Parathyroid and Calcium

Hypercalcemia — PTH-dependent (PTH inappropriately normal or high)

• Primary hyperparathyroidism: the most common cause in ambulatory outpatients; a solitary chief-cell adenoma accounts for the large majority, with four-gland hyperplasia and rare parathyroid carcinoma making up the remainder
• Familial hypocalciuric hypercalcemia: inactivating CaSR mutation raises the set point for calcium sensing, so PTH is mildly high and renal calcium reabsorption is inappropriately avid
• Tertiary hyperparathyroidism: autonomous glands after longstanding CKD-driven secondary stimulation (KDIGO CKD-MBD framing)
• Lithium: shifts the CaSR set point, producing a biochemical picture that mimics primary hyperparathyroidism

Hypercalcemia — PTH-independent (PTH suppressed)

• Malignancy: the dominant cause in hospitalized patients — humoral hypercalcemia from PTHrP (classically squamous cell carcinoma, renal cell, bladder), osteolytic metastases/myeloma via local RANKL, or unregulated 1α-hydroxylase in lymphoma
• Granulomatous disease: sarcoidosis, tuberculosis, histoplasmosis — macrophage 1α-hydroxylase escapes PTH and FGF23 feedback
• Excess intake or turnover: vitamin D or calcium-alkali (milk-alkali) ingestion, vitamin A toxicity, thyrotoxicosis, immobilization, adrenal insufficiency

Hypocalcemia by mechanism

• PTH deficiency: post-surgical (thyroidectomy/parathyroidectomy/neck dissection) is by far the most common; also autoimmune polyglandular syndrome type 1, 22q11.2 deletion (DiGeorge), infiltration, radiation
• PTH resistance: pseudohypoparathyroidism (Gsα defect, high PTH with low calcium) and hypomagnesemia, which both impairs PTH release and blunts end-organ response
• Vitamin D deficiency/impaired activation: malabsorption, bariatric surgery, liver disease, CKD, anticonvulsants
• Sequestration/chelation: acute pancreatitis, tumor lysis, rhabdomyolysis, massive citrated transfusion, hungry bone syndrome

Risk factors

• Non-modifiable: age over 50, female sex, prior neck irradiation, family history, and germline syndromes — MEN1, MEN2A (RET), and hyperparathyroidism–jaw tumor syndrome
• Modifiable: thiazides, lithium, high-dose vitamin D or calcium supplements, prolonged immobilization, low sun exposure/dietary vitamin D deficiency, and alcohol-related pancreatitis

Normal Calcium Physiology

• Approximately 99% of body calcium is stored in bone as hydroxyapatite; only 0.1% exists in extracellular fluid, but this fraction is tightly regulated
• Ionized (free) calcium is the physiologically active form; total serum calcium must be corrected for albumin concentration using: Corrected Ca = Total Ca + 0.8(4 - Albumin in g/dL)
• Serum calcium is maintained within 8.5-10.5 mg/dL through three main sites of action: intestine (absorption), kidney (reabsorption), and bone (mobilization/deposition)

Parathyroid Hormone (PTH) Actions

• PTH is released by chief cells in response to decreased ionized calcium and acts via G-protein coupled receptors on target tissues
• In kidney: increases proximal tubule 1α-hydroxylase activity (activating vitamin D to 1,25-dihydroxyvitamin D [calcitriol]), increases distal tubule calcium reabsorption via calcium-sensing receptor signaling, and decreases phosphate reabsorption
• In bone: stimulates osteoblasts to produce RANKL, which recruits and activates osteoclasts, leading to increased bone resorption and calcium release
• In intestine: indirectly increases calcium absorption by promoting vitamin D activation
• PTH also increases serum phosphate clearance, leading to hypophosphatemia

