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Hypercalcemic Crisis

Medizinische Universitätsklinik und Poliklinik, Heidelberg, Germany.

Correspondence to Dr. Reinhard Ziegler, Medizinische Universitätsklinik und Poliklinik, Bergheimer Strasse 58, D-69115 Heidelberg, Germany. Phone: 6221-568601; Fax: 6221-56522; E-mail: sekretariat_ziegler{at}med.uni-heidelberg.de

Abstract

Abstract. Hypercalcemia may decompensate from a more or less chronic status into a critical and life-threatening condition, hypercalcemic crisis. In the majority of cases, primary hyperparathyroidism is the cause; humoral hypercalcemia of malignancy or rarer conditions of hypercalcemia will decompensate less often. The leading symptoms that characterize the crisis are oliguria and anuria as well as somnolence and coma. After a hypercalcemic crisis is recognized, an emergency diagnostic program has to be followed either to prove or to exclude primary hyperparathyroidism. In the first case, surgical neck exploration is the only way to avoid fatal outcome. The diagnostic program should be performed within hours; during this time, serum calcium should be lowered. Treatment of choice is hemodialysis against a calcium-free dialysate. Bisphosphonates could be useful as adjuvant drugs.

Hypercalcemic crisis is a condition involving the decompensation of hypercalcemia, which could have existed for longer periods or could be acute at the first instance of this electrolyte disturbance. Compensated hypercalcemia is caused by malignancies in 70% of cases, by primary hyperparathyroidism (pHPT) in 20% of cases, and by other (rarer) conditions in the remaining 10% (1); the majority of cases of hypercalcemic crisis are caused by pHPT (2). The disease is then parathyrotoxic crisis. The following case history should illustrate this situation (3).

A 42-yr-old woman had experienced episodes of nausea and stomach pain for approximately 1 yr. Three months before admission, she felt weak and lost initiative; these symptoms were related to professional and familial stress. An outpatient examination revealed increased alkaline phosphatase levels. Because other liver function test results were normal, the alkaline phosphatase was thought to be of skeletal origin. Skeletal scintigraphy demonstrated only nonspecific spots near the ankles. Further examinations were refused. The patient developed tiredness, vomiting, weight loss, and dehydration, and she needed to be admitted to the hospital. Clinical chemistry assays revealed extreme hypercalcemia of 5.9 mM, mild hypokalemia of 3.1 mM, and borderline creatinine and urea concentrations. Fluid supply for rehydration decreased the calcium concentration only to 5.4 mM; the patient was oliguric. Three days later, she was transferred to our hospital, presenting with hypercalcemic crisis. Renal insufficiency and somnolence were the primary symptoms. From the history of the patient, previous goiter resection must be noted.

A diagnostic program to exclude causes other than pHPT was initiated. To decrease the calcium concentrations, the patient received (in addition to intravenously administered saline solution and furosemide) 300 mg of clodronate administered intravenously, 100 mg of prednisolone administered intravenously, and 100 units of calcitonin administered subcutaneously. Because diuresis did not begin within 6 h, hemodialysis was performed, using a calcium-free dialysate. After 12 h, arteriovenous hemofiltration was performed for further lowering of the serum calcium concentrations, and then hemodialysis was repeated. Clodronate (300 mg) administration was repeated after 12 h, and calcitonin (100 U) was administered subcutaneously every 4 h.

Meanwhile, the diagnostic procedure led to the diagnosis of parathyroid toxicosis. There was no evidence for tumoral hypercalcemia, and parathyroid hormone (PTH) levels, measured in a fast assay, were 2.5-fold elevated. Neck surgery was performed. The patient was asystolic for seconds when anesthesia was initiated, but the operation could be performed. A parathyroid adenoma of 8.3 g was found and removed. Post-operatively, the patient again became asystolic. Despite all efforts at resuscitation, the patient could not be revived. An autopsy revealed nephrocalcinosis and severe myocardial calcinosis.

Approximately 20 yr ago, there were more reports of hypercalcemic crisis (2). It is evident that the current use of earlier fluid supply for critically ill patients and optimized strategies for intensive care medicine have made hypercalcemic crisis a rare event. However, the life-threatening condition requires rapid action, to avoid a lethal course such as in this case.

Pathophysiologic Features and Clinical Findings

Calcium homeostasis has been a very stable system from early periods of evolution. Our extracellular fluid, including the circulation, conserves the calcium content of the primordial ocean. When life left that ocean to live on land, systems for the maintenance of optimal calcium concentrations in body fluids were developed. Calcium was no longer the content of the surrounding water; it needed to be taken in and conserved from food. The skeleton had the double tasks of taking up calcium for stability and acting as a depot for times of poor calcium supply.

