Endocrine Abstracts

JOINT1630

Parathyroid gland insufficiency is a frequent complication following thyroid surgery (total/near-total thyroidectomy) and the leading cause of secondary hypoparathyroidism with its consequence, hypocalcaemia. Surgical precautions devised to protect parathyroid glands from traumatic injury have largely failed to eliminate the problem. We propose a mechanism behind postoperative hypoparathyroidism that may account for the high incidence rate and the transient course it takes in most of the instances. After its closure the surgical wound regularly fills with fluid bound to soak parathyroid gland parenchyma. Wound exudate differs from blood plasma by its low pH and because it is replete with products from ongoing enzymatic proteolysis. Hence contact with wound fluid may expose the calcium-sensing receptor on the parathyroid epithelial cells to potential activators such as protons, polyamines, amino acids and/or peptides. Wound fluid-mediated receptor activation would result in an inadvertent suppression of parathyroid hormone secretion. To explore this possibility, we assayed the levels of receptor-activating compounds in thyroid drainage fluid which comprises wound exudate. The human calcium-sensing receptor heterologously expressed in HEK293 cells was used as an experimental model to assay receptor activation, NPS-2143, a negative allosteric modulator to ascertain receptor specificity of the effects. In addition, we reviewed patient records collected during an uninterrupted case series of thyroidectomies, which was done to identify surgery-inherent variables that may impinge on the risk of hypoparathyroidism. The patient records showed that on day one after surgery the levels of both parathyroid hormone and serum calcium were lower than the respective preoperative values in 83 and 90% of the patients, respectively. Consistent with these rates we found that from a set of thyroid drainage fluid specimens the majority of the samples (some 80%) was capable of activating the calcium-sensing receptor. Receptor activation was attributable to a subfraction of drainage fluid with acidic pH and rich in hydrophilic amino acids. Probing the molecular mechanism, we observed that glutamate and aspartate at millimolar concentrations enhanced proton-dependent receptor activation (pH₅₀ ~ 6.0) that was completely blocked by NPS-2143. The concentrations in drainage fluid of calcium ions and of spermine, the cognate agonists however were below the activation threshold. The data support the assumption that wound fluid can produce secretory insufficiency of the parathyroid glands. A clinical trial of a calcilytic drug to inhibit aberrant activation of the calcium-sensing receptor in thyroidectomy patients is called for to test the hypothesis and assess the option for a preventive treatment.