Hyperparathyroidism

• Hyperparathyroidism means the parathyroid glands make too much parathyroid hormone (PTH). PTH raises blood calcium by mobilising bone calcium, reclaiming calcium in the kidney and boosting active vitamin D, so PTH excess leads to raised or inappropriately normal calcium.
• Primary hyperparathyroidism (PHPT) is the gland itself failing: most often one benign adenoma, less often hyperplasia or several adenomas, and less than 1% carcinoma. It is the commonest outpatient cause of hypercalcaemia.
• Secondary hyperparathyroidism is the glands working correctly but pushed by low calcium or high phosphate, as in chronic kidney disease or vitamin D deficiency.
• Tertiary hyperparathyroidism is secondary disease that has become autonomous and now causes hypercalcaemia.
• Most PHPT is found incidentally and is mild; the classic "stones, bones, groans and moans" belong to severe or long-standing disease.
• Parathyroidectomy is the only cure; cinacalcet normalises calcium in about 70% of mild to moderate cases but does not improve bone density. ^[3]

By the end of this page you should be able to:

1. Define hyperparathyroidism and sort it into primary, secondary and tertiary disease.
2. Read a calcium, phosphate, PTH and vitamin D panel and say which state it represents.
3. Explain the symptoms and bone and kidney findings from the effects of PTH.
4. Plan the investigation of suspected disease, including the urine test that separates PHPT from familial hypocalciuric hypercalcaemia (FHH).
5. Apply current surgery criteria (Fifth International Workshop 2022, NICE) and outline conservative management.
6. Recognise and manage postoperative hypocalcaemia and hungry bone syndrome.
7. Outline treatment of secondary disease in chronic kidney disease and vitamin D deficiency.
8. Adjust management for MEN syndromes, pregnancy, children, older adults and low-resource settings.

Primary hyperparathyroidism (PHPT) is autonomous overproduction of PTH from abnormal parathyroid tissue. It usually means blood calcium is raised or at the top of the normal range, with an unsuppressed PTH.

Secondary hyperparathyroidism (SHPT) is a compensatory rise in PTH driven by low or falling blood calcium, high phosphate or low active vitamin D, most often in chronic kidney disease or vitamin D deficiency. Blood calcium is usually normal or low.

Tertiary hyperparathyroidism is SHPT that has persisted so long that one or more glands have become autonomous and now secrete PTH despite normal or high calcium.

There is also a normocalcemic variant, with normal calcium and vitamin D alongside persistently raised PTH, diagnosed only after secondary causes have been excluded. ^[5]

FHH (familial hypocalciuric hypercalcaemia) is not hyperparathyroidism but a differential: an autosomal dominant calcium-sensing receptor defect that raises the calcium set point. It is lifelong, usually asymptomatic and must be separated from PHPT because surgery does not help. ^[5]

Age-adjusted prevalence of PHPT in the United States is roughly 233 per 100,000 women and 85 per 100,000 men. ^[1] Most are women in the sixth decade, and most cases are now found on routine blood testing, so severe disease is uncommon in countries that screen. Where calcium is not routinely measured, PHPT is rarer and more symptomatic. ^[1]

Hyperparathyroidism is one of the most common causes of hypercalcaemia in the general population. Overall hypercalcaemia affects up to 1 in 1,000 people and about 0.6% of acute medical admissions. ^[3]

Among patients on dialysis, secondary hyperparathyroidism is very common, reaching high prevalence as kidney function falls; the CKD-MBD (chronic kidney disease-mineral and bone disorder) framework treats mineral abnormalities as a single syndrome. ^[6]

About 85% of PHPT is a single benign adenoma, about 15% multiple adenomas or four-gland hyperplasia, and less than 1% parathyroid carcinoma. ^[1][3]

A proportion is familial. Up to about 10% of PHPT presenting below 45 years arises on a germline mutation, and nine causal genes are now recognised. ^[3] The relevant syndromes are:

• MEN1 (Menin), MEN2A (RET) and MEN4 (CDKN1B), with multi-gland disease, so bilateral exploration with total or subtotal parathyroidectomy is needed. ^[1][3]
• Hyperparathyroidism-jaw tumour syndrome (CDC73): high parathyroid carcinoma risk, so early and more extensive surgery. ^[1]
• Familial isolated hyperparathyroidism (FIHPT), from mutations in several genes including CASR, CDC73 and CDKN1B/2B/2C. ^[1][3]
• FHH and neonatal severe hyperparathyroidism (CASR, GNA11, AP2S1): parathyroidectomy is either contraindicated or an emergency, depending on severity. ^[3]

