17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/1jvnwmb7jnkpz.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T5736,## Summary Primary hyperparathyroidism (PHPT) is autonomous or relatively autonomous parathyroid hormone (PTH) secretion, most often from a solitary adenoma and less often from multigland disease. In classic PHPT, serum calcium is elevated and PTH is elevated or **inappropriately nonsuppressed**. A PTH value within the laboratory reference interval is abnormal in the setting of hypercalcemia because normal parathyroid tissue should suppress secretion.[1] PHPT is a **biochemical diagnosis**. Neck ultrasound, sestamibi imaging, 4-dimensional CT, and other localization studies are performed only after a decision for surgery; a negative localization study does not exclude PHPT or remove a valid surgical indication.[1,2] After confirming PHPT, assess skeletal and renal target-organ involvement, vitamin D status, kidney function, stone risk, and whether familial hypocalciuric hypercalcemia (FHH) or another PTH-dependent disorder is plausible. A calcium-to-creatinine clearance ratio (CCCR) below approximately 0.01 supports FHH but is not definitive; vitamin D deficiency, CKD, low calcium intake, and thiazide use can also lower urinary calcium.[1] **Parathyroidectomy is the only definitive cure.** The 2022 Fifth International Workshop recommends surgery for symptomatic PHPT and for asymptomatic hypercalcemic PHPT when any one of the following is present: serum calcium **>1.0 mg/dL (0.25 mmol/L) above the upper reference limit**, vertebral fracture or T-score **≤−2.5**, creatinine clearance/eGFR **<60 mL/min**, nephrolithiasis or nephrocalcinosis, urinary calcium **>250 mg/day in women or >300 mg/day in men**, or **age <50 years**.[1] Surgery remains an option outside these thresholds when the diagnosis is secure, operative risk is acceptable, and patient and clinician prefer definitive treatment.[1] NICE uses a different referral framework: symptoms of hypercalcemia, end-organ disease, or albumin-adjusted calcium **≥2.85 mmol/L** are direct referral triggers, while surgery can also be considered outside those categories.[2] These frameworks should not be blended into a single invented threshold. Patients managed without surgery need structured surveillance. The Fifth Workshop recommends annual calcium and 25-hydroxyvitamin D, annual renal assessment, and three-site DXA every 1–2 years unless bone density is normal; renal imaging and 24-hour urine calcium are repeated when clinically indicated.[1] Maintain normal nutritional calcium intake rather than severe restriction and keep 25-hydroxyvitamin D generally **>30 ng/mL** while below the local upper reference limit.[1] > **Caution:** Severe symptomatic hypercalcemia is an acute problem independent of the elective PHPT pathway. Treat dehydration, neurologic or cardiac effects, and kidney injury immediately; definitive parathyroid planning follows stabilization. See [Hypercalcemia in Adults](hypercalcemia-in-adults.md). ## Biochemical phenotypes ### Hypercalcemic PHPT The diagnosis is supported by: - elevated albumin-adjusted total calcium or elevated ionized calcium; - elevated or inappropriately normal PTH; - confirmation on repeat testing when the patient is clinically stable and the result is not explained by a transient factor.[1] The Fifth Workshop recommends confirmation on at least two occasions separated by at least 2 weeks in typical stable presentations.[1] ### Normocalcemic PHPT Normocalcemic PHPT requires: - persistently normal adjusted total and ionized calcium; - elevated PTH on repeated measurements over approximately 3–6 months; - exclusion of secondary causes of PTH elevation.[1] Common confounders include: - vitamin D deficiency; - CKD, particularly stage 3 or worse; - low calcium intake; - malabsorption or bariatric surgery; - antiresorptive therapy; - lithium; - other drug or metabolic causes of secondary hyperparathyroidism.[1] The Fifth Workshop does **not** provide universal surgical criteria for normocalcemic PHPT because evidence is insufficient.[1] ## Pathophysiology PTH secretion is normally governed by extracellular ionized calcium through the calcium-sensing receptor. PTH raises extracellular calcium by: - increasing distal renal calcium reabsorption; - decreasing proximal phosphate reabsorption, producing phosphaturia; - stimulating renal 1-alpha hydroxylase and calcitriol production; - increasing bone turnover through osteoblast-lineage signaling that promotes osteoclast activation. In PHPT, abnormal parathyroid tissue continues PTH secretion despite a calcium concentration that should suppress it. Consequences can include: - hypercalcemia; - low-normal or low serum phosphate; - hypercalciuria; - nephrolithiasis and nephrocalcinosis; - cortical bone loss and fragility fracture; - progressive renal and skeletal morbidity.[1] The distal one-third radius is a clinically useful DXA site because PHPT often affects cortical bone prominently.[1] ## Etiology and hereditary disease Most sporadic PHPT reflects a single benign adenoma. Multigland hyperplasia and multiple adenomas account for much of the remainder. Parathyroid carcinoma is rare. Consider hereditary disease when PHPT is: - unusually early in onset; - multiglandular; - recurrent after apparently successful surgery; - strongly familial; - associated with pituitary, pancreatic neuroendocrine, medullary thyroid, jaw, renal, uterine, or other syndrome-linked tumors. Relevant disorders include MEN1, MEN2A, CDC73-related hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism. Features raising concern for parathyroid carcinoma include very marked calcium/PTH elevation, a firm invasive neck mass, preoperative vocal-cord dysfunction, invasive imaging features, or a compatible CDC73 phenotype. Suspected carcinoma should be referred to an experienced endocrine-surgery center. Percutaneous