- Email: [email protected]
Metals
P.L.C.M. van Riel
23 Aluminium (SED-11, 437; SEDA-12, 185;
SEDA-13, 191) An excellent review article about aluminium toxicity in children was published by Freundlich in 1988 (IR). The patients who are at risk, the most important clinical manifestations of aluminium toxicity in prematures and infants and the prevention and treatment with deferoxamine are discussed.
Endocrine metabolic In a study of 12 children with chronic renal failure, the effect of two phosphate binders (aluminium hydroxide and calcium carbonate) on bone turnover and 1,25dihydroxycholecalciferol were compared (2c). Both phosphate binders, in addition to mild dietary phosphorus restriction and small doses of vitamin D supplement, effectively suppressed the secondary hyperparathyroidism. However, in both treatment groups a mild mineralization defect present before treatment worsened, with a decrease in mineral appositional rate and increase in mineralization lag time. In spite of this it is suggested that the observed mineralization defect is due to aluminium toxicity. An argument for this may be the raised serum aluminium level in both groups due to treatment with aluminium hydroxide before this study began. Since calcium carbonate appeared to be as effective as aluminium hydroxide one should give preference to the less toxic calcium carbonate for the treatment of hyperphosphatemia. Liver Besides effects on the central nervous system and bones aluminium may also affect the liver in which organ it is also accumulated. A study in rats sought to determine whether chronic intravenous administration of aluminium could produce hepatic or biliary dysfunction (3r 9 1990 Elsevier Science Publishers B.V. (Biomedical Division) Side Effects of Drugs Annual 14 M.N.G. Dukes and L. Beeley, editors
Metals Aluminium caused a dose- and time-dependent elevation of the total serum bile acid concentration and a decrease of the bile flow. On account of these findings it seemspossible that aluminium has a role in the pathogenesis of parenteral nutrition-induced hepatobiliary dysfunction.
Skin and appendages A patient was described with persistent itchy, eczematous and slightly pigmented lesions at the sites of previous injections of DTP triple vaccine (5c). Aluminium hypersensitivity was suggested and confirmed by patch testing. Miscellaneous Recently a causal association between aluminium and Alzheimer's disease has been suggested (4R). However, due to the many limitations of the study design, this association is still a matter of dispute. A prospective study is needed to give a decisive answer.
Bismuth (SED-11, 439) (see also Chapter 38) Bismuth has been used in the treatment of dyspepsia for decades. Having fallen out of favor in the 1970s because of reports of encephalopathy it is regaining popularity in recent years because of the proven efficacy of the colloidal bismuth in the treatment of gastrointestinal ulcer disease, especially since it is known to have an effect on Campylobacter pylori. In a review article the pharmacokineticsdynamics and toxicity of the bismuth salts have been discussed (6R). In Chapter 38 of this Volume some speculation as to the long-term safety of the preparations currently in use is discussed. Gold (SED-11, 443; SEDA-12, 186; SEDA-13,
191) Gold has evolved from an elixer of life which could cure all known diseases to a scientifically proven efficaceous drug in the treatment of a few diseases, notably rheumatoid arthritis and 188
Metals Chapter23 psoriatic arthritis (7R). Several review articles on the use o f gold in the treatment of rheumatoid arthritis have been published (8 ~, 9 R, 10R). In a double blind study o f 26 weeks' duration 40 patients with rheumatoid arthritis were randomly treated with weekly intramuscular injections of either 10 mg methotrexate or sodium aurothiomalate (1 ICR). Methotrexate turned out to be as effective as sodium aurothiomalate; however, significantly more patients in the gold group had to be withdrawn from the study due to adverse reactions (7 vs. 2 patients). It has been suggested that the concentration of 'free' gold might be a useful parameter for monitoring patients during chrysotherapy (12). A method has been described which makes it possible to obtain reliable measures of free gold concentrations (13cR). In the retrospective study which used the method, 6 out o f the 7 patients with a higher free-to-total serum gold ratio turned out to have developed an adverse reaction. Prospective studies are needed to show whether the correlation indeed does exist.
Immune system (SED-11, 447; SEDA-12, 186;
SEDA-13, 191)
151 white and 14 black rheumatoid arthritis patients treated with gold were studied to throw light on the relationship between H L A antigens and adverse reactions (14CR). Gold-induced dermatitis and stomatitis occurred with similar frequency among black and white patients; no association was found between H I A antigens and this adverse reaction. This study confirms the association between H L A - D R 3 and gold-induced thrombocytopenia and proteinuria in whites. In addition a reduced frequency o f H L A - D R 7 was found a m o n g dermatitis patients in both racial groups suggesting a weak protective effect of this antigen. Due to the small number of black patients included in this study no conclusions could be reached with respect to the more u n c o m m o n adverse reactions such as thrombocytopenia and proteinuria.
