Pathophysiology
Summary
Calcium metabolism disorders encompass two primary conditions: hypocalcemia and hypercalcemia, each with distinct etiologies and clinical implications. Normal total serum calcium levels range from 8.5 to 10.2 mg/dL. Of this, ~50% exists as ionized calcium (‘free’ calcium), which is the metabolically active form. The remaining 50% of serum calcium includes calcium bound to albumin (45%) and anions (5%).
Hypocalcemia is defined as a total serum calcium level > 10.5 mg/dL or ionized calcium > 1.4 mg/dL. In hypoparathyroidism, PTH deficiency leads to decreased calcium absorption in the intestines and gut. In the absence of PTH, which normally aids in renal phosphate excretion, there is increased phosphate reabsorption and subsequent hyperphosphatemia.
Albright hereditary osteodystrophy (pseudohypoparathyroidism), results from a G-protein mutation affecting PTH receptor signaling, resulting in PTH resistance. It is only inherited from the mother due to genetic imprinting, and presents with shortened 4th & 5th digits, short stature, and obesity. Chronic kidney disease (CKD), which can disrupt 1-alpha hydroxylase activity, as well as vitamin D deficiency can cause hypocalcemia due to a decrease in bioactive vitamin D (calcitriol). Blood transfusion, (complexing of calcium with citrate), and severe acute pancreatitis (calcium binding fatty acids) as well as medications like loop diuretics & bisphosphonates, can also cause hypocalcemia
Hypercalcemia is defined as a total serum calcium level > 10.5 mg/dL or ionized calcium > 1.4 mg/dL. The most common cause is primary hyperparathyroidism, accounting for over 95% of cases. Hypercalcemia of malignancy represent the second leading cause, often linked to the production of ectopic PTH-related protein (PTHrP) or the presence of osteolytic bone metastases, such as in multiple myeloma.
An inherited form of hypercalcemia is familial hypocalciuric hypercalcemia (FHH), an autosomal dominant mutation in the calcium-sensing receptors (CaSR) in the kidneys and parathyroid gland. This results in abnormal calcium sensing in the kidney, leading to inappropriate calcium reabsorption and PTH release. Certain drugs like thiazide diuretics and conditions like vitamin D toxicity or milk alkali syndrome can also induce hypercalcemia.
Lesson Outline
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FAQs
Approximately 45% of serum calcium is bound to albumin, while around 5% is bound to anions such as phosphate. The remaining 50% circulates in its ionized or "free" form, which is the metabolically active form of calcium. Disruptions in acid-base balance can affect serum calcium levels: acidosis can prompt albumin to unbind calcium, increasing the concentration of ionized calcium in the blood and potentially leading to hypercalcemia, while alkalosis can lead to more calcium bound to albumin and less in the blood, causing hypocalcemia.
In hypoparathyroidism, such as in primary hypoparathyroidism, the deficiency of PTH influences calcium and phosphate metabolism various ways. PTH deficiency results in less calcium released from bones, decreased calcium reabsorption in the kidneys, and decreased active vitamin D and subsequent calcium absorption in the gut, resulting in hypocalcemia. Concurrently, the absence of PTH, which normally promotes phosphate excretion in the kidneys, leads to an increase in phosphate reabsorption and subsequent hyperphosphatemia.
Albright hereditary osteodystrophy, specifically referred to as pseudohypoparathyroidism type 1A, is a condition caused by an autosomal dominant mutation that affects the Gs alpha subunit of a G-protein coupled receptor involved in parathyroid hormone (PTH) signaling. This mutation disrupts the normal response to PTH, leading to a state of PTH resistance. The resistance to PTH results in decreased absorption of calcium in the intestines and kidneys, leading to hypocalcemia. Concurrently, the decrease in excretion of phosphate in the kidneys leads to hyperphosphatemia. Unique to this disorder is the phenomenon of genetic imprinting, where the mutated gene is typically inherited only from the mother.
Familial hypocalciuric hypercalcemia is an autosomal dominant disorder caused by mutations in the calcium-sensing receptors (CaSR) in the kidneys and parathyroid glands. This leads to inappropriate reabsorption of calcium in the kidneys, resulting in low urinary calcium excretion and elevated blood calcium levels. Diagnosis is typically made by measuring low 24-hour calcium excretion in the presence of high serum calcium, distinguishing it from primary hyperparathyroidism, which usually features increased urinary calcium excretion.
Hypercalcemia is defined as a total serum calcium level > 10.5 mg/dL or an ionized calcium level > 1.4 mg/dL. The most prevalent cause is primary hyperparathyroidism, responsible for over 95% of cases, typically due to a parathyroid adenoma. The second most common cause is hypercalcemia of malignancy, which is often more severe and may arise from ectopic production of parathyroid hormone-related protein or from osteolytic bone metastases.
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