- Email: [email protected]
Primary Hyperparathyroidism
Primary Hyperparathyroidism FRANK H. LAHEY ROSEMARY MURPHY
THE importance of making the early diagnosis of hyperparathyroidism lies in the fact that it is one of the surgically curable diseases. At least, it is curable when treatment is undertaken before irreversible changes have become established. The diagnosis may be simple or obscure. It is simple when extensive bone disease or renal calculi direct attention to disturbances of calcium and phosphorus metabolism. It is obscure when there is no evidence of renal calculi and bone disease is minimal, atypical or absent. In a similar manner the treatment, which is always surgical, may be simple or somewhat difficult. It is simple when an adenoma is found on exploration of the neck. It is difficult when the adenoma is embedded completely in the thyroid gland, or is located in an aberrant position in the mediastinum, or the disease is due to hyperplasia of all of the parathyroids, a situation which occurs in about 8 per cent of the cases. MEDICAL ASPECTS
Primary hyperparathyroidism is the clinical condition which results from an overproduction of the parathyroid hormone. Usually, this is associated with the presence of one (usually one) or more adenomas of the parathyroid glands. Occasionally, there may be hyperplasia of the parathyroid tissue, and rarely a hyperfunctioning carcinoma. As a result of the excessive production of parathyroid hormone, there occur profound changes in calcium and phosphorus metabolism. The direct effect of the hormone on the renal tubular mechanisms produces a fall in serum phosphorus concentration and an elevation in the serum calcium concentration. This may result in a depression of the calciumphosphorus product and a secondary increase in bone catabolism to restore equilibrium. This effect, along with a direct effect of the hormone on bone, produces the characteristic bony defects (demineralization). In addition, the quantity of calcium and phosphorus in the urine may exceed their solubility and renal calculi, or diffuse renal calcinosis, may develop. 723
724
Frank H. Lahey, Rosemary Murphy
Clinical Characteristics
In the original cases of hyperparathyroidism, the bony deformities were so striking that attention was directed primarily toward those patients with bone disease-spontaneous fractures or osteitis fibrosa cystica. Subsequently, patients with renal calculi became a source of suspicion. When all such patients, either with definite bone disease or renal
Fig. 184. Dental roentgenograms showing normal lamina dura and absence of lamina dura.
calculi, are screened for this suspicion, a certain number will be found to have parathyroid disease. There remains, however, a vague and obscure group, without bone disease and without kidney disease, which presents a real diagnostic challenge. Skeletal Disease
Skeletal disease still ranks first as a source of symptoms. Among 29 proved cases at the Lahey Clinic 16 complained of bone pain and 5 of bony deformities; 4 noted loss of stature from involvement of the spine; 5 noted lumps in the jaw, and 2 had had fractures. A total of 22 patients
Primary Hyperparathyroidism
725
showed some evidence of bone disease, either osteoporosis alone or accompanied by cysts. Attention should be directed toward three abnormalities of the bone which may serve as clues to the diagnosis. The first is the absence of the lamina dura (Fig. 184). While not diagnostic its absence may be an early sign of bone disease, and all dental x-ray films should be scrutinized with this in mind. The second is the presence of mandibular cysts (Fig. 185). The occurrence of such cysts commonly leads the patient to seek
Fig. 185. Large mandibular cyst. (From Murphy, Hurxthal and Bell, 1952, with permission of Archives of Internal Medicine.)
dental care. Unless the possibility of parathyroid disease is considered, the diagnosis may be unduly delayed for several years. The third (Fig. 186) is the report of a giant cell tumor on a biopsy of a bone cyst. It is important to remember that bone anabolism may be marked and, consequently, numerous giant cells may be found in the biopsy material. Although the classical picture of osteitis fibrosa cystica (Fig. 187) certainly is spectacular, it may also be extremely deforming (Fig. 188) and certainly undesirable. Consequently, every effort should be made to diagnose the disease before disfiguring changes occur. A less spectacular, but equally significant, manifestation of skeletal disease may be a diffuse demineralization of the skeleton (Fig. 189). When these condi-
726
Frank H. Lahey, Rosemary Murphy
Fig. 186. Cyst in tibia diagnosed as giant cell tumor on biopsy.
Fig. a with Fig. 187. 1 7. Osteitis Osteitis fibrosa fibro a cystic cy ica with deformity deformi y of of pelvic pelvic bones. bones.
Primary Hyperparathyroidism
727
Fig. with marked of th the ch chest. Fig. 188. 1 . Osteitis fibrosa cystic Lh mark d ddeformity f rmi y of t. i aa wi
Fig. 189. Osteoporosis of the spine with resultant kyphosis.
tions exist, the patient commonly presents himself to an orthopedic surgeon or to a dental surgeon rather than to an internist, and so the disease often escapes early detection. Consequently, it is incumbent upon these surgeons to bear the diagnosis in mind and to carry out the laboratory studies necessary for diagnosis.
728
Frank H. Lahey, Rosemary Murphy
Renal Disease
The next most common manifestation of the disease is renal (Fig. 190). In the Lahey Clinic series, 13 patients had evidence of renal calculi, 9 in association with bone disease and 4 without. The calculi may be single or multiple, unilateral or bilateral, symptomatic or asymptomatic, discrete or diffuse. They may be accompanied by infection or evidence of renal insufficiency. The latter is one of the most serious end results of parathyroid disease and may lead to a fatal termination in spite of correction of the underlying difficulty by surgical removal of a hyperfunc-
Fig. 190. Bilateral renal calculi.
