Hypercalcaemia (includes hyperparathyroidism)

• Defined as calcium >2.6 mmol/L
• Calcium >3.5 mmol/L is an emergency, always admit
• Corrected calcium used most in the UK, although correcting for albumin is controversial
• Consider admission if moderately high (3-3.5) – depending on how well tolerated, which is related to the rate of increase
• Milder hypercalacaemia can be managed in primary care or via SDEC

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Clinical features

• Symptoms are rare if calcium <3
• If short history and severe symptoms – more likely malignancy
• If no symptoms, consider pseudohypercalcaemia (see below)
• ‘Bones, stones, groans, and psychic moans’
  • • Bones – Aches and pains, fractures (osteomalacia / osteoporosis / osteitis fibrosa cystica – rare)
    • Renal stones – nephrocalcinosis on xray, AVP resistance
    • Groans – Abdominal pain, constipation, vomiting, anorexia, thirst, peptic ulcers, pancreatitis, pseudogout
    • Moans – Depression, drowsiness, weakness, delirium
• Additionally: Calcium band keratopathy, hypertension (if not hypovolaemic)

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ECG changes

• Short QT interval
• J waves (just after R wave)
• Prolonged QRS interval
• Flat T waves
• AV-block
• VF, VT, PEA and asystole

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Causes

• In 85% of cases, the cause is primary hyperparathyroidism or malignancy (but there are lots of others)
• Hyperparathyroidism
  • • Primary
    • Tertiary (very high PTH, occurs in advanced CKD)
    • Don’t forget MEN1 and MEN2A
• Malignancy
  • • Especially associated with advanced disease and a poor prognostic sign (median survival 3-4 months)
    • 80% PTH related peptide mediated especially in squamous cell carcinomas, lung, renal
    • 20% humoral mediated osteoclast activity – especially breast and myeloma
    • Also seen in bony metastases, parathyroid cancer, lymphoma
    • Can be caused by activation of extra-renal vitamin D (lymphoma)
    • Very rare in prostate cancer
    • 65% of inpatient hypercalcaemia
• Less common causes include
  • • Granulomatous disease (especially sarcoid, TB, GPA)
    • Immobility (high rate of bone turnover)
    • Vitamin D toxicity
    • Calcium supplementation and Milk-alkali syndrome
    • Vitamin A toxicity
    • Endocrine – hyperthyroidism, Addison’s, phaeochromocytoma
    • Familial Hypocalciuric hypercalcaemia
    • Ectopic PTH
    • Drugs (lithium, thiazides, theophylline, all-trans retinoic acid, teriparatide)
    • Rhabdomyolysis
    • Renal failure
    • HTLV1 infection
    • CYP24A1 mutations (high serum Ca, high Ca in urine, renal stones)
    • Pseudo-hypercalcaemia – corrected calcium high, ionised calcium normal. Occurs in myeloma, as the paraprotein binds calcium

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Investigations

• Always send phosphate, PTH level, TFTs, LFTs (alk phos), vitamin D, magnesium
• VBG (a metabolic acidosis or normal ionised calcium may be clues to the cause)
• Phosphate should be inversely proportional to PTH in absence of renal disease
  • • So low phosphate suggests hyperparathyroidism, some malignancies (if PTH-related peptide hypercalcaemia), milk alkali syndrome
    • High phosphate can occur in any of the other causes
• ECG for all
• Parathyroid hormone level (PTH)
  • • If elevated calcium, PTH should be low
    • If PTH is normal/unsuppressed or high – this suggests hyperparathyroidism (but also exclude FHH, and consider tertiary hyperparathyroidism, parathyroid cancer, drugs like lithium)
    • If PTH is suppressed with high calcium – generally a bad sign as this suggests malignancy (especially breast, thyroid and bone) but it could also be a rare cause
• Other tests
  • • Send magnesium as low levels can mask primary hyperparathyroidism
    • If corrected calcium high but ionised calcium normal – do myeloma screen (pseudohypercalcaemia)
    • Myeloma screen – ESR, serum protein electrophoresis, immunoglobulins, serum free light chains
    • Consider serum ACE, cortisol
    • 24 hr urinary calcium – this is typically high. Can be low in vitamin D deficiency and FHH
    • Do a spot urine calcium and calculate the calcium:creatinine ratio to exclude FHH
      • • Ensure vitamin D replete first
        • Can be be falsely low in pregnancy, if on diuretics and in CKD
        • This can exclude 98% of FHH and 66% of primary hyperparathyroidism
        • In FHH the CCCR is < 0.02 (and if so, do a genetic test for known mutations)
• Imaging  to consider
  • • CxR – sarcoid, TB, cancer
    • Renal USS – nephrocalcinosis, calculi
    • CT CAP for malignancy
    • DEXA scan
    • Parathyroid imaging – only useful if parathyroid cancer suspected or planning surgery (so only if surgical candidate). Can do a Sestamibi scan and US neck

