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The normal and pathologic physiology of the parathyroid glands
THE
NORMAL
F.
RAYMOND
AND PATHOLOGIC PHYSIOLOGY PARATHYROID GLANDS KEATING, JR., M.D.,”
ROCHESTER,
OF THE
QUINN.
T
HE various endocrine glands secrete into the circulation specific substances which act as regulators and co-ordinators of numerous vital functions related to growth, reproduction, and metabolism. Diseases of these structures sometimes produce spectacular and profound changes far out of proportion to the extent of the causative lesion or the relatively small size of the affected gland. This is particularly notable in the case of the parathyroid glands, which comprise the smallest endocrine organ in the body. ANATOMIC
CONSIDERATIONS
In man, the parathyroids are usually four in number and their combined weight varies from 120 to 150 mg. Each glandule measures approximately 6 by 4 by 3 mm. Because of their minute size, both their existence and their function were overlooked until comparatively recent times. The parathyroids originate from the branchial clefts in close association with the anlagen of the thyroid gland and the thymus. Ordinarily they occupy positions on the dorsal surface of the lateral lobes of the thyroid, an inferior pair near the lower poles and a superior pair between the middle and upper portions. Sometimes more or less than four glands exist and, occasionally, one or more of them may occupy anomalous positions either within the thyroid or distant from it. Parathyroids occasionally occur within the upper mediastinum, sometimes in or near the thymus. These variations in anatomic relationships are of critical importance in the surgical management of hyperparathyroidism and greatly complicate the technical details of parathyroid surgery. Each parathyroid glandule is a soft, buff-colored structure, which on microscopic examination is found to consist of columns or clumps of cells separated by loose connective tissue containing numerous fat cells. The parathyroid cells are of three principal types : (1) chief cells, which are small, dark-staining cells with relatively scant protoplasm ; (2) oqphiZ cells, which are much larger than the chief cells, have smaller nuclei, and stain intensely with acid dyes, and cells, which are still larger and are (3) “ wasserhelle ” cells, or water-clear characterized by a large amount of water-clear protoplasm containing many vacuoles. Intermediate forms of the foregoing types are also to be found. The chief cells are ordinarily the most abundant. The oxyphil cells do not appear Palm
Read before the Third Annual Seminar Springs. Calif., Oct. 7, 1946. *Division of Medicine, Mayo Clinic.
for
1.29
the
Study
and
Practice
of
Dental
Medicine,
130
%. Raymond
Keating,
Jr.
until puberty, after which they increase in number with helle” cells usually remain relatively few. The functional cell types is not well understood. PARATHYROID
age. The “wassersignificance of these
HORMONE
The parathyroid glands exert their effects by secreting a specific substance, parathyroid hormone, into the blood. The existence of this hormone was demonstrated independently by Hansen and by Collip more than twenty years ago. The hormone is a protein with a small molecule (molecular weight about 20,000) .*1 Studies have shown that the presence of free amino groups is necessary to its activity, but no definite prosthetic groups have been recognized. It is destroyed by protein digestion and is therefore ineffective if given by mouth. Parathyroid hormone has a marked effect on the metabolism of calcium and phosphorus and directly or indirectly, on the metabolism of bone. CALCIUM
METABOLISM”
I4
Calcium is the most abundant mineral in the body, comprising 1.7 per cent of body weight and about 40 per cent of the total ash of the body. More than 99.5 per cent of the calcium in the body is stored in bones and teeth, where, deposited in solid form, it contributes to the physical characteristics of these The relatively minute quantity of calcium not stored in the bones structures. or teeth is in solution in the fluids of the body, where it influences a number of vital functions. These include the permeability of membranes, ‘the excitability of nerve and muscle, the action of the heart, and the coagulability of the blood. Blood serum contains 10.0 mg. plus or minus 0.5 mg. of calcium per 100 cc. Calcium in serum is distributed in two fractions: one, comprising 55 per cent of the total, is rather firmly bound to serum proteins as a salt, calcium proteinate. This fraction is neither diffusible nor ionizable and is apparently relatively inert. The second fraction is diffusible and, for the most part, is ionized; it is generally called ion calcium, and comprises 45 per cent of the total calcium in serum. Ion calcium is directly affected by parathyroid hormone and is directly related to most, if not all, of the effects mentioned previously. Under ordinary circumstances, ion calcium remains remarkably constant despite loss or gain of calcium to the body. This is in part accounted for by the skeleton, which, besides its other functions, acts as a reservoir from which calcium may be withdrawn or into which it may be replaced in order to preserve the normal concentration of ion calcium in serum and body fluids. Parathyroid hormone appears to serve directly or indirectly as a device for regulating the concentration of ion calcium. There is considerable indirect evidence that the stimulus causing the parathyroid glands to produce more hormone is a concentration of ion calcium in serum below normal. Calcium is constantly lost in the urine (10 per cent) and feces (90 per cent). That in the feces usually consists largely, if not entirely, of dietary calcium which was unabsorbed. Under some circumstances fecal calcium may actually represent loss of endogenous stores of calcium. Calcium may also be lost from the body through the placenta and the lactating breast.
