MARY F. CARROLL, M.D., Jap New Mexico Medical Middle, Roswell, New Mexico.
DAVID S. SCHADE, M.D., College of New Mexico College of Medication and Well being Sciences Middle, Albuquerque, New Mexico
Hypercalcemia is a dysfunction generally encountered by major care physicians. Roughly one in 500 sufferers who’re handled in a common medication clinic have undiagnosed major hyperparathyroidism, the main explanation for hypercalcemia.1–4 The analysis of hypercalcemia most frequently is made by the way when a excessive calcium stage is detected in blood samples. The principal challenges within the administration of hypercalcemia are distinguishing major hyperparathyroidism from circumstances that won’t reply to parathyroidectomy and understanding when it’s acceptable to refer the affected person for surgical procedure. It’s important that physicians know find out how to consider and optimally handle sufferers with hypercalcemia, as a result of therapy and prognosis differ in accordance with the underlying dysfunction.
Hypercalcemia is a dysfunction generally encountered by major care physicians. The analysis usually is made by the way in asymptomatic sufferers. Scientific manifestations have an effect on the neuromuscular, gastrointestinal, renal, skeletal, and cardiovascular techniques. The most typical causes of hypercalcemia are major hyper-parathyroidism and malignancy. Another necessary causes of hypercalcemia are drugs and familial hypocalciuric hypercalcemia. An preliminary diagnostic work-up ought to embody measurement of intact parathyroid hormone, and any drugs which can be more likely to be causative must be discontinued. Parathyroid hormone is suppressed in malignancy-associated hypercalcemia and elevated in major hyperparathyroidism. It’s important to exclude different causes earlier than contemplating parathyroid surgical procedure, and sufferers must be referred for parathyroidectomy provided that they meet sure standards. Many sufferers with major hyperparathyroidism have a benign course and don’t want surgical procedure. Hypercalcemic disaster is a life-threatening emergency. Aggressive intravenous rehydration is the mainstay of administration in extreme hypercalcemia, and antiresorptive brokers, resembling calcitonin and bisphosphonates, steadily can alleviate the scientific manifestations of hypercalcemic issues.
Pathophysiology of Hypercalcemia
The skeleton incorporates 98 p.c of complete physique calcium; the remaining 2 p.c circulates all through the physique. One half of circulating calcium is free (ionized) calcium, the one type that has physiologic results. The rest is certain to albumin, globulin, and different inorganic molecules. Low albumin ranges can have an effect on the overall serum calcium stage. Immediately measuring the free calcium stage is extra handy and correct, however the next formulation can be utilized to calculate the corrected complete serum calcium stage:
Corrected calcium = (4.0 g per dL –[plasma albumin]) 3 0.8 + [serum calcium] Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D3 (calcitriol), and calcitonin management calcium homeostasis within the physique (Desk 1). Elevated bone resorption, elevated gastrointestinal absorption of calcium, and decreased renal excretion of calcium trigger hypercalcemia. Regular serum calcium ranges are 8 to 10 mg per dL (2.0 to 2.5 mmol per L, Determine 1), though the precise vary can differ amongst laboratories. Regular ionized calcium ranges are 4 to five.6 mg per dL (1 to 1.4 mmol per L). Hypercalcemia is taken into account gentle if the overall serum calcium stage is between 10.5 and 12 mg per dL (2.63 and three mmol per L).5 Ranges greater than 14 mg per dL (3.5 mmol per L) might be life threatening.
PTH is an 84-amino acid hormone produced by the 4 pea-sized parathyroid glands posterior to the thyroid gland. In response to low serum calcium ranges, PTH raises calcium ranges by accelerating osteoclastic bone resorption and growing renal tubular resorption of calcium. It additionally will increase calcitriol, which not directly raises serum calcium ranges. PTH causes phosphate loss by the kidneys. Thus, in sufferers with PTH-mediated hypercalcemia, serum phosphate ranges are usually low.
Vitamin D is a steroid hormone that’s obtained by the weight-reduction plan or produced by the motion of daylight on vitamin D precursors within the pores and skin. Calcitriol, the energetic type of vitamin D, is derived from successive hydroxylation of the precursor cholecalciferol, first within the liver (25-hydroxylation), then within the kidneys (1-hydroxylation). Ample vitamin D is important for bone formation. Nevertheless, the principal goal for vitamin D is the intestine, the place it will increase the absorption of calcium and phosphate. Thus, in vitamin D-mediated hypercalcemia, serum phosphate ranges are usually excessive.
Calcitonin is a 32-amino acid hormone produced by the parafollicular C cells of the thyroid. Calcitonin is a weak inhibitor of osteoclast activation and opposes the consequences of PTH on the kidneys, thereby selling calcium and phosphate excretion. Calcitonin ranges may be elevated in pregnant sufferers and in sufferers with medullary carcinoma of the thyroid. Nevertheless, there are not any direct scientific sequelae, and serum calcium ranges normally are regular.
PTH-related peptide (PTHrP) is the principal mediator in hypercalcemia related to stable tumors.6 PTHrP is homologous with PTH on the amino terminus, the area that includes the receptor-binding area. PTHrP binds the PTH receptor and mimics the biologic results of PTH on bones and the kidneys.