biopsy of a suspected parathyroid malignancy is generally avoided because it can disrupt tissue planes and complicate definitive en-bloc surgery. ## Clinical features Many patients are identified through routine chemistry testing and have few specific symptoms. Manifestations can include: - polyuria, polydipsia, and dehydration; - constipation, nausea, or anorexia; - fatigue and proximal weakness; - cognitive slowing or lethargy in more marked hypercalcemia; - nephrolithiasis or renal colic; - osteoporosis or fragility fracture; - bone pain in advanced skeletal disease; - arrhythmia or neurologic dysfunction in severe acute hypercalcemia. Fatigue, sleep disturbance, mood symptoms, impaired concentration, and hypertension are reported in PHPT but are nonspecific. The Fifth Workshop does not recommend surgery solely to improve neurocognitive, quality-of-life, or cardiovascular indices because evidence is inconclusive.[1] ## Diagnostic pathway ```text Elevated serum calcium | v Confirm calcium abnormality and assess hydration/albumin context | v Measure intact PTH concurrently | +--> PTH suppressed | -> pursue PTH-independent hypercalcemia | +--> PTH elevated or inappropriately normal -> review medications, vitamin D, renal function -> consider PHPT, FHH, lithium effect, tertiary disease -> assess bone and kidney target organs -> decide on definitive surgery versus surveillance ``` ### Initial laboratory set | Test | Clinical purpose | Interpretation / next action | |---|---|---| | Adjusted total calcium ± ionized calcium | Confirm phenotype and severity | Repeat if needed; acute severe hypercalcemia follows emergency pathway | | Intact PTH | Establish PTH dependence | Suppressed PTH redirects to non-parathyroid causes | | Creatinine/eGFR or measured/estimated CrCl | Detect renal involvement and secondary PTH causes | <60 mL/min meets Fifth Workshop surgical criterion in hypercalcemic PHPT[1] | | Phosphate | Physiologic context | Low or low-normal level is common but not diagnostic | | 25-hydroxyvitamin D | Detect a frequent secondary driver of PTH elevation | Replace cautiously and reassess calcium | | 24-hour urine calcium | FHH context, stone risk, surgical criterion | Interpret with kidney function, vitamin D, diet, and thiazides | Review calcium/vitamin D supplements and drugs that influence calcium or PTH, particularly lithium and thiazide diuretics. ## Distinguishing FHH Familial hypocalciuric hypercalcemia is usually a lifelong, mild hypercalcemic disorder caused by altered calcium-sensing pathways. PTH may be normal or mildly elevated and urinary calcium is commonly low. A commonly used CCCR is: ```text CCCR = (urine calcium × serum creatinine) / (serum calcium × urine creatinine) ``` A CCCR **<0.01** supports FHH, while higher values favor PHPT, but there is clinically important overlap.[1] Low vitamin D, reduced kidney function, low calcium intake, and thiazides can falsely lower urinary calcium. Consider genetic testing when biochemical distinction remains uncertain, the patient is young, family history is suggestive, or surgery is being contemplated despite a low CCCR. > **Caution:** Parathyroidectomy generally does not correct FHH. Do not proceed to surgery solely because calcium is high and PTH is nonsuppressed when FHH remains credible. ## Target-organ assessment ### Skeletal assessment The Fifth Workshop recommends skeletal assessment including:[1] - DXA at lumbar spine, total hip/femoral neck, and distal one-third radius; - vertebral imaging or vertebral-fracture assessment when clinically indicated; - review of prior fragility fracture. For premenopausal women and men younger than 50 years, Z-scores are generally used to describe BMD relative to age, but age <50 years independently meets the Fifth Workshop surgical criterion once hypercalcemic PHPT is established.[1] ### Renal assessment - creatinine clearance or eGFR; - renal imaging for nephrolithiasis or nephrocalcinosis; - 24-hour urinary calcium when needed for stone risk, FHH distinction, or surgical criteria.[1,2] NICE specifically recommends renal-tract ultrasound after confirmed PHPT.[2] ## Imaging: localization after diagnosis Preoperative imaging answers **where the abnormal gland is**, not **whether PHPT exists**.[1,2] Common modalities include: - high-resolution neck ultrasound; - technetium-99m sestamibi scintigraphy, often with SPECT/CT; - 4-dimensional CT in selected patients; - advanced localization at expert centers for reoperative or difficult disease.[1] A negative localization study does not invalidate the biochemical diagnosis or a surgical indication. NICE recommends proceeding with surgery by a surgeon experienced in four-gland exploration when imaging does not identify a single adenoma rather than repeatedly adding localization tests.[2] ## Indications for parathyroidectomy ### Fifth International Workshop framework Parathyroidectomy is recommended for symptomatic PHPT and advised for asymptomatic hypercalcemic PHPT when **any one** criterion is present:[1] | Domain | Surgical criterion | |---|---| | Serum calcium | >1.0 mg/dL (0.25 mmol/L) above laboratory upper reference limit | | Vertebral fracture | Vertebral fracture on appropriate imaging | | Bone density | T-score ≤−2.5 at any accepted skeletal site | | Kidney function | Creatinine clearance or eGFR <60 mL/min | | Renal stones | Nephrolithiasis or nephrocalcinosis on imaging | | Urinary calcium | >250 mg/day in women or >300 mg/day in men | | Age | <50 years | Only one criterion is required. Surgery is also reasonable outside these criteria when the diagnosis is secure, patient preference favors cure, and operative risk is acceptable.[1] ### NICE framework NICE recommends referral to an experienced parathyroid surgeon when confirmed PHPT is accompanied by:[2] - symptoms of hypercalcemia; - end-organ disease such as renal stones, osteoporosis, or fragility fracture; - albumin-adjusted calcium **≥2.85 mmol/L**. NICE also advises considering surgical referral in patients outside these categories.