Hypercalcemia is a serum concentration of total calcium> 10.4 mg / dl (> 2.60 mmol / l) or a concentration of ionized calcium in the serum> 5.2 mg / dl (> 1.30 mmol / l). The main causes are hyperparathyroidism, vitamin D intoxication and malignancies. The clinical symptoms are polyuria, constipation, muscle weakness, confusion and coma. The diagnosis is made by measuring the serum concentration of ionized calcium and by determination of parathyroid hormone concentration. The therapy with the promoted calcium excretion and absorption of calcium from the bones to be reduced, involves the administration of saline solutions, promoting Natriumdiurese and the use of drugs such. B. Zoledronate.
(See also overview of disorders of the calcium concentration.)
Hypercalcemia is a serum concentration of total calcium> 10.4 mg / dl (> 2.60 mmol / l) or a concentration of ionized calcium in the serum> 5.2 mg / dl (> 1.30 mmol / l). The main causes are hyperparathyroidism, vitamin D intoxication and malignancies. The clinical symptoms are polyuria, constipation, muscle weakness, confusion and coma. The diagnosis is made by measuring the serum concentration of ionized calcium and by determination of parathyroid hormone concentration. The therapy with the promoted calcium excretion and absorption of calcium from the bones to be reduced, involves the administration of saline solutions, promoting Natriumdiurese and the use of drugs such. B. Zoledronate. (See also overview of disorders of the calcium concentration.) Etiology Hypercalcemia usually occurs due to excessive absorption from the bones. There are many causes of hypercalcemia (see Table: Major causes of hypercalcemia), but the most common are hyperparathyroidism cancer Important causes of hypercalcemia mechanism Category examples excessive bone resorption humoral hypercalcemia of malignancy bladder breast leukemia lymphoma ovarian renal cell carcinoma (lung, head and neck) osteolytic Hypercalcemia of cancer, due to bone metastases or hematological cancer leukemia lymphoma metastatic breast, prostate, non-small cell lung cancer multiple myeloma Increased mobilization of calcium from the bones immobilization (eg. B. orthopedic “casting traction”) Paget’s disease of bone osteoporosis in the elderly paraplegia or quadriplegia Rapid growth during childhood and adolescence. Hyperthyroidism parathyroid hormone excess Familial hypercalcemia hypokalziurische Parathyreoidales carcinoma Primary hyperparathyroidism Secondary hyperparathyroidism Tertiary hyperparathyroidism Vitamin poisoning Vitamin A toxicity vitamin D intoxication Excessive calcium absorption and / or absorption in the gastrointestinal tract sarcoidosis other granulomatous diseases beryllium disease coccidioidomycosis histoplasmosis leprosy silicosis TB Other diseases: milk-alkali syndrome vitamin D poisoning Increased plasma protein concentration: uncertain mechanism drug lithium poisoning Theophyllinvergiftung therapy with thiazides Endocrine dysfunction Addison’s disease Cushing’s disease, postoperative (myxedema) Other diseases: Aluminum-induced osteomalacia Idiopathic e infantile hypercalcemia Neuroleptic Malignant Syndrome artifacts – contaminated with blood sample vessels Lange venous stasis for venipuncture pathophysiology Primary hyperparathyroidism The primary hyperparathyroidism leads to a generalized disturbance of the electrolyte and bone metabolism, which is caused by excessive secretion of PTH from one or more parathyroid glands. This is probably the most common cause of hypercalcemia, particularly in patients who are not admitted to a hospital. The incidence increases with age and is higher in postmenopausal women. The disease also occurs with increasing frequency ? 3 decades after irradiation of the neck region. There are familial and sporadic forms. Familial forms due parathyreoidaler adenomas occur in patients with other endocrine tumors (overview of multiple endocrine neoplasia). A primary hyperparathyroidism caused hypophosphatemia and excessive bone resorption. Although asymptomatic hypercalcemia is the most common form of onset, nephrolithiasis first symptom may be a long existing hypercalcemia and hypercalciuria. Histological examination shows at 85% of patients with primary hyperparathyroidism a parathyreoidales adenoma. Sometimes it can be very difficult to distinguish an adenoma of normal glandular tissue. Approximately 15% of cases are caused by hyperplasia of ? 