Eduovisual
Endocrine
Hyperparathyroidism: primary vs secondary vs tertiary
— Primary (1°): Autonomous PTH oversecretion from a parathyroid adenoma (85%), hyperplasia (10–15%), or carcinoma (<1%). Results in high Ca, low/normal phosphate, high or inappropriately normal PTH.
— Secondary (2°): Appropriate PTH elevation in response to hypocalcemia, vitamin D deficiency, or hyperphosphatemia—most commonly chronic kidney disease (CKD) stages 3–5. Calcium is low or normal.
— Tertiary (3°): Autonomous parathyroid function developing after years of secondary stimulation (typically post-renal transplant or long-standing CKD/dialysis). PTH and calcium are both high.
— Incidental hypercalcemia on routine chemistry panel (most common 1° presentation in the US—asymptomatic).
— Recurrent nephrolithiasis (especially calcium-phosphate or calcium-oxalate stones), unexplained osteoporosis, fragility fractures.
— Vague "stones, bones, abdominal groans, psychic moans" — fatigue, constipation, depression, polyuria.
— CKD patient with rising PTH despite phosphate binders and vitamin D analogs → think evolving 3°.
— Post–renal transplant patient with persistent hypercalcemia >12 months → classic 3°.
Board pearl: The single most common cause of outpatient hypercalcemia is primary hyperparathyroidism; the most common cause of inpatient hypercalcemia is malignancy. Use PTH level to triage: high/normal PTH → 1° or 3°; suppressed PTH → malignancy, granulomatous disease, vitamin D toxicity.
Step 3 management: On finding incidental hypercalcemia in an ambulatory adult, repeat calcium with albumin (or ionized Ca), then check intact PTH, 25-OH vitamin D, phosphate, creatinine, and 24-hour urine calcium before any imaging or referral.
— Asymptomatic (80%): Detected by routine labs. Mild hypercalcemia (10.5–11.5 mg/dL).
— Symptomatic classic: "Stones, bones, abdominal groans, psychic moans, fatigue overtones."
· Renal: nephrolithiasis, nephrocalcinosis, polyuria, polydipsia, decreased GFR.
· Skeletal: osteoporosis (cortical bone—distal radius—affected more than trabecular), osteitis fibrosa cystica (rare today, brown tumors, salt-and-pepper skull).
· GI: anorexia, nausea, constipation, peptic ulcers, pancreatitis.
· Neuropsych: depression, poor concentration, memory loss, proximal muscle weakness.
— Normocalcemic 1°: Persistently elevated PTH with normal Ca after excluding vitamin D deficiency, CKD, thiazides, lithium, malabsorption.
— Known CKD (especially eGFR <60), dialysis dependence, vitamin D deficiency (limited sun, malabsorption, dark skin, obesity, post-bariatric surgery), inadequate dietary calcium.
— Symptoms relate to underlying cause: bone pain, proximal myopathy, pruritus (uremic), calciphylaxis in advanced cases.
— Long-standing dialysis (often >10 years) or post-renal transplant with persistent hypercalcemia/hypophosphatemia.
— Bone pain, fractures, pruritus, soft-tissue/vascular calcifications.
— Lithium and thiazides can unmask or mimic 1°—always ask.
— Family history of hypercalcemia at young age, pituitary tumors, pancreatic islet tumors → MEN1; medullary thyroid cancer/pheochromocytoma → MEN2A.
— Jaw tumors + parathyroid carcinoma → HPT-jaw tumor syndrome.
Key distinction: Familial hypocalciuric hypercalcemia (FHH) mimics 1° (high Ca, normal/high PTH) but has low 24-hour urine calcium (<100 mg/day) and calcium/creatinine clearance ratio <0.01. Parathyroidectomy does NOT cure FHH—missing this is a board-classic error.
Step 3 management: In any patient under age 40 with primary hyperparathyroidism, screen for MEN1 (prolactin, IGF-1, fasting glucose/insulin, gastrin) and obtain genetic counseling referral.
— Often normal in mild/asymptomatic disease.
— In severe hypercalcemia (>14 mg/dL): lethargy, confusion, dehydration, weakness.
— Cachexia or palpable neck mass → suspect parathyroid carcinoma (rare, but a palpable parathyroid is almost always malignant since normal/adenomatous glands are not palpable).
— Hypovolemia is the rule in symptomatic hypercalcemia—Ca-induced nephrogenic diabetes insipidus → polyuria → dehydration.
— Dry mucous membranes, flat neck veins, orthostasis, tachycardia.
— Hypertension is common in 1° (vascular calcification, RAAS effects).
— Proximal muscle weakness, hyporeflexia (hypercalcemia depresses neuromuscular excitability—opposite of hypocalcemia).
— Altered mentation in severe disease.
— In 2°/3° with low or fluctuating calcium: Chvostek and Trousseau signs may be elicited during over-correction or post-parathyroidectomy "hungry bone."
— Bone tenderness (osteitis fibrosa cystica), kyphosis from vertebral fractures.
— Joint findings of chondrocalcinosis (pseudogout)—calcium pyrophosphate deposition is associated with 1°.
— Excoriations from uremic pruritus.