Physiology
of Parathyroid
Glands
131
Since calcium is constantly being iost from the body, the depletion of stores of calcium can be avoided only by the constant absorption of calcium from the diet. The minimal daily requirement for calcium in adults is approximately 0.7 Gm.13 The absorption of calcium from the diet involves a number of factors, including the concentration of calcium, phosphorus, and hydrogen ions in the serum, the anatomic and functional integrity of the digestive tract, etc. The most important factor, however, is vitamin D, which acts directly on the digestive tract t.o facilitate absorption of calcium. Since calcium in body fluids is kept remarkably constant and constitutes a relatively minute quantity, it follows that a positive or negative calcium balance can mean only that calcium is entering or leaving the bones (and in special circumstances, the teeth). PHOSPHORUS
METABOLISM”
I4
Phosphorus resembles calcium in that very large amounts are stored in the skeleton and teeth and very small quantities circulate in body fluids. It differs from calcium in t,hat relatively large amounts also occur in all of the cells of the body, where it exists in many organic phosphorus compounds such as phospholipids, phosphoproteins, and phosphate esters, and is actively involved in many metabolic processes. Large quantities of phosphorus compounds exist in the erythrocytes and certain organic phosphorus compounds also occur in serum, but the phosphorus fraction most intimately related to parathyroid hormone and to calcium is the inorganic phosphate of serum. Serum normally contains 3.2 plus or minus 0.7 mg. of inorganic phosphate (expressed as phosphorus) per 100 cc. Phosphorus is also constantly lost from the body in the urine (60 per cent) and feces (40 per cent), and therefore, like calcium, is an essential constituent of the diet. The minimal daily requirement of adults is 1.32 Gm.13 Inasmuch as the skeleton is not the sole reservoir for phosphorus, a positive or negative phosphorus balance does not necessarily imply gain or loss of phosphorus from the skeleton. Partly because of the insolubility of calcium phosphate, the concentrations of ion calcium and of inorganic phosphate are intimately related, as they occur both in serum and elsewhere. Under most circumstances, an increase of one in serum is accompanied by a reduction of the other. METABOLISM
OF BONE
The growing bone of children is easy to recognize as an active tissue but, too often, adult bone is looked on as inert, almost lifeless material. On the contrary, adult bone, as Albrightl has pointed out, is characterized by active metaplasia, new bone constantly being laid down in some localities and reabsorbed from others at the same time. There is no comparable metaplasia of tissue in the teeth. The tissues of adult bone comprise three chief elements: (1) osteoblasts, (2) osteoclasts, and (3) osteoid. Osteoblasts are mononuclear cells which are generally considered to produce the osteoid. They also elaborate an enzyme,
132
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Jr.
phosphatase, which is probably involved in the mechanism of calcification. Osteoclasts are multinuclear cells which are obviously related in some way to the reabsorption of bone. Their actual role is a matter of dispute; by some they are thought to destroy bone actively, either by biochemical means or by actual phagocytosis. By others they are looked on as aggregations of osteocytes surviving regions of bone previously destroyed. Osteoid is a homogeneous matrix of protein in which is laid down the characteristic mineral of bone, a complex mineral salt containing calcium phosphate and calcium carbonate. The deposition of bone salt may be aided by phosphatase, which, by splitting ester phosphates, may provide a local excess of phosphate ions. The physical and chemical factors which promote calcification on the one hand and decalcification on the other are complex and not well understood. Changes in calcium, phosphate, carbonate, and hydrogen ion concentration alter the rate of resorption of bone but, according to Albright, have relatively little effect on deposition of bone. Deposition of bone seems more related to the state of the body as a whole: the presence of health or disease, the state of nutrition, and the availability of protein. Locally, the amount of mechanical stresses and strains appears to have a specific effect on formation of bone. THE
ACTION
OF PARATHYROID
HORMONE
Knowledge of the action of the parathyroids is based on three sorts of observations: (1) the study of the effects of experimental parathyroidectomy, (2) the study of the effects of administering parathyroid hormone experimentally to normal or parathyroidectomized animals, and (3) clinical observations of parathyroid insufficiency and hyperfunction occurring in man as the result of disease. The Efects of P’arathyroidectomy.-Experimental parathyroidectomy in laboratory animals, or the inadvertent removal of the parathyroids in man, results in a remarkable syndrome known as tetany. The general characteristics of tetany are the same in most species of animals, although considerable variation occurs in its intensity and speed of appearance. Surgical removal of the parathyroids from a dog, for example, is followed after a latent period of several days by loss of appetite, by refusal of food and water, and sometimes by vomiting. Body temperature falls; fibrillary twitchings occur in the muscles of the head, back, and tail, followed by fine contractions of the legs. The peripheral nerves become hyperexcitable to mechanical stimulation and still more so to electrical stimulation. Twitchings become coarser and many muscles go into a state of clonic contractures ; the gait becomes awkward and the animal may fall in a generalized epileptiform convulsion. During convulsions the breathing is rapid and panting ; if the seizure persists, death may occur as a result of spasm of the larynx, diaphragm, or cardiac muscles. If the subject recovers from one attack, symptoms may be minimal or absent for several days, only to reappear in their original severity. A similar train of events follows accidental removal or injury of the parathyroid glands in man such as occasionally follows thyroidectomy for goiter. The patient first complains of numbness and tingling of the fingers and toes,
Physiology
of
Parathyroid
Glands
133
later of the mouth, and eventually of much of the body, but especially the extremities. This is followed by contractions or spasms of muscles, particularly in the hands and feet, where the contractures have a form characteristic of tetany, called carpopedal spasm. Occasionall-, similar spasms affect other muscles or even the musculature in gcncral. Laryngospasm is particularly likely to OCCLI~ in children. When it does occur,‘it frequently produces great difficulty in breathing, which may result in cyanosis and death. Spasms have also been observed to occur in the muscles of the eyes, the esophagus, the stomach, bronchi, intestine, and heart,. Severe tetany may terminate in generalized epileptiform convulsions. The foregoing train of symptoms occurring in man is termed acute or manifest tetany ; it may appear soon after parathyroid ablation and reappear in acute episodes from time to time. In many cases, such acute episodes are very mild and in cases of long standing mar be virtually absent. In the absence of manifest tetany, or in the intervals between attacks, the condition is called latent Many. Latent tetany is accompanied by vague symptoms which of themselves do not provide any clue to the diagnosis. li’atigue and muscular weakness are the most constant of these symptoms. In the presence of latent tetany, however, the characteristic hyperexcitability of nerve and muscle may be demonstrated by three clinical procedures : (1) Chvostek’s sign, which is a twitch of the facial muscles elicited by tapping the facial nerve; (2) Trousseau’s sign, which is a characteristic carpal spasm brought on bp mechanical occlusion of the circulation of the arm ; and (3) Erb’s sign, which is an alteration in the response to stimulation of muscle by galvanic current. Epileptic seizures most often accompany chronic tetany of long standing. Chronic tetany is also accompanied by degenerative or trophic disturbances, which include (1) bilateral symmetrical cerebral calcification, (2) cataracts, (3) defects of hair and nails, and (4) defects in the teeth. In addition, it is reasonably certain that chronic tetang of lon g standing is accompanied by abnormally thick and dense bones. The dental changes which occur in chronic tetany are of special interest and have been discussed at length by Kronfeld.8 Such changes in the teeth result only when tetany is present durin g their developmental period, prior to eruption. This is the case because, during their development, human teeth are very sensitive to variations in the calcium supply. This is not true of erupted teeth of adults, which, as a consequence, appear immune to disturbances of parathyroid function. l?leischmannG was the first to show that rachitic tetany could cause hypoplasia of enamel. Erdheimj was able to produce hypoplasia of enamel experimentally in rats by parathyroidectomy. Defective calcification of dentine also occurred. The similarity of the changes in parathyroidectomized rats to the findings in human teeth suggested that in some instances hypoplasia of enamel in human beings is the result of hypoparathyroidism at the time of formation of enamel. Albright and Strock3 confirmed and extended these observations. They found that subjects who had parathyroid insufficiency occurring during
134
P. Raymond
Keating,
Jr.
