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Hyperparathyroidism
HYPERPARATHYROIDISM EDMUND
B.
FLINK,
M.D.*
HYPERPARATHYROIDISM is a disease of the parathyroid glands with its chief manifestations in the musculoskeletal and genitourinary systems. Von Recklinghausen1 first described the skeletal manifestations of the disease in 1891 and differentiated osteitis fibrosa cystica from osteomalacia and osteoclastic metastases to bone. Askanazy2 was the first to comment on the presence of a parathyroid turn or in a case of osteitis fibrosa cystica. Erdheim 3 pointed out that the parathyroids undergo hyperplasia in osteomalacia and other bone diseases. He postulated that the abnormal amounts of calcium and phosphorus liberated from the decalcified skeleton caused hyperplasia of the parathyroids and thought therefore that in osteitis fibrosa cystic a the parathyroid enlargement was a secondary phenomenon. Successful surgical removal of a parathyroid adenoma by Mandl 4 in 1925 with subsequent recovery of the patient disproved the belief that the parathyroid pathology was secondary to the bone disease. During the past nineteen years a great number of cases have been reported. As an illustration of the prevalence of the disease, the group of investigators at the Massachusetts General Hospital alone have treated over seventy such patients. 5 REPORT OF CASES
In order to illustrate certain diagnostic criteria and results of treatment six cases seen during the past four years at the University of Minnesota Hospitals will be reported. Particular note should be given to the skeletal and genitourinary symptoms in these cases. CASE I.-F. W., a 45 year old woman, was admitted to the hospital in June 1940. Her illness had begun insidiously six years earlier, manifesting itself as muscular weakness. She had had bilateral chronic otitis media since childhood. In 1935 she had an episode of urinary frequency and nocturia but no polyuria at any time. In January 1940 an epulis was removed from the right maxilla. In March 1940 pain and a vague mass appeared in the right thigh. In April 1940 she fractured the shaft of the femur on arising from a chair. A hip spica cast was applied at another hospital. Menopause began in April 1940. On examination the pulse and temperature were normal. The blood pressure was 104/70. There was bilateral chronic otitis media with drumhead perforations and serous drainage from each ear. Hearing was impaired moderately. A hip spica enveloped the lower body and right lower extremity. The rest of the general examination was negative.
From the Department of Medicine, University of Minnesota Hospitals, Minncapolis, Minnesota. " Assistant Professor of Medicine, University of Minnesota. 389
390
EDMUND B. FLINK
Urinalysis and blood chemistries are recorded in Tables I and 2 for this and subsequent cases. The hcmoglobin level was 11.4 gm. per 100 cc., erythrocytes numbered 4,590,000; there were normal leukocyte and differential counts. X-rays showed pathologic fracture of the right femur at the site of a cyst; generalized decalcification of the skeleton; coarsening of the trabeculation especially in the bones of the hands, feet and left tibia; thinning of the cortex of all bones and absence of the usual diploic marking of the skull. All these indicated a typical example of osteitis fibrosa cystica generalisata. In addition there was chronic mastoiditis. On July I, 1940, Dr. John R. Paine removed an adenoma of the parathyroid located in the lower pole of the right lobe of the thyroid. The adenoma weighed 3 gm. and was composed of chief cells predominantly. The postoperative course was complicated by mild tetany which was controlled satisfactorily by dihydrotachysterol and calcium lactate orally. The femur fracture gradually healed. The patient's· skeleton has not become completely normal after two years of follow-up, but the biochemical findings returned to normal. A mastoidectomy was carried out in 1941. CASE II.-R. S., a 38 year old woman, was admitted to the hospital in December 1941. She had noticed weakness, marked fatigability and tenderness of her knees for two years or more together with polydipsia and polyuria for seven or eight years. She had been moderately constipated for three or four years. Her principal presenting complaint was a mass in the region of the lower right molars noted first in September 1940. This mass when biopsied proved to be a giant cell tumor. X-rays of the skeleton were obtained elsewhere and she was sent to the hospital with the tentative diagnosis of hyperparathyroidism. On examination the patient was well developed and her pulse and temperature were normal. Her blood pressure was 164/90. There was a small hard mass near the middle of the right mandible. A small mass palpated in the right side of the neck moved on swallowing. There were no areas of skeletal tenderness. The liver margin was palpable at the costal margin. The tendon reflexes were hyperactive. The hemoglobin level was 13.5 gm. per 100 cc.; leukocytes and differential counts were normal. The Wassermann reaction was negative. Electrocardiograms before operation showed a first degree heart block (P-R interval 0.22 and 0.23 seconds) and an inverted P3. Seventeen days after operation the P-R interval had returned to normal (0.16 seconds), Ps was upright, and the amplitude of the QRS complexes and the T waves in all leads was greater than on the initial tracing. X-rays films of the pelvis, skull, mandible, hands, long bones, vertebral column and chest revealed multiple cysts in these bones, striking nodular decalcification of the skull and generalized decalcification of the whole skeleton. There were multiple areas of calcification in the kidney parenchyma and stones in the pelvis of the right kidney. Dr. John R. Paine carried out a subtotal resection of a large parathyroid adenoma on December 17, 1941. Ten grams were removed from the adenoma of the right superior parathyroid gland. The patient did not develop tetany postoperatively. She was readmitted to the hospital in June 1942 for removal of the remainder of the adenoma which weighed I gm. The adenoma was composed of chief cells predominantly. At the second admission she had renal colic and hematuria. In April 1942 there was a remarkable improvement in the appearance of the skull and in July 1942 the appearance of the whole skeleton had returned nearly to normal. The patient's weight has increased, she is able to do all of her own work, she no longer is troubled with constipation, her polydipsia is alleviated and her strength is normal. Her blood pressure was 200/1I0 in January 1944 and at the last visit to the clinic in August it was 146/92.
HYPERPARATHYROIDISM
391
CASE IlL-A. S., a 57 year old woman, had noted a mass in the left side of her neck for five or six years. Eructations of food began in April 1942 and vomiting after meals with serious dehydration developed in July 1942. After a period of hospitalization elsewhere her condition improved symptomatic ally but she was an invalid most of the time until her admission to this hospital in December 1942. Vomiting after meals and marked anorexia continued until this time. She had lost about 30 pounds of weight in all, was unusually nervous and irritable and so weak that she could not work at all. She had been constipated for many years. For five years she had noted polyuria and polydipsia but no renal colic at any time. Only on direct questioning did she admit having had some aching pains in the extremities and back. On examination the patient's pulse was IOO and her temperature was normal. Her blood pressure was 196/114. She was tall and very malnourished, weighing 87 pounds on admission. The retinal arterioles were attenuated and there were moderate arteriosclerotic changes. A small nodular mass was located just below the thyroid cartilage on the left side in the region of the medial portion of the left lobe of the thyroid. The heart was moderately enlarged to the left. There was some thoracic kyphosis. Slowly moving peristaltic waves were visible over the stomach and small intestine. Neurologic examination was essentially negative. Hemoglobin was 9.0 gm. per IOO cc.; erythrocytes numbered 4,400,000; there were normal leukocyte and differential counts. The blood urea nitrogen obtained during the period of dehydration and eventual oliguria from fluid restriction and polyuria rose from 22 mg. per IOO cc. to 56 mg. per 100 cc. but returned to normal in twelve days. The basal metabolic rate was plus 3 per cent. X-ray films of the skull, hands, mandible, spine and long bones showed only osteoporosis consistent with her age and sex. The excretory urogram revealed poor excretion and stippled areas of calcification throughout the cortical portions of both kidI1eys. Chest films revealed metastatic calcification in the bronchi. The gastrointestinal tract was negative for intrinsic lesions but there was definite hypomotility of both stomach and intestine with very slow emptying time. During preliminary investigation fluids were restricted for various reasons on four successive days. The polyuria was so marked that the patient lost 8 pounds of weight in that period and exhibited definite dehydration phenomena. On December 29, 1942, Dr. Richard Varco removed a chief cell adenoma composed of four lobules and weighing 4 gm. Three normal-appearing parathyroid glands were identified. The postoperative course was uneventful. The patient developed a moderate amount of edema during the subsequent month, but this subsided following simple salt restriction and has not recurred. In four months she had gained 20 pounds in weight, was much stronger, was able to be up all day, was able to eat ·without vomiting and was no longer constipated. She has no polydipsia now. She is able to work as a maid all the time and her only symptom is the occurrence of an occasional severe headache. Her blood pressure was 220/120 at the last clinic visit twenty-one months after operation. CASE IV.-I. 0., a 57 year old woman, noted the onset of pain in the right wrist in July, 1942 and in the right leg in September 1942. Severe pain on weight bearing developed in February 1943, causing her to become an invalid partially bedridden. She had noted swellings in the right forearm and right leg about the same time, and had lost 25 pounds in a year. She had polyuria and polydipsia on occasion but no renal colic or hematuria. A biopsy of the mass on her arm performed by her own physician revealed a giant cell tumor. On examination the pulse and temperature were normal. The blood pressure was 114/78. Fusiform swellings were palpated along the mid portion of the right leg and right forearm. The masses were definitely warmer than the surrounding tissue, and weight bearing caused pain. The hemoglobin was 10.9 gm. per IOO cc.;
392
EDMUND B. FUNK
erythrocytes numbered 3,800,000; leukocytes 4100, with neutrophiIs 40 per cent, lymphocytes 56 per cent, monocytes 4 per cent. X-ray examination showed multiple cysts of the long bones, pelvis, skull, mandible, ribs and hands with generalized decalcification and coarsening of trabeculi. Very large multiloculated cysts in the right ulna and right tibia and multiple stones throughout both kidneys were also present. Fluoroscopy revealed a mass in the posterior superior mediastinum behind and to the right of the esophagus. A parathyroid adenoma weighing 3 gm. was removed by Drs. B. G. Lannin and C. Dennis on May 26, 1943. Postoperative tetany did not develop though the serum calcium dropped as Iow as 8.5 mg. per 100 cc. The patient did not return to the clinic until October and then she was having recurrent pain in the right arm and leg. X-rays revealed further decalcification and new cyst formation, and she had suffered a fracture of the right tibia by stepping on a scale. She was readmitted to the hospital. A mass in the mediastinum was again demonstrated. On November 13, 1943, Dr. Dennis found a parathyroid tumor in the posterior superior mediastinum and another in the substance of the left lobe of the thyroid, weighing 18 gm. and 2 gm. respectively. One apparently normalsized parathyroid was identified in the right superior position. The true pathologic nature of the tumor was not appreciated until review of the sections immediately after the second operation. The histological appearance was typical of that described by Castleman and Mallory 6 as primary hyperplasia of the "wasserhelle" cells. Postoperative tetany did not occur. The patient improved gradually and gained weight, but has had bone pain from time to time. A letter from her in August 1944 stated that she was feeling better than she had for a long time, but she had not returned to the clinic for determinations of serum calcium, and so on. One cannot say that she is cured at the present time, but she is improved. CASE V.-S. F. (Reported through the courtesy of Dr. George Levitt of St. Paul, Minnesota.) This 40 year old woman was admitted to the University Hospital in December 1943 for the confirmation of a diagnosis of hyperparathryoidism. In the early part of 1940 she had a vaginal hysterectomy for excessive uterine bleeding (benign). Immediately thereafter she noted severe pains in her lower back and left hip and thigh. These pains were excruciating on any kind of weight-bearing but were present to some degree all the time. Muscle weakness since the onset in 1940 had prevented her from performing more than a part of her household duties and had resulted in complete exhaustion on walking two blocks. During 1943 the pains in the legs, hips, ribs and upper back were constantly present, and deformity of the terminal phalanges of both hands began and progressed without any noticeable joint involvement. Since 1940 she had had bouts of polydipsia and polyuria but no other renal symptoms. On examination the pulse and temperature were normal. The blood pressure was 138/80. A moderate thoracic kyphosis was evident. A mass which was vaguely defined was present under the origin of the sternocleidomastoid muscle in the region of the lower pole of the left lobe of the thyroid. Tendon reflexes were equal but slightly hyperactive. There was marked deformity of the hands, most marked in some of the terminal phalanges but also present in some of the middle phalanges. The hemoglobin was 13.6 gm. per 100 cc.; leukocytes numbered 4350, with neutrophiIs 60 per cent, lymphocytes 36 per cent, monocytes 2 per cent and eosinophils 2 per cent. The Kline exclusion test was negative. X-ray films taken elsewhere in 1941 showed changes in the skull, ribs, hum-