2 glands. A parathyreoidales malignancy occurs in <1% of cases auf.Familiäre hypokalziurische hypercalcemia The syndrome of familial hypokalzurischen hypercalcemia (FHH) is an autosomal dominant. In most cases, an inactivating mutation of the gene for the calcium measured receptor occurs, leading to an increase in serum calcium levels at which the secretion is inhibited by parathyroid hormone. The following PTH secretion causes renal phosphate excretion. Occur persistent hypercalcemia (usually asymptomatic) and is already common in the early years of normal to slightly elevated parathyroid hormone concentrations and Hypokalzurie hypermagnesemia on. Renal function is normal and nephrolithiasis unusual. Every now and then occurs a severe pancreatitis. This syndrome, which is associated with parathyroid hyperplasia, is improving after subtotal parathyroidectomy nicht.Sekundärer hyperparathyroidism A secondary hyperparathyroidism is most common in advanced chronic kidney disease when a reduced formation of active vitamin D in the kidneys and other factors to hypocalcemia and cause chronic stimulation of PTH secretion. Hyperphosphatemia that develops as a result of chronic kidney disease, also contributes. Once established, hypercalcemia or normocalcaemia may occur. The sensitivity of the parathyroid gland to calcium may be reduced due to the significant glandular hyperplasia, leading to an increase in the limit for calcium, from the secretion of parathyroid hormone inhibited wird.Tertiärer hyperparathyroidism A tertiary hyperparathyroidism due to a secondary autonomous hypersecretion of PTH, which not oriented at serum calcium concentrations. A tertiary hyperparathyroidism usually occurs in patients with a long existing secondary hyperparathyroidism, z. As in patients with an existing terminal for several years Niereninsuffizienz.Krebs malignancies can be a cause of hypercalcemia, particularly in hospital patients be. There are various causes, but ultimately the elevated serum calcium values ??are based on an excessive bone resorption. The humoral hypercalcemia of malignancy occurs (z. B. hypercalcemia without or with very small bone metastases) in squamous cell carcinoma, renal cell carcinomas, breast carcinomas, prostate and ovarian carcinomas. Many cases of humoral hypercalcemia of malignancy were formerly attributed to ectopic PTH production. Some of these tumors secrete a PTH-like peptide that binds to PTH receptors in the kidney and bone and many effects of the hormone, including of osteoclastic bone resorption, imitated. Osteolytic hypercalcemia may be caused by metastatic solid tumors (eg. As breast and prostate tumors, non-small cell lung cancer) or hematological cancers, mostly multiple myeloma, as well as certain lymphomas and lymphosarcoma. Hypercalcemia can absorb from a local release of osteoclast-activating cytokines or prostaglandins, which stimulates osteoclasts to bone, its direct bone resorption of the tumor cells caused or both. Diffuse osteopenia can also auftreten.Vitamin-D poisoning A vitamin D poisoning can be caused by high concentrations of endogenous 1,25 (OH) 2D. Although the serum concentrations in most patients is low with solid tumors, patients with lymphoma and T-cell leukemia due to a dysregulation of the 1-alpha-hydroxylase enzyme sometimes increased in the tumor cells concentrations. Exogenous vitamin D in pharmacological doses caused both excessive bone resorption and increased intestinal Kalziumesorption what führt.Granulomatöse to hypercalcemia and hypercalciuria Diseases Granulomatous diseases such. B. sarcoidosis, tuberculosis, leprosy, berylliosis, histoplasmosis and Kokzidioidomykosen produce hypercalcemia and hypercalciuria. In sarcoidosis hypercalcemia and hypercalciuria appear to arise to 1,25 (OH) 2D due to unregulated conversion of 25 (OH) D. Presumably, the reason is the expression of the 1-alpha-hydroxylase enzyme in the mononuclear cells of the Sarkoidosegranulome. In a similar way was also reported in hypercalcemic patients with tuberculosis and silicosis through increased serum concentrations of 1,25 (OH) 2D. In other cases, other mechanisms for hypercalcemia must lead