Hypercalcaemia, hypocalcaemia and endocrine causes of renal stones

Overview

Serum calcium is kept in a narrow range (about 2.2–2.6 mmol/L) mainly by parathyroid hormone (PTH) and vitamin D. High calcium is far more common than low calcium, and is often found by chance on routine bloods.

Only about 40% of calcium is ionised (the active form); the rest is bound, mostly to albumin. So the total calcium must be corrected for albumin, and the result must always be read together with PTH.

Physiology in brief

PTH comes from the chief cells of the four parathyroid glands. A calcium-sensing receptor on these cells detects ionised calcium; when calcium falls, PTH rises. PTH raises calcium by:

• increasing bone resorption (osteoclasts, a fast effect);
• increasing renal calcium reabsorption and increasing phosphate excretion;
• stimulating renal 1α-hydroxylase, making more 1,25-dihydroxyvitamin D, which increases gut calcium absorption (a slow effect).

Correcting calcium for albumin

Corrected calcium = measured calcium + 0.02 × (40 − albumin in g/L)

Reading calcium, phosphate and PTH together

Hypercalcaemia

Causes

Primary hyperparathyroidism and malignancy cause over 90%.

• Too much PTH: primary hyperparathyroidism (single adenoma in over 80%, hyperplasia of all four glands in 15–20%, carcinoma rare); tertiary hyperparathyroidism; part of MEN 1 or MEN 2A.
• Malignancy (PTH low): PTH-related peptide (classically squamous cell lung cancer, breast, kidney); bone metastases (breast, lung, prostate, kidney, thyroid); myeloma; lymphoma (makes calcitriol).
• Vitamin D excess: over-treatment; granulomas (sarcoidosis, TB), where macrophages make 1,25-dihydroxyvitamin D.
• Drugs: thiazides, lithium, vitamin A, vitamin D analogues; calcium and alkali (milk-alkali syndrome).
• Other endocrine (mild): thyrotoxicosis, Addison disease.
• Prolonged immobilisation, familial hypocalciuric hypercalcaemia.

Clinical features

Mild hypercalcaemia (below about 3 mmol/L) is often symptomless. Higher levels cause:

• Renal: polyuria and thirst (a form of nephrogenic diabetes insipidus), dehydration, renal stones, nephrocalcinosis, kidney injury.
• Gut: anorexia, nausea, vomiting, constipation, abdominal pain, peptic ulcer, pancreatitis.
• Neuropsychiatric: tiredness, depression, confusion, drowsiness, coma.
• Bone (hyperparathyroidism): bone pain, osteoporosis, subperiosteal erosions of the phalanges and, only in advanced disease, brown tumours and bone cysts (osteitis fibrosa cystica).
• Cardiovascular: hypertension, short QT interval, arrhythmias.
• Eye: band keratopathy (corneal calcification) in long-standing cases.

Investigations

• Repeat corrected calcium, phosphate, PTH (intact molecule), renal function, alkaline phosphatase.
• 24-hour urinary calcium (or calcium : creatinine clearance ratio) when a younger person has a mild rise in both calcium and PTH, to rule out familial hypocalciuric hypercalcaemia.
• If PTH is suppressed: serum and urine protein electrophoresis (myeloma), chest X-ray and CT (cancer, sarcoidosis), serum ACE, TSH, 09:00 cortisol.
• Localising a parathyroid adenoma before surgery: 99mTc-sestamibi scan (detects most adenomas), neck ultrasound, CT or MRI.
• DXA (bone density) and imaging for renal stones in hyperparathyroidism.

Management of severe or symptomatic hypercalcaemia

Treat urgently if the calcium is above about 3.5 mmol/L or the patient is unwell.

1. Rehydrate with IV 0.9% saline: several litres on the first day (Kumar suggests 4–6 L), with careful fluid balance; this alone lowers calcium and restores urine flow.
2. IV bisphosphonate: pamidronate (60–90 mg infusion) or zoledronic acid. Effect starts after 1–3 days and lasts about 2 weeks. Drug of choice in malignancy or unknown cause.
3. Glucocorticoids (prednisolone) if the cause is myeloma, sarcoidosis, lymphoma or vitamin D excess.
4. Calcitonin: works within hours but the effect wears off quickly; little used.
5. Denosumab for resistant cases; dialysis in renal failure.
6. Treat the cause; stop thiazides, lithium, calcium and vitamin D.

Management of primary hyperparathyroidism

Parathyroidectomy (by an experienced surgeon; success over 90%) is indicated for:

• symptoms of hypercalcaemia;
• end-organ damage: renal stones, osteoporosis or fragility fracture, reduced kidney function;
• an albumin-adjusted calcium of 2.85 mmol/L or higher;
• younger patients and those with marked hypercalciuria.

Single adenoma → remove it (minimally invasive surgery); four-gland hyperplasia → remove all hyperplastic glands. Cinacalcet (calcimimetic acting on the calcium-sensing receptor) is used when surgery is not possible, in parathyroid carcinoma and in dialysis patients. Older patients with mild, symptomless disease may be watched with calcium, renal function and bone density, and advised to drink plenty.

