disorders of. calcium homeostasis

• Clinical manifestations of hypercalcaemia can be summarised by stones, bones, abdominal moans and psychic groans
• Clinical manifestations of hypercalcaemia

  • muscle weakness (striated and smooth)
  • central effects (anorexia, nausea, mood changes, depression)
  • renal effects (impaired water concentration; renal stone formation)
  • bone involvement
  • abdominal pain
  • ECG changes (shortened QT interval)
• factitious hypercalcaemia is non-pathological can can occur due to venous stasis, dehydration and IV albumin
• factitious hypercalcaemia results in raised Ca due to high plasma albumin as it can bind to Ca and give an high total Ca level
• primary hyperparathyroidism is an autonomous and inappropriate over production of PTH that commonly affects people over 50
• Primary hyperparathyroidism affects 1 in 500 to 1 in 1000, affecting more women than men in a 3:2 ratio
• Primary hyperparathyroidism is normally found many patients found on routine screening with minimal symptoms
• 90% of primary hyperparathyroidism is due to solitary adenoma in parathyroid gland, parathyroid gland hyperplasia is less common, and carcinoma is rare
• secondary hyperparathyroidism an appropriate increase in PTH in response to hypocalcaemia
• tertiary hyperparathyroidism is rare but refers to the situation where a secondary overactive gland becomes autonomous and overactive (produces PTH in the absence of hypocalcaemia)
• Radiology of hyperparathyroidism presents as loss of normal bone structure (especially cortical bone) as it becomes very resorbed and weak (osteopenia)
• Osteoclast activity increases in hyperparathyroidism, leading to increased bone resorption
• hyperparathyroidism leads to increased formation of renal calcium stone, due to the increased secretion of PTH and subsequent increase in calcium levels
• Diagnosis of primary hyperparathyroidism:

  • raised Ca with inappropriately increased PTH
  • phosphate and bicarbonate tend to be low in serum (increased renal excretion)
  • alkaline phosphatase normal or moderately increased in more severe disease
  • further investigations: parathyroid imaging scan (Sestamibi, 99mTc-MIBI)
• treatment of primary hyperparathyroidism:

  • acutely, high ionised calcium through rehydration and hypercalcaemia drugs
  • definitive treatment is removal of parathyroid adenoma (surgery)
• mild cases of hypercalcaemia may be managed by repeated follow-up of serum Ca/PTH
• if surgery for hypercalcaemia is difficult drugs to lower Ca levels can be given
• available hypercalcaemia drugs

  • bisphosphonates ( inhibit osteoclast action and bone resorption); after rehydration this is key drug for longer-term control
  • furosemide (inhibits distal Ca resorption; requires care and patient must be hydrated first)
  • calcitonin (inhibits osteoclast action); tolerance may develop but useful for immediate, short-term management
  • glucocorticoids (inhibit vitamin D conversion to calcitriol; can prolong calcitonin action)
• newer hypercalcaemia drug:

  • calcimimetic drug which bind to Ca sensor and inhibit PTH release, restricted use (e.g., parathyroid carcinomas)
• malignant disease is the commonest cause of hypercalcaemia in hospital patients
• up to 20-30% cancer patients may develop hypercalcaemia during course of illness
• two broad reasons for malignant disease leading to hypercalcaemia:

  • endocrine factors secreted by malignant cells acting on bone
  • metastatic tumour deposits in bone locally stimulating resorption via osteoclast activation
• lung, breast and haematological tumours are more associated with hypercalcaemia
• endocrine factors in malignant hypercalcaemia:

  • solid tumours may secrete PTH-related peptide (or PTHrP) (e.g., breast; squamous tumours of lung, head and neck)
  • PTHrP shows structural homology to PTH and shares similar actions but is distinct (PTH itself is suppressed)
  • where PTHrP is the cause this is known as humoral hypercalcaemia of malignancy
  • some tumours (especially, Hodgkin’s lymphoma) possess 1-OHase activity and synthesise calcitriol
• malignant hypercalcaemia associated with bony metastases:

