Acute Hyperparathyroidism: A Surgical Emergency

Acute Hyperparathyroidism: A Surgical Emergency THOMAS J. ANGLEM, M.D., F.A.C.S. *

Hyperparathyroidism is not generally regarded as a lifethreatening disease. Recognized principally in its chronic forms associated with the characteristic skeletal changes of osteitis fibrosa cystica and renal calculus disease, and more recently with a variety of gastrointestinal disturbances, especially duodenal ulcer and pancreatitis, its potential for culminating in the extremely lethal complication of acute hypercalcemic crisis is not widely recognized. That there is a general lack of awareness of the lethal character of acute hyperparathyroidism and of the symptom complex which should lead to its recognition is borne out by the record of past experience. Of 82 cases recorded in the literature, 47 or 57 per cent have terminated fatally and of 40 cases reported since 1960, 21 or 52 per cent ended in death. Hypercalcemic crisis of hyperparathyroidism, with extremely rare exceptions, terminates fatally unlAss the hyperfunctioning parathyroid tissue is removed surgically. Early recognition and immediate surgical intervention are imperative, not only to save life, but also to prevent irreversible renal damage, which develops at an alarmingly rapid pace during the period of crisis. That the syndrome of acute hyperparathyroidism is not more widely known among surgeons is unfortunate, but in a measure it is understandable; first, because of its infrequent occurrence, and secondly, because of the extreme variability and subtle onset of its manifestations.

HISTORY Only ten years ago, James and Richards44 could find reports in the literature of only 14 cases of acute hyperparathyroidism to which they added one of their own. It is something of a paradox, too, that the recorded reports of a syndrome,

* Associate Clinical Professor of Surgery,

Boston University School of Medicine; Staff, Massachusetts Memorial, New England Deaconess and Baptist Hospitals, Boston, Massachusetts

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which represents an acute surgical emergency and for which the sole effective treatment is surgical, should have appeared predominantly in nonsurgical journals. Of 27 reports in the English language literature prior to 1960, only four were in surgical journals and two were in a urological journal. Since 1960, only 10 of 22 additional reports have appeared in surgical journals. The first account of the grave consequences of hypercalcemic poisoning was recorded by Dawson and Struthers24 in 1923. A male patient of 49, who had been treated for delayed union of a fracture of the left humerus and later for a second fracture 2 inches above the first, was admitted to the hospital for a third time in collapse with a rapid, feeble pulse and died the next day. At autopsy, a parathyroid adenoma the size of a walnut was found, and, in addition, extensive generalized calcification in virtually all of the internal organs, including the heart, lungs, spleen, liver, kidneys, and walls of the medium and small arteries. This antedated by three years CoUip'sl4· 15 experimental production of parathyroid poisoning by injection of his preparation of thyroid extract into dogs. The injections produced vomiting, diarrhea and marked muscular atony. Serum calcium levels became elevated to about 20 mg. per 100 ml., but declined somewhat prior to death. Marked dehydration and hemoconcentration occurred and the serum phosphorus and nonprotein nitrogen became elevated prior to death. Postmortem studies revealed calcium deposition in the heart, lungs, kidneys and stomach. Cantarow, Stewart and Housell l injected from 100 to 300 units of parathyroid extract into dogs four times daily for a period of three days, and observed in postmortem studies varying degrees of congestion, hemorrhage, edema and calcium deposition. They found no evidence that the extensive regressive changes in the myocardium, stomach or kidneys were dependent on vascular phenomena such as stasis and thrombosis. Degeneration in these and other organs they believed to be a direct toxic effect of the parathyroid hormone. Varying degrees of calcification were found in heart muscle and kidneys, especially the renal tubular epithelium, and in the stomach, duodenum and thyroid. They made the interesting observation of the absence of either degeneration or calcification in nine living fetuses removed from one of the experimental animals and concluded from this that the parathyroid hormone does not pass the placental barrier and that the changes observed in the experimental animal are not dependent upon the hypercalcemia per se, but are the result of a direct effect of the parathyroid hormone. The earliest recorded clinical cases of acute hyperparathyroidism were reported by Wanke 82 in 1930 and Bergstrand 6 in 1931. Four years prior to Wanke's first case, Felix Mandl 64 had done the first operation for removal of a parathryoid tumor for osteofibrosa cystica. Lowenberg and Ginsburg 51 in 1932 reported the first case in the English literature-in this instance, an inadvertent clinical counterpart of the Collip experiment resulting from the accidental overdosage of a boy being treated with parathyroid extract for purpura hemorrhagica. By the third day of treatment the child became listless. On the fourth day vomiting was pronounced and general physical depression was severe. By the fifth day he had developed a high, irregular fever and his condition was considered critical. On the sixth day the error in dosage was discovered and his serum calcium was found to be 19.6 mg. per 100 ml. His condition improved rapidly after discontinuance of the parathyroid extract and by the ninth day thereafter his serum calcium was 9.7 mg. In 1939, Hanes36 reported one case and Oliver59 two cases of an acute para~ thyroid crisis due to a parathyroid adenoma. All three cases terminated fatally,. and all three at postmortem showed the classical findings of widespread tisSlle injury and generalized calcifications of internal organs similar to those observed in Dawson and Struther's case and strikingly similar to the findings in the experimental animals.

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In a survey of the literature in 1964, Payne and Fitchett 60 recorded reports of 70 cases of acute hyperparathyroidism, including the case of Lowenberg and Ginsburg. One of the three cases of Waife's80 which were included did not seem to us to fulfill the requirements for inclusion. Since then the additional cases reported by Naik,58 Kleppel,45 Kutner,48 Chodack, Attie and Groder,12 and Henley,40 and several other cases previously reported but not included in Payne and Fitchett's report, seemed to us valid examples of acute hyperparathyroidism. We have found a total of 69 cases in the English literature and 82 cases altogether including accessible reported cases from the foreign literature.