tioning parathyroid tumor. For the above stated reasons, every individual with renal calculi should be thoroughly investigated as a parathyroid suspect in order to correct the metabolic abnormality before irreversible renal damage occurs. On the other hand, the finding of nitrogen retention is not a contraindication to exploration if the diagnosis is established. This is attested by one patient in the Lahey Clinic series who, at the age of 53 years, had a parathyroidectomy in spite of evidence of poor renal function and a nonprotein nitrogen of 70 mg. per 100 cc. She did well for four and a half years after operation in spite of persistent chronic uremia. Because of the more or less specific nature of the renal complaints, patients with renal calculi usually seek urologic advice. Consequently,
Primary Hyperparathyroidism
729
the urologist's patients become the second best source for discovery of the disease. If all such patients have appropriate biochemical studies, it is relatively simple to discover those with parathyroid disease. Systemic Symptoms
Systemic symptoms are exceedingly common in patients with hyperparathyroidism. They are vague and nonspecific, such as weakness and apathy, muscle aches and pains, loss of weight, polyuria and polydipsia, and a variety of gastrointestinal complaints (anorexia, nausea, vomiting, constipation, cramplike abdominal pain and ulcerlike symptoms). The association of duodenal ulcer with hyperparathyroidism may be more than fortuitous. It occurred in 2 of the 29 patients in the Lahey Clinic series. When the systemic symptoms are associated with skeletal or renal symptoms, they may be overshadowed by the more dramatic aspects of the bone and renal disease. However, those patients with systemic symptoms unassociated with bone or kidney disease form a vague group who are likely to be tagged with functional diagnoses and may escape detection for a long period. They are seen by the general practitioner and the internist; they travel from physician to physician seeking help until someone with a "high index of suspicion" does the proper metabolic studies. These patients represent the group that is difficult to diagnose because they lack symptoms which suggest the diagnosis. N~verthe]ess, they present the ideal situation for early diagnosis since they can be cured prior to the development of any complications of the disease. LABORATORY DIAGNOSIS
In the last analysis, the preoperative diagnosis of hyperparathyroidism depends upon the laboratory verification of a typical disturbance in calcium and phosphorus metabolism. For fasting adults, the normal total serum calcium is 8.5 to 10.2 mg. per 100 cc., the serum inorganic phosphorus is 3.0 to 4.0 mg. per 100 cc., and the serum alkaline phosphatase is 2.0 to 4.5 Bodansky units per 100 cc. 1 With respect to calcium, it is the level of the total serum ionized calcium which is most significant. Since a portion of the total serum calcium is combined with protein, it is apparent that the determination of the total value is valid only when the total serum protein is normal. In the presence of a low serum protein, the total serum calcium might give a falsely normal value, and in the presence of a high serum protein, a falsely elevated level. The application of the nomogram (Fig. 191) of McLean and Hastings2 is an aid in evaluating the serum ionized calcium level with reference to the serum protein level. In the presence of renal insufficiency, the depression of the serum
ti I
730
Frank H. Lahey, Rosemary Murphy
phosphorus may be obscured by a tendency toward phosphorus retention. The phosphorus might fall within the normal range, or even be slightly elevated. Consequently, in order to interpret correctly the serum phosphorus level, it is necessary to evaluate renal function. The determination of the serum nonprotein nitrogen usually suffices for this evaluation. When bone disease is present, the alkaline phosphatase is usually elevated. It is normal when bone disease is absent. Consequently, it is
J
oJ
o
~~~~~~~~~~~r.,~~~~rl :
IY
"-
riJ
~'F---ccT"'-,--!;;7"'::'-'---lF
'+' +. '0
8
~~-+~~=~~~4-~~~~-4~~4 ~
r. o
Z.O'----4.J..o--L5L.O--".J..O---7L.O--5..J.O--~9.0 TOTAL PROTEIN - ~"". per 100 ce.
Fig. 191. Chart for determination of calcium-ion concentration from total protein and total calcium values of serum. (From McLean and Hastings, 1935, with permission of American Journal of Medical Sciences.)
well to remember that it is not essential to have an elevated value in order to establish the diagnosis of hyperparathyroidism. The significant urinary findings are an increase in the excretion of calcium and phosphorus. Since both of these vary with the dietary intake, they have diagnostic significance only when the patient has been on a low intake. For practical purposes, the estimation of calcium excretion alone is sufficient. After the patient has been on a low calcium intake for three days, the urinary calcium may be estimated qualitatively, by means of the Sulkowitch test, or quantitatively. In the presence of parathyroid disease, the renal excretion of calcium usually is greater than 200 mg. per twenty-four hours. Roentgenographic studies often give the first clue to the diagnosis,
Primary Hyperparathyroidism
731
although it is essential to remember that neither the demonstration of bone disease nor of renal calculi is a requisite for the diagnosis. When bone disease is present, there may be diffuse osteoporosis alone, or osteoporosis associated with single or multiple cysts. In addition, there may be fractures or deformities. In long-standing cases with severe bone disease, the latter may be extreme. When renal calculi are present, they may be discrete, large or small, or diffusely scattered throughout the renal parenchyma. Differential Diagnosis
In the process of discovering patients with primary hyperparathyroidism, a variety of diseases must be differentiated. Renal rickets, metastatic carcinoma, multiple myeloma, hypervitaminosis D must he distinguished because hypercalcemia may occur in these diseases. When an elevated alkaline phosphatase is found, osteomalacia and Paget's disease must be differentiated in addition to the diseases previously mentioned. With increased experience in the diagnosis of hyperparathyroidism, it becomes apparent that the manifestations of the disease are many and varied. It may occur at any age and in either sex. The symptoms may be striking and immediately suggest the diagnosis, or vague and obscure and mimic such conditions as diabetes, gastrointestinal diseases, rheumatism or neurasthenia. Only the more frequent determinations of serum calcium and phosphorus will lead to the discovery of patients belonging to this nonspecific group. With the recognition of the protean nature of the disease should come a more concerted effort to find the undiagnosed patient. This, as in the case of any curable disease, is exceedingly rewarding. SURGICAL TREATMENT
Before discussing the problem of finding and removing hyperfunctioning parathyroid adenomas we would like to establish some things concerning the background of our experience with locating, demonstrating and preserving parathyroid glands. In our experience consisting of operations on 32,000 patients for thyroid disease it has been impossible not to have acquired a very large experience with the location and the characteristic appearance of parathyroid glands. We have been through two enlightening experiences with parathyroid operations which have broadened our knowledge concerning the ability to find and demonstrate these bodies. The first one is related to the fact that for a number of years we thoroughly searched all removed thyroid specimens for a possible parathyroid gland, took a section from what we thought was the parathyroid and sent it to the laboratory, and transplanted the structure presumed to be a parathyroid into the belly of the left sternomastoid
