Spectrum of Hyperparathyroidism

ERIC REISS, M.D.

JANET M. CANTERBURY, Ph.D

Miami, Florida

From the Department of Medicine, University of

Miami School of Medicine, Miami, Florida. The

original work reported here was supported in

part by Grant AM-16768 from the National Insti-

tutes of Health, Public Health Service. Requests

for reprints should be addressed to Dr. E. Reiss,

Department of Medicine, University of Miami

School of Medicine, P.O. Box 520875, Biscayne

Annex, Miami, Florida 33 152.

Presented at the Third F. Raymond Keating,

Jr., Memorial Symposium-Parathyroid Hor-

mone, Calcitonin and Vitamin D: Clinical Consid-

erations, Mayo Clinic, Rochester, Minnesota,

September 10-12, 1973.

A new classification of hyperparathyroidism is proposed, based on data obtained by immunoassay of parathyroid hormone (PTH). The customary modifiers “primary,” “secondary” and “tertiary” are avoided because they no longer have precise meaning. The frequency of transition from one form of hyperparathyroidism to another is described as maladaptation to a variety of possible stimulators of PTH secretion. The need for clinical research fo- cused on the antecedents of hypercalcemia is stressed.

Dr. Keating, who contributed so much to our knowledge, would be

pleased with the progress in our understanding of the nature of hy-

perparathyroidism. Since the first F. Raymond Keating, Jr., Memori-

al Symposium [ 11, much new information has been obtained con-

cerning the biosynthesis, chemistry, secretion and metabolism of

parathyroid hormone (PTH) [2-41. Application of the radioimmu-

noassay of circulating PTH to clinical investigation has resolved

some questions but, more interestingly, has raised new questions

that can be approached experimentally with the methods now

available. During the past year, the reasons for the apparently di-

vergent results obtained with various immunoassays of PTH have

been elucidated [ 3-61. As reviewed elsewhere in this symposium,

recognition of the existence of circulating PTH fragments and of the

differences in affinity characteristics of different antiserums has re-

solved much confusion.

Our assignment is to speculate on the nature of hyperparathy-

roidism. This is treacherous under the best of circumstances; it is

especially so in a field that is evolving very rapidly. Despite the

large amount of new information, the available data are not suffi-

cient for the formulation of a firm hypothesis. However, enough is

known to permit reasonable projections.

NOMENCLATURE

A proposed new classification of hyperparathyroidism, based on

immunoassay data combined with recent clinical experience, is

given in Table I. In the future, modifiers such as “primary,” “secon-

dary” and “tertiary” probably should be avoided. These adjectives

have lost their usefulness and now obscure rather than enlighten.

Traditionally, primary hyperparathyroidism was synonymous with

the hypercalcemic form of the disease. Secondary hyperparathy- roidism, by definition, was normocalcemic because it represented a

normal adaptive response to a hypocalcemic stimulus. However, since the pathogenesis of some types of hypercalcemic hyper-

parathyroidism is beginning to be understood, the modifier “pri- mary” is no longer appropriate. Conversely, patients with normo-

calcemic hyperparathyroidism may have undefined abnormalities of parathyroid function and, hence, a “primary” problem [ 13,151. Furthermore, with the passage of time, some patients with hypo-

794 June 1974 The American Journal of Medicine Volume 56

calcemic or normocalcemic hyperparathyroidism be-

come hypercalcemic. Patients with renal disease fol-

low this course with unusual frequency, but hypercal- cemia is also a late result of other forms of normo-

calcemic hyperparathyroidism [ 221. This transition

from normocalcemia to hypercalcemia was formerly

called “tertiary” hyperparathyroidism, a once popu-

lar term now in disrepute. The term may be bad, but

the concept is very important.

Besides simplicity, the proposed classification has

the advantage of suggesting avenues of research

and of therapy. It now appears likely that most forms

of hyperparathyroidism are initiated by some form of

chronic or intermittent stimulation of the parathyroid

glands. What begins as a normal adaptive response

of increased PTH secretion becomes maladaptation

in a few patients. This is evidenced by hypercalce-

mia. With the methods now available, clinical re-

search should be increasingly focused on physiologic

derangements that can lead to long-term stimulation

of PTH secretion. It is now possible by long-range

studies to investigate how commonly the transition

from normocalcemia to hypercalcetiia actually oc-

curs.