Respiratory (SED-tl, 445; SEDA-12, 186) Another case o f bronchiolitis obliterans during chrysotherapy has been described (15cr). A 49-year-old woman with a severe seropositive rheumatoid arthritis was treated with naproxen 500 mg b.i.d., pulse methylprednisolone and gold sodiumthiomalate. After 2 months she experienced in-
189 sidious onset of dyspnea on exertion and scant dry cough without upper respiratory symptoms. On examination, temperature was 38~ cardiac and pulmonary examinations were normal. On chest radiograph soft nodular densities in both lung fields and faint air bronchogram were seen. A complete blood count was normal except for 5% eosinophilia. Naproxen and gold were discontinued. However, the respiratory symptoms persisted and the chest X-ray 1 week later showed progression. Pulmonary function test revealed no obstruction and a slightly decreased diffusion capacity. Bronchoscopy was normal and transbronchial biopsy was non-diagnostic. Bronchopulmonary lavage demonstrated an increased total cell count with a predominant increase in the percentage lymphocytes. Three weeks after the onset of respiratory symptoms an open lung biopsy was performed. A bronchiolitis obliterans with small bronchioles occluded by inflammatory cells, their walls thickened by granulation tissue, was found. In addition aberrations consistent with interstitial fibrosis were found. The patient was treated with methylprednisolone and cyclophosphamide and could be discharged after a 4-month hospital stay. The results of the bronchoalveolar lavage, namely an increase in the total cell count as well as an increase in the percentage lymphocytes, make it very likely that the bronchiolitis obliterans was due to a gold adverse reaction. Whether the interstitial fibrosis was part of the adverse reaction or just a coincidence remains uncertain.
Liver (SED-11, 446)
Another case o f hepatitis with onset 3 weeks after the start of aurothiomalate treatment was published (16c). N o alternative causes for the hepatitis were found. Five weeks after discontinuation of the gold therapy the hepatitis had resolved completely. Urinary (SED-11, 446; SEDA-12, 187; SEDA13, 192) In an editorial on gold nephropathy attention has been paid to clinical features, the various histopathological lesions, pathogenetic mechanisms and the management o f this adverse reaction (17vt). Renal damage by gold, presenting as proteinuria or microscopic hematuria, accounts for about 10% of all adverse reactions to gold treatment. Gold nephropathy occurs in 70~; of the patients within the first year of treatment. It runs a benign course, usually resolving within 2 years after discontinuation of gold treatment without obvious damage to renal function. In 70% of the patients renal biopsy shows a membranous glomerulonephritis. As a pathogenetic mechanism it has been suggested that gold causes renal tubular damage, just as do such other heavy
Chapter 23 P.L.C.M. van Riel
190 metals as lead, bismuth and mercury. This leads to release of renal tubular epithelial (RTE) cells. The RTE cells act as an autoantigen which induces the formation of RTE antigen-antibody immune complexes, and these localize in the glomerular subepithelial space, leading to membranous glomerulonephritis. Other renal lesions found in patients with gold nephropathy, and probably due to different pathogenetic mechanisms comprise mesangial glomerulonephritis, minimal change nephropathy and tubulointerstitial disease. In the majority of the cases withdrawal of gold treatment is the only measure needed and there is certainly no need for corticosteroids or immunosuppressivedrugs. In 20 rheumatoid arthritis patients, 10 treated with sodium aurothiomalate and the others with D-penicillamine, the effects of these medications on renal function and arachidonic acid metabolism were studied (18cr). No influence of aurothiomalate treatment could be detected on N-acetyl-fl-glucosaminidase activity or on the fl-2-microglobulin concentrations in serum and urine, which are sensitive indicators of glomerular and tubular damage respectively. Nor did aurothiomalate treatment affect renal prostanoid excretion. Miscellaneous (SED-11,447) Recently a case of lupus erythematosus perhaps induced by gold has been described (19Or).
A 12-year-oldpatient with a seronegativejuvenile chronic arthritis after 10 months of gold sodium thiomalate treatment developed pericarditis and high titers of antinuclear antibodies as well as antibodies to native double-stranded DNA. After withdrawal of the gold medication the clinical symptoms disappeared and the titers of autoantibodies decreased to normal levels. However, in addition to withdrawal of the gold treatment the patient was also treated with high-dose corticosteroids and azathioprine, which makes drug induction of the lupus less likely. A rheumatoid arthritis patient was described who had been on long-term intramuscular gold therapy and whose mammogram showed a nodule resembling an intramammary lymph node with microcalcifications (20cr). A biopsy of the lesion was performed; histopathology showed a normal breast parenchyma without microcalcifications and an intramammary lymph node was indeed found. In the lymph node granular-dense black particles were found
which by means of X-ray microanalysis were shown to be gold particles. A patient was described who after 4 injections of aurothiomalate developed a diffuse urticarial skin eruption and interstitial lung disease (21~). Despite intensive supportive treatment and high doses of corticosteroids the patient died after 7 days. At autopsy nonbacterial thrombotic endocarditis of the mitral valve was found, supposed to be due to gold-induced immune complex depositions. A patient with panhypogammaglobulinemia detected after he had been treated with a cumulative dose of 1020 mg aurothiomalate was described (22crt). Although no data as to the immunoglobulin levels were available prior to the start of the gold therapy, the panhypogammaglobulinemia was thought to have developed during the gold treatment as the patient started to complain of recurrent upper respiratory tract infections, a herpes zoster infection and a pneumococcal pneumonia shortly after the gold treatment was begun. Use in children A retrospective study of the treatment of juvenile chronic arthritis with slow-acting antirheumatic drugs (gold, penicillamine, antimalarials, and sulfasalazine) and a review of the literature on this subject has been published (23CR). Due to lack of sufficient placebo-controlled and comparative studies, definite conclusions as to the efficacy of the different drugs cannot be made. However, gold appears to be one of the most efficacious of these drugs. More general agreement does exist with respect to toxicity. Discontinuation occurred most frequently with gold (21%) and least frequently with antimalarials (7 %). Auranofin (SED-11, 448; SEDA-12, 189;
SEDA-13, 194) In an open multicenter study 90 rheumatoid arthritis patients were treated with auranofin 6 mg daily for one year (24Cr). Over 35 % of the patients developed adverse reactions, mainly between months 3 and 6 of the treatment; 50% of them had to be withdrawn from the investigation. The reported side effects were in order of decreasing frequency: gastrointestinal, skin and hematological in nature. Efficacy was more pronounced in the patient group with a disease duration of less than 2 years.