PTH is one of the principal factors in the prevention of hypocalcemia. By decreasing calcium excretion, increasing calcium absorption (via calcitriol), and resorbing depot calcium from the skeleton in cases of emergency, it is a major contributor to normocalcemia. If PTH is autonomously secreted in excess, e.g., in pHPT, hypercalcemia develops.

Renal PTH effects are threefold. In addition to the increase in calcium reabsorption, PTH stimulates phosphaturia. Phosphate loss favors an increase in blood calcium levels via the constancy of the calcium x phosphorus ion product. Being a glandotrophic hormone, PTH activates renal 1--hydroxylase and increases the formation of calcitriol. Normal concentrations of PTH stimulate bone turnover without bone loss, whereas PTH excess induces bone resorption to an extent that cannot be compensated for by new bone formation. In this situation, the released calcium is needed for the prevention of hypocalcemia and is not recycled into the newly formed bone.

The kidneys act as one of the regulatory elements of calcium homeostasis by increasing or decreasing calciuria. If calciuria is abruptly stopped because of renal insufficiency, stored calcium may induce a phase of hypercalcemia until the other regulatory links have adapted and counter-regulated levels.

Intestinal calcium absorption is increased if higher levels of calcitriol are present. Whether increased calcitriol concentrations result from hyperparathyroidism or diseases with increased calcitriol formation (sarcoidosis and other diseases) does not make a difference. With the complexity of malignant diseases, several mechanisms may lead to hypercalcemia, including the paraneoplastic production and secretion of calcitriol, the production of PTH-related peptide (PTHrP), and the production of hypercalcemic cytokines such as interleukin-1, interleukin-6, tumor necrosis factor-, and prostaglandins (4).

In addition to these endogenous causes of hypercalcemia, exogenous factors may play causative roles. One factor consists of medications that induce hypercalcemia (vitamin D and its analogs and vitamin A). Another factor involves immobilization of individuals with labile calcium homeostasis. Immobilization reduces the inflow of calcium into the skeletal tissue, and calcium is released into the circulation. If the homeostatic capacity of a patient is already under stress because of preexisting diseases (severe osteoporosis, acute severe fractures, or Paget's disease of the bone), immobilization can be accompanied by hypercalcemia. Furthermore, endocrinopathies can be accompanied by hypercalcemia. Thyroid hormone in excess accelerates bone turnover; therefore, severe thyrotoxicosis can be accompanied by hypercalcemia. Glucocorticoids are involved in calcium homeostasis, with a calcium-lowering activity (antagonism to PTH). If glucocorticoid levels are acutely decreased, hypercalcemia can result (acute Addison's disease or acute removal of adrenal tumors with hypercortisolism).

All of these conditions have the character of diseases; the only exception is benign familial hypocalciuric hypercalcemia (FHH) (5). Because of an inherited defect of the calcium sensor of parathyroid cells, the inhibitory feedback effects of calcium on PTH secretion begin only at hypercalcemia. Calciuria is decreased and contributes to this hypercalcemia. This condition is a disturbance but not a disease.

Hypercalcemia induces functional disturbances in a group of organs, which are considered together as the "hypercalcemic syndrome" (2). Single components are often nonspecific and are also observed in many other diseases. If several components of the syndrome are present, hypercalcemia is suggested (Table 1). Because serum calcium concentration determinations are not very expensive, they should be performed in cases with single symptoms and in all cases of the syndrome.

Renal symptoms are polyuria and polydipsia. Diabetes hypercalcemicus must be investigated in any case of polyuria, especially when diabetes mellitus, diabetes insipidus, and tubulopathies have been excluded. Diuresis attributable to hypercalcemia is accompanied by potassium loss; hypercalcemia generally leads to hypokalemia.

Intestinal symptoms are nausea, vomiting, and constipation more than diarrhea. The secretion of gastric acid and pancreatic enzymes is increased.

Central nervous system symptoms are less characteristic, including tiredness, headache, components of an endocrine psychologic syndrome (e.g., loss of initiative), and depression. Cardiac symptoms also are nonspecific. The QT interval is shortened, and tachycardias may be observed. The increased sensitivity to digitalis is relevant. The mechanism of hypertension accompanying chronic hypercalcemia attributable to pHPT is unclear. Chondrocalcinosis (pseudogout) is occasionally observed.