732
Frank H. Lahey, Rosemary Murphy
muscle. This plan, later discarded, was followed for a number of years with the result that we acquired a very large experience with the determination of what was a parathyroid gland and what was not, based upon our opinion at the time of removal and the pathologic report which soon followed. With this large experience we became quite expert in settling what was a parathyroid, what was a lymph node, and what was thymic tissue, the structures most often confused with a possible parathyroid gland. After considerable experience with this plan and animal experimentation in an endeavor to settle the viability of such transplanted normal parathyroid glands, we abandoned this policy and concentrated more intently upon the preservation of parathyroids with intact blood supply during the operation upon the thyroid. As a result of this acquired ability to recognize parathyroids and greater ability to find them, we have been able to preserve these structures to such an extent that in a series of cases done within the last few years, the incidence of permanent tetany in all types of thyroid disease has been reduced to 0.8 per cent. This figure includes those patients who have had, here and elsewhere, inadequate thyroidectomies and have further removals of thyroid tissue here. This experience with the surgical demonstration of parathyroids has been of great assistance to us in searching for, finding and removing hyperfunctioning parathyroid adenomas and in demonstrating what normal parathyroids look like. It has been of great service to us in establishing a background of experience as to their probable position and location, which is useful in searches for hyperfunctioning parathyroid adenoma. Mter routinely demonstrating several hundred parathyroids, one of us (F. H. L.) feels safe in saying that the most constant parathyroid, in terms of ability to demonstrate it as undoubtedly such a structure, is the superior parathyroid (Fig. 192). The most constant place to find it and identify it is at the point where the recurrent laryngeal nerve passes under the lowest fibers of the inferior constrictor muscle as it is attached to the horn of the thyroid cartilage. At this point the upper parathyroid gland is directly behind the upper pole of the thyroid gland and can usually be demonstrated only by tying and severing the superior thyroid artery and vein and turning down the attachment of the upper pole of the thyroid gland to the thyroid cartilage, by rolling over the upper pole of the thyroid gland toward the midline where it is lifted off the inferior constrictor muscle and where the parathyroid gland can frequently be demonstrated only by turning the body of the thyroid inward toward the midline or by detaching, carefully and deliberately, the point where the body of the thyroid joins the upper pole until the point where the nerve enters the larynx is demonstrated. It is at this point that the upper parathyroid can most consistently be found and demonstrated as truly such a structure.
Primary Hyperparathyroidism
733
The next most constant position of the parathyroid is that of the inferior parathyroid, at the point where the inferior thyroid artery enters the body of the thyroid gland. The demonstration of this parathyroid is much less dependably possible than the superior parathyroid, as the inferior parathyroid gland may be located almost anywhere about the lower pole of the thyroid. It may be between the branches of the inferior thyroid arteries as they divide to enter the body of the gland; it may be under the inferior thyroid artery; it may be behind the notch made by the division of the inferior thyroid ~ivessels; it may be above this division, or it may be at the point where the lower division of the inferior
Fig. 192. Demonstration of superior parathyroid gland on posterior surface of thyroid.
thyroid artery descends to enter the gland at the lowest point of the thyroid body where it joins with the isthmus and, as has frequently been spoken of in discussions of parathyroids, it may even be below the isthmus, beneath the upper portion of the sternum in the mediastinum, or it may be completely intramediastinal. Another point which must be remembered in searching for hyperfunctioning parathyroid adenomas is the occasional, but rare, occurrence of an intrathyroid parathyroid. We were first made aware of the occurrence of intrathyroid parathyroids by Dr. Cattell when, under the tutelage system, he was assigned to the senior author in his fourth year in Harvard Medical School to work on an investigative problem dealing with milligrams of iodine per gram of dried gland in relation to the elevation of
734
Frank H. Lahey, Rosemary Murphy
metabolism and the degree of hyperplasia. From this experience of slicing thyroid specimens he then, many years ago, demonstrated and reported to us the occasional intrathyroid location of a parathyroid gland. In our own experience with hyperparathyroidism we have twice demonstrated the intra thyroid location of superior parathyroid adenomas which were actively overfunctioning. There have been reports from others (Mayo Clinic) demonstrating the occasional, if rare, occurrence of intrathyroid hyperfunctioning parathyroid adenomas. For this reason no search for hyperfunctioning parathyroid adenoma should be abandoned without mobilizing the upper pole and making sure by palpation of the poles and body of the thyroid through and through that there is not at this location an intrathyroid parathyroid adenoma. One of the most difficult and disturbing situations in which to be is to search the neck for a hyperfunctioning parathyroid adenoma with good clinical and good laboratory evidence that hyperparathyroidism almost certainly exists in such a patient and at the same time not be able to demonstrate one in the neck. The uncertainty of this position is based upon the question as to when one should open the mediastinum and search for a mediastinal adenoma in such a position. Such is the experience today of skilled thoracic surgeons that exploration of the superior mediastinum can be done with very little increase in the surgical risk of the exploration. In those patients with all the clinical evidences of the disease, that is, with a convincingly high caleium, a eonvineingly low phosphorus, a high phosphatase, "together with the other findings whieh almost promise that a hyperfundioning parathyroid adenoma is present, sueh as bone deealeification and inereased urinary output of calcium, it is urgently indicated that such a search for a hyperfunctioning parathyroid adenoma or parathyroid hyperplasia is not complete without investigation of the mediastinum. When, however, one of the borderline cases which are met not infrequently without bone changes, without convincing laboratory evidence of the disease, that is, with very slight alkaline phosphatase elevation, with relatively slight depression of phosphorus levels and with unstriking elevations of the serum calcium, the situation is much more difficult and doubtful. One does not feel that he can be as positive in the statement of the need of exposing the mediastinum, as stated above, and the decision to open the mediastinum if a hyperfunctioning parathyroid adenoma cannot be demonstrated in the neck must be based largely upon the clinician's decision as to how likely it is that the symptoms are truly related to a possible hyperparathyroidism or to some other possible cause. It is our belief at this clinic that no patient should be submitted to an exploration for a possible hyperfunctioning hyperparathyroid adenoma unless the operator himself is sufficiently skilled and experienced to split
r !
