Pagetic Pain\p=m-\APhonetic Discomfort If Sir James Paget were alive today, would he be shocked to see his name transmuted into an eponymic adjective? Would he be appalled to find a reference (Lancet 2:213, 1978) to "pagetic pain"? We have no way of knowing, although rumor has it that the sound of a body turning in its grave can on occasion be heard near the cemetery where the renowned English surgeon lies buried. Why, one might ask, should there be shock, even surprise, at the sight of an eponymic adjective? So many of the world's famous and infamous have bequeathed their names for such adjectival use. We engage in socratic dialogue, profess platonic love, entertain napoleonic ambitions, connive in machiavellian intrigues, strike byronic poses, undertake herculean labors, and watch out for freudian slips. As physicians we encounter our own
eponymic adjectives\p=m-\parkinsoniantremor, pavlovian
reflexes, pickwickian syndrome\p=m-\ingreat
profusion.
Our exposure to adjectivized eponyms should inure us to new arrivals. After taking "cushingoid" in our stride, need we be apologetic for "pagetic"? Yet we hesitate. Phonetic resonances create unease. If we put up with "pagetic pain," there will be nothing to stop us from accepting "monetic influences on abstract expressionism," "manetic impact on theories of art," "daudetic imprints on the naturalistic novel," and, to add semantic confusion to the
phonetic embarrassment, "genetic (with apologies to Jean Genet) insights into the aberrant mind." The pain of Paget's disease arouses compassion. It belongs in the realm of the pathetic. Why make it sound bathetic by labeling it "pagetic"?
Samuel Vaisrub, MD
Zinc Interference With
Copper Metabolism
Elsewhere in this issue of The Journal, Prasad et al (p 2166) describe a manifestation of the toxic effects of zinc in humans that has not been generally appreciated. They report the occurrence of copper deficiency (hypocupremia, leukopenia, and anemia) in a patient treated with ten times the recommended dietary allowance for zinc1 during a prolonged interval. In other patients given similar therapy, they found decreased levels of plasma copper and ceruloplasmin. Their observations were consistent with other recent reports.2 It has long been known from studies in animals that high levels of zinc can interfere with metabolism and absorption of copper.3 Zinc will induce the synthesis of metallothein.4 Metallothein may regulate the amounts of zinc and copper absorbed into the body from intestinal epithelial cells in a manner
Address editorial communications to the Editor, 535 N Dearborn
analogous to the regulation of iron absorption by ferritin.5 At physiological levels, zinc bound to metallothein can apparently be displaced by copper because of the higher binding strength
of copper to thiolate sulfur.6 The aforementioned observations suggest the following explanation for the induction of copper deficiency by high doses of zinc. High levels of zinc induce the synthesis of metaliothein in intestinal mucosal cells. Copper, which enters the mucosal cells, displaces the zinc from the metaliothein. Copper complexed with the metaliothein is then retained in the intestinal mucosal cells and is ultimately lost into the lumen of the intestine as the cells turn over. Evidence of such a phenomenon has been reported from experiments when cadmium was used as the inducer of metaliothein.7 Copper has been shown to displace cadmium from metaliothein in a manner similar to its displacement of zinc.6 As zinc and cadmium behave similarly with regard to the induction of metaliothein synthesis, it seems likely that the previously mentioned events occurred in the cases reported by Prasad and his associates. Another possibility is that a high intake of zinc might cause an increased excretion of copper in bile. Complexes of metalio¬ thein and copper in the liver may be taken up by lysosomes8 and the copper excreted into the bile canaliculi.9 High intakes of zinc, which induce metaliothein synthesis in liver, might facilitate copper excretion through the exchange of copper for zinc on binding sites of liver metaliothein6 and the subsequent uptake of metallothein-copper complexes by lysosomes. The signs of copper deficiency observed by Prasad et al were similar to those reported by Cordano et al.10 Other findings described by Cordano et al'° included osteopenia and patho¬ logic fracture. Another effect of copper deficiency verified in experimental animals" but not as yet described in humans is myocardial degeneration with necrosis and scarring. These observations suggest that caution should be exercised in giving pharmacologie amounts of elements that interfere with copper metabolism. In retrospect, it does not seem reasonable to give ten times the recommended allowance for zinc (15 mg)1 to patients who have a normally functioning gastrointestinal tract. The use of such large doses has been empirical. It seems more reasonable to be therapeutically conservative and not give more than two to three times the recommended allowance for zinc where the condition under therapy is probably nutritional in origin and not due to metabolic inhibition, intestinal malabsorption, or excessive losses caused by impaired conserving mechanisms. Studies concerning persons with dwarfism and hypogonadism due to nutritional zinc deficiency showed that therapy with approximately 30 mg of zinc daily was sufficient.12 Recently,
St, Chicago, IL 60610.
