Non-Parathyroid Causes of Hypercalcemia & Hypocalcemia

Measuring calcium: albumin and pH

Three fractions. About 40% of serum calcium is bound to proteins, chiefly albumin, about 10% is complexed with anions such as phosphate and citrate, and about 50% circulates as free ionized Ca2+, the only physiologically active fraction and the one PTH regulates. Total calcium therefore falls whenever albumin falls (cirrhosis, nephrotic syndrome, malnutrition), even though the ionized level may be normal.

Correcting for albumin. Corrected calcium = measured calcium + 0.8 × (4 − albumin in g/dL). The formula is only an estimate; when albumin or pH is abnormal, or in critical illness, ionized calcium should be measured directly.

pH shifts binding. In alkalosis, albumin releases hydrogen ions and exposes more negatively charged sites, so more calcium binds and ionized calcium falls while total calcium is unchanged. This is why hyperventilation during panic or pain causes perioral tingling and carpopedal spasm. Acidosis does the reverse and raises ionized calcium.

PTH-independent hypercalcemia

The principle. A suppressed PTH means the parathyroids are responding normally and the calcium is entering from gut, bone or kidney under some other driver. Malignancy is the most common cause in this group, mostly through PTHrP (squamous cell cancers, renal cell and breast cancer) and less often through osteolytic metastases or myeloma.

Granulomatous disease and lymphoma. Activated macrophages in sarcoidosis, tuberculosis and fungal granulomas, and some lymphoma cells, express 1α-hydroxylase (CYP27B1). Unlike the renal enzyme, it ignores PTH, phosphate and calcium feedback, so 1,25-(OH)2D rises, intestinal calcium absorption increases, and hypercalciuria precedes hypercalcemia. Sunlight supplies more 25-OH D substrate, so levels often rise in summer. Glucocorticoids inhibit the macrophage enzyme and gut calcium absorption and correct the problem quickly.

Vitamin D intoxication. Megadose supplements or fortification errors raise 25-OH D, often above 150 ng/mL. At such levels 25-OH D itself activates the vitamin D receptor and displaces 1,25-(OH)2D from vitamin D–binding protein, so the free active hormone rises even when measured calcitriol is normal. Because vitamin D is stored in fat, hypercalcemia can last for months; treatment is stopping intake, hydration and glucocorticoids.

Milk-alkali syndrome. Heavy intake of calcium carbonate, as antacids or osteoporosis supplements, produces the triad of hypercalcemia, metabolic alkalosis and acute kidney injury, with PTH suppressed. The problem sustains itself: hypercalcemia causes natriuresis and volume depletion, which maintain bicarbonate reabsorption, and alkalosis in turn increases distal calcium reabsorption. Stopping the calcium and alkali and giving saline breaks the cycle.

Calcium-sensing receptor disorders

Familial hypocalciuric hypercalcemia (FHH). Heterozygous inactivating mutations of the calcium-sensing receptor (CaSR), inherited in an autosomal dominant pattern, make both the parathyroids and the kidney read calcium as low. The result is lifelong mild hypercalcemia, a normal or mildly elevated PTH, mild hypermagnesemia and strikingly low urinary calcium, because the loss of CaSR signaling in the thick ascending limb increases calcium reabsorption. A calcium/creatinine clearance ratio below 0.01 favors FHH, and one above 0.02 favors primary hyperparathyroidism. FHH is benign, relatives share the labs, and parathyroidectomy does not cure it. Inheriting two mutant copies causes neonatal severe hyperparathyroidism, a life-threatening hypercalcemia treated with parathyroidectomy.

Lithium. Lithium blunts CaSR signaling and shifts the parathyroid set point to the right, so higher calcium is needed to suppress PTH. The hypercalcemia is PTH-mediated with low urinary calcium, resembling FHH, and long-term use can lead to parathyroid hyperplasia or adenoma. Lithium also causes nephrogenic diabetes insipidus and hypothyroidism.

Activating CaSR mutations. Gain-of-function mutations (autosomal dominant hypocalcemia) are the mirror image: calcium is sensed as high, PTH stays low-normal despite hypocalcemia, and urinary calcium is inappropriately high. Giving calcium and vitamin D raises urinary calcium further and causes nephrocalcinosis and stones, so treatment is reserved for symptoms.

Non-parathyroid hypocalcemia

Magnesium disorders. Severe hypomagnesemia, from alcohol use disorder, proton pump inhibitors, diuretics, diarrhea, cisplatin or aminoglycosides, impairs PTH secretion and causes end-organ PTH resistance. Hypocalcemia, often with hypokalemia, will not correct until magnesium is replaced. High magnesium also lowers calcium: IV magnesium sulfate for preeclampsia activates the CaSR and suppresses PTH.

Hungry bone syndrome. After removal of a long-standing parathyroid adenoma, especially with osteitis fibrosa cystica, or after surgery for thyrotoxicosis, bone resorption stops abruptly while formation continues. The skeleton takes up calcium, phosphate and magnesium, producing prolonged hypocalcemia with low phosphate and high alkaline phosphatase. Low phosphate distinguishes it from postsurgical hypoparathyroidism, in which phosphate is high.

Chelation and precipitation. In acute pancreatitis, lipase frees fatty acids that bind calcium in peripancreatic fat necrosis (saponification), and hypocalcemia marks severe disease. Massive transfusion and plasmapheresis deliver citrate, which chelates ionized calcium, especially when liver dysfunction or hypothermia slows citrate metabolism; total calcium may look normal, so ionized calcium is measured. Hyperphosphatemia from rhabdomyolysis, tumor lysis syndrome, CKD or phosphate enemas precipitates calcium phosphate in tissues and suppresses 1α-hydroxylase. Calcium is given only for symptoms, because it adds to metastatic calcification, and patients recovering from rhabdomyolysis can swing to hypercalcemia as deposits dissolve.

Recognizing hypocalcemia. Neuromuscular irritability dominates: perioral and acral paresthesias, muscle cramps, carpopedal spasm, laryngospasm and seizures. Chvostek sign is twitching at the corner of the mouth when the facial nerve is tapped in front of the ear; it occurs in some normal people. Trousseau sign, carpal spasm after a blood pressure cuff is held above systolic pressure for 3 minutes, is more specific. The ECG shows a prolonged QT from a lengthened ST segment, whereas hypercalcemia shortens the QT.

Treating hypercalcemia by mechanism

Loop diuretics are added only after volume is restored; given to a dehydrated patient they worsen volume depletion and reduce calcium excretion. Stop thiazides and calcium supplements.