Refer to: Trace elements-Medical Staff Conference, University of California, San Francisco. West J Med 128:223-227, Mar 1978
Medical Staf Conference
Trace Elements These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California, San Francisco. Taken from transcriptions, they are prepared by Drs. David W. Martin, Jr., Associate Professor of Medicine, and Robert C. Siegel, Associate Professor of Medicine and Orthopaedic Surgery, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine. Requests for reprints should be sent to the Department of Medicine, University of California, San Francisco, CA 94143.
DR. SMITH: * Diseases with associated abnormalities in trace metal metabolism are ubiquitous although actual deficiency states are rare. Dr. Faith Fitzgerald will lead today's discussion about recent progress in the clinical significance of trace metals. DR. FITZGERALD:t Trace elements are those elements essential to normal biologic function whose total concentration in the hypothetical 70-kg man is less than four grams. To date, some 17 of these have been described (Table 1), although some are
disputed. The deficiency and excess states of vanadium, tin, molybdenum and silicon are most familiar as depletion states created experimentally in rats. Deficiency states of selenium, chromium and manganese are more likely capable of creating recognizable syndromes in human beings. A toxic excess syndrome has been clearly described for manganese,' and seems probable for selenium as well.2 Gallium, cobalt and fluorine have found *Lloyd
H. Smith, Jr., MD, Professor & Chairman, Department of Medicine. tFaith Fitzgerald, MD, Director, Inpatient Services, Assistant Professor of Medicine, The University of Michigan Medical School, Ann Arbor. Dr. Fitzgerald was formerly Assistant Professor of Medicine, University of California, San Francisco.
use in clinical diagnosis and therapy. The best defined deficiency syndromes involving trace elements are those of copper, zinc and iodine. Iodine deficiency has been well described and needs no further comment here. Studies in trace elements are carried out in several ways: The usual mode of investigation is by artificial deprivation studies in animals both prenatally and postnatally. More rarely, naturally acquired deficiencies are discerned in animals and man. These are the "experiments of nature," genetic defects and malnutritional states, which give some clue as to the natural requirement for a given element. The third circumstance in which trace elemental deficiencies have been recognized and described are the recently burgeoning "experiments of medicine" or iatrogenic deficiencies. These have been particularly prevalent since the advent of parenteral hyperalimentation.
Zinc Normal Values The adult human body normally contains 2 to 3 grams of zinc (Table 2). The adult requirement THE WESTERN JOURNAL OF MEDICINE
TRACE ELEMENTS TABLE 1.-Trace Elements Believed Essential to Normal Biologic Function
Chromium Cobalt Copper Fluorine Gallium
Iodine Manganese Molybdenum Selenium
Silicon Tin Vanadium Zinc
is estimated at 15 to 20 mg per day and is readily obtainable from meats, whole grains, legumes and seafood. Absorption occurs principally in the small intestine. Normal circulating blood levels of zinc range from 80 to 110 jug per dl. Urinary excretion on a normal intake is about 500 ppm in 24 hours. Function Zinc is a cofactor or component of more than 70 known enzymes, including aldolases, dehydrogenases, phosphorylases, peptidases, an isomerase, and aspartate transcarbamylase.3 It is present in deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). It participates in carbohydrate, lipid, protein and nucleic acid synthesis and degradation.