Downloaded From: http://jama.jamanetwork.com/ by a Monash University Library User on 06/18/2015
successfully treated a patient with iatrogenic zinc and deficiency impaired cell-mediated immunity with 22.7 mg of zinc daily. The findings reported by Prasad et al emphasize the need for prudent assessment of the amount of zinc supplementation needed by a patient. If amounts greatly in excess of the Pekarek
et
al"
recommended allowance are necessary, the copper status of the patient should be carefully monitored. It is not known whether doses of zinc as low as two to three times the recommended allowance are entirely benign. Harold H. Sandstead, MD US Department of Agriculture Science and Education Administration Grand Forks, ND 1. Recommended Dietary Allowances. US National Research Council, National Academy of Sciences, 1974. 2. Greger J, Zaikis SC, Bennett OA, et al: Mineral and nitrogen balances of
adolescent females fed two levels of zinc, abstracted. Fed Proc 37:220, 1978. 3. Magee AC, Matrone G: Studies on growth, copper metabolism and iron metabolism of rats fed high levels of zinc.J Nutr 72:233-242, 1960. 4. Cherian MG: Studies on the synthesis and metabolism of zinc-thionein in rats.J Nutr 107:965-972, 1977. 5. Evans GW, Johnson PE: Copper- and zinc-binding ligands in the intestinal mucosa, in Kirchgessner M (ed): Trace Element Metabolism in Animals-III. To
published.
be
6. Hartman HJ, Weser U: Copper-thionein from fetal bovine liver. Biochim Biophys Acta 491:211-222, 1977. 7. Davies NT, Campbell KJ: The effect of cadmium on intestinal copper absorption and binding in the rat. Life Sci 20:955-960, 1977. 8. Porter H: The particulate half-cystine copper protein of newborn liver. Biochem Biophys Res Commun 56:661-668, 1974. 9. Evans GW: Biological regulation of copper homeostasis in the rat, in Bourne G (ed): World Review of Nutrition and Dietetics. Basel, Switzerland, S Karger, 1973, vol 17, pp 225-249. 10. Cordano A, Baertl JM, Graham GG: Copper deficiency in infancy. Pediatrics 34:324-336, 1974. 11. Allen KGD, Klevay LM: Cholesterolemia and cardiovascular abnormalities in rats caused by copper deficiency. Atherosclerosis 29:81-93, 1978. 12. Sandstead HH, Prasad AS, Schulert AR, et al: Human zinc deficiency, endocrine manifestations and response to treatment. Am J Clin Nutr 20:422-442,
1967.
13. Pekarek R, Jacob R, Barcome D, et al: Effect of acquired zinc deficiency the cellular immune response, abstracted. Am J Clin Nutr 30:612, 1977.
on
An Element of Pleasure of zinc, which began centuries ago with the fumbling empiricism of local therapy for wounds and various skin lesions, is now entering an era of oral and parenteral therapy based on indications of specific deficiency in need of replenishment. Zinc has proved effective in acrodermatitis enteropathica of genetic origin1 as well as in the acquired variant associated with prolonged intravenous alimentation.2 Watery diarrhea and skin lesions characteristic of these zincdepleted states have responded well to replacement therapy as have the syndrome of growth retardation and hypogonadism reported from the Middle East3 and in similar malfunctions complicating sickle cell disease.4 Improvement with zinc has also been noted in refractory cases of celiac disease' and in children with protein-energy malnutrition whose zinc-deficient state is associated with thymic atrophy and susceptibility to infection.6 True to its first love, the skin, zinc still maintains its precarious contact (albeit not as a local application but as a systemic medication) in the treatment of wounds and skin Medicinal
uses
disorders.