Scientific Manifestations of Hypercalcemia
The optimum focus of serum ionized calcium is important for regular mobile operate. Hypercalcemia results in hyperpolarization of cell membranes. Sufferers with ranges of calcium between 10.5 and 12 mg per dL might be asymptomatic.7 When the serum calcium stage rises above this stage, multisystem manifestations change into obvious (Desk 2). This constellation of signs has led to the mnemonic “Stones, bones, abdominal moans, and psychic groans,” which is used to recall the indicators and signs of hypercalcemia, significantly on account of major hyperparathyroidism.
Neuromuscular results embody impaired focus, confusion, corneal calcification, fatigue, and muscle weak spot.8 Nausea, belly ache, anorexia, constipation, and, not often, peptic ulcer illness or pancreatitis are among the many gastrointestinal manifestations. An important renal results are polydipsia and polyuria ensuing from nephrogenic diabetes insipidus, and nephrolithiasis ensuing from hypercalciuria. Different renal results embody dehydration and nephrocalcinosis. Cardiovascular results embody hypertension, vascular calcification, and a shortened QT interval on the electrocardiogram. Cardiac arrhythmias are uncommon. Bone ache can happen in sufferers with hyperparathyroidism or malignancy. Osteoporosis of cortical bone, such because the wrist, is especially related to major hyperparathyroidism.9 Extra PTH additionally may end up in subperiosteal resorption, resulting in osteitis fibrosa cystica with bone cysts and brown tumors of the lengthy bones.
Differential Prognosis for Hypercalcemia
Main hyperparathyroidism and malignancy account for greater than 90 p.c of hypercalcemia circumstances. These circumstances should be differentiated early to supply the affected person with optimum therapy and correct prognosis. Humoral hypercalcemia of malignancy implies a really restricted life expectancy—usually solely a matter of weeks. Alternatively, major hyperparathyroidism has a comparatively benign course.
The causes of hypercalcemia might be divided into seven classes: hyperparathyroidism, vitamin D-related causes, malignancy, drugs, different endocrine issues, genetic issues, and miscellaneous causes (Desk 3). Analysis of a affected person with hypercalcemia (Determine 2) ought to embody a cautious historical past and bodily examination specializing in scientific manifestations of hypercalcemia, danger elements for malignancy, causative drugs, and a household historical past of hypercalcemia-associated circumstances (e.g., kidney stones).
HYPERPARATHYROIDISM
Elevated screening of calcium ranges and extensive availability of dependable assays for intact PTH ranges have led to extra frequent and earlier diagnoses of major hyperparathyroidism. In 80 p.c of circumstances, a single parathyroid adenoma is accountable. Nevertheless, hyperparathyroidism additionally may end up from hyperplasia of the parathyroid glands or, not often, parathyroid carcinoma. In major or tertiary hyperparathyroidism, PTH ranges are regular or excessive within the setting of hypercalcemia (Determine 3).
In lots of sufferers, major hyperparathyroidism progresses very slowly. Sufferers must be thought-about for parathyroidectomy provided that they meet standards really useful by the Nationwide Institutes of Well being Consensus Improvement Convention (Desk 4).10 [Evidence level C, consensus opinion] The illness will progress in roughly one fourth of sufferers who don’t endure surgical procedure.11 Pre-operative nuclear imaging of the parathyroids with a sestamibi scan (Determine 4) permits the surgeon to carry out unilateral neck dissection, which leads to diminished operative time and fewer morbidity.12 Dangers of parathyroid surgical procedure embody everlasting hypoparathyroidism and injury to the recurrent laryngeal nerve.
Persistent renal failure usually causes hypocalcemia. If untreated, extended excessive phosphate and low vitamin D ranges can result in elevated PTH secretion and subsequent hypercalcemia. That is termed tertiary hyperparathyroidism.
VITAMIN D-MEDIATED CAUSES
Probably the most generally out there vitamin D dietary supplements encompass 25-hydroxyvitamin D2. In suspected overdose of over-the-counter vitamin D, the extent of 25-hydroxyvitamin D3 (not 1,25-dihydroxyvitamin D3) must be measured. Macrophages may cause granuloma-forming (i.e., sarcoidosis, tuberculosis, Hodgkin’s lymphoma) elevated extra-renal conversion of 25-hydroxyvitamin D3 to calcitriol. PTH ranges are suppressed, and ranges of 1,25-dihydroxyvitamin D3 are elevated. Hypercalcemia mediated by extreme vitamin D responds to a brief course of glucocorticoids if the underlying illness is handled.
HYPERCALCEMIA OF MALIGNANCY
Hypercalcemia of malignancy happens in a number of settings.13 It’s mediated mostly by systemic PTHrP in sufferers with stable tumors. This is called the humoral hypercalcemia of malignancy. PTHrP mimics the bone and renal results of PTH. In distinction to major hyperparathyroidism, the humoral hypercalcemia of malignancy is related to suppressed PTH ranges and regular calcitriol ranges. In depth bone lysis can also trigger malignancy-associated hypercalcemia. A number of myeloma and metastatic breast most cancers can current on this approach. In osteolytic hypercalcemia, the alkaline phosphatase stage is normally markedly elevated. Hodgkin’s lymphoma causes hypercalcemia by elevated manufacturing of calcitriol.