HYPERPARATHYROIDISM
393
erus, pelvis and thoracolumbar spine with decalcification and tendency to cyst formation. Typical changes of osteitis fibrosa cystica generalisata with especially marked changes in the phalanges of the hands were present in 1943. The patient was referred to Dr. Oliver Cope of the Massachusetts General Hospital, who removed a chief-cell adenoma of a parathyroid gland. Mild symptoms of tetany developed immediately postoperatively, but the symptoms have been completely alleviated. Eight months after operation the calcium, phosphorus and phosphatase values were normal. CASE VI.-G. M., a 59 year old man, was admitted to the hospital on April 2, 1944. Two years before he fell and injured his left knee. The injury was treated by the application of a cast, but it was not certain whether he had a fracture. Since that time he had had pain in the lower back, in the hips and both lower extremities. The pain was deep-seated, often shooting in character, and severe enough to require opiates for relief. The patient had been weak for twelve years and for three years the weakness had been progressively interfering with his work. For twenty-five years he had had polydipsia of varying intensity, and had had to drink as much as 2 gallons of water some days. There had been no other renal symptoms. He had lost 30 pounds during the past several years in spite of a good appetite. E:xamination showed a well developed but very poorly nourished man weighing 120 pounds. I-lis blood pressure was 113/72. A small mass was palpable below the right sternocleidomastoid muscle at the level of the lower pole of the right lobe of the thyroid. This mass moved on swallowing. He had a lumbar lordosis and a slight thoracic kyphosis. There was slight inequality of the tendon reflexes, but sensory examination was normal. Hemoglobin was 12.1 gm. per 100 cc.; erythrocytes numbered 3,760.000; leukocytes and differential count were normal. The blood urea nitrogen was 45 mg. per 100 cc. and the creatinine 2.3 mg. per 100 cc. before surgery. Several weeks after surgery the blood urea nitrogen had decreased to 17 mg. per 100 cc. An electrocardiogram revealed a P-R interval of 0.20 seconds. On x-ray the skull showed an extremely granular appearance similar to that of patient 11. Some rarefaction of the mandible was evident as well as a marked osteoporosis of the hands with thinning of the cortices of the small bones, erosion of many. of the distal phalanges and fracture of some of the terminal tufts. Both tibiae and fibulae showed extensive decalcification with some granularity and thinning of the cortex. There was evidence therefore of a severe form of osteitis fibrosa cystica generalisata. In May 1944 Dr. Richard Varco removed a parathyroid tumor weighing 20 gm. from the region of the lower pole of the right lobe of the thyroid and the subclavicular area. The adenoma was composed of chief cells predominantly. In some areas there was a tendency to rosette formation and gland formation. Normal parathyroid glands were identified on the left side. On the seventh postoperative day the patient had definite but mild symptoms of tetany. For several days his Chvostek and Trousseau signs had been positive and remained positive for four or five days thereafter. He received 1 gm. of calcium gluconate on three occasions with satisfactory response. On the day of operation and during the whole postoperative period he received 3.75 mg. of dihydrotachysterol and 6 to 24 gm. of calcium lactate orally every day. In the three-month period from operation to the last clinic visit he had gained 15 pounds, was much stronger, was practically free of pain and his morale was much better. There had been a remarkable increase in the calcification of the skull and skeleton in general, but not a complete return to normal.
394
EDMUND B. FLINK
COMMENT
Diagnosis.-A clue to the diagnosis depends on the symptomatology which is characteristic of the disease. The musculoskeletal and genitourinary symptoms predominate, but gastrointestinal and cardiovascular symptoms may occur and may even be the presenting complaints. The most prominent symptom of all is pain in the bones and joints. The six patients had a variable amount of pain. In Case VI the patient had so much pain that he had to take codeine frequently and was disabled for two years. His pain was erroneously thought to be due to polyneuritis when he was first seen at this hospital. In all of the patients the pains were not constant but were severe at times and practically absent at other times. Pain on weight bearing is an important symptom and should suggest some form of bone disease. This symptom could be elicited from five of the six patients. Direct questioning in Case III was necessary to elicit the history of mild pain in the bones and joints. All patients exhibited muscular weakness which was marked enough to interfere with work, and even caused semi-invalidism of several patients. The muscular weakness is probably related to the hypercalcemia. It is interesting that some of the patients had hyperactive tendon reflexes. An epulis was removed in the first two patients some time before the true nature of the disease was recognized. Epulides are well known in a small percentage of cases of hyperparathyroidism. Thannhauser 7 reports the presence of epulis-like lesions in cases of bone disease associated with neurofibromatosis. Deformities of any part of the skeleton may occur. There have been many patients with progressive decline in stature because of compression of the vertebral bodies, coxa vara, and bowing of the long bones. None of the six patients in the present series complained of change of stature, but several had moderate kyphosis. Deformities of the hands in Cases V and VI and tu me factions in some of the long bones in Case IV and in the femur in Case I were noted. A pathologic fracture of the right femur was responsible for bringing the first patient to the care of physicians. Interestingly enough it was thought that she had metastatic carcinoma of the femur and she was transferred to this hospital for palliative x-ray therapy. Fractures sustained by little or no trauma certainly should suggest the possibility of hyperparathyroidism or some other decalcifying or cyst-forming process. They constitute presenting complaints of a fair percentage of patients with this disease. Genitourinary Symptoms.-A better understanding of the symptomatology referable to the genitourinary tract has resulted from the classification proposed for the renal pathology by Albright and associates. 8 There are three main groups of lesions: (1) pyelonephritis secondary to formation of calcium phosphate stones; (2) nephrocalcinosis,
HYPERPARATHYROIDISM
395
differing from the previous type in that the calcium deposits are in the kidney parenchyma rather than in the pelvis, and causing inflammatory changes, sclerosis and contracted kidneys; (3) acute parathyroid poisoning with calcium deposits in the kidney and all other organs, resulting in anuria and death. The symptoms associated with formation of stones in the pelvis or ureters are the same as those from any stone. Renal insufficiency may occur from hydronephrosis and pyelonephritis. Particular attention should be given to the symptoms of polydipsia and polyuria. Five of the six patients in this series had polyuria either constantly or intermittently before operation. The urine volumes were as high as 3000 cc. per day but averaged 1500 to 2000 cc. during hospital stay before operation. The cause of the polyuria is not entirely understood, but it was present in a patient with normal renal function and was alleviated after operation in all but one patient. It must be related in some way to hypercalcemia, hypercalcinuria and hyperphosphaturia. In two patients (Cases III and VI) these symptoms were the first real clue to the diagnosis. It is entirely possible that a correct diagnosis would not have been made in Case III if they had not attracted attention to the possibility of hyperparathyroidism. The polyuria was so marked that dehydration occurred when fluids were restricted. The sixth patient was in the hospital for twenty days before the symptom complex of pain in the extremities and polyuria was recognized. Cardiac irregularities and conduction defects occur occasionally. In Case Il,the patient had a prolonged P-R interval which returned to normal after operation. Elsom, Wood and Ravdin 9 reported a patient with prolonged P-R conduction time which did not return to normal after removal of a parathyroid adenoma. Hypertension is related to renal insufficiency, but patients IV and VI, with renal insufficiency of a severity comparable to that of the two hypertensive subjects, had normal blood pressures. Snapper 10 followed a patient with hypertension for two years after removal of a parathyroid adenoma and found persistence of the hypertension. The absence of hypertension in some patients with severe renal insufficiency has been noted by others. 7 , 9, 10 No striking improvement in renal function occurred in the patient reported by Elsom and his coworkers9 in one year following removal of a parathyroid adenoma. This has been the experience of others. s, 10 It is reasonable, however, to expect cessation of the progress of renal insufficiency by successful surgical treatment of hyperparathyroidism. In Cases III and VI a moderate improvement in renal function has been evidenced by a decrease in blood urea nitrogen to normal and an increase in phenolsulfonphthalein dye excretion. Hypertension has persisted in Cases Il and Ill. Many patients have constipation and flatulence, and some have marked anorexia, nausea and bouts of 'vomiting. The third patient had unusually severe gastrointestinal symptoms. She was admitted to the
396
EDMUND B. FLINK
hospital because of recurrent vomiting. She said "The food just doesn't go down." Pyloric obstruction was suspected clinically and a gastrointestinal study by barium meal was carried out. There was no obstruction but the stomach and bowel motility was very slow. Morelle and Beyerinckl l have each reported an instance of similar severe gastrointestinal symptoms. One must consider this disease in patients with symptoms suggesting pyloric or intestinal obstruction. Roentgenologic Diagnosis.-The roentgenologist often suggests the diagnosis of hyperparathyroidism when it has been unsuspected clinically. Osteitis fibrosa cystica generalisata does not occur in all cases as illustrated in Case Ill, and especially in cases reported by Albright and his coworkers.12 The bone lesions are generalized when they are demonstrable. There is widening of the bone marrow space with thinning of the cortex. The diffuse widening of the Haversian canals becomes evident as increased porosity of the bones and increase in the coarseness of the trabeculation of bone. Cysts and giant cell tumors occur frequently but these are not necessarily present. The skull often has a very characteristic appearance. Unusual skull changes were seen in Cases 11 and VI. X-ray demonstration of renal calcification, calcium phosphate stones in the renal pelvis and metastatic calcification in other organs is very important information. Fluoroscopy, x-rays, and planograms of the upper mediastinum are valuable in trying to locate adenomas in the mediastinum. Biochemical Diagnosis.-As valuable as x-ray diagnosis is in this disease, confirmation of the diagnosis depends on the biochemical findings in any given case. The essential features of the biochemical syndrome are as follows: (1) hypercalcemia, (2) hypophosphatemia, (3) hypercalcinuiia, (4) hyperphosphaturia and (5) increase in the phosphatase content of the serum. Parathormone causes an increase in the serum calcium, reduces the serum phosphate, and in young animals especially will cause widespread bone disease similar to osteitis fibrosa cystica. Furthermore it has been amply demonstrated that parathormone causes a phosphate diuresis. A complete calcium balance study was not carried out in any case of the present series, nor was phosphorus excretion studied. In Table 1 the chemical findings in the six cases are summarized. There are some unexplainable variations in the data, but for the most part the findings are self-evident. McLean and Hastings 13 have demonstrated the importance of a consideration of serum protein in conjunction with serum calcium determinations, since the nondiffllsible portion of the total calcium depends entirely on the protein concentration. In other words, lowering of serum proteins will lower the total calcium approximately 0.75 mg. for each gram of protein. The importance of this factor is especially evident in the interpretations of the serum calcium in Case Ill; when the calcium concentration was 9.8 mg. per 100 cc., the total serum protein was only 5 gm. per 100 cc.
