3rd April 2024

Calcium Metabolism

Background 

Highly sensitive calcium-sensing receptors (CaSR) on the parathyroid glands are responsible for detecting any changes in calcium concentration and regulating secretion of PTH. Together with calcitriol (1,25-dihydroxyvitamin D) and fibroblast growth factor 23 (FGF23), PTH regulates calcium and phosphate homeostasis. PTH acts to counter detected hypocalcaemia via three mechanisms:

• Increased bone resorption: targets osteoblasts and osteocytes, particularly in cortical bone, to enhance bone remodelling
• Decreased urinary calcium excretion: PTH increases calcium reabsorption in the distal tubule, as well as inhibiting proximal tubular reabsorption of phosphate
• Increased intestinal calcium and phosphate absorption: mediated by increased activated vitamin D

Vitamin D Metabolism 

In response to reduced extracellular calcium, PTH increases the activity of the renal enzyme responsible for hydroxylation (1-alpha-hydroxylase) and, thus, activation of calcidiol to calcitriol. Activated vitamin D (1,25-dihydroxyvitamin D) increases intestinal calcium absorption and osteoclastic bone resorption. Under normal physiological conditions, calcitriol acts via a negative feedback loop to decrease PTH production.

Vitamin D deficiency

This is the most common nutritional deficiency worldwide. Vitamin D may be ingested from certain plant products (as ergocalciferol), with subsequent hepatic and renal hydroxylation, or as cholecalciferol from animal products such as fish and eggs or by endogenous synthesis in the skin when exposed to sunlight. Therefore, deficiency may arise due to reduced intake or intestinal absorption, reduced sun exposure, or decreased endogenous synthesis. 

Persistent vitamin D deficiency may result in osteomalacia, with patients commonly presenting with percussion tenderness, bony pain and proximal muscle weakness, which may combine to cause a waddling gait. Such individuals are at an increased risk of fragility fractures. Resultant hypocalcaemia leads to a compensatory rise in PTH.

Management 

Regular vitamin D supplementation of 600-800 IU per day is recommended to prevent deficiency in at-risk patients. National consensus guidelines recommend 50,000 IU vitamin D2 or vitamin D3 once weekly for 7 weeks, with those with malabsorption syndromes or other comorbidities utilising a higher dose regimen.

Hypocalcaemia

This is defined as calcium levels <2.20mmol/mol in the presence of normal serum plasma protein concentrations. It is crucial to check serum albumin levels and adjust accordingly, as over 40% of circulating calcium is bound to albumin. 

Both the absolute level and rate of the fall in adjusted serum calcium levels are important, with symptoms typically developing if AdjCa ≤1.9mmol/L or if there is a rapid decrease. 

Measuring PTH level is crucial to identifying the cause of hypocalcaemia. Causes of hypocalcaemia with a low PTH have been previously described in the hypoparathyroidism section.  Causes of hypocalcaemia with high PTH include:

• Vitamin D deficiency/chronic kidney disease: resulting in secondary hyperparathyroidism
• Pseudohypoparathyroidism, where impaired PTH response results in renal calcium excretion  
• Acute pancreatitis: hypocalcaemia due to calcium saponification 
• Sepsis and severe burns: multifactorial causes of hypocalcaemia

Complications

Severe or symptomatic hypocalcaemia may result in life-threatening complications. It characteristically causes prolonged QT interval, which can lead to life-threatening dysrhythmias such as torsades de pointes and ventricular fibrillation. 

Management 

Treatment of severe or symptomatic hypocalcaemia is a medical emergency, managed with 10% calcium gluconate, with repeated doses given until a patient is asymptomatic, or calcium level has normalised. Chronic, or mild/asymptomatic hypocalcaemia can be managed with oral calcium and vitamin D supplements.

Care must be exercised as overzealous calcium replacement, particularly when given via the intravenous route, can also lead to serious arrhythmias.

Hypercalcaemia

Severe hypercalcaemia is defined as >3.5mmol/L. Patients may tolerate high calcium levels if there has been a slow increase, however more rapid rises, despite the overall level, often result in a patient being symptomatic. Malignancy-related hypercalcaemia often rises more rapidly, resulting in patients becoming highly symptomatic.

Rarely, patients with ESRF who develop hypercalcaemia, hyperphosphatemia or hyperparathyroidism may present with skin ischaemia and necrosis. This complication, known as calciphylaxis, is due to arteriolar calcification, resulting in microvascular occlusion.

Acute hypercalcaemia also directly shortens the QT interval. 

Causes

Hypercalcaemia is caused by either primary hyperparathyroidism or cancer in over 90% of cases. Malignancy-related hypercalcaemia occurs more commonly in patients with multiple myeloma, leukaemia, lung or breast cancers and may be due to PTHrP secretion or bony metastases. Other causes include:

• Excessive vitamin D or calcium supplementation 
• Thyrotoxicosis : due to rapid bone turnover
• Sarcoidosis: increased vitamin D activation by macrophages
• Hypercalcaemia of immobility: commonly in young patients who develop massive bone demineralisation following prolonged immobility 
• Familial hypocalciuric hypercalcaemia: autosomal dominant cause of mild hypercalcaemia and hypocalciuria

Management 

Emergency treatment is discussed above (see The Parathyroid Gland: Hyperparathyroidism).

If there is poor response to initial rehydration, intravenous bisphosphonates may be used, which inhibit osteoclastic bone resorption, but have a more delayed onset of action.

Glucocorticoids may be beneficial in the management of calcitriol-induced hypercalcaemia secondary to sarcoidosis, tuberculosis, and lymphomas. Cinacalcet increases the sensitivity of CaSRs on the parathyroid gland to calcium, thus are useful in patients with secondary hyperparathyroidism.

References

• UpToDate. Parathyroid hormone secretion and action. https://www.uptodate.com/contents/parathyroid-hormone-secretion-and-action
• BMJ Best Practice. (2021) Assessment of hypocalcaemia. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/160/urgent-considerations
• Goltzman, D. (2021). Treatment of hypocalcaemia. UpToDate. https://www.uptodate.com/contents/treatment-of-hypocalcemia#H596754