MEDICATIONS
Thiazide diuretics enhance renal calcium resorption and trigger gentle hypercalcemia that ought to resolve when the remedy is discontinued. Thiazide diuretic remedy can unmask many circumstances of major hyperparathyroidism. Consumption of huge quantities of calcium carbonate by way of calcium-containing antacids can result in hypercalcemia, alkalosis, and renal insufficiency—an unusual dysfunction termed milk-alkali syndrome.14 Lithium use may cause hypercalcemia by growing the set level of PTH,15 requiring a better serum calcium stage to change off PTH secretion. Giant doses of vitamin A and its analogs may cause hypercalcemia, which seems to be mediated by elevated bone resorption.
OTHER ENDOCRINE DISORDERS
Thyrotoxicosis-induced bone resorption may end up in gentle hypercalcemia. Quantity growth and glucocorticoid substitute can right the hypercalcemia that often happens in sufferers with adrenal insufficiency. Pheo-chromocytoma is believed to trigger hypercalcemia by the manufacturing of PTHrP. Pheochromocytoma could also be related to major hyperparathyroidism as a part of sort 1 a number of endocrine neoplasia syndrome.
FAMILIAL HYPOCALCIURIC HYPERCALCEMIA
Familial hypocalciuric hypercalcemia16 (FHH) is an autosomal-dominant situation with nearly one hundred pc penetrance. Most circumstances are brought on by a mutation within the calcium-sensing receptor gene. Sufferers have average hypercalcemia from an early age however comparatively low urinary calcium excretion. PTH ranges might be regular or solely mildly elevated regardless of the hypercalcemia. This gentle elevation can result in an inaccurate analysis of major hyperparathyroidism. The circumstances might be differentiated by use of a 24-hour urinary assortment for calcium; calcium ranges shall be excessive or regular in sufferers with hyperparathyroidism and low in sufferers with FHH. Parathyroidectomy isn’t useful in sufferers with FHH.
MISCELLANEOUS CAUSES
In circumstances of excessive bone turnover, resembling Paget’s illness and regular development in kids, immobilization may cause hypercalcemia. Hypercalcemia can also happen within the restoration section of rhabdomyolysis-induced renal harm, when calcium deposited in gentle tissue is mobilized.
Therapy of Hypercalcemia
Asymptomatic sufferers with gentle hypercalcemia usually don’t profit from normalization of their serum calcium ranges. Sufferers with calcium ranges higher than 14 mg per dL or symptomatic sufferers with calcium ranges higher than 12 mg per dL (Desk 5) must be instantly and aggressively handled.17 The most secure and handiest therapy of hypercalcemic disaster is saline rehydration adopted by furosemide (Lasix) diuresis, calcitonin, and bisphosphonates.
HYDRATION AND DIURESIS
In sufferers with gentle hypercalcemia, ample hydration must be inspired and immobilization discouraged. In symptomatic sufferers, a loop diuretic (e.g., furosemide) might be prescribed. Current proof means that estrogen-replacement remedy may be useful in postmenopausal ladies with major hyperparathyroidism.18 [Evidence level B, lower-quality randomized controlled trial] In sufferers with extreme hypercalcemia, the mainstay of administration is aggressive intravenous rehydration. Regular saline must be used to realize a urine output of 200 mL per hour. Solely when the intravascular quantity has been restored ought to a loop diuretic be utilized in low dosages (e.g., furosemide, 10 to twenty mg) to additional decrease the serum calcium stage if crucial.
PHARMACOLOGIC AGENTS
In malignancy-associated hypercalcemia, intravenous pamidronate (Aredia), 60 to 90 mg, might be given by four-hour infusion.13 This agent usually will normalize the serum calcium stage, however peak results don’t happen till 48 to 72 hours after infusion. Warning should be used with bisphosphonates19 in sufferers with renal impairment. In extreme hypercalcemia refractory to saline diuresis, calcitonin (Calcimar, Miacalcin) might be given each six hours. This therapy has a speedy onset however brief period of impact, and sufferers develop tolerance to the calcium-lowering impact. Different antiresorptive brokers which can be used often embody plicamycin (Mithracin) and gallium nitrate (Ganite). In hypercalcemia mediated by vitamin D and in hematologic malignancies (e.g., myeloma, lymphoma), glucocorticoids are the primary line of remedy after fluids.
DIALYSIS
In circumstances of resistant, life-threatening hypercalcemia, hemodialysis in opposition to a low-calcium dialysate is more practical than peritoneal dialysis in reducing serum calcium ranges. Remedy for the underlying situation must be instituted as quickly as attainable. Session with an endocrinologist is really useful.
SURGERY
In circumstances of hypercalcemic disaster ensuing from major hyperparathyroidism, pressing parathyroidectomy is probably healing.20
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