Hypoparathyroidism and Hyperparathyroidism

• PTH synthesis and secretion defects (Hypoparathyroidism): Genetic mutations affecting PTH gene expression, parathyroid gland development (DiGeorge/22q11 deletion), or parathyroid hormone-related peptide (PTHrP) signaling result in inadequate PTH production despite low serum calcium. The hypocalcemia fails to trigger appropriate PTH release, creating a fundamental sensing or production failure. In pseudohypoparathyroidism (PHP), PTH is elevated but target organs (kidney, bone) exhibit end-organ resistance due to impaired GNAS1 gene signaling, preventing normal PTH receptor (PTHR1) coupling to adenylyl cyclase and second messenger generation. This creates a unique biochemical picture: high PTH with low calcium (opposite of classic hypoparathyroidism).

• PTH receptor insensitivity and adenylyl cyclase signaling disruption: PHP variants involve defects in heterotrimeric G-protein coupling; PHP Type 1a involves mutations in GNAS1 (alpha-subunit of stimulatory G-protein), causing resistance not only to PTH but also to other hormones sharing this pathway (TSH, GHRH, ACTH), clinically manifesting as Albright hereditary osteodystrophy with characteristic short stature, subcutaneous ossifications, and round face. The kidney cannot increase 1,25-dihydroxyvitamin D production or decrease phosphate reabsorption in response to elevated PTH.

• Excessive PTH secretion (Hyperparathyroidism): In primary hyperparathyroidism, autonomous PTH production occurs from adenomatous (80-85%), hyperplastic (10-20%), or rarely carcinomatous (1-5%) parathyroid tissue independent of normal calcium feedback inhibition. Somatic mutations in CDKN1B (p27), MEN1 (menin protein), or other cell cycle regulators cause uncontrolled PTH synthesis. The consequence is continuous PTH action on kidneys (increasing 1,25-vitamin D production and urinary calcium excretion capacity while decreasing phosphate reabsorption) and bone (activating osteoclasts via RANKL-mediated pathways), resulting in progressive hypercalcemia and hypophosphatemia despite PTH's negative feedback attempt to suppress itself.

• Vitamin D metabolism disturbances: In hypoparathyroidism, low PTH fails to stimulate renal 1-alpha-hydroxylase in proximal tubules, preventing conversion of 25-hydroxyvitamin D to its active 1,25-dihydroxyvitamin D form. This compounds hypocalcemia because vitamin D is essential for intestinal calcium absorption. In hyperparathyroidism, excess PTH drives robust 1-alpha-hydroxylase activity, producing excess 1,25-vitamin D that enhances intestinal calcium absorption (further raising serum calcium) and promotes osteoclast activation.

• Renal calcium and phosphate handling: PTH acts on renal collecting duct principal cells to increase calcium reabsorption via TRPV5 channels and on proximal tubule cells to decrease phosphate reabsorption (blocking NaPi-II cotransporters). In hypoparathyroidism, this mechanism is absent or ineffective, leading to urinary calcium wasting and phosphate retention despite hypocalcemia. The fractional excretion of calcium is paradoxically high. In hyperparathyroidism, PTH maximally increases urinary phosphate excretion (producing hyperphosphaturia despite hypophosphatemia) while promoting calcium reabsorption, creating hypercalcemia and relative phosphate depletion.

• Bone metabolism alterations: PTH acts on osteoblasts expressing PTHR1, which then secrete RANKL (receptor activator of NF-κB ligand), activating osteoclasts for bone resorption. Chronic PTH excess in hyperparathyroidism causes high bone turnover with net resorption exceeding formation, increasing serum calcium and phosphate from bone; this is particularly prominent at the cortical bone level. In hypoparathyroidism, absent PTH leads to decreased bone resorption and secondary increased bone density (osteosclerosis), though bone quality may be paradoxically impaired due to abnormal mineralization from phosphate retention and vitamin D deficiency.

• Calcium-sensing receptor dysfunction: Activating mutations in CASR (coding for calcium-sensing receptor) cause familial hypocalciuric hypercalcemia (FHH), a form of hyperparathyroidism where parathyroid tissue and kidney tubules "sense" a set point for calcium that is elevated, appropriately secreting PTH and reabsorbing calcium at a higher threshold. This impairs PTH suppression despite elevated serum calcium. Conversely, inactivating CASR mutations can cause autosomal dominant hypocalcemia with secondary hyperparathyroidism despite low serum calcium (the parathyroids perceive low calcium as normal and fail to produce adequate PTH).