Metals Chapter23 In a 24-month double-blind placebo-controlled trial the effect o f early initiation o f auranofin therapy in 138 patients with early rheumatoid arthritis was evaluated (25CR). After 2 years 52% of the patients in the auranofin group were still on the original drug, 25% had been withdrawn due to side effects and 19% due to lack of efficacy. In the placebo-treated group 37 % of the patients were still taking the original 'drug'. Patients in both treatment groups withdrawn due to lack of effect or side effects were treated, on an intention-totreat policy, with o-penicillamine or hydroxyehloroquine. At the end of the study period patients in the auranofin group had improved more than in the placebo group with respect to several clinical variables as well as in such outcome measurements as radiological progression. The authors concluded that early initiation of auranofin treatment compared to delayed initiation of second-line treatment in early rheumatoid arthritis modifies the course of the disease after 2 years as expressed by a lesser degree of r adiological damage.
Gastrointestinal symptoms, mainly diarrhea and loose stools, are the most frequent adverse reactions of auranofin therapy. 137 rheumatoid arthritis patients treated with auranofin were prospectively followed with the aim to acquire more information, by means of a questionnaire, on this adverse reaction in long term treatment (26cr). The definition of diarrhea used in this study was: 'any report of diarrhea, loose, runny, soft or semi-formed stools'. 101 patients (74%) reported at least 1 episode of diarrhea, usually within 1 month after the start of treatment. The prevalence diminished from 30-40 % in the first 6 months of therapy to about 20% for patients treated for 1 year and 10% for those treated for more than 18 months. Only 8% of the patients had to be withdrawn due to this adverse reduction. The diarrhea usually responded well to temporary dose reduction and/or antidiarrheal medication. Seventeen patients with pemphigus vulgaris were treated with 6 mg auranofin daily; 15 of them were also treated with a lower than usual dose of methylprednisolone: 45 mg daily (27CR). Clinical remission was observed in 14 patients. Mild side effects were seen in 2 patients. It is possible that adding auranofin to the corticosteroid treatment in pemphigus vulgaris has a corticosteroid-saving effect with minor adverse reactions.
191 Iron (SED-11, 451; SEDA-12, 190; SEDA-13,
195) The administration of iron dextran intramuscularly or by intravenous infusion is frequently On up to 30% o f cases) accompanied by adverse reactions. These are divided into acute reactions (such as anaphylaxis and headache), delayed reactions (such as arthralgia, myalgia, fever and nausea) and local reactions including pain and skin staining at the site o f injection and phlebitis. A patient has been presented who experienced adverse reactions to an intravenous infusion (50 mg/d) of iron dextran, but tolerated without any problems a low dose of iron dextran (2 mg/d) in total parenteral nutrition (28cr). These authors also reviewed the literature on parenteral iron suppletion and found that iron dextran supplemented total parenteral nutrition up to doses of 100 m g / d was not associated with adverse reactions. This is probably due to the smaller iron dose used and the much longer administration period which is customary when iron is given to support total parenteral nutrition. Experience with total dose intravenous infusion of iron dextran in a prospective study of 87 patients with anemia has been described (29CR). Two patients developed anaphylactoid reactions shortly after the test dose of 1500 mg elemental iron. In 37 patients (42%) mild delayed adverse reactions (myalgia, arthralgia and fever) developed within 24 hours after infusion. In most instances these symptoms resolved soon after administration of a non-steroidal anti-inflammatory drug. Delayed reactions occurred in 4 patients. Pretreatment with aspirin, diphenhydramine or steroids did not appear to influence the incidence of delayed adverse reactions. A patient was described with local necrosis and ulceration secondary to massive doses of intramuscularly-administered iron dextran (350 injections over a period of 5 years) (30c). Pathological examination revealed dense fibrosis, ulceration and massive accumulation o f iron in the dermis. F o u r patients with erythropoietic protoporphyria have been published in w h o m oral iron produced clinical and biochemical deterioration (31cr). As some patients with this disease do improve on oral iron suppletion, this obser-
192 vation suggests that there are at least 2 different subgroups of patients with erythropoietic protoporphyria distinguished by their response to oral iron. The toxicity of acute iron overload has been studied in an animal model (32). It was hypothesized that the toxicity of acute iron overload might be due primarily to hepatocellular damage, particularly of the mitochondrial membrane, resulting in lactic acidosis and probably also in cardiac toxicity. Silver (SED-11, 456) A report on a patient who developed a ureteral stenosis after retrograde intrapelvic instillation of silver nitrate and a review of the literature on this therapy has been published (33CR). Silver nitrate administered by retrograde injection in the ureter is being used in the treatment of essential hematuria although there is some controversy concerning its efficacy. The supposed mechanism of action is cauterization. Complications are minor (transient flank pain and nausea) provided the silver nitrate has been installed in the right place (i.e. not intravesically or retroperitoneally) and in the right dosage (0.125 - 1% silver nitrate). The patient described in the case-report had been treated with 2.5 % silver nitrate. Zinc ( S E D - 1 f , 456; SEDA-12, 191) M a n y people today regularly take a variety of vitamins and other non-prescribed supplements to maintain health and to prevent or treat disease. Recently a patient was reported who, after taking pharmacological doses of zinc to prevent prostatitis, developed copper deficiency anemia and neutropenia (34c). A 44-year-old man developed fatigue and a sore throat. A blood count was obtained that revealed neutropenia and anemia. There was no alcohol abuse and
