Plasma Trace Elements During Total Parenteral Nutrition \I
Russel Allinson, RPh
Requests for reprints should be addressed to Russel Allinson, RPh. Hospital Pltarmacy Resident. Department of PharnZacy, Riverside hfethodist Hospital, Colunibus. Ohio 43214.
TO begin a discussion of the use of essential trace elements in total’p’arentFra1 nutrition (TPN) we must first define a n essential trace elEment,For a trace element to be essential, it must meet the definition established by Cotzias’ that: I. I t is present in all healthy tissues of all living things. 2. Its concentration from one animal t o the next is fairly consistent. 3. If its withdrawal from the body induces reproducibly the same structural and physiologic abnormalities, regardless of the species studied. 4. Its addition either prevents or reverses these abnormalities. 5. The abnormalities induced by deficiency are always accompanied by pertinent, specific, biochemical changes. 6. These biochemical changes can be prevented or cured when the deficiency is prevented o r cured. At the present time, ten trace elements have been classified as essential: iron, iodine, copper, zinc, manganese, cobalt, molybdenum, selenium, chromium and In addition, there are 20 t o 30 other trace elements that have been found consistently in various concentrations in living tissue. Generally, depending on the specific element, its dose and the nutritional state of the animal in question, the action of these elements may be thought to occur as a spectrum. Venchikov described this spectrum as a curve with two maxima.-’ The initial rise of the curve shows increasing effect with increasing dose until a plateau is reached; at this point, there is optimal biologicaction and normal function. Beyond the plateau, the curve rises and the element acts as a drug, with its own pharmacologic properties and independent of a deficiency state. As the dose is increased, toxicity develops which may ultimately result in death. With this description in mind, one can easily understand the necessity of maintaining trace element concentrations within specific limits. “Continued ingestion of diets that are deficient, imbalanced o r excessively high in a particular trace element invariably induces changes in the functioning forms, activities or concentrations of that element in the body tissue or fluids, so that they fall below o r rise above the permissible limits.” -’ Therefore, in patients on TPN, continued feeding with diets deficient in trace elements would beexpected t o alter the concentration of those trace elements. Solomons has postulated that in addition t o decreased intake, there is increased excretion, increased utilization and redistribution, and decreased plasma binding, all of which contribute t o a decreased trace element concentration during With these possibilities in mind, clinicians-pharmacists and physicians-must monitor
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HISTORICAL PERSPECTIVES PLASMA TRACE ELEMENTS IN T P N
TABLE I
V 23
Cr -.
Mn
24
25
Fe 26
Co 27
Ni 28
Cu 29
Zn
30
,‘I
patients on T P N to ensure that trace element concentrations are maintained within the critical limits. Often, monitoring requires only a careful awareness of the patient’s condition and the importance and necessity of essential trace elements. “In essence, the most important requisite in making a diagnosis of trace element abnormalities at the present time is a high index of suspicion of their presence.”’ Of the ten essential trace elements, three (iron, iodine and cobalt) have been widely discussed physiologically and pharmacologically in many texts and publications and warrant no’ further discussion here; this does not, however, preclude their importance in T P N patients. Of the remaining seven trace elements, copper, zinc and manganese have been widely studied and utilized in replacement regimen^.^" Therefore, the attention of this paper will be focused o n the properties of these three trace elements and the signs and symptoms indicative of their deficiency. MANGANESE Manganese belongs t o the first long series in the periodic chart of elements, “transition elements.” It is interesting t o note that manganese is surrounded in this series by several of the other trace elements (Table I),’ Early studies conducted in the 30’s revealed the relationship of manganese t o growth, reproduction, skeletal development and carbohydrate and lipid metabolism. To date, the exact mechanism and locus of its absorption have not been determined. Estimates of daily intake vary greatly with the type of diet; a n estimated daily intake would be 0.7 t o 2.2 mg/day. Under conditions of minimal intake, 20 pg/day would be retained.* Distribution and storage of this element is dependent on the characteristics of the organ; those rich in mitochondria tend to have the highest concentration of manganese. The bones, liver, kidney, pancreas and pituitary gland normally have higher concentrations than other tissues. The extent ofthis distribution and storage is not nearly as great as copper and zinc. A 70 kg adult human has 12 t o 20 mg of manganese; this is only 1/5 the total of copper and only 1/100 the total of zinc.3 Manganese does not accumulate t o the extent of copper and zinc in the lungs and its storage in the liver is also much less. Several studies show that normal whole blood
levels are low (8.44 2 2.73 pg/l); manganese circulates in blood bound selectively and almost totally t o a PI globulin. Finally, radioactive studies show that manganese appears to be in a dynamic, highly mobile state with two major pools being the blood and the liver mitochondria.’ Total body levels of manganese are regulated almost entirely by intestinal excretion via several routes. The main route of excretion is bile flow; when this route of excretion is blocked or overloaded, manganese may be excreted by pancreatic juices or the duodenum and jejunum.’ Under normal conditions, there is n o expected urinary excretion of mangan-ese. Although manganese has been combined in trace element s ~ p p l e m e n t a t i o n s , ~there ’ ~ have not been any reported deficiencies as a result of T P N without supplementation. Furthermore, one report indicated that in five of six patients who were on TPN, there was a n elevation of manganese levels. It was the authors’ opinion that the high levels of manganese were probably due to its high content in the nutrient solutions.” There has been only one case of manganese deficiency reported in humans which occurred because of a n inadvertent omission of manganese salts from a vitamin K-deficient diet on a metabolic ward. The patient in this case had increased cholesterol, weight loss, transient dermatitis, occasional nausea and vomiting and changes in hair and beard color. The authors concluded that “an extreme degree of deficiency is necessary t o produce a deficiency state.” COPPER Copper is so widely distributed in foods of the daily diet that severe nutritional deficiency is virtually impossible.” The precise daily intake of copper varies with diet and geographic location; however, an average daily diet contains between 2 and 4 mg. When compared t o the recommended dietary allowance (RDA) of at least 2 mg/day,’* the average daily intake is sufficient. Absorption of the element occurs in the stomach and upper gut t o the extent of about 32%” After absorption, there is a wide tissue distribution of copper in the body with 23 mg total in the liver, heart, spleen, kidney, brain and blood. Of the 23 mg total, 8 mg are in the brain and the liver. Normal plasma concentration is 109 k 17 pg p e r ~ e n t In . ~ the plasma, copper exists in two forms, with one bound firmly and the other bound more loosely. The loosely bound copper is that which is bound t o albumin; copper migrates into this pool from the intestine after absorption. The copper which is bound t o albumin is considered “transport copper”; in this form, the element may be distributed into and out of the tissues. When copper is transported t o the liver, it may either be stored VOLUhlE 2 / NUMBER I / 1978