After surgery: watch for hypocalcaemia, especially "hungry bone syndrome" in those with severe bone disease or vitamin D deficiency. Other risks: bleeding and recurrent laryngeal nerve injury.

Familial hypocalciuric hypercalcaemia (FHH)

Autosomal dominant; the calcium-sensing receptor is inactivated by mutation. Mild lifelong hypercalcaemia, normal or slightly raised PTH, low urinary calcium, family members affected. It is benign and surgery is not indicated.

Hypocalcaemia

Causes

• Chronic kidney disease (commonest): phosphate retention and reduced 1α-hydroxylation of vitamin D.
• Hypoparathyroidism: after thyroid or parathyroid surgery (common, usually transient); autoimmune (with candidiasis and vitiligo); DiGeorge syndrome (22q11 deletion: thymic aplasia, cardiac outflow defects, low calcium); infiltration.
• Severe hypomagnesaemia: magnesium is needed to secrete PTH and for PTH to act.
• Vitamin D deficiency: osteomalacia and rickets; malabsorption; lack of sunlight.
• Pseudohypoparathyroidism: end-organ resistance to PTH (GNAS mutation); short stature, round face, short fourth and fifth metacarpals, subcutaneous calcification, learning difficulty. Pseudo-pseudohypoparathyroidism has the same body features with normal calcium.
• Others: acute pancreatitis, massive transfusion of citrated blood, tumour lysis syndrome and rhabdomyolysis (phosphate release), drugs (bisphosphonates, calcitonin, denosumab), low albumin (spurious).

Clinical features

• Neuromuscular irritability: perioral and finger paraesthesia, cramps, carpopedal spasm (tetany), laryngospasm (stridor), seizures.
• Chvostek's sign: tapping over the facial nerve in front of the ear makes the facial muscles twitch.
• Trousseau's sign: inflating a BP cuff above systolic pressure for 3 minutes produces spasm of the hand and wrist.
• Anxiety, depression, psychosis; papilloedema in severe cases.
• Long QT interval, arrhythmias.
• Chronic: cataracts, basal ganglia calcification, dry skin.

Investigations

• Corrected calcium, phosphate, PTH, magnesium, creatinine, 25-hydroxyvitamin D, alkaline phosphatase.
• ECG for QT prolongation.
• Hand X-ray for short metacarpals if pseudohypoparathyroidism is suspected.

Management

• Severe or symptomatic (tetany, seizures, stridor, long QT): IV calcium gluconate 10%, 10 mL given slowly (with ECG monitoring), followed by an infusion if needed. Do not mix with bicarbonate.
• Replace magnesium if low; otherwise calcium will not stay up.
• Vitamin D deficiency: colecalciferol with calcium.
• Hypoparathyroidism and CKD: alfacalcidol (1α-hydroxycholecalciferol) or calcitriol, because the kidney cannot hydroxylate vitamin D adequately; usual maintenance 0.25–2 μg a day of alfacalcidol, with frequent calcium checks to avoid overshoot.
• CKD: also control phosphate (diet, binders).

Renal stones: endocrine and metabolic causes

Background

About two-thirds of stones are calcium oxalate (often mixed with phosphate); others are calcium phosphate, struvite (infection with urea-splitting organisms such as Proteus), uric acid (radiolucent on plain film) and cystine. Men are affected about twice as often as women. Recurrence is common.

Causes to look for

Work-up of a stone former

• All: urinalysis and culture, serum calcium, urate, urea and electrolytes, bicarbonate; analyse any passed stone.
• Imaging: non-contrast CT-KUB is the best test; ultrasound is used first in the young and in pregnancy.
• Young or recurrent stone formers: two 24-hour urine collections for calcium, oxalate, urate, citrate and volume; PTH if calcium is high or high-normal; cystine screen; urine pH.

Prevention

• Drink enough to pass 2–2.5 L of urine a day.
• Do not restrict dietary calcium in idiopathic hypercalciuria (low calcium intake increases oxalate absorption); cut salt and excess animal protein; avoid oxalate-rich foods.
• Thiazide diuretic to reduce urinary calcium if hypercalciuric stones keep forming.
• Allopurinol (or febuxostat) and urine alkalinisation for uric acid stones; potassium citrate for low urinary citrate and RTA.
• Treat the cause: parathyroidectomy for hyperparathyroidism.

Quick revision

• Corrected Ca = measured Ca + 0.02 × (40 − albumin).
• High Ca + high or normal PTH = primary hyperparathyroidism; high Ca + low PTH = malignancy, sarcoid, vitamin D, myeloma.
• Severe hypercalcaemia: saline first, then IV pamidronate or zoledronic acid; steroids in myeloma, sarcoid, vitamin D excess.
• Parathyroidectomy: symptoms, stones, osteoporosis, calcium 2.85 or more, young patients.
• FHH: low urinary calcium; leave alone.
• Hypocalcaemia: CKD commonest; post-thyroidectomy; low magnesium; tetany, Chvostek, Trousseau, long QT.
• Emergency: 10 mL 10% calcium gluconate IV slowly; then oral calcium and alfacalcidol or colecalciferol.
• Stones: hyperparathyroidism, idiopathic hypercalciuria, RTA type 1, Cushing, gout; fluids, normal calcium diet, thiazide.

Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).

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