Hypercalcaemia Algorithm

1

Safety

Screen for life-threatening hypercalcaemia & can't-miss diagnoses

Done

Hypercalcaemia can be asymptomatic or life-threatening. Confirm with corrected calcium (or ionised calcium if albumin abnormal). Act on the level and the symptoms.

Corrected Ca²⁺ >3.5 mmol/L (severe) Confusion, drowsiness, coma, QTc shortening, cardiac arrhythmia → 999 / acute admission

Corrected Ca²⁺ >3.0 mmol/L (moderate–severe) Vomiting, dehydration, ECG changes, renal failure → Same-day urgent review / MAU referral

Suspected malignancy Weight loss, night sweats, known cancer, lymphadenopathy, bone pain, hypercalcaemia in absence of PTH rise → 2WW / urgent oncology (NICE NG12)

Renal failure (AKI) Oliguric, creatinine rising, dehydration — Ca²⁺ nephrotoxic at high levels → Same-day U&E / admit if AKI

Cardiac arrhythmia Palpitations, syncope, short QTc on ECG → 999 / cardiac monitoring

Altered consciousness / seizure Severe hypercalcaemia causes coma → 999 immediately

Addisonian crisis Postural hypotension, weakness, hyponatraemia + hypercalcaemia → Same-day admission — check SST

Sarcoidosis with severe hypercalcaemia Known sarcoid, ACE elevated, hypercalciuria → Same-day / urgent respiratory

Thiazide / lithium toxicity On thiazide or lithium, rising Ca²⁺ → Stop drug, same-day review

Prolonged bed rest / immobility Osteoporosis, Paget's, spinal cord injury → Admit if Ca²⁺ >3.0

Calcium >3.5 mmol/L is a medical emergency. At this level, cardiac arrhythmias and coma can occur within hours. Malignancy accounts for ~20% of hypercalcaemia and is the most common cause in hospitalised patients — missing it delays treatment of potentially curable disease. Primary hyperparathyroidism (PHPT) is the most common cause in outpatients but rarely presents acutely. The key distinction is: PTH-mediated (PHPT, tertiary) vs non-PTH-mediated (malignancy, granulomatous, drugs). Corrected calcium = measured Ca + 0.02 × (40 − albumin g/L). Always correct for albumin to avoid missing true hypercalcaemia in hypoalbuminaemia.

2

Diagnose

Confirm hypercalcaemia & classify severity

Done

Confirm on at least two occasions (unless symptomatic / severe). Use corrected calcium formula or ionised calcium if concern about albumin accuracy.

Corrected calcium

Measured Ca²⁺ + 0.02 × (40 − albumin g/L). Normal: 2.2–2.6 mmol/L

Severity: Mild

2.6–3.0 mmol/L Usually asymptomatic. Outpatient workup appropriate if well.

Severity: Moderate

3.0–3.5 mmol/L Often symptomatic. Consider same-day review; IV fluids likely needed.

Severity: Severe

≥3.5 mmol/L Medical emergency. Admit for IV saline, bisphosphonates, monitoring.

Ionised calcium

Use if albumin very low / high. Normal: 1.16–1.32 mmol/L. More accurate in critical illness.

Confirm twice?

Yes — repeat in 2–4 weeks if mild, asymptomatic, first detection. One repeat is sufficient to confirm chronicity.

Repeat interval

If first Ca²⁺ 2.6–3.0: repeat bloods + PTH within 2 weeks. If symptoms present, act on first result.

Albumin-corrected calcium prevents under- or over-diagnosis. Ionised calcium is the physiologically active fraction but requires special sample handling (anaerobic, on ice). A single elevated reading in an asymptomatic patient may represent lab error or transient causes (dehydration, prolonged tourniquet). Confirmation on two occasions before committing to diagnosis and expensive investigation is standard practice per NICE CKS. However, if the patient is symptomatic or Ca²⁺ >3.0, act on the first result.

3

Diagnose

Classify the aetiology — PTH-mediated vs non-PTH-mediated

Done

PTH is the critical branch point. Order PTH simultaneously with the confirming Ca²⁺ (must be sent together, fasting, correct sample tube).