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ALLINSON
there or released for incorporation into cellular enzymes, erythrocuprein or ceruloplasmin. Ceruloplasmin is produced by the liver in response to body copper levels; it is a true oxidase which catalyzes the oxidation of several biologic compounds including serotonin',?nd epinephrine." Although 80% of serum coppe; is bound to ceruloplasmin, this complex does not play a major role in the absorption or transport of copper. Excretion of the element is primarily biliary; copper is bound t o protein macromolecules and, t o a lesser extent, amino acids, and excreted in the feces with n o reabsorption via enterohepatic circulation.' Intravenous injection of copper results in increased biliary and consequently, fecal excretion, with no increase in urine excretion. Urine "-excretion of copper is minimal, only 0.01 t o 0.06 mg of the daily dose.I3 Copper functions physiologically as a component of many cuproenzymes. 'These enzymes participate in three areas of human health: (1) development and maintenance of cardiovascular and skeletal integrity, (2) central nervous system (CNS) structure and function and (3) erythropoietic function, including m e t a b ~ l i s m .While ~ long-term copper deficiency in man and animals may cause cardiovascular, skeletal or CNS symptoms, decreased copper intake secondary t o T P N therapy is generally manifested in two clinical conditions, anemia and n e ~ t r o p e n i a . ' ~ ' ' ~ As ' ' ~ previously indicated, in a condition of copper deficiency, there will be decreased ceruloplasmin p r o d ~ c t i o n . 'Ceruloplasmin ~ is felt t o be responsible for the oxidation of iron from the ferrous t o the ferric state; transferrin will only accept iron in the ferric state. Therefore, the intestinal absorption of iron will be decreased in a condition of copper deficiency probably because of decreased ceruloplasmin.I6 In addition t o decreased iron absorption, there also appears to be decreased iron uptake by erythrocytes. In animal studies" of the localization of iron in developing erythrocytes of normal and copper-deficient rats by electron microscopy, the copper-deficient animals appeared t o have an impaired uptake of iron by mitrochondria where it combines with protoporphyrin t o form heme. Consequently, the copper deficiency resulted in a hypochromic, microcytic anemia similar t o that described by hemoglobin deficiencies. Two mechanisms are combining, therefore, t o produce anemia in copper-deficient patients. In a report from Mexico, there were a number of cases of neutropenia in recovering malnourished infants on a n almost exclusive milk diet.'' When treating the copper deficiency, neutropenia was the earliest and most consistent indicator of treatment adequacy. Two other reports in patients on T P N indicated that anemia, neutropenia and leukopenia occurred and were corrected
by the addition of ~ 0 p p e r . I ~As" ~yet, a mechanism for the relationship between copper deficiency and neutropenia and leukopenia has not been established. A recent case presented by Vilter er all6 is indicative of the relationship between copper deficiency, neutropenia and leukopenia. The patient presented with systemic sclerosis of the intestine and malabsorption. T P N therapy was initiated in November of 1972; later analysis of the solution revealed that the patient was receiving only 0.1 mg/day of copper ( R D A = 2 mg/day). The white blood count (WBC) and neutrophils continued to fall until mid January when signs of severe copper deficiency were evident. For the next four months, prior to the administration of copper, the patient had leukopenia (WBC, 1,700), neutropenia (neutrophils, 600) and anemia, red blood kount (3.4 X i06/mm3; hemoglobin, 10.2 g/ 100; hematocrit, 32.4%). At this time, the patient's serum copper was very low (0.2 pglml), her ceruloplasmin was reported t o be zero and her serum zinc was low (0.54 pg/ ml); no bone demineralization was noted. On May 29, 1973, nearly six months after starting T P N therapy, supplementation with 1 mg/day of IV copper sulfate was started. There was a n immediate rise in WBC and neutrophils, and seven days later the levels were normal (WBC, 6,000; neutrophils, 5,000). One further clinical symptom that may be indicative of copper deficiency is taste abnormality. Henkin ei a1 described a group of patients with scleroderma, cystinuria or rheumatoid arthritis who were treated with dpenicillamine." Before treatment, the patients had normal or elevated serum ceruloplasmin and normal taste acuity; after therapy, several groups had ceruloplasmin levels below normal and a significant decrease in taste acuity. When compared with a group with Wilson's disease who were treated with d-penicillamine, the taste abnormality was almost uniformly associated with a decrease in ceruloplasmin a n d / o r copper.
ZINC It was over 100 years ago that zinc deficiency in vivo was first described.' Since then, 70 known zinc enzymes have been identified, and it is also known that zinc is present in DNA and RNA. Of the 70 known zinc enzymes present in the body, 90% of enzymatic zinc is present in the erythrocyte as carbonic anhydrase.20 The remainder of the zinc is present in leukocytes, platelets and plasma. About one third of plasma zinc is loosely associated with serum albumins, the remainder with globulins. It is interesting t o note that dramatic changes in the zinc content of plasma occur in several disease states: atherosclerosis, malignant tumors, chronic and acute infections, postalcoholic cirrhosis and other liver diseases. Studies have also shown that women in the third
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HISTORICAL PERSPECTlVES PLAShlA TRACE ELEhlENTS IN TPN
