(178b) Differential Diagnosis of Primary Hyperparathyroidism and Extent of Progression Through Short-Term Calcium Loading

In the human body, total plasma calcium is maintained within a specific range (8.5-10.3 mg/dl) [1] via a regulatory system that employs parathyroid hormone (PTH) and calcitriol (CTL) to moderate Ca flux between the plasma and each of the organs: kidneys, intestines and bones. Disorders in the regulatory organs cause increased hormonal activity which subsequently leads to chronic imbalances in plasma Ca levels. For example, enlarged parathyroid glands (PTG) associated with primary hyperparathyroidism (PHPT) cause over secretion of PTH which leads to high plasma Ca levels (hypercalcemia)[2].    

A common feature in the major pathologies associated with hypercalcemia is the excess secretion of PTH and/or PTH-related protein, leading to increased plasma Ca. The three most common pathologies, accounting for 90% of hypercalcemic cases are Familial Benign Hypercalcemia (FBH), Humoral Hypercalcemia of Malignancy (HHM) and PHPT. FBH is a missense mutation of the calcium-sensing receptor, located on the surface of the parathyroid cells, causing increased PTH secretion. HHM is caused by cancerous tumors producing PTH-related protein (PTHrP). PHPT is often confused with FBH and/or HHM during the early stages of progression because the three pathologies have an identical effect on Ca-related biochemistries. A series of biochemical tests and family history checks are usually necessary to differentiate among these diseases [2].

Previously, we used an engineering control system framework to represent physiological plasma Ca regulation [3]. This framework describes the dynamics of PTH from the PTG, calcitriol from the kidneys, bone cells (osteoblasts and osteoclasts) and plasma calcium. These are mapped onto the controller, the actuators and the process. Following validation of the overall model with published clinical data we successfully simulated Ca-related pathologies through induced defects in the control system components (sensor, controller and/or actuator).

In this presentation, we provide a systematic approach for differentiating among FBH, HHM and PHPT based on the unique hormone/ion responses to short-term Ca disturbance in each pathology model. Additionally, based on the changes in intrinsic parameters associated with PTG behavior, we show that the extent of PHPT progression can be reasonably predicted and the enlarged gland size estimated a priori.

We hypothesize that the proposed disease diagnosis strategy would be useful for (a) early detection of PHPT in at-risk or asymptomatic patients and, (b) differential diagnosis of FBH, HHM and PHPT where the pathologies have identical presentations and are difficult to distinguish using existing clinical methods.

1. Kovacs, W.J. and S.R. Ojeda, Textbook of Endocrine Physiology. 6th ed2012, Oxford: Oxford University Press. xii, 462 p.

2. Fraser, W.D., Hyperparathyroidism. Lancet, 2009. 374(9684): p. 145-58.

3. Christie, C.R., L.E.K. Achenie, and B.A. Ogunnaike, A Control Engineering Perspective to Modeling Calcium Regulation and Related Pathologies, in Annual Meeting  October 28-    November 2,2012.