Chapter 23 P.L.C.M. van Riel
the patient denied exposure to toxins. He was taking L-lysine 2 g/d to control genital herpes. He was also taking non-prescribed vitamin E, A, B complex, folic acid and pyridoxine. In addition he had used 200-300 mg zinc gluconate as a single daily dose for at least 2 years. Physical examination was normal except for pallor. Laboratory studies showed a total white blood cell count of 2000/jul, with 6% segmented neutrophils, 78% lymphoeytes, 7% monocytes, 7% eosinophils, hemoglobin 9.0 g/dl hematocrit 25.7 %, mean corpuscular volume 100, reticutocyte count 0.2% and platelet count 352000/pl. Bone marrow morphology showed prominent cytoplasmic vacuoles in eary myeloid and erythroid forms. There were numerous ringed sideroblasts. Serum zinc was 262/tg/dl (normal 50-160), serum copper 15/~g/dl (normal 70-155), ceruloplasmin 2/tg/dl (normal 15-50), serum iron 32 /tg/dl, and total iron binding capacity 212 /tg/dl. Lead level was within the normal range. The patient discontinued all the nutritional supplements except pyridoxine and folic acid. Within 4 weeks the peripheral blood values returned to normal and a repeat examination of the bone marrow after 7 weeks as well as serum levels of zinc, copper and ceruloplasmin showed a return to normal. Ingestion of large quantities of zinc leads to induction of the synthesis of the protein metallothionein in the mucosal cells. Because zinc b o u n d to metallothionein is not absorbed in the intestine, zinc absorption is regulated by the induction of this protein. However, the metallothionein protein has a stronger affinity for copper than for zinc, resulting in copper depletion. It is the copper deficiency which causes anemia and neutropenia, The mechanism of the neutropenia is unknown; the anemia is thought to be due to reduced mobilization of iron from liver stores and impaired mitochondrial iron metabolism. The induction of decreased copper absorption by prolonged oral zinc administration is used in the treatment of Wilson's disease (35c). Recently a case of successful treatment of Wilson's disease with oral zinc sulphate 600 m g daily in a patient having serious adverse reactions to D-penicillamine was reported (36cr).
REFERENCES 1. Freundlich M (1988) The spectrum of aluminum toxicity in pediatrics. Int. J. Pediatr. 3, 41. 2. Turner C, Compston J, Mak RH et al (1988) Bone turnover and 1,25-dihydroxycholecalciferol
during treatment with phosphate binders. Kidney Int., 33, 989. 3. Klein GL, Heyman MB, Lee TC et al (1988) Aluminum-associated hepatobiliary dysfunction in rats:
Metals
Chapter 23
193
21. KolIefMH, Irvine T, Cragun WH (1988) Nonrelationships to dosage and duration of exposure. bacterial thrombotic endocarditis associated with Pediatr. Res., 23, 275. gold-induced pulmonary disease. Ann. Intern. Med., 4. Martyn C, Osmond C, Edwardson JA et al 106, 903. (1989) Geographical relation between Alzheimer's 22. Pearson SL, Stewart IC, Kellett RJ (1988) Pandisease and aluminium in drinking water. Lancet, 1, hypogammaglobulinaemia caused by gold therapy. 59. Scot. Med. J., 33, 343. 5. Cox NH, Moss C (1988) Cutaneous reactions to 23. Grondin C, Malleson P, Petty RE (1988) Slowaluminium in vaccines: an avoidable problem. Lanacting antirheumatic drugs in chronic arthritis of cet, 2, 43. childhood. Semin. Arthritis Rheum., 18, 38. 6. Borsch G (1988) Ubersicht. Alte und neue Ma24. Klein G, Schwann H, Thumb N et al (1988) gentherapie mit Wismutsalzen. Pharmakokinetik, Klinische Wirksamkeit und Vertr/iglichkeit yon AuPharmakodynamik, Toxizit/it. Med. Kiln., 83, 605. ranofin bei Patienten mit chronischer Polyarthritis. 7. Hillson RM (1988) Gold, frankincense and Ergebnisse einer multizentrischen Langzeitstudie. myrrh. J. R. Soc. Med., 81, 542. Z. RheumatoL, 47, 342. 8. Davis P (I988) Gold therapy in the treatment of 25. Borg G, A/lander E, Lund Bet al (1988) Auranrheumatoid arthritis. Can. Faro. Physician, 34, 445. ofin improves outcome in early rheumatoid arthri9. Grasedyck K (1988) Wirkweise und Sicherheit tis. Results from a 2-year, double blind, placebo der parenteralen Goldtherapie. Aktuel. RheumatoL, controlled study. J. RheumatoL, 15, 1747. 13, 157. 26. Wallin BA, McCafferty JP, Fox MJ et al (1988) 10. Rau R (1988) Goldtherapie in der Praxis des Incidence and management of diarrhea during long niedergelassenen Arztes. Akt. RheumatoL, 13, 214. term auranofin therapy. J. RheumatoL, 15, 1755. 11. Suarez-Almazor ME, Fitzgerald A, Grace M e t 27. Magnin PH, Spillman DH, Oxilia MR (1988) al (1988) A randomized controlled trial of parenAureoterapia oral en el penfigo. Rev. Argent. Derteral methotrexate compared with sodium aurothiomatoL, 69, 184. malate (Myochrysine) in the treatment of rheuma28. Porter KA, Blackburn GL, Bristian BR (1988) toid arthritis. 