is in the differential diagnosis of hypercalcaemia. Initial evaluations of the new assays for intact parathyroid hormone showed improved clinical discrimination ...
therapy or neoadjuvant chemotherapy followed by surgery with or without thoracic irradiation. Certainly the results of cancer treatment policies are depressingly poor. GRAHAM CROMPTON Consultant Physician, Respiratorv Unit, Northern General Hospital, Edinburgh EH5 2DQ Lconard RCF. Small ccll lung canccr.
Brj Cancer 1989;59:487-90.
2 1'rasad US, Navlor AR, Walker \WS, Lamb 1), Cameron EX!J, \W'albanim P'R. Long term snirvival after pulmonary resection for small cell carcinoma o(t' thc lttig. Ttorax 1989;44:784-7. 3 Sm\ith JF, Fowlic SM, Gregor A. ct a/. Thc impact of clicinothcrapy ot[ small ccl carciinomna o f'thc bronchus. QJ,Med 1986;61:969-76. 4 Setlter EJ, Ihde DC. Therapy of small ccll lting cancer. A perspective on tso decadcs of clinical research. Sernin O)icol 1988;15:278-99. 5 Holove PY, Kalbfleisch J. 'I'he infltuence of myelossupprcssion on the response to chemotherapy in small ccll bronchogenic carcinoma. Ca(ncer 1984;54:41 1-5. 6 Fox W, Scadding JC. Medical Research Council comparativc trial of surgerv aild radiotherapy ftor primary treatment of small-celled or oat-celled carcinoma of' bronchus. Ian(ct 1973;ii.63-5. 7 Mountain CF. Clinical biology of small cell carcinoma: relationship to surgical therapv S ?imti ( tol 1978;5:272-9. 8 Sorensci HR, Lund C. Alstrup 1. Sursival in small ccll lumig carcimioma after suirgery TItorux 1986;41:479-82. 9 Edinburgh Lung Cancer Group. Patients presenting with lung cancer in south east Scotland. JI'horx 19X7;42:853-7.
Intact parathyroid hormone assays Interpretation must take account of biological variation Since their first development in 1963 parathyroid hormone immunoassays have been invaluable in assessing patients with disorders of calcium metabolism. ' The interpretation of the results of these immunoassays has, however, been complicated by the molecular heterogeneity of circulating parathyroid hormone. As a result of the proteolytic metabolism of parathyroid hormone, both within the parathyroid gland and elsewhere in the body, the circulation contains amine and carboxy terminal fragments of parathyroid hormone in addition to the intact parathyroid hormone (1-84) peptide.2 In an attempt to improve clinical discrimination immunoassays were developed with specificities for amino terminal and mid-terminal or carboxy terminal parathyroid hormone. In general these assays either lacked the required sensitivity or showed overlap between values in normal people and in groups of patients. The recently developed two site immunometric assays for parathyroid hormone allow the intact parathyroid hormone (1-84) peptide to be measured without interference from fragments.3' The sensitivities of these assays are in the low picomolar range-sufficient to measure the hormone in normal people. The main application of parathyroid hormone assays is in the differential diagnosis of hypercalcaemia. Initial evaluations of the new assays for intact parathyroid hormone showed improved clinical discrimination between patients with hyperparathyroidism and hypercalcaemia of malignancy.`~The distinction was not, however, complete; though the concentrations of intact parathyroid hormone in these groups are well separated, 3-5% of patients with hyperparathyroidism have values at the upper end of the reference range for normal people and 20-30% of patients with hypercalcaemia of malignancy have low but detectable concentrations of intact parathyroid hormone. Secondary hyperparathyroidism is a consistent feature of advanced renal failure. In the past the measurement of parathyroid hormone in patients with renal failure has been compromised by the presence of an excess of biologically inactive carboxy terminal fragments. Because the new assays are not affected by parathyroid hormone fragments they should overcome this problem. In patients with renal failure they should be sufficiently specific to follow either the clearance of intact parathyroid hormone after parathyroidectomy6 or the suppression of intact parathyroid hormone after treatment with calcium.7 This may not be the case for all
assays.'