— Calciphylaxis: painful violaceous retiform purpura, eschar—high mortality.
— Tertiary disease may show metastatic calcifications: periarticular, conjunctival ("band keratopathy"), vascular.
— Short QT interval on bedside cardiac exam considerations; rarely arrhythmia at very high Ca.
— Listen for vascular bruits—calcified vessels in CKD.
— Routinely normal in 1° (adenomas are deep and small). Examine thyroid—coexisting thyroid disease is common and influences surgical planning.
Board pearl: A palpable parathyroid gland + Ca >14 mg/dL + PTH >5× normal is parathyroid carcinoma until proven otherwise—requires en bloc resection, not minimally invasive parathyroidectomy.
Step 3 management: Begin isotonic saline at 200–300 mL/hr in any symptomatic hypercalcemic patient before pursuing further workup; assess urine output and lung exam q2–4h to titrate.
— Serum calcium (corrected for albumin: add 0.8 mg/dL per 1 g/dL albumin <4) or ionized calcium.
— Intact PTH (iPTH) — central to diagnosis.
— Phosphate, magnesium, creatinine/eGFR.
— 25-OH vitamin D (substrate status); 1,25-(OH)₂ vitamin D if granulomatous disease suspected.
— Alkaline phosphatase (elevated in high-turnover bone disease).
— 24-hour urine calcium and creatinine → calculate Ca/Cr clearance ratio to exclude FHH.
— 1°: ↑Ca, ↑ or inappropriately normal PTH, ↓ or low-normal phosphate, ↑ urine Ca, ↑ ALP.
— 2° (CKD): ↓/normal Ca, ↑ PTH, ↑ phosphate, ↓ 1,25-vit D, ↓/normal 25-vit D, ↑ FGF-23.
— 2° (vit D deficiency): ↓/normal Ca, ↑ PTH, ↓ phosphate, ↓ 25-vit D (<20 ng/mL), normal Cr.
— 3°: ↑Ca, markedly ↑ PTH, variable phosphate (low if good renal function post-transplant; high if dialysis).
— Malignancy: ↑Ca, suppressed PTH, ± ↑ PTHrP, abnormal SPEP/UPEP if myeloma.
— ECG: short QT, bradyarrhythmias, Osborn waves at extreme hypercalcemia.
— DEXA scan at lumbar spine, hip, and distal one-third radius (cortical site preferentially affected in 1°).
— Renal ultrasound or non-contrast CT if stones/nephrocalcinosis suspected.
— Thiazides and lithium elevate Ca/PTH—repeat after 2–3 month washout when feasible.
— Vitamin D deficiency suppresses Ca and elevates PTH; replete before labeling as 1°.
— Tourniquet time and lab handling can falsely elevate Ca; confirm on a fasting, untourniqueted draw.
Key distinction: PTH-mediated hypercalcemia (1°, 3°, FHH, lithium) vs PTH-independent (malignancy, granulomatous, vitamin D toxicity, milk-alkali, hyperthyroidism, immobilization). The single most useful triage test is intact PTH.
Step 3 management: Before referring for parathyroidectomy, document two separate elevated calcium levels, an elevated/inappropriate PTH, normal 25-OH vitamin D (>30 ng/mL), and a 24-hour urine calcium to exclude FHH.
— Diagnosis is biochemical, not radiographic. Imaging is for surgical planning only—never to make the diagnosis.
— If FHH suspected (urine Ca/Cr clearance <0.01), order CASR gene testing.
— Sestamibi (99m-Tc) scintigraphy with SPECT/CT: identifies hyperfunctioning adenomas; sensitivity ~80% for single adenomas, lower for hyperplasia.
— High-resolution neck ultrasound: complementary; operator-dependent; also evaluates thyroid.
— 4D-CT: highest sensitivity, used when sestamibi/US are discordant or for re-operative cases.
— Selective venous sampling for PTH: reserved for failed prior surgery.
— Intraoperative PTH (ioPTH) monitoring: drop of >50% from baseline within 10 minutes of gland excision confirms cure (PTH t½ ≈ 3–5 min).
— Confirm CKD stage, dialysis vintage, phosphate control, vitamin D status.
— FGF-23 may be measured in research/complex cases—markedly elevated in CKD-MBD.
— Bone biopsy with tetracycline labeling is gold standard for renal osteodystrophy classification (adynamic vs high-turnover) but rarely needed.
— Imaging for soft-tissue calcifications: hand films (subperiosteal resorption of radial phalanges, "salt-and-pepper" skull), abdominal films for vascular calcifications.
— MEN1: MEN1 gene; screen for pituitary and pancreatic NETs.
— MEN2A: RET proto-oncogene; screen for medullary thyroid Ca (calcitonin) and pheochromocytoma (plasma metanephrines) before any neck surgery.
— HPT-JT syndrome: CDC73/HRPT2 mutation—high risk of parathyroid carcinoma.
Board pearl: Always rule out pheochromocytoma before neck or adrenal surgery in MEN2. Operating on a pheo unprepared = hypertensive crisis and death. This is a recurring Step 3 vignette twist.
