Endocrinology & General Surgery & Internal Medicine
Hyperparathyroidism
Hyperparathyroidism is a state of excessive secretion of parathyroid hormone (PTH) by one or more parathyroid glands, leading to disruption of phosphocalcium metabolism. A distinction is made between three forms, depending on the mechanism: primary hyperparathyroidism (HPT1), the most frequent in outpatient practice, results from autonomous, inappropriate secretion of PTH - most often by a solitary parathyroid adenoma (85 % of cases) - irrespective of calcium level; secondary hyperparathyroidism (HPT2) is a compensatory physiological response to chronic hypocalcemia - mainly in chronic renal failure - where PTH is elevated in a reactive manner; tertiary hyperparathyroidism (HPT3) occurs when the hyperplastic parathyroid glands in HPT2 acquire secretory autonomy, even after correction of the initial cause (notably after renal transplantation). HPT1 is the third most common endocrinopathy after diabetes and thyroid disease - its prevalence is around 1-4 per 1,000 people in the general population, with a strong female predominance (F/H ratio ≈ 3:1) after the menopause. Thanks to the systematic measurement of serum calcium in routine check-ups, over 80 % of HPT1s are now asymptomatic at the time of diagnosis - a major advance on the classic historical pictures of «bones, stones, groans and psychic moans».
Physiology of PTH, Calcium, and Biological Diagnosis
- Physiology of PTH and Calcium Homeostasis: parathyroid glands: 4 glands (superior + inferior) located behind the thyroid → normal total weight: 120-150 mg → embryological origin: 3rd branchial pouch (inferior parathyroids + thymus) and 4th branchial pouch (superior parathyroids) → important anatomical variants: 10-15 % of individuals have ectopic glands (mediastinum + intraglandular thyroid + retroesophagus + carotid) → major surgical implication; PTH (parathormone): 84 amino acid polypeptide (PTH 1-84) + N-terminal active fragment (PTH 1-34) → secretion regulated by membrane calcium-sensing receptor (CaSR) of parathyroid principal cells: CaSR activated by high Ca²⁺ → inhibits PTH secretion + CaSR inactivated by low Ca²⁺ → PTH release; PTH actions: bone: stimulates osteoclasts (via RANKL on osteoblasts) → bone resorption → release of Ca²⁺ and phosphate → kidney: proximal tubule: inhibits phosphate reabsorption (phosphaturia) → distal tubule: stimulates calcium reabsorption + activates renal 1α-hydroxylase → conversion of 25-OH-vitamin D to 1,25-(OH)₂-vitamin D (calcitriol) → intestine (via calcitriol): increased intestinal absorption of Ca²⁺ and phosphate → net result: hypercalcemia + hypophosphatemia (phosphaturia) + hypercalciuria (if HPT1); total serum calcium: 2.20-2.55 mmol/L → ionized calcium (Ca²⁺): 1.15-1.35 mmol/L → correct total calcium for albumin: corrected calcium = measured calcium + 0.02 × (40 - albumin g/L) → or measure ionized calcium directly (gasometry + dedicated analyzer) → preferable if albumin abnormal
- Biological diagnosis of hyperparathyroidism — integrated interpretation: 1st-line workup in hypercalcemia: total + ionized + albumin + intact PTH (iPTH 1-84) + phosphorus + creatinine + 24h calciuria + phosphaturia + magnesium + 25-OH-vitamin D; PTH - calcium interpretation: HPT1: Ca²⁺ high + PTH high or inappropriately normal (not suppressed) → Ca²⁺ should suppress PTH → «normal» PTH in presence of hypercalcemia = inappropriate + HPT2: Low or normal Ca²⁺ + high PTH (reactive and appropriate) + HPT3: High Ca²⁺ + very high PTH (autonomous) + post-transplant or long-term CKD context + malignant hypercalcemia (PTHrP): Ca²⁺ very high + PTH collapsed (suppressed) + PTHrP high → PTHrP dosage if tumor suspected (lung + kidney + breast + lymphoma) + hypercalcemia of granulomatoses (sarcoidosis + tuberculosis): elevated Ca²⁺ + suppressed PTH + elevated 1,25-(OH)₂-vitamin D + elevated ACE + familial hypocalciuric hypercalcemia (FHH - CaSR inactivating mutation): elevated Ca²⁺ + normal or slightly elevated PTH + very low 24h calciuria + urinary Ca/creatinine ratio 500-1,000 pg/mL + blood calcium >3.0 mmol/L; 25-OH-vitamin D: often low in HPT1 → vitamin D deficiency worsens PTH secretion → correct vitamin D before reassessing PTH → target: 25-OH-D >75 nmol/L (30 ng/mL) → supplement cautiously (vitamin D3 1,000-2,000 IU/d) → monitor calcium levels when supplementing in HPT1 (modest but monitored risk of worsening)
