mineral metabolic effects of thyroidectomy and long-term
TRANSCRIPT
Henry Ford Hospital Medical Journal Henry Ford Hospital Medical Journal
Volume 40 Number 3 Article 26
9-1992
Mineral Metabolic Effects of Thyroidectomy and Long-term Mineral Metabolic Effects of Thyroidectomy and Long-term
Outcomes in a Family with MEN 2A Outcomes in a Family with MEN 2A
Henry G. Bone III
Leonard J. Deftos
William H. Snyder
Charles Y. C. Pak
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Recommended Citation Recommended Citation Bone, Henry G. III; Deftos, Leonard J.; Snyder, William H.; and Pak, Charles Y. C. (1992) "Mineral Metabolic Effects of Thyroidectomy and Long-term Outcomes in a Family with MEN 2A," Henry Ford Hospital Medical Journal : Vol. 40 : No. 3 , 258-260. Available at: https://scholarlycommons.henryford.com/hfhmedjournal/vol40/iss3/26
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Mineral Metabolic Effects of Thyroidectomy and Long-term Outcomes in a Family with MEN 2A
Henry G. Bone, HI,* Leonard J. Deftos,* William H. Snyder,̂ and Charles Y. C. Pak*
We have followed a family with multiple endocrine neoplasia type 2A for 18 years. Four members have undergone total thyroidectomy for medullary thyroid carcinoma or C-cell hyperplasia, and one has required bilateral adrenalectomy for pheochromoctyoma. None has developed hypercalcemic hyperparathyroidism, although parathyroid hormone levels were relatively high prethyroidectomy and fell postoperatively in the patients with high calcitonin levels. In three of the four cases, intestinal calcium absorption decreased following thyroidectomy. (Henry Ford Hosp MedJ 1992;40:258-60)
L ittle information is available in the literature conceming calcium metabolism in patients with multiple endocrine
neoplasia type 2A (MEN 2A). Authors have previously described hypercalcemic hyperparathyroidism in affected individuals (1). However, the patients in whom this occurred appear likely to have had fairly advanced C-cell disea.se which could not be detected earlier due to the insensitivity of the calcitonin (CT) assays available at that time. Medullary thyroid carcinoma (MTC) has not been reported in patients who underwent early curative total thyroidectomy for C-cell hyperplasia (2). These observations raise the possibility that the hyperparathyroidism might be secondary to the C-cell disease in some way.
Subjects Three generations of a single family were studied (Figure).
The propositus was evaluated because members of another branch of his family had been found to have MEN 2A. He was found to have MTC at surgery and developed signs and symptoms of pheochromocytoma three years later. Although urinary metanephrine levels were never elevated, adrenal venograms were abnormal and bilateral pheochromocytomas were resected. Each of his three children had elevated CT levels after provocative testing and underwent total thyroidectomy. On pathological examination, clusters of C-cells were noted in I I - l and II-2 and larger nodules were noted in II-3 (Figure) leading to a diagnosis of C-cell hyperplasia in each case. None of the second generation has developed pheochromocytomas so far. To date, no member of the third generation has had a positive provocative test for CT.
Methods Plasma CT was measured in the University of Califomia-San
Diego Endocrine Research Laboratories at the San Diego VA Medical Center as described previously (3,4). Levels of > 200 pg/mL after pentagastrin or 10-minute calcium infusion were considered sufficiently abnormal to warrant surgery (5). Frac
tional intestinal calcium absorption was measured at the General Clinical Research Center (GCRC), University of Texas Health Science Center, and Parkland Hospital, Dallas, TX, as described (6). The normal range for adults is 43% to 57%.
Parathyroid hormone (PTH) was measured by different methods over the course of the f 8 years. Baseline studies used the method of Pak et al (7). Recent data are based on the Nichols two-site Allegro Assay (8) as performed in the Bone and Mineral Research Laboratory at Henry Ford Hospital. The upper limit of the pertinent normal range is presented with the results for each test.
Results Both calcium infusions and pentagastrin injections (5) were
used as provocative tests for CT secretion. The highest level attained by either method is presented in Tables 1 and 2.
Table 1 displays the preoperative and postoperative CT, PTH, and calcium absorption results for members ofthe first two generations, as well as recent data. In each case, a substantial drop in PTH was noted after thyroidectomy, although the parathyroid glands were left intact. In I - l and II-3 the basal PTH levels were frankly elevated. Calcium absorption fell after thyroidectomy in I - l , I I - 1 , and II-2, but was unchanged in the adolescent male I I -3. The results of provocative testing are presented for the third generation in Table 2.