Genetic testing should be considered in patients under 30, with multi-gland disease, or with a family history of hypercalcaemia or a related syndrome. ^[1]

Other acquired associations include lithium therapy and previous head or neck radiation. Multi-gland disease and young age are red flags for an inherited cause. ^[3]

• Chronic kidney disease: declining eGFR reduces 1-alpha hydroxylation, so active vitamin D falls, calcium falls and phosphate rises, driving PTH. ^[5]
• Vitamin D deficiency: low 25-hydroxyvitamin D reduces calcium absorption and raises PTH. ^[5]
• Calcium malabsorption: coeliac disease, inflammatory bowel disease, bariatric surgery, low calcium intake. ^[5]
• Medications: non-thiazide diuretics, lithium, anticonvulsants, bisphosphonates, denosumab, SGLT2 inhibitors and proton pump inhibitors. ^[5]
• Phosphate disorders and elevated FGF-23. ^[5]

Long-standing secondary disease, usually in advanced CKD or after malabsorption, in which hyperplastic glands become autonomous and raise calcium. ^[5]

The fundamental defect in PHPT is the loss of normal feedback at the calcium-sensing receptor. Parathyroid tissue grows clonally, expresses fewer receptors, and secretes PTH inappropriately into normal or high calcium. ^[1]

PTH excess then acts on three targets:

• Bone: increased remodelling, cortical thinning and osteoporosis, with raised bone turnover markers. Cortical sites such as the distal one-third radius are most affected. Osteitis fibrosa cystica and brown tumours are now rare. ^[1]
• Kidney: increased calcium reabsorption and phosphate wasting, hypercalciuria that promotes stones and nephrocalcinosis, and impaired renal function. Mild proximal tubular acidosis may occur. ^[1]
• Gut: PTH drives conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, increasing calcium absorption and accounting in part for hypercalcaemia. ^[1]

In CKD, secondary disease begins with phosphate retention and falling active vitamin D; hyperparathyroidism is initially compensatory. Over time gland hyperplasia and reduced receptor expression make it resistant to normal signals, sliding into tertiary autonomy. Hyperphosphataemia also promotes vascular calcification. ^[6][5]

The old mnemonic is "stones, bones, groans and moans", meaning nephrolithiasis or nephrocalcinosis, bone pain or fracture, abdominal pain or constipation, and mood or cognitive change. ^[3]

Stones: polyuria and polydipsia from nephrogenic diabetes insipidus, renal colic, stones and nephrocalcinosis, renal impairment in 12 to 20.6% of patients. ^[1][3]

Bones: bone pain, proximal myopathy, osteoporosis in 50 to 65% of patients, pathological or low-trauma fractures at the forearm and vertebrae, subperiosteal resorption, brown tumours in severe disease. ^[1]

Groans: anorexia, nausea, vomiting, constipation, abdominal pain, peptic ulcer disease, cholelithiasis and pancreatitis. ^[1]

Moans: fatigue, low mood, anxiety, irritability, memory difficulty, sleep disturbance, reduced quality of life; psychosis or delirium at high calcium. ^[1]

Hypercalcaemic crisis occurs rarely, usually when serum calcium exceeds 14 mg per dL, with oliguria, somnolence and coma. ^[1]

In well-screened populations most PHPT is asymptomatic: mild hypercalcaemia with a normal or slightly raised PTH, found on routine testing, with only subtle or no organ involvement detectable on careful investigation. ^[1][3]

Severity depends on both level and speed of rise. A chronic calcium of 2.8 mmol per L may cause only non-specific symptoms, while a rapid rise to the same level can be dramatic. ^[3]

On examination, findings are often minimal: hypertension, band keratopathy (rare), or signs of the underlying cause. In secondary and tertiary disease the picture is dominated by the underlying disorder: the bone and vascular features of CKD-MBD. ^[3]

These patients have raised PTH with normal calcium and vitamin D and no secondary cause. They are usually found during evaluation for osteoporosis or stones. The condition can progress slowly and is diagnosed over months. ^[5]

The single most useful discriminator is the PTH result.

