Hyperparathyroidism and its clinical effects

Hyperparathyroidism Clinical CHARLES

MARKS,

and Its

Effects

M.D.,* Milwaukee, Wisconsin

From the Departmeftt of Surgery, Marquette University School of Medicine and Marquette University Afiliated Hospitals, Milwaukee, Wisconsin.

his co-workers [S] in 1934 emphas zed the importance of renal complications in hyperparathyroidism. They demonstrated that parathormone, a polypeptide with a molecular weight of 9,000 could elevate the serum calcium level and produce an increased secretion of phosphate by the kidney. The latter effect they attributed to an inhibition of tubular resorption of phosphate without in any way affecting glomerular filtration rate. This direct renal tubular effect was confirmed by Lavender et al. [7] who infused parathormone into the renal artery of a dog with an immediate unilateral phosphaturia in the absence of renal hemodynamic changes. Epstein et al. [8] demonstrated that the administration of parathyroid extract in dogs could compromise the renal concentrating mechanism within twentyfour hours with associated focal tubular lesions in the ascending loop of Henle as well as in the distal and collecting tubules. The presence of hypercalcemia leads secondarily to a corresponding hypercalcinuria with subsequent development of nephrolithiasis and nephrocalcinosis. The physiologic relationship between parathyroid hormone and the intestinal tract is less finite, calcium absorption occurring from the upper intestinal tract in the presence of a permissive amount of vitamin D. This fact has been well demonstrated by Schachter and Rosen [9] in their study of the active transport of Ca45 by the small intestine. Nevertheless, clinical experience and experimenta study have shown important relationships between the parathyroid hormone and the gastrointestinal tract.

EsPmE an increasing awareness of the diverse clinical manifestations attributable to hyperparathyroidism and the ready cure of this condition by excisional surgery of the affected parathyroid tissue, many problems continue to confront the clinician in maintaining a high index of suspicion regarding this diagnosis and in finding the appropriate lesion at surgical exploration. Since the first description of the histologic pattern of a parathyroid adenoma by Askenazi [I 1, followed in 1926 by the first successful excision of such a lesion by Mandl [Z], clinical emphasis has equated hyperparathyroidism with generalized osteitis fibrosa cystica. The work of Barnicott [3] demonstrated that parathyroid hormone, previously identified and extracted by Collip [P] and his co-workers, exerted a direct chemical effect on bone with dissolution of osseous tissue at points of contact with transplanted parathyroid tissue. Grollman [5] confirmed this direct effect on bone by demonstrating that parenteral administration of parathormone would cause direct mobilization of calcium from the skeleton in bilaterally nephrectomized animals. There is now general awareness that the development of hyperparathyroidism may occur insidiously over many years or decades without the development of major bone changes especially in people whose bones are protected by an adequate intake of milk and milk products. On the basis of physiologic studies complemented by clinical investigation, Albright and

D

* PRESENT ADDRESS: Division of Surgery, Mount Sinai Hospital Western Reserve University School of Medicine, Cleveland, Ohio.

40

of

Cleveland,

and

Department

The American

of

Journal

Surgery,

of Swgevy

Hyperparathyroidism Schiii’rin [lOJ has documented that parenteral administration of parathyroid extract in the dog leads to marked hyperplasia of the gastric chief cells with increased secretion of gastric pepsin but decreased secretion of acid, associated \vith intense hyperemia and necrosis in these areas as well as calcification in the fundic $anrls. This experimental evidence of gastric tissue response to parathormone has its counterpart in the frequent clinical association bet\vrcn hyperparathyroidism and peptic ulcer I\-itha similar correlative relationship between hyperparathyroidism and acute pancreatitis. Calcium intoxication may affect cerebral tissue causing personality changes and psychosis, and occasionally culminating in terminal clelirium and coma, representing a hypercalcemic crisis. In the past ten years, twenty-eight patients I\-ith established diagnosis of primary hyperparathryoidism who have undergone surgical therapy have been studied at the Marquette University group of affiliated institutions, and this paper reviews the experience gained in the diagnostic and therapeutic aspects of this disease. ‘ CLINICAL