CLINICAL FEATURES

The outstanding characteristic of acute hyperparathyroidism is the almost infinite variety of its clinical manifestations involving, in varying degree, bewildering combinations of symptoms referable to the skeletal, renal, gastrointestinal or neuromuscular systems. In the vast majority of cases there is an antecedent history involving one or more of these systems extending back over a period of months or years, which mayor may not be recognized as manifestations of chronic hyperparathyroidism. In the earlier reported cases, in the period when hyperparathyroidism was considered synonymous with Von Recklinghausen's osteitis fibrosa cystica, the antecedent history, as would be expected, was usually related to the skeletal system and consisted of pain, aching in character, referred to the chest, shoulders, back or extremities. Stiffness of the knees and arms, and generalized bone tenderness were common. Patients were often considered to have "rheumatism." Pathological fractures and bony swellings, especially of the jaws and in the ends of the long bones, were frequently noted. After Albright's2 recognition of the association of hyperparathyroidism and renal disease, more and more patients were seen in whose antecedent history recurrent episodes of renal or ureteral colic, hematuria or repeated passage of stones or operative removal of renal or ureteral calculi were prominent. More often than not, the symptoms preceding the onset of acute hypercalcemia are mixed and not limited to one system. As early as 1934 Gutman, Swenson and Parsons34 emphasized the occurrence of nausea and vomiting and reported that in six of their cases sharp pain in the abdomen appeared, and stated that the gastrointestinal symptoms may so dominate the picture as to suggest duodenal ulcer or acute appendicitis. In 1946, Rogers 65 reported two cases of acute hyperparathyroidism, in neither of which was the disease recognized during life nor did the history suggest osseous or renal disease. In each instance treatment for duodenal ulcer with a diet high in calcium and phosphorus produced an exacerbation of the symptoms of nausea, vomiting, lethargy, prostration and azotemia . . In 1954, St. Goar 76 reviewed 1137 case records of hyperparathyroidism at the Massachusetts General Hospital and found 12 patients with peptic

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ulcers demonstrated roentgenographically, and five others with clinically evident peptic ulcers that were not confirmed by x-ray. In a later review of 45 cases from the Presbyterian Hospital in N ew York, 76 he found four peptic ulcers and 16 cases, or more than one-third, in which gastrointestinal symptoms were prominent. In the 69 cases from the English literature reviewed here, duodenal ulcer was present in 13 or 19 per cent; ulcer-like symptoms occurred in another eight patients. The 21 patients in these two groups are 30 per cent of the total. Gastrointestinal symptoms of some kind occurred in 63 per cent of the cases. St. Goar 76 emphasized, in particular, the association of gastrointestinal symptoms with acute hyperparathyroidism, and felt that hypercalcemia was the cause, pointing out that an increase in calcium ion concentration in the sympathetic ganglia impedes transmission of afferent stimuli and diminishes efferent discharge of a constant amount of acetylcholine. This effect, plus the effect of hypercalcemia in reducing neuromuscular excitability, presumably leads to decreased tone of the gastrointestinal tract. Chronic constipation was thought to be due to chronic bowel atony. Gastric atony was believed to lead to "dyspepsia," and to nausea and vomiting. In 1957, Copel7 and his associates first reported the association of pancreatitis and hyperparathyroidism and called attention to previous isolated reports in the literature. They felt that the hyperparathyroidism was the primary disease and that the pancreatitis was a complication of this disease and suggested the following sequence of events as an explanation: (1) development of hyperparathyroidism, (2) formation of pancreatic calculi either superimposed on tissue injury or as a primary precipitation, and (3) ductal obstruction leading to pancreatitis. In 1962, reporting on further experience, Mixter, Keynes and Cope67 reported nine additional cases in which the association existed and felt that the relationship was firmly enough establiRhed to regard pancreatitis as another clue suggesting a possible coexistent hyperparathyroidism. A year before, Fink and Finfrock29 had reported a case associated with acute hyperparathyroidism. In the material surveyed here, eight cases of pancreatitis were found in association with acute hyperparathyroidism, including the case of Fink and Finfrock, an incidence of 11.5 per cent. In 1962, Turchi et al. 79 reported 27 cases of coexistent pancreatitis and hyperparathyroidism. They called attention to a point of considerable importance with respect to diagnosis when these two diseases are associated; that is, that the serum calcium which is usually elevated in hyperparathyroidism may be lowered to normal or subnormal levels as a result of the calcium-lowering effect of the pancreatitis. Coffey 13 cites an instance of acute crisis associated with acute pancreatitis in which a normal serum calcium level gave a false assurance, and in which the diagnosis was finally established only through the persistence of the house officer after the pancreatitis subsided. The acute phase of the hypercalcemic crisis is typically vague in its

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early manifestations, which include, usually, fatigue, lassitude, weakness, often profound and progressive; anorexia, weight loss, nausea and vomiting. As the crisis deepens, lassitude gives way to somnolence, confusion, disorientation, stupor and coma. Convulsions have also been reported and appear to be more likely to occur in the young. Harmon39 and Lee and McIlhenney 49 have each reported a case of acute hyperparathyroidism in children aged 7 and 8 respectively, in which convulsive seizures were a prominent symptom. Each of these children developed permanent blindness as a complication of the acute hypercalcemia. Rogers 65 observed transient blindness in one of his cases. Marked muscular hypotonia often leads to severe lower backache. Generalized aching and tenderness over the entire body, especially in the lower extremities, is common and at times may be extreme. Snapper 70 describes a case in which this symptom was so severe that the patient could not bear to have his bed made. Headache, mental depression, personality change and frank psychosis are all observed with considerable frequency. These mental symptoms may so dominate the picture that primary mental illness is considered to be the basic problem. A patient reported by Fitz and Hallman30 had, as a presenting complaint, serious personality change with alternating periods of great elation and depression, with complete recovery after removal of the parathyroid adenoma. They also report a second patient, not in crisis, whose other symptoms were overshadowed by a paranoid personality manifested by delusions that people were plotting against him and trying to kill him, with remarkable mental clearing after operation. In Young and Halpert'sS5 case, mental confusion led to the patient's admission to a psychiatric institution before the diagnosis of hyperparathyroidism was made. Reilly and Wilson 64 reported three cases of severe mental symptoms relieved by removal of the parathyroid adenoma. Mandel53 has described a case accompanied by recurrent psychotic depression over a period of six months in which a diagnosis of hyperparathyroidism was eventually made. After operation the patient was completely relieved, and had no further recurrence of depression. With acute hypercalcemia characteristic changes in the electrocardiogram occur, the most conspicuous of which are shortening of the Q-T interval and an almost absent S-T segment. In the case reported by Bradlaw and Segel,!O changes in the electrocardiogram were the clue which indicated the diagnosis. Conjunctival and corneal lesions, which are characteristic of hypercalcemia, are observed with considerable frequency. Walsh and HowardS! in 1947 reported that in the previous ten years they had observed distinctive phenomena in the eyes in approximately half of the patients seen with hypercalcemia. The most commonly observed changes are band keratopathy and conjunctival lesions, which occur as small glasslike particles within the conjunctiva of the palpebral fissure region.

