42.5 and 28.5 years, respectively. At least one patient in each family with hereditary medullary thyroid carcinoma had proved pheochromocytoma or late
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1 Urinary Epinephrine and Norepinephrine Excretion in Patients with Medullary Thyroid Carcinoma and Their Relatives Akira MIYAUCHI1), Kazuko MASUO2), Toshio OGIHARA2) Shin-ichiro TAKAI3), Fumio MATSUZUKA4), Kanji KUMA4) Masazumi MAEDA1), Yuichi KUMAHARA2) and Goro KOSAKI3) 1) The Second Department of Surgery, Kagawa Medical School, Kagawa ) Department of Medicine and Geriatrics, Osaka University Medical School, Osaka 553 3) The Second Department of Surgery, Osaka University Medical School, Osaka 553 4) Kuma Hospital, Kobe 650 Japan Medullary thyroid carcinoma can arise as a component of multiple endocrine neoplasia (MEN) syndrome which includes adrenal pheochromocytoma. Familial medullary thyroid carcinoma with no association of other components of MEN syndrome is also reported. Epinephrine and norepinephrine excreted in 24 hour urine and/or randomly voided urine were measured for screening of pheochromocytoma in patients with medullary thyroid carcinoma of either the hereditary or sporadic type and in their relatives. Six patients with clinical symptoms and signs suggesting pheochromocytoma had a markedly increased epinephrine and epinephrine/norepinephrine (E/N) ratio and a less dominant increase of norepinephrine in 24 hour urine. The diagnosis of pheochromocytoma was proved later at surgery. Among 10 patients with hereditary medullary thyroid carcinoma without any clinical symptoms and signs for pheochromocytoma, 6 patients had increased epinephrine and E/N ratio and normal norepinephrine, and the remaining 4 had normal epinephrine, norepinephrine and E/N ratio in 24 hour urine. The six patients with increased epinephrine and E/N ratios were regarded as having latent adrenal medullary hyperfunction. The mean ages of the 6 patients with proved pheochromocytoma, the 6 with latent adrenal medullary hyperfunction and the 4 with normal urinary catecholamine fractions were 51.3,
2 42.5 and 28.5 years, respectively. At least one patient in each family with hereditary medullary thyroid carcinoma had proved pheochromocytoma or latent adrenal medullary hyperfunction, leaving no family with hereditary medullary thyroid carcinoma only. Urinary epinephrine, norepinephrine and E/N ratios in patients with sporadic medullary thyroid carcinoma and relatives of patients with medullary thyroid carcinoma were not higher than those in normal subjects. Measurements of epinephrine and norepinephrine in randomly voided urine are also a valuable and convenient method for the screening of pheochromocytoma in patients with medullary thyroid carcinoma and their relatives, because they gave results similar to those in 24 hour urine. NA. E.
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4 Fig. 1. Epinephrine excreted in 24 hour urine in patients with medullary thyroid carcinoma and their relatives. MTC-H: hereditary medullary thyroid carcinoma, MTC-S: sporadic MTC, MTC & Pheochromocytoma: MTC associated with pheochromocytoma. Bars give mean and SEM.
5 Fig. 2. Norepinephrine excreted in 24 hour urine in patients with medullary thyroid carcinoma and their relatives. Bars give mean and SEM. Fig. 3. Epinephrine/itorepinephrine ratio in 24 hour urine in patients with medullary thyroid carcinoma and their relatives. Bars give mean and SEM.
6 Table Catecholamines excreted in single-voided urine in patients with medullary thyroid carcinoma and their relatives.
7 Fig. 4. Epinephrine and norepinephrine excreted in single-voided urine in patients with medullary thyroid carcinoma of hereditary type () and sporadic type (x). Shaded area indicates distribution in patients with thyroid adenoma.