3". RheumatoL, 15, 753. Safety of iron dextran in total parenteral nutrition: 12. Pedersen MP (1986) Binding of sodium aurotha case report. J. Am. Coll. Nutr., 7, 107. iomalate to human serum albumin in vitro at phy29. Auerbach M, Witt D, Toler Wet al (1988) Clinsiological conditions. Ann. Rheum. Dis., 45, 712. ical use of the total dose intravenous infusion of 13. Heath MJ (1988) Measurement of 'free' gold in iron dextran. J. Lab. Clin. Med., 111, 566. patients receiving disodium aurothiomalate and the association of high free to total gold levels with tox30. Fuller JD, Williams HJ, McRory TI (1988) icity. Ann. Rheum. Dis., 47, 18. Necrotic bilateral buttocks ulcerations occurring 14. Fraser PA, Stern SH, Coblyn JS et al (1988) Imafter multiple intramuscular iron dextran injections. munogenetics and racial determinants of gold toxiArch. DermatoL, 124, 1722. city in rheumatoid arthritis. J. NatL Meal. Assoc., 31. Milligan A, Graham-Brown RAC, Sarkany 1 et 80, 162. al (1988) Erythropoietic protoporphyria exacerbat15. Fort JG, Scovern H, Abruzzo JL (1988) Ined by oral iron therapy. Br. J. DermatoL, 119, 63. travenous cyclophosphamide and methylpredniso32. Rosenmund A, Brand B, Werner Straub P lone for the treatment of bronchiolitis obliterans (1988) Hyperlactataemia, hyperkalaemia and heart and interstitial fibrosis associated with chrysotheblock in acute iron overload: the fatal role of the herapy. J. RheumatoL, 15, 850. patic iron-incorporation rate in rats on ferric citrate 16. Tebib J, Coison F, Noel E et al. (t988) Un nouinfusions. Fur. J. Ctin. Invest., 18, 69. veau cas d'hbpatite aurique an cours du traitement 33. Vijan SR, Keating MA, Althausen AF (1988) d'une polyarthrite rhumatoide. Rev. Rhum., 55, 705. Ureteral stenosis after silver nitrate instillation in 17, Hall CL (1988) Gold nephropathy. Nephron, the treatment of essential hematuria. J. UroL, 139, 50, 265. 1015. 18. Seppala E, Lehtinen K, Isomaki H et al (1988) 34. Simon SR, Branda RF, Tindle BH et al (1988) Effects of long-term aurothiomalate and o-penicilCopper deficiency and sideroblastic anemia assolamine treatments on renal function and urinary exciated with zinc ingestion, Am. J. Hematol., 28, cretion of prostanoids in patients with rheumatoid 181. arthritis. Int. J. Clin. Invest., 3, I49. 35. Hoogenraad TU, Van der Hamer CJ, Van Hat19. Korholz D, Nurnberger W, Gobel U et al turn J (1984) Effective treatment of Wilson's disease (1988) Gold-induzierter systemischer Lupus erythewith oral zinc sulphate: two case reports. Br. Med. matodes. Monatsschr. Kinderheilkd., 136, 644. J. 289, 273. 20. Bolen JW, Shaw de Paredes E, Carter T (1988) 36. Kaur U, Bambery P, Bhushnurrnath SR et al Mammographic determination of gold deposits si(1988) Successful long term oral zinc in florid WiImulating malignant calcifications in an intramamson's disease: a case report. Trop. Geogr. Meal., 40, mary lymph node. Breast Dis., 1, 105. 161.
23 Aluminium (SED-11, 437; SEDA-12, 185;
SEDA-13, 191) An excellent review article about aluminium toxicity in children was published by Freundlich in 1988 (IR). The patients who are at risk, the most important clinical manifestations of aluminium toxicity in prematures and infants and the prevention and treatment with deferoxamine are discussed.
Endocrine metabolic In a study of 12 children with chronic renal failure, the effect of two phosphate binders (aluminium hydroxide and calcium carbonate) on bone turnover and 1,25dihydroxycholecalciferol were compared (2c). Both phosphate binders, in addition to mild dietary phosphorus restriction and small doses of vitamin D supplement, effectively suppressed the secondary hyperparathyroidism. However, in both treatment groups a mild mineralization defect present before treatment worsened, with a decrease in mineral appositional rate and increase in mineralization lag time. In spite of this it is suggested that the observed mineralization defect is due to aluminium toxicity. An argument for this may be the raised serum aluminium level in both groups due to treatment with aluminium hydroxide before this study began. Since calcium carbonate appeared to be as effective as aluminium hydroxide one should give preference to the less toxic calcium carbonate for the treatment of hyperphosphatemia. Liver Besides effects on the central nervous system and bones aluminium may also affect the liver in which organ it is also accumulated. A study in rats sought to determine whether chronic intravenous administration of aluminium could produce hepatic or biliary dysfunction (3r 9 1990 Elsevier Science Publishers B.V. (Biomedical Division) Side Effects of Drugs Annual 14 M.N.G. Dukes and L. Beeley, editors
Metals Aluminium caused a dose- and time-dependent elevation of the total serum bile acid concentration and a decrease of the bile flow. On account of these findings it seemspossible that aluminium has a role in the pathogenesis of parenteral nutrition-induced hepatobiliary dysfunction.
Skin and appendages A patient was described with persistent itchy, eczematous and slightly pigmented lesions at the sites of previous injections of DTP triple vaccine (5c). Aluminium hypersensitivity was suggested and confirmed by patch testing. Miscellaneous Recently a causal association between aluminium and Alzheimer's disease has been suggested (4R). However, due to the many limitations of the study design, this association is still a matter of dispute. A prospective study is needed to give a decisive answer.