Primary Hyperparathyroidism
735
the sternum and expose the upper mediastinum, or unless a surgeon with skill and experience is at hand should the hyperfunctioning parathyroid adenoma not be found within the neck. Size of the Adenoma. We would be inclined to say from our experience that the degree of hyperparathyroidism effect, although not entirely related to the size of the adenoma, is at least in some measure linked with such increase in size. That this is not entirely dependable is demonstrated by the fact that we have removed adenomas of the parathyroid about 2.5 cm. in size with no increase in function in the form of hyperparathyroidism in any way demonstrated, that we have cases of cysts of the parathyroids of similar size but with no increase in parathyroid function. It is likewise true that with relatively small hyperfunctioning parathyroid adenomas, about 1 cm. in size, there have occurred calcinosis of the kidney pelvis, multiple renal stones and, in a young man, very definite symptoms of a quite active degree of hyperfunctioning parathyroidism. Based upon this experience, we believe it is possible to say that, while there may be some relative relationship between the size and the degree of hyperfunction of a parathyroid adenoma, this relationship is not dependable. We would from our experience feel more positive about the statement that the length of time that patients have had a hyperfunctioning parathyroid adenoma is more important than the size in the production of its effect. The question of palpability comes under the same heading. When a discrete tumor is palpable either at the upper or the lower pole on either side of the thyroid, in the presence of chemical findings and clinical signs indicating this disease, it is to be seriously suspected that this is a hyperfunctioning parathyroid adenoma. These hyperfunctioning adenomas of the parathyroid have varied in size from that of a little fingernail to that of a large English walnut or larger. In any operation for possible hyperparathyroidism, a pathologist should be present to whom the specimen can be submitted for immediate report, many of which will be disappointing in that the diagnosis will be thyroid adenoma or adenomatous goiter. It is assumed today that no parathyroid which appears normal should be removed until a small specimen has been submitted to the pathologist to determine whether or not that state of hyperparathyroidism which is only occasionally present, that is hyperplasia of all four parathyroids, should justify subtotal parathyroidectomy. In closing, we would like to call attention to a point with which everyone who has had much experience with this disease is familiar and one which we have repeatedly stressed, but one which can be and frequently is overlooked, that is, the anticipation in a majority of the cases following removal of the hyperfunctioning parathyroid adenoma that varying degrees of tetany will occur. It is to be remembered, as has been demon-
Frank H. Lahey, Rosemary Murphy
736
strated in a parallel situation of hyperfunctioning adenomas of the adrenal gland, that with such an excessive production of the element so essential to normal existence, parahormone, by a single hyperfunctioning parathyroid adenoma, there is a lack of glandular activity in the remaining parathyroid body. This can frequently be demonstrated by the lack of cellular activity, the pale color, and flabbiness which one sees ill the uninvolved parathyroids which can be demonstrated not HYPER PARATHYROI OISM COURSE OF SERUM CALCIUM AFTER OPERATION
I NOVEMBER
I
DAYS SERUM CALCIUM MG.lIOO CC.
15
16
17
OPERATION
I
2
P.M.
A.M.
A.M.
P.M.
A.M.
P.M.
18 16 14 12 10 8
\
\
\
\
~
""
TETANY
r"..
~
Fig. 193. Chart illustrating the rapid fall in serum calcium which may occur in the first twenty-four to forty-eight hours after parathyroidectomy.
infrequently in the search for the hyperfunctioning parathyroid adenoma. Such can be the pallor, flabbiness and fat deposits in active parathyroids that, although they may retain the same physical characteristics, they cannot be demonstrated easily because of the lack of the characteristically pale brownish color or evidences of glandular activity. Figure 193 shows very dramatically how promptly calcium levels descend with removal of the hyperfunctioning parathyroid adenoma and demonstrates quite conclusively the inability of the remaining uninvolved parathyroids to assume the production of parahormone at sufficient levels to maintain normal parathyroid function. In the instance here illustrated, it was not possible to relinquish the administration of a
Primary H ype:rparathyroidism
737
calcium elevating agent such as calcium lactate itself, vitamin D in 50,000 to 150,000 units, or AT-lO. We have seen postoperative tetany occur so often in varying degrees ·of intensity that we watch for it closely, and upon the appearance of any signs suggestive of it we put the patients on calcium-sustaining treatment. We have urged several times that after the removal of hyperfunctioning parathyroid adenomas it is wrong not to keep in mind the possibility of occurrence of tetany since real tetany is such a frightening thing to the patient and to the relatives. We would urge, therefore, that everyone who removes hyperfunctioning parathyroid adenomas havein mind the need to supply a substitute for parahormone, gradually lowering the dosage until it can be withdrawn without the occurrence of tetany. CONCLUSIONS
The physiology of parathyroid function is discussed. The effect of abnormal hyperfunction of these structures upon calcium, phosphorus and alkaline phosphatase levels together with calcium balance is commented upon. The effect of hyperparathyroidism upon the skeletal system is discussed and illustrated by roentgenograms of patients with hyperparathyroidism. The various bone changes suggestive of this disease are described, as are the renal manifestations. A group of vague general symptoms, at one time often not considered significant, which should make us aware of the possible presence of hyperparathyroidism is discussed, as are the laboratory findings in the various stages and phases of hyperparathyroidism. The approach to the only method of treatment of this disease (surgical) is discussed, with a report of our experiences in finding and removing these tumors which represent the cause of hyperparathyroidism in 92 per cent of the cases .. BIBLIOGRAPHY 1. McLean, F. C. and Hastings, A. B.: Clinical estimation and significance of calcium-ion concentrations in the blood. Am. J. M. Sc. 189: 601-613 (May) 1935. 2. Talbot, N. B., Sobel, E. H., McArthur, J. W. and Crawford, J. D.: Functional Endocrinology. Cambridge, Mass., Harvard University Press, 1952.
