DISORDERS OF CALCIUM METABOLISM - Clinical features, Investigations

The concentration of calcium in the serum is regulated by the action of parathyroid hormone (PTH) and vitamin D on the kidneys, bones and gastro-intestinal tract. PTH increases serum calcium concentration by stimulation of calcium reabsorption and activation of vitamin D in the kidney, and increasing calcium release from bone. The most active form of vitamin D (1,25-dihydroxyvitamin D) increases intestinal calcium absorption. Total plasma calcium is normally 2.2-2.6 mmol/L. Usually only 40% of total plasma calcium is ionized and physiologically relevant; the remainder is bound to albumin and thus unavailable to the tissues. Routine analytical methods measure total plasma calcium and this must be corrected for the serum albumin concentration: add or subtract 0.02 mmol/L for every 1 g/L by which the simultaneous albumin lies below or above 40 g/L. For critical measurements, samples should be taken in the fasting state without the use of an occluding cuff, which may increase the local plasma protein concentration.

Hypercalcaemia

Mild asymptomatic hypercalcaemia occurs in about 1 in 1000 of the popula-tion, especially elderly women, and is usually the result of primary hyperparathyroidism.

Aetiology

Primary hyperparathyroidism and malignancy account for >90% of cases (Table 14.14). Tumour-related hypercalcaemia is caused by the secretion of a peptide with PTH-like activity, or by direct invasion of bone and production of local factors that mobilize calcium. Ectopic PTH secretion by tumours is

Table 14.14 Causes of hypercalcaemia
Excess PTH
Primary hyperparathyroidism (commonest cause)
Tertiary hyperparathyroidism
Ectopic PTH (very rare)
Malignant disease
Multiple myeloma
Secondary deposits in bone
Production of osteoclastic factors by tumours
PTH-related protein secretion
Excess action of vitamin D
Self-administered vitamin D
Granulomatous disease, e.g. sarcoidosis, TB
Lymphoma
Other endocrine disease (mild hypercalcaemia only)
Thyrotoxicosis
Addison’s disease
Drugs
Thiazides – reduced renal tubular excretion of Ca2+
Vitamin D analogues
Lithium – increased PTH secretion
Vitamin A
Miscellaneous
Long-term immobility
Familial hypocalciuric hypercalcaemia (rare)

very rare. Severe hypercalcaemia (>3.5 mmol/L) is usually caused by malignancy.

Hyperparathyroidism may be primary, secondary or tertiary.

Primary hyperparathyroidism affects about 0.1% of the population and is usually caused by a single parathyroid gland adenoma, occasionally hyper-plasia, and rarely carcinoma. It may be associated with a hereditary syn-drome e.g. MEN (p. 658).

Secondary hyperparathyroidism is physiological compensatory hyper-trophy of all the glands in response to prolonged hypocalcaemia (e.g. in chronic kidney disease or vitamin D deficiency). Calcium is low or low-normal.

Tertiary hyperparathyroidism is the development of apparently autono-mous parathyroid hyperplasia after longstanding secondary hyperpara-thyroidism, most often in renal disease. Plasma calcium and PTH are both raised. Treatment is parathyroidectomy.

Clinical features

Mild hypercalcaemia (corrected serum calcium <3 mmol/L) is often asymp-tomatic and discovered on biochemical screening. More severe hypercal-caemia produces symptoms of general malaise and depression, bone pain, abdominal pain, nausea and constipation. Calcium deposition in the renal tubules causes polyuria and nocturia. Renal calculi and chronic kidney disease may develop. With very high levels (>3.8 mmol/L) there is dehydra-tion, confusion, clouding of consciousness and a risk of cardiac arrest. Hypercalcaemia is rarely the presenting feature of malignancy which is usually clinically apparent when the hypercalcaemia is first noted. Thus, hypercalcaemia in an otherwise well outpatient is most likely to be due to primary hyperparathyroidism.

Investigations

■ Several fasting serum calcium and phosphate samples are performed to confirm mild hypercalcaemia. The serum phosphate is low in primary hyperparathyroidism and some cases of malignancy. It is normal or high in other causes of hypercalcaemia.

■ Serum PTH. Normal or elevated levels during hypercalcaemia are inappropriate and imply hyperparathyroidism. When this combination is present in an asymptomatic patient then further investigation is usually unnecessary.

■ 24-hour urinary calcium is measured in young patients and those with a family history of hypercalcaemia to exclude familial hypocalciuric hyper-calcaemia in which PTH levels are also raised. Urinary calcium excretion is markedly low but normal or raised in primary hyperparathyroidism.

■ A low concentration of PTH excludes primary hyperparathyroidism and other causes need to be investigated. The following tests may help in the diagnosis:

■ Protein electrophoresis for myeloma

■ TSH to exclude hyperthyroidism

■ Tetracosactide test to exclude Addison's disease

■ Hydrocortisone suppression test: hydrocortisone 40 mg orally three times daily for 10 days leads to suppression of plasma calcium in sarcoidosis, vitamin D-mediated hypercalcaemia and some malignancies.