HYPOPARATHYROIDISM

• Surgical or radiotherapy-induced hypoparathyroidism: The most common cause in clinical practice. Inadvertent removal, devascularization, or injury of parathyroid glands during thyroidectomy, parathyroidectomy, neck dissection, or radiation to the neck damages or ablates functional parathyroid tissue. Typically manifests within days to weeks post-operatively with acute symptomatic hypocalcemia. Risk varies by surgeon experience; permanent hypoparathyroidism occurs in 0.3-3% of thyroid surgeries.

• DiGeorge syndrome (22q11 deletion syndrome): Microdeletion of chromosome 22q11 disrupts embryologic development of the third and fourth pharyngeal pouches, affecting parathyroid gland formation and thymic development. Presents with congenital hypoparathyroidism, cardiac abnormalities (conotruncal defects), cleft palate, and immune deficiency. Variable penetrance and expressivity lead to spectrum from mild to severe disease.

• Autoimmune polyglandular syndrome Type 1 (APS-1): AIRE gene (autoimmune regulator) mutations lead to autoimmune destruction of multiple endocrine tissues including parathyroids, pancreatic beta cells, and adrenal cortex. Characterized by hypoparathyroidism, adrenal insufficiency, and autoimmune thyroid disease. Typically presents in childhood with mucocutaneous candidiasis followed by organ-specific autoimmunity.

• Idiopathic hypoparathyroidism: Sporadic or familial cases without identified syndromic features, likely representing genetic mutations in PTH synthesis genes or parathyroid development genes (PTH, GCMB, CASR activating mutations).

• Pseudohypoparathyroidism (PHP) Type 1a (GNAS1 mutations): Autosomal dominant; features Albright osteodystrophy phenotype (short stature, subcutaneous ossifications, round face, metacarpal/metatarsal shortening, developmental delay, subcutaneous exostoses) plus hormone resistance to PTH, TSH, GHRH, and ACTH. Biochemically presents with elevated PTH, low calcium, and hyperphosphatemia (mimicking classic hypoparathyroidism but with high PTH distinguishing it).

• Pseudohypoparathyroidism Type 1b (GNAS1-imprinting defects): Patients lack the typical Albright features but have PTH resistance with normal GNAS1 coding sequences; defects in methylation-sensitive imprinting regions impair paternal GNAS1 expression specifically in renal tissue, causing tissue-specific PTH resistance.

• PHP Type 2: Rare; PTH resistance without GNAS1 mutations; mechanism uncertain.

• Magnesium depletion: Severe hypomagnesemia (often <1.0 mg/dL) impairs both PTH secretion and PTH action at target tissues. Common in chronic diarrhea, diuretic use, proton pump inhibitor therapy, and chemotherapy (cisplatin, amphotericin B). Hypocalcemia cannot be corrected until magnesium is repleted.

• Activating calcium-sensing receptor mutations: Rare; cause autosomal dominant hypocalcemia with secondary hyperparathyroidism (elevated PTH in response to low calcium set point). CASR mutations increase receptor sensitivity to extracellular calcium, making the parathyroids "think" calcium is higher than it actually is, paradoxically suppressing PTH despite true hypocalcemia.

HYPERPARATHYROIDISM

• Primary hyperparathyroidism - adenoma (80-85% of cases): Single parathyroid adenoma autonomously secreting PTH without normal calcium-mediated feedback suppression. Sporadic adenomas usually involve chromosome 12 (CDKN1B, PTH1A locus) or chromosome 1 (CASR inactivating mutations). Present across all ages but peak incidence in fifth to seventh decades with female predominance (3:1).

• Primary hyperparathyroidism - hyperplasia (10-20%): All four parathyroid glands are enlarged and hyperfunctional. Often associated with hereditary syndromes: MEN1 (mutations in MEN1 gene encoding menin protein, affecting parathyroid, anterior pituitary, and pancreatic islets), MEN2A (RET proto-oncogene mutation with medullary thyroid carcinoma, pheochromocytoma, and hyperparathyroidism), and familial hypocalciuric hypercalcemia (CASR activating mutations or AP2S1 mutations affecting G-protein signaling).

• Familial hypocalciuric hypercalcemia (FHH): Autosomal dominant; CASR activating mutations (85-90% of cases), AP2S1 mutations, or GNA11 mutations cause parathyroid cells and renal tubules to "sense" a higher set point for calcium suppression of PTH. Results in mild-to-moderate hypercalcemia with PTH inappropriately normal or mildly elevated (not suppressed as it should be), combined with low urinary calcium excretion (urine calcium-to-creatinine ratio <0.01). Distinguished from primary hyperparathyroidism by urinary calcium excretion pattern and benign course; surgical parathyroidectomy is not effective and not indicated.