trimester of pregnancy and women taking oral contraceptives exhibit below normal levels of zinc.3 It has been estimated that the whole body content of zinc in a 70 kg adult is 1.4 t o 2.3 gm. In relation t o other trace elements, this is about half theFmount ofiron, 10 t o 15 times’that of copper and 100 tiAes that of manganese. Absorption of zinc occurs mainly in the small intestine, predominantly in the duodenum and may be affected by three factors: (1) level of elemental intake; (2) amounts and proportions of several other elements and dietary components; and (3) the chemical form of the zinc.3 The exact mechanism for zinc absorption is unknown. Excretion of zinc occurs mainly in the feces, and is composed mainly of unabsorbed oral zinc. The amount of zinc which appears in the urine in healthy adults is very small; 0.1 to 0.7 mg/day compared with the normal daily intake of 10 t o 15 mglday. As mentioned previously, disease states alter the amount of zinc in the urine and it may be increased t o as much as 2.1 mg/day in alb~minurics.~ Presently, zinc has been shown t o be involved in many body functions. There is a definite relationship between zinc and bone growth and it has been shown t o be intimately involved in protein, RNA and DNA synthesk6 Additionally, Prasad and Overleas have correlated a relationship between zinc deficiency in man and a condition of hypogonadism, hepatosplenomegaly, iron deficiency anemia and shortened stature,Z1and related the growth reduction and gonadal hypofunction t o zinc insufficiency. There has also been a recent report from Denver demonstrating low hair zinc levels with poor growth and diminished taste acuity in children.” (Hair levels of zinc are often measured in man t o determine body levels of zinc.)23 With zinc supplementation, there was a n increased taste acuity, improved appetite and growth. With the exception of diminished taste acuity, the conditions described by Prasad and Overleas” and Hambridge ef alZZare long-term deficiency complications During the administration of TPN, some more acute problems of decreased zinc intake might be expected t o occur. One consequence of zinc deficiency may actually serve as a clinical indication of the need fo; replacement therapy. Henkin et al described in 1971 “a new syndrome”’‘ of idiopathic hypogeusia, dysgeusia, hyposmia and dysosmia. Through previous Henkin and his associates knew of the importance of transition metals (zinc, copper and nickel) in the sensation of taste and the subjective changes that can occur with trace element deficiency. In the group of patients they reported, it is useful t o note the changes that occurred in thesense of taste and smell. The dysgeusia was characterized by a n abhorrent taste quality generally associated with non-
tolerant foods, eg, rancid or spoiled. Usually the patients reported persistent metallic, bitter, sour or salty taste which they could not remove. AS would be expected, patients with hypogeusia reported their food t o be tasteless, similar t o eating sawdust o r swallowing flour -paste, and often needed t o add excess salt or sugar. The patients with dysosmia complained of a persistent obnoxious odor similar t o gasoline, dust, sweat or tar; some foods were particularly abhorrent: bacon, onion and garlic. Finally, those patients experiencing hyposmia exhibited a decreased ability to obtain flavor from foods, to distinguish between fresh and spoiled and t o detect the aroma of cooked and uncooked. They also had difficulty using proper amounts of perfumes and colognes. Henkin e f al began treatment with zinc for two reasons: ( I ) because’ it was known t o be involved in the mechanisms of taste and smell and (2) because it was less toxic than nickel and copper. After treatment with zinc, all of the abnormalities were corrected. Another aspect of this is interesting, and that is that more than 50% of the patients had had a recent upper respiratory infection. Hypogeusia and dysgeusia are common in patients following infection, presumably because infections lowers body zinc levels.26 Because of this important association between the trace element zinc and Henkin’s “new syndrome,” at least one author has suggested that serum zinc levels, together with taste acuity tests, be used t o diagnose low zinc levels.6 Another action of zinc, which was proposed initially by Pories et a/,” is its ability t o catalyze wound healing. In this role, zinc probably acts primarily at the wound site where it is incorporated into enzyme systems. Indeed, it has been suggested that there is a n increased metabolic demand for zinc in wound healing and that zinc deficiency is a common cause of delayed tissue repair.3 Investigations have shown that zinc is preferentially concentrated in healing tissues, with a peak activity at seven days after injury. This increase is temporary and is followed by a gradual decrease until there is no increase evident about 100 days after injury. There has been much discussion as to the importance of zinc in the wound healing process; however, a recent report by Arakawa et al reveals the importance zinc may play, especially in patients being treated with TPN.” They reported two case studies; in each, a n infant had suffered from intractable diarrhea for three to four months, which may have contributed t o low zinc levels prior t o T P N therapy. O n the 22nd day of TPN, one patient became febrile, with stomatitis and a strawberry red tongue; two days later, erythema, vesicles and pustules were found around orifices and over the genital region, fingers and toes. Culture of pus from the skin lesions revealed Slapfiylococcirsmireus. The rash became VOLUME 2 I NUhlBER I I 1978
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more severe until the 53rd day of therapy when oral zinc (35 mg/day) was initiated, with a dramatic improvement in the rash and a return t o normal body temperature in five days. The second patient had diarrhea ten times daily from 1 t o 3 months of age. T P N was initiattd and on the 25th day of therapy the patient became febrile and irritable. Vesicle culture revealed S. airreus. Chylosis and stomatitis developed on the 28th day of T P N therapy; however, the lesions were less severe than those in the first patient. Treatment with oral zinc (35 mg/day) was begun on the 39th day of T P N therapy and the skin lesions cleared in a few days. The authors drew several conclusions from these studies. First, the acute onset of symptoms could have been due to decreased zinc levels prior t o T P N therapy. Then, since the rash developed during periods of rapid weight gain, T P N therapy complicated the low zinc levels by further draining body stores of zinc. The second conclusion was that since both beds were in the same room and both patients had the same infectingorganism, they may have been .cross-infected. It seems possible, therefore, that zinc deficiency impaired the resistance of the infants’ skin t o opportunistic infection.
RECENT INVESTIGATIONS
authors calculated the mean decline ofserum copper to be 10.8 pg/dl/wk. The range of the decline was 5.6 to 20 pg/dl/wk and normal copper level at that institution was 75 pg/dl. Zinc levels were also determined for all eight patients; four maintained zinc levels within normal limits in spite of T P N for three t o ten weeks. Mean decline of serum zinc was calculated to be 6.6 pg/dl/wk; the range for decline was 0.33 t o 20 pg/dl/wk with the normal serum level at 70 pg/dl. The results from these early studies indicate that plasma trace element levels d o decline, but that the declines are extremely variable because of the individual’s condition. One final consideration that must be taken into account is possible trace element loss due to the T P N solution itself. In a tecent article by Freeman et al, the investigators noted increased urinary zinc losses during TPN,” and calculated the urinary zinc excretion t o be 4,500 pg/day (normal is 0.1 t o 0.7 mg/day). This excessive excretion followed T P N with either protein hydrolysates or crystalline amino acids previously autoclaved rvirlt dextrose. Upon chemical analysis of the T P N solutions, the investigators found sugar amine compounds and postulated that these may have chelated the zinc, thereby increasing its urinary excretion.