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Severe thirst, polydipsia and polyuria occur with great frequency in acute hyperparathyroidism and are due to the diuretic effect resulting from increased urinary excretion of calcium and phosphate and the impaired concentrating ability of the kidney. As the acute phase progresses, as the serum calcium rises, and renal tubular damage increases, the polyuria gives way to progressive oliguria, profound hemoconcentration. azotemia and, unless interrupted by surgical intervention, death. A high irregular fever is often present in the late stage of crisis.

BIOCHEMICAL FEATURES

The progression of symptoms described above is the result of an increased output of parathyroid hormone by the adenoma or hyperfunctioning parathyroid glands, and is accompanied by characteristic biochemical changes. Albright and Reifenstein4 described the sequence of events leading up to death as follows: first, an increasingly high serum calcium value, inspissation of the blood dependent on the hypercalcemia, and a resulting acute failure of kidney filtration, and, finally, rising serum phosphorus and nonprotein nitrogen levels. The combination at the same time of high levels of serum calcium and serum phosphorus results in the precipitation of calcium phosphate in the tissues and chemical death. The symptoms associated with acute hypercalcemia are usually first noted when the level of serum calcium reaches 16 to 17 mg. per 100 ml. The classical biochemical findings in chronic hyperparathyroidism are an elevated serum calcium and an increased excretion of calcium and phosphorus in the urine, resulting in a lowered serum phosphorus and hypercalcemia. The absence of hypophosphatemia cannot be relied on as valid evidence against the diagnosis of hyperparathyroidism since the level of serum phosphorus is influenced by the state of renal function of the patient (Goldman et al,32). They report that 60 per cent of their patients with proven hyperparathyroidism had serum phosphorus levels in the range of normal. Grollman33 in 1927 showed that, at high levels of serum calcium of about 18 mg. per 100 mI., phosphate was no longer filterable. This, it was believed, resulted in the precipitation of calcium wherever there was localized alkalinity of tissues. This was believed to account for the predilection for the deposition of calcium in acid-secreting organs, such as the stomach, kidney and pulmonary alveoli. Shelling 69 in 1938 disagreed with the prevailing concept that the symptoms of acute overdosage with parathyroid extract were related to renal damage because of the usual presence of anuria or oliguria, retention of nonprotein nitrogen in the blood, and often, also, lime salt deposition in the kidneys. Based on observations resulting from injection of parathyroid extract into dogs at four-hour intervals for periods from 24 to 52 hours, he

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concluded that the important factor in acute parathyroid intoxication was the profound dehydration and electrolyte loss resulting from the diuretic effect of the parathyroid extract. He showed that concomitant administration of 200 cc. of saline intravenously every four hours during the period of the experiment protected the animals, and two animals so treated survived when those not given the saline died.

REPORTS OF CASES

Two of the three cases of acute hyperparathyroidism in the author's experience have been previously reported by Lemann and Donatelli50 (their Cases 3 and 4). The third, which is actually the first in point of time, is reported here for the first time, and the two previously reported will be reviewed briefly. CASE I. A 59 year old man was admitted to the hospital on April 22, 1960. Six months previously he had become aware of a hard swelling in his left wrist, painful on motion. One year previously he had first noticed a lump in the left side of his neck. He had had symptoms of Parkinson's disease for 5 years. There was also a history of peptic ulcer of 20 years' duration with 2 episodes of bleeding within the previous 4 years. For at least 1 year, he had also complained of urinary frequency and had nocturia 2 or 3 times nightly. For the past year he had also suffered from intense headaches. He was usually constipated. On examination, a stare was present and he had an intention tremor. Blood pressure was 160/80; pulse, 84. In the left neck there was an egg-shaped mass in the left lower thyroid area. Examination was otherwise negative, except for prostatic enlargement and the presence of a 3-cm., firm, bony mass in the distal end of the left ulna. He also had cogwheel movement of the extremities. Laboratory: Hemoglobin was 12.2 gm., white blood count 7500; urine-specific gravity 1.010, albumin 0.032, sugar 0, sediment showed 1 to 6 hyaline casts. Alkaline phosphatase was 19.313odansky units; serum phosphorus 2.5 and 2.7 mg./lOO ml.; serum calcium 19.3 mg./IOO ml.; electrolytes were within normal limits. Roentgenograms showed some osteoporosis of skull, spine, pelvis, and especially of the skull. On 4/25, excretory urograms showed the kidneys fairly well outlined. An expanded cystic lesion at the outer end of the right 11th rib was noted and a similar area in the distal end of the left ulna. Films of the hand showed small areas of subperiosteal resorption of bone in the phalanges. A diagnosis of hyperparathyroidism was made and the patient was operated on 4/29/60. The mass in the left lower neck proved to be a large parathyroid adenoma and was removed. Search for additional adenomas in this part of the neck was carried out. Progress for the first 3 days appeared to be very satisfactory. On the third postoperative day the patient seemed improved and even his parkinsonism seemed better. On 5/5/60 some concern was felt because of failure of the serum calcium level to fall. This was 16.2 mg./lOO ml. on 5/4/60. Because of the large size of his tumor and the expectation that serum calcium would fall precipitously to tetanic levels, he had been given calciferol and calcium lactate by mouth for the first few days postoperatively. These were discontinued and on 5/6/60 serum calcium showed a slight decrease to 15.5 mg./lOO ml. and the blood urea nitrogen, which had been 46.5 on 5/5/60, fell to 38. This slight improvement was of short duration,