FEATURES

Iicnd Efects. There is little doubt that the effects of renal calculus provide the most common clinical manifestations with colic, hematuria, urinary infection, and renal failure. The calculi are predominantly calcium phosphate or calcium oxalate and represent the end point of hypercalcemia and hypercalcuria. In eighteen patients (or 65 per cent of this series) renal calculi precipitated the presentation of the patient for medical advice and treatment. Nephrocalcinosis was present in only one patient whereas the presence of persistent hypertension in four of our cases was attributable to chronic renal changes. Gustrointestinal Symptoms. In a review of forty-five cases of primary hyperparathyroidism, St. Goar [II] emphasized the significance of gastrointestinal symptoms as a clue to the diagnosis of hyperparathyroidism and indicated an incidence of peptic ulcer approximating 30 per cent of patients while other gastrointestinal symptoms would raise this figure to 63 per cent attributing it to an increase in calcium ion concentration which impeded the transmission of afferent stimuli and diminishing efferent discharge of acitylcholine and thereby Vol. 116, July lV6.4’

-CL

reducing neuromuscular excitability with decreased gastrointestinal tone. The high incidence of peptic ulcer is noteworthy being pi-esent in twelve patients in this series comprising an incidence of 43 per cent and especially significant is the presence of stoma1 ulceration occurring in three patients who had previously undergone vagotomy and gastric resection. Only subsequent to definitive gastric surgery was the presence of hyperparathyroidism established and intense metabolic investigation demonstrated the presence of a polyendocrine syndrome in these three patients with associated uleerogenic pancreatic islet cell adenoma or carcinoma as well as pituitary adenoma. Episodes of acute pancreatitis antedated the diagnosis of hyperparathyroidism in five patients, providing an incidence in this series: of 1s per cent; although the causal relationship between hyperparathyroidism and pancreatitis is generally accepted, the mechanism of its causation is as yet obscure. Fink and Finfrock [12] defined the incidence of acute pancreatitis in hyperparathyroidism in their study as 11.5 per cent whereas Turchi et al. [13], in reporting twenty-seven cases of coexistent pancreatitis and hyperparathyroidism, emphasized the fact that hypercalcemia of hyperparathyroidism may be transiently lowered to normal or subnormal levels as a result of calcium lowering the effect of acute pancreatitis. More recently the role of glucagon secretion as a homeostatic mechanism to lower the elevated serum calcium level in hypercalcemia has been considered a pathogenetic factor in causing acute pancreatitis. The presence of cholelithiasis in three of our patients, providing an incidence of 10.5 per cent, is unlikely to be related directly to hyperparathyroidism as the age pattern in this group of patients is such that this incidence of cholelithiasis can be expected. Bone Changes. Homeostasis depends on the interrelationships between adequate intake, intestinal absorption, vitamin D intake, urinary and fecal excretion, as well as osseous deposition and resorption, the interchange depending controlling hormones which include parathormone and calcitonin. The occurrence of bone changes were noted in four of our patients, providing an incidence of 14 per cent. These changes included : (1) generalized demineralization resulting in vague pains in the back and limbs; (2) pathologic fracture through an area

Marks

42

1

2

FIG. 1. Subperiosteal

resorption at outer end of clavicle in hyperparathyroidism.

FIG. 2. Serrated resorption FIG. 3. Radiography FIG. 4. Metastatic

of phalanges.

of teeth demonstrates calcification

loss of dental lamina dura in patient with hyperparathyroidism.

in choroid plexus resultin g from hyperparathyroid

fibrosa cystica; (3) radiologic of osteitis changes: (a) subperiosteal resorption of bone which predominantly affected the phalanges, the outer ends of clavicles, and tibia. (Fig. 1.) The smooth periosteal lining is replaced by a moth-eaten serrated roughened border providing the characteristic “wasp-waist” phalangeal deformity resulting from bone resorption. (Fig. 2.) (b) loss of the dental lamina dura. Although characteristically associated with hyperparathyroidism (Fig. 3), it may be found in hypercalcemia due to other causes as well as a result of local periodontal disorder. Metastatic Calcification. Apart from nephrocalcinosis, metastatic calcification has been noted radiologically in the choroid plexus in one of our patients. (Fig. 4.) Calcification may also affect the tympanic membrane with ensuing deafness and may involve the conjunctivae

hypercalcemia.

over the tarsal plate causing a sensation of eyelid irritation; band keratopathy may be evident on inspection of the cornea. Calcific deposits have been noted along tendons and in the nails whereas involvement of peripheral arteries may lead to claudication, trophic ulceration, or gangrene of a limb. Polyendocrine Syndrome. An adenoma of the parathyroid gland or glands may occur concurrently with similar involvement in other endocrine glands, representing the polyendocrine syndrome described by Cope 1141. Four patients in this classification have been diagnosed in this series and had involvement of the pituitary, pancreas, or adrenal glands. A review of 260 cases of ulcerogenic tumor of the pancreas by Ellison and Wilson [15] disclosed fifteen patients with parathyroid adenoma and eight patients with multiple endocrine adenoThe American