Vitamin D Metabolism

• Vitamin D (cholecalciferol) is synthesized in skin following UV-B exposure or obtained from dietary sources; it undergoes 25-hydroxylation in the liver to form calcifediol (25-hydroxyvitamin D), which is the best marker of vitamin D stores
• 1α-hydroxylation occurs in the proximal tubule of the kidney to produce the active metabolite calcitriol (1,25-dihydroxyvitamin D), a process stimulated by PTH, low phosphate, and low calcium, and inhibited by FGF23
• 24-hydroxylation in kidney and other tissues produces inactive metabolites, representing the major catabolism of active vitamin D
• Calcitriol increases intestinal calcium and phosphate absorption, stimulates bone mineralization, and suppresses PTH secretion through negative feedback

Calcium-Sensing Receptor (CaSR) Function

• The CaSR on the surface of chief cells and throughout the kidney senses extracellular calcium and acts as the primary regulator of PTH secretion
• Decreased ionized calcium → decreased CaSR signaling → increased PTH secretion and renal calcium reabsorption
• Increased ionized calcium → increased CaSR signaling → suppressed PTH secretion and increased urinary calcium excretion
• Mutations in CaSR cause familial hypocalciuric hypercalcemia (FHH) or autosomal dominant hypocalcemia (ADHH)

FGF23 Regulation

• Fibroblast growth factor 23 (FGF23), produced by osteocytes in response to high phosphate and calcitriol, acts on kidneys to suppress 1α-hydroxylase and promote 24-hydroxylase
• FGF23 also increases urinary phosphate wasting and decreases PTH secretion
• This creates a coordinated response to maintain both calcium and phosphate homeostasis

Hypercalcemia (>10.5 mg/dL or >5.2 mmol/L)

• Neuropsychiatric symptoms: "stones, bones, groans, and psychiatric overtones" — manifestations include nephrolithiasis, bone pain/osteoporosis, abdominal pain/nausea/vomiting, and depression, anxiety, or confusion
• Neuromuscular manifestations: weakness, fatigue, myalgia, and hyporeflexia result from increased threshold for nerve depolarization; severe hypercalcemia can cause stupor or coma
• Cardiovascular effects: shortened QT interval on ECG (classic finding), hypertension, and in severe cases, arrhythmias or cardiac arrest
• Renal effects: nephrogenic diabetes insipidus leading to polyuria and polydipsia (PTH-mediated); chronic hypercalcemia causes nephrolithiasis and nephrocalcinosis
• Gastrointestinal symptoms: nausea, vomiting, constipation, and anorexia; chronic hypercalcemia may lead to peptic ulcer disease
• Bone manifestations: increased bone resorption may cause osteoporosis, increased fracture risk, and in severe primary hyperparathyroidism, osteitis fibrosa cystica (brown tumors — lytic lesions with increased bone turnover)
• Classic presentation: asymptomatic patient discovered on screening lab, or symptomatic with nephrolithiasis and/or bone disease

Hypocalcemia (<8.5 mg/dL or <2.1 mmol/L)

• Neuromuscular hyperexcitability: paresthesias (perioral and distal extremities are early signs), tetany, muscle spasms, and seizures result from decreased threshold for nerve depolarization
• Cardiac manifestations: prolonged QT interval (torsades de pointes risk), bradycardia, and heart failure in severe cases
• Laryngeal stridor and bronchospasm: due to laryngeal and bronchial muscle spasm; can be life-threatening
• Physical examination findings: Trousseau sign (carpopedal spasm after 3 minutes of blood pressure cuff inflation) and Chvostek sign (facial muscle twitch when tapping facial nerve anterior to ear) indicate neuromuscular irritability
• Skin findings: dry skin, brittle nails, and in chronic hypocalcemia, subcutaneous ossifications
• Dental abnormalities: enamel hypoplasia and delayed tooth eruption if hypocalcemia occurs during tooth development
• Psychiatric symptoms: anxiety, depression, and personality changes, especially in chronic hypocalcemia
• Acute severe hypocalcemia: life-threatening with seizures, tetany, laryngospasm, or arrhythmias