CCS pearl: For an inpatient with calcium >14 or symptomatic hypercalcemia, order CBC, CMP, intact PTH, PTHrP, SPEP/UPEP, 25-OH and 1,25-OH vitamin D, TSH, and CT chest/abdomen/pelvis when malignancy work-up is part of the differential—don't anchor on parathyroid disease.
— Parathyroidectomy is indicated if ANY of:
· Serum Ca >1 mg/dL above upper limit of normal.
· Age <50 years.
· DEXA T-score ≤ −2.5 at any site, or vertebral fracture by imaging.
· eGFR <60 mL/min, 24-h urine Ca >400 mg/day with elevated stone risk, or nephrolithiasis/nephrocalcinosis on imaging.
· Symptomatic disease (overt skeletal, renal, neuromuscular).
— All symptomatic patients and all surgical candidates with parathyroid carcinoma → surgery regardless of biochemistry.
— Patients not meeting criteria: observation with annual Ca, Cr, and biennial DEXA; offer surgery if patient prefers (cure rate >95%).
— Treat modifiable causes first: hyperphosphatemia, hypocalcemia, vitamin D deficiency, acidosis.
— PTH target in dialysis: roughly 2–9× upper limit of normal (avoid both extremes—adynamic bone disease if over-suppressed).
— Phosphate: lower toward normal range.
— 25-OH vit D: maintain >30 ng/mL.
— Trial of cinacalcet first if stable post-transplant.
— Parathyroidectomy indicated for: persistent hypercalcemia >1 year post-transplant, symptomatic bone disease, calciphylaxis, intractable pruritus, progressive vascular calcification, or threat to allograft from hypercalcemia.
— IV isotonic saline 200–300 mL/hr → maintain UOP 100–150 mL/hr.
— Calcitonin 4 IU/kg SC/IM q12h (fast onset, tachyphylaxis in 48 h).
— IV bisphosphonate (zoledronic acid 4 mg, or pamidronate 60–90 mg) — onset 24–72 h, durable.
— Denosumab if renal failure or bisphosphonate-refractory.
— Loop diuretics ONLY after euvolemia, and only if volume overload develops—no longer routine.
Step 3 management: Don't reflexively give furosemide for hypercalcemia—saline alone usually suffices and loops can worsen dehydration. Reserve for documented volume overload.
— Cinacalcet (calcimimetic): activates the calcium-sensing receptor on parathyroid cells → ↓ PTH and Ca. Indicated when surgery declined/contraindicated, or for parathyroid carcinoma with hypercalcemia. Lowers Ca but does not improve bone density.
— Bisphosphonates (alendronate, risedronate): improve BMD in 1° with osteoporosis when surgery deferred; do not reliably lower Ca.
— Adequate hydration (>2 L/day), moderate dietary calcium (1000–1200 mg/day—do NOT restrict, which paradoxically worsens PTH), vitamin D repletion to 25-OH D >30 ng/mL (safe even in 1° with judicious monitoring).
— Avoid thiazides and lithium when possible.
— Phosphate control: dietary phosphate restriction + non-calcium-based binders preferred (sevelamer, lanthanum, ferric citrate) in adults; calcium-based binders (calcium acetate/carbonate) limited due to vascular calcification risk.
— Vitamin D:
· Nutritional vit D (cholecalciferol/ergocalciferol) for 25-OH D <30.
· Active vit D analogs (calcitriol, paricalcitol, doxercalciferol) once 25-OH D repleted and phosphate controlled.
— Calcimimetics: cinacalcet (oral) or etelcalcetide (IV, dialysis only)—suppress PTH without raising Ca/phosphate; first-line for dialysis 2° with persistently elevated PTH.
— Manage acidosis (bicarbonate target 22–26).
— Cinacalcet is the medical mainstay—lowers Ca and PTH; particularly useful post-transplant.
— Adjust vitamin D and phosphate as above.
— Pre-load calcitriol and oral calcium carbonate 1–2 weeks before surgery in high-risk patients (severe bone disease, high ALP, long-standing 2°/3°).
Board pearl: Cinacalcet lowers calcium; bisphosphonates lower bone turnover and improve BMD. They address different problems—don't conflate them on test questions.
Step 3 management: In dialysis 2° with PTH >9× ULN despite phosphate binders and active vit D, add etelcalcetide post-HD or oral cinacalcet; reassess PTH and Ca in 4 weeks.
— Minimally invasive parathyroidectomy (MIP): small unilateral incision targeting a single adenoma localized pre-op by sestamibi/US/4D-CT, confirmed by ioPTH drop >50%. Outpatient, shortest recovery.
— Bilateral neck exploration: all four glands visualized—used for negative/discordant imaging, suspected multigland disease, familial syndromes (MEN1, MEN2A).
— Subtotal parathyroidectomy (3.5 glands) or total parathyroidectomy with autotransplantation (forearm) for 2°/3° and hyperplasia/MEN1—preserves some PTH function while reducing recurrence.
— En bloc resection with ipsilateral thyroid lobectomy for parathyroid carcinoma—do NOT shell out; capsule rupture seeds recurrence.
— Experienced surgeons (high volume): >95% cure in sporadic 1°.