[2] > **Current practice:** The Fifth Workshop and NICE use different thresholds and health-system assumptions. Document which framework is being applied rather than combining criteria selectively. ## Operative management Parathyroidectomy is the definitive treatment. The operative plan depends on localization, hereditary risk, likelihood of multigland disease, prior neck surgery, and surgeon expertise. ### Focused versus bilateral exploration A focused operation is appropriate for selected, well-localized sporadic single-gland disease. Bilateral/four-gland exploration is favored when: - imaging is nonlocalizing or discordant; - hereditary or multigland disease is likely; - prior operative/pathologic findings suggest multigland disease; - local surgical strategy favors formal exploration.[1,2] The Fifth Workshop permits selective parathyroidectomy with or without intraoperative PTH monitoring in experienced hands.[1] NICE does not recommend routine intraoperative PTH monitoring during first-time surgery and recommends four-gland exploration when preoperative imaging does not identify a single adenoma.[2] ### Postoperative complications | Complication | Recognition | Immediate action | |---|---|---| | Cervical hematoma | Rapid neck swelling, dysphonia, dyspnea, stridor | Airway emergency; immediate surgical response | | Hypocalcemia | Perioral tingling, cramps, tetany, QT prolongation, seizure | Check calcium, magnesium, phosphate; replace according to severity | | Hungry bone syndrome | Prolonged hypocalcemia with high skeletal uptake after high-turnover disease | Intensive calcium ± calcitriol and electrolyte monitoring | | Recurrent-laryngeal-nerve injury | Persistent hoarseness or aspiration symptoms | Laryngeal assessment and surgical review | | Persistent PHPT | Hypercalcemia never normalizes after surgery | Reassess diagnosis, pathology, operative findings, localization | | Recurrent PHPT | Hypercalcemia returns after an interval of cure | Specialist reoperative workup | NICE advises calcium and PTH before discharge, adjusted calcium at **3–6 months** to confirm success, and annual adjusted calcium thereafter after successful surgery.[2] ## Management when surgery is not performed Observation is reasonable for selected patients who do not meet operative criteria, decline surgery, or have prohibitive operative risk, provided surveillance is reliable.[1] ### Calcium intake Do not severely restrict dietary calcium. The Fifth Workshop recommends nutritional intake consistent with population guidance: approximately **800 mg/day for women <50 and men <70 years**, and **1000 mg/day for women >50 and men >70 years** in the cited framework.[1] Severe restriction can increase PTH and worsen skeletal health. ### Vitamin D Maintain 25-hydroxyvitamin D generally **>30 ng/mL** and below the laboratory upper reference limit.[1] Replace cautiously, particularly with marked hypercalcemia or hypercalciuria, and recheck calcium after clinically important dose changes. ### Cinacalcet Cinacalcet activates the calcium-sensing receptor and lowers serum calcium. It does **not** reliably improve bone density and does not cure PHPT.[1,2] The Fifth Workshop supports cinacalcet when serum calcium needs reduction in patients who are not having surgery.[1] NICE uses a more explicit access framework: consider cinacalcet when surgery has failed, is unsuitable, or is declined and adjusted calcium is: - **≥2.85 mmol/L with hypercalcemic symptoms**, or - **≥3.0 mmol/L with or without symptoms**.[2] Continue only when symptoms and/or calcium improve according to the applicable pathway. Monitor calcium after initiation and dose adjustment and use current product labeling for contraindications and interactions. ### Antiresorptive therapy Alendronate or denosumab can increase BMD in selected patients with PHPT but do not correct autonomous PTH secretion.[1] NICE supports bisphosphonate treatment for increased fracture risk but not as a chronic strategy solely to lower serum calcium.[2] When both hypercalcemia and low BMD require treatment and surgery is not undertaken, specialist-directed combination therapy may be reasonable because calcium control and skeletal protection may require different agents.[1] ## Surveillance without surgery ### Fifth Workshop monitoring | Domain | Suggested monitoring | |---|---| | Calcium | Annually | | 25-hydroxyvitamin D | Annually | | PTH | As clinically indicated | | Creatinine clearance (preferred) or eGFR | Annually | | DXA at 3 sites | Every 1–2 years unless BMD is normal | | Vertebral imaging | When clinically indicated | | Renal imaging | When clinically indicated | | 24-hour urine calcium | When clinically indicated | Reconsider surgery if:[1] - calcium becomes consistently >1.0 mg/dL (0.25 mmol/L) above the upper reference limit; - a low-trauma fracture occurs; - a kidney stone develops; - BMD falls to T-score ≤−2.5; - kidney function declines significantly toward/below the surgical threshold. NICE uses annual calcium plus eGFR/creatinine in nonsurgical patients and considers DXA every 2–3 years, with additional specialist monitoring for osteoporosis or renal stones.[2] ## Acute severe hypercalcemia Severe hypercalcemia can cause dehydration, vomiting, delirium, profound weakness, acute kidney injury, and cardiac conduction effects. Immediate priorities are: 1. assess airway, circulation, mental state, and volume status; 2. obtain calcium, electrolytes, creatinine, phosphate, magnesium, and ECG; 3. restore intravascular volume with isotonic crystalloid when appropriate, adjusted to cardiac and renal status; 4. use additional calcium-lowering therapy according to severity, cause, renal function, and local protocol; 5. reserve loop diuretics for clinically important volume overload rather than routine calcium lowering; 6. return to definitive PHPT management once stabilized. Use [Hypercalcemia in Adults](hypercalcemia-in-adults.md) for detailed emergency treatment. ## Pregnancy and reproductive planning NICE recommends offering parathyroid surgery to women with PHPT who are considering pregnancy.