Deficiency States Zinc has been known to be essential to the growth of lower organisms since 1869. Deficiency states in animals and human beings have been more recently recognized.4-9 Genetic Acrodermatitis enteropathica is a potentially lethal disease of infants which is characterized by watery diarrhea and seborrheic skin lesions on the acral areas and around body orifices. In 1974 Moynahan5 reported complete clearing of the skin lesions and restoration of normal bowel function in afflicted infants given supplemental dietary zinc. Studies strongly suggested this genetic disorder to be a selective malabsorption of zinc.46
Acquired In 1961 Prasad and co-workers7 described patients from Iran and Egypt with short stature, pronounced hypogonadism, roughened skin and hepatosplenomegaly. Serum, red cell, hair and urinary zinc levels were all decreased. The zinc deficiency was attributed to a diet high in phytates which bound zinc in the lumen of the gut, leading to a malabsorption of that metal. Because there were no good controls and because there concurrently existed an iron deficiency, there remains some question as to the validity of this syndrome. 224
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More recently, Hanbridge and associates8 showed low levels of zinc in the hair of children with poor growth and diminished taste acuity in Denver. They speculated that even such relatively affluent children, who were from middle and upper class families, might have dietary zinc deficiency. In patients with malabsorption and starvation, failure to thrive and poor wound healing have been attributed to an acquired zinc deficiency.9'10 An interesting syndrome of decreased acuity of taste (hypogeusia) and impaired olfactory acuity (hyposmia), often following upper respiratory tract infections, in some patients may respond to oral zinc supplements." Finally, the iatrogenic analogue to acrodermatitis enteropathica has recently been reported in a patient who had been hyperalimented.12 Because of multiple enterocutaneous fistulae, this young man had been parenterally fed for eight months. He developed alopecia and acrodermatitis-like skin lesions. Serum and hair zinc levels were low, and zinc supplementation led to reversal of the skin abnormalities. There are some intriguing speculations in the literature about zinc deficient states:1-3 Alcoholics with Laennec cirrhosis have long been known to be hyperzincuric with correspondingly low serum zinc levels.'4 Might the hypogonadism, poor wound healing and loss of body hair in patients with cirrhosis be, in part, secondary to zinc deficiency? Similarly, lymphocytopenia is not infrequent in patients with cirrhosis, and has been reported in rats rendered experimentally zinc deficient.'5 A preliminary study in normal volunteers on a low zinc diet suggests that zinc deficiency might lead to a decrease in blood urea nitrogen (BUN) and increase in blood ammonia.'6 Is zinc required for urea synthesis in the liver, and are the low BUN levels and hyperammonemia in severe Laennec cirrhosis a consequence of zinc deficiency? Zinc deficient rats have low plasma vitamin A levels,'7 and both retinal-binding protein and vitamin A levels are diminished in persons with cirrhosis.'8 Is there a connection between these two findings? Obviously, the answers to these questions require further study. Some researchers believe that the growth retardation, hypogonadism and poor wound healing in patients with sickle cell anemia may be related to the total body zinc deficiency that results from an associated hyperzincuria in these patients. Red
TABLE 2.-Normal Values for Zinc and Copper Content in 70-kg Man
Zinc . 2-3 grams Copper . . 100 mg
15-20 mg 2 mg
80-110 jug per dl* 79-149 ,ug per dlt (ceruloplasmin: 20-50 mg per dl)
500 ,ug/24 hours Less than 50,ug/24 hours
*Increased in hemolysis, tissue breakdown. Decreased in acute inflammatory states, corticosteroid therapy. tlncreased in biliary cirrhosis, acute and chronic infection, inflammatory rheumatoid arthritis, myocardial infarction, anemias, liver disease, leukemia, lymphoma.
cell zinc concentration is normally higher than that in plasma. There is an increase in urinary zinc in patients with sickle cell anemia, presumably consequent to the greater presentation of zinc to the glomerulus from the hemolytic state. There may altematively be a specific tubular defect in these patients leading to zinc wasting. According to some investigators,16 there is a rough correlation between the degree of zinc deficiency and the severity of the sickle cell disease. Perhaps zinc has a role, they speculate, in decreasing hemoglobin binding to red cell membranes. A controlled study of the efficacy of zinc supplementation in sickle cell disease would be illuminating. Although there are experimental data supportive of poor wound healing in zinc deficient animals,1" studies attempting to show that supplemental zinc facilitates wound healing in human beings already zinc sufficient10 have been justly criticized.