because wurden.Immobilisation in some patients with hypercalcemia and leprosy found decreased concentrations of 1,25 (OH) 2D immobilization, particularly a long-lasting complete bed rest (in predisposed patients see Table: Major causes of hypercalcemia) can lead to hypercalcemia and accelerated bone resorption. The hypercalcemia develops within days or weeks after the onset of bed rest. The hypercalcemia repaired promptly when the bed rest is canceled. Young adults with multiple fractures and people with Paget's disease of the bone are during bed rest especially vulnerable to Hyperkalzämie.Idiopathische infantile hypercalcemia Idiopathic infantile hypercalcemia (Williams Syndrome see Table: Examples of microdeletion syndromes) is a very rare, sporadic disorder with facial dysmorphism , cardiovascular changes, renal hypertension and hypercalcemia. PTH and vitamin D metabolism are normal, but the reaction of calcitonin to a calcium infusion can pathologically sein.Milch-alkali syndrome When milk-alkali syndrome are received very large amounts of calcium and absorbable alkali, it was mostly under prevent self-prescribed therapy against dyspepsia with calcium carbonate antacids or osteoporosis. This leads to hypercalcemia, metabolic alkalosis and renal insufficiency. The availability of effective drugs against peptic ulcers and osteoporosis has led to a significant reduction in the incidence of the syndrome. Symptoms and discomfort during a low-grade malignancy are many patients asymptomatic. The clinical manifestations of hypercalcemia include constipation, anorexia, nausea, vomiting, abdominal pain and ileus. Impairment of renal concentration leads to polyuria, nocturia and polydipsia. An increase in the serum calcium> 12 mg / dl (> 3.00 mmol / l) may cause emotional lability, confusion, delirium, psychosis, stupor, and coma. Hypercalcemia may cause neuromuscular symptoms including weakness of skeletal muscles. A hypercalciuria with nephrolithiasis is frequent. Less commonly occurs during prolonged or severe hypercalcemia in reversible acute renal failure, or irreversible kidney damage in a nephrocalcinosis (precipitation of calcium salts within the renal parenchyma). Peptic ulcers and pancreatitis may occur with a hyperparathyroidism in patients. The reason for this is not the hypercalcemia. The severe hypercalcemia leads to a shortening of the QTc interval on the electrocardiogram, particularly in patients with a Glykosidtherapie also arrhythmias can be triggered. Hypercalcemia> 18 mg / dl (> 4.50 mmol / l) can be used for circulatory shock, renal failure and finally death. Diagnosis Total serum (and sometimes ionized) -Kalzium concentration chest X-ray; Determination of electrolytes, blood urea nitrogen, creatinine, ionized calcium, phosphate, PTH, alkaline phosphatase and serum protein immunoelectrophoresis to determine the cause Occasionally PTH and urinary excretion of calcium, with or without phosphate Hypercalcemia is a concentration of the serum calcium diagnosed of> 10.4 mg / dl (> 2.60 mmol / l) or the ionized serum calcium of> 5.2 mg / dl (> 1.30 mmol / l). Hypercalcemia is often discovered by a routine laboratory test. The elevation of serum calcium may be an artifact (see table: laboratory and clinical findings of disorders that cause hypercalcemia). A real ionized hypercalcemia may be masked by low serum proteins. When protein and albumin are pathological and when ionized hypercalcemia is suspected based on clinical findings (eg. As because of the symptoms of hypercalcemia), ionized serum calcium should be determined. Initial examination Initial investigations should include review of medical history, especially of the last serum calcium concentration Physical examination Chest x-ray laboratory tests including electrolytes, blood urea nitrogen, creatinine, ionized calcium, phosphate, PTH, alkaline phosphatase and serum protein immunoelectrophoresis is In ? 