When hypercalcemia reaches a critical level (>4 mM), two organs are at risk for decompensation. Polyuria may develop into oliguria and finally anuria, especially in case of exsiccosis. Untreated hypercalcemic renal insufficiency is lethal. The other organ at risk is the brain. Psychologic disturbances may develop into somnolence and finally coma. For all patients with comas of questionable cause, a calcium-related coma must be excluded.

When these symptoms of the hypercalcemic syndrome are accompanied by additional symptoms that are characteristic of a causal disease, the final diagnosis is facilitated. The so-called organ manifestations of pHPT, such as renal stones, hyperparathyroid bone disease, and recurrent peptic ulcers, may indicate pHPT. Hyperthyroidism presents with its typical symptoms. Hypercalcemia of malignancy must be considered in cases with histories of, for example, previous breast cancer (for women) or lung cancer or myeloma (for both men and women).

Diagnosis

The introduction of immunoassays for intact PTH-1-84 was a breakthrough in the diagnosis of hypercalcemic states. The simultaneous occurrence of hypercalcemia and increased (or nonsuppressed) PTH levels proves the parathyroid origin of the hypercalcemia. The parathyroid glands are at least contributing, even if another cause may be involved. If intact PTH levels are low and suppressed, parathyroid involvement is excluded and other possibilities must then be investigated (Table 2). As a rule, elevated PTH levels in hypercalcemia are caused by pHPT. A variant is tertiary hyperparathyroidism after a history of long-lasting renal insufficiency. Extremely rare is the paraneoplastic production of true PTH (6). FHH is sometimes a trap. The lack of true symptoms and organ manifestations must be taken into consideration; the best diagnostic clue is the calcium clearance/creatinine clearance ratio, which is <0.01 in FHH.

Most patients who present with nonparathyroidal hypercalcemia suffer from a malignant disease. In cases in which there are no symptoms indicating pHPT, the search for a malignant disease should be initiated early. Approximately one-half of the patients have elevated blood levels of PTHrP. This finding is observed in many cases of cancer of the lung, esophagus, skin, kidney, pancreas, liver, colon, or ovary. Even hemoblastosis may produce PTHrP. If PTHrP levels are low, other osteolytic factors may be produced by the tumor. Calcitriol levels are sometimes increased. Other cases demonstrate the production of interleukin-1, -6, or -11, transforming growth factor- or -, interferon, or granulocyte/macrophage colony-stimulating factor. We recommend only the measurement of PTHrP; the measurements of the other factors are expensive and not as reliable. The result is of no importance for the treatment, which should be uniformly performed with bisphosphonates.

The rare nonmalignant, non-parathyroid-related hypercalcemias generally provide some hints in the clinical findings. Difficulties may arise in cases of iatrogenic hypercalcemia. If the patient does not reveal that he or she took, for example, vitamin D (as in Münchausen's syndrome), diagnosis may be difficult (7). It is not too rare for hypercalcemia to be caused by more than one disease (e.g., immobilization in osteopathies). In cases of severe hypercalcemia in which PTH levels are only mildly elevated, the possibility of a second diagnosis should be considered. There have been frequent reports of the coincidence of pHPT and sarcoidosis (8), thyrotoxicosis (9), and other conditions.

In cases of compensated hypercalcemia without relevant renal insufficiency, diagnoses can be made in a conventional way. However, hypercalcemic crises require early treatment, so that the life of the patient is not at risk.

Because hypercalcemic crises are predominantly parathyrotoxic crises, pHPT must be proven or excluded. Proven pHPT requires emergency surgery performed by an experienced surgeon. Surgeons who do not often perform parathyroid exploration should refer their patients elsewhere.

The following diagnostic program is recommended: (1) careful history and examination; (2) x-rays of the head, thorax, vertebral column, pelvis, and long bones, to exclude osteolytic lesions attributable to pHPT, metastases, myeloma, or lung cancer; (3) ultrasound examination of the abdominal organs, to exclude hepatic, pancreatic, renal, or gynecologic tumors (occasionally, kidney stones or nephrocalcinosis indicates pHPT); and (4) laboratory studies such as phosphate, potassium, creatinine, urea, alkaline phosphatase, sedimentation rate, and proteinuria measurements (hypercalcemia is known) and blood smears. Fast PTH measurement is only occasionally available.

If all findings are generally normal and no tumor is found, pHPT should be suspected. Ultrasound examination of the neck region is recommended; it reveals a hypoechogenic nodule, consistent with a parathyroid adenoma, in approximately two-thirds of cases. Experienced surgeons are content with this result, but inexperienced surgeons are not more satisfied after computed tomographic and magnetic resonance imaging examinations, which cause further delay.

