order to proliferate; therefore, the body is considered to be an anti-infectious vitamin, can removes this nutrient source from the serum.22 23 specifically be categorized as anti-viral. This is Secondarily, serum copper rises due to its also true of vitamin C and zinc. However, zinc, removal from storage tissues thereby improving vitamin C, and vitamin A are mutually the capability to mount an attack and overcome antagonistic to copper; if taken in excessively the invading organism. The opposite is seen in high dosages by individuals with a copper the tissue mineral concentrations. In chronic deficiency, they can actually promote infectious infectious states, the tissue iron increases while processes — especially those of bacterial origin. the tissue copper decreases. This tissue mineral TMA studies have shown that chronic pattern (elevated iron/copper ratio), is strongly candidiasis is frequently associated with copper indicative of a chronic infection. The most excess. Therefore, minerals and common source of chronic infections have been antagonistic to copper can be considered to have dental abscesses often present for years without anti-fungal and anti-yeast properties (see figure 1 the patient's knowledge. and 2).

Infections — Viral Malignancies and Copper Viral infections produce an anabolic response, Low TMA copper levels are also frequently while bacterial infections produce a catabolic found in some types of malignancies, response. Tissue copper deficiency is commonly seen with chronic bacterial infections,24 25 26 27 100 The Nutritional Relationships of Copper most of which are of the catabolic or highly infarcts. Klevay has reported that a relative metastatic type. High tissue iron/ copper may or copper deficiency may contribute to ischemic may not be present depending upon the type of heart disease.36 A deficiency of copper relative malignancy. There have been reports that tissue to zinc produces a decrease in HDL (high iron accumulation is found in tissues and lymph density lipoproteins) and an increase in LDL nodes with Hodgkins disease.29 TMA research is (low density lipoproteins).37 revealing the increased requirements for copper in Copper excess may also contribute to some malignancy conditions. The necessity for cardiovascular problems from hypercho- copper is obvious due to its role in respiratory lesterolemia, which is associated with hy- enzyme systems and its participation in superoxide pothyroidism. Copper in excess has adverse dismutase activity, which helps protect the cell effects upon thyroid activity and zinc status. from damage from oxygen toxicity. Cytochrome c oxidase, the terminal oxidase in the electron Orthopedic Disturbances and Copper transport chain, is copper dependent. A reduction Imbalance in cytochrome c oxidase activity results in the As mentioned previously, adequate copper is mitochondria becoming enlarged and deformed required for the normal production and integrity with advanced copper deficiency. Animal studies of and , which are components have confirmed the effects of some copper of ligaments and the nucleus pulposus of the compounds as an anti-neoplastic agent. The intervertebral disc. Other minerals and vitamins addition of copper decreased tumor growth, are also involved in collagen and elastin decreased metastasis, and increased survival of synthesis. As an example, vitamin C is required animals with certain types of neoplasms.30 Several for the hydroxylation of proline to hydroxy- reports indicate that serum copper levels rise with proline, which forms chains of tropollo-gen. the severity of some malignancies and return to Vitamin C, iron, and manganese are all normal with remission.31 32 involved in the conversion of lysine to hydroxylysine. Manganese is required for the activity of glactosyltransferase and One of the early signs of copper deficiency is glucosyltransferase, and zinc is involved in osteoporosis.33 34 A number of enzymes involved in protein synthesis. Each of these nutrients is collagen synthesis and cross-linking of the organic affected by copper (see figure 1 and 2). matrix of bone require copper. Bone changes in Davies38 reported studies of lathyrism, which copper deficiency include a loss of trabecular apparently produces copper deficiency resulting formation with thinning of the cortex. It is common in structural skeletal abnormalities including to find low tissue levels of calcium in conjunction scoliosis, spondylosis, and kyphoscoliosis. with low tissue levels of copper on TMA studies. Excessive tissue copper is also associated Through TMA studies, osteoporosis has been with structural skeletal defects. Pratt and linked with both copper deficiency and copper Phippen reported findings in which elevated excess and has been categorized as type I or type II hair copper occurred with idiopathic scoliosis.39 osteoporosis respectively.35 Copper and estrogen probably act synergistically in contributing to scoliosis. Cardiovascular During pregnancy, estrogen is known to The structure and integrity of the vascular produce relaxation of the pelvic ligaments at the system is intimately related to copper. An adequate sacroiliac joints and symphysis pubis40 in amount of copper is required for the production of preparation for the birthing process. The the enzyme , which is involved in the resulting elasticity allows less resistance for the quality and quantity of elastin formation and fetus when passing through the birth canal. The collagen cross-linking. Therefore, copper effect of estrogen is, of course, not confined deficiency is related to vascular defects such as only to the pelvis. By antagonizing or , heart enlargement, heart failure, and producing 101 Journal of Orthomolecular Medicine Vol. 4, No. 2, 1989 deficiencies of other nutrients (see figure 1 and conditions commonly seen with low tissue copper 2), copper elevation also contributes to levels. These include gout, hypertension, ligamentous laxity throughout the skeletal antibiotic sensitivity, hyperactivity, structure. Therefore, any factor that contributes to hyperglycemia, emotional disturbances (manic increased copper retention such as, oral disorders), type I insomnia, and increased contraceptive and IUD use, pregnancy, sympathetic neuroendocrine activity. cholestasis, etc., can result in structural skeletal instability and ligamentous laxity. Factors Contributing to Copper Deficiency