Laboratory Studies The laboratory determination of zinc deficiency is not easy. Serum zinc may be decreased in acute inflammatory states20'2' or increased transiently in hemolysis or tissue breakdown.20 Hair levels of zinc, often cited in the literature as a reflection of total body zinc are demonstrative of the chronic zinc sufficient or deficient states, and do not reflect more acute changes. Urinary and serum zinc values may be increased in spite of the fact that total body zinc levels are low, as evidenced by the hyperzincuria and hyperzincemia of cirrhosis and hemolysis. Probably the best method of determining zinc deficiency in an individual patient is to check all three: serum, urine and hair zinc values. Therapy Doses of supplemental zinc have ranged from 15 mg to several grams per day given orally, usually as zinc sulfide. There is a large therapeutic margin, and zinc toxicity from overdose is rare.
Copper Normal Values There are an estimated 100 mg of copper in the hypothetical 70-kg man (Table 2). Total recommended dietary intake is about 2 mg per day, readily available in most meats, especially liver and kidney. There is also ample copper in shellfish, nuts, raisins, legumes and cereals. Normal serum copper in most laboratories ranges between 79 and 149 ,g per dl. The normal level of the carrier protein ceruloplasmin is between 20 and 50 mg per dl. There is usually less than 50 4g of copper per 24 hours in the urine. Function Copper is an integral component of at least 16 essential metaloproteins in mammals, including cytochrome oxidase, monoamine oxidase, lysyl oxidase, tyrosinase and ceruloplasmin.22 It may be an important participant in prostaglandin synthesis as well.28 The major copper-containing enzymes are believed to have their primary activity in the formation of connective tissues, in the function of the central nervous system, and in hematopoiesis in mammals.
Deficiency States If the functions of copper enzymes are affected in states of copper deprivation, one may predict the metabolic defects and pathologic changes that could occur as a consequence of these deficiencies.24 Lysyl oxidase participates in cross-link formation in collagen and elastin, so one might expect skeletal and vascular defects to be evident in copper deficiency. Similarly, if dopamine-betahydroxylase and cytochrome oxidase require copper, a derangement of catecholamine metabolism and resultant central nervous system dysfunctioni could be predicted. If an essential ferroxidase cannot be formed without copper, then abnormalities in iron utilization might reflect copper status in an animal or man. Tyrosinase and sulfTHE WESTERN JOURNAL OF MEDICINE
hydryl oxidase deficiencies would logically lead to defects in the formation and pigmentation of hairs. There is considerable scientific satisfaction in the awareness that a copper deficiency state exists that fulfills all of these predictions.
Genetic Menkes disease (steely hair syndrome) is a genetic disorder that is manifest clinically between 6 weeks and 6 months of life in infant boys. It was described by Menkes in 196225 as an X-linked defect characterized by kinky hair, developmental regression, focal cerebral and cerebellar degenerative changes, seizures, temperature instability, arterial intimal abnormalities and scorbutic bone changes. In these children there were severely diminished copper concentrations in blood, brain and liver.26 In this genetic circumstance, the copper deficiency evidently results from impaired intestinal absorption of copper and is probably related to defective transport across the serosal cell membrane.27 Supplementing copper in children with the steely hair syndrome has shown variable results. One may generally achieve an increase in serum copper and ceruloplasmin levels, but little in the way of neurologic improvement is realized. The best known genetically determined abnormality of copper metabolism is Wilson disease. In this autosomal recessive disorder, there is a defect in the incorporation of copper into ceruloplasmin and an abnormal biliary excretion of copper. This disease, in which the major pathologic changes are consequent upon abnormal tissue levels of toxic unbound copper, is excellently and extensively reviewed elsewhere.28
