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Prevalence of Monoclonal Gammopathy in Patients With Primary Hyperparathyroidism
A Prospective Study
Bertrand Arnulf, MD;
Djaouida Bengoufa, MD;
Emile Sarfati, MD;
Marie-Elisabeth Toubert, MD;
Véronique Meignin, MD;
Jean-Claude Brouet, MD, PhD;
Jean-Paul Fermand, MD
Arch Intern Med. 2002;162:464-467.
ABSTRACT
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Background The association between primary hyperparathyroidism (PHPT) and monoclonal
gammopathy has been reported, but whether it is fortuitous remains unsettled.
We conducted a prospective study to determine the prevalence of monoclonal
gammopathies in patients with surgically proved PHPT.
Methods In 101 consecutive patients with PHPT, serum immunoglobulins were systematically
studied using agarose gel electrophoresis and immunofixation before and, when
appropriate, after parathyroid surgery. The PHPT population was compared with
a control series of patients with other diseases requiring surgery and with
a group of patients with benign disease of the thyroid gland matched for age
and sex to the PHPT population.
Results Monoclonal immunoglobulin was detected in 10 (10%) of 101 patients with
PHPT (including 2 with multiple myeloma) compared with 2 (2%) of 127 patients
who underwent other surgery (P = .005) and 3 (3%)
of 101 patients with benign thyroid diseases (P =
.04).
Conclusions The prevalence of monoclonal gammopathies is high in patients with PHPT.
At minimum, sensitive serum protein electrophoresis should be performed routinely
in all patients with PHPT. Conversely, in patients with monoclonal gammopathy
who have hypercalcemia but no other symptoms of progressive disease, clinicians
must seek PHPT.
INTRODUCTION
MONOCLONAL gammopathy may be detected in the absence of any overt lymphoid
disorder, defining the so-called monoclonal gammopathies of undetermined significance,
or in association with B-cell malignancies, mostly multiple myeloma and Waldenström
macroglobulinemia. The prevalence of monoclonal gammopathies, which is about
1% in the general adult population, increases with age and with some pathological
conditions, particularly in patients with hepatitis C virus infection, in
whom it may exceed 10%.1
Primary hyperparathyroidism (PHPT) is also a relatively frequent disease.
The introduction of automated serum calcium measurements in the 1970s greatly
modified the prevalence and the clinical spectrum of this condition. Primary
hyperparathyroidism affects approximately 1 in 10 000 persons, most of
whom have an asymptomatic and uncomplicated disease identified because of
the fortuitous discovery of a mild increase in the serum calcium level.
The association of monoclonal gammopathies with PHPT is mentioned in
current medical textbooks.2 It was first described
in 1964 in a patient with monoclonal gammopathies of undetermined significance
in whom the monoclonal immunoglobulin (MIg) disappeared after surgical resection
of a parathyroid adenoma, suggesting a possible link between the 2 conditions.3 However, no similar postoperative outcome was observed
in any of the additional cases that were published. Therefore, the association
between the 2 disorders is still controversial.4-11
This prompted us to prospectively evaluate the prevalence of monoclonal gammopathies
in patients with surgically proved PHPT.
PATIENTS AND METHODS
PATIENTS
Between June 1, 1997, and June 1, 1998, all consecutive patients referred
to the Department of Surgery, Hôpital Saint-Louis, Paris, for treatment
of PHPT were included in the study. Patients who underwent surgery because
of hyperparathyroidism secondary to renal insufficiency were not included.
All studied patients had hypercalcemia (reference range, 8.80-10.40 mg/dL
[2.20-2.60 mmol/L]) with an inappropriately elevated serum parathyroid hormone
level (>60 pg/mL [6.3 ng/L] by intact hormone radioimmunoassay). Surgical
exploration of the 4 parathyroid glands, with standard histopathological analysis
of removed tissue, was performed in all patients. After the surgical procedure,
follow-up letters requesting information and a serum sample were sent to all
patients with MIg and their physicians.
The prevalence of MIg in the PHPT population was compared with that
in 2 control groups: the surgical group included patients without features
of PHPT selected at random among patients older than 40 years in the same
surgical department, and the thyroid group was selected among patients who
were diagnosed in the nuclear medicine department of the hospital as having
a thyroid tumor. This was either a toxic adenoma or a cold nodule with no
cytological criteria for malignancy. In the thyroid group, patients were matched
1 to 1 for sex and age with patients with PHPT. In both control groups, patients
with known hematological disorders, previous chemotherapy, or chronic liver
diseases were excluded. All patients gave informed consent.
STUDY OF IMMUNOGLOBULINS
Serum specimens were obtained from all patients in the PHPT group before
the surgical procedure and from all patients in each control group and were
studied using electrophoresis of proteins on agarose gel (Paragon SPE; Beckman
Coulter Inc, Fullerton, Calif) and using immunofixation to detect the MIg
component (Paragon IFE; Beckman Coulter Inc).
