Case 17.6 – Disorders of Calcium Metabolism

Symptoms and signs of hypercalcaemia include:

• Polyuria and polydipsia
• Renal colic
• Lethargy
• Anorexia
• Nausea
• Dyspepsia and peptic ulceration
• Constipation
• Depression
• Drowsiness and impaired cognition

Malignant hypercalcaemia:

• Patients can have a rapid onset of symptoms
• May have clinical features that help to localise the tumour

Primary hyperparathyroidism:

• Patients may have a chronic, non-specific history
• Symptoms described by the adage 'bones, stones and abdominal groans'
• About 50% of patients with primary hyperparathyroidism are asymptomatic
• In others, symptoms may go unrecognised until patients present with renal calculi:
  • 5% of first stone formers have primary hyperparathyroidism
  • 15% of recurrent stone formers have primary hyperparathyroidism
• Hypertension is common in hyperparathyroidism
• Parathyroid tumours are almost never palpable
• A family history of hypercalcaemia raises the possibility of FHH (familial hypocalciuric hypercalcaemia) or MEN (multiple endocrine neoplasia)

Normal calcium metabolism:

• Oral intake: Calcium from diet
• Vitamin D: Obtained from sunlight on skin and diet
• Liver: Vitamin D 25-hydroxylase converts vitamin D to 25(OH) vitamin D (inactive)
• Kidney: Vitamin D 1α-hydroxylase converts 25(OH) vitamin D to 1,25(OH)₂ vitamin D (active)
• Active vitamin D actions:
  • Increases calcium absorption from gut
  • Increases calcium reabsorption from bone
  • Increases serum calcium
• Parathyroid glands: Have calcium-sensing receptors
  • When serum calcium is low, PTH secretion increases
  • When serum calcium is high, PTH secretion decreases (negative feedback)
• PTH actions:
  • Stimulates bone resorption (releases calcium from bone)
  • Increases renal calcium reabsorption
  • Increases renal phosphate excretion
  • Stimulates 1α-hydroxylase in kidney (increases active vitamin D)

In hyperparathyroidism (explaining Austin's results):

• Elevated serum calcium (3.20 mmol/l): Due to excess PTH causing:
  • Increased bone resorption
  • Increased renal calcium reabsorption
  • Increased gut calcium absorption (via increased vitamin D activation)
• Low serum phosphate (0.65 mmol/L): Due to PTH increasing renal phosphate excretion
  • This is a key diagnostic feature - the PTH is causing phosphate wasting in the kidneys
• Recurrent renal calculi: Due to:
  • High serum calcium → hypercalciuria
  • Calcium precipitates in urine forming stones

CAUSES OF HYPERCALCAEMIA:

With normal or elevated (i.e. inappropriate) PTH levels:

• Primary or tertiary hyperparathyroidism
• Lithium-induced hyperparathyroidism
• Familial hypocalciuric hypercalcaemia

With low (i.e. suppressed) PTH levels:

• Malignancy (e.g. lung, breast, renal, ovarian, colonic and thyroid carcinoma, lymphoma, multiple myeloma)
• Elevated 1,25(OH)₂ vitamin D (e.g. vitamin D intoxication, sarcoidosis, HIV)
• Thyrotoxicosis
• Paget's disease with immobilisation
• Milk-alkali syndrome
• Thiazide diuretics
• Glucocorticoid deficiency

INVESTIGATIONS:

Initial biochemistry:

• Low plasma phosphate and elevated alkaline phosphatase support a diagnosis of primary hyperparathyroidism or malignancy
• High plasma phosphate and alkaline phosphatase accompanied by renal impairment suggest tertiary hyperparathyroidism
• Hypercalcaemia may cause nephrocalcinosis and renal tubular impairment resulting in hyperuricaemia and hyperchloraemia

Most discriminant investigation:

