Mrs. Chu, a 76 yr. old female was referred to our emergency department for ESWL on Mar. 23, 1991 due to sudden onset of generalized abdominal pain of 1 day. She had history of right nephrolithiasis and left ureterolithiasis to which the anorexia, nausea, and vomiting were ascribed at Chia-yi VH. Physical exam revealed an ill-looking and apprehensive individual with diffuse abdominal tenderness and abdominal distension. Bowel sounds was noted to be absent with rebounding pain. Lab data revealed marked leukocytosis of 33,000 with neutrophil 83%, BUN and Creatinine were at 52 and 3.1 mg/dl respectively. She remained hypotensive despite fluid resuscitation. Sonogram of abdomen revealed intra-abdominal fluid accumulation. Under the impression of perforated peptic ulcer, emergent laparotomy was done which revealed a 1 cm perforated hole at the duodenal bulb with turbid ascites. Hence, hemigastrectomy with B-II anastomosis was done. Patient recovered smoothly from the abdominal operation until 1 week later, she was noted to be drowsy and weak. Laboratory data revealed hypercalcemia at 13.6 mg/dl, alkaline phosphatase: 138 mg/dl. Under the impression of hypercalcemic crisis, aggressive medical treatment with hydration, furosemide, calcitonin were given but failed to offer any improvement. In fact, serum calcium went up to as high as 17.2 mg/dl. Hence, emergency neck exploration was done with removal of a 23 gm of parathyroid adenoma resulting in prompt improvement in consciousness within 24 hours. Post-op hypocalcemia was noted which needed calcium replacement. Unfortunately, upper gastrointestinal bleeding was repeatedly noted with progressive deterioration in renal function necessitating hemodialysis. Despite aggressive H2 blocker treatment, tarry stool persisted and serum gastrin level determination revealed normal result which negated our suspicion of Zollinger-Ellison's syndrome. She was treated supportively until 2 weeks after parathyroidectomy, patient started to have deterioration in level of consciousness and rapidly lapsed into coma. Laboratory data revealed BUN and Creatinine up to 118 and 4.4 mg/dl respectively. Chest X-ray revealed pulmonary edema. Despite aggressive treatment, patient went into multiorgan failure and died one month later.

Hypercalcemia is a frequently neglected medical problem, especially in those hospitals without routine serum calcium measurements. Among its many causes (Table 1), by far, the most common (80-90%) are malignancy and primary hyperparathyroidism (primary HPT). In Western countries, primary HPT comprises the majority of hypercalcemic patients among the ambulating population, but malignancy consists up to 65% of such patients admitted in the hospital. Acute hypercalcemia is most often caused by the former but it can be caused by the latter, or rarely by other disorders. In Taiwan and also other Asian countries, the prevalence of primary HPT is low. However, in the emergency setting of VGH. Taipei, it accounts for a significant percentage (6%) of those with hypercalcemic crisis necessitating urgent attention.(Table 2) The acute hypercalcemia due to 1primary HPT is named parathyroid crisis according to Bilezikian. Its synonyms included hyperparathyroid crisis, acute HPT or pernicious HPT. Since its symptoms and signs is similar to the patient of parathyroid hormone intoxication described by Hanes in 1939, it is also called parathormone intoxication.

Most patients with parathyroid crisis have remarkable elevation of serum concentration of PTH ( ten times of normal ), whereas virtually in all patients with cancer-related hypercalcemia, the serum PTH level are low. Hypercalcemia in patients with cancer is usually due to secretion of parathyroid hormone related protein (PTH-rP) by the tumor. Less often, it is caused by the secretion of other bone-resorbing substances by the tumor (osteolytic activating factors, OAF ), 1-a-hydroxylase which converts 25-OH-vit D to 1,25-(OH)2 vit D by the tumor, or the local effects of osteolytic bone metastases. The process leading to hypercalcemic crisis is initiated by accelerated bone resorption due to activation of osteoclasts by PTH, PTH-rP. Excessive absorption of calcium from GI tract is usually not an important cause of hypercalcemia unless the patient has vit D intoxication without restriction of calcium intake. Hypercalcemia develops when the entry of calcium from bone into the extracellular space overwhelms the normal mechanisms that maintain normocalcemia. One of these mechanisms--the suppression of parathyroid hormone secretion by calcium--is obviously negated when the cause of accelerated bone resorption is parathyroid hormone. In cancer-associated hypercalcemia, the secretion of parathyroid hormone is suppressed, but the humoral factors that activate osteoclasts are secreted autonomously. In the setting of accelerated bone resorption, the kidney becomes the principal defense against hypercalcemia. When renal function is normal, the tendency for the serum calcium level to rise is attenuated by increased urinary excretion of calcium.