— Recurrence higher in MEN1 (50% at 10 years) and parathyroid carcinoma.
— Improves BMD, reduces stone risk, modest neuropsychiatric benefit.
— Pre-op: vitamin D repletion (reduces hungry bone risk), screen for pheochromocytoma in MEN2.
— Intra-op: ioPTH monitoring, recurrent laryngeal nerve identification.
— Post-op: monitor Ca q6–12h × 24 h; check Mg.
— Hungry bone syndrome: severe, prolonged hypocalcemia + hypophosphatemia + hypomagnesemia from rapid bone remineralization. Requires IV calcium gluconate and oral calcium + calcitriol for weeks.
— Transient hypoparathyroidism: mild, self-limited.
— Permanent hypoparathyroidism: ~1–3%, more common after total/4-gland surgery.
— RLN injury (hoarseness): <1% in expert hands.
— Hematoma, infection.
CCS pearl: Post-parathyroidectomy patient with perioral numbness and positive Chvostek → check ionized Ca, Mg, and phosphate; treat with IV calcium gluconate 1–2 g if symptomatic, then transition to oral calcium carbonate 1–2 g TID + calcitriol 0.25–0.5 mcg BID, and recheck Ca q6h until stable.
— More likely to present asymptomatically on routine labs but also more likely to have occult osteoporosis, cognitive symptoms, and fall/fracture risk.
— Age alone is not a contraindication to parathyroidectomy—minimally invasive surgery under local/regional anesthesia is well tolerated.
— Weigh frailty, anesthesia risk, and life expectancy; surgery generally favored if >5-year life expectancy and any indication is met.
— Medical management with cinacalcet ± bisphosphonate/denosumab is reasonable for non-surgical candidates.
— Begin monitoring Ca, P, PTH, and 25-OH vit D at eGFR <60 (KDIGO).
— Drug adjustments:
· Bisphosphonates contraindicated when eGFR <30–35; consider denosumab (renally safe but risk of severe hypocalcemia—pre-treat with calcium + vit D and monitor).
· Cinacalcet dose unchanged in renal impairment; main side effect is hypocalcemia—monitor closely.
· Etelcalcetide only for hemodialysis patients (administered post-dialysis).
· Avoid magnesium-containing antacids; check Mg before correcting Ca.
— Phosphate binders preferred: non-calcium-based (sevelamer, lanthanum, ferric citrate) to limit vascular calcification.
— Cinacalcet metabolized by CYP3A4—use with caution in severe hepatic impairment (Child-Pugh C); start low, monitor PTH and Ca more frequently.
— Vitamin D activation (25-hydroxylation) occurs in liver—severe cirrhosis can impair 25-OH-D generation; cholecalciferol may be less effective; consider calcifediol or active analogs.
— Most cases resolve within 6–12 months. If PTH and Ca remain elevated >1 year, label as 3° and treat with cinacalcet or refer for parathyroidectomy (typically subtotal).
— Persistent hypercalcemia threatens allograft (calcium-phosphate deposition).
Board pearl: Denosumab can cause severe, prolonged hypocalcemia in advanced CKD—check Ca, vit D, and Mg before each dose; supplement aggressively. This is a Step 3 trap.
Step 3 management: In a CKD stage 4 patient with osteoporosis and 2° HPT, avoid bisphosphonates; correct vit D and phosphate, treat HPT, and consider denosumab with careful Ca monitoring.
— Untreated 1° HPT in pregnancy carries risk of miscarriage, preeclampsia, fetal growth restriction, preterm labor, and neonatal hypocalcemic tetany (maternal hypercalcemia suppresses fetal parathyroid development—neonate decompensates after delivery).
— Diagnosis: elevated ionized Ca + elevated/inappropriate PTH. Note: total Ca normally falls in pregnancy (low albumin); always use ionized.
— Management:
· Mild (Ca <11): hydration, dietary moderation, monitor.
· Moderate–severe or symptomatic: parathyroidectomy in second trimester is preferred definitive therapy.
· Avoid bisphosphonates (cross placenta, fetal bone effects) and cinacalcet (limited safety data; avoid).
· Calcitonin can be used short-term (does not cross placenta).
— Inform pediatrics: monitor neonate for hypocalcemia in the first week.
— 1° HPT in children is rare and almost always points to a genetic syndrome (MEN1, MEN2A, FHH, HPT-JT, neonatal severe hyperparathyroidism—homozygous CASR mutation).
— Neonatal severe HPT (NSHPT): life-threatening hypercalcemia in newborns; emergency total parathyroidectomy may be required.
— Refer to pediatric endocrinology and genetics for any pediatric hypercalcemia.
— MEN1 (3 P's): Parathyroid (95%, multigland), Pituitary, Pancreatic NETs. Surgery: subtotal or total parathyroidectomy with autotransplantation; high recurrence.
— MEN2A: Medullary thyroid carcinoma + pheochromocytoma + parathyroid (less common). Always screen for pheo before any surgery (plasma fractionated metanephrines).
— HPT-JT (CDC73/HRPT2): Jaw fibromas, parathyroid carcinoma in ~15%, renal cysts/tumors.
— Familial isolated hyperparathyroidism: diagnosis of exclusion.