Bismuth (SED-11, 439) (see also Chapter 38) Bismuth has been used in the treatment of dyspepsia for decades. Having fallen out of favor in the 1970s because of reports of encephalopathy it is regaining popularity in recent years because of the proven efficacy of the colloidal bismuth in the treatment of gastrointestinal ulcer disease, especially since it is known to have an effect on Campylobacter pylori. In a review article the pharmacokineticsdynamics and toxicity of the bismuth salts have been discussed (6R). In Chapter 38 of this Volume some speculation as to the long-term safety of the preparations currently in use is discussed. Gold (SED-11, 443; SEDA-12, 186; SEDA-13,
191) Gold has evolved from an elixer of life which could cure all known diseases to a scientifically proven efficaceous drug in the treatment of a few diseases, notably rheumatoid arthritis and 188
Metals Chapter23 psoriatic arthritis (7R). Several review articles on the use o f gold in the treatment of rheumatoid arthritis have been published (8 ~, 9 R, 10R). In a double blind study o f 26 weeks' duration 40 patients with rheumatoid arthritis were randomly treated with weekly intramuscular injections of either 10 mg methotrexate or sodium aurothiomalate (1 ICR). Methotrexate turned out to be as effective as sodium aurothiomalate; however, significantly more patients in the gold group had to be withdrawn from the study due to adverse reactions (7 vs. 2 patients). It has been suggested that the concentration of 'free' gold might be a useful parameter for monitoring patients during chrysotherapy (12). A method has been described which makes it possible to obtain reliable measures of free gold concentrations (13cR). In the retrospective study which used the method, 6 out o f the 7 patients with a higher free-to-total serum gold ratio turned out to have developed an adverse reaction. Prospective studies are needed to show whether the correlation indeed does exist.
Immune system (SED-11, 447; SEDA-12, 186;
SEDA-13, 191)
151 white and 14 black rheumatoid arthritis patients treated with gold were studied to throw light on the relationship between H L A antigens and adverse reactions (14CR). Gold-induced dermatitis and stomatitis occurred with similar frequency among black and white patients; no association was found between H I A antigens and this adverse reaction. This study confirms the association between H L A - D R 3 and gold-induced thrombocytopenia and proteinuria in whites. In addition a reduced frequency o f H L A - D R 7 was found a m o n g dermatitis patients in both racial groups suggesting a weak protective effect of this antigen. Due to the small number of black patients included in this study no conclusions could be reached with respect to the more u n c o m m o n adverse reactions such as thrombocytopenia and proteinuria.
Respiratory (SED-tl, 445; SEDA-12, 186) Another case o f bronchiolitis obliterans during chrysotherapy has been described (15cr). A 49-year-old woman with a severe seropositive rheumatoid arthritis was treated with naproxen 500 mg b.i.d., pulse methylprednisolone and gold sodiumthiomalate. After 2 months she experienced in-
189 sidious onset of dyspnea on exertion and scant dry cough without upper respiratory symptoms. On examination, temperature was 38~ cardiac and pulmonary examinations were normal. On chest radiograph soft nodular densities in both lung fields and faint air bronchogram were seen. A complete blood count was normal except for 5% eosinophilia. Naproxen and gold were discontinued. However, the respiratory symptoms persisted and the chest X-ray 1 week later showed progression. Pulmonary function test revealed no obstruction and a slightly decreased diffusion capacity. Bronchoscopy was normal and transbronchial biopsy was non-diagnostic. Bronchopulmonary lavage demonstrated an increased total cell count with a predominant increase in the percentage lymphocytes. Three weeks after the onset of respiratory symptoms an open lung biopsy was performed. A bronchiolitis obliterans with small bronchioles occluded by inflammatory cells, their walls thickened by granulation tissue, was found. In addition aberrations consistent with interstitial fibrosis were found. The patient was treated with methylprednisolone and cyclophosphamide and could be discharged after a 4-month hospital stay. The results of the bronchoalveolar lavage, namely an increase in the total cell count as well as an increase in the percentage lymphocytes, make it very likely that the bronchiolitis obliterans was due to a gold adverse reaction. Whether the interstitial fibrosis was part of the adverse reaction or just a coincidence remains uncertain.
Liver (SED-11, 446)
Another case o f hepatitis with onset 3 weeks after the start of aurothiomalate treatment was published (16c). N o alternative causes for the hepatitis were found. Five weeks after discontinuation of the gold therapy the hepatitis had resolved completely. Urinary (SED-11, 446; SEDA-12, 187; SEDA13, 192) In an editorial on gold nephropathy attention has been paid to clinical features, the various histopathological lesions, pathogenetic mechanisms and the management o f this adverse reaction (17vt). Renal damage by gold, presenting as proteinuria or microscopic hematuria, accounts for about 10% of all adverse reactions to gold treatment. Gold nephropathy occurs in 70~; of the patients within the first year of treatment. It runs a benign course, usually resolving within 2 years after discontinuation of gold treatment without obvious damage to renal function. In 70% of the patients renal biopsy shows a membranous glomerulonephritis. As a pathogenetic mechanism it has been suggested that gold causes renal tubular damage, just as do such other heavy
Chapter 23 P.L.C.M. van Riel
190 metals as lead, bismuth and mercury. This leads to release of renal tubular epithelial (RTE) cells. The RTE cells act as an autoantigen which induces the formation of RTE antigen-antibody immune complexes, and these localize in the glomerular subepithelial space, leading to membranous glomerulonephritis. Other renal lesions found in patients with gold nephropathy, and probably due to different pathogenetic mechanisms comprise mesangial glomerulonephritis, minimal change nephropathy and tubulointerstitial disease. In the majority of the cases withdrawal of gold treatment is the only measure needed and there is certainly no need for corticosteroids or immunosuppressivedrugs. In 20 rheumatoid arthritis patients, 10 treated with sodium aurothiomalate and the others with D-penicillamine, the effects of these medications on renal function and arachidonic acid metabolism were studied (18cr). No influence of aurothiomalate treatment could be detected on N-acetyl-fl-glucosaminidase activity or on the fl-2-microglobulin concentrations in serum and urine, which are sensitive indicators of glomerular and tubular damage respectively. Nor did aurothiomalate treatment affect renal prostanoid excretion. Miscellaneous (SED-11,447) Recently a case of lupus erythematosus perhaps induced by gold has been described (19Or).