Therapeutically, the classification is useful be-

cause hypercalcemia generally requires consider-

ation of surgical therapy. In this respect, changing

patterns of clinical practice are discussed elsewhere

in this symposium. With few exceptions, normocal-

cemic hyperparathyroidism requires either no treat-

ment or medical therapy to remove the stimulus for

increased PTH secretion.

The proposed classification contains no clinical

type of “hyperparathyroidism with bone disease.”

Osteitis fibrosa, the characteristic skeletal abnormali-

ty associated with PTH excess, may occur whenever

PTH secretion is increased. The determinants of the

severity of osteitis fibrosa are largely unknown. Di-

etary influences, particularly vitamin D, are likely to

be very important. PTH influences the metabolism of

vitamin D, and, conversely, vitamin D is required for

PTH to exert its characteristic effect on bone [23-

251. A second determining factor in the development

of bone disease may be the rate of development of

hyperparathyroidism. According to Lloyd [ 261, rapidly

enlarging parathyroid glands are more likely to cause

overt bone disease than are more slowly growing

ones.

SOME SPECIFIC CLINICAL TYPES OF

HYPERPARATHYROIDISM

Nephrolithiasis. Until recently, nephrolithiasis was

the most common type of hypercalcemic hyperpara-

thyroidism. At present, owing to earlier diagnosis,

asymptomatic hypercalcemic hyperparathyroidism is

probably even more common. Recognition of hyper-

SPECTRUM OF HYPERPARATHYROIDISM-REISS, CANTERBURY

TABLE I Classification of Hyperparathyroidism*

Hypercalcemic

Nephrolithiasis [7]

Emotional disturbances [7]

Asymptomatic (81

Peptic ulceration [7,9,10]

Renal disease ill,121

Normocalcemic

Nephrolithiasis j13-151

Renal disease [l&17]

Rickets/osteomalacia 118)

Pregnancy [19]

Dietary 1201

Hypocaicemic

Renal disease (16,171

Pseudohypoparathyroidism [Zl]

* Hyperparathyroidism is defined as any condition as-

sociated with persistently increased levels of circulating

PTH. This list is likely to be incomplete; with advancing

knowledge it will enlarge. Only some forrns ot hyperpara-

thyroidism are discussed in the text. Note that renal disease

appears in all three categories.

calcemic hyperparathyroidism associated with

nephrolithiasis is particularly important because cura-

tive surgical treatment decreases the rate of stone

formation [ 271. The generally accepted pathogene-

sis of stone formation in patients with hyperparathy-

roidism is that hypercalcemia causes hypercalciuria

which, in turn, promotes stone formation.

In the population of patients who have calcium

stones, hypercalcemia is rare. By contrast, the syn-

drome of idiopathic hypercalciuria is common; it oc-

curs in roughly one third of patients with nephrolithi-

asis as well as in many asymptomatic subjects [ 281.

A distinguishing feature of the syndrome is persistent

normocalcemia. In a study of 40 consecutive patients

with nephrolithiasis who had the syndrome of idio-

pathic hypercalciuria, Coe et al. [ 151 documented

some increase in serum PTH in roughly two thirds of

the patients. Those with higher average calcium ex-

cretions tended to have higher serum PTH levels. Treatment with thiazide diuretics abolished the hyper-

calciuria and decreased the serum PTH levels toward normal (Figure 1). In patients with normal serum PTH

values, thiazide therapy did not affecl serum PTH (not

illustrated).

Although the mechanism of hyperparathyroidism in

some patients with idiopathic hypercalciuria is not

fully understood, the studies of Coe et al. [ 151

suggest that excessive urinary calcium excretion triggers increased PTH secretion. When hypercalci-

uria was induced in normal subjects by volume ex- pansion and furosemide administration, serum PTH

increased to a range commonly observed in patients with idiopathic hypercalciuria (Figure 2). A hypocal-

cemic stimulus for PTH secretion was not docu-

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SPECTRUM OF HYPERPARATHYROIDISM-REISS, CANTERBURY

mented, presumably because serum calcium was not

measured sufficiently frequently.