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Treatment

• Consider a cardiac monitor
• Management depends on symptoms as well as the calcium level
  • • Patients with chronic hypercalcaemic can tolerate levels of 3-3.5, and don’t necessarily need emergency treatment
• In peri-arrest situations where there is a risk of cardiac arrest treat hypercalcaemia with
  • • IV fluids
    • Furosemide 1 mg / kg
    • Hydrocortisone 200-300 mg IV
    • ICU review – consider dialysis
    • and treat the underlying cause
• Stop calcium supplements (plus vitamin D, vitamin A, and any other causative medications if possible) – this is often forgotten
• IV fluids is the mainstay of treatment
  • • Aim to give 4-6L/24 hours if possible (for at least first 2 days) – aiming urine output 100-150ml/hour
    • Patients will be dry initially. Once euvolaemic, you want urine output to match fluid input (or risk of overload)
    • Normal saline fluid of choice (you need the Na for calcium excretion). Avoid Hartman’s. If the patient also has a high sodium, can give dextrose as well
    • Keep going with fluids if you don’t know the diagnosis. They can take a while to work and calcium will continue to gradually fall. Aim is also to prevent an AKI
    • Give even if history of HF (can use loop diuretics alongside fluid if clinically overloaded)
    • Reduce IV fluid later once bisphosphonates are working
    • Consider catheter and carefully monitor urine output
• Frusemide 1mg/kg
  • • Often used if the patient has HF (allows you to give more fluids, also mildly brings calcium down itself but not much)
    • However, controversial, and some have suggested it might cause more harm than good
• IV bisphosphonates
  • • Arguably overused, but if calcium very high (>3.6) definitely give, and give if not responding to fluids
    • Lower threshold to use if cancer causative
    • Usually start once patient is rehydrated
    • Can take a few days at least to have an impact
    • Zolendronate (4mg IV over 15 minutes, or 60 minutes) is useful for malignancy-induced hypercalcaemia (do not give if diagnosis unclear because it can cause hypocalcaemia in hyperparathyroidism. Can drop magnesium and phosphate too). Reduce the dose in renal impairment
    • Useful in pain of malignancy too
    • Pamidronate (60-90mg) is an alternative – maybe a better choice in severe renal dysfunction (can divide doses), but less effective (though it is cheaper). Adjust dose if renal impairment (and might avoid if eGFR <30)
    • Can repeat bisphosphonates but must wait 5 days at least
    • They can cause bone pain, fever or flu-like symptoms, and can cause hypocalcaemia if vitamin D deficient or PTH suppressed
    • Doesn’t fix the underlying cause of high calcium – so consider that whilst treating, or else hypercalcaemia can recur
    • Avoid in milk alkali syndrome
• Steroids
  • • Generally used 2^nd line
    • Work though multiple pathways, including inhibiting calcium absorption and increasing urinary calcium excretion
    • Prednisolone 20-60mg OD
    • Only really works in myeloma, lymphoma, sarcoid and vitamin D excess
    • Effective in 2-4 days
• Calcitonin 200 IU TDS s/c injection
  • • Used in cases of resistant hypercalcaemia (2-3 days post bisphosphonates). Often used for a few days only
    • Risk of rebound hypocalcaemia, and poorly tolerated (nausea and vomiting is the main issue)
• Denosumab (120mg s/c injection once)
  • • In the latest US guidance, this is used in preference to bisphosphonates in hypercalcaemia of malignancy
    • Also used in resistant cases, and those with severe renal failure
    • Risk of hypocalcaemia (especially if vitamin D deficient)
    • Works quite slowly (might take a week to reach full effect)
• Dialysis if extremely resistant or anuric (especially if calcium > 4.5) or severe AKI
• Cinacalcet
  • • Indicated in symptomatic primary and tertiary hyperparathyroidism if surgery inappropriate, or as bridge to surgery, or in parathyroid cancer
    • More below
• Parathyroidectomy – used for fractures, renal stones, keratopathy, pancreatitis (see PH section below)
• Consider bone protection long term
• Chemotherapy – can be useful in malignancy associated hypercalcaemia
• RANK-L inhibitors if refractory