Since the new assays are sensitive enough to measure intact parathyroid hormone concentrations in normal people and 210
follow changes within the reference range they have been used to study the physiology and control of its secretion.9 This work has defined the circadian rhythm of intact parathyroid hormone secretion in normal men. It was shown to rise in a broad peak outside the reference range from 0200 to 0600. This was accompanied by a parallel rise in concentrations of nephrogenous cyclic AMP, indicating that the intact parathyroid hormone released was biologically active. There was considerable variation in the return to baseline concentrations among normal people, with the period between 0600 and 1000 characterised by great variability among individuals. The assessment of the intact parathyroid hormone concentrations in an individual must take this variability into account. Early morning samples, such as those typically collected from patients in hospital, may have spuriously raised concentrations. Further studies have shown the absence of a synchronised circadian rhythm in patients with primary hyperparathyroidism.' Comparison of 24 hour profiles indicates that the best discrimination between normal people and patients with hyperparathyroidism is achieved when samples are taken between 1100 and 1400. Most patients screened for hypercalcaemia of malignancy have undetectable concentrations of intact parathyroid hormone. Finding detectable intact parathyroid hormone in such patients has been ascribed to a change in the calcium set point of the parathyroid glands." In patients with hypercalcaemia of malignancy with undetectable intact parathyroid hormone concentrations studies of the effects of treatment to lower calcium have confirmed that an increase in intact parathyroid hormone concentration occurs as the calcium decreases but while the patient remains hypercalcaemic.'2 When assessing these patients, therefore, intact parathyroid hormone concentrations should be measured before giving any treatment to lower calcium. Although intact parathyroid hormone seems more stable than previously suspected,3"' there is some variability. Short delays in separation and freezing of samples would not normally be expected to have substantial adverse effects on the clinical value of the assays, but such delays might lead to the misclassification of patients with only borderline increases in circulating intact parathyroid hormone concentration.' The development of assays of intact parathyroid hormone is an important advance in the laboratory assessment of calcium disorders. The improved sensitivity and specificity of the new assays make it possible to achieve better discrimination between clinical groups. But the use of these assays has also highlighted the extent of biological variation in intact parathyroid hormone and its rapid response to treatment. The BMJ VOLUME 300
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taking of blood samples must be carefully timed if the results of the assays are to be of maximum clinical value. Clinicians should contact their local laboratory to confirm the method in use and for recommendations on the handling and timing of specimens. FRASER C LOGUE Senior Biochemist
GRAHAM H BEASTALL Top Grade Biochemist WILLIAM D FRASER Senior Registrar DENIS S i J O'REILLY Consultant
Endocrine Section, Institute of Biochemistry, Royal Infirmary, Glasgow G4 OSF 1 Berson SA, Yalow RS, Aurbach GD, Potts JT. Immunoassav of bovine and human parathyroid hormone. Proc Nai lAcad Sci USA 1963;49:613-7. 2 Silverman R, Yalow RS. Heterogeneity of parathvroid hormone. Clinical and physiological implications. .7 Clin Invest 1973;52:1958-71.
3 Brown RC, Aston JP, Weeks I, Woodhead JS. CircuLlating intact parathyroid hormone measuLred by a two-sitc immunochemiluminometric assay. 7 Clin Endocrinol Metab 1987;65:407-14. 4 Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. Highly sensitive two-site immunoradiometric assay of parathyrin and its clinical utility in evaluating patients with hypercalcaemia. flin Chem
1987;33:1364-7. 5 Logue FC, Perry B, Chapman RS, James K, Beastall GH. The dcvelopment of a two-sitc immunometric assay JIRMA for intact 1-84 human parathyroid hormone using monoclonal antibodies. ] Endocn'nol 1988;117(suppl):67. 6 Lundberg PA, Lindstedt G, Jansson S, Tisell LE. Assay of 'intact" parathvrin in the immediate and long-term postoperative follow-up of patients treated for hyperparathyroidism or thyroid tumour. Clin Chem 1989;35:340-1. 7 Vati der Mlerwe W, Rodgers RSC, Grant AC, et al. Hvpocalcaemic dialysate in combination with high-dose oral calcitriol in the treatment of secondary hyperparathyroidism in chronic haemodialvsis patients. Scoitish Renal Association Bulletin 1988 Oct:9. 8 Ratcliffe WVA, Heath DA, Pugh J. Evaluation of N-tact parathyroid hormone IRMA (INCS-FAR) [Abstract]. In: Halloran SP, ed. Proceedings of the national meeting. London: Association of Clinical Biochemists, 1989:79. 9 Logue FC, Fraser WD, O'Reilly DStJ, Beastall GH. The circadian rhythm of intact parathyroid hormone (1-84) and iiephrogenoiis cyclic adenosine monophosphate in normal men.] Endocrinol 1989;121:R1-3. 10 Logue FC, Fraser Wl), O'Reilly DStJ, Beastall GH, Gallacher SJ, Boyle IT. Loss of circadian rhythm of PTH (1-84) and nephrogenous cyclic adenosine monophosphate in hyperparathyroidism [Abstract]. Endocrinol 1989;121(suppl): 157. 11 Brown EM. Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. j Clin EndocnnolMletab 1983;56:572-81. 12 Logue FC, Fraser WD, Gallacher SJ, est al. Bisphosphonate effects on calcium, PTH (1-84) and nephrogenous cAMP in patients with hypercalcaemia of malignancy and Paget's disease [Abstract]. In: Halloran SP, ed. Proceedings of the national meeting. London: Association of Clinical Biochemists, 1989:78. 13 Newman DJ, Ashbv JP. Clinical atld laboratory evaluation of a two-site immunoradiometric assay for intact parathvroid hormone. Ann Clin Biuochem 1988;25:654-60.
