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Anna-MariKoski

Hypocalcaemia, Hypoparathyroidism and Vitamin D Deficiency

Essentials

  • Hypocalcaemia is diagnosed by measuring the concentration of serum ionized calcium or plasma albumin-corrected calcium.
    • Mild pseudohypocalcaemia due to albumin deficiency is often associated with severe illness and malnutrition. When plasma albumin decreases by 10 g/l, plasma calcium decreases by 0.2 mmol/l. This explains the mild, asymptomatic decrease in total plasma calcium associated with these conditions.
    • Plasma albumin-corrected calcium is suitable as an initial test, but if accurate calcium concentration is required for diagnostics or acute situations, serum ionized calcium should be measured.
  • The main regulators of calcium levels are parathyroid hormone (PTH), vitamin D, phosphate and the fibroblast growth factor FGF-23, which regulates phosphate metabolism. Medication can also cause hypocalcaemia.
  • Treatment of acute, severe hypocalcaemia (muscle spasm, laryngeal stridor, seizure, ventricular arrhythmias), requires calcium gluconate infusion.
  • Long-term management of hypoparathyroidism should aim for calcium levels at the lower end of the reference range.

Aetiology of hypocalcaemia

Hypoparathyroidism

Vitamin D deficiency

  • Leads to secondary hyperparathyroidism and osteomalacia. Even mild deficiency (25-OH vitamin D < 50 nmol/l) increases the risk of osteoporosis. Concentrations < 20 nmol/l of 25-OH vitamin D indicate severe deficiency.
  • The target level of 25-OH vitamin D is at least >50 nmol/l, and in patients with osteoporosis 75-120 nmol/l.
  • Causes of vitamin D deficiency
    • Lack of sunlight and unbalanced diet (in institutionalized elderly people)
    • Absorption problems: coeliac disease, undernutrition, and intestinal diseases
    • Abnormal vitamin D synthesis (hepatic disease, renal failure)
    • Vitamin D resistance
    • Phenytoin and carbamazepine used for the treatment of epilepsy may cause or worsen vitamin D deficiency by inducing the excretion of vitamin D. In users of these drugs, determination of 25-OH-D levels or vitamin D supplementation should be considered.
  • Symptoms include bone pain, osteomalacia, muscular weakness, osteoporosis, fractures and deformities.

Renal failure

  • GFR < 30-40 ml/min (GFR calculator Gfr Calculator).
  • In patients with renal failure, vitamin D levels are exceptionally defined by measuring the serum vitamin D-1.25-OH concentration. The production of active vitamin D (1.25-(OH)2-vitamin D, calcitriol) decreases. This results in hypocalcaemia and secondary hyperparathyroidism which is treated with calcium carbonate and alfacalcidol (see Treatment of chronic renal failure)Treatment of Chronic Renal Failure. Hyperphosphataemia is also a part of the complex; it is treated by restricting phosphate intake.
    • Hyperphosphataemia and increased formation of FGF-23 contribute to the development of hyperparathyroidism, in the worst case resulting in renal osteodystrophy.

Other rare causes

  • Recovery phase of a metabolic bone disease (increased need for calcium by the bones after surgery on the parathyroid gland, "hungry bones")
  • Sepsis, shock, pancreatitis and other severe illnesses requiring intensive care
  • Osteosclerotic metastases
  • Bisphosphonates and denosumab (especially if the patient has concurrent vitamin D deficiency), cinacalcet, cytostatic drugs, such as cisplatin, as well as foscarnet.
  • Neonatal hypocalcaemia

Symptoms and signs of acute hypocalcaemia

  • The symptoms of mild hypocalcaemia (serum ionized calcium < 1.05 mmol/l, but ≥ 0.9 mmol/l) include paraesthesias and hyperreflexia: tingling, numbness and muscle spasms around the mouth as well as in the fingers and toes.
  • Severe symptoms normally appear at serum ionized calcium levels of < 0.9 mmol/l (plasma calcium < 1.8 mmol/l).
  • Tetany and laryngospasm are serious, life threatening symptoms of severe hypocalcaemia, as are ventricular arrhythmias caused by prolonged QT interval.
  • Clinical tests
    • The Chvostek sign: a buccal muscle spasm can be elicited by tapping lightly at the zygoma with a reflex hammer.
    • The Trousseau sign: the pressure in a blood pressure cuff is raised slightly above systolic blood pressure. A tetanic spasm can be observed in the hand after 2-3 minutes.
    • The sensitivity of both tests is low.

