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Hypocalcaemia and hypoparathyroidism

PATHOPHYSIOLOGY

Hypocalcaemia may be due to deficiencies of calcium homeostatic mechanisms, secondary to high phosphate levels or other causes of hypocalcaemia. Hypoparathyroidism is uncommon.

Paget's disease

Paget’s disease

CAUSES

1 Renal failure is the commonest cause of hypocalcaemia.
2 Immediately following thyroidectomy and parathyroidectomy, hypocalcaemia is usually transient.
3 Idiopathic hypoparathyroidism is one of the rarer autoimmune disorders. Vitiligo, cutaneous moniliasis and other autoimmune diseases are often seen.
4 The DiGeorge syndrome is a familial condition and associated with intellectual impairment, cataracts, calcified basal ganglia and occasionally with organ-specific autoimmune disease.
S Pseudohypoparathyroidism is a syndrome of endorgan resistance to PTH. It is associated with short stature, short metacarpals and intellectual impairment.

Pseudopseudohypoparathyroidism describes the phenotypic defects without the calcium abnormalities.

Causes of hypocalcaemia.

Causes of hypocalcaemia.

CLINICAL FEATURES

The symptoms are those of neuromuscular irritability and neuropsychiatric manifestations. Paraesthesiae, circumoral numbness, cramps, anxiety and tetany are followed by convulsions, laryngeal stridor, dystonia and psychosis. Two important signs of hypocalcaemia are Chvostek’s sign-gentle tapping over the facial nerve causes twitching of the facial muscles-and Trousseau’s sign, where inflation of the sphygmomanometer cuff above diastolic blood pressure for 3 min induces tetanic spasm of the fingers and wrist. Severe hypocalcaemia may cause papilloedema and a prolonged Q-T interval on the ECG.

INVESTIGATION

The clinical picture is usually diagnostic and is confirmed by a low serum calcium. Additional tests include:

• Serum urea and creatinine
• High phosphate levels
• Absent or low PTH levels
• Parathyroid antibodies (not widely available)
• Vitamin D metabolite levels
• X-rays of metacarpals showing short fourth metacarpals, which occur in pseudo hypoparathyroidism

TREATMENT

Urgency of treatment depends upon severity of symptoms and degree of hypocalcaemia. If severe, e.g. tetany, intravenous calcium (10 ml initially, then 10-40 ml of 10% calcium gluconate in I litre of 150 mmol litre ” saline over 4-8 hours) is given. Oral calcium supplements (2- 10 g daily, 40-200 mmol Ca2+) are rarely sufficient alone. l o-Hydroxylated derivatives of vitamin D are preferred for their shorter half-life. Usual daily maintenance doses are I J-Lgfor la(OH)D3 (alfacalcidol) and 1,25(OH)2D3 (calcitriol) and 0.25 mg of dihydrotachysterol. During treatment, plasma calcium must be monitored frequently to prevent hypercalcaemia.

Hyperparathyroidism and hypercalcaemia

Hypercalcaemia is much commoner than hypocalcaemia and is frequently detected incidentally with multichannel chemical analysers, Mild, asymptomatic hypercalcaemia occurs in about 1 in 1000 of the population, especially elderly females, and is usually due to primary hyperparathyroidism. True hypercalcaemia should always be confirmed on a carefully collected specimen.

PATHOPHYSIOLOGY AND CAUSES

Major causes of hypercalcaemia are listed; primary hyperparathyroidism and malignant disease are the commonest.
Hyperparathyroidism may be primary, secondary or tertiary.
PRIMARY HYPERPARATHYROIDISM is caused by single (80%+) or multiple (5%) parathyroid adenomas or by hyperplasia (10%). Parathyroid carcinoma is rare (2%) though usually with severe hypercalcaemia.
SECONDARY HYPERPARATHYROIDISM is physiological compensatory hypertrophy of all four parathyroids due to hypocalcaemia (e.g. in renal failure or vitamin D deficiency). PTH levels are raised, but calcium levels are low or normal; PTH levels fall to normal after correction of the cause of hypocalcaemia.
TERTIARY HYPERPARATHYROIDISM is the development of apparently autonomous parathyroid hyperplasia after long-standing secondary hyperparathyroidism, most often in renal failure. Plasma calcium and PTH are both raised, the latter often grossly so. Parathyroidectomy is necessary at this stage.

Causes of hypercalcaemia.

Causes of hypercalcaemia.