TABLE 1.-cJIEMICAL FINDINGS - - - - - - - - - - - - - - ---
Preoperative
Postoperative
Case No.
Calcium mg./IOO cc.
Serum
Serum Phosphorus mg./l00 cc.
I
12.4 12.8
2.3 2.0
Il
12-.5 16.0 15.2
1.8 2.6 2.3
III
15.7 11.8 9.6 9.8 11.0
4.0 3.4 1.9 3.4 3.4
12.8 13.8 12.1 11 .6
2.9 2.1 2.0
6.6
14.1 11.7 13.7
2.7 1.6 2.7
7.0
12.5 13.0
1.7 1.9
7.0
IV
1st admission
2nd admission
V VI
17.6 16.5 14.5
4.2 2.2
Serum Protein gm./100 cc.
Serum· Phosphatase units/lOO cc.
Urinet Calcium mg./day
Phosphorus mg./l00 cc.
7.1 9.7 10.1 (25)t
2.3 4.5 3.7(25)
20 13.5(25)
I
11.2 9.4
2.1 3.6
54 8
!
38 B.U.'
6.2
77 89
525 387 311 259
5.5
8 10
491 431 269 308 274 269
5.0
6.7
39 50
246 321 392
67
104
50
._-
-
Serum· Phosphatase units/lOO cc.
Serum Calcium mg./l00 cc.
-
Serum
10.2(14)
2.4(14)
10.7 11.0 9.6 8.5 8.5 11 .1 (22)
3.3 2.9 3.4 3.4 3.4 2.9(22)
7.7(14)
Urinet Calcium mg./day
I
I
0 52
:r:
I
I
I I
I 8.9(22)
5. i 65.0 li .0(9)
II
225 193 56 63 75
58
'd M :>:l 'd
;.:>:l ;....,
8.4
2.7
12.7
2.3
237 184 263
10.7 9.1 9.6 8.1(2)
2.3 2.8 2.4 1.5(2)
53 59
!
57 190
[/}
45(5)
I
236(5)
~
248 180 180 228
10.1(8)
4.7(8)
14(8)
256 208 161
10.8 9.7 7.5 7.0 9.8(1) 8.5(3)
1.6 2.8(1) 3.6(3)
I
I I
I
I I
40(3)
,
I
I
198 164
><
:r: ><
:>:l
8:;;) .....
+0 0 0
trace
, Serum alkaline phosphatase units are expressed as King-Armstrong units/lOO cc. serum in all instances except the first marked B.U. = Bodansky Units. t Preoperative values on snccessive days were obtained when the patient was eating a low calcium nentral ash diet and the postoperative values were obtained when the patient was eating a general diet often with extra calcium. t Numbers in parentheses indicate number of months after operation.
VJ
'-0
'-.J
398
EDMUND B. FLINK
In a review of 114 cases of hyperparathyroidism in which the serum calcium concentration was recorded, Gutman and coworkers 14 found that 109 had over 11 mg. and 91 had over 12 mg. per 100 cc. In 79 cases in which the serum inorganic phosphorus was recorded 35 cases had values less than 2.5 mg. per 100 cc. Albright and associates 12 reported a number of instances of proven hyperparathyroidism in which the average calcium concentration of the serum was below 12 mg. per 100 cc. and in which the serum phosphatase activity was entirely normal. These patients had symptoms referable to genitourinary tract calculi and were classed as "cases with a minimal degree of hyperparathyroidism." The average preoperative serum calcium values reported in this series of 35 cases ranged from 10.6 to 17.3 mg. per 100 cc. It is important to recognize that when serious renal insufficiency and uremia supervene, the phosphorus may be normal or even high and consequently the serum calcium may be normal or even low. Many authors have emphasized the importance of repeated calcium determinations in a case of suspected hyperparathyroidism and one can understand the importance of this when one reviews the data in Case III and in other reported cases. For instance Wilder and associates lri reported a case with extreme skeletal decalcification having serum calcium values of 11.5, 11.0, 10.6 and 11.0 mg. per 100 cc. Calcium excretion in the urine is an important confirmatory test especially when the results of the chemical analysis of the serum are unconvincing. This was of crucial importance in Case Ill. The qualitative Sulkowitch test 16 indicates roughly the presence of abnormal amounts of calcium, but because of variations in specific gravity and volume of the urine from time to time, quantitative information is to be preferred. The urine calcium determinations in the present study were carried out by an adaptation of the Sulkowitch test for use with the Evelyn photoelectric colorimeter. The turbidity formed by the calcium oxalate precipitate depends on the quantity of calcium oxalate and can be measured with the colorimeter quite accurately. A lowcalcium neutral-ash diet was given preoperatively but high calcium intakes were given postoperatively. A normal person excretes 100 mg. calcium or less in the urine daily when taking the above diet. All of the patients in the present series had increased excretion of calcium. It may be noted that patient VI had lower calcium excretion than the others but his renal function was seriously impaired. Snapper10 reported a case in which the urine calcium excretion was ~ntirely normal, but his patient had renal insufficiency as evidenced by slightly elevated blood urea and nonprotein nitrogen. Downs and Scott17 reported a case with an excretion of but 24 mg. of calcium per day during the phase of uremia. A negative calcium balance and a high excretion of calcium in the urine also occur in hyperthyroidism in multiple myeloma, and in Paget's disease of bone. These conditions have to be dif-
TABLE 2.-RENAL STATUS Renal Function
Urinalysis
Case No. I II
III
I I
I I
Phenolsulfonphthalein Specific Gravity
Albumin
Sediment 15 Minutes
1004-1026
o-trace
o to many W.B.C.
1005-1013
0-1+
o to many R.B.C.
1015·-1008
o-trace
0
0-1+ trace
o to many R.B.C. o to many R.B.C. 0
IV
I. 1006-1011 II. 1006-1011
V
1010-1018
0
VI
1008-1013
o-trace
o to occasional R.B.C.
2 Hours
Blood Urea Nitrogen
60% 70% (2)t
10
48% 30%(6)
22 24
4% 5%
14% 15%
56" 22 19(18) 16(22)
5%
45% 33%
15% 10%
50%(30min) 2% 2%
Urea Clearance
~
~
Cs 27% Cs 20%
68% 10% 24%01)
I
I ~
45 17(J1) 21(1)
" The patient was dehydrated and bad an oliguria at time of these determinations. t Numbers in parentheses indicates number of months after operation.