Two recent studies have been reported in which the authors attempted t o quantitate plasma trace element dynamics during TPN.29’30When evaluating their data, one must remember that the patient’s overall physical condition determines the dynamics of his plasma trace elements. Therefore, it is very difficult t o determine “normal” or “expected” rates of loss since the patients studied had such a variety of disease states. The results do, however, represent the first attempts t o quantitate plasma trace element dynamics during TPN. In the Fleming29study, eight patients received T P N for at least three weeks (average 7 weeks). Copper and zinc levels of the T P N solution were determined; copper was unobtainable and zinc was 0.63 t o 1 mg/l, which would yield a total of 3 mg/day or 20% of the RDA.” All eight patients showed a decline of serum copper levels; two had a mild hypocupremia and three had a severe hypocupremia. Two of the three patients with severe hypocupremia had conditions similar to those described by Dunlap et al” and Vilter er ~ 1 , that ’ ~ is, one patient may have lost excessive copper through a high-output duodenocutaneous fistula; the other experienced chronic diarrhea and a 40 Ib weight loss associated with a short bowel syndrome. Ceruloplasmin levels were determined for the three patients with severe hypocupremia; and, as would be expected, they too were well below normal. Additionally, the tw&p&e$s v X h s e % - r F h ~ o c i ~ e G i a had declines in hemoglobin concentration. Finally, the
We have presented the dynamics of zinc, copper and manganese, along with the necessity for maintaining their levels within a critical range. During T P N therapy, several processes occur which disrupt the normal plasma concentrations of these trace elements: ( I ) decreased intake of trace elements; (2) increased need for trace elements during the anabolic processes that occur with TPN; and (3) increased excretion of trace elements due t o either the patient’s physical condition, chemical composition of the T P N solution or concurrent drug therapy. The existence of any one or a combination of these conditions will alter plasma trace element concentration. The most obvious question remaining is when are trace element dynamics so upset that replacement therapy must be initiated? Unfortunately, at the present time, replacement of trace elements remains more of a n art than a science, for it is difficult t o determine precisely when and how much supplementation is appropriate. One prominent clinician in the field of TPN” feels that the initial physical presentation of the patient is the most important determinant at the present time. Certain populations would be expected t o require supplementation, and would include those with Crohn’s disease, surgical resection, impaired digestion o r malabsorption. These patients are then given the standard supplement from the first day of therapy. Additionally, it has been his
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RECOMMENDATIONS
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HISTORICAL PERSPECTIVES PLAShlA TRACE ELEhlENTS I N T P N
experience that patients with high-output fistulas are notorious zinc losers and may have requirements beyond those present in the standard supplement. Premature infants with respiratory distress syndrome are also started o n trace element supplement immeiliately, and may have a zinc requirement beyond that present in the supplement. For other patients on TI" who would not be expected t o require trace element supplementation, awareness is the watchword-awareness primarily of the importance of trace elements, the fact that their concentration may be altered during T P N and of the patient's physical condition so that signs and symptoms such as those presented may be recognized as manifestations of trace element deficiencies. This overall awareness, coupled with periodic (2-4 weeks32)plasma trace element levels, should assist the clinician in effectively monitoring his patient for trace element abnormalities during T P N therapy.
REFERENCES 1. Cotzias G C In Hemphill DD (ed): Proc 1st Annu Conf Trace
2. 3. 4.
5. 6. 7.
8. 9. 10.
Substances and Environmental Health. Columbia, hlissouri, 1967, p 5. Mertz W: Trace element in health and disease: Contributions and problems of analysis. Clin Chem 21:468-475, 1975. Underwood EJ: Trace Elements in Human and Animal Nutrition, ed 3. New York, Academic Press, 1971, pp 1-13, 57-106, 177-252. Solomons NW, Layden TJ, Rosenberg IH et al: Plasma trace minerals during total parenteral alimentation. Gastroenterology 70:1022-1025, 1976. Burch RE, Sullivan KF: Trace elements. Med Clin North Am 60:655-660, 675-685, 687-703, 713-727, 1976. Hull RL: Use of trace elements in intravenous hyperalimentation solutions. Am J Hosp Pharm 31:759-761, 1974. Shils M, Wright W, Turball A: Long term parenteral nutrition through an external arteriovenous shunt. N Engl J Med 283:341344, 1970. Burch RE, Hahn HJK, Sullivan JF: Newer aspects of the roles of zinc, manganese, and copper in human nutrition. Clin Chem 21:501-520, 1975. Bertinchamps AJ, Miller ST, Cotzias GC: Interdependence of routes excreting manganese. Am J Physiol 21 1:217-224, 1966. Hankins DA, Riella MC, Scribner BH et al: Whole blood trace element concentrations during total parenteral nutrition. Surgery 79674-677, 1976.
1 I. Dunlap Whl, James GW, Hume Dhl: Anemia and neutropenia
caused by copper deficiency. Ann Intern hled 80:47&477, 1974. 12. Recommended Dietary Allowances, ed 8. Washington, DC, Natl Acad Sci Res Council, 1974. 13. Cartwrigh! GE, Wintrobe hlM: Copper metabolism in normal subjects. Am J Clin Nutr 14:224-233, 1964. 14. Evans GW: Copper homeostasis in the mammalian system. Physiol Rev 53535471, 1973. 15. Karpel JT, Peden VG: Copper deficiency in long term total parenteral nutrition. J Pediatr 80:32-36, 1972. 16. Vilter RW, Bozian RC, Hess EV et al: Manifestations of copper deficiency in a patient with systemic sclerosis on intravenous hyperalimentation. N Engl J hled 291:188-191, 1974. 17. Goodman J R , Dallman PR: Role of copper in iron localization in developing erythrocytes. Blogd 34:747-753, 1969. 18. Cordano : Hypocupremia and neutropenia in copper deficiency. Blood 28:28&283, 1966. 19. Henkin RI, Graziader PPG, Bradley: The molecular basis of taste and its abnormalities. Ann Intern bled 71:791-821, 1969. 20. Widdowson Rhl: Trace elements in foetal and early postnatal development. Nutr SOCProc 33:275-284, 1974. 21. Prasad AS, Oberleas D: Zinc: human nutrition and metabolic effects. Ann Intern hled 73:631-637, 1970. 22. Hambridge hl, Hambridge C, Jacobs M et al: Low levels ofzincin hair, anorexia, poor growth, and hypogeusia in children. Pediatr Res 6868-874, 1972. 23. Smith H: The distribution of antimony, arsenic, copper, and zinc in human tissue. J Forensic Sci SOC7:97-102, 1967: 24. Henkin RI, Schechter PJ, Hoye R et al: Idiopathic hypogeusia, dysgeusia, hyposmia, and dysosmia. A new syndrome. J A h l A 2 17:434-440, I97 1. 25. Henkin RI: Hypogeusia corrected by nickel and zinc. Life Sci 9:701-709, 1970. 26. Hambidge Khl: The clinical significance of trace element deficiencies in man. Nutr SOCProc 33:249-256, 1974. 27. Pories WJ, Henzel J H , Rob CG et al: Acceleration of wound healing with zinc sulfate. Ann Surg 165:432-436, 1967. 28. Arakawa T, Tamura T, lgarashi Y et al: Zinc deficiency in two infants during total parenteral nutrition for diarrhea. Am J Clin Nutr 29:197-204, 1976. 29. Fleming CR, Hodges RE, Hurley LS: A prospective study of serum copper and zinc in patients receiving total parenteral nutrition. Am J Clin Nutr 29:70-77, 1976. 30. Solomons N, Vo-Khactu K, Layden T et al: Plasma trace metal dynamics during total parenteral alimentation. Am J Clin Nutr 28:421, 1975 (abstr). 31. Freeman JB, Stegink LD, Meyer PD et al: Excessive urinary zinc losses during parenteral alimentation. J Surg Res 18:463-469, 1975. 32. Burke A: Personal interview, March 29, 1977.