STATISTICAL ANALYSIS
The prevalence of monoclonal gammopathies in patients with PHPT was
compared with the prevalence of MIg in the surgical and thyroid groups using  2 analysis or the Fisher exact test. P<.05
was considered statistically significant.
RESULTS
Serum samples from 101 patients (72 women and 29 men) with PHPT were
studied. There were 3 black patients, and the remainder were white. The median
patient age was 58 years (range, 30-92 years), and 14 were older than 70 years.
Two patients had a familial or personal history that might suggest multiple
endocrine neoplasia type I.12 The preoperative
highest serum calcium level varied between 10.44 and 14.00 mg/dL (2.61 and
3.50 mmol/L) (median, 12.00 mg/dL [3.00 mmol/L]). Parathyroid hormone levels
were between 60 and 1030 pg/mL (6.3 and 108.5 ng/L) (median, 200 pg/mL [21.1
ng/L]). Histological analysis of removed parathyroid tissues showed a solitary
adenoma, multiple adenomas, and a diffuse proliferation of chief cells suggestive
of hyperplasia in 96 (96%), 3 (3%), and 2 (2%) patients, respectively.
Serum MIg was detected in 10 (10%) of 101 patients. The main characteristics
of these patients are given in Table 1.
None of these patients had evidence of liver disease, chronic viral infection,
or any other nonhematological conditions. Serologic test results for hepatitis
B and C and human immunodeficiency virus infection were negative in all cases.
Complete blood cell counts were always normal. The monoclonal protein produced
a detectable narrow band on electrophoretic screening in 7 patients, whereas
the MIg was detected by immunofixation only in 3. The serum level of polyclonal
immunoglobulins was within reference limits in all patients but 2. In these
2 patients, stage I indolent multiple myeloma was diagnosed because bone marrow
smears showed abnormal plasma cells, whereas bone radiographs did not disclose
any lytic lesions. The 8 remaining patients had monoclonal gammopathies of
undetermined significance, according to Southwest Oncology Group criteria.13 A control serum immunoglobulin study was performed
within 3 months or more after the surgical procedure in 5 patients and showed
the persistence of the MIg in all.
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Clinical, Laboratory, and Histological Features of Patients With Monoclonal
Immunoglobulin and Primary Hyperparathyroidism
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The surgical control group comprised 127 patients (66 women and 61 men),
with a median age of 60 years (range, 40-78 years). Sixty patients (47%) had
a solid tumor. Two patients (2%) had serum MIg, which was detectable on electrophoretic
screening in only 1. In both patients, the isotype of the monoclonal components
was IgG . Associated pathological conditions were thyroid carcinoma
in 1 patient and a myxoid muscular tumor in the other.
The age- and sex-matched thyroid control group comprised 101 patients
(median age, 56 years; range, 32-89 years), of whom three-quarters had a toxic
nodule, either unique or within a multinodular goiter. All others had cytologically
benign cold thyroid nodules. In this group, 3 women aged approximately 60
years with toxic multinodular goiters had an MIg (2 IgG and 1 IgA)
that was detected only by immunofixation.
The prevalence of monoclonal gammopathies in patients with PHPT and
in control patients was significantly different; comparing the PHPT group
with the surgical group and thyroid group, P .005
(10% vs 2%) and P.04 (10% vs 3%), respectively.
COMMENT
The prevalence of monoclonal gammopathies in the population of healthy
or hospitalized adult patients has been estimated to be approximately 1% by
several large analyses of electrophoretic data performed in Sweden, Italy,
the United States, and France.14-16
This prevalence increases with patient age and varies according to sex and
race, being higher in men than women and in black patients than white patients.17 In a recent large US study18
using agarose gel electrophoresis and immunofixation, the frequency of a monoclonal
protein in healthy individuals older than 70 years was 6.1% (3.8% in white
subjects and 8.4% in black subjects). Frequency can reach nearly 15% in persons
older than 90 years.19 In contrast, the prevalence
of MIg in persons younger than 50 years is low (approximately 0.2%).20
The present study reports a prevalence of monoclonal gammopathies of
10% in a series of consecutive patients with PHPT. This high prevalence is
all the more striking because most of these patients were white and two thirds
were female. In addition, their median age was younger than 60 years, as expected
for patients with PHPT.21-22 All
patients but 1 with MIg were women. One patient was very young (32 years old),
whereas 4 (of the 14 patients of the series) were older than 70 years.
The prevalence of MIg in patients with PHPT was significantly higher
than that of a control population randomly selected among patients who underwent
surgery for various reasons. Compared with a healthy population, the frequency
of MIg in this group (2%) was probably slightly high, but many patients, including
the 2 with MIg, had a nonhematological solid tumor, a condition that might
be associated with an increased frequency of monoclonal gammopathies.23 The prevalence of MIg in the PHPT population was
also significantly higher than that in the thyroid control group, which was
more suitable than that in the surgical control group because this group was
matched for age and sex and selected among patients with another cervical
disorder, namely, a thyroid tumor. In addition, patients in the thyroid group
had benign tumor, in most cases toxic adenoma.
