The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 7 2278-2282
Copyright © 1999 by The Endocrine Society
Who Needs Parathyroid Surgery? The Case for Parathyroidectomy in Nonclassical Primary Hyperparathyroidismb
Henry G. Bone
Michigan Bone and Mineral Clinic at St. John Medical
Center Detroit, Michigan 48236
Gary B. Talpos
Henry Ford Hospital
Detroit, Michigan 48236
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Introduction
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THE clinical spectrum of primary hyperparathyroidism (PHPT) includes not
only patients with the classical clinical presentation, but also many
with nonclassical symptoms, or adverse metabolic effects without overt
symptoms, as well as those with minimal clinical manifestations. Apart
from the direct effects of PHPT on health, even mildly affected
patients may be at increased risk of mortality associated with
cardiovascular disease and malignancies. Parathyroidectomy is the only
effective treatment for this condition and is generally recommended
when clinical sequelae are apparent. Taking into account the subtle
adverse effects of PHPT, the excellent surgical results in experienced
hands, and the difficulty of maintaining follow-up, the weight of
evidence generally favors parathyroidectomy by a skilled surgeon even
in nonclassical cases. If surgery is deferred, vigilant follow-up is
mandatory.
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Classical PHPT
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Primary hyperparathyroidism is a classical endocrine
disorder resulting from adenomatous or hyperplastic glands, which
secrete excess hormone, producing clinical signs and symptoms. For many
years, the diagnosis of primary hyperparathyroidism typically resulted
from the investigation of a symptomatic patient. Classical PHPT is
characterized by frank hypercalcemia and hypercalciuria, often with
phosphate depletion, as well as clinical features such as urolithiasis,
renal injury, and skeletal effects ranging from osteoporosis to
osteitis fibrosa. Gastric hypersecretion with peptic ulcer disease,
pancreatitis, and severe constipation are described, as are psychiatric
disturbances. Surgical cure generally produces gratifying results,
leading to the general recommendation of parathyroidectomy in such
cases of "kidney stones, aching bones, abdominal groans, and psychic
moans."
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The Changing Spectrum of PHPT: Earlier Detection vs. Milder
Disease
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Our perception of PHPT has been radically altered by the
development of automated chemistry panels, including serum Ca
measurements and modern serum PTH assays. What amounts to an
unintentional national screening program has detected many cases of
hypercalcemia. Most are due to primary hyperparathyroidism, confirmed
by elevated or nonsuppressed serum PTH levels. The prevalence of PHPT
in the general population is now estimated to be 1 or more per thousand
(1, 2, 3, 4), and among older women it appears to exceed 1% (3, 4, 5, 6). However,
the number of patients presenting with classical symptoms has not
increased in proportion to the total. Instead, the spectrum of PHPT has
greatly expanded, encompassing patients with classical features who are
detected by screening rather than clinical presentation, patients with
nonclassical symptoms, or physiological sequelae detectable only by
biochemical measurements and bone densitometry, and patients in whom
clinical consequences are minimal or not demonstrable. As this
phenomenon began, it was unclear how many patients would progress to
classical features and how many had intrinsically less aggressive
disease. It was also unclear whether nonclassical or "asymptomatic"
PHPT would impose additional health risks with less apparent
relationship to known PTH effects. Interestingly, a recent study
suggests that the apparent incidence of PHPT, having risen sharply, has
subsequently declined. This may be the result of "sweeping" the
population of prevalent but previously unrecognized cases, but the
authors raise the possibility of a decline in the true incidence (7).
Looking forward, it may be that efforts to reduce the use of automated
chemistry panels will tend to decrease ascertainment of cases in which
overt symptoms are not prominent.