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VOLUhlE 2 / NUMBER I / 1978
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I
Russel Allinson, RPh
Requests for reprints should be addressed to Russel Allinson, RPh. Hospital Pltarmacy Resident. Department of PharnZacy, Riverside hfethodist Hospital, Colunibus. Ohio 43214.
TO begin a discussion of the use of essential trace elements in total’p’arentFra1 nutrition (TPN) we must first define a n essential trace elEment,For a trace element to be essential, it must meet the definition established by Cotzias’ that: I. I t is present in all healthy tissues of all living things. 2. Its concentration from one animal t o the next is fairly consistent. 3. If its withdrawal from the body induces reproducibly the same structural and physiologic abnormalities, regardless of the species studied. 4. Its addition either prevents or reverses these abnormalities. 5. The abnormalities induced by deficiency are always accompanied by pertinent, specific, biochemical changes. 6. These biochemical changes can be prevented or cured when the deficiency is prevented o r cured. At the present time, ten trace elements have been classified as essential: iron, iodine, copper, zinc, manganese, cobalt, molybdenum, selenium, chromium and In addition, there are 20 t o 30 other trace elements that have been found consistently in various concentrations in living tissue. Generally, depending on the specific element, its dose and the nutritional state of the animal in question, the action of these elements may be thought to occur as a spectrum. Venchikov described this spectrum as a curve with two maxima.-’ The initial rise of the curve shows increasing effect with increasing dose until a plateau is reached; at this point, there is optimal biologicaction and normal function. Beyond the plateau, the curve rises and the element acts as a drug, with its own pharmacologic properties and independent of a deficiency state. As the dose is increased, toxicity develops which may ultimately result in death. With this description in mind, one can easily understand the necessity of maintaining trace element concentrations within specific limits. “Continued ingestion of diets that are deficient, imbalanced o r excessively high in a particular trace element invariably induces changes in the functioning forms, activities or concentrations of that element in the body tissue or fluids, so that they fall below o r rise above the permissible limits.” -’ Therefore, in patients on TPN, continued feeding with diets deficient in trace elements would beexpected t o alter the concentration of those trace elements. Solomons has postulated that in addition t o decreased intake, there is increased excretion, increased utilization and redistribution, and decreased plasma binding, all of which contribute t o a decreased trace element concentration during With these possibilities in mind, clinicians-pharmacists and physicians-must monitor
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HISTORICAL PERSPECTIVES PLASMA TRACE ELEMENTS IN T P N
TABLE I
V 23
Cr -.
Mn
24
25
Fe 26
Co 27
Ni 28
Cu 29
Zn
30
,‘I
patients on T P N to ensure that trace element concentrations are maintained within the critical limits. Often, monitoring requires only a careful awareness of the patient’s condition and the importance and necessity of essential trace elements. “In essence, the most important requisite in making a diagnosis of trace element abnormalities at the present time is a high index of suspicion of their presence.”’ Of the ten essential trace elements, three (iron, iodine and cobalt) have been widely discussed physiologically and pharmacologically in many texts and publications and warrant no’ further discussion here; this does not, however, preclude their importance in T P N patients. Of the remaining seven trace elements, copper, zinc and manganese have been widely studied and utilized in replacement regimen^.^" Therefore, the attention of this paper will be focused o n the properties of these three trace elements and the signs and symptoms indicative of their deficiency. MANGANESE Manganese belongs t o the first long series in the periodic chart of elements, “transition elements.” It is interesting t o note that manganese is surrounded in this series by several of the other trace elements (Table I),’ Early studies conducted in the 30’s revealed the relationship of manganese t o growth, reproduction, skeletal development and carbohydrate and lipid metabolism. To date, the exact mechanism and locus of its absorption have not been determined. Estimates of daily intake vary greatly with the type of diet; a n estimated daily intake would be 0.7 t o 2.2 mg/day. Under conditions of minimal intake, 20 pg/day would be retained.* Distribution and storage of this element is dependent on the characteristics of the organ; those rich in mitochondria tend to have the highest concentration of manganese. The bones, liver, kidney, pancreas and pituitary gland normally have higher concentrations than other tissues. The extent ofthis distribution and storage is not nearly as great as copper and zinc. A 70 kg adult human has 12 t o 20 mg of manganese; this is only 1/5 the total of copper and only 1/100 the total of zinc.3 Manganese does not accumulate t o the extent of copper and zinc in the lungs and its storage in the liver is also much less. Several studies show that normal whole blood
levels are low (8.44 2 2.73 pg/l); manganese circulates in blood bound selectively and almost totally t o a PI globulin. Finally, radioactive studies show that manganese appears to be in a dynamic, highly mobile state with two major pools being the blood and the liver mitochondria.’ Total body levels of manganese are regulated almost entirely by intestinal excretion via several routes. The main route of excretion is bile flow; when this route of excretion is blocked or overloaded, manganese may be excreted by pancreatic juices or the duodenum and jejunum.’ Under normal conditions, there is n o expected urinary excretion of mangan-ese. Although manganese has been combined in trace element s ~ p p l e m e n t a t i o n s , ~there ’ ~ have not been any reported deficiencies as a result of T P N without supplementation. Furthermore, one report indicated that in five of six patients who were on TPN, there was a n elevation of manganese levels. It was the authors’ opinion that the high levels of manganese were probably due to its high content in the nutrient solutions.” There has been only one case of manganese deficiency reported in humans which occurred because of a n inadvertent omission of manganese salts from a vitamin K-deficient diet on a metabolic ward. The patient in this case had increased cholesterol, weight loss, transient dermatitis, occasional nausea and vomiting and changes in hair and beard color. The authors concluded that “an extreme degree of deficiency is necessary t o produce a deficiency state.” COPPER Copper is so widely distributed in foods of the daily diet that severe nutritional deficiency is virtually impossible.” The precise daily intake of copper varies with diet and geographic location; however, an average daily diet contains between 2 and 4 mg. When compared t o the recommended dietary allowance (RDA) of at least 2 mg/day,’* the average daily intake is sufficient. Absorption of the element occurs in the stomach and upper gut t o the extent of about 32%” After absorption, there is a wide tissue distribution of copper in the body with 23 mg total in the liver, heart, spleen, kidney, brain and blood. Of the 23 mg total, 8 mg are in the brain and the liver. Normal plasma concentration is 109 k 17 pg p e r ~ e n t In . ~ the plasma, copper exists in two forms, with one bound firmly and the other bound more loosely. The loosely bound copper is that which is bound t o albumin; copper migrates into this pool from the intestine after absorption. The copper which is bound t o albumin is considered “transport copper”; in this form, the element may be distributed into and out of the tissues. When copper is transported t o the liver, it may either be stored VOLUhlE 2 / NUMBER I / 1978