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however, and on 5/9/60, his serum calcium rose to 21 mg./100 mI. There was no longer any doubt that hyperfunctioning parathyroid tissue was still present; it was thought probably to be in the mediastinum. It was elected, however, to attempt to reduce the serum calcium by forcing fluids and by the use of a chelating agent before reoperating on him. Intravenous fluids were pushed, and on 5/11/60,2 gm. of ethylenediaminetetracetic acid (EDTA) were given, despite which his condition deteriorated extremely rapidly; he developed pulmonary edema and expired on 5/12/60. At postmortem examination 2 additional adenomas were found, one on the left inferior area, 1 by 0.5 by 0.5 em., and the second posteriorly in the groove between the trachea and thyroid, 4 by 2 by 1 cm. Other findings were kidney failure secondary to hypercalcemia, osteitis fibrosa cystica, calcifications in stomach, sclerae, hepatic blood vessels and heart, focal acute myocarditis, acute pulmonary edema with early bronchopneumonia, renal tubular degeneration, and acute necrotizing renal glomerulitis. CASE II. (Previously reported in detail by Lemann and Donatelli60). A 62 year old woman was admitted to the hospital on 3/19/62 with a past history of heartburn and constipation for 20 years. For 6 days prior to admission, constipation was very severe and nausea and vomiting had been present for 3 days. There had been a 30-pound weight loss in the previous 4 months and she had been mentally depressed. She had polyuria for 2 days prior to entry. On examination, band keratopathy was observed. Laboratory findings: The highest level of serum calcium was 14 mg. and the lowest serum phosphorus was 2.2 mg. She also had hypokalemia, mild azotemia, and hypercalcemia. Hand films showed minimal demineralization. While the patient was still in the hospital, her serum calcium and phosphorus levels spontaneously returned to normal and her symptoms subsided completely. Three months later she developed acute recurrence of nausea, vomiting, thirst, polyuria and constipation, and was readmitted to the hospital on 6/11/62. Physical examination was unchanged. Her symptoms increased in severity. On her third hospital day she was operated on. The highest serum calcium noted on this admission was 16.4 mg.jlOO mI. and the lowest serum phosphorus was 2.7. At operation, a 4.3-gm. parathyroid adenoma was found in the area of the right lower thyroid lobe. In the center of the tumor there was a small hemorrhagic necrotic area. She made a full and complete recovery. CASE III. (Previously reported by Lemann and DonatellifiO ). A 59 year old woman was admitted to the hospital on March 15, 1963. She had had hypertension and fatigue for S months. One month prior to entry she begal). to have intermittent vomiting, and 2 weeks before entry she complained of constipation and increasing fatigue. Three days before admission, she became lethargic and confused. Laboratory studies showed serum sodium of 120 mEq./L., potassium 2.1 mEq./L., blood urea. nitrogen 40 mg./lOO mI., serum phosphorus 5.6 mg./lOO mI. On March 15, serum calcium of 19 mg./lOO mI. was reported and she was transferred to the Massachusetts Memorial Hospital. On admission, she was acutely ill and slightly confused. Blood pressure was 70/50, pulse 84. Additional studies showed serum calcium of 16.4 mg.jlOO ml. X-rays of the hand showed typical subperiosteal bone resorption. Serum phosphorus was 6.5 mg./100 mI., blood urea nitrogen 64 mg./100 mI., serum sodium 129, chloride 88 and potassium 2.4 mg.jlOO mI. In spite of rapid inflow of 1500 cc. saline containing 30 mEq./L. of potassium chloride, blood pressure rose only transiently to 130 systolic and then fell to approximately 60-90 mm. Emergency surgery was carried out approximately 4 hours after admission. Immediately after induction of anesthesia and before the actual surgery was begun, the patient developed acute pulmonary edema and required continuous

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positive pressure throughout the operation. A large, right parathyroid adenoma weighing 39.5 gm. was found and removed. The patient remained hypotensive throughout the operation. Pulmonary edema occurred whenever positive pressure respiration was discontinued. Her blood pressure gradually fell and she died about 8 hours after admission to the hospital.

Comment CASE 1. The history in this case illustrates the protean character of the overall manifestations so frequently exhibited in acute hyperparathyroidism with symptoms and signs of classical osteitis fibrosa cystic a, urinary frequency and nocturia for the previous year, a history of duodenal ulcer going back 20 years, and a long history of constipation. The fact that two additional adenomas had been missed in a careful search emphasized the absolute necessity of identifying all normal parathyroids by biopsy if any doubt exists. The anticipatory use of calcium postoperatively to prevent the development of tetany was obviously unwise, and although continued for only a few days, it may well have been a factor in precipitating the crisis. A fall of the serum calcium to tetanic levels postoperatively should be welcomed as clear evidence that all of the hyperfunctioning parathyroid tissue has been removed, and treatment of tetany should be withheld until it is proved to be present by the finding of a lowered serum calcium. CASE II is of particular interest because of the spontaneous remission of all of the patient's symptoms along with return of her serum calcium level to normal. The abrupt return of symptoms three months later and the finding of an area of hemorrhagic necrosis in the removed adenoma raises a question as to whether this small hemorrhagic area might have been related to a sudden increase in output of hormone by the tumor. Even if one accepts this, the explanation of the spontaneous remission three months earlier remains obscure. Many other authors have commented on the frequent evidence of intermittent activity of parathyroid tumors, and the finding of hemorrhagic cystic areas in the removed adenomas has been observed frequently.

Howard43 has reported a remarkable case of a woman aged 57, admitted to the hospital on 10/5/51 with a typical story of hyperparathyroidism. She was seen initially for treatment of a peptic ulcer and a nodule in the right side of the thyroid isthmus was noted. She was treated medically and ulcer symptoms were controlled. Serum calcium on her admission was 14 mg./l00 ml. On 10/20/51, she had soreness in the region of the nodule in the neck with nausea, vomiting and tachycardia, which led to a sudden rise in serum calcium to 20 mg./lOO ml. Following this, the serum calcium fell equally precipitously during the next 3 days to 10.7 mg. and in six days to 8.2 mg. The serum phosphorus fell to 1.5 mg. At operation, a 6-gm. parathyroid adenoma containing a large amount of necrotic tissue with a mixture of viable tumor cells was found. It was presumed that there must have been a massive discharge of parathyroid hormone as a result of the acute necrosis followed by a decline in the discharge as the necrosis was fully developed. Harmon39 has reported a case of a child with very severe hyperparathyroidism

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who had 3 recurring cycles of gastrointestinal symptoms. Each cycle lasted approximately 10 days. Atsmon 5 has also described a case with 3 recurrent attacks of gastrointestinal disturbances with remissions between the attacks. Each of these attacks lasted about 2 months. Complete and permanent remission occurred after the removal of a parathyroid adenoma. Mansberger 55 has also reported a similar case with 3 episodes of recurring symptoms characteristic in retrospect of acute hyperparathyroid crises extending over a period of a year with symptoms regressing in between. The diagnosis was not made until the third attack. Serum calcium was 20 mg. per 100 ml. Nine months after operation the patient was well, except for persistent hypertension. CASE III illustrates dramatically the frightening speed with which acute hyperparathyroid crisis may run its course to a fatal termination.