A cascade of events is responsible for the development of severe hypercalcemia. First, the factors that induce osteoclast-mediated bone resorption, such as parathyroid hormone or parathyroid hormone-related protein, also stimulate renal tubular reabsorption of calcium, impairing the ability of the kidneys to excrete the increased filtered load of calcium. Second, the hypercalcemic state interferes with the renal mechanisms for the reabsorption of sodium and water, leading to polyuria. This polyuria may not be matched by a commensurate oral intake of fluid because of anorexia and nausea, frequent symptoms of hypercalcemia. The result is a depletion in the volume of extracellular fluid and a reduction in the glomerular filtration rate, which further increases the serum calcium concentration. Hypercalcemia may be exacerbated by immobilization, another stimulus for the loss of bone-related calcium, in severely illed patients. To a greater or lesser extent, these pathophysiologic mechanisms are operative in virtually all patients with severe hypercalcemia.

The most generally accepted criteria of hypercalcemic crisis include an extreme high concentration of serum calcium, usually >14 mg/dl or ionized calcium above 7.5 mg/dl, associated with acute symptoms and signs that are reversible with correction of the hypercalcemia. The acute clinical findings invariably included of volume depletion, metabolic encephalopathy, and gastrointestinal symptoms. There may be associated renal and cardiovascular manifestations beyond those attributable to volume contraction. The term crisis connotes clinical instability in which decisive intervention must take place to avoid irreversible damage. In this setting, the volume depletion, neurologic manifestation, and cardiac arrhythmias all contribute to this life threatening situation. Initially, the patient commonly have anorexia, nausea, vomiting and constipation. Fatigue and muscle weakness, polyuria and polydipsia were frequently observed. As hypercalcemia progress, dehydration, decreased renal function and deterioration of mental status begin to manifestate. Confusion, coma, and if untreated, death ensues.

Invariably, the patient may have hypercalcemia in the past but left untreated or inadequately treated. Often there is no apparent reason for sudden progression of hyperparathyroidism to critical state except parathyroid cancer. In English literature, there were case reports of parathyroid tumor with acute elevation of serum calcium after irradiation therapy, over manipulation during teaching round and fine needle aspiration biopsy. This signifies the possibility of induction of crisis by local stimulation. According to Romanus, about 1/4 of the patients with parathyroid crisis had their life threatening condition occurred soon after previous operations, trauma or other critical diseases. The author summarizes as followings ( Table 3 ) the intercurrent diseases or events before parathyroid crisis documented in English literatures as well as his own experiences in this hospital:

1. Medical conditions precipitate hypercalcemia ( number of patients )
   1. upper respiratory tract infection (4)
   2. myocardial infarction (2)
   3. upper GI bleeding (1)
   4. hyperthyroidism (1)
   5. pulmonary embolism (1)
   6. abdominal sepsis (1)
2. Surgical conditions precipitating hypercalcemia
   1. ureterolithotomy (4)
   2. multiple trauma (2)
   3. bilateral total hip replacement (1)
   4. thoracotomy (1)

It seems that the occurrence of hyperparathyroid crisis is related to severe dehydration, physiologic stress and long term immobilization.

In general, the higher the level of serum calcium, the more likely that malignancy is the underlying cause for the hypercalcemia. Nevertheless, acute primary HPT with marked elevation of PTH is associated with equally severe hypercalcemia. The majority of patients with acute HPT have long-standing hypercalcemia, very large parathyroid adenomas (40%), radiographic evidence of osteitis fibrosa cystica (OFC) (50%) and a history of urolithiasis (60%). This presentation is similar to that observed in parathyoid cancer. OFC is virtually never seen in hypercalcemia associated with malignancy. Serum Cl, P, Cl/P ratio, and urinary C-AMP are not helpful in the differential diagnosis of hypercalcemia because of the overlap values in HPT and hypercalcemia caused by PTH-rP. Serum 1,25(OH)2D level are normal or elevated in patients with HPT and low in hypercalcemia of malignancy. Therefore, in patients with low PTH, measurement of serum 1,25(OH)2D may be useful in distinguishing sarcoidosis ( or other granulomatous disease ) and some lymphomas in which 1,25(OH)2 are high. The glucocorticoid suppression test has been used to separate patients with certain malignancy and granulomatous disease from HPT. The administration of hydrocortisone (40mg, tid) to patients with breast cancer, myeloma, lymphoma or granulomatous disease will lead to normalization of serum calcium, while rarely in HPT. HPT is associated with an increased occurrence of malignancy up to 50 times of normal population. On occasion, hypercalcemia has been attributable to cancer when underlying HPT is responsible. In case of emergency, if the serum alk-P level is elevated, roentogenogram of hands should be obtained. The presence of subperiosteal resorption suggests the diagnosis of an HPT. Nevertheless, there are occasions an OFC may simulate metastatic cancer and mislead the management.

Immediate and effective therapy directed toward the pathophysiology of hypercalcemia is essential. General measures must be implemented to reverse the dehydration, to promote urinary calcium excretion, to avoid prolonged immobilization, and to identify the underlying cause of hypercalcemia. Specific measures directed at inhibiting bone resorption, increasing renal sodium and calcium excretion, and occasionally at decreasing intestinal absorption of calcium or blocking vit D metabolism should also be implemented.( Table 4 )

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3. Management of acute hypercalcemia Bilezikian JP. N Engl J Med 326:1196-1203, 1992
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