Prospective study of surgery for primary hyperparathyroidism (HPT) in multiple endocrine neoplasia-type 1 and Zollinger-Ellison syndrome: long-term outcome of a more virulent form of HPT

Abstract

Background: Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) patients with Zollinger-Ellison syndrome (ZES) is caused by parathyroid hyperplasia. Surgery for parathyroid hyperplasia is tricky and difficult. Long-term outcome in ZES/MEN1/HPT is not well known.

Methods: Eighty-four consecutive patients (49 F/35 M) with ZES/MEN1/HPT underwent initial parathyroidectomy (PTX) and were followed at 1- to 3-year intervals.

Results: Age at PTX was 36 +/- 2 years. Mean follow-up was 17 +/- 1 years. Before PTX, mean Ca = 2.8 mmol/L (normal level (nl <2.5), PTH i = 243 pg/mL (nl <65), and gastrin = 6950 pg/mL (nl < 100). Sixty-one percent had nephrolithiasis. Each patient had parathyroid hyperplasia. Fifty-eight percent of patients had 4 parathyroid glands identified. Nine of 84 (11%) had 4 glands removed with immediate autograft, 40/84 (47%) 3 to 3.5 glands, whereas 35/84 (42%) <3 glands removed. Persistent/recurrent HPT occurred in 42%/48% of patients with <3 glands, 12%/44% with 3 to 3.5 glands, and 0%/55% with 4 glands removed. Hypoparathyroidism occurred in 3%, 10%, and 22%, respectively. The disease-free interval after surgery was significantly longer if >3 glands were removed. After surgery to correct the HPT, each biochemical parameter of ZES was improved and 20% of patients no longer had laboratory evidence of ZES.

Conclusions: HPT/MEN1/ZES is a severe form of parathyroid hyperplasia with a high rate of nephrolithiasis, persistent and recurrent HPT. Surgery to correct the hypercalcemia significantly ameliorates the ZES. Removal of less than 3.5 glands has an unacceptably high incidence of persistent HPT (42%), whereas 4-gland resection and transplant has a high rate of permanent hypoparathyroidism (22%). More than 3-gland resection has a longer disease-free interval. The surgical procedure of choice for patients with HPT/MEN1/ZES is 3.5-gland parathyroidectomy. Careful long-term follow-up is necessary as a significant proportion will develop recurrent HPT.

Figure 1

The disease-free survival (left panels) and recurrence rate (right panels) following initial surgery for hyperparathyroidism in MEN-1 patients with HPT and ZES. The two upper panels show the overall percent who are either free of disease (left panel) or with recurrent HPT (right panel) at follow-up in years. The lower two panels show the same data divided as to whether >3 or <3 glands were removed. It demonstrates that the disease-free survival (but not the recurrence rate) was greater if 3 or more than 3 parathyroid glands were removed compared to <3 glands removed (p=0.018).

Figure 2

Effect of parathyroidectomy on fasting gastrin level, BAO and Δ secretin in MEN1/ZES patients without or without the hypercalcemia corrected postparathyroidectomy. Results are shown from 50 patients of whom HPT was corrected in 43 and not corrected in 7 patients. Panels A1/A2 show the mean fasting gastrin levels pre- and post-PTX in 49 patients. The horizontal line shows the median value pre- and post-PTX which were 925 and 247 pg/mL for the corrected HPT group and 842 and 740 pg/mL for the uncorrected group. Eight patients had gastrin levels return to the normal range (i.e. <100 pg/mL)(shaded area) post PTX. Panels B1/B2 shows the effect on the BAO in 22 patients. The horizontal line is the mean±SEM and for the HPT corrected group (n=19) was 30.2 ± 4.5 and 9.5 ± 1.6 mEq/hr and for the uncorrected HPT group (n=3) was 40.6 ± 17.4 and 43.3 ±15.9 mEq/hr. Panels C1/C2 show results of the Δ secretin in 18 patients. The horizontal line is the mean ± SEM which was 1175 ± 294 and 745 ± 286 for the HPT corrected group Eight patients demonstrated a negative secretin test post PTX using the criterion of ≥200 pg/mL increase postsecretin (shaded area) and 3 patients using the recently proposed criterion of ≥ 120 pg/mL increase. ,