Ex Vivo Intact Tissue Analysis Reveals Alternative Calcium-sensing Behaviors in Parathyroid Adenomas.

Abstract

CONTEXT:

The biochemical basis for clinical variability in primary hyperparathyroidism (PHPT) is poorly understood.

OBJECTIVE:

This study aimed to define parathyroid tumor biochemical properties associated with calcium-sensing failure in PHPT patients, and to relate differences in these profiles to variations in clinical presentation.

METHODS:

Preoperative clinical data from a sequential series of 39 patients undergoing surgery for PHPT at an endocrine surgery referral center in a large, public university hospital were evaluated for correlation to parathyroid tumor biochemical behavior. An intact tissue, ex vivo interrogative assay was employed to evaluate the calcium-sensing capacity of parathyroid adenomas relative to normal donor glands. Tumors were functionally classified based on calcium dose-response curve profiles, and clinical parameters were compared among the respective classes. Changes in the relative expression of 3 key components in the calcium/parathyroid hormone (PTH) signaling axis-CASR, RGS5, and RCAN1-were evaluated as potential mechanisms for calcium-sensing failure.

RESULTS:

Parathyroid adenomas grouped into 3 distinct functional classes. Tumors with diminished calcium sensitivity were the most common (18 of 39) and were strongly associated with reduced bone mineral density (P = 0.0009). Tumors with no calcium-sensing deficit (11 of 39) were associated with higher preoperative PTH (P = 0.036). A third group (6/39) displayed a nonsigmoid calcium/PTH response curve; 4 of these 6 tumors expressed elevated RCAN1.

CONCLUSION:

Calcium-sensing capacity varies among parathyroid tumors but downregulation of the calcium-sensing receptor (CASR) is not an obligate underlying mechanism. Differences in tumor calcium responsiveness may contribute to variations in PHPT clinical presentation.

• Authors: James Koh, Run Zhang, Sanziana Roman, Quan-Yang Duh, Jessica Gosnell, Wen Shen, Insoo Suh, Julie A Sosa
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 106 Issue 11 Pg. 3168-3183 (10 21 2021) ISSN: 1945-7197 [Electronic] United States
• PMID: 34272844 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Biomarkers
• DNA-Binding Proteins
• Muscle Proteins
• Parathyroid Hormone
• RCAN1 protein, human
• RGS Proteins
• RGS5 protein, human
• Receptors, Calcium-Sensing
• Calcium

Topics

• Adenoma (metabolism, pathology)
• Aged
• Biomarkers (metabolism)
• Calcium (metabolism)
• Case-Control Studies
• DNA-Binding Proteins (metabolism)
• Female
• Follow-Up Studies
• Humans
• Hyperparathyroidism, Primary (metabolism, pathology)
• Male
• Middle Aged
• Muscle Proteins (metabolism)
• Parathyroid Hormone (metabolism)
• Parathyroid Neoplasms (metabolism, pathology)
• Prognosis
• RGS Proteins (metabolism)
• Receptors, Calcium-Sensing (metabolism)
• Signal Transduction