DIAGNOSIS

The most indispensable elements for establishing an early diagnosis of acute hyperparathyroid crisis are a high index of suspicion and thorough familiarity with the protean character of its clinical manifestations, not only of the acute phase but also of the characteristic antecedent history in which the tell-tale clue to the diagnosis is often the presence of skeletal, renal, gastrointestinal or central nervous system complaints. With well-developed osteitis fibrosa cystica, the diagnosis may often be made with confidence on clinical grounds alone, but in most cases confirmation of the diagnosis must be based on biochemical findings. The classical biochemical changes in chronic hyperparathyroidism are hypercalcemia, hypophosphatemia and hypercalciuria. Also, when skeletal disease is present in a significant degree, an elevated alkaline phosphatase is usually found. In acute hyperparathyroidism, serum calcium levels are, with few exceptions, greater than 17 mg. per 100 ml. In the 63 cases studied in which serum calcium levels are reported, the highest level was less than 17 mg. in only six cases. Hypophosphatemia, although commonly present in chronic hyperparathyroidism, is a less reliable indicator in acute toxicity since, as the acute phase progresses, increasing renal tubular damage is reflected in a rising serum phosphorus as well as progressively increasing azotemia so that serum phosphorus levels are often in the normal range or elevated. N evertheless, in 53 cases in which serum phosphorus levels were determined, the lowest level was less than 2.5 mg. per 100 ml. in 20 or approximately 40 per cent. Where serial determinations were made, initial levels in the hypophosphatemic range were invariably followed by rising levels as the acute phase progressed. The difficulties frequently encountered in chronic hyperparathyroidism with borderline chemical changes are not a problem in acute hyperparathyroidism and the more complicated and sophisticated tests such as the tubular reabsorption of phosphorus test (TRP), the phosphate deprivation

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test and urinary calcium excretion tests are of little help in acute hypercalcemia. Also, calcium loading tests may be positively harmful. Thomas, Connor and Morgan46 felt that these tests have been of little value in differentiating patients even with chronic hyperparathyroidism from those with other causes of hypercalcemia and felt that other methods of establishing the correct diagnosis must be established. They stress the great importance of expert interpretation of roentgenograms and suggest that resorption of bone at the distal end of the clavicle may precede other distinctive radiologic manifestations of hyperparathyroidism. Other early characteristic roentgenologic findings, which when present are reliable indications of parathyroid disease, are erosions of the lateral (radial) aspect of the middle phalanges and the tufts of the distal phalanges. In patients with minimal involvement, according to Steinbach et aI., 73 erosion is seen only near the phalangeal base in the transitional zone between the wide epiphyseal end and the slender shaft. Similar erosions may be observed in the lamina dura surrounding the teeth. Other strongly suggestive evidences of hyperparathyroidism are a general demineralization of the skeleton and a so-called ground-glass appearance of the skull. The keystone in the diagnosis of acute hyperparathyroidism is the finding of a serum calcium level in the neighborhood of 17 mg. per 100 ml. or higher in association with the characteristic symptoms of hypercalcemia. The chief problem in differential diagnosis of acute hypercalcemia of hyperparathyroidism is the problem of ruling out other nonparathyroid causes of hypercalcemia.

Differential Diagnosis of Hypercalcemia Other causes of hypercalcemia which must often be considered are listed by Thomas et aU 8 as follows: (1) laboratory error; (2) neoplastic disease (with or without skeletal metastases), lymphoma, leukemia, multiple myeloma, carcinoma of the lung, kidney, gastrointestinal tract, ovary, breast, etc.; (3) sarcoidosis; (4) milk-alkali syndrome; (5) hyperthyroidism, (6) idiopathic hypercalcemia of infants, and (7) acute skeletal atrophy of disuse. In the great majority of patients in these various categories the diagnosis will not be in doubt, but in occasional cases other causes of hypercalcemia may be obscure. Coffey 13 reports five negative explorations in a series of 48 cases in patients considered to have unequivocal biochemical evidence of hyperparathyroid disease. Royster 66 in a discussion of papers by Payne and Fitchett 60 commented on this experience of Coffey's and reported five similar cases of his own in patients who had hypercalcemia without bone disease, three of whom were operated on for parathyroid adenoma with negative results, only later to be found at postmortem examination or by clinical course to have cancers. Similar cases have been observed sporadically since 1936 when Gutman et al. 35 reported a case of unexplained hypercalcemia associated with carcinoma of the bronchus and without skeletal metastases.

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Hypervitaminosis-D may occasionally cause difficulty. A careful history will in most instances uncover this cause of hypercalcemia, but at times the history may be overlooked. Royster, in the discussion mentioned above, also reported two cases of vitamin-D intoxication, in one of which a negative exploration for parathyroid adenoma was carried out, and in the second the patient narrowly escaped exploration. Previous examiners had asked these patients if they were taking any drugs, and the answer was in the negative. However, through the alertness of one of the interns in asking if they were taking any pills, the second patient answered, "yes." David23 also reports a patient with vitamin-D poisoning who had a negative exploration of the neck, and who was later found to have been taking up to 300,000 units of vitamin D daily for three years. Albright, Burnett, Cope and Parsons3 have described a boy who had a negative exploration of the neck for persistent hypercalcemia following prolonged immobilization for a fracture. The serum calcium returned to normal after ambulation. Careful interrogation, physical examination and appropriate roentgenographic study are usually sufficient to rule out the milk-alkali syndrome, sarcoidosis and metastatic malignancy, as well as most of the less common causes of hypercalcemia. Henley,40 in a discussion of the differential diagnosis of hypercalcemia, made the very significant observation that in a series of 153 patients, 120 of whom had hyperparathyroidism, only four in the nonparathyroid group had serum calcium levels above 16 mg. per 100 m!. Despite all of the inherent difficulties in the diagnosis of acute hyperparathyroid crisis which have been described, when large numbers of case histories are studied a distinct pattern emerges which when once clearly recognized is not likely to be confused with any other syndrome.

TREATMENT

Acute hyperparathyroid crisis is a surgical emergency comparable in urgency to acute intestinal obstruction, and in the later phases of the crisis when the serum calcium rises above 20 mg. per 100 m!. the need for immediate surgical intervention is not less than in strangulating obstruction. At the present time there are no proven medical measures which can be relied on to influence the underlying metabolic disturbance in acute hyperparathyroid crisis, although there is a possibility that such agents may soon be available. (This will be discussed further, below.) Patients with acute parathyroid poisoning are almost invariably dehydrated and show varying degrees of electrolytic abnormalities. These defects should be corrected rapidly during the period of investigation by the administration of appropriate intravenous fluids. Once the conclusion has been reached that the hypercalcemia is due to hyperparathyroidism, any prolonged further at-

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tempt to deal with the problem by medical measures is not likely to be helpful, and if persisted in may deprive the patient of his only chance for survival. This error in management was a common cause of fatality in many of the reported cases, as well as in one of our own. Since Shelling's69 report of the protective effect of simultaneous saline infusions in dogs poisoned by overdosage of parathyroid extract, the use of intravenous saline has been the mainstay of medical efforts in dealing with hypercalcemia. It is important to recognize, however, that in the Shelling experiment the overdosage of parathyroid extract extended over a span of only 52 hours or less. It is probable that the use of saline would have resulted only in a delay of a fatal outcome if the overdosage of parathyroid hormone had been continued as it does continue in acute hyperparathyroidism from hyperfunctioning adenoma. It seems doubtful that saline infusion confers any benefit beyond correction of dehydration and maintenance of hydration, except perhaps that there may be some slight reduction in the level of serum calcium through dilution and possibly by some slight increase in excretion of calcium.