childhood might show hypoplasia, aplasia, and various other defects of enamel. Kronfeld pointed out that these changes are a direct result of the lowered level of serum calcium. My colleagues and I have recently studied spontaneous parathyroid insufficiency occurring in two sisters. The dental changes encountered in these cases have been analyzed by Lovestedt.9 The younger sister, 15 years of age, had had symptoms of severe parathyroid tetany since the age of 3 years. Amelogenesis appeared to have been unaltered until the age of 3 years. All the teeth that had had enamel formed since that time showed defects in the enamel; several teeth were unerupted and these appeared devoid of any enamel. The older sister, 28 years of age, also had a history of tetany beginning in early childhood, but, since the symptoms were milder, the time of onset could not be ascertained with certainty. There was a decreased amount of enamel over the surfaces of all the teeth, and enamel seemed entirely lacking on the unerupted but unimpacted third molars (Fig. 1). Other members of the family were examined and found to have both normal paratliyroid function and normal teeth.
Fig.
l.-Hypoplasia
of
enamel
resulting early
from spontaneous parathyroid childhood (see text).
tetany
which
began
in
Parathyroid insufficiency is characterized by a low level of calcium and an increase of inorganic phosphorus in serum. There is little or no calcium in the urine, but excretion of phosphorus may be normal. Parathyroid tetany is solely a consequence of the hypocalcemia. Tetany may be treated by the administration of calcium, or by employing agents which elevate the serum calcium. Viatmin D and dihydrotachysterol, or A. T. 20, are usually employed for this purpose. The syndrome of tetany is not peculiar to parathyroid insufficiency. It may also be caused by other conditions, notably rickets, osteomalacia, sprue, steatorrhea, renal disease, and alkalosis. Parathyroid tetany occurring in man may result from (1) spontaneous parathyroid insufficiency, which is caused by atrophy or destruction of the para-
Physiology
of Parathyroid
Glands
135
thyroid glands, cause unknown ; (2) postoperative parathyroid insufficiency, following surgical removal of the parathyroids, and (3) pseudohypoparathyroidism, which, as described by Albright, is due, not to an intrinsic lack of parathyroid hormone, but to an inability, apparently inborn, of the tissues to utilize t,he hormone available.2 The Efects of an Excess of Parathyyoid Elo~nlone.12-The injection into a dog of 25 units of parathyroid hormone every four hours provokes a rapid increase of the concentration of calcium in serum, accompanied by a slight increase of potassium and magnesium and a reduction of inorganic phosphorus. The urinary excretion of phosphorus and later of calcium is much increased. If injections are continued until the serum calcium reaches a critical range (usually near 20 mg. per 100 cc. of serum), the level of inorganic phosphorus begins to climb swiftly, and urinary excretion of both calcium and phosphorus diminishes abruptly. The initial phase of administration of the hormone is accompanied by weakness, trembling, diuresis, nausea, and vomiting. As injections are repeated, these manifestations are followed by muscular atony, lassitude, oliguria, and the clinical and chemical evidences of renal failure. Renal failure, circulatory collapse, and death ensue swiftly once the concentration of phosphorus in serum begins to increase. Necropsy discloses metastatic deposits of calcium phosphate in kidneys,~ lungs, stomach, interstitial connective tissue, heart muscle, and arterial walls. The excess of calcium which appears in the blood and is excreted in the urine is derived from the skeleton. The bones arc found markedly decalcified; the bone marrow is hyperemic or hemorrhagic. Repeated daily injections of sublethal quantities of parathyroid hormone produce remarkable resorption of both spongy and cortical bone, with fibrosis and formation of giant-cell tumors. In 1926, Hannon, Shorr, McClellan, and DuBois’ studied a man who had osteitis fibrosa cystica generalisata, an uncommon malady of bone characterized by decalcification, fibrosis, and the formation of multiple cysts and tumors in bone. They were impressed by the similarit,y of the patient’s symptoms to the phenomena described in animals chronically poisoned by injection of parathyroid hormone. By careful studies they were able to show that the physiologic abnormalities exhibited by their patient corresponded in almost every particular to those observed in experimental hyperparathyroidism. These observations were confirmed on the same subject by Bauer, Albright, and Aub.’ A diagnosis of hyperparathyroidism was made, but repeated surgical explorations had to be performed over a period of several years before the hyperfunctioning lesion, a parathyroid adcnoma, could be found and removed. It was found deep in the mediastinum. Credit for providing final proof that this condition was produced by hyperparathyroidism goes to Mandl,l” who first effected a spectacular remission in a patient having osteitis fibrosa cystica by removing a parathyroid tumor. Primary hyperparathyroidism in man may be the result of hyperfunction of tumors of one or more parathyroid glands, or of hyperplasia of ‘fwasserhelle” cells affecting all of them. The cause of either lesion is unknown. Secondary
136
P. Raymond
Keating,
Jr.