Journal of Surgery

Hyperparathyroidism

matosis or U;ermer’s disease [16]. The coexistence of an ulcerogenic pancreatic tumor representing the Zolhnger-Ellison syndrome 1171, once suspected, can be confirmed by gastric secretory studies demonstrating a high twelve hour overnight secretion, the presence of high free acid, and little response to the augmented histamine tests as well as by the gastrointestinal radiologic changes described by Amberg et al. [IU]. One patient in this series, after undergoing total gustrectomy for duodenal ulceration attributable to multiple adenomas of the pancreas, subsequently had parathyroidectomy because of hyperparathyroid hypercalcemia and is at present undergoing irradiation for an adenoma of the pituitary. A second patient had a long-standing history of gastric resections complemented by vagotomy with subsequent demonstration of a parathyroid adenoma which was removed with control of the hypercalcemia. The patient presented ten years later with acute perforation of a stoma1 ulcer for which plication was performed, and appropriate gastric secretory studies later confirmed the presence of the ZollingerEllison syndrome. At subsequently planned exploratory operation a malignant &erogenic tumor of the pancreas with metastases to the lymph nodes was found, necessitating total gastric resection. The third patient presented with massive

43

gastrointestinal hemorrhage after having previously undergone gastrojejunostomy with revision gastric resection for recurrent peptic ulceration. A coin lesion noted radiologically in the right lung led to lobcctomy with Irathologic identification of the lesion as a metastatic carcinoma. Diagnostic work-up subsequently demonstrated a fasting blood sugar of 54 mg. per cent and serum calcium of 12.7’ mg. per cent; however, the patient rapidly tlietl of massive gastrointestinal hemorrhage. At autopsy a malignant islet cell carcinoma of the pancreas with metastases to the liver as well as bilateral adrenocortical adenomas and adrenomas involving each of the four parathyroid glands 1%.asfound. The fourth patient was a thirty-two year old man who presented with the clinical features of Gushing’s syndrome with a blood pressure of I CiCi,/lOS mm. Hg, hyperglycemia, truncal obesity, and abdominal striae as well as multiple rib fractures, generalized osteoporosis, nephrolithiasis, and bleeding duodenal ulcer. Serum calcium was 12.5 mg. per cent with a phosphorus content of 2.3 mg. and a fasting blood sugar of 192 per cent; there ~vas marked elevation in the serum ketosteroicl level suggesting the dependence of hyperadrcnalism on pituitary stimulation. Bilateral adrenalectomy and excision of an islet cell tumor of the pancreas were performed, and subsequently a parathyroid adenoma was removed. This con-

Marks current existence of adenomas in other endocrine organs should lead to a thorough and comprehensive assessment of the patient before definitive therapy is commenced so that the possibility of further extirpative surgery can be considered and, if necessary, carried out. Psychologic Changes. Hypercalcemia due to hyperparathyroidism is known to affect the central nervous system. Personality changes with psychic disorder may occur and progress to delirium, coma, and death. Although dramatic improvement may follow a fall in serum calcium, the lethality of such an acute hyperparathyroid crisis is borne out by the fact that over 50 per cent of such cases terminate fatally. Lemann and Donatelli [19] have described the features of calcium intoxication due to primary hyperparathyroidism and Payne and Fitchett [ZO], in their review of the hyperparathyroid crisis, reported eighty-two cases with a 52 per cent fatal termination. In a hypercalcemic crisis the vague symptoms of lassitude, weakness, fatigability, and anorexia may progress to nausea and vomiting with the development of somnolence, confusion, disorientation, stupor, and coma. Convulsive seizures are rare and occur usually in the young. Although personality changes and frank psychosis may be marked, reversion to normal may occur after parathyroidectomy. Two patients in this series presented with acute central nervous system disorder due to hyperparathyroidism. The first was a sixty-eight year old white man who was admitted on March 5, 1965 in a confused, disoriented state. During the previous fifteen years he had had multiple fractures of the radius, patella, and tibia, and examination at this admission disclosed marked deformity of the left clavicle as well as the right leg with internal rotation of the foot. Serum calcium at this time was 15 mg. per cent and serum phosphorus 2.3 mg. per cent. In view of the critical condition of the patient, an emergency selenium scan was carried out without demonstrable localization of the isotope in the parathyroid glands. Accordingly, on the following day exploration of the neck and total thyroidectomy were performed, with removal of a contained parathyroid adenoma. The functional status of this adenoma was emphasized by a dramatic drop of the serum calcium to 5.4 mg. per cent with marked tetany so that calcium gluconate and parathormone were administered with elevation of