PTH elevated / normal-high

Primary hyperparathyroidism (PHPT) — most common in outpatients (80%). Single adenoma in 80%, 4-gland hyperplasia in 15–20%, carcinoma <1%. PTH inappropriately elevated for Ca²⁺ level

PTH elevated, very high Ca²⁺

Tertiary hyperparathyroidism — in chronic kidney disease (autonomous PTH secretion). Usually on renal pathway already.

PTH suppressed <1.5 pmol/L

Non-PTH-mediated → must exclude malignancy urgently. Differential: PTHrP (squamous/renal/breast Ca), bone mets, myeloma, lymphoma, granulomatous disease (sarcoid, TB), vitamin D toxicity, milk-alkali, drugs.

PTHrP elevated

Paraneoplastic hypercalcaemia — urgent 2WW malignancy workup. Most common: lung (squamous), breast, renal, bladder, head & neck.

FHH

Familial Hypocalciuric Hypercalcaemia — benign. Ca²⁺/Cr clearance ratio <0.01 (24h urine). PTH normal/mildly elevated. No intervention needed. Check family history.

Drug causes

Thiazides, lithium, calcium supplements, vitamin D toxicity (especially with granulomatous disease), milk-alkali syndrome (calcium carbonate excess).

Granulomatous

Sarcoidosis, TB, histoplasmosis — 1,25-OH vitamin D elevated (macrophage production). Check ACE, CXR, urine calcium.

PTH result drives the entire management pathway. PTH elevated + hypercalcaemia = PHPT until proven otherwise. PTH suppressed + hypercalcaemia = malignancy must be excluded. This distinction determines whether the patient needs surgical referral (PHPT) or urgent oncology workup (malignancy). Missing malignancy as a cause of hypercalcaemia is a serious patient safety failure. FHH is a common mimic of PHPT — differentiating them with a 24h urine calcium-to-creatinine clearance ratio prevents unnecessary parathyroid surgery.

4

Diagnose

Targeted examination — systemic & directed

Done

Physical examination directs urgency and guides the differential diagnosis. Pay particular attention to signs of malignancy and haemodynamic status.

Vital signs

HR, BP (postural drop → dehydration/Addison's), RR, O₂ sat, GCS. Tachycardia + hypotension = severe/emergency

Hydration status

Mucous membranes, skin turgor, JVP, UO — dehydration worsens hypercalcaemia (reduced renal Ca²⁺ excretion)

Lymphadenopathy

Cervical, axillary, inguinal — lymphoma, sarcoidosis, metastatic malignancy. Firm, fixed nodes = malignancy concern

Neck palpation

Thyroid mass (thyrotoxicosis), parathyroid lesion (rarely palpable — only if carcinoma, large adenoma)

Chest / lungs

Pleural effusion, consolidation — lung malignancy, sarcoidosis

Abdomen

Hepatomegaly, splenomegaly — lymphoma, malignancy. Nephrolithiasis tenderness (PHPT complication)

Skin / eyes

Band keratopathy (corneal Ca²⁺, seen with slit lamp — refers), erythema nodosum (sarcoid), skin lesions (malignancy, sarcoid)

Neurological

Confusion, proximal weakness (hypercalcaemic myopathy), hyporeflexia — indicates severity, need for admission

Bone tenderness

Percussion over spine, long bones — metastatic disease, myeloma, osteitis fibrosa cystica (severe PHPT)

Examination findings in hypercalcaemia often provide the diagnosis before investigations return. Lymphadenopathy with suppressed PTH = lymphoma or sarcoidosis until proven otherwise. Dehydration significantly worsens hypercalcaemia by reducing urinary calcium clearance — spotting this drives immediate fluid management. Neurological signs (confusion, weakness) indicate severity and need for same-day admission regardless of the exact calcium level. Band keratopathy is a chronic sign indicating long-standing hypercalcaemia, typically PHPT.

5

Diagnose

Investigations — tier 1 first, tier 2 if needed

Done

First-line bloods establish the cause in most cases. Tier 2 tests for malignancy workup or unusual aetiologies. Order tier 1 in primary care; tier 2 may require specialist guidance.