-.0 -.0
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EDMUND B. FLINK
ferentiated from hyperparathyroidism by serum calcium and phosphorus determinations and evidence obtained by x-ray examinations. The alkaline phosphatase activity ot the serum is considered to indicate the activity of the mechanism of bone repair even though in hyperparathyroidism osteoclasis is the process most evident histologically and by x-ray. There are many other conditions of the bone in which the phosphatase activity is increased, particularly in Paget's disease of bone, in rickets, in osteomalacia, in certain cases with carcinomatosis of the skeleton and in extensive fractures. In multiple myeloma and Ewing's tumor the phosphatase activity is usually within normal limits. Cope and Churchill 18 • 1\) and Albright and coworkers 12 have shown that the higher the phosphatase activity preoperatively the greater is the possibility of tetany after complete removal of an adenoma or subtotal removal of hyperplastic tissue. No correlation exists, however, between the height of the serum calcium and the probability of tetany. Thus if the preoperative phosphatase determination is high, postoperative tetany should be looked for and treated as soon as premonitory symptoms develop. Pathology.- The total weight of the normal parathyroid glands is 0.11 to 0.13 gm. There are usually four glands but as few as two and as many as six have been found in a given subject. The glands are composed of four kinds of cells: the chief or principal cell, the "wasserhelle" cell, the pale oxyphil cell, and the dark oxyphil cell. The pathology of the parathyroid tumors has been worked out by Castleman and Mallory.6 "It was found possible to divide the cases sharply into two groups: one of them characterized by diffuse uniform changes throughout all the glandular tissue-an obvious hyperplastic process-the second by a proliferative area limited to one gland, frequently even to a portion of it, or rarely involving parts of two glands -neoplasia." Seven of seventy cases reported by Cope" were examples of diffuse hyperplasia of the water-clear cells. Patient IV reported above had primary hyperplasia of the wasserhelle cell type. It is noteworthy that this was not recognized at the first operation making a second operation necessary. The pathologic condition now recognized as primary hyperplasia, usually of the wasserhelle cells, is extremely important in that failure to recognize it will account for failure to correct the disease. Two adenomas of chief cell type may occur in the same patient and may account for residual disease after removal of a single adenoma. 18 Adenomas usually weigh from 0.5 to 20 gm. but one weighing 101 grams 30 has been reported. They are composed predominantly of chief cells but in rare instances oxyphil cells predominate. Rosette formation and pseudoglandular appearance, as in Case VI, occurs in some cases. Gentile and associates 21 reported a case with typical symptoms of hyperparathyroidism caused by a malignant parathyroid tumor which metastasized locally, resulting in recurrence of symptoms cor-
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rected by a second operation. Many malignant parathyroid tumors without hyperparathyroidism have been reported. Secondary hyperplasia of the parathyroid glands occurs in renal insufficiency, in rickets, Paget's disease, osteomalacia and occasional instances of metastatic cancer of the bones. This hyperplasia is characterized by a predominance of chief cells in contradistinction of the predominance of wasserhelle cells in primary hyperplasia. Differential Diagnosis.-Of course many bone diseases have to be considered in the differential diagnosis of hyperparathyroidism with skeletal involvement. Paget'S disease is never generalized. The x-ray appearance is diagnostic, there is no disturbance of serum calcium and inorganic phosphorus concentrations, but there usually is considerable increase in serum phosphatase. Multiple myeloma may be generalized but the x-ray appearance is usually diagnostic. The phosphatase is usually normal and serum inorganic phosphorus is normal. Hypercalcemia and hypercalcinuria may occur rarely. In addition there is often hyperglobulinemia, so that the erythrocyte sedimentation rate is very rapid and excessive rouleau formation is noted (so-called "greasy" blood smear). Bence-Jones protein is present in the urine of a majority of patients. Generalized cancer metastases to bone rarely cause generalized decalcification. The serum inorganic phosphorus is almost always normal even though the calcium may be increased. Histological evidence of metastases may be the only diagnostic feature, but usually the x-ray appearance and clinical features suffice to differentiate this bone disease from the others. Hyperthyroidism offers a special problem in that nervousness and irritability are common to bbth diseases. The skeleton may be very extensively decalcified. The serum inorganic phosphorus is normal, the phosphatase is normal or very slightly elevated, and of course calcium excretion in the urine usually is considerably increased. Of course the usual evidence of hyperthyroidism is very important. Lipoid granulomatosis, i.e. Hand-Schuller-Christian disease, can be differentiated readily by x-ray examination. Osteomalacia and renal osteodystrophy have characteristic biochemical findings. A condition variously named osteitis fibrosa cystica disseminata, fibrous dysplasia of bone, and Albright's disease has caused much confusion and has led to erroneous diagnoses of hyperparathyroidism. This disease is characterized by brown spots (cafe au lait spots) on the body, soft tissue tumors (neurofibromata), occasionally precocious puberty in females, and involvement of any part of the skeleton, often just .on one side of the body but never generalized. It is a variant of neurofibromatosis. An excellent review of this disease has recently been provided by Thannhauser. 7 Treatment.-Surgery.-The principles and technic of surgery of the parathyroids have been thoroughly discussed by Cope and Churchill18 ,19 and the reader is referred to their papers. The preoperative diagnosis must be firmly established, for in this disease the diagnosis
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cannot be excluded by a single exploratory operation. The surgeon should be thoroughly convinced of the accuracy of the diagnosis. The most meticulous and thorough dissection is necessary in order to find small adenomas and, more important still, in order to identify and not interfere with normal parathyroid tissue. Cope has discussed the practical relations of embryology of the glands to possible aberrant positions. Sixteen out of sixty patients had tumors in the anterior or posterior mediastinum. Four out of fifty-four had two adenomas. When one fails to find a tumor or hyperplasia in the neck region, the posterior superior mediastinum can be explored from the neck, but when this fails also, a second operation with reflection of the upper part of the sternum for exploration of the anterior mediastinum must be carried out. Subtotal resection of a solitary adenoma. is recommended if no normal parathyroid tissue is recognized or if there is a very high phosphatase and renal insufficiency. It is extremely important to have rapidly frozen sections and histologic examination of any tissue removed at operation to identify it as parathyroid tissue and also to detect primary hyperplasia. Oliguria and retention of nonprotein nitrogenous products may be serious complications in the immediate postoperative period. During the operation the administration of 5 per cent glucose solution in distilled water intravenously by constant drip and after the operation the administration of 3000 cc. or more of fluids per day, parenterally as necessary, are important measures in preventing oliguria. Calcium salts for intravenous use should be available for prompt administration to alleviate tetany if it is severe. Prevention of Tetany.- The surgical principles and technic outlined by Cope and Churchill were followed in most of the present cases but in Cases I and VI total resections were carried out even though tetany was to be expected. Normal parathyroids were identified in each instance. Particularly in Case VI expectation of the development of tetany was great and, to be sure, he did develop mild tetany on the seventh day, but he was carefully watched and vigorously treated from the onset. In Case I the mild symptoms of tetany were easily controlled by the administration of 1.25 mg. of dihydrotachysterol and 6 gm. of calcium lactate orally each day for one month. Patient VI received dihydrotachysterol continuously from the day immediately before surgery in a dose of 3.75 mg. per day for the first month. Then the dose was reduced to 1.25 mg. per day. Calcium lactate in doses ranging from 6 to 24 gm. per day was also given orally. It was necessary to administer calcium gluconate intravenously on three occasions for the control of minor tetanic symptoms. Because of the calcemic effect vitamin O 2 could be used in large doses (from 100,000 to 400,000 units a day) to as good advantage for it has been demonstrated that such doses are just as effective as dihydrotachysterol,22 It is suggested that prophylactic administration of either substance together with cal-
HYPERP ARATHYROID ISM
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cium salts, from the day of or the day following surgery until the danger of tetany is passed, may prove to be of definite benefit in preventing or minimizing tetany postoperatively. The use of the Sulkowitch test at frequent intervals is of much assistance in anticipating the onset of tetany and in judging a safe dose of the drug; complete absence of a precipitate indicates serum calcium of 8 mg. per 100 cc. or lower and a heavy precipitate indicates high calcium levels. If a tumor is not found at operation no harm can be done by a single or even several doses of dihydrotachysterol and the drug can be discontinued. Follow-up Program.-A follow-up of every patient for a number of years is necessary to be sure that recovery has occurred or that recurrence does not go on untreated. It is difficult to define an adequate follow-up program, but certainly the main features of the biochemical syndrome should be checked every three months for a year and then every six months for a while. X-rays of the skeleton should be taken according to the symptoms and other progress. The first patient has been lost sight of and the fourth patient has failed to return at the appointed interval, so that our own follow-up has not been ideal. Improvement of the skeleton can be attained without surgery by the administration of large amounts of calcium, but such treatment has resulted in further renal damage and certainly should not be pursued. X-ray treatment of the region of the neck has been without avail in carefully studied cases and should be abandoned as a form of treatment, for it can only delay adequate surgical treatment and delay may be costly, particularly as far as the kidneys are concerned. SUMMARY
Six cases of hyperparathyroidism are described. Many of the problems, some of the pitfalls, most of the symptoms, and the major pathologic groups of the disease have been encountered. Stress has been placed on the symptomatology referable to the skeletal and the genitourinary systems as the most important clue to diagnosis. Polyuria as a single symptom was the initial clue in two patients who had been diagnostic problems at this and other hospitals and clinics. The biochemical findings in each case were diagnostic. Osteitis fibrosa cystica generalisata was present in five cases. One patient has osteoporosis comparable in severity to that which could be expected normally at her agt;; furthermore, the phosphatase activity of her serum was normal. A method of prophylaxis or amelioration of postoperative tetany has been suggested and tried in several patients, and should be given further trial. The use of the Sulkowitch test at frequent intervals to anticipate hypocalcemia and tetany in the postoperative period has been found to be very valuable.
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1. Von Recklinghausen, F.: Festschrift der Assistenten fUr Virchow. Berlin, 1891. Cited by Snapper,IO p. 5.
2. Askanazy, M.: Arbeiten auf dem Gebiete der pathologischen Anatomie und Bakteriologie, Vo!. 4, page 398, 1904. Cited by Snapper,lO p. 10. 3. Erdheim, ].: Rachitis and Epithelikorporchen. Vienna, 1914. Cited by Snapper/ o p. 1. 4. Mandl, F.: Arch. f. klin. Chir., 143:245, 1926. 5. Cope, 0.: Clinics, 1 :1168, 1943. 6. Castleman, B. and Mallory, T. B.: Am. ]. Path., 11:1, 1935. 7. Thannhauser, S. J.: Medicine, 23:105, 1944. 8. Albright, F., Baird, P., Cope, O. and Bloomberg, E.: Am. ]. Med. Sci., 187:49,
1934. 9. EIsom, K. A., '''ood, F. C. and Ravdin, I. S.: Am. ]. M. Se., 191:49, 1936. 10. Snapper, I.: Medical Clinics on Bone Diseases. New York, Interscience Publishers, 1943. 11. Morelle, ]. and Beyerinck, C. W.: Cited by Snapper,lO p. 69. 12. Albright, F., Sulkowitch, H. "W". and Bloomberg, E.: Am. ]. M. Sci., 193:800, 1937. 13. McLean, F. C. and Hastings, A. 8.: Am. ]. M. Sci., 189:601, 1935. 14. Gutman, A. B., Tyson, T. L. and Gutman, E. 8.: Arch. Int. Med., 57:379, 1936. 15. Wilder, R. M., Camp, ]. D., Robertson, H. E. and Adams, M.: Proc. Staff Meet., Mayo Clinic, 7:597, 1932. 16. Barnay, ]. D. and Sulkowitch, H. W.: ]. Uro!., 37:746, 1937. 17. Qowns, R. S. and Scott, V.: Arch. Int. Med., 67:658, 1941. 18. Cope, 0.: Ann. Surg., 114:706, 1941. 19. Churchill, E. D. and Cope, 0.: Ann. Surg., 104:9, 1936. 20. SneH, A. M. and Mayo, C. W.: Proc. Staff Meet., the Mayo Clinic. 11:633, 1936. 21. Gentile, R. ]., Skinner, H. L. and Ashburn, L. L.: Surgery, 10:793, 1941. 22. McLcan, F. ].A.M.A., 117:609, 1941.
c.:
B.