- Genetic forms and NEM — syndromic hyperparathyroidism: the majority of HPT1 are sporadic - but 10-15 % are part of hereditary syndromes whose recognition is crucial; NEM1 (multiple endocrine neoplasia type 1 - Wermer syndrome): mutation of MEN1 gene (menin - tumor suppressor - chromosome 11q13) → autosomal dominant transmission → triad: HPT1 (95-100 % of NEM1 patients - hyperplasia of all 4 glands) + enteropancreatic tumors (gastrinoma → Zollinger-Ellison syndrome ++ + insulinoma + glucagonoma) + pituitary tumors (prolactin adenoma ++ + GH + ACTH) → annual screening: calcemia + PTH + gastrin + chromogranin A + prolactin + IGF-1 → pituitary MRI every 3-5 years → first-degree family genotyping + NEM2A (Sipple syndrome): RET mutation (proto-oncogene - chromosome 10q11) → CMT (medullary thyroid carcinoma) + pheochromocytoma + HPT1 (20-30 % - hyperplasia 4 glands) → less severe than NEM1; HPT-JT (hyperparathyroidism - jaw tumor): HRPT2/CDC73 (parafibromin) mutation → HPT1 with risk of parathyroid carcinoma (15-25 %) + ossifying fibroma of the jaw → systematic screening for carcinoma → aggressive surgery (en bloc excision); familial isolated hyperparathyroidism (FIHP): MEN1 + CDC73 + CaSR mutations → non-syndromic forms → genetic counseling; parathyroid carcinoma: rare (5× LSN) + very high Ca²⁺ (>3.5 mmol/L) + palpable cervical mass + CDC73 mutation → radical surgery + high risk of recurrence
Clinical presentation, imaging, and treatment
| Clinical situation | Evaluation and Decision | Treatment and monitoring |
|---|---|---|
| Asymptomatic HPT1 — surgical indications and monitoring Guidelines AAES 2022 — DXA — calciuria — active surveillance |
More than 80 % of HPT1 are discovered incidentally during a routine laboratory work-up - management is based on the benefit/risk balance of surgery vs. monitoring; «modern presentation» clinical picture of asymptomatic HPT1: nonspecific fatigue + mild cognitive impairment + mild depressive mood + sleep disorders + diffuse musculoskeletal pain → these symptoms are often retrospectively improved after parathyroidectomy even if considered «non-classical»; surgical indications for parathyroidectomy in asymptomatic HPT1 (4th International Conference on Asymptomatic HPT1 - Bilezikian 2014 + AAES 2022 update): at least one criterion is sufficient to recommend surgery → calcemia >0.25 mmol/L above LSN (i.e. Ca >2.85 mmol/L if LSN 2.60 mmol/L) + DXA: T-score ≤-2.5 at any site (lumbar spine + femoral neck + total hip + 1/3 distal radius) or documented fragility fracture + eGFR 400 mg/d (10 mmol/d) + renal lithiasis or nephrocalcinosis (ultrasound or CT scan) + age <50 years → in practice: almost all patients <50 years of age are operated on, as the duration of exposure to hypercalcemia is long and the cumulative bone risk high; active monitoring if no surgical indication: calcemia + creatinine + eGFR every 6-12 months + DXA every 1-2 years + annual renal ultrasound → surgery if any of the criteria evolve + monitoring is defined as an acceptable option - not as a preferred treatment for all → parathyroidectomy improves quality of life, bone mineral density and reduces the risk of lithiasis even in asymptomatic forms (Rubin 2008 - Journal of Bone and Mineral Research + Westerdahl 2012) | Preoperative localization imaging - localize before operating: parathyroid scintigraphy with ⁹⁹ᵐTc-sestamibi (MIBI): tracer concentrated in hyperactive glands → planar scintigraphy ± SPECT-CT → sensitivity for solitary adenoma: 75-88 % + specificity: 90-95 % (Eslamy 2008 - Journal of Nuclear Medicine) → less reliable if multiglandular hyperplasia + NEM-type involvement + high-resolution cervical ultrasound (7-15 MHz): sensitivity 70-80 % → less reliable for ectopic glands (mediastinum) → complements MIBI → concordant correlation MIBI + echo → guides minimally invasive surgery + cervical 4D-CT: quadriphasic acquisition → excellent sensitivity for ectopic adenomas and glands not seen on MIBI/echo → sensitivity 87-94 % (Hunter 2012 - Journal of Surgical Oncology) → non-negligible irradiation → indicated if discordant or recurrent + ¹⁸F-fluorocholine PET-CT (FCH-PET): new modality → very high sensitivity for parathyroid adenomas (sensitivity 90-96 % - Quak 2018 + Grimaldi 2018 - Journal of Nuclear Medicine) → particularly useful in case of conventional negative exploration + recurrence → increasingly available in tertiary centers in Quebec (CHUM + CHU de Québec); surgical protocol - parathyroidectomy: focused minimally invasive parathyroidectomy (MIP): gold standard if concordant localization MIBI + echo → unilateral approach → excision of localized adenoma only → under local or general anesthesia → intraoperative guide: rapid PTH assay (Quick PTH - Irvin 1994) → PTH assay before excision + at 10 min and 20 min after → fall ≥50 % from maximum value or return to normal → biochemical cure → if PTH does not fall → bilateral exploration → classic bilateral surgery: if non-matching localization + NEM1 (4-gland hyperplasia) + carcinoma → 4-gland exploration + 3.5-gland excision (multiglandular HPT1) or excision + autotransplantation |
| Symptomatic HPT1 - bone and kidney manifestations Fibrocystic osteitis — lithiasis — nephrocalcinosis — fractures |
While modern HPT1 is often asymptomatic, classic presentations remain - and some patients develop complications before diagnosis; bone manifestations (subcortical and trabecular): fibrocystic osteitis (severe historical form): rare today (3.0 mmol/L) → historical mnemonic: «bones + stones + groans + psychic moans» → «groans» = abdominal pain + «moans» = neuropsychiatric symptoms | Parathyroidectomy results and biochemical cure: surgical cure rate: parathyroidectomy by experienced surgeon (volume ≥30 parathyroidectomies/year) → biochemical cure (normocalcemia at 6 months): 95-98 % + recurrence rate: 1.05 mmol/L → usually resolves in weeks to months depending on initial severity of osteopathy; surgical complications: transient hypocalcemia (20-30 % → resolves) + permanent hypoparathyroidism (1-5 % depending on extent of surgery) + recurrent laryngeal nerve injury (dysphonia - 1-2 % → preoperative laryngeal ultrasound recommended) + cervical hematoma (rare) |
| Secondary hyperparathyroidism (SHPT) — chronic kidney disease KDIGO — cinacalcet — phosphate binders — active vitamin D |
HPT2 is almost universal in advanced CKD - its management is complex and guided by KDIGO (Kidney Disease: Improving Global Outcomes) recommendations; mechanism of HPT2 in CKD: reduced GFR → phosphate accumulation → hypocalcemia (Ca²⁺-PO₄ binding) + decreased renal 1α-hydroxylase → reduced calcitriol → less intestinal Ca²⁺ absorption → hypocalcemia → parathyroid stimulation + increased FGF-23 (Fibroblast Growth Factor 23) from early stages of CKD → inhibits 1α-hydroxylase → worsens calcitriol deficiency → vicious circle → progressive hyperplasia of parathyroid glands → in advanced stages : nodular hyperplasia → somatic mutation acquisitions → secretory autonomy → HPT3; therapeutic targets according to KDIGO 2017: intact PTH (iPTH): KDIGO CKD-MBD 2017 → CKD stage 3-5 (pre-dialysis): maintain within normal limits × 2-9 → CKD