Two previous studies,6, 8
conducted in the 1970s, addressed the issue of the frequency of monoclonal
gammopathies in patients with PHPT. Johansson and Wermer6
reported MIg in 6 (2%) of 350 patients, and Mundis and Kyle8
found a prevalence of MIg of 1% in a series of 911 patients older than 50
years with surgically proved parathyroid adenoma. Both studies were retrospective;
the first study did not include systematic laboratory tests for immunoglobulins,
whereas the second was based on eventual reexamination (if the  - or  -globulin
levels were above the reference limits) of previously performed electrophoretic
cellulose acetate strips. Serum immunoelectrophoresis was performed only when
the electrophoretic data showed a pattern suggesting monoclonal gammopathy.
The present study was prospective and used a more sensitive approach
for serum MIg detection by combining agarose gel electrophoresis with immunofixation.
These methodological differences likely explain the higher prevalence of MIg
in our series. Indeed, because of its low level, the MIg would have been missed
in at least 3 of our patients if only standard electrophoresis had been used.
Urine proteins were not systematically studied, which could have led to detection
of additional monoclonal gammopathies characterized by the presence of immunoglobulin
monoclonal light chains only, as in 4 patients reported in the literature.24
This study has several limitations. First, the sample size should have
been larger to definitely rule out a chance association between monoclonal
gammopathies and PHPT. In addition, the prevalence of PHPT in patients with
monoclonal gammopathies of undetermined significance or myeloma was not determined.
Of note, PHPT may not be rare because 10 patients referred to the Department
of Immuno-Hematology, Hôpital Saint-Louis, during the past 3 years for
MIg and hypercalcemia in fact had PHPT (B.A. and J.-P.F., unpublished data,
2000). Another possible limitation of this study is that patients referred
for surgery may not be representative of the entire spectrum of patients with
PHPT. However, the present PHPT population was similar to the large series
of PHPT reported in the literature,21-22
particularly with regard to age and serum calcium level. Indeed, in our area,
and as recently proposed,25 parathyroidectomy
is usually considered in most patients with PHPT, whether they are symptomatic
or not.
The relationship between monoclonal gammopathy and PHPT remains speculative.
Soluble factors secreted by one type of tumor cell (or their environment)
may trigger the growth of the other tumor population. For instance, the MIg
may act as a growth factor for the parathyroid cells, as does the IgG so-called
thyroid-stimulating immunoglobulin on thyroid cells in Basedow disease.26 To test this hypothesis, we performed immunofluorescence
studies on parathyroid tissue sections, but, like Dexter et al,5
we found no binding of immunoglobulin, including on adenoma sections derived
from patients with MIg (data not shown). Alternatively, parathyroid hormone
stimulates stromal-osteoblastic cells to secrete interleukin 6,27
and patients with PHPT have high circulating levels of interleukin 6.28 Because this cytokine plays a key role in the development
of plasma cell dyscrasias,29 high parathyroid
hormone levels may facilitate the emergence and growth of a plasma cell clone.
The latter possibility may argue in favor of systematic parathyroid
surgery in all patients with PHPT and monoclonal gammopathy in an attempt
to limit the risk of development of overt myeloma. However, because clearing
of MIg seems to be rare after parathyroidectomy, the discovery of MIg in a
patient with PHPT cannot be presently considered as a strong argument for
surgery. In any case, the prevalence of the association of monoclonal gammopathy
and PHPT may justify the systematic study of serum immunoglobulins in patients
with PHPT. Such study may lead to the discovery of multiple myeloma, as in
2 patients of our series. Finally, our experience indicates that in patients
with MIg who have an elevated serum calcium level but no other symptoms of
a progressive disease, PHPT must be sought.
AUTHOR INFORMATION
Accepted for publication July 12, 2001.
We thank Paul Landais, MD, Department of Biostatistics, Necker Hospital,
Paris, France, and Vincent Levy, MD, Department of Biostatistics, Saint-Louis
Hospital, for helpful discussions, and Muriel Bargis-Touchard for secretarial
assistance.
Corresponding author and reprints: Jean-Paul Fermand, MD, Service
d'Immuno-Hématologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux,
75475 Paris, Cedex 10, France (e-mail: jpfermand{at}yahoo.fr).
From the Service d'Immuno-Hématologie (Drs Arnulf, Brouet, and
Fermand), Laboratoire d'Immuno-Histocompatibilité (Dr Bengoufa), Service
de Chirurgie Viscérale (Dr Sarfati), Service de Médecine Nucléaire
(Dr Toubert), and Service d'Anatomopathologie (Dr Meignin), Hôpital
Saint-Louis, Paris, France.
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