Discussion Heath et al (9) described nonsuppressible C-terminal iPTH
levels prior to thyroidectomy in six normocalcemic patients with MEN 2A. Al l patients were from kindreds with parathyroid di.sease, and evidence of parathyroid hyperplasia was observed
*Bone and Mineral Division, Henry Ford Hospital. tUniversity of Califomia and VA Medical Cenler. San Diego, CA, ^University of Texas Health Science Center, Dallas, TX. Address coiTespondence to Dr. Bone, Bone and Mineral Division, Henry Ford Hospital,
2799 W Grand Blvd, Detroit, MI 48202.
258 Henry Ford Hosp Med 1—Vol 40, Nos 3 & 4,1992 Thyroidectomy in MEN 2A—Bone et al
Table 1 Pre- and Post-thyroidectomy and Long-term Follow-up Studies in Generations I and II
Pattern Age/Sex Phase
Basal Calcium (mg/dL)
Basal Pentagastrin
(mg/dL) Peak HCT
(pg/mL) Basal Parathyroid
Hormone (versus nL) Calcium
Absorption
I- l 50/M Pretreatment 9.4 3.1 3,800 2,169 (< 1,000) 68% Posttreatment 9.1 2,8 < 15 771 (< 1,000) 51%
67 Latest 8.9 3.2 27 44(<55) n-l 29/M Pretreatment y.3 3.5 370 180 (< 1,000) 63.5%
Posttreatment y.d 4.7 S7 76 (< 1,000) 47.3% 43 Latest 8.6 3.6 53 27 (< 55)
II-2 26/F Pretreatment 9.3 3.8 330 390 (< 1,000) 57% Posttreatment S.7 3.5 33 102 (< 1,000) 37%
40 Latest 8.0 3.0 39 35(<55) II-3 16/M Pretreatment 9.9 4.0 1,013 2,251 (< I.OOO) 66.3%
Posttreatment 10.1 3.9 44 885 (< 1,000) 67.4% 31 Latest 9.0 3.3 33 31 (<55)
HCT = human calcitonin.
Table 2 Screening Studies in Generation II
Basal Basal Intact Calcium Pentagastrin PTH Peak HCT
Patient Age/Sex (mg/dL) (mg/dL) (pg/mL) (pg/mL)
III- l 21/M 9.8 2.0 14 62 III-2 20/F 'Ml 3.4 21 39 III-3 15/M 9.7 3.6 74 54 III-4 15/M 8.9 4,3 37 37 III-5 5/F lO.I 4.4. 13 77
PTH = parathyroid hormone: HCT = human calcitonii
at surgery. After discussing the possibility that CT might stimulate PTH secretion, the authors interpreted their results as suggesting the hyperparathyroidism of MEN 2A may be genetic. The normal suppressibility of PTH in patients with MEN 2B argues against PTH stimulation by CT alone. However, the authors' findings are completely consistent with PTH stimulation by some other tumor product, as has been reported for bFGF (10). One cannot know with certainty what the long-term outcome would have been in Heath's patients if the parathyroid glands had been left intact when curative total thyroidectomies were performed. Deftos and Parthemore (11) reported a rise in PTH in some, but not all, of a series of MEN 2A patients who underwent calcium infusions. These studies suggest that a tumor secretory product may stimulate PTH secretion. Since all of our patients underwent early total thyroidectomy, we cannot say whether they would have developed overt hyperparathyroidism had their thyroid C-cell disease been allowed to persist or progress. However, Heath et al's findings of abnormal parathyroid function in normocalcemic MEN 2A patients do resemble the results in at least two of our patients, suggesting a similarity between our patients and theirs.
Our results make several points. First, there appear to be reversible effects of C-cell disease on parathyroid function and calcium absorption. Second, the benefits of early detection of
III 6 6 o a PHEOCHROMOCYTOMA
LEGEND: B € MEDULLARY THYROID CANCER 0 0 C-CELL HYPERPLASIA
Figure—Family pedigree for the propositus and his descendants.
disease and total thyroidectomy are confirmed by the lack of recurrence of thyroid disease. Third, none of our patients developed hypercalcemic hyperparathyroidism. The decline in PTH levels postsurgery (with the elevated preoperative PTH levels in two normocalcemic individuals) suggests that either the elevated CT levels or some other C-cell product may have directly or indirectly stimulated PTH secretion. The calcium absorption data may reflect the combined effects of CT and PTH. We have described hyperabsorption of calcium in primary hyperparathyroidism (6), and a positive effect of CT on calcium absorption has also been noted (12). Our data are consistent with the possibility that the hyperparathyroidism of MEN 2A is secondary to the C-cell disease in some way. These data do not exclude the possibility that some patients have a form of MEN 2A in which hyperparathyroidism is genetically programmed. The existence of two forms of MEN 2A would imply either different mutations at the same locus or possibly some difference in mutation site as suggested by Jackson and Norum (13). The definitive answer to
Henry Ford Hosp Med 1—Vol 40, Nos 3 & 4, 1992 Thyroidectomy in MEN 2A—Bone et al 259
this question must await complete characterization of the gene or genes for MEN 2A.
Acknowledgments This work was supported in part by U.S. Public Health Ser
vice grants AM00383, RR00633, PK2054, AR16061, CA47373, CA49474,and ARI 5888.
We gratefully acknowledge the important roles of Carol Parcel, RN, BSN, Sharon Haynes RN, ASN, and Betty Valek, BS, Department of Surgery, GCRC, University of Texas Health Science Center, Dallas; Cheryl Chalberg, BS, Endocrine Laboratory, VA Medical Center, San Diego; and Paulette Wilson, MS, Bone and Mineral Laboratory, Henry Ford Hospital. The cooperation and assistance of Ned Breslau, MD, Director GCRC, Dallas, was essential to the completion of these studies.
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260 Henry Ford Ho.sp Med J—Vol 40. Nos 3 & 4,1992 Thyroidectomy in MEN 2A—Bone et al