THE importance of making the early diagnosis of hyperparathyroidism lies in the fact that it is one of the surgically curable diseases. At least, it is curable when treatment is undertaken before irreversible changes have become established. The diagnosis may be simple or obscure. It is simple when extensive bone disease or renal calculi direct attention to disturbances of calcium and phosphorus metabolism. It is obscure when there is no evidence of renal calculi and bone disease is minimal, atypical or absent. In a similar manner the treatment, which is always surgical, may be simple or somewhat difficult. It is simple when an adenoma is found on exploration of the neck. It is difficult when the adenoma is embedded completely in the thyroid gland, or is located in an aberrant position in the mediastinum, or the disease is due to hyperplasia of all of the parathyroids, a situation which occurs in about 8 per cent of the cases. MEDICAL ASPECTS
Primary hyperparathyroidism is the clinical condition which results from an overproduction of the parathyroid hormone. Usually, this is associated with the presence of one (usually one) or more adenomas of the parathyroid glands. Occasionally, there may be hyperplasia of the parathyroid tissue, and rarely a hyperfunctioning carcinoma. As a result of the excessive production of parathyroid hormone, there occur profound changes in calcium and phosphorus metabolism. The direct effect of the hormone on the renal tubular mechanisms produces a fall in serum phosphorus concentration and an elevation in the serum calcium concentration. This may result in a depression of the calciumphosphorus product and a secondary increase in bone catabolism to restore equilibrium. This effect, along with a direct effect of the hormone on bone, produces the characteristic bony defects (demineralization). In addition, the quantity of calcium and phosphorus in the urine may exceed their solubility and renal calculi, or diffuse renal calcinosis, may develop. 723
724
Frank H. Lahey, Rosemary Murphy
Clinical Characteristics
In the original cases of hyperparathyroidism, the bony deformities were so striking that attention was directed primarily toward those patients with bone disease-spontaneous fractures or osteitis fibrosa cystica. Subsequently, patients with renal calculi became a source of suspicion. When all such patients, either with definite bone disease or renal
Fig. 184. Dental roentgenograms showing normal lamina dura and absence of lamina dura.
calculi, are screened for this suspicion, a certain number will be found to have parathyroid disease. There remains, however, a vague and obscure group, without bone disease and without kidney disease, which presents a real diagnostic challenge. Skeletal Disease
Skeletal disease still ranks first as a source of symptoms. Among 29 proved cases at the Lahey Clinic 16 complained of bone pain and 5 of bony deformities; 4 noted loss of stature from involvement of the spine; 5 noted lumps in the jaw, and 2 had had fractures. A total of 22 patients
Primary Hyperparathyroidism
725
showed some evidence of bone disease, either osteoporosis alone or accompanied by cysts. Attention should be directed toward three abnormalities of the bone which may serve as clues to the diagnosis. The first is the absence of the lamina dura (Fig. 184). While not diagnostic its absence may be an early sign of bone disease, and all dental x-ray films should be scrutinized with this in mind. The second is the presence of mandibular cysts (Fig. 185). The occurrence of such cysts commonly leads the patient to seek
Fig. 185. Large mandibular cyst. (From Murphy, Hurxthal and Bell, 1952, with permission of Archives of Internal Medicine.)
dental care. Unless the possibility of parathyroid disease is considered, the diagnosis may be unduly delayed for several years. The third (Fig. 186) is the report of a giant cell tumor on a biopsy of a bone cyst. It is important to remember that bone anabolism may be marked and, consequently, numerous giant cells may be found in the biopsy material. Although the classical picture of osteitis fibrosa cystica (Fig. 187) certainly is spectacular, it may also be extremely deforming (Fig. 188) and certainly undesirable. Consequently, every effort should be made to diagnose the disease before disfiguring changes occur. A less spectacular, but equally significant, manifestation of skeletal disease may be a diffuse demineralization of the skeleton (Fig. 189). When these condi-
726
Frank H. Lahey, Rosemary Murphy
Fig. 186. Cyst in tibia diagnosed as giant cell tumor on biopsy.
Fig. a with Fig. 187. 1 7. Osteitis Osteitis fibrosa fibro a cystic cy ica with deformity deformi y of of pelvic pelvic bones. bones.
Primary Hyperparathyroidism
727
Fig. with marked of th the ch chest. Fig. 188. 1 . Osteitis fibrosa cystic Lh mark d ddeformity f rmi y of t. i aa wi
Fig. 189. Osteoporosis of the spine with resultant kyphosis.
tions exist, the patient commonly presents himself to an orthopedic surgeon or to a dental surgeon rather than to an internist, and so the disease often escapes early detection. Consequently, it is incumbent upon these surgeons to bear the diagnosis in mind and to carry out the laboratory studies necessary for diagnosis.
728
Frank H. Lahey, Rosemary Murphy
Renal Disease
The next most common manifestation of the disease is renal (Fig. 190). In the Lahey Clinic series, 13 patients had evidence of renal calculi, 9 in association with bone disease and 4 without. The calculi may be single or multiple, unilateral or bilateral, symptomatic or asymptomatic, discrete or diffuse. They may be accompanied by infection or evidence of renal insufficiency. The latter is one of the most serious end results of parathyroid disease and may lead to a fatal termination in spite of correction of the underlying difficulty by surgical removal of a hyperfunc-
Fig. 190. Bilateral renal calculi.