CLINICAL FEATURES

The symptoms and signs of hypercalcaemia are now moreoften mild and general rather than the severe renal and  bone problems seen years ago:

GENERAL-malaise, depression.
RENAL- renal colic from stones, polyuria/nocturia, haematuria and hypertension. The polyuria results from the effect of hypercalcaemia on the renal tubules reducing concentrating ability, a form of nephrogenic diabetes insipidus.
BONEs-bone pain.
ABDOMINAL -abdominal pain, sometimes due to peptic ulceration.
Particular points of note are:
MALIGNANT DISEASE is usually advanced by the time hypercalcaemia occurs as a result of bony metastases. The common primary tumours are bronchus, breast, myeloma, oesophagus, thyroid, prostate, lymphoma and renal cell carcinoma. ‘Ectopic PTH secretion’ is very rare. There is evidence of a PTH-related protein, a 141 amino acid polypeptide, the sequence of which
shows an initial approximate homology with PTH. The biological action appears to lie in the first 34 amino acids. Local bone-resorbing cytokines and prostaglandins may be important locally where there are metastatic skeletal lesions leading to local mobilization of calcium by osteolysis with subsequent hypercalcaemia. They probably rarely cause hypercalcaemia by a generalized ‘hormonal’ action as previously thought. EVERE HYPERCALCAEMIA (>3 mmollitre-1) is usually associated with malignant disease, hyperparathyroidism, renal dialysis or vitamin D therapy.
CORNEAL CALCIFICATION is a marker of long-standing hypercalcaemia.
1:-< PRIMARY HYPERPARATHYROIDISM, only 5-10% have definite bony lesions and 20-40% renal involvement.

INVESTIGATION AND DIFFERENTIAL

DIAGNOSIS

EVERAL FASTING SERUM CALCIUM AND PHOSPHATE SAMPLES should be taken. Hypophosphataemia
is common in primary hyperparathyroidism.
-ERUM PTH LEVELS should be measured. Detectable levels during hypercalcaemia are inappropriate and imply hyperparathyroidism.
ABDOMINAL X-RAYS may show renal calculi or nephrocalcinosis. Renal function must be measured.
HIGH-DEFINITION HAND X-RAYS may show subperiosteal erosions in the middle or terminal phalanges.
HYDROCORTISONE SUPPRESSION TEST is often helpful;
plasma calcium in hyperparathyroidism is resistant to suppression by steroids (10 days of hydrocortisone 40 mg three times daily); this also occurs with some malignancies. In sarcoidosis, vitamin D-mediated hypercalcaemia and some malignancies, suppression to normal or near-normal levels is seen.

PROTEIN ELECTROPHORESIS FOR MYELOMA.
SERUM TSH, T 3 FOR THYROTOXICOSIS.
BIOPSY TO EXCLUDE SARCOIDOSIS.
PLASMA CHLORIDE is elevated and the bicarbonate reduced in primary hyperparathyroidism due to PTH which reduces renal tubular reabsorption of bicarbonate. If primary hyperparathyroidism is confirmed, the following may be helpful in localization, although adenomas are usually small:
ULTRASOUND, though insensitive to small tumours, is simple and safe.
CT SCAN, though very high resolution is needed. MRI may prove more sensitive. RADIOISOTOPE ‘SUBTRACTION’ SCANS: a picture of the parathyroid tissue is derived from the difference in uptake between thallium-201 (taken up by thyroid and parathyroid) and technetium-99m (thyroid only). Reports on its efficacy are conflicting. BARIUM SWALLOW may show indentation of the oesophagus by an adenoma.
VENOUS CATHETERIZATION of parathyroids to measure PTH. This is usually reserved for previous operative failures.

TREATMENT OF PRIMARY

HYPERPARATHYROIDISM

Indications for surgery in hyperparathyroidism remain controversial. All agree that with renal disease or bone involvent surgery is indicated, there being no longterm medical treatment. The situation in which the plasma calcium is mildly raised (2.65-3.0 mmol litre “) is disputed; most physicians feel that probable symptoms of hypercalcaemia, which may be mild and non- specific, should lead to parathyroidectomy. Those who are asymptomatic should receive careful follow-up; development of renal, bone or other symptoms then warrants surgery.

Surgery

Parathyroid surgery should only be performed by experienced surgeons. Ninety per cent of these patients have adenomas rather than hyperplasia, but the minute glands may be very difficult to define. It is also very difficult to distinguish between an adenoma and normal parathyroid. If initial exploration is unsuccessful, venous catheteriz ation for PTH levels may be helpful if CT or MRI is not; a few parathyroids lie in ectopic sites elsewhere in the neck and upper mediastinum.

Treatment of acute hypercalcaemia.

Treatment of acute hypercalcaemia.

Postoperative care

The main danger postoperatively is hypocalcaemia :
CHVOSTEK AND TROUSSEAU SIGNS should be sought regularly.
DAILY PLASMA CALCIUM MEASUREMENTS are needed for 2-5 days.
MILD TRANSIENT HYPOPARATHYROIDISM often occurs for 1-2 weeks, possibly owing to suppression of other parathyroids. Depending on severity, oral or intravenous calcium should be given temporarily.
LONG-STANDING SURGICAL HYPOPARATHYROIDISM develops in a few patients.

TREATMENT OF ACUTE HYPERCALCAEMIA 
TREATMENT OF SECONDARY
HYPERPARATHYROIDISM

Treatment depends upon the primary pathology, although steroids are often useful. Emergency treatment is discussed below.

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