• Tertiary hyperparathyroidism: Secondary hyperparathyroidism from chronic kidney disease (CKD) or vitamin D deficiency becomes autonomous when parathyroid glands become hyperplastic and refractory to calcium and vitamin D suppression. Occurs in advanced CKD (stages 4-5) when declining GFR impairs phosphate excretion, phosphate retention stimulates PTH, and uremic toxins promote parathyroid proliferation. Persistent secondary hyperparathyroidism after kidney transplantation (when renal function is restored but parathyroid hypertrophy persists) is also considered tertiary hyperparathyroidism.

• Lithium therapy: Lithium shifts the set point for calcium-mediated PTH suppression to a higher level, effectively causing secondary hyperparathyroidism. Occurs in ~20-30% of patients on chronic lithium; presents as persistent mild-to-moderate hypercalcemia with high-normal or elevated PTH despite high serum calcium (the set point elevation mimics FHH but is iatrogenic).

• Vitamin D intoxication: Excessive vitamin D intake (from supplements, mega-dosing, or fortified foods) or granulomatous diseases producing calcitriol (sarcoidosis, tuberculosis, histoplasmosis, coccidioidomycosis) lead to hypercalcemia. High vitamin D increases intestinal calcium absorption and potentiates bone resorption; PTH is suppressed (distinguishing from primary hyperparathyroidism), and 1,25-vitamin D is elevated (suppressed in granulomatous disease due to local extra-renal production).

• Hyperthyroidism and thyroiditis: Increased bone turnover in thyroid hormone excess promotes calcium release. Subacute thyroiditis with initial thyroid hormone leak can transiently raise serum calcium and suppress PTH.

• Immobilization: Particularly in young people with high bone turnover; immobilization (spinal cord injury, paralysis, extended bed rest) causes rapid bone resorption with calcium release, suppressing PTH and causing hypercalcemia. Self-limited, lasting weeks to months.

• Vitamin A intoxication: Excessive retinol activates osteoclasts and increases bone resorption, causing hypercalcemia with suppressed PTH. Can occur from chronic supplement use or consumption of animal liver (Arctic explorers, vitamin A supplements).

• Theophylline toxicity: Theophylline overdose increases bone resorption and raises serum calcium.

• Paget disease with immobilization: Immobilization of patients with Paget disease (high baseline bone turnover) causes surge in calcium release.

• Malignancy-related hypercalcemia: PTHrP-secreting malignancies (squamous cell cancers of lung, head/neck, kidney; breast cancer), lymphomas producing calcitriol, and osteolytic lesions (multiple myeloma, lymphomas) cause malignancy-associated hypercalcemia with suppressed PTH (not elevated as in primary hyperparathyroidism). This is the critical distinguishing feature.

HYPOPARATHYROIDISM

• Acute hypocalcemia symptoms (calcium <7.0 mg/dL or ionized calcium <3.2 mg/dL): Manifestations result from increased neuromuscular excitability. Paresthesias (perioral, in extremities) are often the earliest symptom, followed by muscle cramps, tetany, and seizures. Severity correlates with acuity and degree of hypocalcemia; chronic mild hypocalcemia may be asymptomatic. Symptoms may be precipitated by respiratory alkalosis (hyperventilation increases calcium binding to albumin, lowering ionized calcium).

• Chvostek sign: Tapping the facial nerve anterior to the ear (just below the zygomatic arch) elicits ipsilateral lip twitch due to facial nerve hyperexcitability. Present in ~10% of healthy individuals but highly specific (95%) when present in hypocalcemia context.

• Trousseau sign: Inflation of a blood pressure cuff above systolic pressure for 3-5 minutes triggers carpopedal spasm of the hand, reflecting increased neuromuscular excitability. More sensitive than Chvostek sign (~4% false positive in healthy population).

• Cardiac manifestations: Prolonged QT interval on ECG from slowed ventricular repolarization; in severe acute hypocalcemia, may progress to cardiac arrhythmias including torsades de pointes. Hypocalcemia increases atrial automaticity and predisposes to atrial fibrillation.

• Seizures: Generalized tonic-clonic seizures occur when hypocalcemia is severe or acute. EEG may show epileptiform activity even without clinical seizures.

• Basal ganglia calcifications: Chronic hypoparathyroidism (especially surgical or idiopathic forms) produces characteristic **bilateral, symmetric calcifications in basal ganglia (

Step 1 — confirm the calcium abnormality

• Albumin-corrected or ionized calcium: correct measured calcium upward by roughly 0.8 mg/dL for every 1 g/dL the albumin falls below 4 g/dL; when albumin or binding is unreliable (cirrhosis, myeloma, alkalosis), measure ionized calcium directly. Repeat before acting — a single value is never diagnostic.