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Primary Hyperparathyroidism

• Rarely causes severe acute hypercalcaemia, but a common cause of chronic elevation in levels
• 45% of patients are symptomatic
• Correlates with an increased risk of CV disease, stroke, renal failure and stones, psychiatric disturbance, hypertension, fractures, cancer, diabetes, mortality
• Although might be more likely to be diagnosed in patients who are already sick with something else
• Usually due to
  • • Solitary adenoma (85%)
    • 2 gland adenomas
    • Hyperplasia (10-15% – especially MEN1)
    • Parathyroid cancer (<1%)
• Familial in 1% – and may be associated with MEN1 or MEN 2A
• Complications
  • • Osteopenia
    • Rarely osteitis fibrosa cystica
    • Renal stones (hypercalciuria is found in 60% of patients with renal stones)
• MEN1
  • • Parathyroid, pancreas, pituitary (need 2 glands involved to make diagnosis)
    • Hyperparathyroidism is the most common finding (in 90%) and often recurrent
    • Enteropancreatic tumours found in 70%
    • 15-20% have pituitary tumours
    • Patients should be under surveillance
    • If suspected, check VIP, pancreatic polypeptide, gastrin, glucagon, somatostatin, chromogranin A and B, pituitary hormones
• Investigations
  • • Usually either high PTH, or high calcium with unsuppressed PTH
    • However… 15% have normal calcium and 15% have normal PTH
    • Check vitamin D level
      • • Especially if calcium normal as elevated PTH is associated with vitamin D deficiency as well as primary hyperparathyroidism
        • Concomitant Vitamin D deficiency can mask the diagnosis
    • Check paired serum calcium and creatinine and urine calcium
      • • Helps exclude FHH
        • Calcium creatinine clearance ratio  should be >0.02 in PH. FHH usually has a ratio of <0.01.
        • If 0.01-0.02 might repeat test in 2 weeks
        • Some have suggested that 24 hour collection is preferable to spot calcium testing – it’s more accurate, but also gives some information on the risk of stones
        • 40% have increased urinary calcium
    • Do parathyroid USS and MIBI scan if patient is surgical candidate (not for diagnosis).
      • • Imaging may not identify an adenoma if there’s an ectopic gland, less activity/less severe disease, germline genomic variants (multi-gland disease, needs MDT discussion)
• Management
  • • Work up for complications (can be high yield)
      • • DEXA (distal third of radius best)
        • Renal US or CT (stones, nephrocalcinosis)
        • Consider germline testing
    • If asymptomatic, usually surgery advised if
      • • Calcium > 2.85 or >3 (depend on centre)
        • Bone Mineral Density T score < 2.5 or fracture history
        • eGFR <60
        • 24 hour urinary calcium >10mmol
        • Stones/nephrocalcinosis
        • Patient aged <50
    • If asymptomatic, corrected calcium is < 3, no stones and bone mineral density is normal – do not need treatment (though you might treat a younger person)
    • Surgery if fit
      • • Remove a gland to remove the adenoma
        • If calcium doesn’t normalise, remove all parathyroids
        • Imaging can guide surgical options
        • Can be done under local, but frail patients might not be suitable
        • Expectation management – not all symptoms will necessarily melt away post-op, some, like low mood or energy may not have been related to the calcium. Stones can still form for a year or two post-op too
        • Proven benefits include improved bone mineral density and quality of life, less risk of stones
    • Medical treatment if not fit for surgery, or surgery declined
      • • Cinacalcet, 30-90mg BD
          • • 73% respond well and normalise calcium within 2 weeks
            • Can also be used short term pre-surgery to see if/which symptoms disappear with normalisation of calcium – this is off label use
            • Also used in parathyroid cancer and secondary hyperparathyroidism.
            • Commonly causes nausea
        • Consider bisphosphonate to reduce fracture risk (but not to treat chronic hypercalcaemia)
        • Consider HRT
        • Advise calcium intake as per the general population (do not restrict) and replace vitamin D (do not let them run low in the hope of controlling calcium)