Management

This involves lowering of the calcium levels to near normal and treatment of the underlying cause. Severe hypercalcaemia (>3.5 mmol/L) is a medical emergency which must be treated aggressively whatever the underlying cause (Emergency Box 14.3).

Emergency Box 14.3

Management of acute severe hypercalcaemia
• Rehydrate with intravenous fluid (0.9% saline)
4–6 L of intravenous saline over 24 h, then
3–4 L for several days thereafter
Amount and rate depend on clinical assessment and measurement of serum urea and electrolytes
• Bisphosphonate – only after rehydration, usually a minimum of 2 L
Pamidronate disodium 60–90 mg as an intravenous infusion in 0.5 L
0.9% saline over 2–8 h
• Measure
Serum urea and electrolytes at least daily
Measure serum calcium at least 48 h after initiation of treatment, normalization may take 3–5 days, mean duration of action 28 days
• Prednisolone (30–60 mg daily)
May be useful in some cases (myeloma, sarcoidosis and vitamin D excess) but in most cases ineffective
• Prevent recurrence
Treat underlying cause if possible
With untreatable malignancy consider maintenance treatment with bisphosphonates

Treat underlying cause if possible

With untreatable malignancy consider maintenance treatment with bisphosphonates

Treatment of primary hyperparathyroidism

The treatment of a symptomatic parathyroid adenoma is surgical removal. Conservative therapy may be indicated in asymptomatic patients older than 50 years with mildly raised serum calcium levels (2.65-3 mmol/L). In those with parathyroid hyperplasia all four glands are removed.

Hypocalcaemia and hypoparathyroidism

Aetiology

Causes of hypocalcaemia are listed in Table 14.15. Chronic kidney disease is the most common cause and results from inadequate production of active vitamin D and renal phosphate retention, leading to microprecipitation of calcium phosphate in the tissues. Mild transient hypocalcaemia often occurs after parathyroidectomy, and a few patients develop longstanding hypoparathyroidism.

Clinical features

Hypocalcaemia causes increased excitability of muscles and nerves. There is numbness around the mouth and in the extremities, followed by cramps,

Table 14.15 Causes of hypocalcaemia
Increased serum phosphate levels
Chronic kidney disease*
Phosphate therapy
Reduced PTH function
Post-thyroidectomy and parathyroidectomy (usually transient)*
Congenital deficiency (DiGeorge syndrome)
Idiopathic hypoparathyroidism (autoimmune)
Severe hypomagnesaemia (inhibits PTH release)
Pseudohypoparathyroidism (end-organ resistance to PTH)
Vitamin D deficiency
Reduced exposure to ultraviolet light
Malabsorption
Antiepileptic drugs (induce enzymes that increase vitamin D metabolism)
Vitamin D resistance (rare)
Drugs
Calcitonin
Bisphosphonates
Miscellaneous
Acute pancreatitis*
Citrated blood in massive transfusion
*Indicates common cause of hypocalcaemia

tetany (carpopedal spasm: opposition of the thumb, extension of the inter-phalangeal and flexion of the metacarpophalangeal joints), convulsions and death if untreated. Chvostek's (tapping over the facial nerve in the region of the parotid gland causes twitching of the ipsilateral facial muscles) and Trousseau's sign (carpopedal spasm induced by inflation of the sphygmoma-nometer cuff to a level above systolic blood pressure) test for neuromuscular excitability. Severe hypocalcaemia may cause papilloedema and a prolonged QT interval on the ECG.

Other causes of tetany are alkalosis, potassium and magnesium deficiency and hyperventilation which decreases ionized fraction of calcium (total plasma calcium is normal) by altering the protein binding of calcium such that the ionized fraction is decreased.

Investigations

The cause of hypocalcaemia is often apparent from the history and physical examination together with measurement of serum creatinine and eGFR (to look for chronic kidney disease) and magnesium. Figure 14.10 shows an algorithm for subsequent investigation.

Fig 14.10 Algorithm for the investigation of hypocalcaemia.

Management

Acute (e.g. with tetany): 10 mL of 10% calcium gluconate (2.25 mmol) diluted in 50-100 mL 5% glucose and administered intravenously over 10 minutes with ECG monitoring. Treatment can be repeated until symptoms have resolved and continued as an infusion over 4 hours.

Persistent hypocalcaemia In vitamin D deficiency, treatment is with either ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) 50 000 IU orally once a week for 8 weeks. This treatment is ineffective in patients with hypoparathyroidism because PTH is needed for conversion to 1,25-dihydroxyvitamin D. Treatment is with alfacalcidol (1 a-hydroxycholecalciferol) 0.25-2 μg daily to maintain serum calcium within the lower part of the normal range. Calcium levels should be checked initially weekly and 3-6 monthly once a stable dose is reached.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology



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