95% of patients can be the cause of hypercalcemia identified by the hospital and the test results. In patients in whom no cause of hypercalcemia was found by these investigations, the values ??for intact PTH and calcium in 24-h urine should be measured. If no match is obvious, serum calcium comprises <11 mg / dl (<2.75 mmol / l) at a hyperparathyroidism, or other non-malignant causes out while serum calcium> 13 mg / dl (> 3.25 mmol / l) a malignancy probably makes. Asymptomatic hypercalcemia that is many years or occur in several members of a family that raises the suspicion of a family hypokalzurische hypercalcemia. A primary hyperparathyroidism is usually later in life, but may already exist for many years before it becomes symptomatic. The determination of the levels of the intact PTH may in distinguishing the PTH-mediated hypercalcemia (z. B. due to hyperparathyroidism or a family hypokalzurischen hypercalcemia), wherein the PTH levels are high or normal-high (from most other PTH- independent) causes be helpful. In PTH-independent causes pg / ml, the values ??are usually <20th The chest x-ray is therefore useful in the cause of clarification, since this is where most granulomatous diseases such. reveal as tuberculosis, sarcoidosis and silicosis, as well as primary malignancies of the lung, lytic lesions or lesions by Paget's disease to shoulder, ribs and thoracic spine. In the radiograph of the chest and bone (z. B. skull, extremities) can also watch the bony changes of secondary hyperparathyroidism, usually in for years dialysis patients show. In the osteitis fibrosa cystica in the context of a primary hyperparathyroidism increased by parathyroid hormone hyperstimulation induced osteoclastic activity causes a decrease in bone mass with fibrous degeneration and cystic and fibrous nodules. Since characteristic bone lesions occur only in already far advanced disease, an X-ray examination of the bones is recommended only in symptomatic patients. X-ray images typically exhibit bone cysts in the proximal diaphysis of the long bones, heterogeneous changes in the skull and subperiosteal Knochenresorptionszonen to the phalanges and the distal Schlüsselbeinen.Hyperparathyreoidismus When hyperparathyroidism the serum calcium rarely is> 12 mg / dl (> 3.00 mmol / l), however, is the ionized serum calcium almost always increased. Low serum phosphate concentrations are suggestive of hyperparathyroidism, particularly when they occur in association with increased renal phosphate excretion. When a hyperparathyroidism to increased bone turnover results in the alkaline phosphatase is elevated in serum mostly. Increased intact PTH, particularly when unexpected increase (i. E. A high concentration in the absence of hypocalcemia), or an unduly high concentration of normal (i. E. Despite hypercalcemia) is diagnostically effective. Calcium excretion in the urine is normal or high in hyperparathyroidism usually. Chronic kidney disease makes secondary hyperparathyroidism likely, yet also a primary hyperparathyroidism may occur. In patients with chronic kidney disease indicate a high serum calcium and normal values ??for serum phosphate to a primary hyperparathyroidism, while elevated serum phosphate suggests secondary hyperparathyroidism. The need for the localization of parathyroid tissue prior to surgery on the parathyroid glands is judged different. High-resolution ultrasound, scintigraphic techniques, high-resolution CT scans with or without CT-guided biopsy and immunoassay of thyroid venous outflow, MRI scans and digital subtraction angiography are applied and have proven to be helpful. But this was already high usually cure rate of parathyroidectomy, which can be achieved by experienced surgeons, not increase. Technetium-99 sestamibi, a radionuclide for display parathyroid tissue is more sensitive and specific than older substances that may be helpful in identifying solitary adenomas and today enables minimally invasive surgical techniques. Composed after the operation continues to be a hyperparathyroidism or occurs again, the use of imaging techniques is again necessary and often shows a pathological activity parathyroid gland tissue in unusual places of the neck and mediastinum. Technetium-99-Sestamibi is probably the most sensitive imaging methods. Occasionally, the use of multiple imaging method (MRI, CT or high-resolution ultrasound in addition to investigating with technetium-99m sestamibi) before retrying a parathyroidectomy sein.Malignome indicated a serum calcium> 13 mg / dl (> 3.00 mmol / l ) points to other causes of hypercalcemia as hyperparathyroidism. Calcium excretion in the urine is normal or high with malignancies in general. In the