the serum calcium to 9.9 mg. per cent. On discharge ten days later the patient’s cerebral condition was normal and has remained so to date with the serum calcium remaining at 9 mg. per cent and serum phosphorus at 4 mg. per cent. The second patient was a sixty-one year old Negro woman who had been institutionalized with a psychiatric diagnosis of delusional psychosis in May 1941. In March 1962, surgery for pyloric obstruction due to long-standing peptic ulcer was proposed and vagotomy and pyloroplasty were carried out. At this time serum calcium was 12.5 mg. per cent and serum phosphorus 2.3 mg. per cent. Biochemical confirmation of hyperparathyroidism was established and neck exploration performed, a large parathyroid adenoma being found behind the superior part of the right lobe of the thyroid. Follow-up study of this patient has continued to the present with serum calcium remaining constant at 9.4 mg. per cent, serum phosphorus at 3.6 mg. per cent, and a cerebral status which is considered reasonably normal. BIOCHEMICAL

FINDINGS

Biochemical disturbances are characteristic of primary hyperparathyroidism and include hypercalcemia, hypophosphatemia, hypercalcinuria, and hyperphosphaturia. The serum alkaline phosphatase has been elevated only in the presence of severe bone disease. In acceptSerum Calcium and Phosphorus. ing hypercalcemia and hypophosphatemia as the requisites for the diagnosis of hyperparathyroidism, a realistic upper limit of normal serum calcium level needs to be set at 10.5 mg. per cent. In the presence of low serum protein levels, however, a lower figure of serum calcium may represent an abnormally high level. Hypophosphatemia is represented by a serum phosphorus of less than 3 mg. per cent. These tests should be carried out with the patient in the fasting state and the blood collected without occlusion of the veins to prevent spurious elevation of the serum calcium level. As hyperparathyroidism with repeatedly normal serum calcium levels is known to occur especially in the presence of low serum albumin levels or renal failure, the estimation of ionizable fractions of serum calcium in these borderline cases may be necessary. Although hypercalcemia provides the hallThe American

Journal of Surgery

Hyperparathyroidism mark 0i hyperparathyroidisIn, it is important to remember that high blood calcium levels may result from other causes, and differentiation from secondary parathyroid hyperplasia due to renal disease, hypervitaminosis D, milk-alkali syndrome, and osteoporosis due to prolonged immobilization should not generally provide undue diagnostic difficulty. There may on occasion be dificulty in differentiating hypercalcemia due to primary malignant disease. Cortisone test: The hypercalcemia of hyperparathyroidism is resistant to the lowering effects of cortisone because serum calcium elevation is mediated by the bones and kidneys. The cortisone test helps to differentiate the hypercalcemia of Boeck’s sarcoid by rapid response to cortisone therapy as it blocks the activity of vitamin D in the intestinal absorption of calcium; however, in one patient in this series the concurrent presence of Boeck’s sarcoid and a parathyroid adenoma provided diagnostic difficulty. The patient, a fifty-nine year old Negro woman, had had hypertension since 1955, having- a sustained blood pressure of 200/120 mm. Hg. In 1958, for the first time, x-ray examination of the chest demonstrated generalized increase in interstitial markings in both bases suggestive of old chronic inflammatory disease. In the following year, roentgenogram of the chest showed extensive stringy infiltration of both bases which had increased since the previous film was taken. An inclusion cyst of the cheek was removed and histologic study demonstrated a tuberculoid granulomatous inflammation in salivary tissue which demonstrated no acid- or alcohol-fast organisms. For the first time the diagnosis of Boeck’s sarcoid was made. Roentgenograms of the skull, hands, and other bones were negative for the changes consistent with sarcoid disease. In February 1960 a right scalene node biopsy was performed and histologic study demonstrated a noncaseating granuloma of lymph nodes compatible with Boeck’s sarcoid. At this time therapy with cortisone and metacortin was instituted with rapid response and total clearance of the pulmonary lesion. In October 1960 she presented with urinary symptoms. Intravenous pyelography demonstrated an obstructing calculus in the left ureter with delayed filling of the left renal collecting system. The administration of steroids was discontinued because of high blood pressure, the VOL. 116. JtrEy 196X