These studies provide the background for an alter-

native explanation of hypercalcemic hyperparathy-

roidism with nephrolithiasis. Idiopathic hypercalciuria

is a very common abnormality [28]. If the patients of

Coe et al. were representative of the population of

patients with idiopathic hypercalciuria, large numbers

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TIME IN MONTHS Figure 1. Effects of thiazide treatment on urinary calci- um excretion, serum PTH and serum calcium concentra- tion in patients with idiopathic hypercalciuria and increased PTH. Symbols denote individual patients. Urinary calcium excretion decreased in each patient, generally reaching normal values. Serum PTH levels reached normal or near normal values in all but one patient. From Coe et al. [ 151, by permission of the American Society for Clinical Investi- ga tion.

of persons experience chronic stimulation of the

parathyroid glands. One would then expect that a

small fraction of chronically stimulated parathyroid

glands escape from the normal feedback control.

This maladaptation expresses itself as hypercalce-

mia. According to this formulation, hypercalcemia is

at times a result of hypercalciuria rather than its

cause. There is an obvious need for much additional infor-

mation. For example, if hypercalciuria can result in

hypercalcemic hyperparathyroidism, urinary calcium

excretion should return to abnormally high levels

after a successful parathyroidectomy. We are not

aware of any systematic long-range studies of uri-

nary calcium excretion after parathyroidectomy for

150 f- 1

CONTROL FUROSEMIDE

TIME IN DAYS Figure 2. Effects of furosemide-induced hypercalciuria on serum PTH, total and ionized calcium concentrations, and urinary calcium excretion in normal subjects. Urinary calcium excretion is shown for each subject as mean f standard error for 3 consecutive control days and days 7, 8 and 9 of furosemide administration. Serum PTH values are single determinations for each patient. Serum calcium concentrations are shown as mean f standard error for all four subjects during control and experimental periods. B.W. = body weight. From Coe et al. [15], by permission of the American Society for Clinical Investigation.

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SPECTRUM OF HYPERPARATHYROIDISM-REISS. CANTERBURY

hypercalcemic hyperparathyroidism with nephrolithi- asis. Emotional Disturbances. These are common in hy- percalcemic hyperparathyroidism. Albright consid- ered them a complication of hypercalcemia and be- lieved that restoration of normocalcemia by curative surgical treatment restored emotional equilibrium. Our experience, anecdotal only, is different. To be sure, many patients with hypercalcemic hyperpara- thyroidism are emotionally disturbed but most remain so after cure of the hypercalcemia. Critical evalua- tion of the clinical evidence is difficult because most follow-up studies are short-term. Hence, the placebo effect of an operation in an emotionally unstable per- son is difficult to evaluate.

A possible physiologic basis for the association between emotional instability and hyperparathyroid- ism has been provided by the studies of Fischer and his colleagues [29]. They reported that catechol- amines are potent stimulators of PTH secretion. This effect appears to be mediated without a concomitant

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30 40 50 60 70 80

EFFLUENT VOLUME Figure 3. Fractionation of pooled serums from patients with parathyroid adenoma before and during intravenous calcium infusion. Although peak I (glandular hormone) de- creased during the infusion, the rate of decrease was small and distinct/y different from that observed in patients with hyperplasia (Figure 4). From Canterbury and Reiss [4], by permission of the Society for Experimental Biology and Medicine.

change in the concentration of divalent cations. Al- though it obviously is premature to extrapolate from animal studies to the clinical situation, the temptation is irresistible. The emotionally disturbed patient, re- peatedly subjected to stress, may experience fre- quent episodes of catecholamine-stimulated in- creased secretion of PTH. In a small number of per- sons so affected, the control system may fail so that hypercalcemia ensues. Here again, the possibility ex- ists that the accepted cause and effect relationship in fact operates in the reverse direction. Asymptomatic Hyperparathyroidism. Hypercalce- mic hyperparathyroidism without symptoms, once

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Figure 4. Fractionation of pooled serums from patients with primary hyperplasia of the parathyroids before and during intravenous calcium infusion. The base line pattern is similar to that obtained in patients with a single adeno- ma. Peak I (glandular hormone) disappeared during the infusion. From Canterbury and Reiss 1441, by permission of the Society for Experimental Biology and Medicine.