— Common in psychiatric patients. May persist after stopping lithium. Often multigland involvement.
Key distinction: A 25-year-old with hypercalcemia + pituitary adenoma → MEN1, not sporadic. Order MEN1 gene testing and screen family members. Bilateral neck exploration is required—single-gland surgery will recur.
Step 3 management: In any pregnant patient newly diagnosed with 1° HPT and symptomatic or Ca >11, coordinate MFM + endocrine + endocrine surgery for second-trimester parathyroidectomy.
— Osteoporosis and fragility fractures—cortical bone (distal radius, hip) preferentially affected in 1°.
— Osteitis fibrosa cystica (now rare in 1°, still seen in advanced 2°/3°): brown tumors, subperiosteal resorption (radial phalanges), "salt-and-pepper" skull, bone pain.
— Adynamic bone disease in CKD (over-suppressed PTH from calcimimetics/active vit D)—fractures despite normal labs.
— Nephrolithiasis (calcium oxalate/phosphate), nephrocalcinosis, CKD progression, nephrogenic DI from hypercalcemia.
— In 2°/3°: calciphylaxis (calcific uremic arteriolopathy)—catastrophic, painful skin necrosis, ~50% 1-year mortality. Treat with sodium thiosulfate, wound care, urgent parathyroid intervention if PTH markedly elevated, stop warfarin and calcium-based binders.
— Hypertension, LVH, vascular and valvular calcification (especially in 2°/3°—major driver of CV mortality in dialysis patients).
— Arrhythmias at extreme Ca levels (short QT; bradyarrhythmia, asystole).
— Depression, anxiety, cognitive slowing, fatigue—may improve after parathyroidectomy.
— Severe hypercalcemia → confusion, stupor, coma.
— Peptic ulcer disease (calcium stimulates gastrin), pancreatitis (hypercalcemia triggers trypsinogen activation), constipation.
— Hungry bone syndrome (especially in 2°/3° with high pre-op ALP)—severe hypocalcemia for weeks.
— Permanent hypoparathyroidism (1–3%): chronic Ca/vit D dependence.
— RLN injury, hematoma, infection.
— Often presents with Ca >14, PTH >5× ULN, palpable mass.
— Recurrence common; mortality from refractory hypercalcemia rather than metastatic burden.
Board pearl: Calciphylaxis = painful, retiform, violaceous lesions in a dialysis patient with elevated calcium-phosphate product. Sodium thiosulfate IV + multidisciplinary care; warfarin and calcium-based binders should be stopped.
Step 3 management: Any patient post-parathyroidectomy with perioral tingling, carpopedal spasm, or seizure → check ionized Ca and Mg, give IV calcium gluconate 1–2 g over 10–20 min, and start scheduled oral Ca + calcitriol with daily Ca checks.
— Ca >14 mg/dL with altered mental status, hemodynamic instability, AKI, or arrhythmia.
— Severe dehydration with oliguria not responding to initial saline.
— Need for continuous cardiac monitoring at extremes of Ca.
— Calciphylaxis with sepsis or extensive necrosis.
— Symptomatic hypercalcemia (Ca 12–14) requiring IV fluids and bisphosphonates.
— Post-parathyroidectomy patients with severe hungry bone or persistent symptomatic hypocalcemia.
— New nephrolithiasis with AKI; pancreatitis from hypercalcemia.
— Endocrinology — confirm diagnosis, guide medical therapy, coordinate surgical timing, manage CKD-MBD complexity.
— Endocrine surgery — for all surgical candidates; prefer high-volume surgeons (>50/yr) for highest cure and lowest complication rates.
— Nephrology — for 2° and 3°, dialysis adjustments, calciphylaxis management.
— Genetics — for young (<40) patients, multigland disease, or family history.
— Otolaryngology — alternative for parathyroid surgery in many centers.
— MFM — pregnant patients with HPT.
— Palliative care/oncology — parathyroid carcinoma with refractory hypercalcemia.
— Any confirmed PTH-dependent hypercalcemia → endocrine referral within weeks.
— Asymptomatic mild 1° not meeting surgical criteria → endocrine for shared decision-making.
— Post-parathyroidectomy discharge plan: Ca, Mg, vit D supplementation; lab check within 1 week; follow-up with surgeon at 2 weeks and endocrinology at 4–6 weeks; DEXA at 1 year.
— Communicate medication changes (stopping cinacalcet, starting calcitriol) to PCP and pharmacy.
CCS pearl: Inpatient with Ca 16, confused, AKI → IV NS 300 mL/hr, telemetry, calcitonin 4 IU/kg q12h, zoledronic acid 4 mg IV (renal-adjusted), endocrine consult, foley to monitor UOP. Avoid loop diuretics until euvolemic.
Step 3 management: Don't discharge a parathyroidectomy patient on the same day without confirming a post-op Ca trajectory and providing oral calcium + calcitriol prescriptions with a labs-in-1-week plan—failure to do so is a recurring patient-safety pitfall.
— Adenoma 85%, hyperplasia 10–15%, carcinoma <1%.
— ↑Ca, ↑/inappropriately normal PTH, ↓ phosphate, ↑ urine Ca.