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development of moon facies, the total resolution of pulmonary lesions as demonstrated on roentgenogram, and negative bone survey. Biochemical study demonstrated a serum calcium level within the range of 11.5 to 12.4 m::_. per cent and a serum phosphorus of Z.-j nlg. per cent. The cortisone test resulted in no decrease in the serum calcium level. On March 3, I !Ki 1, the neck was explored and a nodular enlarged thyroid with an enlarged parathyroid on its left upper pole was mobilized and removed and left thyroid lobectomy performed. The other parathyroid glands were defined and found to be normal. Postoperatively, the serum calcium dropped to S.9 mg. per cent, and subsequent follow-up study has indicated a serum calcium bearing between 9.4 and 10.6 mg. per cent and a serum phosphorus of 3.9 mg. per cent. Hypercdcinurin. The presence of hypcrcalcinuria with the patient on a balanced diet and without renal disease strongly favors a diagnosis of hyperparathyroidism. It i> important to place the patient on a diet containing less than 130 mg. of calcium per day for four to five days, and the presence of more than 1% mg. of calcium in a twenty-four hour urine specimen in the last two days of this dietary regimen represents hypercalcemia. On this regimen positive results of the Sulkowich test. performed at the patient’s bedside may provide presumptive evidence of hypercalcemia. If glttrnerular filtration is disturbed by renal disease, hypercalcinuria may not occur tle,~l:itr~ the presence of hyperparathyroidism. Hyperphosphnturia. Although hyperphosphaturia may occur in osteomalacia due to vitamin D deficiency and gastrointestinal malabsorption and in renal tubular acidoGs, it is strong presumptive evidence that in the absence of renal disease, diminished tubular reabsorption of phosphorus with corresponding hyperphosphaturia represents hyperparathyroidism. This results from the fact that a functioning parathyroid adenoma will depress the maximal tubular resorptive rate for organic phosphate, and cortisone will fail to reduce this resorptive rate in the patient who is allowed 150 mg. of phosphorus daily for several days before the test. The tubular reabsorption of phosphorus test (TRP) is generally carried out with the patient fasting on the morning of the test and being hydrated so as to produce 5 cc. of urine per minute by the administration of 400 cc. of

46

Marks

water at 6: 00 A.M. and 100 cc. of water per hour for the duration of the test. After discarding the voided urine at 8:OO A.M., all urine is collected for the subsequent two hours and tested for creatinine and phosphorus; a blood sample is taken simultaneously and checked for serum creatinine and phosphorus. A repeated check test is performed by collecting all urine during the subsequent two hours and again taking a blood sample for creatinine and phosphorus estimation. The formula used is as follows : % TRP

= 1 -

;c’,xxs;;

x loo

where U equals urinary, S equals serum, Cr equals creatinine, and P equals phosphorus. Most patients with hyperparathyroidism have a TRP below 80 per cent whereas normal persons will reabsorb 85 to 95 per cent of phosphorus. PREOPERATIVE

IDENTIFICATION

PARATHYROID

OF

ADENOMA

Plain Radiography. Displacement of the trachea would require an adenoma larger than 2 cm. in size and is infrequently noted. It is more frequently associated with a concurrent thyroid adenoma. (Fig. 5.) Similarly, an esophagogram under such circumstances, especially if cinefluoroscopy is utilized, may demAlthough onstrate esophageal deformation. Posen et al. [21] have demonstrated a mediastinal adenoma by pneumomediastinography after injecting CO2 behind the manubrium, this technic is unlikely to have wide appeal. Photoscanning. Bierwaltes [22] and Potchin Adelstein, and Dealy [23] have suggested the use of methionine selenium 75 as a radioactive isotope which might be localized in an overactive parathyroid, thereby aiding its localization. As the thyroid gland competes avidly for uptake of the isotope, thyroid uptake has to be retarded by use of thiouracil or Cytomel@ for a week before administering the isotope. In three patients in this series in whom attempted parathyroid localization was carried out, accurate localization was achieved in only one case. Therefore, although this technic may be helpful, it cannot replace the necessary surgical dissection and identification of parathyroid adenoma. Arteriography. In 1954 Seldinger [24] suc-

cessfully localized a parathyroid adenoma by transbrachial arteriography. It is possible at surgical exploration to inject 10 cc. of radiopaque dye into each inferior thyroid artery and attempt to outline a larger caliber of vessel on the side of the tumor. State [25] has noted that the artery on the affected side may almost double the diameter of the normal side, but Hardy, Snavely, and Langford [26] have indicated that occasionally a hyperfunctioning adenoma may arise in a fifth parathyroid gland with independent arterial supply from the innominate artery. This stresses once again the fact that diagnostic advances should not be permitted to replace total operative identification of all the parathyroid glands. SURGICAL