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11 1) Block, M.A., Horn, R.C., Miller, J.M., Barrett, J.L. and Brush, B.E.: Familial medullary carcinoma of the thyroid. Ann. Surg., 166: , ) Carney, J.A., Sizemore, G.W. and Tyce, G.M.: Bilateral adrenal medullary hyperplasia in multiple endocrine neoplasia, type 2: The precursor of bilateral pheochromocytoma. Mayo Clin. Proc., 50: 3-10, ) Chong, G.C., Beahrs, 0.H., Sizemore, G.W. and Woolner, L.H.: Medullary carcinoma of the thyroid gland. Cancer, 35: , ) DeLellis, R.A., Wolfe, HJ., Gagel, R.F., Feldman, Z.T., Miller, H.H., Gang, D.L. and Reichlin, S.: Adrenal medullary hyperplasis. A morphometric analysis in patients with familial medullary thyroid carcinoma. Am. J. Pathol., 83: , ) DeQuattro, V. and Campese, V.M.: Pheochromocytoma. Diagnosis and therapy Ed, by DeGroot, L.J., Cahill, G.F., Jr., Odell, W.D., Martini, L., Potts, J.T., Jr., Nelson, D.H., Steinberger, E. and Winegrad, A.I.: Endocrinology Vol. 2, Grune & Stratton, New York, ) Engelman, K., Horwitz, D., Ambrose, I.M. and Sjoerdsmam, A.: of urinary epinephrine in screening for pheochromocytoma in multiple endocrine neoplasia type 2. Am. J. Med., 65: , ) Hennessy, J.F., Gray, T.K., Cooper, C.W. and Ontjes, D.A.: Stimulation of thyrocalcitonin secretion by pentagastrin and calcium in two patients with medullary carcimona of thethyroid. J. Clin. Endocrinol. Metab., 36: , ) Gagel, R.F., Melvin, K.E.W., Tashjian, A.H., Jr., Miller, H.H., Feldman, Z.T., Wolfe, H.J., DeLellis, R.A., Cerviskinner, S. and Reichlin, S.: Natural history of the familial medullary thyroid carcinoma-pheochromocytoma syndrome and the identification of preneoplastic stage by screening studies: A five-year report. Trans Miller, H.H. and Tashjian, A.H., Jr.: Early diagnosis of medullary carcinoma of the thyroid gland by means of calcitonin assay. N. Engl. J. Med., 285: , ) Miller, H.H., Melvin, K.E.W., Gibson, J.M. and Tashjian, A.H., Jr.: Surgical approach to early familial medullary carcinoma of the thyroid gland. Am. J. Surg., 123: , ) Miura, Y. et al: Plasma norepinephrine levels and hemodynamics in young patients with essential hypertension. Jpn. Cir. J., 42: 609, Random one-hour urine catecholamine and 4-hydroxy-3-methoxymandelic acid assays for diagnosis of pheochromocytoma. Clin. Chim. Acta, 103: , ) Parthemore, J.G., Bronzert, D., Roberts, G. and Deftos, L.J.: A short calcium infusion
12 in the diagnosis of medullary thyroid carcinoma. J. Clin. Endocrinol. Metab., 39: , ) Sato, T., Kobayashi, K., Miura, Y., Sakuma, H., Yoshinaga, K. and Nakamura, K.: High epinephrine content in the adrenal tumors from Sipple's syndrome. Tohoku J. Exp. Med., 115: 15-19, ) Sever, P.S., Brich, M., Oshikowska, B. and Tunbridge, R.D.G.: Plasma-norepinephrine in essential hypertension. Lancet, 1: 1078 Gordon, H. Perry, H.O., Robertson, D.M., Sayre, G.P., Sheps, S.G. and Weiland, L.H.: Multiple endocrine neoplasia, type 2b: Familial syndrome of multiple mucosal neuromas and connective tissue abnormalities with C-cell hyperplasia or medullary carcinoma of the thyroid gland, pheochromocytoma and normal parathyroid glands. (submitted for publication) Cited by Chong et al., Cancer, 35: , ) Steiner, A.L., Goodman, A.D. and Powers, S.R.: Study of a kindred with pheochromocytoma, medullary thyroid carcinoma, hyperparathyroidism and Cushing's disease. Multiple endocrine neoplasia, type 2. Medicine, 47: , ) Tashjian, A.H., Jr., Howland, B.G., Melvin, K.E.W. and Hill, C.S., Jr.: Immunoassay of human calcitonin. Clinical measurement, relation to serum calcitonin and studies in patients with medullary carcinoma. N. Engl. J. Med., 283: , ) Von Euler, U.S., Franksson, C. and Hellstrom, J.: Adrenaline and noradrenaline output in urine after unilateral and bilateral adrenalectomy in man. Acta Physiol. Scand., 31: 1-5, ) Weidmann, P. et al.: Age versus urinary sodium for judging renin, aldosterone and catecholamine levels: Studies in normal subjects and patients with essential hypertension. Kid. Inter., 14: 619,
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