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there or released for incorporation into cellular enzymes, erythrocuprein or ceruloplasmin. Ceruloplasmin is produced by the liver in response to body copper levels; it is a true oxidase which catalyzes the oxidation of several biologic compounds including serotonin',?nd epinephrine." Although 80% of serum coppe; is bound to ceruloplasmin, this complex does not play a major role in the absorption or transport of copper. Excretion of the element is primarily biliary; copper is bound t o protein macromolecules and, t o a lesser extent, amino acids, and excreted in the feces with n o reabsorption via enterohepatic circulation.' Intravenous injection of copper results in increased biliary and consequently, fecal excretion, with no increase in urine excretion. Urine "-excretion of copper is minimal, only 0.01 t o 0.06 mg of the daily dose.I3 Copper functions physiologically as a component of many cuproenzymes. 'These enzymes participate in three areas of human health: (1) development and maintenance of cardiovascular and skeletal integrity, (2) central nervous system (CNS) structure and function and (3) erythropoietic function, including m e t a b ~ l i s m .While ~ long-term copper deficiency in man and animals may cause cardiovascular, skeletal or CNS symptoms, decreased copper intake secondary t o T P N therapy is generally manifested in two clinical conditions, anemia and n e ~ t r o p e n i a . ' ~ ' ' ~ As ' ' ~ previously indicated, in a condition of copper deficiency, there will be decreased ceruloplasmin p r o d ~ c t i o n . 'Ceruloplasmin ~ is felt t o be responsible for the oxidation of iron from the ferrous t o the ferric state; transferrin will only accept iron in the ferric state. Therefore, the intestinal absorption of iron will be decreased in a condition of copper deficiency probably because of decreased ceruloplasmin.I6 In addition t o decreased iron absorption, there also appears to be decreased iron uptake by erythrocytes. In animal studies" of the localization of iron in developing erythrocytes of normal and copper-deficient rats by electron microscopy, the copper-deficient animals appeared t o have an impaired uptake of iron by mitrochondria where it combines with protoporphyrin t o form heme. Consequently, the copper deficiency resulted in a hypochromic, microcytic anemia similar t o that described by hemoglobin deficiencies. Two mechanisms are combining, therefore, t o produce anemia in copper-deficient patients. In a report from Mexico, there were a number of cases of neutropenia in recovering malnourished infants on a n almost exclusive milk diet.'' When treating the copper deficiency, neutropenia was the earliest and most consistent indicator of treatment adequacy. Two other reports in patients on T P N indicated that anemia, neutropenia and leukopenia occurred and were corrected
by the addition of ~ 0 p p e r . I ~As" ~yet, a mechanism for the relationship between copper deficiency and neutropenia and leukopenia has not been established. A recent case presented by Vilter er all6 is indicative of the relationship between copper deficiency, neutropenia and leukopenia. The patient presented with systemic sclerosis of the intestine and malabsorption. T P N therapy was initiated in November of 1972; later analysis of the solution revealed that the patient was receiving only 0.1 mg/day of copper ( R D A = 2 mg/day). The white blood count (WBC) and neutrophils continued to fall until mid January when signs of severe copper deficiency were evident. For the next four months, prior to the administration of copper, the patient had leukopenia (WBC, 1,700), neutropenia (neutrophils, 600) and anemia, red blood kount (3.4 X i06/mm3; hemoglobin, 10.2 g/ 100; hematocrit, 32.4%). At this time, the patient's serum copper was very low (0.2 pglml), her ceruloplasmin was reported t o be zero and her serum zinc was low (0.54 pg/ ml); no bone demineralization was noted. On May 29, 1973, nearly six months after starting T P N therapy, supplementation with 1 mg/day of IV copper sulfate was started. There was a n immediate rise in WBC and neutrophils, and seven days later the levels were normal (WBC, 6,000; neutrophils, 5,000). One further clinical symptom that may be indicative of copper deficiency is taste abnormality. Henkin ei a1 described a group of patients with scleroderma, cystinuria or rheumatoid arthritis who were treated with dpenicillamine." Before treatment, the patients had normal or elevated serum ceruloplasmin and normal taste acuity; after therapy, several groups had ceruloplasmin levels below normal and a significant decrease in taste acuity. When compared with a group with Wilson's disease who were treated with d-penicillamine, the taste abnormality was almost uniformly associated with a decrease in ceruloplasmin a n d / o r copper.
ZINC It was over 100 years ago that zinc deficiency in vivo was first described.' Since then, 70 known zinc enzymes have been identified, and it is also known that zinc is present in DNA and RNA. Of the 70 known zinc enzymes present in the body, 90% of enzymatic zinc is present in the erythrocyte as carbonic anhydrase.20 The remainder of the zinc is present in leukocytes, platelets and plasma. About one third of plasma zinc is loosely associated with serum albumins, the remainder with globulins. It is interesting t o note that dramatic changes in the zinc content of plasma occur in several disease states: atherosclerosis, malignant tumors, chronic and acute infections, postalcoholic cirrhosis and other liver diseases. Studies have also shown that women in the third
