What is the pathophysiology of humoral-mediated hypercalcemia?

From the Guidelines

Humoral mediated hypercalcemia is primarily caused by the tumor production of parathyroid hormone-related protein (PTHrP), which mimics the action of parathyroid hormone (PTH) and leads to increased bone resorption and calcium release into the bloodstream, as seen in patients with squamous cell lung cancer 1. The pathophysiology of humoral mediated hypercalcemia involves the secretion of factors by tumors that increase calcium levels in the blood without directly invading bone.

• The primary mechanism involves tumor production of PTHrP, which binds to PTH receptors in bone and kidneys, stimulating osteoclast activity and increasing bone resorption, and enhancing calcium reabsorption while reducing phosphate reabsorption in the kidneys.
• Unlike primary hyperparathyroidism, PTHrP-mediated hypercalcemia typically suppresses PTH secretion and 1,25-dihydroxyvitamin D production, as indicated by a suppressed intact parathyroid hormone (iPTH) level and a low or normal calcitriol level 1.
• Other tumor-secreted factors that can cause humoral hypercalcemia include 1,25-dihydroxyvitamin D, cytokines like IL-1, IL-6, and TNF-α, and prostaglandins. The clinical symptoms of hypercalcemia depend on the severity and acuity of onset, and can include polyuria, polydipsia, nausea, confusion, vomiting, abdominal pain, and myalgia, with severe dehydration and acute renal failure possible in patients with lung cancer 1. Treatment of humoral mediated hypercalcemia focuses on addressing the underlying malignancy while managing acute hypercalcemia with aggressive hydration, bisphosphonates, and calcitonin, as well as considering additional therapeutic options such as glucocorticoids and gallium nitrate 1.

From the Research

Pathophysiology of Humoral Mediated Hypercalcemia

• Hypercalcemia of malignancy (HM) is a complex condition involving increased bone resorption, which can be caused by extensive local bone destruction or humoral factors 2.
• Tumor extracts from patients with humoral hypercalcemia of malignancy (HHM) often contain parathyroid hormone (PTH)-like bioactivity, and the cDNAs coding for a PTH-related protein (PTH-rP) have been cloned 2.
• PTH-rP has a considerable homology with human PTH and is recognized as a major mediator of hypercalcemia of malignancy 2, 3.
• Other bone-resorbing factors, including prostaglandins, transforming growth factors, colony-stimulating factors, leucocyte cytokines, and 1,25-dihydroxyvitamin D, may be involved in different types of malignancy 2.

Mechanisms of Hypercalcemia

• Hypercalcemia can be caused by primary hyperparathyroidism, malignancies, and other conditions, leading to an increase in serum calcium concentration >10.5 mg/dL 4.
• The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption and enhanced renal tubular reabsorption of calcium (Ca) 3.
• PTH-related protein (PTHrP) is a key factor in the development of hypercalcemia of malignancy, and its levels are often elevated in patients with this condition 3.

Diagnosis and Treatment

• The diagnosis of hypercalcemia of malignancy involves assessing serum PTHrP levels, calcium levels, and other biochemical markers 3.
• Treatment of hypercalcemia of malignancy typically involves rehydration, bisphosphonates, calcitonin, and other medications to reduce bone resorption and lower calcium levels 4, 2.
• The treatment approach should be individualized, taking into account the pathophysiological mechanisms involved, the extent of hypercalcemia, and renal failure, as well as the prognosis related to the malignant disease 2.