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

This Article is brought to you for free and open access by Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Henry Ford Hospital Medical Journal by an authorized editor of Henry Ford Health System Scholarly Commons.

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.

References 1. Melvin KE, Tashjian AH Jr, Miller HA, Studies in familial thyroid cancer.

Trans Assoc Am Physicians 1971;84:144-51, 2, Gagel RF, Tashjian AH Jr, Cummings T, et al. The clinical outcome of pro­

spective screening for multiple endocrine neoplasia type 2a: An 18-year experi­ence, N Engl J Med 1988;318:478-84.

3. Deftos LJ. Immunoassay for human calcitonin. 1. Method. Metabolism 1971;20:1122-8.

4. Deftos LJ. Bury AE. Habener JF. Singer FR. Potts JT Jr. Immunoassay for human calcitonin. I I . Clinical .studies. Metabolism 197l;20:1129-37.

5. Deftos LJ. Supression and stimulation of calcitonin secretion and medul­lary thyroid carcinoma. Metabolism 1971;20:428-31.

6. Bone HG III . Zerwekh, JE, Haussler MR, Pak CYC, Effect of parathyroid­ectomy on serum la,25-dihydroxyvitamin D and intesdnal calcium absorption in primary hyperparathyroidism. J Clin Endocrinol Metab 1979;48:877-9.

7. Pak CY, Oata M, Lawrence EC, Snyder W. The hypercalciurias. Causes, parathyroid functions, and diagnostic criteria, J Clin Invest 1974;54:387-400.

8. Nussbaum SR, Zahradnik RJ, Lavigne JR, et al. Highly sensitive two-site immunoradiometric assay of parathyrin, and its clinical utility in evaluating pa­tients with hypercalcei-nia. Clin Chem I987;33:1364-7.

9. Heath H, Sizemore GW, Camey JA. Preoperative diagnosis of occult para­thyroid hyperplasia by calcium infusion in patients with multiple endocrine neo­plasia, type 2A, J Clin Endocrinol Metab 1976;43:428-35.

10. Zimering MB, Brandi ML, DeGrange DA, et al. Circulating fibroblast growth factor-like substance in familial multiple endocrine neoplasia type I . J Clin Endocrinol Metab 1990;70:149-54.

11. Deftos LJ, Parthemore JG. Secretion of parathyroid hormone in patients with medullary thyroid carcinoma. J Clin Invest 1974;54:416-20.

12. Jaeger P, Jones W, Clei-nens TL, Hayslett JP. Evidence that calcitonin stimulates 1,25-dihydroxyvitamin D production and intestinal absorption of cal­cium in vivo. J Clin Invest 1986;78:456-61.

13. Jackson CE, Norum RA. Genetic mechanisms of neoplasia in MEN 2. Henry Ford Hosp Med J 1989;37:116-9.

260 Henry Ford Ho.sp Med J—Vol 40. Nos 3 & 4,1992 Thyroidectomy in MEN 2A—Bone et al