[2] Pregnancy with active PHPT warrants specialist multidisciplinary care because maternal hypercalcemia is associated with hypertensive disease and fetal/neonatal complications. Key principles: - establish the biochemical diagnosis carefully because albumin and calcium physiology change during pregnancy; - avoid unnecessary ionizing localization imaging; - use specialist surgical planning when intervention is required; - do not use cinacalcet or bisphosphonates in pregnancy under NICE guidance.[2] For a patient with known PHPT planning pregnancy, definitive surgery before conception is generally favored when feasible.[2] ## Chronic kidney disease CKD complicates PTH interpretation because secondary hyperparathyroidism becomes common as kidney function falls. Elevated PTH with normal or low calcium in CKD should not be labeled normocalcemic PHPT until secondary causes are addressed. Longstanding secondary hyperparathyroidism can evolve into autonomous tertiary hyperparathyroidism with hypercalcemia. Distinguish this from sporadic PHPT using the kidney history, biochemical trajectory, phosphate pattern, and clinical context. ## Parathyroid carcinoma Suspect carcinoma when biochemical severity is extreme or there is an invasive neck phenotype. Management differs from routine adenoma surgery because an initial en-bloc oncologic resection offers the best chance of durable local control. Refer to an experienced center when there is: - very high calcium/PTH burden; - a firm or invasive neck mass; - vocal-cord dysfunction before surgery; - recurrent disease with aggressive features; - a relevant hereditary syndrome. Avoid percutaneous biopsy of a suspected parathyroid carcinoma unless an expert center identifies a compelling reason. ## Prognosis Successful parathyroidectomy usually normalizes calcium and reduces future renal and skeletal risk. Bone density often improves after surgery, though recovery varies by baseline disease and skeletal site. Persistent disease means biochemical hyperparathyroidism continues soon after surgery. Recurrent disease means PHPT returns after a period of biochemical cure. Both require specialist review of the original diagnosis, pathology, operative report, hereditary risk, and localization strategy. ## Practical decision pathway **Confirmed hypercalcemic PHPT** → exclude major mimics such as FHH/lithium effect/tertiary disease → assess kidney function, renal imaging, urinary calcium, DXA ± vertebral imaging → if symptomatic or Fifth Workshop surgical criterion present: refer to experienced parathyroid surgeon → if no criterion but patient prefers definitive therapy: surgery remains an option when risk is acceptable → if no surgery: maintain calcium/vitamin D adequacy, monitor calcium/renal function/BMD, use cinacalcet for calcium control and antiresorptive therapy for skeletal indication when appropriate → move to surgery if new fracture, stone, significant renal decline, rising calcium, or BMD threshold develops.[1,2] ## Related library topics - [Hypercalcemia in Adults](hypercalcemia-in-adults.md) - [Osteoporosis](osteoporosis.md) - [Nephrolithiasis](../urology/nephrolithiasis.md) - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Primary Adrenal Insufficiency in Adults](primary-adrenal-insufficiency-in-adults.md) ## References 1. Bilezikian JP, Khan AA, Silverberg SJ, et al; International Workshop on Primary Hyperparathyroidism. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. *J Bone Miner Res.* 2022;37(11):2293-2314. DOI: 10.1002/jbmr.4677. PMID: 36245251. https://pubmed.ncbi.nlm.nih.gov/36245251/ 2. National Institute for Health and Care Excellence. Hyperparathyroidism (primary): diagnosis, assessment and initial management. NICE guideline NG132. Published May 23, 2019; current recommendations accessed September 23, 2026. https://www.nice.org.uk/guidance/ng132/chapter/Recommendations19:T5756,## Summary Primary hyperparathyroidism (PHPT) is autonomous or relatively autonomous parathyroid hormone (PTH) secretion, most often from a solitary adenoma and less often from multigland disease. In classic PHPT, serum calcium is elevated and PTH is elevated or **inappropriately nonsuppressed**. A PTH value within the laboratory reference interval is abnormal in the setting of hypercalcemia because normal parathyroid tissue should suppress secretion.[1] PHPT is a **biochemical diagnosis**. Neck ultrasound, sestamibi imaging, 4-dimensional CT, and other localization studies are performed only after a decision for surgery; a negative localization study does not exclude PHPT or remove a valid surgical indication.[1,2] After confirming PHPT, assess skeletal and renal target-organ involvement, vitamin D status, kidney function, stone risk, and whether familial hypocalciuric hypercalcemia (FHH) or another PTH-dependent disorder is plausible. A calcium-to-creatinine clearance ratio (CCCR) below approximately 0.01 supports FHH but is not definitive; vitamin D deficiency, CKD, low calcium intake, and thiazide use can also lower urinary calcium.[1] **Parathyroidectomy is the only definitive cure.** The 2022 Fifth International Workshop recommends surgery for symptomatic PHPT and for asymptomatic hypercalcemic PHPT when any one of the following is present: serum calcium **>1.0 mg/dL (0.25 mmol/L) above the upper reference limit**, vertebral fracture or T-score **≤−2.5**, creatinine clearance/eGFR **<60 mL/min**, nephrolithiasis or nephrocalcinosis, urinary calcium **>250 mg/day in women or >300 mg/day in men**, or **age <50 years**.