humoral hypercalcemia of malignancy, the PTH is very often reduced or not measurable. Phosphate is usually reduced and metabolic alkalosis, a hypochloraemia and hypoalbuminemia can be found. A supprimiertes PTH differs humoral hypercalcemia of malignancy of a primary hyperparathyroidism. Humoral hypercalcemia of malignancy can be diagnosed by the detection of PTH-related peptides in the serum. Multiple myeloma is assumed by the simultaneous anemia, azotemia and hypercalcemia or monoclonal gammopathy. a myeloma bestätigt.Familiäre hypokalziurische hypercalcemia is a family hypokalzurische hypercalcemia (FHH) by bone marrow examination is very rare, but should be considered in patients with hypercalcemia and elevated or normal-high intact PTH levels into consideration. A FHH is from a primary hyperparathyroidism by the early appearance (it is a lifelong condition), absence of symptoms, the frequency with which there is a hypermagnesemia, and the evidence of hypercalcemia without hypercalciuria in other family members distinguished. The fractional excretion of calcium (ratio of calcium excretion for creatinine) is low at FHH (<1%) and almost always increased when a primary hyperparathyroidism (1-4%). The values ??for intact PTH may be increased or normal, reflecting a change in the feedback mechanisms of the parathyroid glands. Clinical calculator: estimate creatinine clearance with the Cockcroft-Gault equation (SI units) clinical calculator: estimate creatinine clearance by Cockroft-Gault equation clinical calculator: estimation of glomerular filtration rate by the MDRD equation (SI Units) milk-alkali syndrome addition to the history of an increased intake of calcium antacids a combination of hypercalcemia, metabolic alkalosis, and occasionally the occurrence of azotemia with Hypokalzurie is characteristic of the milk-alkali syndrome. The diagnosis is confirmed when the serum calcium concentration back after the completion of calcium and alkali recording quickly back to normal. If a Nephrocalcinosis present, the renal insufficiency may persist. The values ??for circulating PTH are normally reasons supprimiert.Andere A vitamin D intoxication is characterized by elevated 1,25 (OH) 2D concentration. In a hypercalcemia due to a sarcoidosis, granulomatous disease or other in some lymphomas, the serum concentrations of 1,25 (OH) 2D may be increased. In other endocrine causes of hypercalcemia such. As a thyrotoxicosis and Addison's disease, the typical laboratory changes of the underlying disease at diagnosis are critical. Is suspected Mobus Paget, an X-ray radiograph is first prepared, which may have characteristic abnormalities. Laboratory and clinical findings of disorders that cause hypercalcemia cause finding primary hyperparathyroidism increases serum calcium, but <12 mg / dl Ionized serum calcium> 5.2 mg / dL Low serum PO4 (especially at high PO4 excretion via the kidneys) High alkaline phosphatase (often) unexpectedly high PTH normal or high calcium excretion in the urine no endocrine neoplasia family history, no irradiation of the cervical region during childhood, no other obvious causes of hyperparathyroidism (mostly) Secondary Hyperparathyreoi dismus serum Ca low, normal or high, but <12 mg / dl Ionized serum calcium> 5.2 mg / dl High serum PO4 (especially when high PO4 excretion via the kidneys) High alkaline phosphatase (often) unexpectedly high PTH Normal or high calcium excretion via urine Chronic kidney disease (mostly) Humoral hypercalcemia of malignancy serum calcium> 12 mg / dl low Normal PTH or low PO4 If necessary, metabolic alkalosis, hypochloraemia and hypoalbuminemia Family hypokalzurische hypercalcemia ratio of calcium clearance to creatinine clearance <1% hypermagnesemia (often) High or normal PTH Lifetime and asymptomatic hypercalcemia hypercalcemia without hypercalciuria in patients and relatives milk-alkali syndrome No hypercalciuria Metabolic alkalosis azotemia (occasionally) Low PTH (mostly) normalization of serum calcium if the calcium and alkali-taking is terminated High intake of calcium antacids (mostly) Ca = calcium; PO4 = phosphate, PTH = parathyroid hormone. Treatment Oral phosphate at serum calcium <11.5 mg / dl with mild symptoms and without renal disease intravenous saline and furosemide for a faster correction with increased