— Long-standing CKD or post-transplant.
— ↑Ca, markedly ↑ PTH (often >800 in dialysis), variable phosphate.
— Loss-of-function mutation in CASR (calcium-sensing receptor)—the set point for Ca is reset upward.
— ↑Ca (lifelong, often since childhood), normal-to-mildly ↑ PTH, ↓ urine Ca.
— Ca/Cr clearance ratio <0.01 is the discriminator.
— Do NOT operate—surgery does not cure.
— Lithium shifts CASR set point and may unmask underlying adenoma.
— Mild ↑Ca, ↑/inappropriate PTH, low urine Ca (mimics FHH).
— Trial of lithium discontinuation (if psychiatrically safe) or substitution; if Ca/PTH persist after 2–3 months → manage as 1° (cinacalcet or parathyroidectomy).
— ↓ distal tubular Ca excretion → mild ↑Ca.
— Usually modest; recheck after 2–3 month washout. If hypercalcemia persists → underlying 1° likely.
— MEN1: parathyroid + pituitary + pancreas. Multigland disease, younger onset, high recurrence.
— MEN2A: medullary thyroid Ca + pheo + parathyroid.
— HPT-JT: jaw tumors, parathyroid carcinoma risk.
Key distinction: 1° vs FHH hinges on 24-hour urine calcium and Ca/Cr clearance ratio. Operating on FHH is a board-classic error and a real-world patient safety event.
Step 3 management: In any patient under 30 with hypercalcemia + high/normal PTH, always calculate Ca/Cr clearance ratio and consider CASR genetic testing before referring for parathyroidectomy.
When PTH is suppressed, look elsewhere:
— Humoral hypercalcemia of malignancy (PTHrP-mediated): squamous cell carcinomas (lung, head/neck, esophagus, cervix), renal cell, breast, bladder. ↑ PTHrP, ↓ PTH.
— Osteolytic metastases: breast cancer, multiple myeloma. ↑ Ca from local cytokine-mediated resorption.
— 1,25-OH vit D–mediated: lymphomas (Hodgkin and non-Hodgkin)—tumor 1α-hydroxylase activity.
— Ectopic PTH (very rare).
— Workup: SPEP/UPEP, free light chains, CT chest/abdomen/pelvis, mammogram, age-appropriate cancer screening.
— Sarcoidosis, TB, histoplasmosis, berylliosis—macrophages convert 25-OH to 1,25-OH vit D.
— ↑ 1,25-vit D, ↓ PTH, ↓ PTHrP. Treat with steroids and sun avoidance.
— Thyrotoxicosis (increased bone turnover).
— Adrenal insufficiency (hemoconcentration, ↑ protein-bound Ca).
— Pheochromocytoma (rarely, via PTHrP).
Board pearl: PTH suppressed + hypercalcemia → next test is PTHrP and 25-/1,25-OH vit D. The split: high PTHrP = solid tumor humoral hypercalcemia; high 1,25-vit D = lymphoma or granulomatous disease.
Step 3 management: Hypercalcemia + suppressed PTH + weight loss in a 65-year-old smoker → CT chest + PTHrP + age-appropriate cancer screening, NOT parathyroid sestamibi. Avoid imaging anchoring.
— Oral calcium carbonate 1–2 g elemental TID with meals × at least 2 weeks; taper as Ca stabilizes.
— Calcitriol 0.25–0.5 mcg BID for high-risk patients (severe pre-op bone disease, high ALP, 2°/3°)—taper over weeks.
— Vitamin D₃ 1000–2000 IU daily long-term.
— Magnesium oxide if Mg low.
— Stop pre-op cinacalcet, bisphosphonates (for now), and phosphate binders (in transplant patients) as appropriate.
— Activity: ambulation encouraged; avoid heavy lifting × 1 week (hematoma risk).
— Annual serum Ca and creatinine.
— DEXA every 1–2 years (lumbar spine, hip, distal radius).
— Periodic 24-h urine Ca and renal imaging if stone history.
— Hydration ≥2 L/day, moderate dietary Ca 1000–1200 mg/day (low-Ca diets worsen PTH), vit D repletion.
— Avoid thiazides, lithium when feasible; use loop diuretics if BP treatment needed.
— Strict phosphate control with diet and binders; serial PTH, Ca, P, ALP every 3–6 months (more often on dialysis).
— Active vitamin D analogs and/or calcimimetics titrated to KDIGO PTH target (2–9× ULN on dialysis).
— Avoid over-suppression (adynamic bone disease).
— CV risk reduction: hypertension control, lipid management, smoking cessation.
— If post-transplant: cinacalcet trial; if persistent at 12 months → subtotal or total parathyroidectomy with autotransplant.
— Monitor allograft function—hypercalcemia threatens the kidney.
— Vitamin D 1000–2000 IU/day, dietary Ca 1000–1200 mg/day.
— Weight-bearing exercise, fall-prevention counseling.
— Treat osteoporosis after biochemical control: bisphosphonates in 1° post-cure if BMD remains low; denosumab if eGFR <30.
Board pearl: A common board trap is restricting dietary calcium in 1° HPT—doing so increases PTH and worsens disease. Maintain normal Ca intake; correct vit D.