tioning parathyroid tumor. For the above stated reasons, every individual with renal calculi should be thoroughly investigated as a parathyroid suspect in order to correct the metabolic abnormality before irreversible renal damage occurs. On the other hand, the finding of nitrogen retention is not a contraindication to exploration if the diagnosis is established. This is attested by one patient in the Lahey Clinic series who, at the age of 53 years, had a parathyroidectomy in spite of evidence of poor renal function and a nonprotein nitrogen of 70 mg. per 100 cc. She did well for four and a half years after operation in spite of persistent chronic uremia. Because of the more or less specific nature of the renal complaints, patients with renal calculi usually seek urologic advice. Consequently,
Primary Hyperparathyroidism
729
the urologist's patients become the second best source for discovery of the disease. If all such patients have appropriate biochemical studies, it is relatively simple to discover those with parathyroid disease. Systemic Symptoms
Systemic symptoms are exceedingly common in patients with hyperparathyroidism. They are vague and nonspecific, such as weakness and apathy, muscle aches and pains, loss of weight, polyuria and polydipsia, and a variety of gastrointestinal complaints (anorexia, nausea, vomiting, constipation, cramplike abdominal pain and ulcerlike symptoms). The association of duodenal ulcer with hyperparathyroidism may be more than fortuitous. It occurred in 2 of the 29 patients in the Lahey Clinic series. When the systemic symptoms are associated with skeletal or renal symptoms, they may be overshadowed by the more dramatic aspects of the bone and renal disease. However, those patients with systemic symptoms unassociated with bone or kidney disease form a vague group who are likely to be tagged with functional diagnoses and may escape detection for a long period. They are seen by the general practitioner and the internist; they travel from physician to physician seeking help until someone with a "high index of suspicion" does the proper metabolic studies. These patients represent the group that is difficult to diagnose because they lack symptoms which suggest the diagnosis. N~verthe]ess, they present the ideal situation for early diagnosis since they can be cured prior to the development of any complications of the disease. LABORATORY DIAGNOSIS
In the last analysis, the preoperative diagnosis of hyperparathyroidism depends upon the laboratory verification of a typical disturbance in calcium and phosphorus metabolism. For fasting adults, the normal total serum calcium is 8.5 to 10.2 mg. per 100 cc., the serum inorganic phosphorus is 3.0 to 4.0 mg. per 100 cc., and the serum alkaline phosphatase is 2.0 to 4.5 Bodansky units per 100 cc. 1 With respect to calcium, it is the level of the total serum ionized calcium which is most significant. Since a portion of the total serum calcium is combined with protein, it is apparent that the determination of the total value is valid only when the total serum protein is normal. In the presence of a low serum protein, the total serum calcium might give a falsely normal value, and in the presence of a high serum protein, a falsely elevated level. The application of the nomogram (Fig. 191) of McLean and Hastings2 is an aid in evaluating the serum ionized calcium level with reference to the serum protein level. In the presence of renal insufficiency, the depression of the serum
ti I
730
Frank H. Lahey, Rosemary Murphy
phosphorus may be obscured by a tendency toward phosphorus retention. The phosphorus might fall within the normal range, or even be slightly elevated. Consequently, in order to interpret correctly the serum phosphorus level, it is necessary to evaluate renal function. The determination of the serum nonprotein nitrogen usually suffices for this evaluation. When bone disease is present, the alkaline phosphatase is usually elevated. It is normal when bone disease is absent. Consequently, it is
J
oJ
o
~~~~~~~~~~~r.,~~~~rl :
IY
"-
riJ
~'F---ccT"'-,--!;;7"'::'-'---lF
'+' +. '0
8
~~-+~~=~~~4-~~~~-4~~4 ~
r. o
Z.O'----4.J..o--L5L.O--".J..O---7L.O--5..J.O--~9.0 TOTAL PROTEIN - ~"". per 100 ce.
Fig. 191. Chart for determination of calcium-ion concentration from total protein and total calcium values of serum. (From McLean and Hastings, 1935, with permission of American Journal of Medical Sciences.)
well to remember that it is not essential to have an elevated value in order to establish the diagnosis of hyperparathyroidism. The significant urinary findings are an increase in the excretion of calcium and phosphorus. Since both of these vary with the dietary intake, they have diagnostic significance only when the patient has been on a low intake. For practical purposes, the estimation of calcium excretion alone is sufficient. After the patient has been on a low calcium intake for three days, the urinary calcium may be estimated qualitatively, by means of the Sulkowitch test, or quantitatively. In the presence of parathyroid disease, the renal excretion of calcium usually is greater than 200 mg. per twenty-four hours. Roentgenographic studies often give the first clue to the diagnosis,
Primary Hyperparathyroidism
731
although it is essential to remember that neither the demonstration of bone disease nor of renal calculi is a requisite for the diagnosis. When bone disease is present, there may be diffuse osteoporosis alone, or osteoporosis associated with single or multiple cysts. In addition, there may be fractures or deformities. In long-standing cases with severe bone disease, the latter may be extreme. When renal calculi are present, they may be discrete, large or small, or diffusely scattered throughout the renal parenchyma. Differential Diagnosis
In the process of discovering patients with primary hyperparathyroidism, a variety of diseases must be differentiated. Renal rickets, metastatic carcinoma, multiple myeloma, hypervitaminosis D must he distinguished because hypercalcemia may occur in these diseases. When an elevated alkaline phosphatase is found, osteomalacia and Paget's disease must be differentiated in addition to the diseases previously mentioned. With increased experience in the diagnosis of hyperparathyroidism, it becomes apparent that the manifestations of the disease are many and varied. It may occur at any age and in either sex. The symptoms may be striking and immediately suggest the diagnosis, or vague and obscure and mimic such conditions as diabetes, gastrointestinal diseases, rheumatism or neurasthenia. Only the more frequent determinations of serum calcium and phosphorus will lead to the discovery of patients belonging to this nonspecific group. With the recognition of the protean nature of the disease should come a more concerted effort to find the undiagnosed patient. This, as in the case of any curable disease, is exceedingly rewarding. SURGICAL TREATMENT
Before discussing the problem of finding and removing hyperfunctioning parathyroid adenomas we would like to establish some things concerning the background of our experience with locating, demonstrating and preserving parathyroid glands. In our experience consisting of operations on 32,000 patients for thyroid disease it has been impossible not to have acquired a very large experience with the location and the characteristic appearance of parathyroid glands. We have been through two enlightening experiences with parathyroid operations which have broadened our knowledge concerning the ability to find and demonstrate these bodies. The first one is related to the fact that for a number of years we thoroughly searched all removed thyroid specimens for a possible parathyroid gland, took a section from what we thought was the parathyroid and sent it to the laboratory, and transplanted the structure presumed to be a parathyroid into the belly of the left sternomastoid