A 12-year-oldpatient with a seronegativejuvenile chronic arthritis after 10 months of gold sodium thiomalate treatment developed pericarditis and high titers of antinuclear antibodies as well as antibodies to native double-stranded DNA. After withdrawal of the gold medication the clinical symptoms disappeared and the titers of autoantibodies decreased to normal levels. However, in addition to withdrawal of the gold treatment the patient was also treated with high-dose corticosteroids and azathioprine, which makes drug induction of the lupus less likely. A rheumatoid arthritis patient was described who had been on long-term intramuscular gold therapy and whose mammogram showed a nodule resembling an intramammary lymph node with microcalcifications (20cr). A biopsy of the lesion was performed; histopathology showed a normal breast parenchyma without microcalcifications and an intramammary lymph node was indeed found. In the lymph node granular-dense black particles were found
which by means of X-ray microanalysis were shown to be gold particles. A patient was described who after 4 injections of aurothiomalate developed a diffuse urticarial skin eruption and interstitial lung disease (21~). Despite intensive supportive treatment and high doses of corticosteroids the patient died after 7 days. At autopsy nonbacterial thrombotic endocarditis of the mitral valve was found, supposed to be due to gold-induced immune complex depositions. A patient with panhypogammaglobulinemia detected after he had been treated with a cumulative dose of 1020 mg aurothiomalate was described (22crt). Although no data as to the immunoglobulin levels were available prior to the start of the gold therapy, the panhypogammaglobulinemia was thought to have developed during the gold treatment as the patient started to complain of recurrent upper respiratory tract infections, a herpes zoster infection and a pneumococcal pneumonia shortly after the gold treatment was begun. Use in children A retrospective study of the treatment of juvenile chronic arthritis with slow-acting antirheumatic drugs (gold, penicillamine, antimalarials, and sulfasalazine) and a review of the literature on this subject has been published (23CR). Due to lack of sufficient placebo-controlled and comparative studies, definite conclusions as to the efficacy of the different drugs cannot be made. However, gold appears to be one of the most efficacious of these drugs. More general agreement does exist with respect to toxicity. Discontinuation occurred most frequently with gold (21%) and least frequently with antimalarials (7 %). Auranofin (SED-11, 448; SEDA-12, 189;
SEDA-13, 194) In an open multicenter study 90 rheumatoid arthritis patients were treated with auranofin 6 mg daily for one year (24Cr). Over 35 % of the patients developed adverse reactions, mainly between months 3 and 6 of the treatment; 50% of them had to be withdrawn from the investigation. The reported side effects were in order of decreasing frequency: gastrointestinal, skin and hematological in nature. Efficacy was more pronounced in the patient group with a disease duration of less than 2 years.
Metals Chapter23 In a 24-month double-blind placebo-controlled trial the effect o f early initiation o f auranofin therapy in 138 patients with early rheumatoid arthritis was evaluated (25CR). After 2 years 52% of the patients in the auranofin group were still on the original drug, 25% had been withdrawn due to side effects and 19% due to lack of efficacy. In the placebo-treated group 37 % of the patients were still taking the original 'drug'. Patients in both treatment groups withdrawn due to lack of effect or side effects were treated, on an intention-totreat policy, with o-penicillamine or hydroxyehloroquine. At the end of the study period patients in the auranofin group had improved more than in the placebo group with respect to several clinical variables as well as in such outcome measurements as radiological progression. The authors concluded that early initiation of auranofin treatment compared to delayed initiation of second-line treatment in early rheumatoid arthritis modifies the course of the disease after 2 years as expressed by a lesser degree of r adiological damage.
Gastrointestinal symptoms, mainly diarrhea and loose stools, are the most frequent adverse reactions of auranofin therapy. 137 rheumatoid arthritis patients treated with auranofin were prospectively followed with the aim to acquire more information, by means of a questionnaire, on this adverse reaction in long term treatment (26cr). The definition of diarrhea used in this study was: 'any report of diarrhea, loose, runny, soft or semi-formed stools'. 101 patients (74%) reported at least 1 episode of diarrhea, usually within 1 month after the start of treatment. The prevalence diminished from 30-40 % in the first 6 months of therapy to about 20% for patients treated for 1 year and 10% for those treated for more than 18 months. Only 8% of the patients had to be withdrawn due to this adverse reduction. The diarrhea usually responded well to temporary dose reduction and/or antidiarrheal medication. Seventeen patients with pemphigus vulgaris were treated with 6 mg auranofin daily; 15 of them were also treated with a lower than usual dose of methylprednisolone: 45 mg daily (27CR). Clinical remission was observed in 14 patients. Mild side effects were seen in 2 patients. It is possible that adding auranofin to the corticosteroid treatment in pemphigus vulgaris has a corticosteroid-saving effect with minor adverse reactions.
