Standard Procedure and the Diagnostic Criteria for the Ellsworth-Howard Test using Human PTH-(1-34) Etsuro OGATA, Michiko YAMAMOTO and Toshio MATSUMOT
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1 Standard Procedure and the Diagnostic Criteria for the Ellsworth-Howard Test using Human PTH-(1-34) Etsuro OGATA, Michiko YAMAMOTO and Toshio MATSUMOTO The Fourth Department of Internal Medicine, Tokyo University School of Medicine, Tokyo, Japan Takuo FUJITA, Masaaki FUKASE and Yoshikazu KINOSHITA The Third Department of Internal Medicine, Kobe University School of Medicine, Kobe, Japan Yohtaro FURUKAWA and Hyo Euy SOHN The Second Department of Internal Medicine, Tohoku University School of Medicine, Sendai, Japan Hironori NAKAJIMA and Toshiyuki YASUDA Department of Pediatrics, Chiba University School of Medicine, Chiba, Japan The present study was undertaken to establish a standard method to perform the Ellsworth-Howard test using human PTH-(1-34). For this purpose we made a survey of literature concerning the Ellsworth Howardtest and then examined the data of the Ellsworth-
2 Howard tests performed on 178 hypoparathyroid patients using human PTH-(1-34). The main items of investigation were: (i) to determine the appropriate dose of PTH for administration to adults and children; and (ii) to define the criteria of practical usefulness for the differential diagnosis of the types of hypoparathyroidism. From the analysis of the data, the following findings and conclusions were obtained. I) The dose of human PTH-(1-34) appropriate for diagnostic use is 100U per person for adults and 100U per body surface area of one square meter (100 U/m2 ) for children. II) The criteria of positive response in the Ellsworth-Howard test are defined as follows. a) phosphaturic response: (U4 + U5) - (U2 + U3) = more than 35 mg/2 h b) cyclic AMP response: U4 - U3 = more than 1 pmol/h, and U4/U3 = more than 10 times In the above formula, U2 - U5 represent the urine samples collected hourly in order. PTH is injected at the time between U3 and U4. For the application of the criteria in children, one should use the values corrected for body surface area of one square meter. III) It is necessary to confirm the following conditions before the application of the criteria: (1) the presence of hypocalcemia and hyperphosphatemia; (2) the lack of phosphate deficiency (basal urinary phosphate excretion more than 10 mg/ 2 h); (3) the accuracy of timed urine collections (ratio of creatinine excretion during 2 hours before PTH to that after PTH administration in the range from 0.8 to 1.2); and (4) the absence of marked diurnal variation in phosphate excretion (difference in phosphate excretion between the two basal hourly urine less than 17.5 mg/h). IV) To ensure the above conditions, medications such as phosphate-binding antacids should be withheld for at least 1 week before the test, and the test should be performed according to the standard procedure described in this paper. V) The diagnosis of pseudohypoparathyroidism Type II should be done cautiously. It is necessary to take account of the high basal urinary cyclic AMP excretion and the elevated serum PTH level along with the results of the Ellsworth-Howard test (positive cyclic AMP response and negative phosphaturic response) for a definite diagnosis of this entity.
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13 1) Albright, F., Burnett, C.H., Smith, P.H. and Parson, W.: Pseudohypoparathyroidism - An example of "Seabright-Bantam syndrome". Endocrinology, 30: , ) Balachandar, V., Pahuja, J. and Maddaiah, V.T.: Pseudohypoparathyroidism with normal serum calcium level. Am. J. Dis. Child., 129: , ) Bethune, J.E., Smith, L.F. and Inoue, H.: Renal phosphaturic response to parathyroid hormone administration and dietary intake of phosphorus in man. J. Clin. Endocrinol. Metab., 24: , ) Bronsky, D., Kushner, D.S., Dublin, A. and Snapper, I.: Idiopathic hypoparathyroidism and pseudohypoparathyroidism: Case reports and review of the literature. Medicine, 37: , ) Chase, LA., Melson, G.L. and Aurbach, G.D.: Pseudohypoparathyroidism: Defective excretion of 3', 5'-AMP in response to parathyroid hormone. J. Clin. Invest., 48: , ) Coulson, R. and Moses, A.M.: Effect of chlorpropamide on renal response to parathyroid hormone in normal subjects and in patients with hypoparathyroidism and pseudohypoparathyroidism. J. Pharma. Exp. Therapau., 194: , ) Drezner, M., Neelon, F.A. and Lebovitz, H.E.: Pseudohypoparathyroidism Type II: A possible defect in the reception of the cyclic AMP signal. N. Engl. J. Med., 289: , ) Ellsworth, R. and Howard, J.E.: Studies on the physiology of the parathyroid glands. Bull. Johns. Hopkins. Hosp., 55: , H.,.Mari, S. and Paul, H.S.: The one hour response to parathyroid extract in hyperparathyroidism and renal disease. Metabolism, 15: , ) Igarashi, T., Yamamoto, M., Yamada, M., Ogata, E. and Katsuragi, S.: Application of newly synthesized 1-34 human parathyroid hormone for diagnostic tests. Pharmatherapeutica, 3: 79-85, ) Kopp, L., Lin, T. and Tucci, J.R.: Circadian rhythms in the urinary excretion of cyclic 3', 5'-adenosine monophosphate (cyclic AMP) and cyclic 3', 5'-guanosine monophosphate (cyclic GMP) in human subjects. J. Clin. Endocrinol. Metab., 44: , ) Lilienfeld-Toal, H., Hesch, R.-D., HUfner, M. and McIntosh, C.: Excretion of cyclic 3', 5'-adenosine monophosphate in renal insufficiency and primary hyperparathyroidism after stimulation with parathyroid hormone. Horm. Metab. Res., 6: , ) Lubell, D.: The spontaneous diurnal variation of urinary rthosphate excretion and its relation to the parathyroid hormone test. Hely. Paediat. Acta, 2: , ) Neer, R.M., Tregear, G.W. and Potts, J.TJr.: Renal effects of native parathyroid hormone and synthetic biologically active fragments in pseudo-
14 Ling and Young, R.: Further studies on the isolation and characterization of parathyroid polypeptides. J. Biol. Chem., 239: , ) Stogmann, W. and Fischer, J.A.: Pseudohypoparathyroidism: Disappearance of the resistance to parathyroid extract during treatment with vitamin D. Am. J. Med., 59: , ) Tomlinson, S., Bailing, P.M., Albano, J.D.M., Brown, B.L. and O'Riordan, J.L.H.: The effect of exogenous parathyroid hormone on plasma and urinary adenosine 3', 5'-cyclic monophosphate in man. Clin. Sci. Molec. Med., 47: , ) Werder, EA., Fischer, J.A., Illig, R., Kind, H.P., Bernasconi, S., Fanconi, A. and Prader, A.: Pseudohypoparathyroidism and idiopathic hypoparathyroidism: Relationship between serum calcium and parathyroid hormone levels and urinary cyclic adenosine-3', 5'-monophosphate response to parathyroid extract. J. Clin. Endocrinol. Metab., 46: , 1978.
1. Albright, F., Burnett, C. H., Smith, P. H. and Parson, W.: Pseudohypoparathyroidism an example of "Seabnght-Bantam syndrome", Endocrino- logy, 30:922-932, 1942. 2. Elrick, H., Albright, F., Bartter,
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