Step 3 management: Discharge any post-parathyroidectomy patient with a written plan for Ca check in 1 week, surgeon visit at 2 weeks, endocrine visit at 4–6 weeks, and DEXA at 12 months—transitions-of-care documentation is exam fodder.
— First week: Ca check at 1–3 days, then 1 week. Symptoms diary for tingling/cramps.
— 6 months: Ca, PTH, 25-OH vit D, creatinine.
— Annually thereafter: Ca, PTH, Cr; DEXA at 1 year (most BMD recovery occurs in first 1–2 years).
— Cure definition: eucalcemia for ≥6 months post-op. Recurrence = hypercalcemia returning after 6 months of normocalcemia.
— Yearly serum Ca and Cr; DEXA every 1–2 years; symptom review.
— Indication review at each visit—criteria for surgery may emerge over time.
— Frequency of Ca, P, PTH:
· CKD 3: Ca/P every 6–12 months; PTH per baseline level.
· CKD 4: Ca/P every 3–6 months; PTH every 6–12 months.
· CKD 5/dialysis: Ca/P monthly; PTH every 3 months; ALP every 12 months.
— Adjust binders, vit D, and calcimimetics to KDIGO ranges.
— Monthly Ca and PTH × 6 months, then every 3 months.
— Re-evaluate at 12 months post-transplant—persistent hypercalcemia → surgical referral.
— Hydration: ≥2 L/day water reduces stone risk and acute hypercalcemic symptoms.
— Medication review: Avoid OTC calcium-containing antacids (milk-alkali risk), high-dose vitamin D supplements unless prescribed.
— Fall prevention and exercise counseling for those with low BMD.
— Dental health: BRONJ (bisphosphonate/denosumab osteonecrosis of the jaw) counseling—dental clearance before long-term antiresorptive therapy.
— Family screening in MEN syndromes or HPT-JT—first-degree relatives.
— Track fatigue, mood, cognition pre- and post-treatment—improvement is common but not universal.
Key distinction: PTH after successful parathyroidectomy may remain transiently elevated (relative hypocalcemia stimulus) even with normal Ca for weeks—do not interpret as failure in isolation. Trend Ca.
Step 3 management: A patient with mild 1° declining surgery should still be offered annual labs, DEXA every 1–2 years, vit D repletion, and shared decision-making at each visit documented in the chart.
— Disclose: cure rates (95% with high-volume surgeon), risks of RLN injury (<1%), permanent hypoparathyroidism (1–3%), hungry bone, hematoma, anesthesia risk, possibility of conversion to bilateral neck exploration, and possibility of needing reoperation if multigland disease.
— In asymptomatic patients, discuss the alternative of observation; document shared decision-making.
— Outcomes correlate strongly with surgeon volume. Step 3-relevant ethical duty: refer to or recommend high-volume parathyroid surgeons (>50 cases/year) when feasible, especially for re-operative cases and parathyroid carcinoma.
— MEN1/2A and HPT-JT carry autosomal dominant inheritance—offer genetic counseling before testing, discuss implications for siblings/children, insurance/GINA protections, and psychological impact.
— Document discussion of cascade testing.
— Balance maternal/fetal risks; engage MFM, anesthesia, endocrine surgery in shared decisions; document risks of untreated disease (preeclampsia, neonatal tetany) vs surgery in second trimester.
— Post-parathyroidectomy discharge without explicit calcium replacement instructions and labs in 1 week is a sentinel patient-safety issue—hypocalcemic seizures and ED revisits result. Use teach-back and written instructions.
— Communicate to PCP: medication changes (stopping cinacalcet, adding calcitriol), pending pathology, and follow-up schedule.
— Denosumab in CKD: severe hypocalcemia risk if vit D deficient—mandate baseline Ca/Mg/25-OH vit D check, repletion, and informed consent about black-box hypocalcemia risk.
— Bisphosphonates: counsel about jaw osteonecrosis and atypical femur fractures; dental clearance before initiation.
— Lithium patients: coordinate with psychiatry before switching agents.
— Severe hypercalcemia can impair cognition—reassess decisional capacity after Ca correction before obtaining consent for elective surgery.
— High mortality; integrate palliative care early; discuss goals of care.
Board pearl: A post-parathyroidectomy patient sent home without scheduled labs and calcium prescriptions who returns with seizures is a classic Step 3 patient-safety vignette. Build the discharge bundle deliberately.
Step 3 management: Document shared decision-making, capacity assessment, and explicit follow-up plan for every parathyroid surgery patient.
— 1°: ↑Ca, ↑PTH, ↓P, ↑urine Ca.
— 2°: ↓/nl Ca, ↑PTH, ↑P (CKD) or ↓P (vit D def), ↓25-OH vit D.
— 3°: ↑Ca, ↑↑PTH, variable P, post-transplant or long-dialysis.
— FHH: ↑Ca, nl/↑PTH, ↓urine Ca, Ca/Cr clearance <0.01.
— Malignancy: ↑Ca, ↓PTH, ↑PTHrP (or ↑1,25-vit D in lymphoma).