732
Frank H. Lahey, Rosemary Murphy
muscle. This plan, later discarded, was followed for a number of years with the result that we acquired a very large experience with the determination of what was a parathyroid gland and what was not, based upon our opinion at the time of removal and the pathologic report which soon followed. With this large experience we became quite expert in settling what was a parathyroid, what was a lymph node, and what was thymic tissue, the structures most often confused with a possible parathyroid gland. After considerable experience with this plan and animal experimentation in an endeavor to settle the viability of such transplanted normal parathyroid glands, we abandoned this policy and concentrated more intently upon the preservation of parathyroids with intact blood supply during the operation upon the thyroid. As a result of this acquired ability to recognize parathyroids and greater ability to find them, we have been able to preserve these structures to such an extent that in a series of cases done within the last few years, the incidence of permanent tetany in all types of thyroid disease has been reduced to 0.8 per cent. This figure includes those patients who have had, here and elsewhere, inadequate thyroidectomies and have further removals of thyroid tissue here. This experience with the surgical demonstration of parathyroids has been of great assistance to us in searching for, finding and removing hyperfunctioning parathyroid adenomas and in demonstrating what normal parathyroids look like. It has been of great service to us in establishing a background of experience as to their probable position and location, which is useful in searches for hyperfunctioning parathyroid adenoma. Mter routinely demonstrating several hundred parathyroids, one of us (F. H. L.) feels safe in saying that the most constant parathyroid, in terms of ability to demonstrate it as undoubtedly such a structure, is the superior parathyroid (Fig. 192). The most constant place to find it and identify it is at the point where the recurrent laryngeal nerve passes under the lowest fibers of the inferior constrictor muscle as it is attached to the horn of the thyroid cartilage. At this point the upper parathyroid gland is directly behind the upper pole of the thyroid gland and can usually be demonstrated only by tying and severing the superior thyroid artery and vein and turning down the attachment of the upper pole of the thyroid gland to the thyroid cartilage, by rolling over the upper pole of the thyroid gland toward the midline where it is lifted off the inferior constrictor muscle and where the parathyroid gland can frequently be demonstrated only by turning the body of the thyroid inward toward the midline or by detaching, carefully and deliberately, the point where the body of the thyroid joins the upper pole until the point where the nerve enters the larynx is demonstrated. It is at this point that the upper parathyroid can most consistently be found and demonstrated as truly such a structure.
Primary Hyperparathyroidism
733
The next most constant position of the parathyroid is that of the inferior parathyroid, at the point where the inferior thyroid artery enters the body of the thyroid gland. The demonstration of this parathyroid is much less dependably possible than the superior parathyroid, as the inferior parathyroid gland may be located almost anywhere about the lower pole of the thyroid. It may be between the branches of the inferior thyroid arteries as they divide to enter the body of the gland; it may be under the inferior thyroid artery; it may be behind the notch made by the division of the inferior thyroid ~ivessels; it may be above this division, or it may be at the point where the lower division of the inferior
Fig. 192. Demonstration of superior parathyroid gland on posterior surface of thyroid.
thyroid artery descends to enter the gland at the lowest point of the thyroid body where it joins with the isthmus and, as has frequently been spoken of in discussions of parathyroids, it may even be below the isthmus, beneath the upper portion of the sternum in the mediastinum, or it may be completely intramediastinal. Another point which must be remembered in searching for hyperfunctioning parathyroid adenomas is the occasional, but rare, occurrence of an intrathyroid parathyroid. We were first made aware of the occurrence of intrathyroid parathyroids by Dr. Cattell when, under the tutelage system, he was assigned to the senior author in his fourth year in Harvard Medical School to work on an investigative problem dealing with milligrams of iodine per gram of dried gland in relation to the elevation of
734
Frank H. Lahey, Rosemary Murphy
metabolism and the degree of hyperplasia. From this experience of slicing thyroid specimens he then, many years ago, demonstrated and reported to us the occasional intrathyroid location of a parathyroid gland. In our own experience with hyperparathyroidism we have twice demonstrated the intra thyroid location of superior parathyroid adenomas which were actively overfunctioning. There have been reports from others (Mayo Clinic) demonstrating the occasional, if rare, occurrence of intrathyroid hyperfunctioning parathyroid adenomas. For this reason no search for hyperfunctioning parathyroid adenoma should be abandoned without mobilizing the upper pole and making sure by palpation of the poles and body of the thyroid through and through that there is not at this location an intrathyroid parathyroid adenoma. One of the most difficult and disturbing situations in which to be is to search the neck for a hyperfunctioning parathyroid adenoma with good clinical and good laboratory evidence that hyperparathyroidism almost certainly exists in such a patient and at the same time not be able to demonstrate one in the neck. The uncertainty of this position is based upon the question as to when one should open the mediastinum and search for a mediastinal adenoma in such a position. Such is the experience today of skilled thoracic surgeons that exploration of the superior mediastinum can be done with very little increase in the surgical risk of the exploration. In those patients with all the clinical evidences of the disease, that is, with a convincingly high caleium, a eonvineingly low phosphorus, a high phosphatase, "together with the other findings whieh almost promise that a hyperfundioning parathyroid adenoma is present, sueh as bone deealeification and inereased urinary output of calcium, it is urgently indicated that such a search for a hyperfunctioning parathyroid adenoma or parathyroid hyperplasia is not complete without investigation of the mediastinum. When, however, one of the borderline cases which are met not infrequently without bone changes, without convincing laboratory evidence of the disease, that is, with very slight alkaline phosphatase elevation, with relatively slight depression of phosphorus levels and with unstriking elevations of the serum calcium, the situation is much more difficult and doubtful. One does not feel that he can be as positive in the statement of the need of exposing the mediastinum, as stated above, and the decision to open the mediastinum if a hyperfunctioning parathyroid adenoma cannot be demonstrated in the neck must be based largely upon the clinician's decision as to how likely it is that the symptoms are truly related to a possible hyperparathyroidism or to some other possible cause. It is our belief at this clinic that no patient should be submitted to an exploration for a possible hyperfunctioning hyperparathyroid adenoma unless the operator himself is sufficiently skilled and experienced to split
r !
