Genetic hypercalcemia

A genetic disorder should be suspected in patients with hypercalcemia, notably those who are young; have family members with hypercalcemia; or have had a tumor of the endocrine pancreas, thyroid, pituitary, adrenal gland, or jaw bone. All forms of hypercalcemia should be interpreted according to the serum level of parathyroid hormone (PTH). Genetic forms are thus classified as related or unrelated to a parathyroid gland disorder. When the PTH level is elevated or is not depressed despite the hypercalcemia, findings that suggest family history of hypercalcemia due to a genetic cause include syndromic manifestations in the patient or family members, parathyroid cancer (either suspected before surgery or confirmed during parathyroidectomy), multiple or recurrent parathyroid tumors, a family history of primary hyperparathyroidism, and the onset of primary hyperthyroidism before 50 years of age. In patients with moderate hypercalcemia, a normal PTH level, and relative hypocalciuria, the first hypothesis is a mutation in the calcium-sensing receptor gene, which is often difficult to distinguish from primary hyperparathyroidism, particularly when there is no known family history of hyperparathyroidism, as is often the case. A low PTH level suggests non-parathyroid hypercalcemia due to a genetic defect in patients with no evidence of other conditions associated with hypercalcemia and low PTH levels and in those whose calcitriol levels are elevated or normal (instead of depressed as expected when PTH is elevated). Patients with hypercalciuria but no evidence of conditions such as granulomatous diseases should be evaluated for increased vitamin D sensitivity due to a CYP 4A1 mutation. Other very rare causes include hypophosphatasia due to ALPL mutations, which is characterized by a low alkaline phosphatase level; and renal phosphate wasting due to an NPT2A mutation, in which serum phosphate levels are low. A thorough analysis of the clinical and laboratory data can point toward a genetic disorder in patients with hypercalcemia. The diagnosis is then confirmed by obtaining genetic tests tailored to the clinical and laboratory test abnormalities. The current development of diagnostic genetic testing is shedding new light on the phenotypes, thereby improving their management.     

The hypercalcemia of malignancy

The hypercalcemia of malignancy is mediated by complex and heterogeneous mechanisms. Once thought of as a simple paraneoplastic syndrome mediated by the effects of tumor production of PTH, it is now clear that multiple mechanisms are involved and that these mechanisms involve abnormalities in calcium transport in bone, kidney, and gut. Calcium homeostasis in normal individuals is complex and tightly regulated. Although much has been learned over the last 20 years about the effects of individual hormones on target organs, much remains to be understood about how these hormonal systems interact to control extracellular fluid calcium. Future studies on disturbances in calcium homeostasis, such as that occurring in association with malignant disease, should do much to clarify how these complex hormonal mechanisms function in the normal individual.     

Parathyroidectomy in familial hypercalcemia with clinical characteristics of primary hyperparathyroidism and familial hypocalciuric hypercalcemia

BACKGROUND: Familial primary hyperparathyroidism is associated with tumor-susceptibility syndromes, which are unrelated to mutations in the calcium receptor gene. This study describes parathyroidectomy in a kindred with hypercalcemia due to a heterozygous point mutation in the calcium receptor gene. METHODS: Seventeen family members were studied, and postoperative follow-up averaged 5.1 years. RESULTS: Radical parathyroid resection with total parathyroid remnants of 10 to 20 mg or total parathyroidectomy with autotransplantation normalized the serum calcium and parathyroid hormone values in 12 family members. Persistent hypercalcemia was noted in 3 of 5 patients subjected to less radical procedures. Diffuse to nodular hyperplasia and microscopic findings, interpreted incorrectly as a single adenoma, were found. Weight of the parathyroid tissue increased with the age of the patients (P <.05), and almost one third of them (29%) had 1 to 3 atypically located glands. There were no patients with recurrent hypercalcemia during follow-up. CONCLUSIONS: The heterozygous inactivating mutation of the calcium receptor gene of this family is accompanied by mild increases in parathyroid gland x weight and diffuse parathyroid hyperplasia with possibly secondary genetic events causing nodule formation. Radical parathyroid resection is advocated in this hypercalcemic disorder, which may represent an intermediary stage between primary hyperparathyroidism and familial hypocalciuric hypercalcemia.     

Humoral hypercalcemia of penile carcinoma

Hypercalcemia is a common life-threatening complication associated with several genitourinary malignancies. Parathyroid-related peptide has been shown to cause hypercalcemia in several solid tumors but rarely in penile cancer. We report a case of advanced penile cancer with hypercalcemia and associated dysphagia. Treatment is clinically challenging and should be definitive as soon as the patient has been stabilized. Serum calcium measurement can be used for monitoring the outcome and follow-up in such patients. Dysphagia is a rare but potential symptom of hypercalcemia, but additional studies are needed to prove this association.     