serum calcium <18 mg / dl bisphosphonates or other calcium-lowering drugs in serum calcium 11.5 to 18 mg / dl and / or moderately severe symptoms hemodialysis in serum calcium> 18 mg / dl Surgical removal at moderately severe, progressive primary hyperparathyroidism and occasionally with mild disease phosphate restriction and binders and occasionally calcitriol in secondary hyperparathyroidism There are 4 basic plenty to do even for lowering serum calcium: reduction of intestinal calcium absorption increased calcium excretion in the urine reducing Kn ochenresorption remove excess calcium by dialysis The applied therapy depends on the severity and cause of hypercalcemia. Volume replacement with saline solution is an essential element of care. Mild hypercalcemia In low-grade hypercalcemia (serum calcium <11.5 mg / dL [<2.88 mmol / l]) with discrete symptoms is pushed to treatment and diagnosis. Once diagnosed the underlying disease is treated. If the symptoms are already pronounced a therapy to reduce serum calcium is required. Oral phosphate administration can be tried. When phosphate is taken with meals, it binds calcium and prevents absorption. The dose at the beginning of 250 mg Phosphate (as sodium or potassium salt) of 4-times daily. The dose may be increased up to 500 mg four times daily as needed until the occurrence of diarrhea. Another treatment option would be to increase the excretion of calcium in urine by means of the common application of isotonic saline and a loop diuretic. be the start of treatment, if no failure is present, if 1-2 L of brine, as almost all patients are hypovolemic with a relevant hypercalcemia. Furosemide iv at a dose of 20-40 mg every 2-4 hours will be administered as needed to a diuresis of about 250 ml / hour (measured hourly) maintain. A volume depletion must be avoided. In order to prevent a hypokalemia and hypomagnesemia, the concentrations of potassium and magnesium during the treatment can be measured every 4 hours, and if necessary, intravenously substituted. The serum calcium begins to drop within 2-4 hours and reached within 24 hours almost normal Werte.Mittelgradige hypercalcemia A moderate hypercalcemia (serum calcium> 11.5 mg / dL [<2.88 mmol / l] and <18 mg / dl [ <4.51 mmol / l]) can with an isotonic saline solution and a loop diuretic, such as at light hypercalcemia be treated. In Abhängigkeit von der Ursache können auch Substanzen verwendet werden, die die Knochenresorption vermindern (gewöhnlich Bisphosphonate, Calcitonin oder eher selten Plicamycin oder Galliumnitrat). Auch Kortikosteroide oder Chloroquin werden verabreicht. Bisphosphonateinhibieren Osteoklasten. Sie sind normalerweise die Medikamente der Wahl in der Therapie der malignomassoziierten Hyperkalzämie. Zoledronat kann in einer Dosierung von 48 mg i.v. verwendet werden und senkt die Serumkalziumspiegel sehr wirksam im Durchschnitt > 40 Tage. Pamidronat kann bei der malignomassoziierten Hyperkalzämie als Einmaldosis von 3090 mg i.v. mit einer Wiederholungsdosis nach 7 Tagen gegeben werden. Es senkt das Serumkalzium für ? 2 Wochen. Ibandronat 46 mg i.v. kann bei malignomassoziierter Hyperkalzämie gegeben werden; es ist für ca. 14 Tage wirksam. Etidronat 7,5 mg/kg i.v. 1-mal täglich für 35 Tage wird bei der Therapie des Morbus Paget und der malignomassoziierten Hyperkalzämie angewendet. Die Erhaltungsdosis beträgt 20 mg/kg p.o. 1-mal/Tag; ist die GFR niedrig, muss die Dosis reduziert werden. Eine wiederholte intravenöse Gabe von Bisphosphonaten zur Behandlung von Hyperkalzämie, die mit Knochenmetastasen oder Myelom assoziiert ist, ist mit einer Osteonekrose des Kiefers in Verbindung gebracht worden. Einige Berichte deuten darauf hin, dass dies häufiger mit Zoledronat auftritt. Bei Patienten, die Zoledronat einnehmen, wurde von renale Toxizität berichtet. Orale Bisphosphonate (z. B. Alendronat oder Risedronat) können versucht werden, um Kalzium im Normalbereich zu halten, werden jedoch nicht allgemein zur akuten Behandlung von Hyperkalzämie verwendet. Denosumab, 120 mg s.c. alle 4 Wochen mit zusätzlichen Dosen an den Tagen 8 und 15 des ersten Behandlungsmonats, ist ein monoklonaler Antikörper-Inhibitor der Osteoklastenaktivität, der für die Krebs-assoziierte Hyperkalzämie verwendet werden kann, die nicht auf Bisphosphonate reagiert. Kalzi