[1] Surgery remains an option outside these thresholds when the diagnosis is secure, operative risk is acceptable, and patient and clinician prefer definitive treatment.[1] NICE uses a different referral framework: symptoms of hypercalcemia, end-organ disease, or albumin-adjusted calcium **≥2.85 mmol/L** are direct referral triggers, while surgery can also be considered outside those categories.[2] These frameworks should not be blended into a single invented threshold. Patients managed without surgery need structured surveillance. The Fifth Workshop recommends annual calcium and 25-hydroxyvitamin D, annual renal assessment, and three-site DXA every 1–2 years unless bone density is normal; renal imaging and 24-hour urine calcium are repeated when clinically indicated.[1] Maintain normal nutritional calcium intake rather than severe restriction and keep 25-hydroxyvitamin D generally **>30 ng/mL** while below the local upper reference limit.[1] > **Caution:** Severe symptomatic hypercalcemia is an acute problem independent of the elective PHPT pathway. Treat dehydration, neurologic or cardiac effects, and kidney injury immediately; definitive parathyroid planning follows stabilization. See [Hypercalcemia in Adults](hypercalcemia-in-adults.md). ## Biochemical phenotypes ### Hypercalcemic PHPT The diagnosis is supported by: - elevated albumin-adjusted total calcium or elevated ionized calcium; - elevated or inappropriately normal PTH; - confirmation on repeat testing when the patient is clinically stable and the result is not explained by a transient factor.[1] The Fifth Workshop recommends confirmation on at least two occasions separated by at least 2 weeks in typical stable presentations.[1] ### Normocalcemic PHPT Normocalcemic PHPT requires: - persistently normal adjusted total and ionized calcium; - elevated PTH on repeated measurements over approximately 3–6 months; - exclusion of secondary causes of PTH elevation.[1] Common confounders include: - vitamin D deficiency; - CKD, particularly stage 3 or worse; - low calcium intake; - malabsorption or bariatric surgery; - antiresorptive therapy; - lithium; - other drug or metabolic causes of secondary hyperparathyroidism.[1] The Fifth Workshop does **not** provide universal surgical criteria for normocalcemic PHPT because evidence is insufficient.[1] ## Pathophysiology PTH secretion is normally governed by extracellular ionized calcium through the calcium-sensing receptor. PTH raises extracellular calcium by: - increasing distal renal calcium reabsorption; - decreasing proximal phosphate reabsorption, producing phosphaturia; - stimulating renal 1-alpha hydroxylase and calcitriol production; - increasing bone turnover through osteoblast-lineage signaling that promotes osteoclast activation. In PHPT, abnormal parathyroid tissue continues PTH secretion despite a calcium concentration that should suppress it. Consequences can include: - hypercalcemia; - low-normal or low serum phosphate; - hypercalciuria; - nephrolithiasis and nephrocalcinosis; - cortical bone loss and fragility fracture; - progressive renal and skeletal morbidity.[1] The distal one-third radius is a clinically useful DXA site because PHPT often affects cortical bone prominently.[1] ## Etiology and hereditary disease Most sporadic PHPT reflects a single benign adenoma. Multigland hyperplasia and multiple adenomas account for much of the remainder. Parathyroid carcinoma is rare. Consider hereditary disease when PHPT is: - unusually early in onset; - multiglandular; - recurrent after apparently successful surgery; - strongly familial; - associated with pituitary, pancreatic neuroendocrine, medullary thyroid, jaw, renal, uterine, or other syndrome-linked tumors. Relevant disorders include MEN1, MEN2A, CDC73-related hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism. Features raising concern for parathyroid carcinoma include very marked calcium/PTH elevation, a firm invasive neck mass, preoperative vocal-cord dysfunction, invasive imaging features, or a compatible CDC73 phenotype. Suspected carcinoma should be referred to an experienced endocrine-surgery center. Percutaneous biopsy of a suspected parathyroid malignancy is generally avoided because it can disrupt tissue planes and complicate definitive en-bloc surgery. ## Clinical features Many patients are identified through routine chemistry testing and have few specific symptoms. Manifestations can include: - polyuria, polydipsia, and dehydration; - constipation, nausea, or anorexia; - fatigue and proximal weakness; - cognitive slowing or lethargy in more marked hypercalcemia; - nephrolithiasis or renal colic; - osteoporosis or fragility fracture; - bone pain in advanced skeletal disease; - arrhythmia or neurologic dysfunction in severe acute hypercalcemia. Fatigue, sleep disturbance, mood symptoms, impaired concentration, and hypertension are reported in PHPT but are nonspecific. The Fifth Workshop does not recommend surgery solely to improve neurocognitive, quality-of-life, or cardiovascular indices because evidence is inconclusive.[1] ## Diagnostic pathway ```text Elevated serum calcium | v Confirm calcium abnormality and assess hydration/albumin context | v Measure intact PTH concurrently | +--> PTH suppressed | -> pursue PTH-independent hypercalcemia | +--> PTH elevated or inappropriately normal -> review medications, vitamin D, renal function -> consider PHPT, FHH, lithium effect, tertiary disease -> assess bone and kidney target organs -> decide on definitive surgery versus surveillance ``` ### Initial laboratory set | Test | Clinical purpose | Interpretation / next action | |---|---|---| | Adjusted total calcium ± ionized calcium | Confirm phenotype and severity | Repeat if needed; acute severe hypercalcemia follows emergency pathway | | Intact PTH | Establish PTH dependence | Suppressed PTH redirects to non-parathyroid causes | | Creatinine/eGFR or measured/estimated CrCl | Detect renal involvement and secondary PTH