hyperparathyroidism. is thought to result from functional hyperplasia of the parathyroids involving chief cells. It occurs in association with rickets, osteomalacia, renal insufficiency, multiple myeloma, and possibly other conditions. The clinical aspects of hyperparathyroidism will be discussed in detail elsewhere. The Site of Action of Parathyroid Hormone.-From the foregoing it is clear that the administration of parathyroid hormone elevates serum calcium, depresses serum phosphorus, increases the renal excretion of both, and drains calcium from the bones. The lack or withdrawal of parathyroid hormone leads to lowered serum calcium, elevated serum phosphorus, reduction of urinary calcium, and increased density of the skeleton. The effects on neuromuscular excitability, the tetany of parathyroid insufficiency and the muscular atony and weakness of hyperparathyroidism, are obviously secondary to the altered concentrations of calcium and phosphorus ions per se. The various other manifestations associated with either state can be regarded with reasonable certainty as secondary to one or another of the primary effects just mentioned. It is generally agreed that the chief if not the sole role of parathyroid hormone is the preservation of the normal concentration of the calcium ions on the body fluids. Much difference of opinion exists as to the mechanism involved. Albright emphasized the chronologic order of events which follows withdrawal or giving of parathyroid hormone. Withdrawal of parathyroid hormone produces the following events, in this order: (1) The excretion of phosphorus (2) The quantity of phosphorus in serum in urine is markedly diminished. increases. (3) The quantity of calcium in serum falls. (4) The quantity of calcium in the urine falls. If one administers parathyroid extract to a normal person, these same four metabolic events are altered in the opposite direction. On the basis of these observations, Albright concluded that the primary effect of parathyroid hormone is on the renal excretion of phosphorus and explained the mechanism as follows: (1) Parathyroid hormone increases the urinary excretion of phosphorus. (2) Increased urinary loss of phosphorus is followed by diminished serum phosphorus. (3) Lowered serum phosphorus would make the serum less saturated with respect to calcium phosphate. (4) According to the rules governing the solubility of this salt, this would permit more calcium phosphate to enter the serum from the gastrointestinal tract or from the skeleton. (5) Addition of calcium phosphate would increase the level of serum cal.cium. (6) The elevated serum calcium would lead to hypercalcinuria. ‘According to this hypothesis, parathyroid hormone does not affect the skeleton directly ; the skeleton yields calcium only when necessary for completion of the changes in chemical equilibria which follow the primary action of the hormone on the kidneys. Other workers have expressed the belief that parathyroid hormone acts primarily to accelerate bone resorption, either by acting on the osteoclasts or by stimulating some other mechanism to this end. According to these workers, the hypothetical sequence of events would be as follows: (1) Parathyroid hormone expedites resorption of bone. (2) Increased calcium from bone elevates
Physiology
of Parathyroid
Glands
137
serum calcium. (3) Elevated serum calcium leads to increased urinary excretion As Albright pointed out, however, it is difficult under these hyof calcium. potheses to explain the association of hyperphosphatnria and hypophosphatemia which also occurs. A number of experimental observations, however, indicate that characteristic bone resorption, as well as changes in swum calcium, may follow the injection of parathyroid hormone, even when the kidneys have been removed. It therefore appears that while there is a primary and initial effect of parathyroid hormone on the kidneys, there is also a primary effect on the skeleton as well. The relative importance of these effects in normal man and in discases of the parathyroids remains to be determined by future studies. The solution of this problem is by no means academic, for on it depend the proper interpretation and understanding of the clinical manifestations of parathyroid insufficiency and hyperparathyroidism. On such understanding, in turn, rests the only opportunity for progress in the diagnosis and treatment of parathyroid disease. REFERENCES
Parathyroids-Physiology and Therapeutics, J. A. M. A. 117: 527, 1941. 1. Albright, F.: Pseudo-hypoparathyroidism2. Albright, F., Burnett, C. H., Smith, P. H., and Parson, W.: Syndrome ’ ’ ; Report of 3 Cases, Endocrinology 30: Example of “ Seabright-Bantam 922, 1942. 3. Albright, Fuller, and Strock, M. 9.: The Association of Acalcification of Dentine With Hypoparathyroidism in Rats and the Cure of Same With Parathormone, With Some Correlated Observations in Man, J. Clin. Investigation 12: 974, 1933. 4. Bauer, Walter, Albright, Fuller, and Aub, J. C.: A Case of Osteitis Fibrosa Cystica (Osteomalacia?) With Evidence of Hyperactivity of the Parathyroid Bodies. Metabolic Study II, J. Clin. Investigation 8: 229, 1930. Quoted by Kronfeld, Rudolf, p. 65.8 5. Erdheim, J.: 6. Fleischmann, L.: Quoted by Kronfeld, Rudolf, p. 65.8 7. Hannon, R. R., Shorr, E., McClellan, W. S., and DuBois, E. F.: A Case of Osteitis Fibrosa Cystica (Osteomalaeia?) With Evidence of Hyperactivity of the Parathyroid Bodies. Metabolic Study I, J. Clin. Investigation 8: 215, 1930. 8. Kronfeld, Rudolf: Histopathology of the Teeth and Their Surrounding Structures, ed. 2, Philadelphia, 1939, Lea & Febiger, pp. 504. 9. Lovestedt, S. A.: Personal communication to the author. 10. Mandl,. Felix: Therapeutischer Versuch bei einem Falle von Ostitis fibrosa generalisata mittels Exstirpation eines Epithelkijrperchentumors, Zentralbl. f. Chir. 53: 260, 1926. 11. Pope, Alfred, and Aub, J. C.: The Parathyroid Glands and Parathormone, New England J. Med. 230: 698, 1944. 12. Shelling, D. H.: The Parathyroids in Health and in Disease, St. Louis, 1935, The C. V. Mosby Co., pp. 335. Chemistry of Food and Nutrit,ion, ed. 6, New York, 1941, The Macmillan 13. Sherman, H. C.: Co., pp. 611. 14. Shohl, A. T.: Mineral Metabolism, New York, 1939, Reinhold Publishing Corp., pp. 384.