important effect of zinc therapy is the improvement in the quality of life for some patients even when it does not cure An
their disease. For instance, zinc alleviates the diminished or distorted sensations of taste and smell that sometimes compli¬ cate viral hepatitis and respiratory infections or occur indepen¬ dently as idiopathic phenomena.7 Nothing can be more welcome to a patient who had shunned food because of its tastelessness or offensiveness than the return of the pleasures of the table. No less welcome is the return of sexual function to a patient whose libido or potency had been depressed by á serious disease. Such a return has been reported recently with zinc therapy in patients with end-stage renal failure. Intrigued by the observed prevalence of impotence in male and of amenorrhea in female uremic patients, Antoniou et al8 conducted a thera¬ peutic trial to ascertain whether the low plasma zinc level generally found in these patients was, in effect, responsible for the gonadal dysfunction. They added zinc chloride to the dialysis baths of four impotent uremic men, with four other impotent uremic patients who received dialysis serving as control subjects. Sexual function improved strikingly in all four treated patients. Their low plasma-zinc levels rose to slightly above normal, and in two of them, low baseline plasma testosterone levels reached normal. By contrast, no clinical or biochemical changes were observed in the control group. Although such a limited study cannot give rise to firm conclusions, it will provide an impetus to further experimental trials. An element that appears to be essential to so basic a pleasure drive merits full exploration. Traditionally committed to the relief of pain rather than to the enhancement of pleasure, the physician is now cast into the unfamiliar role of a pleasure giver. Instead of restricting or proscribing pleasurable activities as he often did in the past, he finds himself aiding and abetting them. Having tried this role, he may like it. Experimental and therapeutic uses of zinc are expanding. Not unexpectedly with this expansion come tidings of adverse effects. One such effect is the lowering of the serum copper level. Elsewhere in this issue, Prasad et al (p 2166) report and Sandstead (p 2188) comments on this preventable complication which should be guarded against. Samuel Vaisrub, MD 1.
Moynahan EJ: Acrodermatitis enteropathica:
A lethal inherited human Lancet 2:399-400, 1974. C, Kay RG: Zinc deficiency and skin lesions. N EnglJ Med
zinc-deficiency disorder. 2.
Tasman-Jones
293:830, 1975. 3. Prasad AS, Halstead JA, Nadimi M: Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 31:532-546, 1961. 4. Prasad AS, Schoomaker EB, Ortega J, et al: Zinc deficiency in sickle cell disease. Clin Chem 21:582-587, 1975. 5. Elmes MF, Golden M, Love AHG: Unresponsive coeliac disease. QJ Med 45:696-697, 1974. 6. Golden MH, Jackson AA, Golden BF: Effect of zinc on thymus of recently malnourished children. Lancet 2:1057-1059, 1977. 7. Henkin RI, Schechter PJ, Hoye R, et al: Idiopathic hypogeusia with dysgeusia, hyposmia, and dysosmia: A new syndrome. JAMA 217:434-440, 1971. 8. Antoniou
impotence by
LD, Sudhakar T, Shalhoub zinc. Lancet 2:895-898, 1977.
Downloaded From: http://jama.jamanetwork.com/ by a Monash University Library User on 06/18/2015
RJ,
et
al: Reversal of uraemic
eponymic adjectives\p=m-\parkinsoniantremor, pavlovian
reflexes, pickwickian syndrome\p=m-\ingreat
profusion.
Our exposure to adjectivized eponyms should inure us to new arrivals. After taking "cushingoid" in our stride, need we be apologetic for "pagetic"? Yet we hesitate. Phonetic resonances create unease. If we put up with "pagetic pain," there will be nothing to stop us from accepting "monetic influences on abstract expressionism," "manetic impact on theories of art," "daudetic imprints on the naturalistic novel," and, to add semantic confusion to the
phonetic embarrassment, "genetic (with apologies to Jean Genet) insights into the aberrant mind." The pain of Paget's disease arouses compassion. It belongs in the realm of the pathetic. Why make it sound bathetic by labeling it "pagetic"?