Measures to Lower Serum Calcium Since the lethal tissue changes which occur with acute hyperparathyroidism are generally attributed to the rising levels of serum calcium, it is entirely logical that therapeutic efforts should be directed toward reduction of the hypercalcemia. Dent25 has reported some success in chronic hyperparathyroidism with disodium hydrogen phosphate given orally, but this does not appear to be applicable to acute intoxication. The disodium salt of edethamil (EDTA), a chelating agent, forms a strong calcium chelate and in sufficient dosage can bring about a reduction in the level of serum calcium, but the effect is extremely transitory. Experience with this agent in acute hypercalcemic crisis has been very limited and not conspicuously successful. In our Case I, there was no evidence of clinical improvement following the use of EDTA. Studies by Spencer et al. 71 suggest that any decrease in ionized calcium is corrected by prompt replenishment from the large skeletal depots. Chodack et aI.12 have reported a case in which EDTA was given. Serum calcium fell from 19.3 to 15.3 mg. per 100 mI., but quickly rebounded to 18.5 mg. per 100 mI. There was no clinical improvement and the patient died. In one of Wilson's83 cases, EDTA was given without either a fall in the level of serum calcium or clinical improvement. Kleppel46 describes a fall of serum calcium from 17 to 10-11 mg. per 100 mI. after the intravenous use of EDTA, but there was no improvement in the clinical condition, and the patient died. Harmon39 and Templeton 77 each have described a case in which EDTA was discontinued; in Harmon's case because of a paradoxical, abrupt rise in blood pressure from 185/140 to 22/180 accompanied by severe abdominal pain; and in Templeton's case because of a rising blood urea nitrogen. Dudley et aI.26 have described nephrotoxic changes following the use of EDTA. Whether a drug capable of producing renal damage should be employed in patients who in most cases already have severely damaged kidneys is open to question.

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PERITONEAL DIALYSIS has also been used to lower serum calcium levels and, as described by Maxwell et al.,56 is effective, although cumbersome. It also suffers from the same defect as binding agents in that the disturbed equilibrium resulting from the removal of ionized calcium from the blood is quickly corrected by replenishment from the inexhaustible stores in the bones when hyperparathyroidism is the cause of the hypercalcemia. ACTINOMYCIN-D. Eisenstein and Passavoy27 have recently described a series of experiments in which control rats were injected with parathyroid extract and others with parathyroid extract and Actinomycin-D in one series and vitamin D and Actinomycin-D in another series. They found that Actinomycin-D inhibits the hypercalcemia induced by large dosages of parathyroid hormone or vitamin D. Rasmussen and Hawker 63 have arrived at similar conclusions. Their findings suggest possible clinical application in hyperparathyroidism. Kunin and Krane47 report that Puromycin also inhibits the hypercalcemic response to parathyroid hormone, but by a different mechanism. CALCITONIN AND THYROCALCITONIN. COpp1S-22 in 1963 reported on experimental work the results of which indicate the existence of a new hormone from the parathyroid glands that lowers blood calcium. Using a precise method for measuring blood calcium, Copp and his associates have shown that the perfusion of high calcium blood through the thyroid and parathyroids causes a prompt fall in the plasma calcium which is not explainable on the basis of suppression of parathyroid hormone production since the effect is significantly different from the effect of total parathyroidectomy. Since no effect is produced when the thyroid alone is perfused, it is believed that the fall in plasma calcium is due to a hypocalcemic factor released only from the parathyroid glands as a result of hypercalcemia. This factor has been demonstrated in the plasma of high calcium parathyroid perfusates, but not in normocalcemic parathyroid perfusates. The hypocalcemic factor in Copp's preparation was fast and shortacting. The maximal fall occurred at 20 minutes and the plasma calcium returned to normal within an hour. The evidence points to a hypocalcemic hormonal agent with a constant effect which is released from the parathyroid gland as a result of the specific stimulus of hypercalcemia. Copp has suggested the name calcitonin for this new hormone. Foster, Baghdantz, Kumar and MacIntyre,31 Kumar, Foster and MacIntyre,46 and MacIntyre, Foster and Kumar,52 have confirmed the existence of calcitonin, but they concluded, contrary to Copp's belief, that the thyroid was probably the source. Subsequent experiments using the goat as the experimental animal demonstrated the existence of the hormone in this species and apparently exclude the parathyroid as the source of calcitonin. Hirsch41 and associates have extracted a plasma calcium-lowering agent from the rat thyroid. They have called it thyrocalcitonin, but believe it to

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be identical with calcitonin. This thyroid factor has since been purified by MacIntyre, Foster, et al.,62 and by Hirsch, Voelkel and Savery,42 who have shown it to be a polypeptide, effective in microgram amounts and extractable from the thyroids of a variety of mammalian species. Since calcitonin lowers plasma phosphate simultaneously with calcium, it is believed that it probably produces its effect by favoring the deposition of calcium phosphate in bone. There is still some dispute as to whether there are two hormones or whether they are identical. In any case, the properties exhibited suggest that, if it becomes available for therapeutic use, it may prove to be an effective agent for the control of acute parathyroid crisis, at least for a long enough time to make emergency surgery under unfavorable conditions unnecessary.

Surgical Aspects A detailed discussion of the surgical technique of removal of parathyroid tumors is beyond the scope of this paper and will not be considered here. Excellent discussions of this aspect of the problem will be found in the publications of Cope,!6 Black,s. 9 Adams and Murphy,! Feind,28 and others.