FLINK,
M.D.*
HYPERPARATHYROIDISM is a disease of the parathyroid glands with its chief manifestations in the musculoskeletal and genitourinary systems. Von Recklinghausen1 first described the skeletal manifestations of the disease in 1891 and differentiated osteitis fibrosa cystica from osteomalacia and osteoclastic metastases to bone. Askanazy2 was the first to comment on the presence of a parathyroid turn or in a case of osteitis fibrosa cystica. Erdheim 3 pointed out that the parathyroids undergo hyperplasia in osteomalacia and other bone diseases. He postulated that the abnormal amounts of calcium and phosphorus liberated from the decalcified skeleton caused hyperplasia of the parathyroids and thought therefore that in osteitis fibrosa cystic a the parathyroid enlargement was a secondary phenomenon. Successful surgical removal of a parathyroid adenoma by Mandl 4 in 1925 with subsequent recovery of the patient disproved the belief that the parathyroid pathology was secondary to the bone disease. During the past nineteen years a great number of cases have been reported. As an illustration of the prevalence of the disease, the group of investigators at the Massachusetts General Hospital alone have treated over seventy such patients. 5 REPORT OF CASES
In order to illustrate certain diagnostic criteria and results of treatment six cases seen during the past four years at the University of Minnesota Hospitals will be reported. Particular note should be given to the skeletal and genitourinary symptoms in these cases. CASE I.-F. W., a 45 year old woman, was admitted to the hospital in June 1940. Her illness had begun insidiously six years earlier, manifesting itself as muscular weakness. She had had bilateral chronic otitis media since childhood. In 1935 she had an episode of urinary frequency and nocturia but no polyuria at any time. In January 1940 an epulis was removed from the right maxilla. In March 1940 pain and a vague mass appeared in the right thigh. In April 1940 she fractured the shaft of the femur on arising from a chair. A hip spica cast was applied at another hospital. Menopause began in April 1940. On examination the pulse and temperature were normal. The blood pressure was 104/70. There was bilateral chronic otitis media with drumhead perforations and serous drainage from each ear. Hearing was impaired moderately. A hip spica enveloped the lower body and right lower extremity. The rest of the general examination was negative.
From the Department of Medicine, University of Minnesota Hospitals, Minncapolis, Minnesota. " Assistant Professor of Medicine, University of Minnesota. 389
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Urinalysis and blood chemistries are recorded in Tables I and 2 for this and subsequent cases. The hcmoglobin level was 11.4 gm. per 100 cc., erythrocytes numbered 4,590,000; there were normal leukocyte and differential counts. X-rays showed pathologic fracture of the right femur at the site of a cyst; generalized decalcification of the skeleton; coarsening of the trabeculation especially in the bones of the hands, feet and left tibia; thinning of the cortex of all bones and absence of the usual diploic marking of the skull. All these indicated a typical example of osteitis fibrosa cystica generalisata. In addition there was chronic mastoiditis. On July I, 1940, Dr. John R. Paine removed an adenoma of the parathyroid located in the lower pole of the right lobe of the thyroid. The adenoma weighed 3 gm. and was composed of chief cells predominantly. The postoperative course was complicated by mild tetany which was controlled satisfactorily by dihydrotachysterol and calcium lactate orally. The femur fracture gradually healed. The patient's· skeleton has not become completely normal after two years of follow-up, but the biochemical findings returned to normal. A mastoidectomy was carried out in 1941. CASE II.-R. S., a 38 year old woman, was admitted to the hospital in December 1941. She had noticed weakness, marked fatigability and tenderness of her knees for two years or more together with polydipsia and polyuria for seven or eight years. She had been moderately constipated for three or four years. Her principal presenting complaint was a mass in the region of the lower right molars noted first in September 1940. This mass when biopsied proved to be a giant cell tumor. X-rays of the skeleton were obtained elsewhere and she was sent to the hospital with the tentative diagnosis of hyperparathyroidism. On examination the patient was well developed and her pulse and temperature were normal. Her blood pressure was 164/90. There was a small hard mass near the middle of the right mandible. A small mass palpated in the right side of the neck moved on swallowing. There were no areas of skeletal tenderness. The liver margin was palpable at the costal margin. The tendon reflexes were hyperactive. The hemoglobin level was 13.5 gm. per 100 cc.; leukocytes and differential counts were normal. The Wassermann reaction was negative. Electrocardiograms before operation showed a first degree heart block (P-R interval 0.22 and 0.23 seconds) and an inverted P3. Seventeen days after operation the P-R interval had returned to normal (0.16 seconds), Ps was upright, and the amplitude of the QRS complexes and the T waves in all leads was greater than on the initial tracing. X-rays films of the pelvis, skull, mandible, hands, long bones, vertebral column and chest revealed multiple cysts in these bones, striking nodular decalcification of the skull and generalized decalcification of the whole skeleton. There were multiple areas of calcification in the kidney parenchyma and stones in the pelvis of the right kidney. Dr. John R. Paine carried out a subtotal resection of a large parathyroid adenoma on December 17, 1941. Ten grams were removed from the adenoma of the right superior parathyroid gland. The patient did not develop tetany postoperatively. She was readmitted to the hospital in June 1942 for removal of the remainder of the adenoma which weighed I gm. The adenoma was composed of chief cells predominantly. At the second admission she had renal colic and hematuria. In April 1942 there was a remarkable improvement in the appearance of the skull and in July 1942 the appearance of the whole skeleton had returned nearly to normal. The patient's weight has increased, she is able to do all of her own work, she no longer is troubled with constipation, her polydipsia is alleviated and her strength is normal. Her blood pressure was 200/1I0 in January 1944 and at the last visit to the clinic in August it was 146/92.
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CASE IlL-A. S., a 57 year old woman, had noted a mass in the left side of her neck for five or six years. Eructations of food began in April 1942 and vomiting after meals with serious dehydration developed in July 1942. After a period of hospitalization elsewhere her condition improved symptomatic ally but she was an invalid most of the time until her admission to this hospital in December 1942. Vomiting after meals and marked anorexia continued until this time. She had lost about 30 pounds of weight in all, was unusually nervous and irritable and so weak that she could not work at all. She had been constipated for many years. For five years she had noted polyuria and polydipsia but no renal colic at any time. Only on direct questioning did she admit having had some aching pains in the extremities and back. On examination the patient's pulse was IOO and her temperature was normal. Her blood pressure was 196/114. She was tall and very malnourished, weighing 87 pounds on admission. The retinal arterioles were attenuated and there were moderate arteriosclerotic changes. A small nodular mass was located just below the thyroid cartilage on the left side in the region of the medial portion of the left lobe of the thyroid. The heart was moderately enlarged to the left. There was some thoracic kyphosis. Slowly moving peristaltic waves were visible over the stomach and small intestine. Neurologic examination was essentially negative. Hemoglobin was 9.0 gm. per IOO cc.; erythrocytes numbered 4,400,000; there were normal leukocyte and differential counts. The blood urea nitrogen obtained during the period of dehydration and eventual oliguria from fluid restriction and polyuria rose from 22 mg. per IOO cc. to 56 mg. per 100 cc. but returned to normal in twelve days. The basal metabolic rate was plus 3 per cent. X-ray films of the skull, hands, mandible, spine and long bones showed only osteoporosis consistent with her age and sex. The excretory urogram revealed poor excretion and stippled areas of calcification throughout the cortical portions of both kidI1eys. Chest films revealed metastatic calcification in the bronchi. The gastrointestinal tract was negative for intrinsic lesions but there was definite hypomotility of both stomach and intestine with very slow emptying time. During preliminary investigation fluids were restricted for various reasons on four successive days. The polyuria was so marked that the patient lost 8 pounds of weight in that period and exhibited definite dehydration phenomena. On December 29, 1942, Dr. Richard Varco removed a chief cell adenoma composed of four lobules and weighing 4 gm. Three normal-appearing parathyroid glands were identified. The postoperative course was uneventful. The patient developed a moderate amount of edema during the subsequent month, but this subsided following simple salt restriction and has not recurred. In four months she had gained 20 pounds in weight, was much stronger, was able to be up all day, was able to eat ·without vomiting and was no longer constipated. She has no polydipsia now. She is able to work as a maid all the time and her only symptom is the occurrence of an occasional severe headache. Her blood pressure was 220/120 at the last clinic visit twenty-one months after operation. CASE IV.-I. 0., a 57 year old woman, noted the onset of pain in the right wrist in July, 1942 and in the right leg in September 1942. Severe pain on weight bearing developed in February 1943, causing her to become an invalid partially bedridden. She had noted swellings in the right forearm and right leg about the same time, and had lost 25 pounds in a year. She had polyuria and polydipsia on occasion but no renal colic or hematuria. A biopsy of the mass on her arm performed by her own physician revealed a giant cell tumor. On examination the pulse and temperature were normal. The blood pressure was 114/78. Fusiform swellings were palpated along the mid portion of the right leg and right forearm. The masses were definitely warmer than the surrounding tissue, and weight bearing caused pain. The hemoglobin was 10.9 gm. per IOO cc.;
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erythrocytes numbered 3,800,000; leukocytes 4100, with neutrophiIs 40 per cent, lymphocytes 56 per cent, monocytes 4 per cent. X-ray examination showed multiple cysts of the long bones, pelvis, skull, mandible, ribs and hands with generalized decalcification and coarsening of trabeculi. Very large multiloculated cysts in the right ulna and right tibia and multiple stones throughout both kidneys were also present. Fluoroscopy revealed a mass in the posterior superior mediastinum behind and to the right of the esophagus. A parathyroid adenoma weighing 3 gm. was removed by Drs. B. G. Lannin and C. Dennis on May 26, 1943. Postoperative tetany did not develop though the serum calcium dropped as Iow as 8.5 mg. per 100 cc. The patient did not return to the clinic until October and then she was having recurrent pain in the right arm and leg. X-rays revealed further decalcification and new cyst formation, and she had suffered a fracture of the right tibia by stepping on a scale. She was readmitted to the hospital. A mass in the mediastinum was again demonstrated. On November 13, 1943, Dr. Dennis found a parathyroid tumor in the posterior superior mediastinum and another in the substance of the left lobe of the thyroid, weighing 18 gm. and 2 gm. respectively. One apparently normalsized parathyroid was identified in the right superior position. The true pathologic nature of the tumor was not appreciated until review of the sections immediately after the second operation. The histological appearance was typical of that described by Castleman and Mallory 6 as primary hyperplasia of the "wasserhelle" cells. Postoperative tetany did not occur. The patient improved gradually and gained weight, but has had bone pain from time to time. A letter from her in August 1944 stated that she was feeling better than she had for a long time, but she had not returned to the clinic for determinations of serum calcium, and so on. One cannot say that she is cured at the present time, but she is improved. CASE V.-S. F. (Reported through the courtesy of Dr. George Levitt of St. Paul, Minnesota.) This 40 year old woman was admitted to the University Hospital in December 1943 for the confirmation of a diagnosis of hyperparathryoidism. In the early part of 1940 she had a vaginal hysterectomy for excessive uterine bleeding (benign). Immediately thereafter she noted severe pains in her lower back and left hip and thigh. These pains were excruciating on any kind of weight-bearing but were present to some degree all the time. Muscle weakness since the onset in 1940 had prevented her from performing more than a part of her household duties and had resulted in complete exhaustion on walking two blocks. During 1943 the pains in the legs, hips, ribs and upper back were constantly present, and deformity of the terminal phalanges of both hands began and progressed without any noticeable joint involvement. Since 1940 she had had bouts of polydipsia and polyuria but no other renal symptoms. On examination the pulse and temperature were normal. The blood pressure was 138/80. A moderate thoracic kyphosis was evident. A mass which was vaguely defined was present under the origin of the sternocleidomastoid muscle in the region of the lower pole of the left lobe of the thyroid. Tendon reflexes were equal but slightly hyperactive. There was marked deformity of the hands, most marked in some of the terminal phalanges but also present in some of the middle phalanges. The hemoglobin was 13.6 gm. per 100 cc.; leukocytes numbered 4350, with neutrophiIs 60 per cent, lymphocytes 36 per cent, monocytes 2 per cent and eosinophils 2 per cent. The Kline exclusion test was negative. X-ray films taken elsewhere in 1941 showed changes in the skull, ribs, hum-