  • approx, 2-% cases malignant hypercalcaemia
  • most commonly associated with breast and lung cancers, multiple myeloma
  • secretion of osteoclast activating cytokines or other factors into the bone micro-environment is key element
  • metastatic breast tumour may locally produce PTHrP
  • myeloma cells produce cytokines and activate osteoclasts (RANKL, IL-3, IL-6)
• hypercalcaemia of malignancy in multiple myeloma:

  • excess production plasma cells, which produce a single clone of antibody or immunoglobulin, called a monoclonal protein. they also produce cytokines
  • poor mortality rates, and diagnosed through analysing a bone marrow biopsy
• diagnosis of malignancy can be done by observing raised Ca with suppressed PTH where phosphate tends to be higher, alkaline phosphatase may be high (liver or bone metastases), and often clear from previous history of malignant disease
• treatment of malignant hypercalcaemia includes:

  • rehydrate the patient
  • if required, use drugs which lower Ca in the blood (as mentioned above)
  • treat underlying malignancy (surgery, chemotherapy)
• causes of hypercalcaemia other than malignancy:

  • granulomatous disease
  • exogenous vitamin d excess
  • familial hypocalciuric hypercalcaemia (FHH)
  • drugs (e.g., lithium, thiazide diuretics)
  • some endocrine disease(thyrotoxicosis, Addison’s disease)
  • immobilisation
• sarcoidosis is a granulomatous disease, which usually affects lungs (90%) and skin (10%), it causes increased Ca with no PTH due to hydroxylation of Vitamin D in granulomas
• familial hypocalciuric hypercalcaemia (FHH) is a rare genetic condition, which causes insensitivity of Ca sensor on parathyroid glands leading to suppression of PTH
• familial hypocalciuric hypercalcaemia (FHH) causes:

  • altered ‘set-point’ for PTH/Ca interaction
  • high normal or slightly raised PTH levels
  • mild increase in plasma ionised calcium
  • low urine Ca excretion (relative to plasma Ca)
• clinical manifestation of hypocalcaemia include:

  • predominantly due to an increase in neuromuscular excitability (increased inward Na movement)
  • Chvostek’s sigh
  • Trousseau’s sign
  • neuromuscular issues
  • mental state changes
  • ECG changes, eye problems
• Chvostek’s sign is twitching (tetany)/ contraction of the muscles of the eyes, mouth or nose by tapping along the facial nerve
• Trousseau’s sign is tested by brachial artery occlusion by a blood pressure cuff, and in hypocalcaemia patient muscles contract (flexion of wrist and fingers)
• neuromuscular signs of hypercalcaemia include

  • numbness and paraesthesiae (tingling) in finger tips, toes, around mouth
  • anxiety and fatigue
  • muscle cramps, carop-pedal spasm, bronchial or laryngeal spasm
  • seizures
• mental state changes in hypercalcaemia include:

  • personality change
  • mental confusion, psychoneurosis
  • impaired intellectual ability
• factitious hypocalcaemia is a consequence of low plasma albumin, which causes:

  • acute phase responce (low albumin)
  • malnutrition or malabsorption (protein deficiency in diet)
  • liver disease (reduced liver synthesis albumin)
  • nephrotic syndrome (albumin lost in urine)
• deficiency of vitamin D amount or action can be caused by:

  • lack of sunlight
  • inadequate dietary source
  • malabsorption
  • chronic renal disease (relatively common)
  • chronic liver disease (rare)
  • defective 1-OHase (very rare)
  • defective 1,25-D3 receptor (very rare)
• risk factors where supplementation may be required include:

  • those confined indoors (e.g., elderly)
  • dark skinned individuals at high latitudes
  • lack of sunlight exposure through dress, high factor sunscreen