NORMAL
F.
RAYMOND
AND PATHOLOGIC PHYSIOLOGY PARATHYROID GLANDS KEATING, JR., M.D.,”
ROCHESTER,
OF THE
QUINN.
T
HE various endocrine glands secrete into the circulation specific substances which act as regulators and co-ordinators of numerous vital functions related to growth, reproduction, and metabolism. Diseases of these structures sometimes produce spectacular and profound changes far out of proportion to the extent of the causative lesion or the relatively small size of the affected gland. This is particularly notable in the case of the parathyroid glands, which comprise the smallest endocrine organ in the body. ANATOMIC
CONSIDERATIONS
In man, the parathyroids are usually four in number and their combined weight varies from 120 to 150 mg. Each glandule measures approximately 6 by 4 by 3 mm. Because of their minute size, both their existence and their function were overlooked until comparatively recent times. The parathyroids originate from the branchial clefts in close association with the anlagen of the thyroid gland and the thymus. Ordinarily they occupy positions on the dorsal surface of the lateral lobes of the thyroid, an inferior pair near the lower poles and a superior pair between the middle and upper portions. Sometimes more or less than four glands exist and, occasionally, one or more of them may occupy anomalous positions either within the thyroid or distant from it. Parathyroids occasionally occur within the upper mediastinum, sometimes in or near the thymus. These variations in anatomic relationships are of critical importance in the surgical management of hyperparathyroidism and greatly complicate the technical details of parathyroid surgery. Each parathyroid glandule is a soft, buff-colored structure, which on microscopic examination is found to consist of columns or clumps of cells separated by loose connective tissue containing numerous fat cells. The parathyroid cells are of three principal types : (1) chief cells, which are small, dark-staining cells with relatively scant protoplasm ; (2) oqphiZ cells, which are much larger than the chief cells, have smaller nuclei, and stain intensely with acid dyes, and cells, which are still larger and are (3) “ wasserhelle ” cells, or water-clear characterized by a large amount of water-clear protoplasm containing many vacuoles. Intermediate forms of the foregoing types are also to be found. The chief cells are ordinarily the most abundant. The oxyphil cells do not appear Palm
Read before the Third Annual Seminar Springs. Calif., Oct. 7, 1946. *Division of Medicine, Mayo Clinic.
for
1.29
the
Study
and
Practice
of
Dental
Medicine,
130
%. Raymond
Keating,
Jr.
until puberty, after which they increase in number with helle” cells usually remain relatively few. The functional cell types is not well understood. PARATHYROID
age. The “wassersignificance of these
HORMONE
The parathyroid glands exert their effects by secreting a specific substance, parathyroid hormone, into the blood. The existence of this hormone was demonstrated independently by Hansen and by Collip more than twenty years ago. The hormone is a protein with a small molecule (molecular weight about 20,000) .*1 Studies have shown that the presence of free amino groups is necessary to its activity, but no definite prosthetic groups have been recognized. It is destroyed by protein digestion and is therefore ineffective if given by mouth. Parathyroid hormone has a marked effect on the metabolism of calcium and phosphorus and directly or indirectly, on the metabolism of bone. CALCIUM
METABOLISM”
I4
Calcium is the most abundant mineral in the body, comprising 1.7 per cent of body weight and about 40 per cent of the total ash of the body. More than 99.5 per cent of the calcium in the body is stored in bones and teeth, where, deposited in solid form, it contributes to the physical characteristics of these The relatively minute quantity of calcium not stored in the bones structures. or teeth is in solution in the fluids of the body, where it influences a number of vital functions. These include the permeability of membranes, ‘the excitability of nerve and muscle, the action of the heart, and the coagulability of the blood. Blood serum contains 10.0 mg. plus or minus 0.5 mg. of calcium per 100 cc. Calcium in serum is distributed in two fractions: one, comprising 55 per cent of the total, is rather firmly bound to serum proteins as a salt, calcium proteinate. This fraction is neither diffusible nor ionizable and is apparently relatively inert. The second fraction is diffusible and, for the most part, is ionized; it is generally called ion calcium, and comprises 45 per cent of the total calcium in serum. Ion calcium is directly affected by parathyroid hormone and is directly related to most, if not all, of the effects mentioned previously. Under ordinary circumstances, ion calcium remains remarkably constant despite loss or gain of calcium to the body. This is in part accounted for by the skeleton, which, besides its other functions, acts as a reservoir from which calcium may be withdrawn or into which it may be replaced in order to preserve the normal concentration of ion calcium in serum and body fluids. Parathyroid hormone appears to serve directly or indirectly as a device for regulating the concentration of ion calcium. There is considerable indirect evidence that the stimulus causing the parathyroid glands to produce more hormone is a concentration of ion calcium in serum below normal. Calcium is constantly lost in the urine (10 per cent) and feces (90 per cent). That in the feces usually consists largely, if not entirely, of dietary calcium which was unabsorbed. Under some circumstances fecal calcium may actually represent loss of endogenous stores of calcium. Calcium may also be lost from the body through the placenta and the lactating breast.