Initial Assessment of Dyskalcemia

• Measure ionized calcium or correct total calcium for albumin and pH; ionized calcium is most accurate but total calcium is commonly used clinically
• Simultaneous PTH level is the single most useful test — divides dyskalcemia into PTH-mediated (primary hyperparathyroidism, secondary hyperparathyroidism) versus non-PTH-mediated causes (malignancy, vitamin D toxicity, granulomatous disease)
• Serum phosphate: elevated in hypocalcemia (except in vitamin D deficiency), normal/low in primary hyperparathyroidism; helps narrow differential
• Alkaline phosphatase and bone-specific alkaline phosphatase: elevated in high bone turnover states (hyperparathyroidism)
• Urinary calcium: low in FHH, high in primary hyperparathyroidism and malignancy-induced hypercalcemia

Hypercalcemia Diagnostic Algorithm

• PTH-mediated hypercalcemia: intact PTH is normal or elevated
• Primary hyperparathyroidism: elevated PTH with elevated calcium; 25-OH vitamin D normal-to-high
• Secondary hyperparathyroidism: elevated PTH with normal-to-low calcium; associated with chronic kidney disease or vitamin D deficiency
• Tertiary hyperparathyroidism: autonomous PTH secretion in setting of longstanding secondary hyperparathyroidism; elevated

Immediate stabilization — severe/symptomatic hypercalcemia

• Isotonic saline volume repletion: first step in every symptomatic patient; hypercalcemia causes nephrogenic DI and volume depletion, which itself worsens calcium retention. ASCO's guideline on hypercalcemia of malignancy endorses hydration plus antiresorptive therapy
• Calcitonin: fastest-acting agent (hours) by blocking osteoclasts and increasing calciuria, but tachyphylaxis develops within about 48 hours — it is a bridge, not a therapy
• IV bisphosphonate (zoledronic acid): definitive antiresorptive for malignancy-associated hypercalcemia; onset is delayed 2–4 days because it requires osteoclast turnover. Dose-adjust or avoid in significant renal impairment
• Denosumab: RANKL monoclonal antibody, preferred in bisphosphonate-refractory disease or advanced CKD; not renally cleared
• Glucocorticoids (prednisone): for calcitriol-mediated hypercalcemia — lymphoma, sarcoidosis, vitamin D intoxication — by suppressing macrophage 1α-hydroxylase
• Hemodialysis with low-calcium bath for hypercalcemic crisis with renal failure or heart failure

Definitive management of primary hyperparathyroidism

• Parathyroidectomy is curative and is recommended by the International Workshop/AAES criteria for symptomatic disease and for asymptomatic patients with calcium more than 1 mg/dL above the upper limit of normal, age under 50, eGFR below 60, osteoporosis or vertebral fracture, or nephrolithiasis/nephrocalcinosis. Sestamibi and ultrasound localize the lesion after biochemical confirmation; intraoperative PTH monitoring confirms cure
• Cinacalcet: calcimimetic for non-surgical candidates and parathyroid carcinoma; lowers calcium but does not improve bone density

Hypocalcemia

• IV calcium gluconate for tetany, seizure, laryngospasm, or prolonged QT; peripheral-safe (calcium chloride is sclerosant and needs central access)
• Replace magnesium — refractory hypocalcemia will not correct until hypomagnesemia is fixed
• Chronic hypoparathyroidism: oral calcium plus active vitamin D (calcitriol), per Endocrine Society guidance; a thiazide with sodium restriction reduces hypercalciuria; PTH analog therapy is reserved for inadequately controlled disease

Avoid

• Routine loop diuretics (only for volume overload), thiazides and lithium in hypercalcemia, and calcium/vitamin D supplements until the cause is defined