• Measurement of PTH using a specific immunoradiometric assay:
  • If PTH is normal or elevated and urinary calcium is elevated → hyperparathyroidism confirmed
  • Low urine calcium excretion indicates likely FHH (can be confirmed by screening family members for hypercalcaemia or genetic analysis of calcium-sensing receptor)
  • If PTH is low and no other cause is apparent → malignancy with or without bony metastases is likely
• PTH-related peptide (often responsible for hypercalcaemia associated with malignancy) is not detected by modern PTH assays, but can be measured by a specific assay (though not usually necessary)

Screen for malignancy if PTH is low:

• Chest X-ray
• Isotope bone scan
• Myeloma screen
• Serum angiotensin-converting enzyme (elevated in sarcoidosis)
• Further imaging as appropriate

Investigation pathway for hypercalcaemia:

Step 1: Measure PTH

If PTH is normal or elevated (inappropriate for high calcium):

• Measure urinary calcium excretion:
  • High urine calcium → Primary hyperparathyroidism
    • Low plasma phosphate
    • Elevated alkaline phosphatase
    • May have renal stones
    • May have bone changes
  • Low urine calcium → Familial hypocalciuric hypercalcaemia (FHH)
    • Screen family members
    • Genetic testing of calcium-sensing receptor
• If renal impairment present with high phosphate → Consider tertiary hyperparathyroidism

If PTH is low (suppressed):

• Screen for malignancy:
  • Chest X-ray
  • Bone scan
  • Myeloma screen (serum/urine electrophoresis)
  • PTH-related peptide if indicated
• Check for other causes:
  • Vitamin D levels (intoxication, sarcoidosis)
  • Thyroid function (thyrotoxicosis)
  • Drug history (thiazides, vitamin D supplements)
  • ACE level (sarcoidosis)

Type	Serum calcium	PTH	Details
Primary	Raised	Not suppressed (inappropriately normal or elevated)	Single adenoma (90%) Multiple adenomas (4%) Nodular hyperplasia (5%) Carcinoma (1%)
Secondary	Low	Raised	Chronic renal failure Malabsorption Osteomalacia and rickets Low calcium → PTH glands increase activity
Tertiary	Raised	Not suppressed (inappropriately normal or elevated)	Progression from 2° hyperparathyroidism PTH glands increased activity → became autonomous Even when underlying cause treated, PTH glands continue over-secreting

TREATMENT OF SEVERE HYPERCALCAEMIA:

1. Rehydration with normal saline

• To replace as much as a 4-6 l deficit
• May need monitoring with central venous pressure in old age or renal impairment

2. Bisphosphonates (e.g. disodium pamidronate 90 mg i.v. over 4 hours)

• Inhibit osteoclast activity → osteoblast activity → take calcium from blood & deposit into bone
• Causes a fall in calcium which is maximal at 2-3 days and lasts a few weeks
• Unless the cause is removed, follow up with an oral bisphosphonate

3. Additional rapid therapy may be required in very ill patients:

• Forced diuresis with saline and furosemide
• Glucocorticoids, e.g. prednisolone 40 mg daily
• Calcitonin (inhibits osteoclast activity - take calcium from blood & deposit into bone)
• Haemodialysis

4. Treat the cause

Management of Primary Hyperparathyroidism:

• Hypercalcaemia in patients with primary hyperparathyroidism responds less well to glucocorticoids and bisphosphonates than in those with malignancy
• Urgent neck surgery is occasionally required, but strenuous attempts should be made to replace fluid deficits and lower the serum calcium concentration before administering an anaesthetic

Long-term management of Primary Hyperparathyroidism:

• Currently, the only long-term therapy is surgery, with excision of a solitary parathyroid adenoma or debulking of hyperplastic glands
• Surgery is indicated for:
  • Young patients (\<50 years)
  • Those with clear-cut symptoms
  • Documented complications: peptic ulceration, renal stones, renal impairment or osteopenia
• Patients with vague symptoms or asymptomatic:
  • Can be reviewed every 6-12 months
  • Assessment of symptoms, renal function, serum calcium and bone mineral density
  • Should be encouraged to maintain a high oral fluid intake to avoid renal stones