Physiology
of Parathyroid
Glands
131
Since calcium is constantly being iost from the body, the depletion of stores of calcium can be avoided only by the constant absorption of calcium from the diet. The minimal daily requirement for calcium in adults is approximately 0.7 Gm.13 The absorption of calcium from the diet involves a number of factors, including the concentration of calcium, phosphorus, and hydrogen ions in the serum, the anatomic and functional integrity of the digestive tract, etc. The most important factor, however, is vitamin D, which acts directly on the digestive tract t.o facilitate absorption of calcium. Since calcium in body fluids is kept remarkably constant and constitutes a relatively minute quantity, it follows that a positive or negative calcium balance can mean only that calcium is entering or leaving the bones (and in special circumstances, the teeth). PHOSPHORUS
METABOLISM”
I4
Phosphorus resembles calcium in that very large amounts are stored in the skeleton and teeth and very small quantities circulate in body fluids. It differs from calcium in t,hat relatively large amounts also occur in all of the cells of the body, where it exists in many organic phosphorus compounds such as phospholipids, phosphoproteins, and phosphate esters, and is actively involved in many metabolic processes. Large quantities of phosphorus compounds exist in the erythrocytes and certain organic phosphorus compounds also occur in serum, but the phosphorus fraction most intimately related to parathyroid hormone and to calcium is the inorganic phosphate of serum. Serum normally contains 3.2 plus or minus 0.7 mg. of inorganic phosphate (expressed as phosphorus) per 100 cc. Phosphorus is also constantly lost from the body in the urine (60 per cent) and feces (40 per cent), and therefore, like calcium, is an essential constituent of the diet. The minimal daily requirement of adults is 1.32 Gm.13 Inasmuch as the skeleton is not the sole reservoir for phosphorus, a positive or negative phosphorus balance does not necessarily imply gain or loss of phosphorus from the skeleton. Partly because of the insolubility of calcium phosphate, the concentrations of ion calcium and of inorganic phosphate are intimately related, as they occur both in serum and elsewhere. Under most circumstances, an increase of one in serum is accompanied by a reduction of the other. METABOLISM
OF BONE
The growing bone of children is easy to recognize as an active tissue but, too often, adult bone is looked on as inert, almost lifeless material. On the contrary, adult bone, as Albrightl has pointed out, is characterized by active metaplasia, new bone constantly being laid down in some localities and reabsorbed from others at the same time. There is no comparable metaplasia of tissue in the teeth. The tissues of adult bone comprise three chief elements: (1) osteoblasts, (2) osteoclasts, and (3) osteoid. Osteoblasts are mononuclear cells which are generally considered to produce the osteoid. They also elaborate an enzyme,
132
P. Raymond
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Jr.
phosphatase, which is probably involved in the mechanism of calcification. Osteoclasts are multinuclear cells which are obviously related in some way to the reabsorption of bone. Their actual role is a matter of dispute; by some they are thought to destroy bone actively, either by biochemical means or by actual phagocytosis. By others they are looked on as aggregations of osteocytes surviving regions of bone previously destroyed. Osteoid is a homogeneous matrix of protein in which is laid down the characteristic mineral of bone, a complex mineral salt containing calcium phosphate and calcium carbonate. The deposition of bone salt may be aided by phosphatase, which, by splitting ester phosphates, may provide a local excess of phosphate ions. The physical and chemical factors which promote calcification on the one hand and decalcification on the other are complex and not well understood. Changes in calcium, phosphate, carbonate, and hydrogen ion concentration alter the rate of resorption of bone but, according to Albright, have relatively little effect on deposition of bone. Deposition of bone seems more related to the state of the body as a whole: the presence of health or disease, the state of nutrition, and the availability of protein. Locally, the amount of mechanical stresses and strains appears to have a specific effect on formation of bone. THE
ACTION
OF PARATHYROID
HORMONE
Knowledge of the action of the parathyroids is based on three sorts of observations: (1) the study of the effects of experimental parathyroidectomy, (2) the study of the effects of administering parathyroid hormone experimentally to normal or parathyroidectomized animals, and (3) clinical observations of parathyroid insufficiency and hyperfunction occurring in man as the result of disease. The Efects of P’arathyroidectomy.-Experimental parathyroidectomy in laboratory animals, or the inadvertent removal of the parathyroids in man, results in a remarkable syndrome known as tetany. The general characteristics of tetany are the same in most species of animals, although considerable variation occurs in its intensity and speed of appearance. Surgical removal of the parathyroids from a dog, for example, is followed after a latent period of several days by loss of appetite, by refusal of food and water, and sometimes by vomiting. Body temperature falls; fibrillary twitchings occur in the muscles of the head, back, and tail, followed by fine contractions of the legs. The peripheral nerves become hyperexcitable to mechanical stimulation and still more so to electrical stimulation. Twitchings become coarser and many muscles go into a state of clonic contractures ; the gait becomes awkward and the animal may fall in a generalized epileptiform convulsion. During convulsions the breathing is rapid and panting ; if the seizure persists, death may occur as a result of spasm of the larynx, diaphragm, or cardiac muscles. If the subject recovers from one attack, symptoms may be minimal or absent for several days, only to reappear in their original severity. A similar train of events follows accidental removal or injury of the parathyroid glands in man such as occasionally follows thyroidectomy for goiter. The patient first complains of numbness and tingling of the fingers and toes,