stage 5D (dialysis): target 2-9× ULN (i.e. 130-585 pg/mL) → exact targets subject to debate (KDIGO 2017 vs. KDIGO 2024 under review) + serum phosphate: maintain within normal range (0.80-1.45 mmol/L) → independently associated with cardiovascular mortality in CKD + serum calcium: target 2.10-2.50 mmol/L + calcium-phosphorus product (Ca × PO₄): <4.4 mmol²/L² (vascular calcifications above) | Pharmacological treatment of HPT2-HPT3: phosphate binders: if hyperphosphatemia despite dietary restrictions → calcium carbonate or calcium acetate: inexpensive → but calcium load → not recommended if hypercalcemia + vascular calcifications + sevelamer (Renvela): non-calcium binder + not absorbed → reduces phosphate + LDL + CRP → superiority data on mortality vs calcium (Suki 2007 - JAMA) → high cost + lanthanum carbonate (Fosrenol): non-calcium + solid data; active vitamin D analogues (vitamin D receptor activators - VDRA): calcitriol (1,25-OH₂-vitamin D) 0.25-2 µg/d oral or IV + paricalcitol (Zemplar): VDR-selective vitamin D analog → less hypercalcemic and hyperphosphatemic effect than calcitriol → possible superiority on cardiovascular survival (Teng 2003 - NEJM) → RAMQ conditionally listed + alfacalcidol (1α-hydroxyvitamin D₃); cinacalcet (Sensipar): oral calcimimetic → CaSR positive allosteric → mimics effect of calcium on parathyroids → PTH suppression → approved for HPT2 in dialysis + post-transplant HPT3 + parathyroid carcinoma → dose: 30 mg/d → titration every 2-4 weeks up to 180 mg/d → side effects: nausea + vomiting (taken with meals) + hypocalcemia → monitor Ca²⁺ → EVOLVE trial (Chertow 2012 - NEJM): reduction in cardiovascular events not statistically significant but reduction in hospitalizations + fractures → benefit on secondary endpoints → RAMQ reimbursement conditional; parathyroidectomy in HPT2-HPT3: indication if HPT2-HPT3 refractory to medical treatment: PTH >800-1,000 pg/mL persistent + hypercalcemia or uncontrolled hyperphosphatemia + calciphylaxis (vascular cutaneous calcinosis) → subtotal (3.5 glands) or total surgery + autotransplantation (forearm) → PTH reduction in the first hours post-op → frequent and severe hungry bone syndrome in HPT2 → aggressive IV calcium protocol |
| Hypercalcemic crisis and severe hypercalcemia IV hydration — bisphosphonates — denosumab — dialysis — emergency |
Hypercalcemic crisis is a metabolic emergency - defined by ionized calcium >1.75 mmol/L (or total calcium >3.5 mmol/L) with severe symptoms; clinical picture of hypercalcemic crisis: confusion + somnolence + coma (calcium encephalopathy) + vomiting + polyuria + severe dehydration + cardiac arrhythmias (shortened QTc + AV block + cardiac arrest) + profound muscle weakness → context: neglected HPT1 + parathyroid carcinoma + malignant hypercalcemia + prolonged immobilization + lithium + vitamin D intoxication; causes of suppressed PTH hypercalcemia: malignancies: PTHrP (lung + kidney + head and neck cancer + lymphoma + myeloma - local osteolysis) + osteolytic bone metastases + granulomatoses (sarcoidosis + tuberculosis + berylliosis) : elevated 1,25-OH₂-D → macrophages express 1α-hydroxylase → FHH (familial hypocalciuric hypercalcemia): mutated CaSR + very low calciuria + normal or slightly elevated PTH → never operate + immobilization + lithium + vitamin D and A intoxication + theophylline | Treatment of hypercalcemic crisis - emergency protocol: step 1 - urgent IV hydration: NaCl 0.9 % 200-300 mL/h → objective: volemic expansion + increase in calciuria → start immediately → input-output assessment + monitor overload (frequent underlying cardiac + renal failure) → furosemide (Lasix): formerly used routinely - currently only if volemic overload documented → no proven role in absence of overload; step 2 - IV bisphosphonates (bone resorption braking): zoledronate (Zometa) 4 mg IV in 15 min → onset of action 