Identification of Tumor There is no doubt, however, that the most difficult problem encountered in surgery of parathyroid tumors is the identification of the tumor at the time of operation, especially if it lies within the substance of the thyroid gland, at a distance from this organ, or in the mediastinum. The advantage of a thorough knowledge of the anatomy and embryology of the parathyroid glands and of the positions in which they are normally found or the positions in which they are likely to be found when not normally placed have been emphasized by many writers on the subject. Nevertheless, even when the surgeon possesses the basic knowledge, the discovery of the tumor may still be a most trying and difficult surgical exercise and may end in failure. Any procedure through which the tumor or tumors can be identified preoperatively must be, obviously, a great advantage, especially in acute hyperparathyroidism when the patient is often desperately ill and a poor subject for prolonged operation. A variety of techniques have been developed with the object of preoperative identification of the position of the parathyroid adenoma. Wyman and Robbins s4 have emphasized the great value of standard roentgen techniques in the localization of parathyroid adenomas. They state, however, that for successful identification by these methods (1) the tumor mass must have attained a certain minimal size of at least 1 em., and usually 2 to 3 em., and (2) it must be located so that it displaces certain readily recognized structures, such as the trachea, esophagus and lungs, and (3) the examination must be complete and include roentgenoscopy, spot

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roentgenograms with barium in the esophagus, and large conventional films of good technical quality of the chest and lower neck. By utilizing these methods, they were able to identify the parathyroid adenoma in 20 of 34 cases. A refinement of this approach is the use of cinefluorography combined with barium swallow as described by Scatliff and Scibetta. 57 They report the successful recognition of one tumor indenting the esophagus, which was only 2 by 2.5 by 1 cm. However, the examination failed to show a second tumor, which was successfully demonstrated six months later. Pneumomediastinography has also been employed for the identification of tumors in this area. Posen, Clubb, Neale and Hare 5! report success in the identification of a parathyroid adenoma in the mediastinum measuring 2.4 by 0.8 by 1.4 cm. by this method. The technique employed is that originally described by Hare and MacKay38 for the assessment of thymic size in myasthenia gravis, and consists in the insufflation of carbon dioxide into the anterior mediastinum under local anesthesia. A curved, 16-gauge needle is introduced into the suprasternal notch and passed downward behind the manubrium sterni. Three hundred to 500 cc. of CO 2 is injected by means of a 100 cc. syringe and a three-way stopcock. Photoscanning after injection by methionine labeled with selenium-75 has been utilized by Bierwaltes 7 and by Potchen, Adelstein and Dealy. 62 Bierwaltes scanned six patients later found to have parathyroid adenomas and was successful in localizing the adenoma in two of these patients. Both had adenomas greater than 3 cm. in diameter, and in both the adenomas were relatively near to the surface of the skin of the neck. Potchen et al. believe that this method shows promise for the localization of parathyroid adenomas. They found it an advantage to reduce the uptake of selenium-75 by the thyroid gland by pretreatment with Cytomel for three to eight days in order to increase the ratio of uptake of the isotope by the parathyroid in relation to the thyroid. They found that in six of 10 cases in which cervicomediastinal scans were utilized after the administration of selenomethionine, the procedure was helpful in localizing abnormal parathyroid tissue. Finally, arteriography has been found to be of distinct value in identifying parathyroid tumors. Seldinger 68 has reported success in defining tumors as small as 1 by 2 cm. His technique, however, requires bilateral brachial punctures and catheterization, a procedure which might be considered too formidable for routine use. Henley,40 in one of his cases, was successful in identifying an adenoma in the neck by a bilateral subclavian arteriogram. The method described by Steiner, Fraser and Aird 68 of operative arteriography at the time of surgery seems simpler and more practical. Arteriography is carried out early in the course of the operative procedure by exposing both inferior thyroid arteries and injecting rapidly 10 cc. of a radiopaque medium (Diomene) through a needle introduced into the artery just distal to a point of temporary occlusion. They point out that the

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inferior thyroid artery is likely to be of a larger caliber on the side of the tumor. State 72 has also emphasized the value of this observation in helping to localize the tumor. In his experience, the artery on the side of the tumor has been nearly twice the diameter of that on the opposite side. Hardy, Snavely and Langford 37 successfully opacified by arteriography a large parathyroid tumor, after it has been surgically exposed. This tumor had a separate blood supply from the innominate artery.

SUMMARY Acute hypercalcemic crisis of hyperparathyroidism is a surgical emergency. Diagnosis is often difficult because of the polymorphous character of the symptoms. The variable clinical features of the syndrome are described emphasizing the frequent occurrence of gastrointestinal symptoms, especially duodenal ulcer or recurring pancreatitis in the antecedent history as well as the better known occurrence of renal and skeletal manifestations, which precede the crisis in all but a few cases. Despite the variability of the clinical manifestations, the total syndrome forms a distinctive pattern which should be recognizable once it is known. Previously reported cases have been reviewed and an additional case reported. The differential diagnosis, aids in identification of the tumor and prospects for more effective control of the hypercalcemia are discussed. At the present time, early surgical removal of the tumor is the only effective treatment.