Neurological Minerals Copper deficiency is known to affect the Figure 1 shows the minerals that are central . Reports of animal studies antagonistic to copper.49 50 Prolonged high intake have shown defects in myelination with copper of these elements, singularly or in combination, deficiency.41 Observation of TMA studies has can produce a copper deficiency, especially if the shown low tissue copper levels in multiple nutritional or tissue copper status is marginal. The sclerosis patients. Douglas, et al, confirmed this nutritional minerals shown in figure 1 can be used finding in their report, in which they found in the treatment of . Copper significant differences in hair copper levels in supplementation, however, can aid in decreasing forty multiple sclerosis patients compared to the toxic effects of some heavy metals as well as forty-two controls.42 Similar observations have inhibiting their absorption. A report by Fields, et been seen on TMA patterns of patients with al, revealed that copper is adversely affected by Parkinson's disease. Information from animal the consumption of fructose. Copper deficiency studies strongly suggests that copper deficiency was exacerbated in animals fed fructose, and can be a factor in Parkinson's disease in humans, contributed to fatty degeneration of the liver. since dopamine levels were found low in both copper deficient animals and patients with Vitamins Parkinson's.43 Vitamins that are considered antagonistic to , also known as Steely Hair copper are shown in figure 2. Excessive intake of disease is an inherited inborn error of copper any one or combination of these vitamins can metabolism in infants. Infants with this condition contribute to or exacerbate an existing copper manifest most of the conditions described with deficiency. The opposite may also occur: excess copper deficiency. This condition is usually fatal copper intake or retention may produce a defi- with a life expectancy of about two years. ciency of any one or combination of these Diagnosis is difficult since these children appear vitamins or increase their requirements. relatively normal after birth and may not manifest It is interesting to note a similarity of copper severe symptoms for several weeks or months.44 deficiency to vitamin C deficiency. Many This condition emphasizes the need for changes as a result of copper deficiency can be nutritional monitoring of the fetus through the described as "-like". Indeed many mother. Baumslag has stated the practicality of symptoms of copper and vitamin C deficiency are using TMA for this purpose. Copper similar and can be difficult to distinguish. High supplementation of the mother should provide vitamin C intake should be approached with cau- this nutrient to the fetus since copper easily tion until copper status is evaluated since vitamin crosses the placenta.45 C is known to affect copper antagonistically,51 52 53 Other conditions reported to be related to and/or enzymes that require copper. The copper deficiency include suppression of immune biochemical defects of copper deficiency can be response46 (cellular), celiac disease, cystic described as a copper deficient scurvy (CDS). fibrosis of the pancreas,47 and loss of Although the mechanisms of the biochemical pigmentation of the hair and skin.48 defects TMA studies have revealed other 102 The Nutritional Relationships of Copper

Figure 1 Figure 2.