2-4 days → duration of effect 2-4 weeks → reduction of calcemia by 0.5-1.5 mmol/L → reference treatment for malignant hypercalcemia and severe pre-surgical HPT1 → monitor: creatinine (nephrotoxicity) + calcemia → or pamidronate 60-90 mg IV in 2-4h + denosumab (Prolia) 60-120 mg SC: anti-RANKL antibody → inhibits osteoclastic resorption → useful if bisphosphonates contraindicated (severe CKD - eGFR <30) or resistant → onset of action comparable to zoledronate → risk of prolonged severe hypocalcemia after discontinuation + calcitonin (Calcimar): 4-8 IU/kg SC or IM every 6-12h → rapid onset of action (<4-6h) → calcemia reduction of 0.3-0.5 mmol/L → tachyphylaxis effect (loses efficacy after 48-72h) → used as a bridge while awaiting the effect of bisphosphonates; dialysis (hemofiltration or dialysis with low-calcium bath): if refractory hypercalcemia + severe CKD + cardiac insufficiency + volume overload → rapid, effective reduction in blood calcium → parallel etiological treatment + emergency surgery (parathyroidectomy): if HPT1 or severe parathyroid carcinoma + cardiovascularly stable → formal indication after initial stabilization |
ℹ️
Familial Hypocalciuric Hypercalcemia (FHH): The Trap Not to Miss: FHH is caused by a heterozygous inactivating mutation of the CaSR, presenting with a clinical picture nearly identical to mild primary HPT1 – hypercalcemia with normal or slightly elevated PTH. The differential diagnosis relies on the 24-hour urinary calcium/creatinine ratio: 0.02 in HPT1. Parathyroidectomy is ineffective and contraindicated in FHH – CaSR genotyping is recommended before any surgery if this ratio is low or if the patient is young with suggestive family history.
Situations requiring urgent medical assessment
Ionized calcium > 1.75 mmol/L (or total calcium > 3.5 mmol/L) + confusion + vomiting + dehydration + shortened QTc → crise hypercalcémique → urgences médicales → NaCl 0,9 % IV en bolus + zolédronate IV + calcitonine en pont → monitoring cardiaque → avis endocrinologie + chirurgie générale si HPT1 confirmée.
Hypercalcemia + suppressed PTH (<15 pg/mL) + weight loss + smoking or known exposure to cancer → Probable malignant hypercalcemia (PTHrP or osteolysis) → Emergency CT scan of the chest, abdomen, and pelvis + PET-CT scan + PTHrP level → Oncology + Internal Medicine → Prognosis related to the underlying cause.
Hypercalcemia >2.85 mmol/L + recurrent nephrolithiasis + DXA T-score ≤-2.5 + elevated PTH → Persistent hypercalcemia, with formal surgical criteria → urgent referral to endocrine surgery + localization imaging (MIBI + ultrasound) → parathyroidectomy within the following weeks.
Tetany + cramps + perioral numbness + prolonged QTc within 24–48 hours post-parathyroidectomy → postoperative hypocalcemia / hungry bone syndrome → calcium gluconate 10 % IV 10–20 mL over 10 min → then maintenance infusion + oral calcitriol → monitor Ca²⁺ every 4–6h → hospitalization.
Consult at Clinique Omicron
Clinique Omicron physicians evaluate and manage calcium and phosphate balance abnormalities—hypercalcemia, elevated PTH, recurrent kidney stones, or unexplained osteoporosis—within the scope of primary care internal medicine or endocrinology consultations. Comprehensive initial workup (intact PTH, ionized calcium, phosphorus, 24-hour calciuria, 25-OH vitamin D, eGFR) and referral to endocrine surgery or specialized endocrinology can be coordinated across multiple service points in Quebec. To book an appointment, visit cliniqueomicron.ca.
The content of this page is for informational purposes only and does not substitute for the advice of a physician, endocrinologist, or endocrine surgeon. The diagnosis and treatment of hyperparathyroidism should be performed by a healthcare professional experienced in endocrinology and parathyroid surgery.
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