1,25(OH)2D, the active form of vitamin D produced in the kidney, acts as a classical hormone on tissues which express the vitamin D receptor (VDR), like bone and intestine. It may also be locally produced by several non- renal cells expressing the 1- α- hydroxylase enzyme. This extrarenal production of 1,25 (OH)2D acts in a paracrine/ autocrine fashion and mediates the so- called extraskeletal effects of vitamin D, which have received great attention in the recent years. Vitamin D- mediated hypercalcaemia is caused by different mechanisms that are discussed next: (i) ectopic 1- α- hydroxylase overactivation, which may occur in granulomatous dis eases and malignant tumours; (ii) intoxication of vitamin D and (iii) inactivating mutations of genes encoding key enzymes of 1,25(OH)2 catabolism and degradation (namely mutations of 24-hydroxylase gene) (see Box 1).
Box1. Aetiological classification of hypercalcaemia
Hypercalcaemia associated with granulomatous diseases. Activation of 1- α- hydroxylase enzyme in macrophage is a well- known cause of hypercalcaemia associated with granulomatous diseases. It was originally described in sarcoidosis, tuberculosis, Crohn’s, and Wegener’s diseases.
Sarcoidosis. The first case of hypercalcaemia associated with sarcoidosis was reported in 1930 and since then several case reports were published, claiming that 10% of patients with sarcoidosis may experience hypercalcaemia. It was subsequently demonstrated that serum levels of 1,25 (OH)2D are increased in patients with sarcoidosis and that the source of vitamin D is extrarenal. Indeed, elevated serum 1,25 (OH)2D levels were shown in anephric patients and in patients with endstage kidney failure. It was shown that sarcoid- associated pulmonary alveolar macrophages produce their own 1- α- hydroxylase, which is stimulated by interferon γ, but not under the control of PTH. Hypercalcaemia is usually mild to moderate, and symptoms and laboratory findings are similar to those of other forms of PTH- independent hypercalcaemia. In addition, the serum level of angiotensin- converting enzyme is increased, and its concentration generally correlates with the severity of the disease. Serum levels of 1,25(OH)2D are increased whereas those of 25(OH)D are either normal or decreased. The activity of sarcoid- associated pulmonary alveolar macrophages is efficiently suppressed by glucocorticoids, which are effective in lowering serum calcium. Ketoconazole has also been successfully used in the management of sarcoidosis- associated hypercalcaemia.
Tuberculosis. Patients with tuberculosis may experience hypercalcaemia with a highly variable (2.3– 48%) prevalence in different studies. Hypercalcaemia is mainly due to the production of 1,25(OH)2D by macrophage of the pleural cavity. 1,25(OH)2D has been shown to have an antimicrobial action on mycobacterium tuberculosis, stimulating the secretion of cathelicidins and other antimicrobial peptides. Rifampicin and isoniazid, the most commonly used drugs in the management of patients with tuberculosis, are also helpful in controlling hypercalcaemia: rifampicin induces enzymes that degrade 25(OH)D, and isoniazid inhibits the synthesis of 1,25(OH)2D.
Other granulomatous diseases. Several other granulomatous diseases have been reported to be associated with hypercalcaemia, including infection (mycobacterium avium- complex disease, leprosy, fungal infections, pneumocystis pneumonia, and cat- scratch disease) as well as non- infectious diseases. A recent meta- analysis reviewed all cases of hypercalcaemia associated to cosmetics injections. The authors identified 23 patients, who mostly used silicon, polymethylmethacrylate, and paraffin oil injected in but tock and breast. Hypercalcaemia was severe with a mean serum Alb- Ca of 3.43 mmol/ L and detected years after the initial injection. In these patient’s serum 1,25(OH)2D was elevated and PTH low or suppressed in the majority of cases. Finally, hypercalcaemia has been reported in some cases of Wegener’s granulomatosis, Chron’s diseases, giant cell polymyositis, and berylliosis.
Malignant hypercalcaemia. Hypercalcaemia complicates up to 13% of non- Hodgkin and 5% of Hodgkin lymphoma, and when occurs is associated with a worse prognosis. The pathogenesis of lymphoma- related hypercalcaemia involves the increased production of ectopic 1,25(OH)2D, probably in lymph nodes, as suggested by in vivo studies. Increased serum levels of 1,25(OH)2D have been demonstrated in 20– 40% of patients with non- Hodgkin and 100% of those with Hodgkin lymphoma.
Hypercalcaemia associated with vitamin D intoxication. Vitamin D insufficiency is very common worldwide in the general population, particularly in older people and in subjects living in the Eastern countries, as well as in patients with several disease states affecting vitamin D absorption and metabolism (celiac diseases, malabsorption, etc.). Guidelines developed by the Institute of Medicine (IOM) in 2011 recommend different dietary vitamin D allowances in children, adults, elderly, and pregnant women and indicate that the daily intake of vitamin D should not be greater of 4000 UI in adults, 3000 UI in children 4– 8 years, 2500 UI in children 1– 3 years, and 100– 1500 UI in infants. Diseases unrelated to bone and calcium homeostasis may be associated with a low vitamin D status and decreased locally produced 1,25(OH)2D by circulating 25OHD may have a pathogenic role in these conditions. This knowledge led to wide use vitamin D supplements not only to correct insufficiency in the general population but also to increase serum 25OHD in patients with several diseases, despite lack of evidence of benefit from vitamin D supplementation. Vitamin D intoxication is a rare event, but when occurring may lead to life- threatening hypercalcaemia. A recent meta- analysis reported 13 patients presenting with severe hypercalcaemia and related symptoms such as vomiting, dehydration, pain, and anorexia. In all cases, vitamin D intoxication was due to either excessive dosing by the patients or the prescribing physicians, and, rarely, by manufacturing errors. The daily dose of vitamin D ranged between 50 000 IU and 2 604 000 IU. Serum calcium ranged between 11.1 and 23.1 mg/ dl and serum 25(OH)D concentration was greater than 150 ng/ ml. Vitamin D intoxication is different from vitamin D hypersensitivity, a condition in which a pre- existing hypercalcaemia is exacerbated by high doses of vitamin D.
Hypercalcaemia associated with CYP24A1 hydroxylase mutations. Idiopathic infantile hypercalcaemia (IIH, OMIM 143880) is a rare disease characterized by hypercalcaemia, hypercalciuria, nephrocalcinosis, usually diagnosed in infant between 3 and 7 months of age. The disease is rare and is related to an impairment of vitamin D catabolism. IIH is a genetic disorder due to loss- of- function mutations in the human cytochrome P450 24 subfamily A member 1 (CYP24A1) gene, encoding the 24- hydroxilase enzyme, which is involved in the catabolism of vitamin D. The diseases can present with different phenotypes ranging from severe forms diagnosed early in the infancy and sometimes lethal to milder forms, often diagnosed in the adulthood during workout for recurrent nephrolithiasis. The first case described in 2011 lead to the identification of the genetic cause and thereafter around 200 cases have been reported leading to an increased insight into the diagnostic and therapeutic management of this disease.