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Is There Progression of Nonclassical PHPT? The Challenge of
Follow-Up
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Can we assess the risk of progression of unoperated mild
asymptomatic PHPT to more classical disease, or perhaps to a decision
point for surgery, without development of overt complications? Although
patients had somewhat reduced initial bone mass (8, 9, 10, 11), and up to 20%
of subjects in some studies had urolithiasis (8, 11), a number of
authors have reported a relatively benign course for most unoperated
nonclassical patients over observation periods of several years (9, 10). In view of the expected lifelong exposure of unoperated patients,
an extremely long observation period would be required to detect low
rates of progression to a more classical clinical profile or gradual
effects on organ function. In some reports of adverse outcomes it is
difficult to isolate the results for those patients with relatively
benign initial presentations (12). Some authors have reported
substantial rates of subtle symptoms and/or incident complications (13, 14). Although overt complications occasionally occur (13), renal
failure and progressively increasing hypercalcemia are infrequent.
Controlled studies describe progressive decreases in bone mineral
density, although results of uncontrolled studies have varied (see
Bone Metabolism below).
An important prospective study of patients with well-defined mild
PHPT conducted at the Mayo Clinic (14) illustrates many of the
challenges of nonoperative management of this condition. Of 147
patients entered into the study, 5 actually exceeded the severity
criteria at entry, 16 had undergone unsuccessful prior surgery,
including 1 who had familial benign hypercalcemia, and in 12 the
diagnosis of PHPT was doubtful, as their abnormal findings resolved
without intervention. Thirty-two died, and 19 were lost or refused
follow-up. Of the 63 previously unoperated subjects with definite PHPT
and known outcomes after 10 yr, 33 had undergone surgery, and 3 more
had reached criteria for referral. Of the remaining 27 patients, 6 had
not completed all the testing specified by the protocol. Another study
followed 174 patients who met the authors’ criteria for asymptomatic
disease (10). The authors did not find evidence of progressive disease,
but stated that only 80 patients had adequate follow-up. Both studies
exemplify the difficulties of long-term monitoring, and the Mayo study
demonstrated a relatively high rate of eventual surgery in those
patients whose follow-up was complete.
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PHPT with Adverse Metabolic Effects in Asymptomatic
Patients
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Bone metabolism. Patients without classical symptoms may well
have adverse metabolic effects of PHPT. Among the best characterized of
these is loss of bone mass. Osteopenia is well-described in studies of
"asymptomatic" PHPT (8, 9, 10, 11). Typically, patients with definite
osteoporosis (defined by clinical fractures or very low bone mineral
density) are excluded from such studies, but most of the included
patients’ bone density measurements nevertheless fall into the lower
half of the pertinent reference ranges. In controlled studies, patients
with PHPT lost bone mass more rapidly than normal subjects (15, 16),
whereas the results of uncontrolled studies have varied (10, 17, 18).
Several groups (9, 19, 20, 21, 22) have found that bone mineral density
increases substantially after parathyroidectomy, although the entire
deficit is generally not repaired. In a small but meticulous
investigation of patients who met strict criteria for asymptomatic
PHPT, Kaplan et al. (21) found subtle but potentially
deleterious abnormalities, correctable by surgery, in all patients
studied. On the whole, the available data indicate unfavorable effects
of expectant management and beneficial effects of surgery on bone
mass.
Renal Effects. Hypercalciuria in PHPT results from the
increased renal filtered load and is corrected by successful surgery,
reducing the risk of urolithiasis and renal injury. The magnitude of
this risk is related to the severity of the hypercalcemia and
hypercalciuria, and would be minimized by the application of strict
criteria for the deferral of surgery. While classical PHPT is clearly
associated with risk of renal failure, impairment of both creatinine
clearance and renal concentrating ability have been well described,
even in patients with relatively mild PHPT and normal serum creatinine
levels (8).
Other Effects. The association of PHPT with hypertension has
been well documented but poorly understood (23, 24, 25). Parathyroidectomy
does not reliably improve hypertension in these patients. It is not
clear whether surgery alters the long-term course of their
hypertension. Must we identify them at an even earlier stage? There is
evidence of impairment of glucose tolerance by PTH. While there is no
well-established link between PHPT and clinical diabetes mellitus (26),
there is evidence of an interaction between serum glucose and calcium
levels and mortality (27). Effects on cardiac function associated with
PHPT have improved after surgery (28, 29, 30, 31), although it may be difficult
to preoperatively estimate the role of PHPT in a particular individual.