Step 2 — intact PTH is the branch point (the single most important test)

• Hypercalcemia with elevated or "inappropriately normal" PTH: PTH-dependent. Primary hyperparathyroidism, lithium effect, or familial hypocalciuric hypercalcemia. Supporting labs: low/low-normal phosphate, high-normal or high 1,25-(OH)₂D, high-normal chloride.
• Hypercalcemia with suppressed PTH: PTH-independent. Next tests are PTHrP, 1,25-(OH)₂D (granulomatous disease, lymphoma), 25-OH D (intoxication), SPEP/free light chains and skeletal survey for myeloma.
• Hypocalcemia with low or inappropriately normal PTH plus hyperphosphatemia and normal renal function: diagnostic of hypoparathyroidism.
• Hypocalcemia with markedly elevated PTH: PTH resistance (pseudohypoparathyroidism), vitamin D deficiency, or CKD. Historically confirmed by the Ellsworth–Howard test (absent urinary cAMP/phosphaturic response to exogenous PTH); today GNAS sequencing/methylation testing is used.
• Always check magnesium: severe hypomagnesemia causes hypocalcemia with low PTH that will not correct until magnesium is repleted.

Step 3 — distinguish FHH from primary hyperparathyroidism

• 24-hour urine calcium and calcium/creatinine clearance ratio: a ratio below roughly 0.01 with a family history and lifelong mild hypercalcemia points to FHH; ratios above about 0.02 favor primary hyperparathyroidism. This step exists to prevent a futile neck exploration.

Step 4 — end-organ assessment and localization

• DXA including the distal one-third radius: the cortical site preferentially lost in hyperparathyroidism; plus vertebral imaging, eGFR/creatinine, and renal ultrasound or CT for silent stones/nephrocalcinosis. These findings drive the surgical criteria of the International Workshop on Primary Hyperparathyroidism (age under 50, calcium more than 1 mg/dL above normal, T-score ≤ −2.5 or vertebral fracture, reduced eGFR, hypercalciuria, or nephrolithiasis).
• Tc-99m sestamibi scan, ultrasound, or 4D-CT: localization only, never diagnosis. Obtain after the biochemical diagnosis is made, to plan a focused parathyroidectomy.
• ECG: prolonged QT in hypocalcemia, shortened QT in hypercalcemia.

Acute symptomatic hypocalcemia (tetany, laryngospasm, seizure, prolonged QT) — emergency

• IV calcium salts: calcium gluconate is preferred peripherally (calcium chloride is sclerosing and needs central access), given as a bolus then an infusion with telemetry, because rapid correction abolishes neuromuscular irritability.
• Replete magnesium first if low: PTH secretion and PTH action are magnesium-dependent; calcium will not correct otherwise.
• Start oral therapy simultaneously: elemental calcium (calcium carbonate with food, calcium citrate if on a PPI or achlorhydric) plus an active vitamin D — calcitriol — since absent PTH means the kidney cannot 1α-hydroxylate.

Chronic hypoparathyroidism (Endocrine Society and international consensus guidance)

• Goal is low-normal or slightly low serum calcium with the patient symptom-free, normal phosphate, and 24-hour urine calcium kept out of the stone range — not normalization at any cost.
• Thiazide diuretic (e.g., hydrochlorothiazide) with sodium restriction reduces hypercalciuria by increasing distal tubular calcium reabsorption.
• PTH replacement (recombinant PTH analogs such as palopegteriparatide) is reserved for patients not controlled on calcium and calcitriol.

Hypercalcemic crisis — emergency

• Isotonic saline volume repletion first: these patients are profoundly volume-depleted from a nephrogenic diabetes insipidus effect.
• Calcitonin for rapid but short-lived lowering (tachyphylaxis within days), bridging to an antiresorptive: IV bisphosphonate (zoledronic acid) or denosumab when renal function is poor. Hemodialysis for refractory cases.
• Contraindicated/avoid: routine loop diuretics (only for fluid overload), thiazides, lithium, volume depletion, and prolonged immobilization.

Definitive management of primary hyperparathyroidism

• Parathyroidectomy is the only cure, indicated for symptomatic disease or when International Workshop criteria are met; intraoperative PTH monitoring confirms success when PTH falls by at least half from baseline.
• Cinacalcet (calcimimetic) lowers calcium in non-surgical candidates but does not improve bone density; add a bisphosphonate or denosumab for skeletal protection.
• Secondary/tertiary hyperparathyroidism in CKD follows KDIGO CKD-MBD: phosphate binders and dietary phosphate restriction, calcitriol/vitamin D analogs, calcimimetics, with subtotal parathyroidectomy for refractory disease.