Samuel Vaisrub, MD
Zinc Interference With
Copper Metabolism
Elsewhere in this issue of The Journal, Prasad et al (p 2166) describe a manifestation of the toxic effects of zinc in humans that has not been generally appreciated. They report the occurrence of copper deficiency (hypocupremia, leukopenia, and anemia) in a patient treated with ten times the recommended dietary allowance for zinc1 during a prolonged interval. In other patients given similar therapy, they found decreased levels of plasma copper and ceruloplasmin. Their observations were consistent with other recent reports.2 It has long been known from studies in animals that high levels of zinc can interfere with metabolism and absorption of copper.3 Zinc will induce the synthesis of metallothein.4 Metallothein may regulate the amounts of zinc and copper absorbed into the body from intestinal epithelial cells in a manner
Address editorial communications to the Editor, 535 N Dearborn
analogous to the regulation of iron absorption by ferritin.5 At physiological levels, zinc bound to metallothein can apparently be displaced by copper because of the higher binding strength
of copper to thiolate sulfur.6 The aforementioned observations suggest the following explanation for the induction of copper deficiency by high doses of zinc. High levels of zinc induce the synthesis of metaliothein in intestinal mucosal cells. Copper, which enters the mucosal cells, displaces the zinc from the metaliothein. Copper complexed with the metaliothein is then retained in the intestinal mucosal cells and is ultimately lost into the lumen of the intestine as the cells turn over. Evidence of such a phenomenon has been reported from experiments when cadmium was used as the inducer of metaliothein.7 Copper has been shown to displace cadmium from metaliothein in a manner similar to its displacement of zinc.6 As zinc and cadmium behave similarly with regard to the induction of metaliothein synthesis, it seems likely that the previously mentioned events occurred in the cases reported by Prasad and his associates. Another possibility is that a high intake of zinc might cause an increased excretion of copper in bile. Complexes of metalio¬ thein and copper in the liver may be taken up by lysosomes8 and the copper excreted into the bile canaliculi.9 High intakes of zinc, which induce metaliothein synthesis in liver, might facilitate copper excretion through the exchange of copper for zinc on binding sites of liver metaliothein6 and the subsequent uptake of metallothein-copper complexes by lysosomes. The signs of copper deficiency observed by Prasad et al were similar to those reported by Cordano et al.10 Other findings described by Cordano et al'° included osteopenia and patho¬ logic fracture. Another effect of copper deficiency verified in experimental animals" but not as yet described in humans is myocardial degeneration with necrosis and scarring. These observations suggest that caution should be exercised in giving pharmacologie amounts of elements that interfere with copper metabolism. In retrospect, it does not seem reasonable to give ten times the recommended allowance for zinc (15 mg)1 to patients who have a normally functioning gastrointestinal tract. The use of such large doses has been empirical. It seems more reasonable to be therapeutically conservative and not give more than two to three times the recommended allowance for zinc where the condition under therapy is probably nutritional in origin and not due to metabolic inhibition, intestinal malabsorption, or excessive losses caused by impaired conserving mechanisms. Studies concerning persons with dwarfism and hypogonadism due to nutritional zinc deficiency showed that therapy with approximately 30 mg of zinc daily was sufficient.12 Recently,
St, Chicago, IL 60610.
Downloaded From: http://jama.jamanetwork.com/ by a Monash University Library User on 06/18/2015
successfully treated a patient with iatrogenic zinc and deficiency impaired cell-mediated immunity with 22.7 mg of zinc daily. The findings reported by Prasad et al emphasize the need for prudent assessment of the amount of zinc supplementation needed by a patient. If amounts greatly in excess of the Pekarek
et
al"
recommended allowance are necessary, the copper status of the patient should be carefully monitored. It is not known whether doses of zinc as low as two to three times the recommended allowance are entirely benign. Harold H. Sandstead, MD US Department of Agriculture Science and Education Administration Grand Forks, ND 1. Recommended Dietary Allowances. US National Research Council, National Academy of Sciences, 1974. 2. Greger J, Zaikis SC, Bennett OA, et al: Mineral and nitrogen balances of
adolescent females fed two levels of zinc, abstracted. Fed Proc 37:220, 1978. 3. Magee AC, Matrone G: Studies on growth, copper metabolism and iron metabolism of rats fed high levels of zinc.J Nutr 72:233-242, 1960. 4. Cherian MG: Studies on the synthesis and metabolism of zinc-thionein in rats.J Nutr 107:965-972, 1977. 5. Evans GW, Johnson PE: Copper- and zinc-binding ligands in the intestinal mucosa, in Kirchgessner M (ed): Trace Element Metabolism in Animals-III. To
published.
be
6. Hartman HJ, Weser U: Copper-thionein from fetal bovine liver. Biochim Biophys Acta 491:211-222, 1977. 7. Davies NT, Campbell KJ: The effect of cadmium on intestinal copper absorption and binding in the rat. Life Sci 20:955-960, 1977. 8. Porter H: The particulate half-cystine copper protein of newborn liver. Biochem Biophys Res Commun 56:661-668, 1974. 9. Evans GW: Biological regulation of copper homeostasis in the rat, in Bourne G (ed): World Review of Nutrition and Dietetics. Basel, Switzerland, S Karger, 1973, vol 17, pp 225-249. 10. Cordano A, Baertl JM, Graham GG: Copper deficiency in infancy. Pediatrics 34:324-336, 1974. 11. Allen KGD, Klevay LM: Cholesterolemia and cardiovascular abnormalities in rats caused by copper deficiency. Atherosclerosis 29:81-93, 1978. 12. Sandstead HH, Prasad AS, Schulert AR, et al: Human zinc deficiency, endocrine manifestations and response to treatment. Am J Clin Nutr 20:422-442,
1967.