Adverse effects on hematopoiesis have been reversed by surgery
(32).
Taken together, the pathophysiologic effects of PHPT generally
favor parathyroidectomy in patients with nonclassical disease, although
the impact in an individual case may be difficult to predict.
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PHPT with non-classical symptoms
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There is considerable evidence that many patients with
nonclassical PHPT have less specific but nonetheless real symptoms.
Such reversible symptoms as lassitude, difficulty with mental
concentration, and mild weakness are well described in classical PHPT.
Similar though more subtle symptoms were detected with symptom
questionnaires in over 90% of patients in a group with predominately
mild to moderate hypercalcemia studied before and after surgery (33).
Most of these patients demonstrated symptomatic improvement after
parathyroidectomy, in contrast to control patients who underwent
thyroidectomy for benign nontoxic disease. These results are similar to
those seen using the SF 36 Health Status Questionnaire pre- and
postoperatively in PHPT patients with mild as well as more severe
hypercalcemia (34). Similarly, psychological symptom distress can be
detected by formal testing and is reduced by surgery (36, 37). In a
small study, post-parathyroidectomy improvement of neuromuscular
function was objectively demonstrated in patients with mild
preoperative hypercalcemia (35). By their very nature it is quite
difficult to predict which less specific symptoms will improve and to
what extent. This makes individual risk-benefit assessments difficult,
but there does appear to be an advantage for surgery for patients as a
group.
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Association of Excess Mortality with PHPT
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An increased risk of death is described in patients with
PHPT, mainly due to cardiovascular disease and cancer. Most studies
have suggested that even after parathyroidectomy, there is a residual
excess risk of mortality (12, 38, 39). Failure to observe this effect
in one large series was attributed by the authors to early surgical
intervention (40). Two population-based Swedish studies have
demonstrated excess long-term mortality in relatively mildly affected
unoperated patients (27, 37, 41). In a large cohort of individuals
identified by population screening for hypercalcemia in Gävle,
Sweden (27, 37), the risk of death for those under 70 yr of age was
about 1.5 times that of matched controls from the same screening group.
Nearly half the survivors failed to remain consistently hypercalcemic
over the 15-yr follow-up period, suggesting that many of the milder
cases may have been over-diagnosed. If so, the relative mortality risk
may actually have been underestimated. This study of unoperated
patients could not evaluate the effect of surgery on mortality. Another
study, following a large group of operated patients (42) with nearly
100% follow-up over an average of 12 yr, found that an excess
mortality rate gradually declined after parathyroidectomy, to about
that of the general population, indicating that successful surgery
eventually ameliorated the excess risk of death in PHPT patients.
Strikingly, this study found a statistically significant mortality
advantage only for the mildly hypercalcemic patients, suggesting that
the greatest benefit might be in those patients for whom surgery is
most likely to be deferred. Based on these studies, it appears that the
magnitude of the potential reduction of long-term mortality by surgery
probably substantially exceeds the extremely low mortality of
parathyroidectomy.
Although American observational/natural history studies have
generally not reported excess mortality, they have not included
concurrent control groups of normal subjects or operated patients. A
study of the Rochester, Minnesota population (43) compared outcomes in
patients with incidentally discovered hypercalcemia with statistics for
white Minnesota residents, adjusted for age and gender. The authors
found an increase in mortality only in the top quartile of patients
ranked by serum calcium. In this quartile 75% of individuals had serum
calcium levels between 11.2 and 11.8 mg/dL, while only 25% were over
11.8 mg/dL. The authors could not demonstrate a clear separation
between higher and lower calcium values as predictors of mortality.
Many clinicians would regard an uncomplaining patient whose serum
calcium level was between 11.2 and 11.8 mg/dL as "asymptomatic" or
"mildly affected". How such patients are classified and treated may
have important implications for outcome.