Complications of hypoparathyroidism

• Laryngospasm and bronchospasm: hypocalcemia lowers the threshold for neuromuscular depolarization; inspiratory stridor after thyroidectomy is an airway emergency.
• Seizures and torsades de pointes: prolonged repolarization from a lengthened ST segment/QT interval; an emergency requiring IV calcium and magnesium.
• **Basal ganglia calcification (Fahr-type)**: chronic hyperphosphatemia with a raised calcium–phosphate product deposits mineral in vessels and brain, presenting as parkinsonism, dystonia, or cognitive decline.
• Posterior subcapsular cataracts and enamel hypoplasia/dental root defects: chronic, especially in childhood-onset disease.

Complications of treating hypoparathyroidism

• Hypercalciuria, nephrolithiasis, nephrocalcinosis, and CKD: without PTH, the distal tubule cannot reabsorb calcium, so any calcium delivered spills into urine. Rising 24-hour urine calcium or a falling eGFR is the signal — this is why guidelines target low-normal serum calcium.
• Calcitriol-induced hypercalcemia: over-replacement causes polyuria, confusion, and acute kidney injury.

Complications of hyperparathyroidism

• Osteitis fibrosa cystica: RANKL-driven cortical resorption producing brown tumors, subperiosteal resorption of the radial side of the middle phalanges, and a salt-and-pepper skull; cortical osteoporosis at the distal radius with fragility fractures.
• Nephrolithiasis and nephrocalcinosis: filtered calcium load exceeds reabsorptive capacity; recurrent calcium stones may be the presenting feature.
• Hypercalcemic crisis: an emergency with volume depletion, obtundation, and short QT.
• Pancreatitis and peptic ulcer disease: calcium activates trypsinogen; gastrinoma in MEN1 is the classic ulcer association.

Complications of parathyroidectomy

• Hungry bone syndrome: after abrupt PTH withdrawal, avid remineralization causes profound hypocalcemia with hypophosphatemia, hypomagnesemia, and a markedly elevated alkaline phosphatase — distinguish from surgical hypoparathyroidism, where phosphate is high. An emergency if tetany develops.
• Recurrent laryngeal nerve injury: hoarseness or, if bilateral, airway obstruction.
• Permanent hypoparathyroidism and persistent/recurrent hyperparathyroidism from missed multiglandular disease or a supernumerary/ectopic mediastinal gland.

• PTH is always the next best step in any calcium disorder: the stem gives you a calcium value and expects you to order intact PTH, not imaging. Sestamibi localizes, it does not diagnose — ordering it before the biochemical diagnosis is the classic distractor.
• Outpatient vs inpatient hypercalcemia: an asymptomatic, incidentally hypercalcemic ambulatory patient has primary hyperparathyroidism until proven otherwise; a hospitalized patient with weight loss and rapidly rising calcium has malignancy. The discriminator is PTH — elevated in primary hyperparathyroidism, suppressed in PTHrP-mediated and osteolytic hypercalcemia.
• "Stones, bones, abdominal groans, and psychiatric overtones" with short QT is hyperparathyroidism; Chvostek and Trousseau signs with long QT are hypocalcemia. Trousseau (carpopedal spasm on cuff inflation) is the more specific of the two.
• Refractory hypocalcemia that will not correct with calcium = check magnesium. Hypomagnesemia blocks both PTH secretion and PTH action; think PPIs, alcohol use, diarrhea, cisplatin, amphotericin B.
• FHH is the trap before surgery: lifelong mild hypercalcemia, non-suppressed PTH, positive family history, and a low urine calcium/creatinine clearance ratio. Parathyroidectomy does not help and is not indicated.
• High PTH with low calcium and high phosphate is not hypoparathyroidism — it is pseudohypoparathyroidism (end-organ resistance). Type 1a carries Albright hereditary osteodystrophy: short stature, round face, and shortened fourth and fifth metacarpals.
• Post-thyroidectomy perioral tingling is the most commonly tested cause of acquired hypoparathyroidism; if instead the patient had a parathyroidectomy for severe bone disease and drops calcium with a low phosphate and high alkaline phosphatase, the answer is hungry bone syndrome.
• MEN associations examiners love: hyperparathyroidism is the most common and usually first manifestation of MEN1 (pituitary, pancreas), and also occurs in MEN2A (medullary thyroid carcinoma, pheochromocytoma) — screen for and treat pheochromocytoma before any neck surgery.