Pneumocystis carinii pneumonia Aerosolised pentamidine gives effective prophylaxis As many as 85% of patients with AIDS will develop pneumonia due to Pneumocystis carinii at some stage in their illness, and the mortality of acute infections ranges from 9% to 35%. I 2 Of those patients who survive, between 40% and 60% develop recurrent disease within one year in spite of the use zidovudine,34 and the mortality of these recurrent episodes is high.356 These figures provide a clear basis for the value of prophylactic treatment. Several systemic agents are effective,6 but all are associated with adverse reactions in a high proportion of patients. 61 Against this background aerosolised pentamidine has been developed as a treatment directed against the site of the disease and one that reduces systemic adverse effects while maintaining therapeutic benefit both as a prophylactic agent8 and as active treatment for mild infections.8'-0 The effects of aerosolised pentamidine for acute mild to moderate P carinii pneumonia were first shown by Montgomery et al.'0 A dose of 600 mg was given daily for 21 days through a Respirgard II nebuliser, and 13 out of 15 patients responded. Plasma pentamidine concentrations were low and no serious systemic adverse effects were recorded, though the patients did have local symptoms such as cough. The results of other small scale uncontrolled studies were variable, perhaps because of the different doses of pentamidine and different nebuliser systems used.9"'2 Recently several larger studies have been presented (K Arasteh et al; J E Conte et al; P Dellamonica et al; L Flemholc et al; P-M Girard et al; A Meyer et al, Vth international conference on AIDS, Montreal, 1989; for the rest of this article all references given in parentheses are abstracts from that conference). In total these studies described the response of 155 patients given doses of 300-600 mg of pentamidine through various nebulisers. The success rates reported ranged from 61% (A Meyer et al) to 89% (J E Conte et al), and the overall figure for pooled results was 72%. The response to treatment seemed less rapid than with the use of systemic treatment (P-M Girard et al), and one study showed a lower cure rate with aerosolised pentamidine than with cotrimoxazole, though the difference was not signficant BMJ VOLUME 300
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(P Dellamonica et al). The incidence of early relapse seemed higher, but adverse effects were less frequent than with cotrimoxazole. Aerosolised pentamidine seemed less effective in patients with abnormal chest radiographs at presentation (P-M Girard et al). The use of aerosolised pentamidine as a secondary prophylaxis (after an acute episode of P carinii pneumonia) has been studied in greater detail. Early uncontrolled clinical studies showed a low incidence of breakthrough of pneumonia in patients given 30-300 mg pentamidine every one to four weeks with a variety of apparatus.'3-5 There was recurrence in only 8% of 382 patients over follow up periods of five to seven months -a substantial improvement over historical controls. Three recent studies are of particular importance: reductions in recurrence of Pneumocystis carinii pneumonia from 34-6% (placebo) to 6% (aerosolised pentamidine) were reported when 60 mg pentamidine was given every two weeks through a Fisoneb ultrasonic nebuliser in 84 patients over 24 months (J S G Montaner et al), and from 61% to 9% with 4 mg/kg pentamidine monthly (every two weeks for the first month) given through an Ultraneb 99 nebuliser in 51 patients over 8-7 to 10 months.4 In a controlled study on 408 patients a substantial reduction in the incidence of recurrent pneumonia was shown with 150 mg every two weeks or 300 mg monthly in comparison with 30 mg every two weeks through a Respirgard II nebuliser (G S Leoung et al). These authors considered that even the 30 mg dose of pentamidine was of some benefit. The results of this study were instrumental in the decision of the United States Food and Drug Administration to license the use of nebulised pentamidine as secondary prophylaxis in a dose of 300 mg monthly given through Respirgard II. Patients with evidence of profound immune deficiency (those with a count of CD4 lymphocytes