causes | <60 mL/min meets Fifth Workshop surgical criterion in hypercalcemic PHPT[1] | | Phosphate | Physiologic context | Low or low-normal level is common but not diagnostic | | 25-hydroxyvitamin D | Detect a frequent secondary driver of PTH elevation | Replace cautiously and reassess calcium | | 24-hour urine calcium | FHH context, stone risk, surgical criterion | Interpret with kidney function, vitamin D, diet, and thiazides | Review calcium/vitamin D supplements and drugs that influence calcium or PTH, particularly lithium and thiazide diuretics. ## Distinguishing FHH Familial hypocalciuric hypercalcemia is usually a lifelong, mild hypercalcemic disorder caused by altered calcium-sensing pathways. PTH may be normal or mildly elevated and urinary calcium is commonly low. A commonly used CCCR is: ```text CCCR = (urine calcium × serum creatinine) / (serum calcium × urine creatinine) ``` A CCCR **<0.01** supports FHH, while higher values favor PHPT, but there is clinically important overlap.[1] Low vitamin D, reduced kidney function, low calcium intake, and thiazides can falsely lower urinary calcium. Consider genetic testing when biochemical distinction remains uncertain, the patient is young, family history is suggestive, or surgery is being contemplated despite a low CCCR. > **Caution:** Parathyroidectomy generally does not correct FHH. Do not proceed to surgery solely because calcium is high and PTH is nonsuppressed when FHH remains credible. ## Target-organ assessment ### Skeletal assessment The Fifth Workshop recommends skeletal assessment including:[1] - DXA at lumbar spine, total hip/femoral neck, and distal one-third radius; - vertebral imaging or vertebral-fracture assessment when clinically indicated; - review of prior fragility fracture. For premenopausal women and men younger than 50 years, Z-scores are generally used to describe BMD relative to age, but age <50 years independently meets the Fifth Workshop surgical criterion once hypercalcemic PHPT is established.[1] ### Renal assessment - creatinine clearance or eGFR; - renal imaging for nephrolithiasis or nephrocalcinosis; - 24-hour urinary calcium when needed for stone risk, FHH distinction, or surgical criteria.[1,2] NICE specifically recommends renal-tract ultrasound after confirmed PHPT.[2] ## Imaging: localization after diagnosis Preoperative imaging answers **where the abnormal gland is**, not **whether PHPT exists**.[1,2] Common modalities include: - high-resolution neck ultrasound; - technetium-99m sestamibi scintigraphy, often with SPECT/CT; - 4-dimensional CT in selected patients; - advanced localization at expert centers for reoperative or difficult disease.[1] A negative localization study does not invalidate the biochemical diagnosis or a surgical indication. NICE recommends proceeding with surgery by a surgeon experienced in four-gland exploration when imaging does not identify a single adenoma rather than repeatedly adding localization tests.[2] ## Indications for parathyroidectomy ### Fifth International Workshop framework Parathyroidectomy is recommended for symptomatic PHPT and advised for asymptomatic hypercalcemic PHPT when **any one** criterion is present:[1] | Domain | Surgical criterion | |---|---| | Serum calcium | >1.0 mg/dL (0.25 mmol/L) above laboratory upper reference limit | | Vertebral fracture | Vertebral fracture on appropriate imaging | | Bone density | T-score ≤−2.5 at any accepted skeletal site | | Kidney function | Creatinine clearance or eGFR <60 mL/min | | Renal stones | Nephrolithiasis or nephrocalcinosis on imaging | | Urinary calcium | >250 mg/day in women or >300 mg/day in men | | Age | <50 years | Only one criterion is required. Surgery is also reasonable outside these criteria when the diagnosis is secure, patient preference favors cure, and operative risk is acceptable.[1] ### NICE framework NICE recommends referral to an experienced parathyroid surgeon when confirmed PHPT is accompanied by:[2] - symptoms of hypercalcemia; - end-organ disease such as renal stones, osteoporosis, or fragility fracture; - albumin-adjusted calcium **≥2.85 mmol/L**. NICE also advises considering surgical referral in patients outside these categories.[2] > **Current practice:** The Fifth Workshop and NICE use different thresholds and health-system assumptions. Document which framework is being applied rather than combining criteria selectively. ## Operative management Parathyroidectomy is the definitive treatment. The operative plan depends on localization, hereditary risk, likelihood of multigland disease, prior neck surgery, and surgeon expertise. ### Focused versus bilateral exploration A focused operation is appropriate for selected, well-localized sporadic single-gland disease. Bilateral/four-gland exploration is favored when: - imaging is nonlocalizing or discordant; - hereditary or multigland disease is likely; - prior operative/pathologic findings suggest multigland disease; - local surgical strategy favors formal exploration.[1,2] The Fifth Workshop permits selective parathyroidectomy with or without intraoperative PTH monitoring in experienced hands.[1] NICE does not recommend routine intraoperative PTH monitoring during first-time surgery and recommends four-gland exploration when preoperative imaging does not identify a single adenoma.[2] ### Postoperative complications | Complication | Recognition | Immediate action | |---|---|---| | Cervical hematoma | Rapid neck swelling, dysphonia, dyspnea, stridor | Airway emergency; immediate surgical response | | Hypocalcemia | Perioral tingling, cramps, tetany, QT prolongation, seizure | Check calcium, magnesium, phosphate; replace according to severity | | Hungry bone syndrome | Prolonged hypocalcemia with high skeletal uptake after high-turnover disease | Intensive calcium ± calcitriol and electrolyte monitoring | | Recurrent-laryngeal-nerve injury | Persistent hoarseness or aspiration symptoms | Laryngeal assessment and surgical review | | Persistent PHPT | Hypercalcemia never normalizes after surgery | Reassess diagnosis, pathology, operative findings, localization | | Recurrent PHPT | Hypercalcemia returns after an interval of cure | Specialist reoperative workup | NICE advises calcium and PTH before discharge, adjusted calcium at **3–6 months** to confirm success, and annual adjusted calcium thereafter after successful surgery.