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erus, pelvis and thoracolumbar spine with decalcification and tendency to cyst formation. Typical changes of osteitis fibrosa cystica generalisata with especially marked changes in the phalanges of the hands were present in 1943. The patient was referred to Dr. Oliver Cope of the Massachusetts General Hospital, who removed a chief-cell adenoma of a parathyroid gland. Mild symptoms of tetany developed immediately postoperatively, but the symptoms have been completely alleviated. Eight months after operation the calcium, phosphorus and phosphatase values were normal. CASE VI.-G. M., a 59 year old man, was admitted to the hospital on April 2, 1944. Two years before he fell and injured his left knee. The injury was treated by the application of a cast, but it was not certain whether he had a fracture. Since that time he had had pain in the lower back, in the hips and both lower extremities. The pain was deep-seated, often shooting in character, and severe enough to require opiates for relief. The patient had been weak for twelve years and for three years the weakness had been progressively interfering with his work. For twenty-five years he had had polydipsia of varying intensity, and had had to drink as much as 2 gallons of water some days. There had been no other renal symptoms. He had lost 30 pounds during the past several years in spite of a good appetite. E:xamination showed a well developed but very poorly nourished man weighing 120 pounds. I-lis blood pressure was 113/72. A small mass was palpable below the right sternocleidomastoid muscle at the level of the lower pole of the right lobe of the thyroid. This mass moved on swallowing. He had a lumbar lordosis and a slight thoracic kyphosis. There was slight inequality of the tendon reflexes, but sensory examination was normal. Hemoglobin was 12.1 gm. per 100 cc.; erythrocytes numbered 3,760.000; leukocytes and differential count were normal. The blood urea nitrogen was 45 mg. per 100 cc. and the creatinine 2.3 mg. per 100 cc. before surgery. Several weeks after surgery the blood urea nitrogen had decreased to 17 mg. per 100 cc. An electrocardiogram revealed a P-R interval of 0.20 seconds. On x-ray the skull showed an extremely granular appearance similar to that of patient 11. Some rarefaction of the mandible was evident as well as a marked osteoporosis of the hands with thinning of the cortices of the small bones, erosion of many. of the distal phalanges and fracture of some of the terminal tufts. Both tibiae and fibulae showed extensive decalcification with some granularity and thinning of the cortex. There was evidence therefore of a severe form of osteitis fibrosa cystica generalisata. In May 1944 Dr. Richard Varco removed a parathyroid tumor weighing 20 gm. from the region of the lower pole of the right lobe of the thyroid and the subclavicular area. The adenoma was composed of chief cells predominantly. In some areas there was a tendency to rosette formation and gland formation. Normal parathyroid glands were identified on the left side. On the seventh postoperative day the patient had definite but mild symptoms of tetany. For several days his Chvostek and Trousseau signs had been positive and remained positive for four or five days thereafter. He received 1 gm. of calcium gluconate on three occasions with satisfactory response. On the day of operation and during the whole postoperative period he received 3.75 mg. of dihydrotachysterol and 6 to 24 gm. of calcium lactate orally every day. In the three-month period from operation to the last clinic visit he had gained 15 pounds, was much stronger, was practically free of pain and his morale was much better. There had been a remarkable increase in the calcification of the skull and skeleton in general, but not a complete return to normal.
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COMMENT
Diagnosis.-A clue to the diagnosis depends on the symptomatology which is characteristic of the disease. The musculoskeletal and genitourinary symptoms predominate, but gastrointestinal and cardiovascular symptoms may occur and may even be the presenting complaints. The most prominent symptom of all is pain in the bones and joints. The six patients had a variable amount of pain. In Case VI the patient had so much pain that he had to take codeine frequently and was disabled for two years. His pain was erroneously thought to be due to polyneuritis when he was first seen at this hospital. In all of the patients the pains were not constant but were severe at times and practically absent at other times. Pain on weight bearing is an important symptom and should suggest some form of bone disease. This symptom could be elicited from five of the six patients. Direct questioning in Case III was necessary to elicit the history of mild pain in the bones and joints. All patients exhibited muscular weakness which was marked enough to interfere with work, and even caused semi-invalidism of several patients. The muscular weakness is probably related to the hypercalcemia. It is interesting that some of the patients had hyperactive tendon reflexes. An epulis was removed in the first two patients some time before the true nature of the disease was recognized. Epulides are well known in a small percentage of cases of hyperparathyroidism. Thannhauser 7 reports the presence of epulis-like lesions in cases of bone disease associated with neurofibromatosis. Deformities of any part of the skeleton may occur. There have been many patients with progressive decline in stature because of compression of the vertebral bodies, coxa vara, and bowing of the long bones. None of the six patients in the present series complained of change of stature, but several had moderate kyphosis. Deformities of the hands in Cases V and VI and tu me factions in some of the long bones in Case IV and in the femur in Case I were noted. A pathologic fracture of the right femur was responsible for bringing the first patient to the care of physicians. Interestingly enough it was thought that she had metastatic carcinoma of the femur and she was transferred to this hospital for palliative x-ray therapy. Fractures sustained by little or no trauma certainly should suggest the possibility of hyperparathyroidism or some other decalcifying or cyst-forming process. They constitute presenting complaints of a fair percentage of patients with this disease. Genitourinary Symptoms.-A better understanding of the symptomatology referable to the genitourinary tract has resulted from the classification proposed for the renal pathology by Albright and associates. 8 There are three main groups of lesions: (1) pyelonephritis secondary to formation of calcium phosphate stones; (2) nephrocalcinosis,
HYPERPARATHYROIDISM
395
differing from the previous type in that the calcium deposits are in the kidney parenchyma rather than in the pelvis, and causing inflammatory changes, sclerosis and contracted kidneys; (3) acute parathyroid poisoning with calcium deposits in the kidney and all other organs, resulting in anuria and death. The symptoms associated with formation of stones in the pelvis or ureters are the same as those from any stone. Renal insufficiency may occur from hydronephrosis and pyelonephritis. Particular attention should be given to the symptoms of polydipsia and polyuria. Five of the six patients in this series had polyuria either constantly or intermittently before operation. The urine volumes were as high as 3000 cc. per day but averaged 1500 to 2000 cc. during hospital stay before operation. The cause of the polyuria is not entirely understood, but it was present in a patient with normal renal function and was alleviated after operation in all but one patient. It must be related in some way to hypercalcemia, hypercalcinuria and hyperphosphaturia. In two patients (Cases III and VI) these symptoms were the first real clue to the diagnosis. It is entirely possible that a correct diagnosis would not have been made in Case III if they had not attracted attention to the possibility of hyperparathyroidism. The polyuria was so marked that dehydration occurred when fluids were restricted. The sixth patient was in the hospital for twenty days before the symptom complex of pain in the extremities and polyuria was recognized. Cardiac irregularities and conduction defects occur occasionally. In Case Il,the patient had a prolonged P-R interval which returned to normal after operation. Elsom, Wood and Ravdin 9 reported a patient with prolonged P-R conduction time which did not return to normal after removal of a parathyroid adenoma. Hypertension is related to renal insufficiency, but patients IV and VI, with renal insufficiency of a severity comparable to that of the two hypertensive subjects, had normal blood pressures. Snapper 10 followed a patient with hypertension for two years after removal of a parathyroid adenoma and found persistence of the hypertension. The absence of hypertension in some patients with severe renal insufficiency has been noted by others. 7 , 9, 10 No striking improvement in renal function occurred in the patient reported by Elsom and his coworkers9 in one year following removal of a parathyroid adenoma. This has been the experience of others. s, 10 It is reasonable, however, to expect cessation of the progress of renal insufficiency by successful surgical treatment of hyperparathyroidism. In Cases III and VI a moderate improvement in renal function has been evidenced by a decrease in blood urea nitrogen to normal and an increase in phenolsulfonphthalein dye excretion. Hypertension has persisted in Cases Il and Ill. Many patients have constipation and flatulence, and some have marked anorexia, nausea and bouts of 'vomiting. The third patient had unusually severe gastrointestinal symptoms. She was admitted to the
396
EDMUND B. FLINK
hospital because of recurrent vomiting. She said "The food just doesn't go down." Pyloric obstruction was suspected clinically and a gastrointestinal study by barium meal was carried out. There was no obstruction but the stomach and bowel motility was very slow. Morelle and Beyerinckl l have each reported an instance of similar severe gastrointestinal symptoms. One must consider this disease in patients with symptoms suggesting pyloric or intestinal obstruction. Roentgenologic Diagnosis.-The roentgenologist often suggests the diagnosis of hyperparathyroidism when it has been unsuspected clinically. Osteitis fibrosa cystica generalisata does not occur in all cases as illustrated in Case Ill, and especially in cases reported by Albright and his coworkers.12 The bone lesions are generalized when they are demonstrable. There is widening of the bone marrow space with thinning of the cortex. The diffuse widening of the Haversian canals becomes evident as increased porosity of the bones and increase in the coarseness of the trabeculation of bone. Cysts and giant cell tumors occur frequently but these are not necessarily present. The skull often has a very characteristic appearance. Unusual skull changes were seen in Cases 11 and VI. X-ray demonstration of renal calcification, calcium phosphate stones in the renal pelvis and metastatic calcification in other organs is very important information. Fluoroscopy, x-rays, and planograms of the upper mediastinum are valuable in trying to locate adenomas in the mediastinum. Biochemical Diagnosis.-As valuable as x-ray diagnosis is in this disease, confirmation of the diagnosis depends on the biochemical findings in any given case. The essential features of the biochemical syndrome are as follows: (1) hypercalcemia, (2) hypophosphatemia, (3) hypercalcinuiia, (4) hyperphosphaturia and (5) increase in the phosphatase content of the serum. Parathormone causes an increase in the serum calcium, reduces the serum phosphate, and in young animals especially will cause widespread bone disease similar to osteitis fibrosa cystica. Furthermore it has been amply demonstrated that parathormone causes a phosphate diuresis. A complete calcium balance study was not carried out in any case of the present series, nor was phosphorus excretion studied. In Table 1 the chemical findings in the six cases are summarized. There are some unexplainable variations in the data, but for the most part the findings are self-evident. McLean and Hastings 13 have demonstrated the importance of a consideration of serum protein in conjunction with serum calcium determinations, since the nondiffllsible portion of the total calcium depends entirely on the protein concentration. In other words, lowering of serum proteins will lower the total calcium approximately 0.75 mg. for each gram of protein. The importance of this factor is especially evident in the interpretations of the serum calcium in Case Ill; when the calcium concentration was 9.8 mg. per 100 cc., the total serum protein was only 5 gm. per 100 cc.
