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In kindreds with familial medullary thyroid carcinoma (MTC), individuals are often detected whose peripheral plasma calcitonin (CT) levels are undetectable in the basal state but increase minimally following provocative testing. The proper management of such patients has been uncertain, but most investigators have advocated repeat testing and evaluation after an interval of several months. The present study was conducted to evaluate the diagnostic implications of these modest increases in plasma calcitonin. In 25 kindred members at direct risk for familial medullary thyroid carcinoma (MTC), basal peripheral plasma calcitonin (CT) levels were less than 240 pg/ml. Following provocative testing with intravenous calcium or pentagastrin or both, calcitonin values remained below 240 pg/ml in eight subjects (Group A), however, they were mildly elevated (260-580 pg/ml) in 12 subjects (Group B) and moderately elevated (700-940 pg/ml) in five subjects (Group C). Following the transfemoral placement of a catheter into the inferior thyroid vein (ITV), provocative testing was repeated, and ITV and peripheral blood samples were collected simultaneously. Basal ITV plasma CT levels were below 240 pg/ml in all patients in Group A, however, they were mildly elevated (500 pg/ml) in one of the 12 patients in Group B and moderately elevated (800 pg/ml, 1400 pg/ml) in two of the five patients in Group C. Following provocation, ITV plasma CT levels became markedly elevated in one patient in Group A and in all of the patients in Groups B(2520+/-635 pg/ml) and C (6322+/-2598 pg/ml). Thyroidectomy was performed in patients whose ITV plasma CT level was elevated following provocative testing. Medullary thyroid carcinoma of C-cell hyperplasia were evident either on microscopic (1/1 patient in Group A;9/12 patients in Group B; and 2/5 patients in Group C), or gross (3/12 patients in Group B;3/5 patients in Group C) examination of thyroidectomy specimens. In only one of 14 patients was metastatic MTC noted on histologic examination of resected cervical lymph nodes. Postoperative peripheral plasma CT levels were unchanged from basal and less than 240 pg/ml following provocative testing in all but one patient. The present study then provides definitive evidence that patients at direct risk for familial MTC who have even minimally abnormal responses in peripheral plasma CT following provocative testing generally harbor some stage of a C-cell proliferative disorder. Identification of such individuals with early disease is important because thyroidectomy offers an extremely high cure rate.