Tier 1 — Bloods

Corrected Ca²⁺ + albumin PTH (intact, fasting) U&E / creatinine / eGFR Phosphate ALP LFTs FBC 25-OH vitamin D TSH

Interpret PTH + Ca²⁺

↑PTH + ↑Ca²⁺ = PHPT. ↓PTH + ↑Ca²⁺ = non-PTH-mediated (malignancy, granulomatous, drugs). ↑Phosphate + ↑Ca²⁺ (+ ↑ALP) = Paget's or metastatic bone disease

Tier 1 — Urine

Urine Ca²⁺/Cr ratio (spot) — if <0.01 suggests FHH. 24h urine calcium — >7.5 mmol/day = hypercalciuria (risk for stones, consider surgery in PHPT)

Tier 1 — ECG

Short QTc (Bazett <390 ms) — marker of severity. Prolonged PR. Osborn waves (rare, severe)

Tier 1 — Imaging

CXR — hilar lymphadenopathy (sarcoid/lymphoma), pulmonary lesions, primary lung tumour. Abdominal XR — nephrocalcinosis (chronic PHPT)

Tier 2 — Malignancy

PTHrP — paraneoplastic. Serum protein electrophoresis + SFLC — myeloma. 1,25-OH vitamin D — granulomatous disease. Bone profile

Tier 2 — Imaging

CT chest/abdomen/pelvis — malignancy staging. USS kidneys — nephrolithiasis (occurs in 15–20% PHPT). DEXA — if PHPT, assess bone density (T-score <−2.5 = surgical indication)

Tier 2 — PHPT workup

Sestamibi parathyroid scan + neck USS — for localising adenoma pre-surgery (ordered by endocrinology/surgeon, not in primary care)

NOT routinely needed

Bone marrow biopsy (unless haematology directed), parathyroid biopsy (risk of cell seeding), invasive venous sampling in primary care

PTH + calcium together determine 80% of the diagnosis. A fasting intact PTH (double-antibody immunoradiometric assay) sent simultaneously with calcium is the single most important test. 25-OH vitamin D should be checked as deficiency paradoxically can mask PHPT by normalising calcium temporarily — correction of vitamin D can then unmask hypercalcaemia. Phosphate is low in PHPT (PTH promotes renal phosphate excretion). Elevated ALP in PHPT may indicate bone involvement (osteitis fibrosa cystica). DEXA scanning is a key surgical criterion in asymptomatic PHPT per NICE NG132 — T-score <−2.5 at any site, or osteoporosis on imaging, indicates parathyroidectomy even without symptoms.

6

Refer

Referral pathway — who, when, and how urgently

Done

The aetiology determines the specialty. PHPT → endocrinology ± surgery. Malignancy → oncology. Granulomatous → respiratory. Unclear → endocrinology.

999 / Admit now

Emergency Ca²⁺ ≥3.5 mmol/L, OR symptomatic (confusion, coma, arrhythmia, vomiting with dehydration, AKI) → 999 or same-day acute medicine. Begin IV 0.9% NaCl en route if possible.

Same-day / MAU

Urgent Ca²⁺ 3.0–3.5 mmol/L + any symptoms, OR asymptomatic Ca²⁺ >3.0 in patient who lives alone / is elderly. Phone acute medicine for advice.

2WW oncology

2 Week Wait Suppressed PTH + no drug cause + weight loss / night sweats / bone pain / known cancer history → urgent cancer pathway (NICE NG12). Consider PTHrP, serum protein electrophoresis, CT.

Urgent endocrinology

Within 2 weeks Confirmed PHPT (raised PTH + Ca²⁺) with symptoms: nephrolithiasis, bone disease, significant osteoporosis, Ca²⁺ >2.85 mmol/L consistently, age <50 years

Routine endocrinology

Routine (6–8 weeks) Asymptomatic PHPT in patient >50y, Ca²⁺ 2.6–2.85, eGFR >60, no bone disease, no stones — may elect for surveillance (conservative management)

Parathyroid surgery

Via endocrinology. Parathyroidectomy is indicated for: symptoms, age <50, Ca²⁺ >0.25 mmol/L above ULN, eGFR <60, DEXA T-score <−2.5, vertebral fracture, 24h urine Ca >10 mmol/day. Per NICE NG132.