13. Pekarek R, Jacob R, Barcome D, et al: Effect of acquired zinc deficiency the cellular immune response, abstracted. Am J Clin Nutr 30:612, 1977.
on
An Element of Pleasure of zinc, which began centuries ago with the fumbling empiricism of local therapy for wounds and various skin lesions, is now entering an era of oral and parenteral therapy based on indications of specific deficiency in need of replenishment. Zinc has proved effective in acrodermatitis enteropathica of genetic origin1 as well as in the acquired variant associated with prolonged intravenous alimentation.2 Watery diarrhea and skin lesions characteristic of these zincdepleted states have responded well to replacement therapy as have the syndrome of growth retardation and hypogonadism reported from the Middle East3 and in similar malfunctions complicating sickle cell disease.4 Improvement with zinc has also been noted in refractory cases of celiac disease' and in children with protein-energy malnutrition whose zinc-deficient state is associated with thymic atrophy and susceptibility to infection.6 True to its first love, the skin, zinc still maintains its precarious contact (albeit not as a local application but as a systemic medication) in the treatment of wounds and skin Medicinal
uses
disorders.
important effect of zinc therapy is the improvement in the quality of life for some patients even when it does not cure An
their disease. For instance, zinc alleviates the diminished or distorted sensations of taste and smell that sometimes compli¬ cate viral hepatitis and respiratory infections or occur indepen¬ dently as idiopathic phenomena.7 Nothing can be more welcome to a patient who had shunned food because of its tastelessness or offensiveness than the return of the pleasures of the table. No less welcome is the return of sexual function to a patient whose libido or potency had been depressed by á serious disease. Such a return has been reported recently with zinc therapy in patients with end-stage renal failure. Intrigued by the observed prevalence of impotence in male and of amenorrhea in female uremic patients, Antoniou et al8 conducted a thera¬ peutic trial to ascertain whether the low plasma zinc level generally found in these patients was, in effect, responsible for the gonadal dysfunction. They added zinc chloride to the dialysis baths of four impotent uremic men, with four other impotent uremic patients who received dialysis serving as control subjects. Sexual function improved strikingly in all four treated patients. Their low plasma-zinc levels rose to slightly above normal, and in two of them, low baseline plasma testosterone levels reached normal. By contrast, no clinical or biochemical changes were observed in the control group. Although such a limited study cannot give rise to firm conclusions, it will provide an impetus to further experimental trials. An element that appears to be essential to so basic a pleasure drive merits full exploration. Traditionally committed to the relief of pain rather than to the enhancement of pleasure, the physician is now cast into the unfamiliar role of a pleasure giver. Instead of restricting or proscribing pleasurable activities as he often did in the past, he finds himself aiding and abetting them. Having tried this role, he may like it. Experimental and therapeutic uses of zinc are expanding. Not unexpectedly with this expansion come tidings of adverse effects. One such effect is the lowering of the serum copper level. Elsewhere in this issue, Prasad et al (p 2166) report and Sandstead (p 2188) comments on this preventable complication which should be guarded against. Samuel Vaisrub, MD 1.
Moynahan EJ: Acrodermatitis enteropathica:
A lethal inherited human Lancet 2:399-400, 1974. C, Kay RG: Zinc deficiency and skin lesions. N EnglJ Med
zinc-deficiency disorder. 2.
Tasman-Jones
293:830, 1975. 3. Prasad AS, Halstead JA, Nadimi M: Syndrome of iron deficiency anemia, hepatosplenomegaly, hypogonadism, dwarfism and geophagia. Am J Med 31:532-546, 1961. 4. Prasad AS, Schoomaker EB, Ortega J, et al: Zinc deficiency in sickle cell disease. Clin Chem 21:582-587, 1975. 5. Elmes MF, Golden M, Love AHG: Unresponsive coeliac disease. QJ Med 45:696-697, 1974. 6. Golden MH, Jackson AA, Golden BF: Effect of zinc on thymus of recently malnourished children. Lancet 2:1057-1059, 1977. 7. Henkin RI, Schechter PJ, Hoye R, et al: Idiopathic hypogeusia with dysgeusia, hyposmia, and dysosmia: A new syndrome. JAMA 217:434-440, 1971. 8. Antoniou
impotence by
LD, Sudhakar T, Shalhoub zinc. Lancet 2:895-898, 1977.
Downloaded From: http://jama.jamanetwork.com/ by a Monash University Library User on 06/18/2015
RJ,
et
al: Reversal of uraemic