Acute renal failure and hypercalcemia

Hypercalcemia can result from excessive bone resorption, renal calcium retention, excessive intestinal calcium absorption, or a combination of these conditions. Hypercalcemia may also provoke acute renal failure (ARF) or hypertension, or aggravate the tubular necrosis that is frequently found in cases of ARF. The association of ARF and hypercalcemia was studied retrospectively in eight patients based in the data in their charts. Data are expressed as median and percentile (25th; 75th). Our results show that ARF associated with hypercalcemia was related with comorbidity in all cases (cancer, multiple myeloma, hyperparathyroidism, sarcoidosis, vitamin D intoxication, and leprosy). Maximum median serum creatinine levels were 3.3 mg/dL (2.7, 3.8 mg/dL) before treatment and 1.1 mg/dL (0.9, 1.3 mg/dL) after treatment. Maximum total median serum calcium was 15.9 mg/dL (13.5, 19.8 mg/dL) before treatment and 9.1 mg/dL (8.4, 9.7 mg/dL) after treatment. Maximum median ionized serum calcium was 2.1 mmol/L (1.8, 2.2 mmol/L) before treatment and 1.1 mmol/L (1.0, 1.2 mmol/L) after treatment. Different kinds of treatment induced a rapid fall in serum calcium concentration. All patients were treated with hydration and diuretics, and three patients also received calcitonin. Serum creatinine concentration always fell simultaneously with the decrease in serum calcium in all cases. All patients progressed with nonoliguric renal failure. In conclusion, in ARF, patients are frequently hypocalcemic. Usually, the presence of hypercalcemia associated with ARF is indicative of the presence of comorbidity, as observed in all eight patients studied here. There was an improvement of renal function in all cases as serum calcium levels decreased.     

Contrasting mechanisms of hypercalcemia in patients with early and advanced humoral hypercalcemia of malignancy

The mechanisms of hypercalcemia were assessed in 15 patients with humoral hypercalcemia of malignancy (HHM) who had tumors at various stages of progression. In patients with early tumors, bone biopsies were generally normal and the hypercalcemia was due to an elevation in renal tubular resorption of calcium. Conversely, osteoclastic resorption was markedly increased in patients with advanced tumors, particularly those in whom the biopsies were obtained postmortem. Osteoclast surface (Oc.S) correlated positively with the stage of tumor progression (r = 0.80, p less than 0.002), degree of immobility (r = 0.87, p less than 0.002), and level of urinary cyclic AMP excretion (r = 0.60, p less than 0.02). When compared with a group of ambulant patients with primary hyperparathyroidism (HPT), osteoblast surface (Ob.S%) in HHM was depressed (median and range): 1.2% (0-11.6%) versus 5.3% (1.1-32.0%) (p less than 0.001). However, a relatively low Ob.S (4%) and raised Oc.S (43.5%) were also seen in an immobilized patient with severe HPT. These data suggest that the PTH-related peptides currently invoked in the pathogenesis of HHM may initially cause hypercalcemia by enhancing renal tubular calcium resorption. The increase in osteoclastic activity and depression of osteoblastic activity that subsequently occurs is probably due to the combined effects of immobilization and higher circulating levels of PTHrP on the skeleton. However, the release of other bone-resorbing factors by the tumor, which have a depressant effect on osteoblastic activity, remains possible.     

Clodronate in hypercalcemia of malignancy

Of the many compounds belonging to the diphosphonate family, clodronate has been widely used in hypercalcemia and osteolysis of malignancy. All published reports indicate that clodronate can normalize plasma calcium in the majority of hypercalcemic, rehydrated cancer patients in whom increased bone resorption is the prevailing disturbed calcium flux. In these patients, clodronate, given intravenously either as a single infusion or as repeated daily administrations, can normalize serum calcium, usually 3–5 days after the onset of therapy. In these good responders, long-term maintenance treatment should be individually adjusted since relapse appears to depend upon the type of tumor, the extent of malignancy and the administration of anticancer therapy. In a subset of well-rehydrated hypercalcemic patients in whom increased tubular calcium reabsorption represents the prevailing disturbed calcium flux, the acute effect of clodronate on plasma calcium is incomplete, despite the normalization of bone resorption. This type of therapeutic response can be experimentally reproduced in diphosphonate-treated animals receiving a constant infusion of parathyroid hormone-related peptide, a peptide isolated from lung, kidney and breast carcinomas. This indicates that, in addition to antiosteolytic drugs, such as clodronate, patients with hypercalcemia of malignancy would benefit from the development of agents that can selectively reduce the renal tubular reabsorption of calcium. In patients displaying a good response to clodronate, the fall in plasma calcium is accompanied by an increase in the calcium-regulating hormones, parathyroid hormone and 1,25-dihydroxyvitamin D₃. This homeostatic reaction probably explains why hypocalcemia rarely occurs in clodronate-treated patients. No serious side effects have been reported in cancer patients receiving oral clodronate, except for the occasional occurrence of mild and transient gastrointestinal upset. A large number of clinical studies indicate that clodronate is a safe and efficacious drug in the treatment of hypercalcemia of malignancy, particularly in cases in which increased bone resorption is the major mechanism disturbing the homeostasis of extracellular calcium.     