Respiratory

Routine–urgent Suspected sarcoidosis (hilar lymphadenopathy, ACE elevated, 1,25-OH VitD high) → respiratory medicine. Suppress Ca²⁺ with prednisolone 30–40 mg OD while awaiting if severe.

Haematology

Urgent Myeloma screen positive (SPEP paraprotein, SFLC elevated, Bence Jones protein) → urgent haematology

Primary care only

Drug-induced hypercalcaemia (thiazide, calcium supplements, vitamin D excess) + Ca²⁺ <3.0 + asymptomatic → stop offending drug, recheck in 4 weeks. No referral needed if normalises.

Most PHPT in the UK is managed conservatively in primary care — the majority of patients are post-menopausal women with asymptomatic mild hypercalcaemia. Surgery is curative (95% success rate) but should only be offered when evidence-based criteria are met. The NICE NG132 (2019) criteria for parathyroid surgery are well-defined and should guide referral discussions. For malignancy-associated hypercalcaemia, calcium often responds poorly to bisphosphonates alone — treatment of the underlying cancer is the definitive intervention. IV denosumab is increasingly used in malignancy-associated hypercalcaemia refractory to bisphosphonates.

7

Treat

Treatment pathway — by severity and aetiology

Done

Acute hypercalcaemia treatment is driven by severity. Chronic/mild PHPT in primary care uses conservative strategies while awaiting specialist input.

Acute / Severe Hypercalcaemia (Ca²⁺ >3.0 mmol/L) — Hospital Treatment

Step 1IV 0.9% NaCl (saline rehydration) — 200–500 mL/hr initially, aiming 3–4 L over first 24h. Monitor UO (target >100 mL/hr), electrolytes 4–6 hourly. This alone reduces Ca²⁺ by 0.3–0.5 mmol/L via dilution and enhanced renal excretion. First-line always

Step 2IV bisphosphonate — Zoledronic acid 4 mg IV over 15 min (once eGFR >35). Onset 24–48h, peak effect 4–7 days. Duration 3–4 weeks. OR Pamidronate 60–90 mg IV over 2–4h if renal impairment. Avoid if eGFR <35 (use denosumab instead). Most effective single agent

Step 3Denosumab 120 mg SC — if bisphosphonate contraindicated (eGFR <30, bisphosphonate resistance, malignancy refractory). Onset 4–10 days. Repeat monthly. Monitor for rebound hypercalcaemia on cessation. Specialist-initiated

Step 4Calcitonin (salmon) 4–8 units/kg SC/IM 6–12 hourly — rapid onset (4–6h), tachyphylaxis within 48h. Use as bridge while awaiting bisphosphonate effect. Short-term bridging only

GranulomatousPrednisolone 30–40 mg OD — suppresses 1-alpha hydroxylase in macrophages, reduces 1,25-OH vitamin D production. Response in 3–7 days. Taper over 4–6 weeks. Sarcoid / TB / lymphoma

DialysisHaemodialysis with low-calcium dialysate — if severe refractory hypercalcaemia + acute renal failure. Last resort. ICU/nephrology decision.

Mild–Moderate PHPT (Ca²⁺ 2.6–3.0) — Primary Care / Conservative

Symptomatic or surgical candidate

Refer to endocrinology Surgery

Parathyroidectomy — curative in 95%. Sestamibi + USS for localisation. Monitor Ca²⁺ post-op (hungry bone syndrome — hypocalcaemia risk).

Asymptomatic, age >50, mild Ca²⁺

Conservative surveillance Primary care

Annual Ca²⁺, PTH, U&E, DEXA every 1–2 years, USS kidneys. Maintain hydration. Avoid thiazides, lithium, calcium supplements >1g/day, immobility, low calcium diet.