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hyperfunctioning tumor representing fifth parathyroid opposite eighth dorsal vertebra with independent arterial supply. Ann. Surg. 159: 310, 1964. Hare, W. S. C. and Mackay, J. R.: Radiological assessment of thymic size in myasthenia gravis and systemic lupus erythematosus. Lancet 1: 746, 1963. * Harmon, M.: Parathyroid adenoma in a child. J. Dis. Child. 91: 313, 1956. * Henley, R. B.: Management of the parathyroid crisis. Am. J. Surg. 108: 183, 1964. Hirsch, P. 1., Voelkel, E. F. and Munson, P. L.: Thyrocalcitonin: Hypocalcemic, hypophosphotemic principle of the thyroid gland. Science 146: 412, 1964. Hirsch, P. F., Voelkel, E. F., Savery, A. and Munson, P. L.: Partial purification of thyrocalcitonin. Fed. Proc. 23: 204 (Abst.), 1964. * Howard, J. E., Follis, R. H., Jr., Yendt, E. R. and Conner, T. B.: Hyperparathyroidism. Case report illustrating remission due to necrosis of adenoma. J. Clin. Endocrinol. 13: 997, 1953. * James, P. R. and Richard, P. G.: Parathyroid crisis. Arch. Surg. 72: 553,1956. * Kleppel, N. H., Goldstein, M. H. and LeVeen, H. H.: Hypercalcemic crisis and pancreatitis. J.A.M.A. 192: 916, 1965. Kumar, M. A., Foster, G. V. and MacIntyre, 1.: Further evidence for calcitonin. A rapid-acting hormone which lowers plasma calcium. Lancet 2: 480, 1963. Kunin, A. S. and Krane, S. M.: Inhibition by puromycin of the calcium mobilizing activity of parathyroid extract. Endocrinology 76: 343, 1965. * Kutner, F. R. and Morton, J. H.: Parathyroid crisis. Arch. Surg. 91: 71, 1965. * Lee, C. M., Jr., McElhenney, W. T. and Gall, E. A.: Unusual manifestations of parathyroid adenoma. Arch. Surg. 71: 475,1955. * Lemann, J., Jr. and Donatelli, A. A.: Calcium intoxication due to primary hyperparathyroidism. Ann. Int. Med. 60: 447, 1964. * Lowenberg, H. and Ginsburg, T. M.: Acute hypercalcemia: Report of a case. J.A.M.A., 99: 1116, 1932. MacIntyre, 1., Foster G. V. and Kumar, M. A.: The thyroid origin of calcitonin. In The Parathyroid Glands, Univ. of Chicago Press, 1965, pp. 89-104. Mandel, M. M.: Recurrent psychotic depression associated with hypercalcemia and parathyroid adenoma. Am. J. Psychiat. 117: 234, 1960-1961. Mandl, F.: Therapeutischer Versuch bei einem Fall von Osteitis fibrosa generalisata mittels Extirpation eines Epithelkorperchentumors. Zentralb. f. Chir. 53: 260, 1926. * Mansberger, A. R., Jr., Lovice, H. and McLaughlin, J. S.: Intermittent acute hypercalcemic crisis. Am. Surg. 30: 167, 1964. Maxwell, M. H., Rockney, R. E., Kleeman, C. R. and Twiss, M. R.: Peritoneal dialysis: Technique and applications. J.A.M.A. 170: 917, 1959. Mixter, C. G, Jr., Keynes, M. W. and Cope, 0.: Further experience with pancreatitis as a diagnostic clue to hyperparathyroidism. New England J. Med. 266: 265, 1962. * Naik, B. K., Sarma, R. N., Golpalrao, V., Paraganoker, P. S. and Gopal, P.: Acute hyperparathyroidism: Report of a fatal case with ECG findings. Arch. Int. Med. 111: 729, 1962. * Oliver, W. A.: Acute hyperparathyroidism. Lancet 2: 240,1939. * Payne, R. L. and Fitchett, C. W.: Hyperthyroid crisis. Ann. Surg. 161: 737,1964. Posen, S., Clubb, J. S., Neale, F. C. and Hare, W. S. C.: Mediastinal parathyroid adenoma demonstrated by pneumomediastinography. Ann. Int. Med. 60: 462, 1964. Potchen, E. J., Adelstein, S. J. and Dealy, J. B.: Radioisotopic localization of the overactive human parathyroid. Am. J. Roentgenol. 93: 955, 1965. Rasmussen, H. and Hawker, C.: Actinomycin-D and the response to parathyroid hormones. Science 144: 1019, 1964. Reilly, E. L. and Wilson, W. P.: Mental symptoms in hyperparathyroidism: A report of three cases. Dis. Nervous System 26: 361, 1965. * Rogers, H. M.: Parathyroid adenoma and hypertrophy of parathyroid·glands. J.A.MA. 130: 22, 1946. Royster, H. P.: Discussion in paper by Payne and Fitchett.50 Scatliff, J. H. and Scibetta, M. P.: Pharyngeal cinefluorography in clinical practice. Am. J. Roentgenol. 90: 823, 1963.

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68. Seldinger, S. 1.: Localization of parathyroid adenomata by arteriography. Acta radiol. 42: 353, 1954. 69. Shelling, D. H., Kajdi, L. and Guth, L.: Calcium and phosphorus studies. XIV. Effect of repeated doses of parathyroid extract on the chemical composition of the dog: An explanation of the cause of death in parathyroid overdosage. Endocrinology 22: 225, 1938. 70. * Snapper, 1.: Parathyroid tumor and changes of the bones. Arch. Int. Med. 46: 506, 1930. 71. Spencer, H., Vankinscott, V., Lewin, I. and Laszlo, D.: Removal of calcium in man by ethylene diamine tetra-acetic acid. J. Clin. Invest. 31: 1023, 1952. 72. State, D.: The enlarged inferior thyroid artery as a. valuable guide in surgery of parathyroid adenomas. Surgery 56: 461, 1964. 73. Steinbach, H. L., Jackson, T. C., Silverman, S. and Goldman, L.: Primary hyperparathyroidism: A correlation of roentgen, clinical and pathological features. Am. J. Roentgenol. 86: 329, 1961. 74. Steiner, R. E., Fraser, R. and Aird, 1.: Operative parathyroid arteriography for location of parathyroid tumor. Brit. M. J. 2: 400, 1956. 75. St. Goar, W. T.: Gastrointestinal symptoms as a clue to the diagnosis of primary hyperparathyroidism. Ann. Int. Med. 46: 102, 1957. 76. St. Goar, W. T.: Was ist die Ursache? J. Clin. Endocrinol. 14: 1569,1954. 77. * Templeton, T. B.: Parathyroid crisis successfully treated by surgery. North Carolina M. J. 23: 22, 1962. 78. Thomas, W. C., Connor, T. B. and Morgan, G. H.: Some observations on patients with hypercalcemia exemplifying problems in differential diagnosis, especially in hyperparathyroidism. J. Lab. & Clin. Med. 52: 11, 1958. 79. Turchi, J. J., Flandreau, R. H., Forte, A. L., French, G. N. and Ludwig, G. D.: Hyperparathyroidism and pancreatitis. J.A.M.A. 180: 799, 1962. 80. * Waife, S. 0.: Parathyrotoxicosis: The syndrome of acute hyperparathyroidism. Am. J. M. Sc. 218: 624,1949. 81. Walsh, F. B. and Howard, J. E.: Conjunctival and corneal lesions in hypercalcemia. J. Clin. Endocrinol. 7: 644, 1947. 82. * Wanke, R.: Beitrag zur Stoffwechsel Untersuchung der Osteodystrophia Fibrosa. Deutsche Ztschr. Chir. 228: 210, 1930. 83. * Wilson, R. E., Bernhard, W. F., Polet, H. and Moore, F. D.: The problem of acute parathyroid intoxication. Ann. Surg. 159: 79, 1964. 84. Wyman, S. M. and Robbins, L. L.: Roentgen recognition of parathyroid adenomas. Am. J. Roentgenol. 71: 777, 1954. 85. * Young, M. O. and Halpert, B.: Parathyroid adenoma with generalized metastatic calcification. Arch. Path. 44: 628, 1947. 110 Francis Street Boston, Massachusetts 02215