of CDS are different from those caused by , include vitamin D, B1, B12, C, and C deficient scurvy, CDS can be produced by folic acid (B10). Supplementation of synergistic excessive vitamin C intake. Conversely, vitamin C vitamins can aid in reducing the effects of copper requirements are increased by excessive copper deficiency and in restoring copper balance. As an intake or tissue accumulation. example, increased adrenal corticosteroid production decreases copper retention56 as well Endocrine Factors as antagonizes vitamin D metabolism.57 Vitamin Copper is normally excreted by the liver via D can antagonize the effect of excessive adrenal stimulation. It has been demonstrated that corticosteroid production, thereby improving copper excretion is increased by the copper retention. This concept can be applied in 54 55 administration of adrenal steroids. Increased helping to reduce the side effects of steroid activity of the sympathetic endocrines tend to therapy. increase the elimination of copper or increase its The synergistic minerals to copper include requirements due to increased metabolic demands. calcium, cobalt, selenium, sodium, and iron. The The sympathetic endocrines include the thyroid, rickettsial bone changes that occur with copper adrenal cortex (glucocorticoids), adrenal medulla, deficiency are probably related to the copper- and anterior pituitary. vitamin D-calcium relationship. Some vitamins and minerals are both Nutrients Synergistic to Copper synergistic and antagonistic. This is due to their Rarely does a single nutrient deficiency develop co- relationship with copper in metabolic exclusively. Other nutritional deficiencies and functions such as the requirement for adequate excess are always involved. Referring to figure 1 amounts of iron and copper for hemoglobin and 2, we can see the potential of vitamin and production. But excessive iron intake antagonizes mineral toxicity that can develop in the presence copper absorption on an intestinal level. of copper deficiency. As an example, the need for vitamin A, C, B6, B3, and B5 is reduced in a Copper Toxicity copper-deficient state. Conversely, hyper- Copper toxicity is common in the United vitaminosis of most of these vitamins can be States. TMA studies show that a large percent of reduced by supplying adequate amounts of copper. the population has excessive tissue copper levels. We can see particularly that the adverse effects of This varies geographically due to high copper or hyper-vitaminosis A can be decreased by copper low zinc soils and hard or soft water regions. The supplementation. Synergistic vitamins, those use of copper water pipes and dental prosthesis whose requirements are increased by copper