Cannot undergo surgery / refuses

Cinacalcet Calcimimetic

Cinacalcet 30 mg OD — reduces Ca²⁺ by sensitising calcium-sensing receptor. Does not improve BMD. Endocrinology-initiated only. Monitor Ca²⁺ monthly initially. Reduces Ca²⁺ by ~0.4 mmol/L.

Drug-induced hypercalcaemia

Thiazide diuretics

Stop thiazide. Recheck Ca²⁺ in 4 weeks. If persistent → evaluate for underlying PHPT (thiazides unmask it).

Lithium

Consider dose reduction or switch (psychiatry input). Lithium increases PTH secretion — may unmask PHPT. Recheck after 3 months.

Vitamin D toxicity

Stop vitamin D supplements. Hydrate. If severe (Ca²⁺ >3.0) — prednisolone 40 mg OD reduces intestinal absorption. Recheck Ca²⁺ 2–4 weekly.

Calcium supplements

Reduce or stop. Common cause especially in elderly women on osteoporosis treatment. Check dietary calcium intake.

IV saline is the cornerstone of acute treatment — it works within hours and is universally safe. Bisphosphonates (zoledronic acid) are the most effective agents for malignancy-associated hypercalcaemia (NNT approximately 2–3 for normalisation of calcium). Calcitonin acts fastest but efficacy wanes within 48h due to downregulation of receptors (tachyphylaxis) — use only as a bridge. Cinacalcet does not reduce fracture risk or stone formation in PHPT, unlike parathyroidectomy, which is definitively curative. Loop diuretics (frusemide) are no longer routinely recommended for hypercalcaemia — they increase calcium excretion but risk worsening dehydration, which paradoxically raises calcium further. Only use after adequate rehydration if fluid overloaded.

8

Lifestyle

Non-pharmacological interventions — essential in all patients

Done

Lifestyle measures directly modify calcium levels and should be emphasised at every consultation — they are treatment, not adjuncts.

Hydration — 2–3 L/day The single most important lifestyle intervention. Adequate fluid intake maintains renal calcium excretion. Dehydration is the most common precipitant of hypercalcaemic crisis. Target pale yellow urine.

Avoid immobility Prolonged bed rest increases bone resorption and worsens hypercalcaemia. Regular weight-bearing activity 30 min/day (walking). Particularly critical during acute illness.

Dietary calcium — do NOT restrict Counter-intuitive but important: low calcium diet increases PTH secretion and worsens PHPT. Aim 700–1000 mg/day (normal intake). Excessive calcium (>1500 mg/day) should be avoided.

Avoid thiazide diuretics Reduce renal calcium excretion — use loop diuretics (furosemide) if a diuretic is needed in a patient with hypercalcaemia. Review diuretic prescription.

Limit vitamin D supplements If vitamin D level is replete (>50 nmol/L), stop supplements. In granulomatous disease (sarcoid), vitamin D may be converted to active form — avoid even moderate supplementation without specialist guidance.

Reduce alcohol intake Alcohol can worsen dehydration, impair renal function, and reduce bone density. Maximum 14 units/week (NICE guidance).

Sun exposure — moderate In sarcoidosis and other granulomatous disease, UV-mediated vitamin D synthesis may worsen hypercalcaemia — advise sun protection. In PHPT, normal sun exposure is safe.

Nephrolithiasis prevention If stone-former (PHPT) — >2.5 L urine/day, reduce dietary sodium (<6g/day reduces urinary calcium), reduce animal protein. Refer to urologist if recurrent stones.

Bone health — weight-bearing exercise In asymptomatic PHPT, 30 min weight-bearing exercise 5x/week reduces bone loss. Swimming does not substitute — must be weight-bearing for skeletal benefit.

Medication review Check: calcium supplements, antacids (calcium carbonate), lithium, thiazides, high-dose vitamin A (retinol). Stop if causative. Document review.