Primary Hyperparathyroidism
735
the sternum and expose the upper mediastinum, or unless a surgeon with skill and experience is at hand should the hyperfunctioning parathyroid adenoma not be found within the neck. Size of the Adenoma. We would be inclined to say from our experience that the degree of hyperparathyroidism effect, although not entirely related to the size of the adenoma, is at least in some measure linked with such increase in size. That this is not entirely dependable is demonstrated by the fact that we have removed adenomas of the parathyroid about 2.5 cm. in size with no increase in function in the form of hyperparathyroidism in any way demonstrated, that we have cases of cysts of the parathyroids of similar size but with no increase in parathyroid function. It is likewise true that with relatively small hyperfunctioning parathyroid adenomas, about 1 cm. in size, there have occurred calcinosis of the kidney pelvis, multiple renal stones and, in a young man, very definite symptoms of a quite active degree of hyperfunctioning parathyroidism. Based upon this experience, we believe it is possible to say that, while there may be some relative relationship between the size and the degree of hyperfunction of a parathyroid adenoma, this relationship is not dependable. We would from our experience feel more positive about the statement that the length of time that patients have had a hyperfunctioning parathyroid adenoma is more important than the size in the production of its effect. The question of palpability comes under the same heading. When a discrete tumor is palpable either at the upper or the lower pole on either side of the thyroid, in the presence of chemical findings and clinical signs indicating this disease, it is to be seriously suspected that this is a hyperfunctioning parathyroid adenoma. These hyperfunctioning adenomas of the parathyroid have varied in size from that of a little fingernail to that of a large English walnut or larger. In any operation for possible hyperparathyroidism, a pathologist should be present to whom the specimen can be submitted for immediate report, many of which will be disappointing in that the diagnosis will be thyroid adenoma or adenomatous goiter. It is assumed today that no parathyroid which appears normal should be removed until a small specimen has been submitted to the pathologist to determine whether or not that state of hyperparathyroidism which is only occasionally present, that is hyperplasia of all four parathyroids, should justify subtotal parathyroidectomy. In closing, we would like to call attention to a point with which everyone who has had much experience with this disease is familiar and one which we have repeatedly stressed, but one which can be and frequently is overlooked, that is, the anticipation in a majority of the cases following removal of the hyperfunctioning parathyroid adenoma that varying degrees of tetany will occur. It is to be remembered, as has been demon-
Frank H. Lahey, Rosemary Murphy
736
strated in a parallel situation of hyperfunctioning adenomas of the adrenal gland, that with such an excessive production of the element so essential to normal existence, parahormone, by a single hyperfunctioning parathyroid adenoma, there is a lack of glandular activity in the remaining parathyroid body. This can frequently be demonstrated by the lack of cellular activity, the pale color, and flabbiness which one sees ill the uninvolved parathyroids which can be demonstrated not HYPER PARATHYROI OISM COURSE OF SERUM CALCIUM AFTER OPERATION
I NOVEMBER
I
DAYS SERUM CALCIUM MG.lIOO CC.
15
16
17
OPERATION
I
2
P.M.
A.M.
A.M.
P.M.
A.M.
P.M.
18 16 14 12 10 8
\
\
\
\
~
""
TETANY
r"..
~
Fig. 193. Chart illustrating the rapid fall in serum calcium which may occur in the first twenty-four to forty-eight hours after parathyroidectomy.
infrequently in the search for the hyperfunctioning parathyroid adenoma. Such can be the pallor, flabbiness and fat deposits in active parathyroids that, although they may retain the same physical characteristics, they cannot be demonstrated easily because of the lack of the characteristically pale brownish color or evidences of glandular activity. Figure 193 shows very dramatically how promptly calcium levels descend with removal of the hyperfunctioning parathyroid adenoma and demonstrates quite conclusively the inability of the remaining uninvolved parathyroids to assume the production of parahormone at sufficient levels to maintain normal parathyroid function. In the instance here illustrated, it was not possible to relinquish the administration of a
Primary H ype:rparathyroidism
737
calcium elevating agent such as calcium lactate itself, vitamin D in 50,000 to 150,000 units, or AT-lO. We have seen postoperative tetany occur so often in varying degrees ·of intensity that we watch for it closely, and upon the appearance of any signs suggestive of it we put the patients on calcium-sustaining treatment. We have urged several times that after the removal of hyperfunctioning parathyroid adenomas it is wrong not to keep in mind the possibility of occurrence of tetany since real tetany is such a frightening thing to the patient and to the relatives. We would urge, therefore, that everyone who removes hyperfunctioning parathyroid adenomas havein mind the need to supply a substitute for parahormone, gradually lowering the dosage until it can be withdrawn without the occurrence of tetany. CONCLUSIONS
The physiology of parathyroid function is discussed. The effect of abnormal hyperfunction of these structures upon calcium, phosphorus and alkaline phosphatase levels together with calcium balance is commented upon. The effect of hyperparathyroidism upon the skeletal system is discussed and illustrated by roentgenograms of patients with hyperparathyroidism. The various bone changes suggestive of this disease are described, as are the renal manifestations. A group of vague general symptoms, at one time often not considered significant, which should make us aware of the possible presence of hyperparathyroidism is discussed, as are the laboratory findings in the various stages and phases of hyperparathyroidism. The approach to the only method of treatment of this disease (surgical) is discussed, with a report of our experiences in finding and removing these tumors which represent the cause of hyperparathyroidism in 92 per cent of the cases .. BIBLIOGRAPHY 1. McLean, F. C. and Hastings, A. B.: Clinical estimation and significance of calcium-ion concentrations in the blood. Am. J. M. Sc. 189: 601-613 (May) 1935. 2. Talbot, N. B., Sobel, E. H., McArthur, J. W. and Crawford, J. D.: Functional Endocrinology. Cambridge, Mass., Harvard University Press, 1952.