TABLE 1.-cJIEMICAL FINDINGS - - - - - - - - - - - - - - ---
Preoperative
Postoperative
Case No.
Calcium mg./IOO cc.
Serum
Serum Phosphorus mg./l00 cc.
I
12.4 12.8
2.3 2.0
Il
12-.5 16.0 15.2
1.8 2.6 2.3
III
15.7 11.8 9.6 9.8 11.0
4.0 3.4 1.9 3.4 3.4
12.8 13.8 12.1 11 .6
2.9 2.1 2.0
6.6
14.1 11.7 13.7
2.7 1.6 2.7
7.0
12.5 13.0
1.7 1.9
7.0
IV
1st admission
2nd admission
V VI
17.6 16.5 14.5
4.2 2.2
Serum Protein gm./100 cc.
Serum· Phosphatase units/lOO cc.
Urinet Calcium mg./day
Phosphorus mg./l00 cc.
7.1 9.7 10.1 (25)t
2.3 4.5 3.7(25)
20 13.5(25)
I
11.2 9.4
2.1 3.6
54 8
!
38 B.U.'
6.2
77 89
525 387 311 259
5.5
8 10
491 431 269 308 274 269
5.0
6.7
39 50
246 321 392
67
104
50
._-
-
Serum· Phosphatase units/lOO cc.
Serum Calcium mg./l00 cc.
-
Serum
10.2(14)
2.4(14)
10.7 11.0 9.6 8.5 8.5 11 .1 (22)
3.3 2.9 3.4 3.4 3.4 2.9(22)
7.7(14)
Urinet Calcium mg./day
I
I
0 52
:r:
I
I
I I
I 8.9(22)
5. i 65.0 li .0(9)
II
225 193 56 63 75
58
'd M :>:l 'd
;.:>:l ;....,
8.4
2.7
12.7
2.3
237 184 263
10.7 9.1 9.6 8.1(2)
2.3 2.8 2.4 1.5(2)
53 59
!
57 190
[/}
45(5)
I
236(5)
~
248 180 180 228
10.1(8)
4.7(8)
14(8)
256 208 161
10.8 9.7 7.5 7.0 9.8(1) 8.5(3)
1.6 2.8(1) 3.6(3)
I
I I
I
I I
40(3)
,
I
I
198 164
><
:r: ><
:>:l
8:;;) .....
+0 0 0
trace
, Serum alkaline phosphatase units are expressed as King-Armstrong units/lOO cc. serum in all instances except the first marked B.U. = Bodansky Units. t Preoperative values on snccessive days were obtained when the patient was eating a low calcium nentral ash diet and the postoperative values were obtained when the patient was eating a general diet often with extra calcium. t Numbers in parentheses indicate number of months after operation.
VJ
'-0
'-.J
398
EDMUND B. FLINK
In a review of 114 cases of hyperparathyroidism in which the serum calcium concentration was recorded, Gutman and coworkers 14 found that 109 had over 11 mg. and 91 had over 12 mg. per 100 cc. In 79 cases in which the serum inorganic phosphorus was recorded 35 cases had values less than 2.5 mg. per 100 cc. Albright and associates 12 reported a number of instances of proven hyperparathyroidism in which the average calcium concentration of the serum was below 12 mg. per 100 cc. and in which the serum phosphatase activity was entirely normal. These patients had symptoms referable to genitourinary tract calculi and were classed as "cases with a minimal degree of hyperparathyroidism." The average preoperative serum calcium values reported in this series of 35 cases ranged from 10.6 to 17.3 mg. per 100 cc. It is important to recognize that when serious renal insufficiency and uremia supervene, the phosphorus may be normal or even high and consequently the serum calcium may be normal or even low. Many authors have emphasized the importance of repeated calcium determinations in a case of suspected hyperparathyroidism and one can understand the importance of this when one reviews the data in Case III and in other reported cases. For instance Wilder and associates lri reported a case with extreme skeletal decalcification having serum calcium values of 11.5, 11.0, 10.6 and 11.0 mg. per 100 cc. Calcium excretion in the urine is an important confirmatory test especially when the results of the chemical analysis of the serum are unconvincing. This was of crucial importance in Case Ill. The qualitative Sulkowitch test 16 indicates roughly the presence of abnormal amounts of calcium, but because of variations in specific gravity and volume of the urine from time to time, quantitative information is to be preferred. The urine calcium determinations in the present study were carried out by an adaptation of the Sulkowitch test for use with the Evelyn photoelectric colorimeter. The turbidity formed by the calcium oxalate precipitate depends on the quantity of calcium oxalate and can be measured with the colorimeter quite accurately. A lowcalcium neutral-ash diet was given preoperatively but high calcium intakes were given postoperatively. A normal person excretes 100 mg. calcium or less in the urine daily when taking the above diet. All of the patients in the present series had increased excretion of calcium. It may be noted that patient VI had lower calcium excretion than the others but his renal function was seriously impaired. Snapper10 reported a case in which the urine calcium excretion was ~ntirely normal, but his patient had renal insufficiency as evidenced by slightly elevated blood urea and nonprotein nitrogen. Downs and Scott17 reported a case with an excretion of but 24 mg. of calcium per day during the phase of uremia. A negative calcium balance and a high excretion of calcium in the urine also occur in hyperthyroidism in multiple myeloma, and in Paget's disease of bone. These conditions have to be dif-
TABLE 2.-RENAL STATUS Renal Function
Urinalysis
Case No. I II
III
I I
I I
Phenolsulfonphthalein Specific Gravity
Albumin
Sediment 15 Minutes
1004-1026
o-trace
o to many W.B.C.
1005-1013
0-1+
o to many R.B.C.
1015·-1008
o-trace
0
0-1+ trace
o to many R.B.C. o to many R.B.C. 0
IV
I. 1006-1011 II. 1006-1011
V
1010-1018
0
VI
1008-1013
o-trace
o to occasional R.B.C.
2 Hours
Blood Urea Nitrogen
60% 70% (2)t
10
48% 30%(6)
22 24
4% 5%
14% 15%
56" 22 19(18) 16(22)
5%
45% 33%
15% 10%
50%(30min) 2% 2%
Urea Clearance
~
~
Cs 27% Cs 20%
68% 10% 24%01)
I
I ~
45 17(J1) 21(1)
" The patient was dehydrated and bad an oliguria at time of these determinations. t Numbers in parentheses indicates number of months after operation.
