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Persistent Parathyroid Hormone Elevation Following Curative Parathyroidectomy for Primary Hyperparathyroidism
Elizabeth A. Mittendorf, MD;
Christopher R. McHenry, MD
Arch Otolaryngol Head Neck Surg. 2002;128:275-279.
ABSTRACT
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Background Persistent elevation of parathyroid hormone (PTH) levels following parathyroidectomy
may indicate residual abnormal parathyroid tissue.
Objective To determine the clinical significance and risk factors for persistent
PTH elevation following curative parathyroidectomy.
Methods A prospective study of consecutive patients with primary hyperparathyroidism
who had resolution of hypercalcemia following parathyroidectomy. Patients
with low or normal serum calcium and increased PTH levels postoperatively
were identified, and serial calcium and PTH levels and clinical course were
monitored. A multivariate analysis was performed to identify features associated
with an elevated postoperative PTH level.
Results Of 85 patients with resolution of hypercalcemia following parathyroidectomy,
postoperative PTH levels were elevated in 23 (27%) (mean, 99 pg/mL; range,
70-194 pg/mL) and normal in 62 (mean, 30 pg/mL; range, 3-65 pg/mL) (P<.001). No significant differences in preoperative
or postoperative calcium or preoperative PTH levels were found between groups.
Among patients with persistent PTH elevation, 18 had adenoma and 5 had multiglandular
disease, compared with 52 with adenoma and 10 with multiglandular disease
in patients with normal postoperative PTH levels (P>.05).
Multivariate analysis demonstrated that black race and musculoskeletal symptoms
were associated with an elevated postoperative PTH level (P = .01. After an average 16-month follow-up, PTH levels normalized
in 13 patients, decreased in 5, and were unchanged in 2. Three patients were
lost to follow-up.
Conclusions Persistent PTH elevation occurs in 27% of patients following curative
parathyroidectomy and is usually a transient phenomenon more common in patients
with musculoskeletal symptoms and of the black race. It is not a manifestation
of persistent disease but is most likely a secondary response to bone remineralization.
INTRODUCTION
PERSISTENTLY elevated parathyroid hormone (PTH) levels with normocalcemia
have previously been documented following parathyroidectomy for primary hyperparathyroidism.1-7
It has been referred to as postoperative secondary hyperparathyroidism, implying
that it occurs as a result of a compensatory response to an abnormality in
calcium homeostasis.6 However, the pathogenesis
of this phenomenon has not been clearly elucidated. The purpose of our study
was to review our experience with the surgical treatment of primary sporadic
hyperparathyroidism and to determine the frequency of occurrence, clinical
significance, and risk factors for development of persistent postoperative
PTH level elevation following apparently curative parathyroidectomy.
PATIENTS AND METHODS
All patients undergoing parathyroidectomy for primary hyperparathyroidism
between January 1991 and March 2001 were evaluated prospectively. Sex, race,
age, and the presence of symptoms associated with hyperparathyroidism were
determined. Preoperative laboratory evaluations included measurement of serum
PTH, calcium, alkaline phosphatase, phosphorus, serum urea nitrogen, and creatinine.
Serum intact PTH levels were measured using a 2-site immunoradiometric assay
(Cleveland Clinic Foundation Laboratory, Cleveland, Ohio).
Assessed perioperative data included the weight and pathologic characteristics
of the resected parathyroid tissue, postoperative calcium levels, and the
presence of symptoms of hypocalcemia. A serum calcium level was routinely
obtained the morning after surgery. Calcium levels were checked again and
PTH levels measured at the initial postoperative visit, which usually occurred
10 to 14 days after surgery. For patients with elevated postoperative PTH
levels (defined as a PTH level  70 pg/mL), serial calcium and PTH levels
were monitored. All patients were evaluated for symptoms associated with hyperparathyroidism.
Clinical and laboratory data in patients with elevated postoperative
PTH levels were compared with those of patients with normal postoperative
PTH levels to assess what factors might affect PTH levels postoperatively.
Pearson correlations were calculated where indicated. Stepwise logistic regression
analysis with a variable entrance criteria of 0.10 was conducted to identify
demographic factors, laboratory values, symptoms, and pathologic findings
associated with an elevated postoperative PTH level (model  2
= 10.7; P = .01). Analyzed variables included age;
sex; presence of symptoms associated with hyperparathyroidism; preoperative
levels of calcium, PTH, alkaline phosphatase, serum urea nitrogen, and creatinine;
and the weight of the resected parathyroid tissue. A P
value lower than .05 was considered statistically significant. Statistical
analysis was performed using SPSS statistical analysis software (SPSS Inc,
Chicago, Ill).