• PTH raised or inappropriately normal with high or high-normal calcium: PHPT, FHH, lithium effect, tertiary disease, multi-gland syndromes. ^[1]
• PTH raised with low or normal calcium: secondary hyperparathyroidism (CKD, vitamin D deficiency, malabsorption, medications).
• Calcium high, PTH suppressed: malignancy-associated hypercalcaemia, granulomatous disease, vitamin D excess, thyrotoxicosis, milk-alkali syndrome, immobilisation, thiazides, adrenal insufficiency. These are covered fully in the hypercalcaemia topic in Renal.

Two traps matter most:

1. A low-normal PTH in the face of high calcium is still abnormal: many assays have a lower limit near their detection limit. Repeat the test or discuss with the laboratory. ^[3]
2. PHPT and FHH can be clinically and biochemically identical. The separator is urine calcium: a calcium to creatinine clearance ratio under 0.01 favours FHH, and over 0.01 favours PHPT; about 18% of confirmed PHPT cases also fall below 0.01. ^[5][3]

1. Repeat the corrected calcium. Use albumin-adjusted calcium, or ionised calcium directly if paraprotein or severe illness is present. Confirm with a second sample. ^[3]
2. PTH as a random sample taken with a concurrent corrected calcium. ^[2]
3. Phosphate, 25-hydroxyvitamin D, creatinine and eGFR. ^[1][2]
4. Urine calcium when FHH is possible: 24-hour urinary calcium, random renal calcium to creatinine ratio, or calcium to creatinine clearance ratio. ^[2]
5. DXA of the lumbar spine, distal radius and hip, plus vertebral imaging for silent fractures. ^[1][2]
6. Renal imaging (ultrasound, with CT as gold standard for stones) for nephrolithiasis or nephrocalcinosis. ^[1][2]
7. Preoperative localisation only when surgery is planned: neck ultrasound first, then sestamibi if it will change the approach. Combined sensitivity for a single adenoma is around 50 to 70% for conventional ultrasound or sestamibi, and SPECT-CT reaches up to 88%. ^[3][1]
8. Genetic testing where appropriate (under 30, multi-gland disease, family history, syndromic features). ^[1]

Normocalcaemic PHPT requires normal adjusted and ionised calcium plus raised PTH on at least two occasions 3 to 6 months apart, after excluding vitamin D deficiency, CKD stage 3 or worse, malabsorption, and relevant drugs. ^[1]

The Fifth International Workshop (2022) recognises three phenotypes of PHPT: symptomatic hypercalcemic disease with skeletal or renal complications; asymptomatic hypercalcemic disease with or without target-organ involvement; and normocalcemic disease. ^[1] Asymptomatic disease is usually mild, with adjusted calcium less than 1 mg per dL (0.25 mmol per L) above the upper limit of normal. ^[1]

Two national-style criteria sets are commonly used for surgery in asymptomatic PHPT.

Normocalcemic PHPT has no surgery guidance beyond case-by-case specialist review, and features such as impaired cognition, poor quality of life or cardiovascular symptoms alone are not yet indications. ^[1]

Parathyroidectomy is the only curative treatment. It is recommended for all symptomatic patients and for asymptomatic patients meeting any criterion above, and is reasonable to consider in almost any patient provided there are no contraindications. Where the patient and clinician agree, offer it; surgery is also the route for MEN and hyperparathyroidism-jaw tumour syndrome, where a more extensive initial procedure is needed. ^[1][2]

Preoperative localisation (ultrasound, then sestamibi when it changes the approach) enables focused surgery but the decision to operate must not depend on the scan. Four-gland exploration remains the fallback when imaging is discordant or negative. ^[2]

Conservative management is acceptable for mild, uncomplicated disease without organ involvement: ^[1]

• No restriction of dietary calcium; standard population intakes (about 800 mg per day under 50 to 70, about 1,000 mg per day after that) are appropriate. ^[1]
• Correct vitamin D deficiency cautiously, aiming for 25-hydroxyvitamin D above 30 ng per mL and below the laboratory upper limit (usually under 50 ng per mL), because large repletion carries a small risk of worsening hypercalcaemia and hypercalciuria. ^{[1][3] [5]}
• Annual calcium, periodic renal checks and DXA every 1 to 2 years, with reassessment if thresholds are crossed. ^[1][2]
• Monitoring in patients not operated should include annual calcium and eGFR, DXA every 2 to 3 years and renal tract imaging when stones are suspected. ^[2]

Conservative follow-up for more than 10 to 15 years is reasonably safe, although up to a third of patients eventually develop overt features. ^[1][3]

Cinacalcet lowers serum calcium in about 70% of mild to moderate cases but only modestly lowers PTH and does not improve bone density; it also reduces urinary calcium. Dosing follows the product label, starting low and titrating. A commonly published scheme is 30 mg twice daily initially, titrating to 90 mg three or four times daily as tolerated. ^[3][4] NICE advises cinacalcet when surgery is unsuitable, declined or unsuccessful and calcium is 2.85 mmol per L or higher with symptoms, or 3.0 mmol per L or higher with or without symptoms; combine with a bone agent when both calcium and bone density need treatment. ^[2] It is limited by nausea, vomiting and cost. ^{[1][2] [5]}

Bisphosphonates (for example alendronate) and denosumab can improve bone mineral density and reduce bone turnover in PHPT and may be used where fracture risk is increased; they are not for chronic control of calcium, and denosumab or intravenous bisphosphonates are reserved for acute hypercalcaemia or bone protection as appropriate. ^[1][2]

Post-parathyroidectomy care: check calcium and PTH before discharge, then calcium at 3 to 6 months to confirm cure; cure means normocalcaemia sustained for at least 6 months. After success, check calcium once a year (and assess bone and renal stone risk locally). ^[2][5]

Hypocalcaemia after parathyroid surgery has two mechanisms that look different on testing: ^[5]

• Hypoparathyroidism (injury or removal of all glands): low or inappropriately normal PTH, high phosphate, normal or high urine calcium with replacement.
• Hungry bone syndrome (HBS): PTH is normal or high, phosphate and magnesium are low, and 24-hour urine calcium is low despite replacement, because calcium is being deposited into bone. Onset is typically on the third to fifth postoperative day. ^[5]

Risk factors for HBS include high preoperative PTH, a large adenoma, high preoperative calcium, radiographic bone disease such as brown tumours or fractures, markedly raised alkaline phosphatase and low preoperative vitamin D. ^[5]

Management is supportive: ensure vitamin D is replete before surgery, monitor calcium multiple times a day for the first postoperative days in high-risk patients, replace calcium intravenously when severe, and step down to oral calcium and active vitamin D as levels allow; magnesium is corrected alongside. HBS can be prolonged, so tapering is gradual and some patients need weeks of high-dose replacement. ^[5]

Permanent hypoparathyroidism is uncommon after first-time surgery but is much more likely after reoperation; autotransplantation of parathyroid tissue may be considered in that setting. ^[5]

Vitamin D deficiency: replete vitamin D, aiming for 25-hydroxyvitamin D of about 30 ng per mL, recheck PTH, and ensure adequate calcium intake (roughly 1,000 to 1,200 mg per day depending on sex and age). PTH can stay raised 6 to 12 months after repletion. ^[5]

Chronic kidney disease: management follows the CKD-MBD approach, integrating calcium, phosphate, PTH and vitamin D rather than treating one number. ^[6]

• Dietary phosphate restriction and phosphate binders (calcium-based such as calcium acetate or carbonate, and non-calcium binders such as sevelamer and lanthanum) to keep phosphate controlled. ^[6]
• Vitamin D analogues (calcitriol, alfacalcidol) and selective analogues such as paricalcitol to suppress PTH, while avoiding over-suppression that drives adynamic bone disease. ^[6]
• Calcimimetics (cinacalcet on dialysis; the intravenous agent etelcalcetide in some units) to lower PTH through the calcium-sensing receptor. ^[6]
• Keep vitamin D stores replete where possible and watch calcium and phosphate trends.

Where medical therapy fails or the gland is autonomous, parathyroidectomy (subtotal or total with autotransplantation) is indicated for refractory tertiary disease, severe hypercalcaemia, progressive bone disease, calciphylaxis, or PTH that remains persistently very high despite treatment. ^[5][6]

• Kidney: stones, nephrocalcinosis, impaired renal function, hypercalciuria. ^[1]
• Bone: osteoporosis, fractures, brown tumours in severe disease, subperiosteal resorption. ^[1]
• Cardiovascular: hypertension, vascular stiffness, left ventricular hypertrophy, calcification, a slightly elevated mortality in more severe disease. ^[1]
• Neuropsychiatric: cognitive and mood disturbance, reduced quality of life. ^[1]
• Gastrointestinal: pancreatitis, peptic ulcer disease, constipation. ^[1]
• Postoperative: temporary or permanent hypoparathyroidism after surgery, especially after reoperation. ^[5]

Mild PHPT managed conservatively has a generally good outlook; severe classical disease carries increased mortality, mainly cardiovascular. ^[1] After successful parathyroidectomy, recurrence of sporadic disease is low (about 0 to 5% in most series, up to about 7.4% in one), while familial and multi-gland disease carries far higher recurrence and needs long-term annual calcium checks. ^[3] Postoperative PTH can remain raised in up to a third of patients without indicating recurrence, so calcium is the monitored variable. ^[5]

• Pregnancy: offer parathyroidectomy to women with PHPT who are considering pregnancy when possible; during pregnancy manage in a multidisciplinary specialist centre, with parathyroidectomy in the second trimester when calcium is high or rising, usually once albumin-adjusted calcium exceeds 2.85 mmol per L. Avoid cinacalcet and bisphosphonates in pregnancy. ^[2][5]
• Children and young adults: think genetic or syndromic disease; more extensive initial surgery and family screening. ^[1][3]
• Older adults and those with CKD or cardiac disease: more cautious hydration, careful bisphosphonate renal dosing, and drug combinations tailored to trends. ^[6]
• MEN and HPT-JT: bilateral exploration from the outset, total or subtotal gland removal. ^[1]
• Parathyroid carcinoma: surgery first, with cinacalcet first-line for mild hypercalcaemia and antiresorptive agents for moderate to severe disease, often in combination. ^[4]

• A single corrected calcium paired with a PTH (where available), phosphate and creatinine goes most of the way. Where PTH assays are unavailable, markedly raised calcium with low phosphate and classic features still makes PHPT likely.
• 24-hour urine calcium needs paired blood and urine samples: if it is not available, a spot calcium to creatinine ratio plus a thorough family history screen for FHH remains useful.
• Ultrasound is cheaper and often available; sestamibi is frequently not. Proceed to surgery with an experienced surgeon and 4-gland exploration when localisation is missing or discordant.
• Cinacalcet, denosumab and advanced vitamin D analogues are often unavailable or unaffordable; know the local formulary. A short course of oral prednisolone is the practical option for calcitriol-mediated disease.
• For CKD-related disease, simpler phosphate binders (calcium-based) and nutritional vitamin D are more affordable than newer agents.
• Vitamin D repletion using standard cholecalciferol is cheap and can be done while calcium is monitored.
• Postoperative calcium checks require frequent measurements for the first few days; if these are scarce, concentrate testing in high-risk patients and ensure oral replacement is prescribed before discharge.
• Refer early to a centre with parathyroid surgery experience rather than pursuing repeated imaging.

• Hyperparathyroidism is excess PTH. Primary disease is an autonomous gland problem; secondary is compensatory, mainly in CKD or vitamin D deficiency; tertiary is autonomy after long-standing secondary disease.
• PHPT is usually a single benign adenoma, more common in women in the sixth decade, and most often found incidentally.
• Symptoms are explained by calcium and phosphate: stones and polyuria from the kidney, bone loss and fractures, gastrointestinal and neurocognitive effects.
• Most patients are now asymptomatic; classical "stones, bones, groans, moans" mark severe or long-standing disease.
• PTH plus calcium is the fork in the road; urine calcium (clearance ratio) separates PHPT from FHH.
• Investigations include calcium, PTH, phosphate, 25-hydroxyvitamin D, eGFR, DXA and renal imaging; localising scans only when surgery is planned.
• Parathyroidectomy is the only cure and any one criterion (adjusted calcium over 0.25 mmol per L above the reference range, renal impairment, stone or nephrocalcinosis, bone density T-score at or below -2.5, age under 50) is enough reason to operate.
• Cinacalcet controls calcium in about 70% of mild to moderate cases but not bone density; bisphosphonates protect bone. Neither replaces surgery where indicated.
• After surgery, beware of hungry bone syndrome: normal or high PTH with low phosphate, low magnesium and low urine calcium, starting on days 3 to 5.
• Secondary disease is treated by correcting cause, phosphate control, vitamin D replacement, vitamin D analogues and calcimimetics.
• Pregnancy and syndromic disease require specialist and often early surgery.

Primary hyperparathyroidism; hypercalcaemia in the renal topic; hypocalcaemia; chronic kidney disease and CKD-MBD; vitamin D deficiency and excess; nephrolithiasis and nephrocalcinosis; multiple endocrine neoplasia; parathyroid carcinoma; osteoporosis.