-.0 -.0
400
EDMUND B. FLINK
ferentiated from hyperparathyroidism by serum calcium and phosphorus determinations and evidence obtained by x-ray examinations. The alkaline phosphatase activity ot the serum is considered to indicate the activity of the mechanism of bone repair even though in hyperparathyroidism osteoclasis is the process most evident histologically and by x-ray. There are many other conditions of the bone in which the phosphatase activity is increased, particularly in Paget's disease of bone, in rickets, in osteomalacia, in certain cases with carcinomatosis of the skeleton and in extensive fractures. In multiple myeloma and Ewing's tumor the phosphatase activity is usually within normal limits. Cope and Churchill 18 • 1\) and Albright and coworkers 12 have shown that the higher the phosphatase activity preoperatively the greater is the possibility of tetany after complete removal of an adenoma or subtotal removal of hyperplastic tissue. No correlation exists, however, between the height of the serum calcium and the probability of tetany. Thus if the preoperative phosphatase determination is high, postoperative tetany should be looked for and treated as soon as premonitory symptoms develop. Pathology.- The total weight of the normal parathyroid glands is 0.11 to 0.13 gm. There are usually four glands but as few as two and as many as six have been found in a given subject. The glands are composed of four kinds of cells: the chief or principal cell, the "wasserhelle" cell, the pale oxyphil cell, and the dark oxyphil cell. The pathology of the parathyroid tumors has been worked out by Castleman and Mallory.6 "It was found possible to divide the cases sharply into two groups: one of them characterized by diffuse uniform changes throughout all the glandular tissue-an obvious hyperplastic process-the second by a proliferative area limited to one gland, frequently even to a portion of it, or rarely involving parts of two glands -neoplasia." Seven of seventy cases reported by Cope" were examples of diffuse hyperplasia of the water-clear cells. Patient IV reported above had primary hyperplasia of the wasserhelle cell type. It is noteworthy that this was not recognized at the first operation making a second operation necessary. The pathologic condition now recognized as primary hyperplasia, usually of the wasserhelle cells, is extremely important in that failure to recognize it will account for failure to correct the disease. Two adenomas of chief cell type may occur in the same patient and may account for residual disease after removal of a single adenoma. 18 Adenomas usually weigh from 0.5 to 20 gm. but one weighing 101 grams 30 has been reported. They are composed predominantly of chief cells but in rare instances oxyphil cells predominate. Rosette formation and pseudoglandular appearance, as in Case VI, occurs in some cases. Gentile and associates 21 reported a case with typical symptoms of hyperparathyroidism caused by a malignant parathyroid tumor which metastasized locally, resulting in recurrence of symptoms cor-
HYPERPARATHYROlDISM
401
rected by a second operation. Many malignant parathyroid tumors without hyperparathyroidism have been reported. Secondary hyperplasia of the parathyroid glands occurs in renal insufficiency, in rickets, Paget's disease, osteomalacia and occasional instances of metastatic cancer of the bones. This hyperplasia is characterized by a predominance of chief cells in contradistinction of the predominance of wasserhelle cells in primary hyperplasia. Differential Diagnosis.-Of course many bone diseases have to be considered in the differential diagnosis of hyperparathyroidism with skeletal involvement. Paget'S disease is never generalized. The x-ray appearance is diagnostic, there is no disturbance of serum calcium and inorganic phosphorus concentrations, but there usually is considerable increase in serum phosphatase. Multiple myeloma may be generalized but the x-ray appearance is usually diagnostic. The phosphatase is usually normal and serum inorganic phosphorus is normal. Hypercalcemia and hypercalcinuria may occur rarely. In addition there is often hyperglobulinemia, so that the erythrocyte sedimentation rate is very rapid and excessive rouleau formation is noted (so-called "greasy" blood smear). Bence-Jones protein is present in the urine of a majority of patients. Generalized cancer metastases to bone rarely cause generalized decalcification. The serum inorganic phosphorus is almost always normal even though the calcium may be increased. Histological evidence of metastases may be the only diagnostic feature, but usually the x-ray appearance and clinical features suffice to differentiate this bone disease from the others. Hyperthyroidism offers a special problem in that nervousness and irritability are common to bbth diseases. The skeleton may be very extensively decalcified. The serum inorganic phosphorus is normal, the phosphatase is normal or very slightly elevated, and of course calcium excretion in the urine usually is considerably increased. Of course the usual evidence of hyperthyroidism is very important. Lipoid granulomatosis, i.e. Hand-Schuller-Christian disease, can be differentiated readily by x-ray examination. Osteomalacia and renal osteodystrophy have characteristic biochemical findings. A condition variously named osteitis fibrosa cystica disseminata, fibrous dysplasia of bone, and Albright's disease has caused much confusion and has led to erroneous diagnoses of hyperparathyroidism. This disease is characterized by brown spots (cafe au lait spots) on the body, soft tissue tumors (neurofibromata), occasionally precocious puberty in females, and involvement of any part of the skeleton, often just .on one side of the body but never generalized. It is a variant of neurofibromatosis. An excellent review of this disease has recently been provided by Thannhauser. 7 Treatment.-Surgery.-The principles and technic of surgery of the parathyroids have been thoroughly discussed by Cope and Churchill18 ,19 and the reader is referred to their papers. The preoperative diagnosis must be firmly established, for in this disease the diagnosis
402
EDMUND B. FLINK
cannot be excluded by a single exploratory operation. The surgeon should be thoroughly convinced of the accuracy of the diagnosis. The most meticulous and thorough dissection is necessary in order to find small adenomas and, more important still, in order to identify and not interfere with normal parathyroid tissue. Cope has discussed the practical relations of embryology of the glands to possible aberrant positions. Sixteen out of sixty patients had tumors in the anterior or posterior mediastinum. Four out of fifty-four had two adenomas. When one fails to find a tumor or hyperplasia in the neck region, the posterior superior mediastinum can be explored from the neck, but when this fails also, a second operation with reflection of the upper part of the sternum for exploration of the anterior mediastinum must be carried out. Subtotal resection of a solitary adenoma. is recommended if no normal parathyroid tissue is recognized or if there is a very high phosphatase and renal insufficiency. It is extremely important to have rapidly frozen sections and histologic examination of any tissue removed at operation to identify it as parathyroid tissue and also to detect primary hyperplasia. Oliguria and retention of nonprotein nitrogenous products may be serious complications in the immediate postoperative period. During the operation the administration of 5 per cent glucose solution in distilled water intravenously by constant drip and after the operation the administration of 3000 cc. or more of fluids per day, parenterally as necessary, are important measures in preventing oliguria. Calcium salts for intravenous use should be available for prompt administration to alleviate tetany if it is severe. Prevention of Tetany.- The surgical principles and technic outlined by Cope and Churchill were followed in most of the present cases but in Cases I and VI total resections were carried out even though tetany was to be expected. Normal parathyroids were identified in each instance. Particularly in Case VI expectation of the development of tetany was great and, to be sure, he did develop mild tetany on the seventh day, but he was carefully watched and vigorously treated from the onset. In Case I the mild symptoms of tetany were easily controlled by the administration of 1.25 mg. of dihydrotachysterol and 6 gm. of calcium lactate orally each day for one month. Patient VI received dihydrotachysterol continuously from the day immediately before surgery in a dose of 3.75 mg. per day for the first month. Then the dose was reduced to 1.25 mg. per day. Calcium lactate in doses ranging from 6 to 24 gm. per day was also given orally. It was necessary to administer calcium gluconate intravenously on three occasions for the control of minor tetanic symptoms. Because of the calcemic effect vitamin O 2 could be used in large doses (from 100,000 to 400,000 units a day) to as good advantage for it has been demonstrated that such doses are just as effective as dihydrotachysterol,22 It is suggested that prophylactic administration of either substance together with cal-
HYPERP ARATHYROID ISM
403
cium salts, from the day of or the day following surgery until the danger of tetany is passed, may prove to be of definite benefit in preventing or minimizing tetany postoperatively. The use of the Sulkowitch test at frequent intervals is of much assistance in anticipating the onset of tetany and in judging a safe dose of the drug; complete absence of a precipitate indicates serum calcium of 8 mg. per 100 cc. or lower and a heavy precipitate indicates high calcium levels. If a tumor is not found at operation no harm can be done by a single or even several doses of dihydrotachysterol and the drug can be discontinued. Follow-up Program.-A follow-up of every patient for a number of years is necessary to be sure that recovery has occurred or that recurrence does not go on untreated. It is difficult to define an adequate follow-up program, but certainly the main features of the biochemical syndrome should be checked every three months for a year and then every six months for a while. X-rays of the skeleton should be taken according to the symptoms and other progress. The first patient has been lost sight of and the fourth patient has failed to return at the appointed interval, so that our own follow-up has not been ideal. Improvement of the skeleton can be attained without surgery by the administration of large amounts of calcium, but such treatment has resulted in further renal damage and certainly should not be pursued. X-ray treatment of the region of the neck has been without avail in carefully studied cases and should be abandoned as a form of treatment, for it can only delay adequate surgical treatment and delay may be costly, particularly as far as the kidneys are concerned. SUMMARY
Six cases of hyperparathyroidism are described. Many of the problems, some of the pitfalls, most of the symptoms, and the major pathologic groups of the disease have been encountered. Stress has been placed on the symptomatology referable to the skeletal and the genitourinary systems as the most important clue to diagnosis. Polyuria as a single symptom was the initial clue in two patients who had been diagnostic problems at this and other hospitals and clinics. The biochemical findings in each case were diagnostic. Osteitis fibrosa cystica generalisata was present in five cases. One patient has osteoporosis comparable in severity to that which could be expected normally at her agt;; furthermore, the phosphatase activity of her serum was normal. A method of prophylaxis or amelioration of postoperative tetany has been suggested and tried in several patients, and should be given further trial. The use of the Sulkowitch test at frequent intervals to anticipate hypocalcemia and tetany in the postoperative period has been found to be very valuable.
404
EDMUND B. FLINK BIBLIOGRAPHY
1. Von Recklinghausen, F.: Festschrift der Assistenten fUr Virchow. Berlin, 1891. Cited by Snapper,IO p. 5.
2. Askanazy, M.: Arbeiten auf dem Gebiete der pathologischen Anatomie und Bakteriologie, Vo!. 4, page 398, 1904. Cited by Snapper,lO p. 10. 3. Erdheim, ].: Rachitis and Epithelikorporchen. Vienna, 1914. Cited by Snapper/ o p. 1. 4. Mandl, F.: Arch. f. klin. Chir., 143:245, 1926. 5. Cope, 0.: Clinics, 1 :1168, 1943. 6. Castleman, B. and Mallory, T. B.: Am. ]. Path., 11:1, 1935. 7. Thannhauser, S. J.: Medicine, 23:105, 1944. 8. Albright, F., Baird, P., Cope, O. and Bloomberg, E.: Am. ]. Med. Sci., 187:49,
1934. 9. EIsom, K. A., '''ood, F. C. and Ravdin, I. S.: Am. ]. M. Se., 191:49, 1936. 10. Snapper, I.: Medical Clinics on Bone Diseases. New York, Interscience Publishers, 1943. 11. Morelle, ]. and Beyerinck, C. W.: Cited by Snapper,lO p. 69. 12. Albright, F., Sulkowitch, H. "W". and Bloomberg, E.: Am. ]. M. Sci., 193:800, 1937. 13. McLean, F. C. and Hastings, A. 8.: Am. ]. M. Sci., 189:601, 1935. 14. Gutman, A. B., Tyson, T. L. and Gutman, E. 8.: Arch. Int. Med., 57:379, 1936. 15. Wilder, R. M., Camp, ]. D., Robertson, H. E. and Adams, M.: Proc. Staff Meet., Mayo Clinic, 7:597, 1932. 16. Barnay, ]. D. and Sulkowitch, H. W.: ]. Uro!., 37:746, 1937. 17. Qowns, R. S. and Scott, V.: Arch. Int. Med., 67:658, 1941. 18. Cope, 0.: Ann. Surg., 114:706, 1941. 19. Churchill, E. D. and Cope, 0.: Ann. Surg., 104:9, 1936. 20. SneH, A. M. and Mayo, C. W.: Proc. Staff Meet., the Mayo Clinic. 11:633, 1936. 21. Gentile, R. ]., Skinner, H. L. and Ashburn, L. L.: Surgery, 10:793, 1941. 22. McLcan, F. ].A.M.A., 117:609, 1941.
c.: