Hiperparatiroidisme

01Pathophysiology

Parathyroid hormone (PTH) is the master regulator of calcium homeostasis. It performs three actions to raise serum calcium: it stimulates osteoclast-mediated bone resorption, increases distal tubular calcium reabsorption while promoting phosphaturia, and upregulates renal 1-alpha-hydroxylase to convert 25(OH)D to 1,25(OH)₂D (calcitriol), which enhances intestinal calcium absorption. Any disease state of hyperparathyroidism is best understood by tracing these three actions.

In primary hyperparathyroidism, an autonomously functioning parathyroid adenoma loses sensitivity to negative feedback from serum calcium. PTH is secreted regardless of calcemic status, producing the cardinal biochemical signature: hypercalcemia with an inappropriately elevated or normal PTH. The accompanying hypophosphatemia results from PTH-induced phosphaturia, a finding that helps distinguish this entity from other causes of hypercalcemia.

The clinical syndrome follows directly from chronic PTH excess. Bone resorption produces osteitis fibrosa cystica, subperiosteal resorption (classically along the radial aspect of the middle phalanx of the second and third digits), brown tumors, and the "salt-and-pepper" skull appearance. Hypercalciuria (despite enhanced renal reabsorption, the filtered load overwhelms tubular capacity) drives calcium oxalate nephrolithiasis and nephrocalcinosis. Hypercalcemia itself causes neuromuscular and gastrointestinal manifestations: fatigue, depression, constipation, peptic ulcer disease, and acute pancreatitis. Calcium also antagonizes ADH at the collecting duct, producing nephrogenic diabetes insipidus and explaining the polyuria and polydipsia.

In secondary hyperparathyroidism, the parathyroid glands are responding appropriately to a chronic hypocalcemic stimulus. The prototype is chronic kidney disease, where reduced 1-alpha-hydroxylase activity decreases calcitriol, impaired phosphate excretion produces hyperphosphatemia (which complexes with calcium), and the resulting hypocalcemia drives compensatory PTH elevation. Vitamin D deficiency causes the same physiology through a different starting point. The biochemistry shows low or normal calcium with high PTH.

In tertiary hyperparathyroidism, prolonged stimulation in chronic secondary disease eventually causes the parathyroid glands to undergo nodular hyperplasia and become autonomous. This is the classic post-renal-transplant patient with persistent hypercalcemia and markedly elevated PTH, even after the original hypocalcemic stimulus has been corrected.

02Classification and Clinical Manifestations

Symptom-based classification of primary disease (mnemonic: Stones, Bones, Groans, Thrones, Psychiatric overtones):

03Diagnostic Workup

The best initial test for any patient with suspected hyperparathyroidism is a serum calcium, ideally corrected for albumin or measured as ionized calcium. Once hypercalcemia is confirmed and repeated, the next step is an intact PTH level, which divides the differential into PTH-dependent (primary, tertiary, lithium-induced, FHH) and PTH-independent (malignancy, granulomatous disease, vitamin D toxicity, milk-alkali) hypercalcemia. An elevated or inappropriately normal PTH in the setting of hypercalcemia is essentially diagnostic of primary hyperparathyroidism.

The most accurate confirmatory step is the combination of biochemistry plus exclusion of mimics. The single most important test to exclude before committing the patient to surgery is the 24-hour urine calcium with calcium-to-creatinine clearance ratio. A ratio below 0.01 in a patient with hypercalcemia and elevated PTH points to familial hypocalciuric hypercalcemia (FHH), a benign autosomal dominant disorder caused by an inactivating mutation of the calcium-sensing receptor. FHH does not benefit from parathyroidectomy, and missing this diagnosis leads to unnecessary surgery.

After the diagnosis is established, localization studies are performed only when surgery is planned. Sestamibi scintigraphy combined with high-resolution neck ultrasound is the standard preoperative pairing. These studies do not diagnose the disease; they guide the surgeon toward minimally invasive parathyroidectomy. Imaging does not have a role in deciding whether to operate.

DEXA scanning, renal imaging, and renal function testing are all part of the workup because they determine surgical eligibility in asymptomatic patients.

04Management and Treatment

Surgery is the only definitive cure for primary hyperparathyroidism. All symptomatic patients should be offered parathyroidectomy. For asymptomatic patients, surgery is recommended if any of the following criteria are met: age younger than 50, serum calcium more than 1 mg/dL above the upper reference limit, T-score of ≤ −2.5 at any site or vertebral fracture by imaging, eGFR less than 60 mL/min/1.73m², 24-hour urine calcium greater than 400 mg/day with increased stone risk, or nephrolithiasis or nephrocalcinosis on imaging.

The standard operation is minimally invasive parathyroidectomy when preoperative imaging localizes a single adenoma, often combined with intraoperative PTH monitoring: a drop of more than 50% from baseline within 10 minutes of gland removal confirms cure. When imaging is non-localizing or 4-gland hyperplasia is suspected (as in MEN syndromes), bilateral neck exploration with subtotal parathyroidectomy is performed.

In the acute hypercalcemic crisis, the next best step is always aggressive volume resuscitation with isotonic saline to restore intravascular volume and promote calciuresis. Loop diuretics are no longer recommended unless overt fluid overload develops. Calcitonin acts within hours but tachyphylaxis develops within 48 hours. Bisphosphonates (zoledronic acid 4 mg IV over 15 minutes is preferred) take 2 to 4 days for full effect but provide durable control. Hemodialysis is reserved for refractory hypercalcemia or coexistent severe kidney injury.

Important contraindications to remember: bisphosphonates are contraindicated in eGFR less than 30 mL/min/1.73m² (use denosumab instead); cinacalcet is the agent of choice in patients with CKD and tertiary or secondary disease; thiazide diuretics and lithium should be discontinued as they elevate calcium and PTH respectively.

For secondary hyperparathyroidism in CKD, treatment targets the underlying drivers: control hyperphosphatemia first (dietary restriction and non-calcium-based binders such as sevelamer in dialysis patients), then replace active vitamin D, and add a calcimimetic if PTH remains elevated. For vitamin D deficiency, replete with cholecalciferol or ergocalciferol; PTH usually normalizes once 25(OH)D exceeds 30 ng/mL.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common error on a hyperparathyroidism question is failing to interpret PTH in the context of the calcium level. The diagnostic insight is that a "normal" PTH is abnormal in the face of hypercalcemia, because a healthy parathyroid gland would suppress PTH below the reference range. Test-writers exploit this by reporting a PTH value within the laboratory reference interval and expecting you to recognize it as inappropriately elevated.

The second classic trap is mistaking familial hypocalciuric hypercalcemia for primary hyperparathyroidism and sending the patient to surgery. Whenever a young patient with a family history of asymptomatic hypercalcemia presents with the classic biochemistry, the next best step is a 24-hour urine calcium, not a sestamibi scan. A urine calcium-to-creatinine clearance ratio below 0.01 should redirect you away from surgery.

A third pitfall involves bone disease assessment. In primary hyperparathyroidism, PTH preferentially targets cortical bone, so the distal third of the radius is the most sensitive DEXA site. Examiners may show normal lumbar spine and femoral neck T-scores while the radius is osteoporotic; missing the radial measurement misses the surgical indication.

A fourth common error is ordering localization imaging before establishing the diagnosis. Sestamibi scans and neck ultrasound are surgical planning tools, not diagnostic tests. The diagnosis is biochemical.

In acute hypercalcemia, the reflex answer in students is often calcitonin or bisphosphonates, but the first step is always isotonic saline volume resuscitation. Bisphosphonates are slow, calcitonin tachyphylaxes, and dialysis is reserved for true refractoriness or coexistent renal failure.

For secondary disease in CKD, the trap is reaching for calcium directly. The correct sequence is to control phosphate first, then replace active vitamin D, and add a calcimimetic for residual PTH elevation. Giving calcium or active vitamin D in the setting of uncontrolled hyperphosphatemia precipitates calcium-phosphate product elevation and accelerates vascular calcification.

The core competency assessed across these questions is biochemical pattern recognition: pair calcium with PTH first, then use phosphate and vitamin D to subclassify. Once the pattern is recognized, the management and operative criteria fall into place automatically.