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trimester of pregnancy and women taking oral contraceptives exhibit below normal levels of zinc.3 It has been estimated that the whole body content of zinc in a 70 kg adult is 1.4 t o 2.3 gm. In relation t o other trace elements, this is about half theFmount ofiron, 10 t o 15 times’that of copper and 100 tiAes that of manganese. Absorption of zinc occurs mainly in the small intestine, predominantly in the duodenum and may be affected by three factors: (1) level of elemental intake; (2) amounts and proportions of several other elements and dietary components; and (3) the chemical form of the zinc.3 The exact mechanism for zinc absorption is unknown. Excretion of zinc occurs mainly in the feces, and is composed mainly of unabsorbed oral zinc. The amount of zinc which appears in the urine in healthy adults is very small; 0.1 to 0.7 mg/day compared with the normal daily intake of 10 t o 15 mglday. As mentioned previously, disease states alter the amount of zinc in the urine and it may be increased t o as much as 2.1 mg/day in alb~minurics.~ Presently, zinc has been shown t o be involved in many body functions. There is a definite relationship between zinc and bone growth and it has been shown t o be intimately involved in protein, RNA and DNA synthesk6 Additionally, Prasad and Overleas have correlated a relationship between zinc deficiency in man and a condition of hypogonadism, hepatosplenomegaly, iron deficiency anemia and shortened stature,Z1and related the growth reduction and gonadal hypofunction t o zinc insufficiency. There has also been a recent report from Denver demonstrating low hair zinc levels with poor growth and diminished taste acuity in children.” (Hair levels of zinc are often measured in man t o determine body levels of zinc.)23 With zinc supplementation, there was a n increased taste acuity, improved appetite and growth. With the exception of diminished taste acuity, the conditions described by Prasad and Overleas” and Hambridge ef alZZare long-term deficiency complications During the administration of TPN, some more acute problems of decreased zinc intake might be expected t o occur. One consequence of zinc deficiency may actually serve as a clinical indication of the need fo; replacement therapy. Henkin et al described in 1971 “a new syndrome”’‘ of idiopathic hypogeusia, dysgeusia, hyposmia and dysosmia. Through previous Henkin and his associates knew of the importance of transition metals (zinc, copper and nickel) in the sensation of taste and the subjective changes that can occur with trace element deficiency. In the group of patients they reported, it is useful t o note the changes that occurred in thesense of taste and smell. The dysgeusia was characterized by a n abhorrent taste quality generally associated with non-
tolerant foods, eg, rancid or spoiled. Usually the patients reported persistent metallic, bitter, sour or salty taste which they could not remove. AS would be expected, patients with hypogeusia reported their food t o be tasteless, similar t o eating sawdust o r swallowing flour -paste, and often needed t o add excess salt or sugar. The patients with dysosmia complained of a persistent obnoxious odor similar t o gasoline, dust, sweat or tar; some foods were particularly abhorrent: bacon, onion and garlic. Finally, those patients experiencing hyposmia exhibited a decreased ability to obtain flavor from foods, to distinguish between fresh and spoiled and t o detect the aroma of cooked and uncooked. They also had difficulty using proper amounts of perfumes and colognes. Henkin e f al began treatment with zinc for two reasons: ( I ) because’ it was known t o be involved in the mechanisms of taste and smell and (2) because it was less toxic than nickel and copper. After treatment with zinc, all of the abnormalities were corrected. Another aspect of this is interesting, and that is that more than 50% of the patients had had a recent upper respiratory infection. Hypogeusia and dysgeusia are common in patients following infection, presumably because infections lowers body zinc levels.26 Because of this important association between the trace element zinc and Henkin’s “new syndrome,” at least one author has suggested that serum zinc levels, together with taste acuity tests, be used t o diagnose low zinc levels.6 Another action of zinc, which was proposed initially by Pories et a/,” is its ability t o catalyze wound healing. In this role, zinc probably acts primarily at the wound site where it is incorporated into enzyme systems. Indeed, it has been suggested that there is a n increased metabolic demand for zinc in wound healing and that zinc deficiency is a common cause of delayed tissue repair.3 Investigations have shown that zinc is preferentially concentrated in healing tissues, with a peak activity at seven days after injury. This increase is temporary and is followed by a gradual decrease until there is no increase evident about 100 days after injury. There has been much discussion as to the importance of zinc in the wound healing process; however, a recent report by Arakawa et al reveals the importance zinc may play, especially in patients being treated with TPN.” They reported two case studies; in each, a n infant had suffered from intractable diarrhea for three to four months, which may have contributed t o low zinc levels prior t o T P N therapy. O n the 22nd day of TPN, one patient became febrile, with stomatitis and a strawberry red tongue; two days later, erythema, vesicles and pustules were found around orifices and over the genital region, fingers and toes. Culture of pus from the skin lesions revealed Slapfiylococcirsmireus. The rash became VOLUME 2 I NUhlBER I I 1978
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more severe until the 53rd day of therapy when oral zinc (35 mg/day) was initiated, with a dramatic improvement in the rash and a return t o normal body temperature in five days. The second patient had diarrhea ten times daily from 1 t o 3 months of age. T P N was initiattd and on the 25th day of therapy the patient became febrile and irritable. Vesicle culture revealed S. airreus. Chylosis and stomatitis developed on the 28th day of T P N therapy; however, the lesions were less severe than those in the first patient. Treatment with oral zinc (35 mg/day) was begun on the 39th day of T P N therapy and the skin lesions cleared in a few days. The authors drew several conclusions from these studies. First, the acute onset of symptoms could have been due to decreased zinc levels prior t o T P N therapy. Then, since the rash developed during periods of rapid weight gain, T P N therapy complicated the low zinc levels by further draining body stores of zinc. The second conclusion was that since both beds were in the same room and both patients had the same infectingorganism, they may have been .cross-infected. It seems possible, therefore, that zinc deficiency impaired the resistance of the infants’ skin t o opportunistic infection.
RECENT INVESTIGATIONS
authors calculated the mean decline ofserum copper to be 10.8 pg/dl/wk. The range of the decline was 5.6 to 20 pg/dl/wk and normal copper level at that institution was 75 pg/dl. Zinc levels were also determined for all eight patients; four maintained zinc levels within normal limits in spite of T P N for three t o ten weeks. Mean decline of serum zinc was calculated to be 6.6 pg/dl/wk; the range for decline was 0.33 t o 20 pg/dl/wk with the normal serum level at 70 pg/dl. The results from these early studies indicate that plasma trace element levels d o decline, but that the declines are extremely variable because of the individual’s condition. One final consideration that must be taken into account is possible trace element loss due to the T P N solution itself. In a tecent article by Freeman et al, the investigators noted increased urinary zinc losses during TPN,” and calculated the urinary zinc excretion t o be 4,500 pg/day (normal is 0.1 t o 0.7 mg/day). This excessive excretion followed T P N with either protein hydrolysates or crystalline amino acids previously autoclaved rvirlt dextrose. Upon chemical analysis of the T P N solutions, the investigators found sugar amine compounds and postulated that these may have chelated the zinc, thereby increasing its urinary excretion.