Differential diagnosis of hypocalcaemia

  • Tests: plasma creatinine (GFRe), fasting plasma PTH, serum 25-OH vitamin D, plasma alkaline phosphatase (ALP), plasma phosphate, plasma magnesium, 24 h urinary calcium, 24 h urinary phosphate
  • A low PTH concentration in a patient with hypocalcaemia is diagnostic for hypoparathyroidism.
  • A high PTH concentration is suggestive of secondary hyperparathyroidism, and the cause of hypocalcaemia should be sought somewhere other than in the parathyroid gland. The most common cause of secondary hyperparathyroidism is vitamin D deficiency.
    • In chronic renal failure, phosphate excretion is diminished leading to hyperphosphataemia and a decrease in plasma calcium, which further leads to an increased PTH concentration.

Laboratory findings

  • See table T1

Laboratory findings in hypocalcaemia of various aetiology

Plasma phosphatePlasma ALPFasting plasma PTH24 h urinary calcium
Hypoparathyroidism (other than PTH resistance)HighNormalLow or normalNormal, low or high
Vitamin D deficiencyLowHighHighLow
Renal failureNormal or highNormal or highHighLow

Treatment (in adults)

Acute condition with distinct symptoms (often postoperatively)

  • The symptoms depend on how quickly the condition develops.
    • E.g. thyroid or parathyroid surgery, pancreatitis
  • Serum ionized calcium < 1.0 mmol/l (often < 0.9 mmol/l)
    • 10 ml of calcium gluconate 100 mg/ml (contains 92 mg of elemental calcium) is administered intravenously over at least 10 minutes.
    • If necessary, treatment can be continued by 100 ml calcium gluconate infusion (notice: 10 × 10 ml ampoules contain 920 mg of elemental calcium = 9.4 g of calcium gluconate) diluted in 1 000 ml of 5% glucose administered over 12 hours.
  • If the symptoms of hypocalcaemia are mild (prickling, numbness) and serum ionized calcium is > 0.9 mmol/l, the treatment should be started with 1-3 g/day of oral calcium carbonate combined with a vitamin D preparation.

Prevention and treatment of vitamin D deficiency

  • Prophylaxis
    • Vitamin D supplementation 20 µg/day (800 IU) all year round for everybody over 75 years of age.
    • Vitamin D supplementation all year round is also recommended for all people under 18 years of age and women who are pregnant or breastfeeding.
    • For patients with osteoporosis, determination of 25-OH vitamin D concentration is recommended; the target level is 75-120 nmol/l.
    • It is probable that all population groups would benefit from vitamin D supplementation at least during the dark season of the year, especially if the diet does not contain vitamin D fortified dairy products and fat spreads on a daily basis, and/or fish 2-3 times a week.
    • In adults, a vitamin D dose of 100 μg/day is considered the safe maximum dose.
  • In severe vitamin D deficiency, high starting doses may be needed (e.g. 50 000 IU/day for 2-3 weeks and then 20 000-50 000 IU/week until the deficiency has been corrected).

Chronic hypocalcaemia in hypoparathyroidism

  • 1-3 g/day calcium
  • If hypocalcaemia continues after 2-3 days, a vitamin D derivative, either dihydrotachysterol or alfacalcidol, should be added to the regimen.
  • The administration of dihydrotachysterol should be started with 1-2 mg/day and continued with 0.2-0.6 mg/day. Likewise, higher initial doses of alfacalcidol, 0.5-2.0 µg/day, should be used.
  • In addition, a low dose of vitamin D3 (10-20 μg) is recommended to keep the bones in good condition.
  • Teriparatide has been used for the treatment of hypoparathyroidism in individual patients and in small studies.
  • The treatment of patients with severe hypoparathyroidism should be started by a specialist in internal diseases.
  • The objective of treatment is calcium concentration at the lower limit of the normal reference range; higher concentrations are associated with a risk of hypercalciuria resulting in nephrocalcinosis which, in turn, will lead to renal failure.
    • Calcium absorption depends on the pH level, and in gastric achlorhydria it may be reduced by 70%: hypocalcaemia may be unexpectedly aggravated when the patient starts taking a proton pump inhibitor or an H2 receptor blocker.
  • Plasma albumin-corrected calcium or serum ionized calcium, plasma phosphate, plasma creatinine (GFRe) and, occasionally, 24 h urinary calcium should be monitored. The tests should initially be carried out as often as once a week, and later at 3-6 month intervals.

    References

    • Goltzman D. Etiology of hypocalcemia in adults. Post TW, ed. UpToDate. Waltham, MA: UpToDate Inc. http://www.uptodate.com/contents/etiology-of-hypocalcemia-in-adults (accessed 8.1.2023).
    • Fong J, Khan A. Hypocalcemia: updates in diagnosis and management for primary care. Can Fam Physician 2012;58(2):158-62. [PubMed]
    • Cooper MS, Gittoes NJ. Diagnosis and management of hypocalcaemia. BMJ 2008;336(7656):1298-302. [PubMed]