[2] ## Management when surgery is not performed Observation is reasonable for selected patients who do not meet operative criteria, decline surgery, or have prohibitive operative risk, provided surveillance is reliable.[1] ### Calcium intake Do not severely restrict dietary calcium. The Fifth Workshop recommends nutritional intake consistent with population guidance: approximately **800 mg/day for women <50 and men <70 years**, and **1000 mg/day for women >50 and men >70 years** in the cited framework.[1] Severe restriction can increase PTH and worsen skeletal health. ### Vitamin D Maintain 25-hydroxyvitamin D generally **>30 ng/mL** and below the laboratory upper reference limit.[1] Replace cautiously, particularly with marked hypercalcemia or hypercalciuria, and recheck calcium after clinically important dose changes. ### Cinacalcet Cinacalcet activates the calcium-sensing receptor and lowers serum calcium. It does **not** reliably improve bone density and does not cure PHPT.[1,2] The Fifth Workshop supports cinacalcet when serum calcium needs reduction in patients who are not having surgery.[1] NICE uses a more explicit access framework: consider cinacalcet when surgery has failed, is unsuitable, or is declined and adjusted calcium is: - **≥2.85 mmol/L with hypercalcemic symptoms**, or - **≥3.0 mmol/L with or without symptoms**.[2] Continue only when symptoms and/or calcium improve according to the applicable pathway. Monitor calcium after initiation and dose adjustment and use current product labeling for contraindications and interactions. ### Antiresorptive therapy Alendronate or denosumab can increase BMD in selected patients with PHPT but do not correct autonomous PTH secretion.[1] NICE supports bisphosphonate treatment for increased fracture risk but not as a chronic strategy solely to lower serum calcium.[2] When both hypercalcemia and low BMD require treatment and surgery is not undertaken, specialist-directed combination therapy may be reasonable because calcium control and skeletal protection may require different agents.[1] ## Surveillance without surgery ### Fifth Workshop monitoring | Domain | Suggested monitoring | |---|---| | Calcium | Annually | | 25-hydroxyvitamin D | Annually | | PTH | As clinically indicated | | Creatinine clearance (preferred) or eGFR | Annually | | DXA at 3 sites | Every 1–2 years unless BMD is normal | | Vertebral imaging | When clinically indicated | | Renal imaging | When clinically indicated | | 24-hour urine calcium | When clinically indicated | Reconsider surgery if:[1] - calcium becomes consistently >1.0 mg/dL (0.25 mmol/L) above the upper reference limit; - a low-trauma fracture occurs; - a kidney stone develops; - BMD falls to T-score ≤−2.5; - kidney function declines significantly toward/below the surgical threshold. NICE uses annual calcium plus eGFR/creatinine in nonsurgical patients and considers DXA every 2–3 years, with additional specialist monitoring for osteoporosis or renal stones.[2] ## Acute severe hypercalcemia Severe hypercalcemia can cause dehydration, vomiting, delirium, profound weakness, [acute kidney injury](/library/acute-kidney-injury), and cardiac conduction effects. Immediate priorities are: 1. assess airway, circulation, mental state, and volume status; 2. obtain calcium, electrolytes, creatinine, phosphate, magnesium, and ECG; 3. restore intravascular volume with isotonic crystalloid when appropriate, adjusted to cardiac and renal status; 4. use additional calcium-lowering therapy according to severity, cause, renal function, and local protocol; 5. reserve loop diuretics for clinically important volume overload rather than routine calcium lowering; 6. return to definitive PHPT management once stabilized. Use [Hypercalcemia in Adults](hypercalcemia-in-adults.md) for detailed emergency treatment. ## Pregnancy and reproductive planning NICE recommends offering parathyroid surgery to women with PHPT who are considering pregnancy.[2] Pregnancy with active PHPT warrants specialist multidisciplinary care because maternal hypercalcemia is associated with hypertensive disease and fetal/neonatal complications. Key principles: - establish the biochemical diagnosis carefully because albumin and calcium physiology change during pregnancy; - avoid unnecessary ionizing localization imaging; - use specialist surgical planning when intervention is required; - do not use cinacalcet or bisphosphonates in pregnancy under NICE guidance.[2] For a patient with known PHPT planning pregnancy, definitive surgery before conception is generally favored when feasible.