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Anna-MariKoski

Hypocalcaemia, Hypoparathyroidism and Vitamin D Deficiency

Essentials

  • The cause of hypocalcaemia should be determined before replacement therapy is initiated.
    • Calcium concentrations are mainly regulated by parathyroid hormone (PTH), vitamin D, and the fibroblast growth factor FGF-23 regulating phosphate metabolism.
  • It must be ensured that the patient does not have pseudohypocalcaemia often associated with severe diseases and undernutrition, and caused by hypoalbuminaemia. Plasma calcium levels are reduced by 0.2 mmol/l for each 10 g/l reduction in serum albumin level. This explains why severe illness and undernutrition are often associated with mild asymptomatic hypocalcaemia; in these cases the concentration of plasma ionized calcium remains normal and should be used for reference.
  • In long-term treatment of hypoparathyroidism, calcium concentrations should not be raised to the normal reference range; instead, the target ionized calcium concentration is 1-1.1 mmol/l.

Aetiology of hypocalcaemia

Hypoparathyroidism

  • PTH deficiency; dysfunction of secretion or peripheral effect
    • Low PTH levels are most commonly due to often transient hypoparathyroidism after thyroid or parathyroid surgery.
    • Familial dysfunction (APS-1 syndrome, PTH gene mutation, calcium-sensing receptor mutation) is rare.
    • Hypoparathyroidism may be associated with storage diseases (haemochromatosis Haemochromatosis, Wilson's disease), malignancies or magnesium deficiency.

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.
  • Opinions about the target level of 25-OH vitamin D vary between 50-100 nmol/l.
  • Due to the geographic position of Finland, the ordinary Finnish diet is not sufficient to cover the need for vitamin D.
  • Causes of vitamin D deficiency
    • Lack of sunlight and unbalanced diet (in institutionalized elderly people)
    • Absorption problems: coeliac disease, undernutrition
    • 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 contributes to the activation of PTH, in the worst case resulting in renal osteodystrophy and itching.

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 if the patient has concurrent vitamin D deficiency
  • Neonatal hypocalcaemia

Symptoms and signs of acute hypocalcaemia

  • The symptoms of mild hypocalcaemia (ionized calcium < 1 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 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 PTH, serum 25-OH vitamin D, plasma alkaline phosphatase (ALP), plasma phosphate, plasma magnesium, 24 h urinary calcium
  • 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. Plasma calcium often remains in the normal range, as does 24 h urinary calcium.

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
  • 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) in 1 000 ml of 5% glucose over 12 hours.
  • If the symptoms of hypocalcaemia are mild (prickling, numbness), 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: 800 IU/day of vitamin D (20 µg) 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. 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 calcium or ionized calcium, plasma phosphate, plasma creatinine 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

  • 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]