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SPECTRUM OF HYPERPARATHYROIDISM-REISS, CANTERBURY

considered a rarity, is now commonplace. Consid- ering the frequency of emotional problems in the population at large, it is possible that some or a large fraction of these patients are really in the category just discussed. Others may represent instances of maladaptation to undiagnosed preexisting hypercalci- uria. Under any circumstance, asymptomatic patients provide an extraordinary challenge to the clinician. Careful, long-term observations may provide clues to etiology. Peptic Ulcer. Hypercalcemic hyperparathyroidism with peptic ulcer disease probably represents a clini- cal type that is a fundamentally different disease from all others. The predominant evidence indicates that most patients with hypercalcemic hyperparathy- roidism have no greater propensity to peptic ulcer- ation than do euparathyroid subjects [9]. An excep- tion to this statement is the occurrence of both hy- perparathyroidism and peptic ulceration in some mul- tiple endocrine adenomatosis syndromes [30]. Re- view of this complex problem is beyond the scope of this discussion, but it is likely that, in these syn- dromes, peptic ulceration and hyperparathyroidism are causally related or that both problems are caus- ally related to other genetic or metabolic distur- bances characterizing the syndromes. A distinctive feature of the hyperparathyroidism of the multiple en- docrine adenomatosis syndrome is the frequency with which more than one parathyroid gland is en- larged. All that matters in this context is that this form of hyperparathyroidism is pathogenetically and clini- cally distinct from the other types.

AUTONOMY, ADENOMA AND HYPERPLASIA

Urgently needed is information concerning the transi- tion of normocalcemic to hypercalcemic hyperpara- thyroidism. This could be readily obtained if there were a clear differentiation between parathyroid function that subserved adaptive needs and parathy- roid function that was clearly maladaptive. Adeno- mas were once believed to function autonomously whereas hyperplastic glands were believed to be suppressible by exogenous hypercalcemia [ 3 11. However, at the first Keating Symposium, Potts and his colleagues [32] reported some suppression of

PTH secretion with intravenous calcium infusions in all patients with hyperparathyroidism studied by them. This has been confirmed by subsequent data. When suppressibility of parathyroid function is tested, polyvalent antiserums possessing recognition sites for glandular hormone as well as its circulating frag- ment can yield misleading results [4]. This is illus- trated in Figures 3 and 4, which show the results of fractionation studies before and during an intrave- nous calcium infusion in patients with parathyroid ad- enomas and patients with parathyroid hyperplasia [4]. In Figure 3, glandular hormone (peak I) was sup- pressed slowly but definitely during the course of the calcium infusion. In patients with hyperplasia (Figure 4) this suppression was more rapid and complete, but comparison of these figures shows that the dif- ference is one of degree rather than of kind. Thus, suppression of PTH secretion by a calcemic stimulus is highly variable and probably represents a contin- uum ranging from a high degree to slight responsive- ness.

Classification of hyperparathyroidism according to histologic criteria has proved increasingly unsatisfac- tory [33]. The clear-cut criteria for differentiating be- tween adenoma and hyperplasia no longer appear to be applicable in many patients. The probable reason for this failure of classification by histologic type is the changing spectrum of hyperparathyroidism en- countered in current clinical practice; the disease is recognized and often treated surgically in earlier stages. Under the circumstances, it is probably best to characterize the disease in specific patients des- criptively. Thus, the old nomenclature of “primary hy- perparathyroidism due to an adenoma” could be sup- planted by “hypercalcemic hyperparathyroidism; one enlarged gland, three normal glands.”

The failure of the concept of autonomy and of pathologic categorizations provides support for the classification of hyperparathyroidism given in Table I. The serum calcium concentration is, after all, the dis- tinguishing feature between adaptation and maladap- tation. Combined with the radioimmunoassay of PTH, the serum calcium concentration provides all the crit- ical laboratory information that is needed for a prag- matic approach to hyperparathyroidism.

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