Board pearl: Memorize that vitamin D deficiency must be repleted before diagnosing 1° HPT—it raises PTH and masks the diagnosis or creates a false positive "normocalcemic 1°."
Step 3 management: When asked the "next best test" in hypercalcemia, the answer is almost always intact PTH.
— 58-year-old woman, routine labs show Ca 10.9, PTH 88 (high), 25-OH vit D 32, Cr 0.9, urine Ca 280. DEXA T-score −2.6 at distal radius.
— Answer: Refer for parathyroidectomy (meets criteria: DEXA ≤ −2.5).
— 22-year-old man with mild lifelong hypercalcemia (Ca 10.8, PTH 70), family history of "borderline calcium," 24-hour urine Ca 80, Ca/Cr clearance 0.008.
— Answer: No surgery; CASR genetic testing/reassurance. FHH.
— 45-year-old on lithium × 8 years for bipolar; Ca 10.7, PTH 85.
— Answer: Coordinate with psychiatry to trial alternative agent; recheck after 2–3 months. If persists, manage as 1°.
— Lung cancer patient, Ca 15.4, confused, AKI.
— Answer: IV NS first, then calcitonin and zoledronic acid; PTH will be suppressed (PTHrP-mediated). Order PTHrP, staging.
— Day 1 post-op, perioral tingling, Trousseau positive, Ca 7.1.
— Answer: IV calcium gluconate, check Mg, start oral Ca + calcitriol—hungry bone vs transient hypoparathyroidism.
— 18 months post-renal transplant, Ca 11.5, PTH 320, P 2.1, on stable tacrolimus.
— Answer: Trial cinacalcet; refer for subtotal parathyroidectomy if persistent.
— 32-year-old with kidney stones, Ca 11.2, PTH 110, amenorrhea + galactorrhea, fasting hypoglycemia.
— Answer: MEN1 syndrome — order prolactin, IGF-1, fasting insulin/glucose, gastrin; refer to genetics; plan subtotal parathyroidectomy with autotransplant (not minimally invasive).
— 26-year-old G1 at 16 weeks, ionized Ca elevated, PTH 90, nephrolithiasis.
— Answer: Second-trimester parathyroidectomy with MFM coordination.
— Dialysis patient × 5 years, PTH 1100, Ca 9.4, P 6.8 despite sevelamer and calcitriol.
— Answer: Add etelcalcetide post-HD; consider surgery if persistent.
— Ca 15, PTH 980, palpable neck mass.
— Answer: En bloc resection with ipsilateral thyroid lobectomy.
Board pearl: When the question gives you a young patient with hypercalcemia, the answer is almost never "sporadic 1° HPT"—think FHH, MEN, or familial syndromes.
Step 3 management: Match the stem to the management pathway: PTH-dependent + surgical criteria + sporadic = MIP; PTH-dependent + young/familial = bilateral exploration + genetics; PTH-suppressed = malignancy workup.
One-line teaching point: Hyperparathyroidism is best framed by the calcium–PTH axis: primary = autonomous PTH oversecretion causing hypercalcemia (cured by parathyroidectomy when criteria are met), secondary = appropriate PTH elevation driven by CKD or vitamin D deficiency (treated by fixing the underlying cause), and tertiary = autonomous PTH after long-standing secondary stimulation, classically post–renal transplant or chronic dialysis (treated with calcimimetics or subtotal parathyroidectomy).
— Diagnosis is biochemical. Always start with corrected/ionized Ca + intact PTH + 25-OH vit D + phosphate + creatinine + 24-h urine Ca. Imaging (sestamibi, US, 4D-CT) is for surgical planning only, never to make the diagnosis.
— Always rule out FHH in young or familial hypercalcemia: Ca/Cr clearance ratio <0.01 → no surgery, CASR testing instead. Operating on FHH is a classic board and real-world error.
— Surgical indications in 1° (2022 Workshop): Ca >1 above ULN, age <50, T-score ≤ −2.5 or vertebral fracture, eGFR <60 or 24-h urine Ca >400 with stone risk, nephrolithiasis/nephrocalcinosis, or symptoms. Parathyroidectomy by a high-volume surgeon offers >95% cure with low complication rates.
— Treat secondary HPT by treating its cause: phosphate control (non-Ca binders), vit D repletion, active vit D analogs, and calcimimetics (cinacalcet/etelcalcetide). KDIGO PTH target on dialysis ≈ 2–9× ULN—avoid over-suppression (adynamic bone disease).
— Post-parathyroidectomy patient safety: Anticipate hungry bone syndrome—discharge with oral calcium + calcitriol, labs in 1 week, and clear written instructions. Watch for permanent hypoparathyroidism and RLN injury.
Board pearl: PTH level is the single most useful triage test in hypercalcemia—high/inappropriate = 1°, 3°, FHH, or lithium; suppressed = malignancy, granulomatous, vit D toxicity, or other non-PTH cause.
Step 3 management: Build every hyperparathyroidism plan around three steps: (1) confirm the biochemical category, (2) treat reversible drivers (vit D, phosphate, lithium/thiazides), and (3) stratify for surgery vs medical therapy with shared decision-making and explicit follow-up.