During this diagnostic procedure, the patient should be receiving symptomatic treatment (see below). The combination of calcium lowering within 12 to 24 h and emergency diagnostic testing should permit surgical treatment of pHPT within 24 h.

Treatment

Except in cases of FHH, hypercalcemia is always a risk for patients. The risk is present even in cases of so-called asymptomatic pHPT. Observation of patients without surgery is permitted (10); the guarantee of regular diuresis and the avoidance of additional factors such as immobilization cannot always be achieved. If patients are hypercalcemic, they must be warned that regular drinking of fluids low in calcium represents a kind of life insurance. Patients should know all symptoms of the hypercalcemic syndrome and should ask their doctors for calcium control in case of any such symptoms.

If hypercalcemia is relevant (>2.8 mM), fluid supply should be defined. Patients should drink approximately 3 liters/d, to produce a urinary volume of 2 to 2.5 liters. Diuresis in this range requires the control of potassium (as well as calcium) in the blood (Table 3).

When the calcium concentration increases above 3 mM, often drinking is no longer sufficient. Nausea and even vomiting may begin; the intravenous infusion of saline solution is the treatment of choice. Again, potassium substitution must be considered.

Diuresis can be increased with furosemide. Lower doses stimulate natriuresis, which is accompanied by calciuresis. A direct calciuretic effect of furosemide should be expected at high doses of 100 mg/h (11).

Especially in cases of humoral hypercalcemia of malignancy, the administration of bisphosphonates should be considered early. Available preparations are clodronate, pamidronate, and ibandronate. Table 3 documents the increase in potency in this family of drugs. The advantage of the morepotent bisphosphonates is the need for smaller amounts, which means that the infusion time can be shortened. In cases with normal renal function, ibandronate can even be administered as a bolus; without time pressures, we prefer to perform infusions in 1 to 2 h. We think that the highly potent bisphosphonates limit the requirement for calcitonin, which may produce side effects and which quickly becomes inactive because of the escape phenomenon (12). Because of the availability of the highly potent bisphosphonates, mithramycin (which was of great utility in the pre-bisphosphonate period) is no longer needed.

Hypercalcemias accompanying neoplasias are often chronic. It is then recommended that the bisphosphonate treatment be accompanied by a reduction in the dietary calcium supply. Diets low in calcium and vitamin D are recommended.

Glucocorticoids exert a calcium-lowering effect by reducing calcium absorption. They are indicated only for rare hypercalcemias such as intoxicosis with vitamin D or its analogs. The treatment of some hemoblastoses, e.g., myeloma, also includes glucocorticoids. They may then exert "cytostatic" effects as well as antiabsorptive effects in the gut.

Hypercalcemic crisis requires a special accelerated strategy. The first question to answer is the following: is diuresis possible and efficient? If yes, intravenous saline treatment, supported by furosemide, should be combined with a potent bisphosphonate.

If diuresis is restricted and does not promise a relevant effect within a few hours, hemodialysis is the treatment of choice. We recommend that hemodialysis be performed in a unit with sufficient expertise. The dialysis bath should be low in or free of calcium, depending on the individual situation.

Contraindicated medications during hypercalcemia are digitalis and hydrochlorothiazides. Digitalis may produce cardiac arrest if administered during hypercalcemia. Thiazides reduce calciuria and thus contribute to the severity of hypercalcemia.

As mentioned, diagnostic testing should proceed in parallel with the symptomatic calcium-lowering treatment. Hypercalcemic crisis is a situation that requires improvement within hours.

Conclusions

Hypercalcemic crisis is a life-threatening condition that is currently rather rare; however, it presents the risk that medical action may be too slow. Most cases of hypercalcemic crisis are attributable to decompensating pHPT. They require neck surgery performed by an experienced endocrine surgeon.

Within 12 to 24 h, two problems must be solved. On one hand, a short diagnostic program should lead to the exclusion of neoplasias producing hypercalcemia. On the other hand, those hours should also be used to lower serum calcium levels. One method is forced diuresis combined with the use of highly potent bisphosphonates; in cases of impaired renal function, calcium-free hemodialysis is the treatment of choice. Hypercalcemic crisis should be treated in a unit with appropriate expertise.

Acknowledgments

This work was presented at the 6th Colloquium Dresden, Intensive Care Nephrology 2000, May 26 to 27, 2000.

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