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later of the mouth, and eventually of much of the body, but especially the extremities. This is followed by contractions or spasms of muscles, particularly in the hands and feet, where the contractures have a form characteristic of tetany, called carpopedal spasm. Occasionall-, similar spasms affect other muscles or even the musculature in gcncral. Laryngospasm is particularly likely to OCCLI~ in children. When it does occur,‘it frequently produces great difficulty in breathing, which may result in cyanosis and death. Spasms have also been observed to occur in the muscles of the eyes, the esophagus, the stomach, bronchi, intestine, and heart,. Severe tetany may terminate in generalized epileptiform convulsions. The foregoing train of symptoms occurring in man is termed acute or manifest tetany ; it may appear soon after parathyroid ablation and reappear in acute episodes from time to time. In many cases, such acute episodes are very mild and in cases of long standing mar be virtually absent. In the absence of manifest tetany, or in the intervals between attacks, the condition is called latent Many. Latent tetany is accompanied by vague symptoms which of themselves do not provide any clue to the diagnosis. li’atigue and muscular weakness are the most constant of these symptoms. In the presence of latent tetany, however, the characteristic hyperexcitability of nerve and muscle may be demonstrated by three clinical procedures : (1) Chvostek’s sign, which is a twitch of the facial muscles elicited by tapping the facial nerve; (2) Trousseau’s sign, which is a characteristic carpal spasm brought on bp mechanical occlusion of the circulation of the arm ; and (3) Erb’s sign, which is an alteration in the response to stimulation of muscle by galvanic current. Epileptic seizures most often accompany chronic tetany of long standing. Chronic tetany is also accompanied by degenerative or trophic disturbances, which include (1) bilateral symmetrical cerebral calcification, (2) cataracts, (3) defects of hair and nails, and (4) defects in the teeth. In addition, it is reasonably certain that chronic tetang of lon g standing is accompanied by abnormally thick and dense bones. The dental changes which occur in chronic tetany are of special interest and have been discussed at length by Kronfeld.8 Such changes in the teeth result only when tetany is present durin g their developmental period, prior to eruption. This is the case because, during their development, human teeth are very sensitive to variations in the calcium supply. This is not true of erupted teeth of adults, which, as a consequence, appear immune to disturbances of parathyroid function. l?leischmannG was the first to show that rachitic tetany could cause hypoplasia of enamel. Erdheimj was able to produce hypoplasia of enamel experimentally in rats by parathyroidectomy. Defective calcification of dentine also occurred. The similarity of the changes in parathyroidectomized rats to the findings in human teeth suggested that in some instances hypoplasia of enamel in human beings is the result of hypoparathyroidism at the time of formation of enamel. Albright and Strock3 confirmed and extended these observations. They found that subjects who had parathyroid insufficiency occurring during
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childhood might show hypoplasia, aplasia, and various other defects of enamel. Kronfeld pointed out that these changes are a direct result of the lowered level of serum calcium. My colleagues and I have recently studied spontaneous parathyroid insufficiency occurring in two sisters. The dental changes encountered in these cases have been analyzed by Lovestedt.9 The younger sister, 15 years of age, had had symptoms of severe parathyroid tetany since the age of 3 years. Amelogenesis appeared to have been unaltered until the age of 3 years. All the teeth that had had enamel formed since that time showed defects in the enamel; several teeth were unerupted and these appeared devoid of any enamel. The older sister, 28 years of age, also had a history of tetany beginning in early childhood, but, since the symptoms were milder, the time of onset could not be ascertained with certainty. There was a decreased amount of enamel over the surfaces of all the teeth, and enamel seemed entirely lacking on the unerupted but unimpacted third molars (Fig. 1). Other members of the family were examined and found to have both normal paratliyroid function and normal teeth.
Fig.
l.-Hypoplasia
of
enamel
resulting early
from spontaneous parathyroid childhood (see text).
tetany
which
began
in
Parathyroid insufficiency is characterized by a low level of calcium and an increase of inorganic phosphorus in serum. There is little or no calcium in the urine, but excretion of phosphorus may be normal. Parathyroid tetany is solely a consequence of the hypocalcemia. Tetany may be treated by the administration of calcium, or by employing agents which elevate the serum calcium. Viatmin D and dihydrotachysterol, or A. T. 20, are usually employed for this purpose. The syndrome of tetany is not peculiar to parathyroid insufficiency. It may also be caused by other conditions, notably rickets, osteomalacia, sprue, steatorrhea, renal disease, and alkalosis. Parathyroid tetany occurring in man may result from (1) spontaneous parathyroid insufficiency, which is caused by atrophy or destruction of the para-
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thyroid glands, cause unknown ; (2) postoperative parathyroid insufficiency, following surgical removal of the parathyroids, and (3) pseudohypoparathyroidism, which, as described by Albright, is due, not to an intrinsic lack of parathyroid hormone, but to an inability, apparently inborn, of the tissues to utilize t,he hormone available.2 The Efects of an Excess of Parathyyoid Elo~nlone.12-The injection into a dog of 25 units of parathyroid hormone every four hours provokes a rapid increase of the concentration of calcium in serum, accompanied by a slight increase of potassium and magnesium and a reduction of inorganic phosphorus. The urinary excretion of phosphorus and later of calcium is much increased. If injections are continued until the serum calcium reaches a critical range (usually near 20 mg. per 100 cc. of serum), the level of inorganic phosphorus begins to climb swiftly, and urinary excretion of both calcium and phosphorus diminishes abruptly. The initial phase of administration of the hormone is accompanied by weakness, trembling, diuresis, nausea, and vomiting. As injections are repeated, these manifestations are followed by muscular atony, lassitude, oliguria, and the clinical and chemical evidences of renal failure. Renal failure, circulatory collapse, and death ensue swiftly once the concentration of phosphorus in serum begins to increase. Necropsy discloses metastatic deposits of calcium phosphate in kidneys,~ lungs, stomach, interstitial connective tissue, heart muscle, and arterial walls. The excess of calcium which appears in the blood and is excreted in the urine is derived from the skeleton. The bones arc found markedly decalcified; the bone marrow is hyperemic or hemorrhagic. Repeated daily injections of sublethal quantities of parathyroid hormone produce remarkable resorption of both spongy and cortical bone, with fibrosis and formation of giant-cell tumors. In 1926, Hannon, Shorr, McClellan, and DuBois’ studied a man who had osteitis fibrosa cystica generalisata, an uncommon malady of bone characterized by decalcification, fibrosis, and the formation of multiple cysts and tumors in bone. They were impressed by the similarit,y of the patient’s symptoms to the phenomena described in animals chronically poisoned by injection of parathyroid hormone. By careful studies they were able to show that the physiologic abnormalities exhibited by their patient corresponded in almost every particular to those observed in experimental hyperparathyroidism. These observations were confirmed on the same subject by Bauer, Albright, and Aub.’ A diagnosis of hyperparathyroidism was made, but repeated surgical explorations had to be performed over a period of several years before the hyperfunctioning lesion, a parathyroid adcnoma, could be found and removed. It was found deep in the mediastinum. Credit for providing final proof that this condition was produced by hyperparathyroidism goes to Mandl,l” who first effected a spectacular remission in a patient having osteitis fibrosa cystica by removing a parathyroid tumor. Primary hyperparathyroidism in man may be the result of hyperfunction of tumors of one or more parathyroid glands, or of hyperplasia of ‘fwasserhelle” cells affecting all of them. The cause of either lesion is unknown. Secondary