191 Iron (SED-11, 451; SEDA-12, 190; SEDA-13,
195) The administration of iron dextran intramuscularly or by intravenous infusion is frequently On up to 30% o f cases) accompanied by adverse reactions. These are divided into acute reactions (such as anaphylaxis and headache), delayed reactions (such as arthralgia, myalgia, fever and nausea) and local reactions including pain and skin staining at the site o f injection and phlebitis. A patient has been presented who experienced adverse reactions to an intravenous infusion (50 mg/d) of iron dextran, but tolerated without any problems a low dose of iron dextran (2 mg/d) in total parenteral nutrition (28cr). These authors also reviewed the literature on parenteral iron suppletion and found that iron dextran supplemented total parenteral nutrition up to doses of 100 m g / d was not associated with adverse reactions. This is probably due to the smaller iron dose used and the much longer administration period which is customary when iron is given to support total parenteral nutrition. Experience with total dose intravenous infusion of iron dextran in a prospective study of 87 patients with anemia has been described (29CR). Two patients developed anaphylactoid reactions shortly after the test dose of 1500 mg elemental iron. In 37 patients (42%) mild delayed adverse reactions (myalgia, arthralgia and fever) developed within 24 hours after infusion. In most instances these symptoms resolved soon after administration of a non-steroidal anti-inflammatory drug. Delayed reactions occurred in 4 patients. Pretreatment with aspirin, diphenhydramine or steroids did not appear to influence the incidence of delayed adverse reactions. A patient was described with local necrosis and ulceration secondary to massive doses of intramuscularly-administered iron dextran (350 injections over a period of 5 years) (30c). Pathological examination revealed dense fibrosis, ulceration and massive accumulation o f iron in the dermis. F o u r patients with erythropoietic protoporphyria have been published in w h o m oral iron produced clinical and biochemical deterioration (31cr). As some patients with this disease do improve on oral iron suppletion, this obser-
192 vation suggests that there are at least 2 different subgroups of patients with erythropoietic protoporphyria distinguished by their response to oral iron. The toxicity of acute iron overload has been studied in an animal model (32). It was hypothesized that the toxicity of acute iron overload might be due primarily to hepatocellular damage, particularly of the mitochondrial membrane, resulting in lactic acidosis and probably also in cardiac toxicity. Silver (SED-11, 456) A report on a patient who developed a ureteral stenosis after retrograde intrapelvic instillation of silver nitrate and a review of the literature on this therapy has been published (33CR). Silver nitrate administered by retrograde injection in the ureter is being used in the treatment of essential hematuria although there is some controversy concerning its efficacy. The supposed mechanism of action is cauterization. Complications are minor (transient flank pain and nausea) provided the silver nitrate has been installed in the right place (i.e. not intravesically or retroperitoneally) and in the right dosage (0.125 - 1% silver nitrate). The patient described in the case-report had been treated with 2.5 % silver nitrate. Zinc ( S E D - 1 f , 456; SEDA-12, 191) M a n y people today regularly take a variety of vitamins and other non-prescribed supplements to maintain health and to prevent or treat disease. Recently a patient was reported who, after taking pharmacological doses of zinc to prevent prostatitis, developed copper deficiency anemia and neutropenia (34c). A 44-year-old man developed fatigue and a sore throat. A blood count was obtained that revealed neutropenia and anemia. There was no alcohol abuse and
Chapter 23 P.L.C.M. van Riel
the patient denied exposure to toxins. He was taking L-lysine 2 g/d to control genital herpes. He was also taking non-prescribed vitamin E, A, B complex, folic acid and pyridoxine. In addition he had used 200-300 mg zinc gluconate as a single daily dose for at least 2 years. Physical examination was normal except for pallor. Laboratory studies showed a total white blood cell count of 2000/jul, with 6% segmented neutrophils, 78% lymphoeytes, 7% monocytes, 7% eosinophils, hemoglobin 9.0 g/dl hematocrit 25.7 %, mean corpuscular volume 100, reticutocyte count 0.2% and platelet count 352000/pl. Bone marrow morphology showed prominent cytoplasmic vacuoles in eary myeloid and erythroid forms. There were numerous ringed sideroblasts. Serum zinc was 262/tg/dl (normal 50-160), serum copper 15/~g/dl (normal 70-155), ceruloplasmin 2/tg/dl (normal 15-50), serum iron 32 /tg/dl, and total iron binding capacity 212 /tg/dl. Lead level was within the normal range. The patient discontinued all the nutritional supplements except pyridoxine and folic acid. Within 4 weeks the peripheral blood values returned to normal and a repeat examination of the bone marrow after 7 weeks as well as serum levels of zinc, copper and ceruloplasmin showed a return to normal. Ingestion of large quantities of zinc leads to induction of the synthesis of the protein metallothionein in the mucosal cells. Because zinc b o u n d to metallothionein is not absorbed in the intestine, zinc absorption is regulated by the induction of this protein. However, the metallothionein protein has a stronger affinity for copper than for zinc, resulting in copper depletion. It is the copper deficiency which causes anemia and neutropenia, The mechanism of the neutropenia is unknown; the anemia is thought to be due to reduced mobilization of iron from liver stores and impaired mitochondrial iron metabolism. The induction of decreased copper absorption by prolonged oral zinc administration is used in the treatment of Wilson's disease (35c). Recently a case of successful treatment of Wilson's disease with oral zinc sulphate 600 m g daily in a patient having serious adverse reactions to D-penicillamine was reported (36cr).
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Metals
Chapter 23
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