Complications of hypercalcemia

• Hypercalcemic crisis (EMERGENCY): calcium typically well above 14 mg/dL with obtundation, oliguric AKI, and arrhythmia; signaled by coma plus a short QT
• Nephrolithiasis and nephrocalcinosis: chronic hypercalciuria precipitates calcium phosphate/oxalate; signaled by recurrent stones or a rising creatinine with medullary calcification on imaging
• Chronic kidney disease and nephrogenic DI: calcium downregulates aquaporin-2, producing polyuria refractory to desmopressin
• Osteitis fibrosa cystica: unopposed RANKL-driven resorption yields subperiosteal bone resorption of the radial phalanges, salt-and-pepper skull, and brown tumors
• Pancreatitis and peptic ulcer disease: calcium activates trypsinogen and stimulates gastrin (the latter is the link to Zollinger-Ellison in MEN1)

Complications of hypocalcemia

• Laryngospasm, tetany, seizure, and torsades de pointes (EMERGENCIES): lowered depolarization threshold; the ECG clue is a long QT from a prolonged ST segment
• **Basal ganglia calcification (Fahr syndrome), cataracts, and papilledema**: complications of chronic untreated hypoparathyroidism

Treatment-related complications

• Hungry bone syndrome: after parathyroidectomy for severe disease, abrupt PTH withdrawal lets remineralizing bone consume calcium — profound, prolonged hypocalcemia with concurrent hypophosphatemia and hypomagnesemia; this is distinguished from surgical hypoparathyroidism by a low, not high, phosphate
• Permanent hypoparathyroidism and recurrent laryngeal nerve injury: post-thyroidectomy hoarseness plus perioral tingling on postoperative day 1
• Bisphosphonates: hypocalcemia (worse if vitamin D deficient), acute-phase flu-like reaction, osteonecrosis of the jaw, atypical subtrochanteric femoral fracture, and nephrotoxicity with rapid infusion
• Denosumab: severe hypocalcemia, particularly in advanced CKD; rebound vertebral fractures after discontinuation
• Calcitriol/calcium therapy for hypoparathyroidism: iatrogenic hypercalciuria and nephrocalcinosis, since the calcium-conserving action of PTH is absent — monitor urinary calcium, not just serum calcium

• PTH is the pivot: a high or inappropriately normal PTH with hypercalcemia means primary hyperparathyroidism or FHH; a suppressed PTH means look for malignancy, granuloma, or vitamin D excess. Order calcium and PTH on the same draw
• Outpatient versus inpatient split: asymptomatic hypercalcemia found on routine chemistry is primary hyperparathyroidism until proven otherwise; hypercalcemia in a sick, weight-losing inpatient is malignancy
• FHH is the classic distractor: a young patient with lifelong mild hypercalcemia, high-normal PTH, and a family history — the discriminator is a 24-hour urinary calcium-to-creatinine clearance ratio below 0.01. The best next step is to confirm hypocalciuria and not operate; parathyroidectomy does not cure it
• Localize only after you diagnose: sestamibi scanning and neck ultrasound are surgical planning tools, never diagnostic tests for hyperparathyroidism — choosing imaging before confirming biochemistry is a favorite wrong answer
• Check magnesium in refractory hypocalcemia: hypomagnesemia (alcohol use, PPIs, diarrhea, aminoglycosides) both blocks PTH secretion and induces PTH resistance, so calcium will not correct until magnesium is replaced
• Pseudohypoparathyroidism type 1A: low calcium, high phosphate, high PTH, plus short fourth/fifth metacarpals, round face, and short stature (Albright hereditary osteodystrophy) from a maternally inherited Gsα defect — the high PTH separates it from true hypoparathyroidism
• The syndrome association examiners test: primary hyperparathyroidism from four-gland hyperplasia in a young patient should trigger screening for MEN1 (parathyroid, pituitary, pancreas) or MEN2A (medullary thyroid carcinoma, pheochromocytoma, RET mutation) — always exclude pheochromocytoma before neck surgery in MEN2A
• Drug clues: thiazides raise calcium (increased distal reabsorption) and lithium resets the CaSR; both should be stopped and calcium rechecked before labeling a patient with hyperparathyroidism