Acquired A microcytic, hypochromic anemia and neutropenia have been described in patients with severe malnutrition, malabsorption, or total dependence on copper-poor intravenous hyperalimentation. Some infants with profound nutritional inadequacy have concurrent demineralization of bone. Copper deficiency has been credited with participation in both the hematopoietic and osseous abnormalities. It is known that copper is essential for several electron transfer systems and that its carrier protein, ceruloplasmin (an alpha-2-globulin) has ferroxidase activity.29 Copper deficient swine fail to absorb dietary iron at a normal rate and a microcytic, hypochromic anemia develops.30 In these 226
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copper deficient animals, mucosal cells of the duodenum accept iron, but do not pass it on to transferrin. Iron is also abnormally retained in reticuloendothelial and hepatic cells, with consequently low serum iron levels in the early stages of copper deficiency. Since iron must be in its oxidized form to be accepted by transferrin, it is possible that deficiency of iron oxidative activity accounts for the poor absorption and release of iron from storage in the copper deficient state.31 As copper deficiency progresses, serum iron levels spontaneously rise, but without a necessary improvement in the hematologic status of the animal. This is thought to be because of poor utilization of iron for hemoglobin formation. The nature of this latter defect is not known. The mechanism of the leukopenia, with decreased bone marrow granulocytosis and "maturation arrest" is also not fully understood.31'32
Laboratory Studies Measured serum copper levels must be interpreted in- the light of the clinical presentation of the patient. Hypercupremia is found in many diverse pathologic conditions: biliary cirrhosis, acute and chronic infections, rheumatoid arthritis, myocardial infarction, anemias of a variety of sorts and liver disease.33 In Hodgkin disease and leukemia, there may be a significant correlation between serum copper levels and disease activity.34 Hypocupremia, as discussed above, may be genetic (Menkes and Wilson diseases) or acquired. Serum, urine and hepatic copper levels may be required in some cases to assess total body copper status accurately. Therapy The treatment of copper deficiency states is with cautious administration of copper supplements, generally 1.25 mg of elemental copper (5 mg of copper sulfate) initially, followed by 0.4 mg of elemental copper (1.6 mg of copper sulfate) per day as maintenance. Excess copper may give rise to an acute toxicity syndrome, with nausea and vomiting, epigastric pain, headache, dizziness, weakness, blue-green diarrheal stools and saliva, acute hemolysis and renal tubular abnormalities. Summary The biochemical intricacies of copper and zinc metabolism have long had major appeal only to laboratory investigators or to those working with
the rather rare deficiency states in man. Should it be true that these metals are of pathological significance in chronic disorders such as cirrhosis, sickle cell disease, malabsorption and iron-deficiency anemia, they will become increasingly pertinent to practicing clinicians. Moreover, physicians using vigorous modern therapies may induce these deficiency states. Therefore, we are even more obliged to identify and repair the depletion of metals which we recognize as trace elements. REFERENCES 1. Hine CH, Pasi A: Manganese intoxication. West J Med 123:101-107, Aug 1975 2. Kilness AW, Hochberg FH: Amyotrophic lateral sclerosis in a high selenium environment. JAMA 237:2843-2844, 1977 3. Vallee BL, Wacker WEC: Metalloproteins, In Neurath H (Ed): The Proteins. Composition, Structure and Function. New York, Academic Press, 1970 4. Moynahan EJ, Barnes PM: Zinc deficiency and a