[2] ## Chronic kidney disease CKD complicates PTH interpretation because secondary hyperparathyroidism becomes common as kidney function falls. Elevated PTH with normal or low calcium in CKD should not be labeled normocalcemic PHPT until secondary causes are addressed. Longstanding secondary hyperparathyroidism can evolve into autonomous tertiary hyperparathyroidism with hypercalcemia. Distinguish this from sporadic PHPT using the kidney history, biochemical trajectory, phosphate pattern, and clinical context. ## Parathyroid carcinoma Suspect carcinoma when biochemical severity is extreme or there is an invasive neck phenotype. Management differs from routine adenoma surgery because an initial en-bloc oncologic resection offers the best chance of durable local control. Refer to an experienced center when there is: - very high calcium/PTH burden; - a firm or invasive neck mass; - vocal-cord dysfunction before surgery; - recurrent disease with aggressive features; - a relevant hereditary syndrome. Avoid percutaneous biopsy of a suspected parathyroid carcinoma unless an expert center identifies a compelling reason. ## Prognosis Successful parathyroidectomy usually normalizes calcium and reduces future renal and skeletal risk. Bone density often improves after surgery, though recovery varies by baseline disease and skeletal site. Persistent disease means biochemical hyperparathyroidism continues soon after surgery. Recurrent disease means PHPT returns after a period of biochemical cure. Both require specialist review of the original diagnosis, pathology, operative report, hereditary risk, and localization strategy. ## Practical decision pathway **Confirmed hypercalcemic PHPT** → exclude major mimics such as FHH/lithium effect/tertiary disease → assess kidney function, renal imaging, urinary calcium, DXA ± vertebral imaging → if symptomatic or Fifth Workshop surgical criterion present: refer to experienced parathyroid surgeon → if no criterion but patient prefers definitive therapy: surgery remains an option when risk is acceptable → if no surgery: maintain calcium/vitamin D adequacy, monitor calcium/renal function/BMD, use cinacalcet for calcium control and antiresorptive therapy for skeletal indication when appropriate → move to surgery if new fracture, stone, significant renal decline, rising calcium, or BMD threshold develops.[1,2] ## Related library topics - [Hypercalcemia in Adults](hypercalcemia-in-adults.md) - [Osteoporosis](osteoporosis.md) - [Nephrolithiasis](../urology/nephrolithiasis.md) - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Primary Adrenal Insufficiency in Adults](primary-adrenal-insufficiency-in-adults.md) ## References 1. Bilezikian JP, Khan AA, Silverberg SJ, et al; International Workshop on Primary Hyperparathyroidism. Evaluation and Management of Primary Hyperparathyroidism: Summary Statement and Guidelines from the Fifth International Workshop. *J Bone Miner Res.* 2022;37(11):2293-2314. DOI: 10.1002/jbmr.4677. PMID: 36245251. https://pubmed.ncbi.nlm.nih.gov/36245251/ 2. National Institute for Health and Care Excellence. Hyperparathyroidism (primary): diagnosis, assessment and initial management. NICE guideline NG132. Published May 23, 2019; current recommendations accessed September 23, 2026. https://www.nice.org.uk/guidance/ng132/chapter/Recommendations7:["$","$L17",null,{"article":{"id":"medical-primary-hyperparathyroidism","title":"Primary Hyperparathyroidism","slug":"primary-hyperparathyroidism","description":"Primary hyperparathyroidism (PHPT) is autonomous or relatively autonomous parathyroid hormone (PTH) secretion, most often from a solitary adenoma and less often from multigland disease. In classic PHPT, serum calcium…","aliases":[],"category":"Endocrinology","tags":["Endocrinology"],"updatedAt":"$undefined","body":"$18","headings":[{"id":"summary","text":"Summary","level":2},{"id":"biochemical-phenotypes","text":"Biochemical phenotypes","level":2},{"id":"hypercalcemic-phpt","text":"Hypercalcemic PHPT","level":3},{"id":"normocalcemic-phpt","text":"Normocalcemic PHPT","level":3},{"id":"pathophysiology","text":"Pathophysiology","level":2},{"id":"etiology-and-hereditary-disease","text":"Etiology and hereditary disease","level":2},{"id":"clinical-features","text":"Clinical features","level":2},{"id":"diagnostic-pathway","text":"Diagnostic pathway","level":2},{"id":"initial-laboratory-set","text":"Initial laboratory set","level":3},{"id":"distinguishing-fhh","text":"Distinguishing FHH","level":2},{"id":"target-organ-assessment","text":"Target-organ assessment","level":2},{"id":"skeletal-assessment","text":"Skeletal assessment","level":3},{"id":"renal-assessment","text":"Renal assessment","level":3},{"id":"imaging-localization-after-diagnosis","text":"Imaging: localization after diagnosis","level":2},{"id":"indications-for-parathyroidectomy","text":"Indications for parathyroidectomy","level":2},{"id":"fifth-international-workshop-framework","text":"Fifth International Workshop framework","level":3},{"id":"nice-framework","text":"NICE framework","level":3},{"id":"operative-management","text":"Operative management","level":2},{"id":"focused-versus-bilateral-exploration","text":"Focused versus bilateral exploration","level":3},{"id":"postoperative-complications","text":"Postoperative complications","level":3},{"id":"management-when-surgery-is-not-performed","text":"Management when surgery is not performed","level":2},{"id":"calcium-intake","text":"Calcium intake","level":3},{"id":"vitamin-d","text":"Vitamin D","level":3},{"id":"cinacalcet","text":"Cinacalcet","level":3},{"id":"antiresorptive-therapy","text":"Antiresorptive therapy","level":3},{"id":"surveillance-without-surgery","text":"Surveillance without surgery","level":2},{"id":"fifth-workshop-monitoring","text":"Fifth Workshop monitoring","level":3},{"id":"acute-severe-hypercalcemia","text":"Acute severe hypercalcemia","level":2},{"id":"pregnancy-and-reproductive-planning","text":"Pregnancy and reproductive planning","level":2},{"id":"chronic-kidney-disease","text":"Chronic kidney disease","level":2},{"id":"parathyroid-carcinoma","text":"Parathyroid carcinoma","level":2},{"id":"prognosis","text":"Prognosis","level":2},{"id":"practical-decision-pathway","text":"Practical decision pathway","level":2},{"id":"related-library-topics","text":"Related library topics","level":2},{"id":"references","text":"References","level":2}],"readingMinutes":13},"linkedMarkdown":"$19","backlinks":[],"related":[],"previewBySlug":{"abcde-approach":{"title":"ABCDE Approach","description":"The ABCDE approach is a structured method for the immediate assessment and treatment of a deteriorating or critically ill patient: Airway, Breathing, Circulation, Disability, Exposure. 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