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hyperparathyroidism. is thought to result from functional hyperplasia of the parathyroids involving chief cells. It occurs in association with rickets, osteomalacia, renal insufficiency, multiple myeloma, and possibly other conditions. The clinical aspects of hyperparathyroidism will be discussed in detail elsewhere. The Site of Action of Parathyroid Hormone.-From the foregoing it is clear that the administration of parathyroid hormone elevates serum calcium, depresses serum phosphorus, increases the renal excretion of both, and drains calcium from the bones. The lack or withdrawal of parathyroid hormone leads to lowered serum calcium, elevated serum phosphorus, reduction of urinary calcium, and increased density of the skeleton. The effects on neuromuscular excitability, the tetany of parathyroid insufficiency and the muscular atony and weakness of hyperparathyroidism, are obviously secondary to the altered concentrations of calcium and phosphorus ions per se. The various other manifestations associated with either state can be regarded with reasonable certainty as secondary to one or another of the primary effects just mentioned. It is generally agreed that the chief if not the sole role of parathyroid hormone is the preservation of the normal concentration of the calcium ions on the body fluids. Much difference of opinion exists as to the mechanism involved. Albright emphasized the chronologic order of events which follows withdrawal or giving of parathyroid hormone. Withdrawal of parathyroid hormone produces the following events, in this order: (1) The excretion of phosphorus (2) The quantity of phosphorus in serum in urine is markedly diminished. increases. (3) The quantity of calcium in serum falls. (4) The quantity of calcium in the urine falls. If one administers parathyroid extract to a normal person, these same four metabolic events are altered in the opposite direction. On the basis of these observations, Albright concluded that the primary effect of parathyroid hormone is on the renal excretion of phosphorus and explained the mechanism as follows: (1) Parathyroid hormone increases the urinary excretion of phosphorus. (2) Increased urinary loss of phosphorus is followed by diminished serum phosphorus. (3) Lowered serum phosphorus would make the serum less saturated with respect to calcium phosphate. (4) According to the rules governing the solubility of this salt, this would permit more calcium phosphate to enter the serum from the gastrointestinal tract or from the skeleton. (5) Addition of calcium phosphate would increase the level of serum cal.cium. (6) The elevated serum calcium would lead to hypercalcinuria. ‘According to this hypothesis, parathyroid hormone does not affect the skeleton directly ; the skeleton yields calcium only when necessary for completion of the changes in chemical equilibria which follow the primary action of the hormone on the kidneys. Other workers have expressed the belief that parathyroid hormone acts primarily to accelerate bone resorption, either by acting on the osteoclasts or by stimulating some other mechanism to this end. According to these workers, the hypothetical sequence of events would be as follows: (1) Parathyroid hormone expedites resorption of bone. (2) Increased calcium from bone elevates
Physiology
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serum calcium. (3) Elevated serum calcium leads to increased urinary excretion As Albright pointed out, however, it is difficult under these hyof calcium. potheses to explain the association of hyperphosphatnria and hypophosphatemia which also occurs. A number of experimental observations, however, indicate that characteristic bone resorption, as well as changes in swum calcium, may follow the injection of parathyroid hormone, even when the kidneys have been removed. It therefore appears that while there is a primary and initial effect of parathyroid hormone on the kidneys, there is also a primary effect on the skeleton as well. The relative importance of these effects in normal man and in discases of the parathyroids remains to be determined by future studies. The solution of this problem is by no means academic, for on it depend the proper interpretation and understanding of the clinical manifestations of parathyroid insufficiency and hyperparathyroidism. On such understanding, in turn, rests the only opportunity for progress in the diagnosis and treatment of parathyroid disease. REFERENCES
Parathyroids-Physiology and Therapeutics, J. A. M. A. 117: 527, 1941. 1. Albright, F.: Pseudo-hypoparathyroidism2. Albright, F., Burnett, C. H., Smith, P. H., and Parson, W.: Syndrome ’ ’ ; Report of 3 Cases, Endocrinology 30: Example of “ Seabright-Bantam 922, 1942. 3. Albright, Fuller, and Strock, M. 9.: The Association of Acalcification of Dentine With Hypoparathyroidism in Rats and the Cure of Same With Parathormone, With Some Correlated Observations in Man, J. Clin. Investigation 12: 974, 1933. 4. Bauer, Walter, Albright, Fuller, and Aub, J. C.: A Case of Osteitis Fibrosa Cystica (Osteomalacia?) With Evidence of Hyperactivity of the Parathyroid Bodies. Metabolic Study II, J. Clin. Investigation 8: 229, 1930. Quoted by Kronfeld, Rudolf, p. 65.8 5. Erdheim, J.: 6. Fleischmann, L.: Quoted by Kronfeld, Rudolf, p. 65.8 7. Hannon, R. R., Shorr, E., McClellan, W. S., and DuBois, E. F.: A Case of Osteitis Fibrosa Cystica (Osteomalaeia?) With Evidence of Hyperactivity of the Parathyroid Bodies. Metabolic Study I, J. Clin. Investigation 8: 215, 1930. 8. Kronfeld, Rudolf: Histopathology of the Teeth and Their Surrounding Structures, ed. 2, Philadelphia, 1939, Lea & Febiger, pp. 504. 9. Lovestedt, S. A.: Personal communication to the author. 10. Mandl,. Felix: Therapeutischer Versuch bei einem Falle von Ostitis fibrosa generalisata mittels Exstirpation eines Epithelkijrperchentumors, Zentralbl. f. Chir. 53: 260, 1926. 11. Pope, Alfred, and Aub, J. C.: The Parathyroid Glands and Parathormone, New England J. Med. 230: 698, 1944. 12. Shelling, D. H.: The Parathyroids in Health and in Disease, St. Louis, 1935, The C. V. Mosby Co., pp. 335. Chemistry of Food and Nutrit,ion, ed. 6, New York, 1941, The Macmillan 13. Sherman, H. C.: Co., pp. 611. 14. Shohl, A. T.: Mineral Metabolism, New York, 1939, Reinhold Publishing Corp., pp. 384.