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Over-Diagnosis and Misdiagnosis
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In clinical practice, over-diagnosis and misdiagnosis of
PHPT are especially problematic in mildly hypercalcemic patients. Even
in the expertly conducted Mayo Clinic prospective study (14), 13
patients’ diagnoses were ultimately regarded as doubtful or incorrect,
leading to the authors’ sensible suggestion that very mildly affected
patients should be followed for at least a year before surgery. It
is increasingly common for patients to be referred for parathyroid
surgery without an endocrinologist’s consultation, often on the basis
of a marginally abnormal serum Ca concentration with an elevated or
nonsuppressed PTH level. If these patients are systematically
evaluated, they are sometimes found to have secondary rather than
primary hyperparathyroidism, and correction of the underlying condition
may result in correction of the calcium and PTH. As described in the
Mayo and Gävle studies, some patients’ laboratory abnormalities
appear to resolve spontaneously. Thus, in patients without demonstrable
symptoms or adverse metabolic effects, it is essential that confounding
diagnoses be excluded, and it may be prudent for surgery to be
recommended only after an adequate observation period.
Of course, any long-term prospective study of PHPT should be
restricted to patients with unambiguous diagnoses, based on persistent
hypercalcemia with normal or nonsuppressed PTH levels, despite
correction of all discernible contributory conditions.
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Surgical Results and Challenges
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Because the surgical trauma is minimal, parathyroidectomy
is generally well tolerated, even by frail elderly patients, and the
operative mortality is extremely low (5, 44, 45, 46, 47). However, the
operation is one of considerable delicacy. Injury to the recurrent
laryngeal nerve may result in transient or even permanent vocal fold
paralysis, but is rare in experienced hands. The variable location of
the parathyroid glands, their small size and inconspicuous appearance
all contribute to the difficulty that may be experienced locating an
adenoma or hyperplastic gland, or especially an ectopic normal gland,
and contribute to the occasional problem of missing glands or (rarely)
inadvertent surgical hypoparathyroidism. The challenge of locating all
abnormal parathyroid glands may be greater in the more subtle
cases.
Preoperative localization procedures using isotopic scanning,
ultrasound, and CT, as well as selective venous sampling, have been
evaluated as aids to the surgeon. Although it is not yet clear that
they have actually improved primary surgical results, the use of these
techniques is increasing, particularly Tc-sestamibi scans (48).
Although results have been impressive in some series, even this
technique has yet to consistently demonstrate reliability equal to the
best surgeons. Unfortunately, such localizing procedures are most
likely to miss exactly those adenomas that are difficult for the
surgeon to find. Their value is most apparent before reoperation for
persistent or recurrent PHPT, when their use is nearly universal (48),
whereas for first operations, the essential localization procedure is
still the identification of an expert surgeon (49).
The probability of surgical success and the risk of surgical
morbidity depend heavily on the surgeon. There are numerous reports of
results from endocrine surgical specialists, but information is more
limited from surgeons who perform parathyroidectomies less frequently.
Expert surgeons generally have performed 100 or more
parathyroidectomies, often performing 25–50 per year. They
should have extremely low operative mortality rates in spite of
operating on a fair proportion of frail patients. They consistently
identify and remove adenomatous or hyperplastic tissue in perhaps 98%
of cases and achieve normal postoperative parathyroid function in about
95% or more. Persistent disease may be related to fifth glands,
inadequate resection for hyperplasia, or an ectopic adenoma that is not
found. Permanent hypoparathyroidism should occur in no more than 1–2%
of patients, and serious complications such as permanent vocal-fold
paralysis are rare. For less experienced surgeons, the likelihood of
persistent disease or complications would be expected to increase in an
inverse relationship to training and experience. Generally,
parathyroidectomies should be referred to surgeons who perform the
procedure with sufficient frequency to maintain a high level of
competence.