TREATMENT

Cure of a hyperfunctioning parathyroid adenoma requires its surgical removal, which in turn necessitates adequate surgical extirpation of the neck. In twenty-three cases in the present series (82 per cent) one adenoma was present, in three cases (11 per cent) two adenomas were found, and in two cases (7 per cent) multiple adenomas were discovered. Four patients in this last group represented examples of the polyendocrine syndrome and were previously described. As it is desirable to identify all four parathyroid glands, a standard cervical collar incision provides adequate access for this purpose. A pathologic frozen section examination may be necessary to differentiate parathyroid from lymphoid tissue; at this time, in the presence of pathologic changes, differentiation between hyperplasia or adenomatous change is possible. (Fig. 6.) The upper parathyroid glands, deriving as they do from the fourth branchial pouch, are usually found on the dorsum of the thyroid gland at the lower level of the cricoid cartilage whereas the inferior glands, which derive from the third branchial pouch arising in common with the thymus gland, are generally situated in the sheath of the thyroid gland at its inferior pole. On occasion, the parathyroid gland can be situated within the lobe of the thyroid gland and on rare occasions may exist in an anomalous or mediastinal situation. In the presence of diffuse hyperplasia it becomes necessary to remove three glands totally whereas the fourth is resected subtotally. If no lesion is found and the diagnosis of hyperparathyroid hypercalcemia is assured, thyroidectomy is performed in the hope that an intraThe American Journal of Surgery

Hyperparathyroidism l~arathyroid adenoma is present. Further procedures are deferred until metabolic 5tudie5 have been repeated and the resected tii;sue appraised microscopically. If calcium and phosphorus studies continue to give abnormal results and differential diagnosis of the hypercalcetnic state excludes all other possible causes, transsternal mediastinotomv is performed and a further diligent search of the mediastinum is carried out. The search for the parathyroid adenoma may necessitate removal of the thymus gland and all lymph nodes and mesodermal tissue in this area for appropriate pathologic study. After removal of the causative parathyroid adenoma it is not uncommon to find a sudden drop in the serum calcium level with occasional development of carpopedal spasm and other features of hypocalcemia. making it necessary to provide infusion of calcium gluconate. Within seventytwo hours, however, the serum calcium gradually ret.urns to normal and generally remains normal. If subsequent elevation of serum calcium develops, necessitating re-exploration of the neck, a careful review of the differential diagnosis of hypercalcemia is in order before a final commitment to re-exploration is made. thyroitl

tion of the neck ib necessary to identifv mal as well as all abnormal parathyrdd

of twenty-eight patients with established diagnosis of primary hyperparathyroidism who have undergone surgical therapy emphasizes the diverse clinical pattern of this disorder. The importance of renal effects and gastrointestinal symptoms caused by hyperparathyroidism is contrasted with the infrequency of overt skeletal changes. The relative frequency of pre-existing peptic ulcer and the not infrequent development of acute pancreatitis have been stressed. The polyendocrine syndrome, in which hyperparathyroidism is associated with other endocrinopathies, particularly involvement of the adrenal and pituitafy glands, is emphasized. The hypercalcemic crlsls, manifested by acute personality changes and psychosis, requires very energetic surgical management of the parathyroid adenoma. Relevant chemical studies and application of the cortisone test and radiographic technics for the preoperative identification of parathyroid adenoma may occasionally be helpful in aiding the surgeon to locate the gland that needs to be removed. As surgical removal of the tumor is the only effective treatment, thorough explora-

all nortissue.

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Marks 19. LEMANN,J., JR. and DONATELLX, A. A. Calcium intoxication due to primary hyperparathyroidism. Ann. Int. Med., 60: 447, 1964. 20. PAYNE, R. L. and FITCHETT,C. W. Hyperparathyroid crisis. Ann. Surg., 161: 737, 1964. 21. 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. 22. BIERWALTES, W. H. Attempts at visualization of the parathyroids and pancreas by photoscanning Northwest Med., 63: 771, 1964. 23. POTCHEN, E. J., ADELSTEIN, S. J., and DEALY,J. B.

Radioisotopic

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