103 Journal of Orthomolecular Medicine Vol. 4, No. 2, 1989 have contributed greatly to increased copper synergistic vitamins and minerals previously intake. Copper also enters the food chain through discussed can also contribute to copper toxicity. the addition of copper to animal feeds and use of These factors should be explored in relation to copper in spraying vegetables and grains for the Wilson's disease, an inborn error of metabolism prevention of fungus and algae growth.58 Reports resulting in toxic amounts of copper have shown that copper intake in the United accumulation in the liver due to a lack of States is approximately three to five milligrams Ceruloplasmin. Elevated hair copper levels do per day. The copper intake in India is higher, not occur with Wilson's disease, but copper accu- averaging almost six milligrams per day and in mulation in tissues and organs other than the liver some areas as much as thirteen milligrams.59 eventually develops. Excessive copper retention We have learned that metabolic differences will often develop in the eye, producing the allow greater copper retention in some Kayser-Fleischer rings in the cornea which is a individuals than others, even with the same diagnostic sign of this disease. Increased copper exposure. We have observed through TMA accumulation has also been noted in individuals studies that vegetarians appear to have a greater with sickle cell anemia.65 tendency to retain copper than non-vegetarians. A reduction or blockage in biliary excretion Henkin60 reported that patients with adrenal can increase copper accumulation, even if copper insufficiency had higher serum copper levels, intake is not excessive. This type of copper which improved with hormonal therapy. An accumulation may develop over prolonged increase in parasympathetic neuroendocrine periods involving several years. Excess estrogens activity would predispose an individual to an are known to contribute to gall bladder stasis as increased copper burden due to a decrease in well as cholesterol and calcium stone formation. copper excretion. The parasympathetic The development of gallstones is found to have a endocrines include the pancreas, parathyroid, and higher incidence in women, especially those who anabolic steroids. Copper is a sedative mineral, have been pregnant.66 67 Elevation in estrogen which when in excess, stimulates anabolic levels during pregnancy68 and oral contraceptive activity and increases parasympathetic activity. use have been reported to consistently produce TMA studies frequently reveal elevated tissue defects in the excretory functions of the liver.69 copper in women taking oral contraceptive agents Increased copper retention can develop as a result which has been confirmed by others,61 62 as well of viral infections such as mononucleosis and in women with copper interuterine devices. Since hepatitis.70 High tissue copper levels are copper levels are noted to rise especially during frequently observed in individuals with a history the last trimester of pregnancy, it is not unusual of these conditions. Whether excess tissue copper to find multigravid women with excessive tissue causes viral manifestation or viral infections copper accumulation, particularly if their cause elevated tissue copper accumulation is pregnancies were not widely spaced. This will speculative at this time, but one wonders if the also contribute to inherited copper toxicity in anti-viral effects of zinc could be due to the children. antagonism of copper by zinc. Copper toxicity can occur when there is a deficiency of the antagonistic nutrients shown in Medications That May Contribute to Copper figure 1 and 2, especially , B3, B5, A, Toxicity and the minerals zinc and iron. The requirements The main excretory route for the removal of for these nutrients are known to increase during copper is through the intestinal tract; therefore, pregnancy, with oral contraceptive use, and any factor that inhibits intrahepatic or estrogen therapy.63 Krishnamachari reported that extrahepatic excretion can potentially contribute in individuals suffering from (B3 to copper toxicity. There are many medications deficiency), copper absorption was increased.64 other than estrogens that can contribute to choles- Excessive intake of many of the tasis. These include phenothiazine derivatives, 104 The Nutritional Relationships of Copper chlordiazepoxide, desipramine, imi-pramine, and therapy.75 76 77 While a direct effect of copper meprobamate, which are contained in upon insulin has not been confirmed at this time, psychotropics, sedatives, and tranquilizers. Their it has been confirmed that estrogen does not common trade names are, Thorazine, Stelazine, produce the insulin rise. An indirect effect of Temaril, Norpramin, Tofranil, Librium, and copper can be suspected due to the copper- Miltown; Trade names for chlorothiazide used in calcium-vitamin D synergistic relationship. It is diuretics and anti-hypertensives are Diupres and apparent from TMA studies that copper increases Diuril; tolbutamide and chlorpropamide are used the tissue retention of calcium, and calcium is in anti-diabetic and oral hypoglycemic agents known to mediate the release of insulin.78 79 with trade names including Diabenese and Vitamin D metabolites (1, 25(OH)2 D3) enhances Orinase; carbamazepine used for the control of the synthesis of insulin, and insulin enhances the convulsive disorders and severe neuralgias, trade synthesis of vitamin D metabolites.80 Since zinc is name Tegretol; thiouracil and methi-mazole, trade required for the storage of insulin, it is possible name Tapazole, is used as an anti-thyroid that antagonism of zinc by copper could be preparation; indomethacine, trade name Indocin, responsible for the flooding of insulin into the used in analgesics and anti-inflammatory plasma. preparations; antifungal preparations which Other conditions commonly observed with contain griseo-fulvin, trade names include excessive tissue copper accumulation via TMA Fulvicin-U/F and Grifulvin. This is only a partial studies include chronic E.B.V. and C.M.V. list of commonly prescribed medications; for fur- infections, emotional disturbances (depressive ther information consult the Physicians' Desk disorders), hypoglycemia, fatigue, fibroid tumors, Reference. low blood pressure, transient high blood pressure, , PMS, AIDS, dermatosis, endometriosis, Thyroid Insufficiency and Copper infertility, , type II insomnia, and frontal For several years it has been noted that headaches. elevated tissue copper is a common finding in Generally it is often noted that adults who conjunction with thyroid insufficiency. Copper's show elevated tissue copper accumulation have a effect upon thyroid function involves multiple tendency to be right brain dominant. They are mechanisms. First, by the copper antagonistic usually emotionally oriented and artistically effect upon iron. Dillman and co-workers have inclined. TMA tests of individuals whose reported that results in thyroid occupation or hobby involves creativity such as insufficiency.71 Other investigators have artists, sculptors, musicians, and actors invariably concluded that iron status and thyroid function have a tendency toward either a high tissue appears to have a reciprocal relationship in that copper or a low zinc to copper ratio, whereas iron deficiency can impair thyroid function, and individuals with a low tissue copper or high iron stores can be reflective of thyroid function.72 zinc/copper ratio tend toward left brain Copper can also affect thyroid function through dominance and often follow intellectual pursuits. an insulin effect. Insulin is known to antagonize thyroid function.73 Through observations of TMA Conclusion patterns, it has been noted that elevated tissue The importance of copper nutriture is obvious copper is associated with increased insulin due to its requirement in enzyme systems. Often secretion by the pancreas; it is conceivable that the adverse effects of copper toxicity are given copper enhances insulin secretion. Studies that more consideration than copper deficiency. show an association of elevated estrogen with However, copper balance is important particularly elevated insulin support this view. Plasma insulin in relationship to other nutrients. Just as much levels are known to be elevated during pregnancy, consideration should be given to the possibility of being highest in the last trimester.74 The same copper deficiency as to copper toxicity. insulin effect is also observed during estrogen

105 Journal of Orthomolecular Medicine Vol. 4, No. 2, 1989

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