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Medical Treatment of PHPT
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We have shown that a medication acting on the calcium
receptor can experimentally depress PTH levels in patients with PHPT
(50). However, such therapy has no immediate prospect of clinical
availability. No other medical treatment controls the underlying
condition. Estrogen can reduce the rate of bone resorption, with a
favorable effect on bone mass, in postmenopausal women with PHPT
(51, 52, 53, 54). However, the available studies have not demonstrated a
long-term overall benefit for estrogen as an alternative to
parathyroidectomy or expectant management. The long-term use of other
potent antiresorptive agents to protect the skeleton in PHPT has not
been adequately evaluated.
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Risks vs. Benefits
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Parathyroidectomy remains the only cure for PHPT. When
performed by an expert surgeon, the risks are minimal and the
probability of success is excellent. The anticipated benefits may be
either improvement of the present condition, prevention of future
complications or both. Surgery is favored without controversy when the
patient is symptomatic or has clinical adverse effects. For patients
who would otherwise develop complications of PHPT, the benefits of
earlier detection and surgical cure surely outweigh operative risks and
morbidity. When the patient is young or has another condition that may
have additive adverse effects, the advantages of surgery have long been
apparent. In nonclassical cases, there is now good evidence for
progressive bone loss without surgery and for improved bone mass after
parathyroidectomy. The evidence indicates that subtle symptoms are very
common in nonclassical patients and are improved by surgery, as are the
adverse physiological effects, which are also common in such patients.
These considerations, together with the evidence for excess long-term
mortality risk even in rather mildly affected unoperated patients,
produce a persuasive argument that the benefits of surgery in expert
hands generally outweigh the risks, even in nonclassical cases. The
risk-benefit balance is harder to estimate when access to
surgery at a high level of skill is not immediate. Obviously,
individual considerations must always be taken into account,
but the remoteness of the benefits and the immediacy of the
risks may result in deferral of surgery in practice to a greater
extent than objective analysis would justify.
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Deferral of Surgery
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It should be understood that deferral of surgery is not a
one-time decision, but rather one that is reviewed and reconsidered
regularly in conjunction with meticulous monitoring. It is only
acceptable in patients without complications, who are carefully
followed to assure that any progression of end-organ effects or
development of a complicating condition is promptly detected. The
difficulties of nonoperation are illustrated by the high rate of
patients lost to follow-up or incompletely evaluated even by
conscientious investigators. These difficulties are further compounded
by patients’ mobility, both geographical and between insurance plans
and health care systems. Depending on the age of the patient, the cost
in time and money for nonoperative follow-up may eventually equal or
exceed that required for surgery. Furthermore, deferral may result in
surgery being performed when a patient is older and in less favorable
general health, after suffering a complication of PHPT, or a
complicating intercurrent condition. These considerations must be
regarded as costs and risks of deferral.
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Summary and Conclusions
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There is little debate about the primacy of surgery in the
management of classical PHPT. Rather, the question has been what to do
about the many patients with nonclassical disease. A 1990 NIH consensus
conference (55) clearly recommended surgery for patients with
significant adverse effects of PHPT, for patients with complicating
coexistent illnesses, for younger patients, and for those in whom
consistent long-term follow-up could not be assured. It allowed that
conscientious surveillance may be justified in patients with minimal
hypercalcemia and no adverse effects, but it recognized that for many
patients, the time and expense involved in rigorous follow-up would
outweigh the burden of surgery. Nine years later, the demonstrated
prevalence of nonclassical symptoms and their reversibility, the
evidence of "asymptomatic" but harmful effects reversible by
surgery, and the accumulating evidence for surgical reduction of
increased long-term mortality risk substantially strengthen the
argument for surgery in such patients. For these reasons,
parathyroidectomy should generally be recommended for patients with a
secure diagnosis of PHPT, even in the absence of classical
symptoms.
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Footnotes
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The authors are grateful to Ms. Cathy
Borawski and Ms. Jennifer Endicott for assistance in manuscript
preparation.
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Introduction
Classical PHPT