Immobilization-induced hypercalcemia and regional osteoporosis

Immobilization hypercalcemia accompanied by unusual hormonal and bony changes complicated the Guillain-Barré syndrome in a 21-year-old woman. Metaphyseal rarefaction appeared in many sites and was severe in the lower limbs. A bone scan showed increased uptake of 99mTc methylene diphosphonate at these sites and throughout the axial skeleton. The literature on experimental metaphyseal rarefaction suggests that osteoclastic resorption and enhanced regional blood flow are associated with immobilization. Suppression of this osteoclastic component of the increased bone turnover, especially if it is widespread, was the rationale for treatment with calcitonin (CT). The patient also became amenorrheic, with low plasma gonadotropin and estrogen levels. Estrogen therapy coincided with a return of plasma calcium to normal.     

Idiopathic infantile hypercalcemia and renal involvement

Idiopathic infantile hypercalcemia is recognized as a rare cause of infantile hypercalcemia. Its renal consequences include nephrocalcinosis with distal tubular dysfunction, nephrolithiasis, and finally renal failure. Herein we report the case of a two-month-old infant presenting with idiopathic infantile hypercalcemia complicated with distal renal tubular acidosis (RTA) and nephrocalcinosis. Despite correction of acidosis and dehydration, the persistant hypercalcemia could only be ameliorated with calcitonin treatment. Early diagnosis and appropriate treatment is life-saving in such cases.     

Management of symptomatic hypercalcemia and hypocalcemia

Symptomatic hypercalcemia is a medical emergency. Knowledge of the alteration in the factors that control normal calcium homeostasis permits selection of a plan of treatment, which includes general supportive measures along with therapeutic agents directed at the specific alteration in calcium homeostasis. The rationale for the selection of various modes of treatment and treatment schedules and the untoward side effects of the therapeutic agents are reviewed.Acutely developing hypocalcemia often requires emergency treatment. Relief of symptoms can be achieved with intravenous calcium preparations. Knowledge of the underlying cause permits selection of appropriate medications when long-term treatment is required. When vitamin D is needed, measurement of serum calcium and phosphate at regular intervals is essential. Hypoparathyroidism may be temporary after thyroid or parathyroid surgery, and efforts should be made 6 to 12 months after operation to determine whether the abnormality is permanent.

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Résumé L'hypercalcémie symptômatique représente une véritable urgence médicale. La connaissance exacte des modifications des facteurs qui contrô lent l'homéostase calcique permet de choisir un traitement adéquat comportant à la fois des mesures générales et des mesures spécifiques propres à traiter ces anomalies. Le choix des modalités thérapeutiques et du détoulement du traitement ainsi que les effets indésirables des agents thérapeutiques susceptibles d'être employés sont passés en revue par les auteurs.L'hypocalcémie a évolution aiguë nécessite également un traitement d'urgence. Elle peut être jugulée par l'injection intraveineuse de préparations calciques. La recherche de la cause de l'hypo calcémie permet de choisir la médication adéquate dès lors qu'un traitement à long terme est indispensable. L'emploi au long cours de la vitamine D impose le dosage de la calcémie et de la phosphorémie à intervalles réguliers. L'hypoparathyroïdie après chirurgie thyroïdienne ou parathyroïdienne est souvent provisoire mais il convient au 6ème et au 12ème moist après l'intervention de vérifier que l'hypocalcémie n'est pas permanente.

     

A model for malignancy-associated humoral hypercalcemia

Summary Tumor tissue from a patient with squamous cell carcinoma of the lung and hypercalcemia has been serially implanted into athymic mice. Tumor-bearing mice develop cachexia, hypercalcemia without bone metastases, hypophosphatemia, increased urinary cyclic adenosine monophosphate (cAMP) to creatinine ratio, and undetectable human immunoreactive parathyroid hormone levels. Radiographs of spines in the tumor-bearing mice demonstrate demineralization, suggesting skeletal resorption as the source of the hypercalcemia. Within 4–8 hours following tumor removal, hypercalcemia is reversed, suggesting that a relatively short-acting humoral substance is responsible for the hypercalcemia. The animals gain weight and become essentially normal within 4 days following tumor removal. The studies demonstrate that this animal model is similar in many aspects to human malignancy-associated humoral hypercalcemia (MAHH) and can provide a useful tool for further investigation of the pathogenesis and treatment of this syndrome.     

Nasal human calcitonin for tumor-induced hypercalcemia

Summary We treated four hypercalcemic cancer patients by nasal hCT, 3×2 mg daily, which has been reported to be active in Paget's disease at lower doses. Only one patient became normocalcemic and mean (± SEM) calcium levels fell from 11.6±0.2 mg/dl before therapy to 10.7±0.6 mg/dl 2–3 days after starting hCT. The tolerance was excellent but, because of insufficient efficacy, we do not recommend this form of therapy for cancer hypercalcemia.