Two recent studies have been reported in which the authors attempted t o quantitate plasma trace element dynamics during TPN.29’30When evaluating their data, one must remember that the patient’s overall physical condition determines the dynamics of his plasma trace elements. Therefore, it is very difficult t o determine “normal” or “expected” rates of loss since the patients studied had such a variety of disease states. The results do, however, represent the first attempts t o quantitate plasma trace element dynamics during TPN. In the Fleming29study, eight patients received T P N for at least three weeks (average 7 weeks). Copper and zinc levels of the T P N solution were determined; copper was unobtainable and zinc was 0.63 t o 1 mg/l, which would yield a total of 3 mg/day or 20% of the RDA.” All eight patients showed a decline of serum copper levels; two had a mild hypocupremia and three had a severe hypocupremia. Two of the three patients with severe hypocupremia had conditions similar to those described by Dunlap et al” and Vilter er ~ 1 , that ’ ~ is, one patient may have lost excessive copper through a high-output duodenocutaneous fistula; the other experienced chronic diarrhea and a 40 Ib weight loss associated with a short bowel syndrome. Ceruloplasmin levels were determined for the three patients with severe hypocupremia; and, as would be expected, they too were well below normal. Additionally, the tw&p&e$s v X h s e % - r F h ~ o c i ~ e G i a had declines in hemoglobin concentration. Finally, the
We have presented the dynamics of zinc, copper and manganese, along with the necessity for maintaining their levels within a critical range. During T P N therapy, several processes occur which disrupt the normal plasma concentrations of these trace elements: ( I ) decreased intake of trace elements; (2) increased need for trace elements during the anabolic processes that occur with TPN; and (3) increased excretion of trace elements due t o either the patient’s physical condition, chemical composition of the T P N solution or concurrent drug therapy. The existence of any one or a combination of these conditions will alter plasma trace element concentration. The most obvious question remaining is when are trace element dynamics so upset that replacement therapy must be initiated? Unfortunately, at the present time, replacement of trace elements remains more of a n art than a science, for it is difficult t o determine precisely when and how much supplementation is appropriate. One prominent clinician in the field of TPN” feels that the initial physical presentation of the patient is the most important determinant at the present time. Certain populations would be expected t o require supplementation, and would include those with Crohn’s disease, surgical resection, impaired digestion o r malabsorption. These patients are then given the standard supplement from the first day of therapy. Additionally, it has been his
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HISTORICAL PERSPECTIVES PLAShlA TRACE ELEhlENTS I N T P N
experience that patients with high-output fistulas are notorious zinc losers and may have requirements beyond those present in the standard supplement. Premature infants with respiratory distress syndrome are also started o n trace element supplement immeiliately, and may have a zinc requirement beyond that present in the supplement. For other patients on TI" who would not be expected t o require trace element supplementation, awareness is the watchword-awareness primarily of the importance of trace elements, the fact that their concentration may be altered during T P N and of the patient's physical condition so that signs and symptoms such as those presented may be recognized as manifestations of trace element deficiencies. This overall awareness, coupled with periodic (2-4 weeks32)plasma trace element levels, should assist the clinician in effectively monitoring his patient for trace element abnormalities during T P N therapy.
REFERENCES 1. Cotzias G C In Hemphill DD (ed): Proc 1st Annu Conf Trace
2. 3. 4.
5. 6. 7.
8. 9. 10.
Substances and Environmental Health. Columbia, hlissouri, 1967, p 5. Mertz W: Trace element in health and disease: Contributions and problems of analysis. Clin Chem 21:468-475, 1975. Underwood EJ: Trace Elements in Human and Animal Nutrition, ed 3. New York, Academic Press, 1971, pp 1-13, 57-106, 177-252. Solomons NW, Layden TJ, Rosenberg IH et al: Plasma trace minerals during total parenteral alimentation. Gastroenterology 70:1022-1025, 1976. Burch RE, Sullivan KF: Trace elements. Med Clin North Am 60:655-660, 675-685, 687-703, 713-727, 1976. Hull RL: Use of trace elements in intravenous hyperalimentation solutions. Am J Hosp Pharm 31:759-761, 1974. Shils M, Wright W, Turball A: Long term parenteral nutrition through an external arteriovenous shunt. N Engl J Med 283:341344, 1970. Burch RE, Hahn HJK, Sullivan JF: Newer aspects of the roles of zinc, manganese, and copper in human nutrition. Clin Chem 21:501-520, 1975. Bertinchamps AJ, Miller ST, Cotzias GC: Interdependence of routes excreting manganese. Am J Physiol 21 1:217-224, 1966. Hankins DA, Riella MC, Scribner BH et al: Whole blood trace element concentrations during total parenteral nutrition. Surgery 79674-677, 1976.
1 I. Dunlap Whl, James GW, Hume Dhl: Anemia and neutropenia
caused by copper deficiency. Ann Intern hled 80:47&477, 1974. 12. Recommended Dietary Allowances, ed 8. Washington, DC, Natl Acad Sci Res Council, 1974. 13. Cartwrigh! GE, Wintrobe hlM: Copper metabolism in normal subjects. Am J Clin Nutr 14:224-233, 1964. 14. Evans GW: Copper homeostasis in the mammalian system. Physiol Rev 53535471, 1973. 15. Karpel JT, Peden VG: Copper deficiency in long term total parenteral nutrition. J Pediatr 80:32-36, 1972. 16. Vilter RW, Bozian RC, Hess EV et al: Manifestations of copper deficiency in a patient with systemic sclerosis on intravenous hyperalimentation. N Engl J hled 291:188-191, 1974. 17. Goodman J R , Dallman PR: Role of copper in iron localization in developing erythrocytes. Blogd 34:747-753, 1969. 18. Cordano : Hypocupremia and neutropenia in copper deficiency. Blood 28:28&283, 1966. 19. Henkin RI, Graziader PPG, Bradley: The molecular basis of taste and its abnormalities. Ann Intern bled 71:791-821, 1969. 20. Widdowson Rhl: Trace elements in foetal and early postnatal development. Nutr SOCProc 33:275-284, 1974. 21. Prasad AS, Oberleas D: Zinc: human nutrition and metabolic effects. Ann Intern hled 73:631-637, 1970. 22. Hambridge hl, Hambridge C, Jacobs M et al: Low levels ofzincin hair, anorexia, poor growth, and hypogeusia in children. Pediatr Res 6868-874, 1972. 23. Smith H: The distribution of antimony, arsenic, copper, and zinc in human tissue. J Forensic Sci SOC7:97-102, 1967: 24. Henkin RI, Schechter PJ, Hoye R et al: Idiopathic hypogeusia, dysgeusia, hyposmia, and dysosmia. A new syndrome. J A h l A 2 17:434-440, I97 1. 25. Henkin RI: Hypogeusia corrected by nickel and zinc. Life Sci 9:701-709, 1970. 26. Hambidge Khl: The clinical significance of trace element deficiencies in man. Nutr SOCProc 33:249-256, 1974. 27. Pories WJ, Henzel J H , Rob CG et al: Acceleration of wound healing with zinc sulfate. Ann Surg 165:432-436, 1967. 28. Arakawa T, Tamura T, lgarashi Y et al: Zinc deficiency in two infants during total parenteral nutrition for diarrhea. Am J Clin Nutr 29:197-204, 1976. 29. Fleming CR, Hodges RE, Hurley LS: A prospective study of serum copper and zinc in patients receiving total parenteral nutrition. Am J Clin Nutr 29:70-77, 1976. 30. Solomons N, Vo-Khactu K, Layden T et al: Plasma trace metal dynamics during total parenteral alimentation. Am J Clin Nutr 28:421, 1975 (abstr). 31. Freeman JB, Stegink LD, Meyer PD et al: Excessive urinary zinc losses during parenteral alimentation. J Surg Res 18:463-469, 1975. 32. Burke A: Personal interview, March 29, 1977.
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