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Familial hypocalciuric hypercalcaemia (FHH)

• Benign condition
• Inherited AD (ask if family members have had high calcium or had unsuccessful parathyroid surgery)
• Prevalence 1:78,000
• Investigations
  • • Mild hypercalcaemia
    • Normal PTH in 75% (slightly up in 25%)
    • Slightly elevated magnesium (unlike hyperparathyroidism where magnesium is generally low)
    • Calcium:  creatinine clearance ratio <0.02, and often <0.01 (if so, follow up with a 24 hours urine collection)
    • Consider genetic testing of patient and relatives
    • Typically normal bone mineral density (unlike hyperparathyroidism)
• Parathyroid can show mild hyperplasia and parathyroid surgery not curative
• If unwell/dehydrated patients can occasionally develop pancreatitis and chondrocalcinosis

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Hypercalcaemia of malignancy

• Causes include
  • Tumour secretion of parathyroid hormone-related peptide and vitamin D
  • Cytokine release in osteolytic metastases
• Most commonly associated with malignancy of the breast, lung, kidneys, myeloma, lymphoma and head & neck cancers
• Standard measures
  • • Stop thiazide diuretics, NSAIDs, vitamin D /calcium supplements
    • IV fluids – aim for urine output > 2L/day
    • Check for low magnesium
• Use bisphosphonates earlier in cancer than you might otherwise. Fluids unlikely to be sufficient in cancer.
  • • Usually give bisphosphonates after patient rehydrated. Might start at 24 hours
    • Zoledronic acid 4mg if calcium > 3 and creatinine clearance >60 (reduce dose in renal impairment)
    • If creatinine clearance <29 consider pamidronate instead, 90mg.
    • They take a while to work – might take 4 days for the full effect. Do not repeat for at least 5 days (some say 7)
• Other options
  • • Steroids – used sometimes in myeloma and lymphoma. Take 1-2 weeks to work.
    • Calcitonin – acts fast but short lived. Give 100 IU TDS subcutaneously or IM. Increase to 400 IU max QDS
    • Denosumab – monoclonal used for bone metastases. Standard dose is 120mg subcutaneously. Can repeat between days 8 and 15 (but only if calcium reduced after first dose)

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Less common causes

• Milk Alkali syndrome
  • • Caused by calcium ingestion eg excessive antacids
    • Triad of hypercalacaemia, AKI and metabolic alkalosis
    • PTH suppressed and normal phosphate
    • CKD is a risk factor
    • Ask about ETOH use (this may be why excessive antacids used)
    • Treat with IV fluids and stop calcium treatments
    • Exclude other causes of hypercalcaemia
    • Avoid giving bisphosphonates
• Vitamin D toxicity / hypervitaminosis D
  • • Can occur at intakes of >10,000 IU/day but patients may have taken much more
    • Send vitamin D level
    • Treat as usual with IV fluids and consider bisphosphonates and steroids
    • Vitamin D is fat soluble so hypercalcaemia can take a long time to correct (weeks) and the patient will need regular monitoring after discharge
    • Look for complications given likely chronic hypercalcaemia
• CYP24A1 mutations
  • • High serum calcium, high calcium in the urine, renal stones
    • Can check ratio of 25-OH-D3 to 24,25 (OH)2D3 – this distinguishes the mutation from hypervitaminosis D (ratio usually greater than 80)
    • Treat with vitamin D restriction and sun protection
    • Can also use ketoconazole, fluconazole and cinacalcet