Hydration alone can reduce calcium by 0.3–0.5 mmol/L in mildly hypercalcaemic patients — this is a clinically meaningful change and can bring mild hypercalcaemia into the normal range without any pharmacological intervention. The instruction to avoid calcium restriction is frequently misunderstood by patients who intuitively restrict dairy — emphasise that normal calcium intake is safe and beneficial. Low dietary calcium paradoxically raises PTH and worsens PHPT. In the UK, a NICE quality statement from NG132 specifically notes that conservative management (including lifestyle) is appropriate first-line for asymptomatic PHPT patients who do not meet surgical criteria.

9

Safety

Follow-up, monitoring & safety-netting

Done

Monitoring intervals depend on aetiology and severity. Asymptomatic mild PHPT in primary care requires long-term annual surveillance. Drug-induced hypercalcaemia should normalise within weeks of stopping the causative drug.

Post-acute discharge

Review within 1 week of hospital discharge — check Ca²⁺, U&E, eGFR. Ensure oral rehydration maintained. Confirm specialist follow-up arranged.

Drug-induced (stopped drug)

Recheck Ca²⁺ in 4 weeks. If normalised → confirm, no further action. If persistent → full PHPT workup (thiazides unmask underlying disease).

Asymptomatic PHPT — surveillance

Annual: corrected Ca²⁺, PTH, U&E/eGFR, 24h urine Ca²⁺. DEXA every 1–2 years. Renal USS every 2–3 years. Review surgical criteria annually.

Post-parathyroidectomy

Inpatient: Ca²⁺ 4–6 hourly for 24–48h (risk of hypocalcaemia — "hungry bone"). Outpatient: Ca²⁺ at 1 week, 1 month, 3 months. Most patients normalise Ca²⁺ within 24h.

Malignancy-associated

Oncology-led monitoring. Ca²⁺ with each chemotherapy cycle. Bisphosphonate/denosumab infusions per regimen. Dental check before bisphosphonate (ONJ risk).

Sarcoidosis

Ca²⁺ every 3 months while on prednisolone. Annual 24h urine Ca²⁺ (hypercalciuria → renal damage). ACE level, CXR 6-monthly. Respiratory OPD follow-up.

When to escalate urgently

Ca²⁺ rising despite treatment. New renal failure. New or worsening confusion. Inability to maintain oral fluids. Bone pain with new neurological deficit.

Safety-net — 999

999 Confusion / coma / collapse. Cardiac arrhythmia / chest pain. Fitting. Severe vomiting unable to maintain fluids. Back pain + leg weakness (spinal cord compression — malignancy)

Safety-net — same-day GP

Same-day Significant worsening of weakness / lethargy. Unable to tolerate fluids / food for >24h. Severe bone pain. Urine output markedly reduced. Ca²⁺ result returns as >3.0 on routine monitoring.

Longer-term review

6 months: Confirm specialist appointment attended. Review medications (calcium, vitamin D). Reinforce hydration, lifestyle. Update care summary. 12 months: Formal annual review — decision to continue surveillance or refer for surgery.

Asymptomatic PHPT can remain stable for decades — studies show that 70–80% of conservatively managed patients do not progress to meet surgical criteria over 10 years. However, the 20–30% who do progress require timely identification. Annual monitoring allows surgical criteria (calcium rise, eGFR decline, bone density loss, nephrolithiasis) to be detected before irreversible complications occur. Post-parathyroidectomy "hungry bone syndrome" is a serious complication: the suddenly parathyroid-suppressed skeleton rapidly takes up calcium, causing severe hypocalcaemia (tetany, seizures). It occurs in 5–25% of cases and is more common in those with pre-operative vitamin D deficiency — another reason to ensure replete vitamin D before surgery. Safety-netting is especially important in hypercalcaemia because patients often adapt to chronically elevated calcium and may not recognise subtle deterioration.

🩺 Reasoning GP — Clinical Algorithms

Screen for life-threatening hypercalcaemia & can't-miss diagnoses

Confirm hypercalcaemia & classify severity

Classify the aetiology — PTH-mediated vs non-PTH-mediated

Targeted examination — systemic & directed

Investigations — tier 1 first, tier 2 if needed

Referral pathway — who, when, and how urgently

Treatment pathway — by severity and aetiology

Non-pharmacological interventions — essential in all patients

Follow-up, monitoring & safety-netting