synthetic diet for lactose intolerance. Lancet 1:676-677, 1973 5. Moynahan EJ: Acrodermatitis enteropathica: A lethal inherited human zinc deficiency disorder. Lancet 2:399-400, 1974 6. Nelder KH, Hambridge KM: Zinc therapy of acrodermatitis enteropathica. N Engl J Med 292:879-882, 1975 7. Prasad AS, Halsted JA, Nadini M: Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 31:532-546, 1961 8. Hambridge KM, Hambridge C, Jacobs M, et al: Low levels of zinc in hair, anorexia, Poor growth and hypogeusia in children. Pediatr Res 6:868-874, 1972 9. McMahon RA, Parker ML, McKinnon MC: Zinc treatment in malabsorption. Med J Austr 2:210-212, 1968
10. Pories WJ, Henzel JH, Rob CG, et al: Acceleration of wound healing in man with zinc sulfate given by mouth. Lancet 1:7482-7485, 1967 11. Henkin RI, Schechter PJ, Hoye R, et al: Idiopathic hypogeusia with dysgeusia, hyposmia and dysosmia.-A new syndrome. JAMA 217:434400, 1971 12. Tucker SB, Schroeler AL, Brown PW, et al: Acquired zinc deficiency. JAMA 235:2399-2402, 1976 13. Prasad AS, Oberleas D: Zinc: Human nutrition and metabolic effects. Ann Intern Med 73:631-636, 1970 14. Sullivan JF, Lankford HG: Urinary excretion of zinc in alcoholism and post-alcoholic cirrhosis. Am J Clin Nutr 10:153-157, 1962
15. Dreosti EE, Tao SH, Hurley LS: Plasma zinc and leukocyte changes in weaning and pregnant rats during zinc deficiency. Proc Soc Exp Biol Med 128:169L174, 1968 16. Prasad AS, Ortega J, Brewer GJ, et al: Trace elements in sickle cell disease. JAMA 235:954-955, 1973 17. Smith JC, McDaniel EG, Fan FF, et al: Zinc: A trace element essential in vitamin A metabolism. Science 181:954-955, 1973 18. Smith FR, Goodman DS: The effects of diseases of the liver, thyroid and kidneys on the transport of vitamin A in human plasma. J Clin Invest 50 2426-2436, 1971 19. Sandstead HH, Shepard GH: The effect of zinc deficiency on the tensile strength of healing surgical incisions in the integument of the rat. Proc Soc Exper Biol Med 128:687-689, 1968 20. Halsted JA, Smith JC: Plasma zinc in health and disease. Lancet 1: 322-324, 1970 21. Falchuk KH: Effect of acute disease and ACTH on serum zinc proteins. N Engl J Med 296:1129-1134, 1977 22. Scheinberg IH: The effects of heredity and environment on copper mnetabolism, In Trace elements. Med Clin N Amer 60:705712, Jul 1976 23. Copper and steely hair (Editorial). Lancet 1:902-903, 1975 24. O'Dell BL: Biochemistry of copper, In Trace elements. Med Clin N Amer 60:687-703, Jul 1976 25. Menkes JH, Alter M, Stergleder GK, et al: A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal -cerebral and cerebellar degeneration. Pediatrics 29: 764-779, 1962 26. Danks DM, Campbell PE, Walker-Smith J, et al: Menkes' kinky hair syndrome. Lancet 1:1100-1103, 1972 27. Lott IT, DiPaolo R, Schwartz D, et al: Copper metabolism in the steely hair syndrome. N Engl J Med 292:197-199, 1975 28. Strickland GT, Leu M: Wilson's disease. Medicine 54:113117, 1975 29. Osaki S, Johnson DA, Frieden R: The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 241:2746-2751, 1966 30. Teague HS, Carpenter LE: Demonstration of a copper deficiency in young growing pigs. J Nutr 43:389-399, 1951 31. Vilter RW, Bozian RC, Hess EV, et al: Manifestations of copper deficiency in a patient with systemic sclerosis on intravenous hyperalimentation. N Engl J Med 291:188-191, 1974 32. Dunlap WM, James GW III, Hume DM: Anemia and neutropenia caused by copper deficiency. Ann Intern Med 80:
470-476, 1974 33. Arras MJ: Clinical pathologic correlations of copper. Postgrad Med 45:55-58, 1969 34. Hrgovcic M, Tessmer CF, Minckler TM, et al: Serum copper levels in lymphoma and leukemia. Cancer 21:743-755, 1968 35. Holtzman NA, Elliott DA, Heller RH: Copper intoxication. N Engl J Med 275:347-352, 1966 36. Stein RS, Jenkins D, Korns ME: Death after use of cupric sulfate as emetic. JAMA 235:801, 1976 37. Blomfield J, Dixon SR, McCredie DA: Potential hepatotoxicity of copper in recurrent hemodialysis. Arch Intern Med 128:555-560, 1971
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