RESULTS
From January 1991 until March 2001, 85 patients (74 women and 11 men;
average age, 56 years; range, 28-76 years) with primary hyperparathyroidism
underwent curative parathyroidectomies. Their presenting manifestations are
listed in Table 1. Only 13 patients
(15%) were asymptomatic. A bilateral neck exploration was performed in all
patients. Patients with a single or double adenoma were treated by adenoma
excision alone. Patients with parathyroid hyperplasia were treated with subtotal
parathyroidectomy and transcervical thymectomy. Manifestations included adenoma
in 70 patients (82%), double adenoma in 8 (9%), and 4-gland hyperplasia in
7 (8%). The average weight of the resected parathyroid tissue was 1588 mg
(range, 70-13 470 mg). All patients had low or normal calcium levels
postoperatively. Using a Pearson correlation, we demonstrated that the level
of preoperative PTH (0.713; P<.001), calcium (0.461; P<.001), and alkaline phosphatase (0.539; P<.001) were directly correlated with the weight of the excised
parathyroid tissue. Phosphorus level (-0.426; P<.001)
was indirectly correlated with gland weight.
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Table 1. Presenting Manifestations in 85 Consecutive Patients With
Primary Hyperparathyroidism
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Twenty-three patients (27%) were found to have persistent postoperative
PTH elevation with a mean PTH level at the time of their initial postoperative
visit of 99 pg/mL (range, 70-194 pg/mL). This contrasted to a mean PTH level
of 30 pg/mL (range, 3-65 pg/mL) in the 62 patients who had normal PTH levels
at the time of their initial postoperative visit (P<.001). Table 2 summarizes the differences in data
collected for the 2 groups. There was no significant difference in their pathologic
diagnoses. Among patients with persistent PTH elevation, 18 had adenoma and
5 had multiglandular disease compared with 52 with adenoma and 10 with multiglandular
disease in patients with normal postoperative PTH levels (P = .52). There was also no significant difference in the weight of
the resected tissue: 1479 mg (range, 70-13 470 mg) vs 1851 mg (range,
100-8900 mg) in those with persistent elevation and normalization of their
PTH levels, respectively (P = .09). We performed
a multivariate analysis and determined that black race (P = .03) and the presence of musculoskeletal symptoms (P = .08) were associated with an elevated postoperative PTH level (2 = 7.76; P = .002). Women were also more likely
to have an elevated postoperative PTH level, although the likelihood was not
statistically significant(P = .13).
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Table 2. Findings in Patients With Normalized PTH Levels vs Those With
Persistently Elevated PTH Levels Following Curative Parathyroidectomy*
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After an average follow-up of 16 months, 20 patients with an elevated
postoperative PTH level had follow-up data available. All 20 were asymptomatic
and had either normal or low calcium levels: 13 experienced normalization
of their PTH levels; 5 showed a progressive decrease; and 2 showed no change.
Three patients were lost to follow-up. No variable was identified that was
predictive of normalization of PTH. Among the 13 patients with normalization
of their PTH levels, 8 had more rigorous follow-up and were shown to experience
normalization of PTH levels within 1 to 5 months following parathyroidectomy.
The remaining 5 patients had interrupted follow-up and were proven to have
normalization of PTH levels within 1 to 8 years following parathyroidectomy.
COMMENT
The postoperative course following successful surgical treatment of
primary hyperparathyroidism is known to be characterized by a rapid decline
in serum PTH and calcium levels. Most patients experience a profound drop
in PTH levels on the evening of surgery. Many patients develop temporary hypoparathyroidism
with PTH levels lower than 10 pg/mL, a phenomenon that occurs as a result
of "bone hunger" or suppression of the normal parathyroid glands by chronic
hypercalcemia.8 Mandal and Udelsman6 demonstrated that 77 (99%) of 78 patients experienced
a drop in PTH levels on the evening of surgery, 55 of whom had intact PTH
levels lower than 10 pg/mL. Most of these patients had experienced rapid normalization
of calcium homeostasis and parathyroid function by the first postoperative
visit.
In the present series, 23 (27%) of 85 patients undergoing curative parathyroidectomy
for primary hyperparathyroidism had elevated PTH levels postoperatively despite
resolution of their hypercalcemia. These findings confirm the results of other
series where persistent elevation of postoperative PTH levels occurred in
11% to 40% of patients (Table 3).1-7
The pathogenesis of this phenomenon remains unclear. Possible explanations
include persistent or impending recurrent hyperparathyroidism, impaired renal
function, and bone remineralization.
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Table 3. Other Reported Experiences With Postoperative PTH Level Elevation
and Normal Calcium Levels Following Curative Parathyroidectomy*
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PERSISTENT OR IMPENDING RECURRENT HYPERPARATHYROIDISM
Previous reports have demonstrated microscopic hyperplasia in the remaining
parathyroid glands after excision of a single adenoma, suggesting the possibility
of persistent disease as an explanation for the elevated PTH levels.9 No patient in our series with persistent PTH level
elevation and a mean 16-month follow-up developed recurrent hypercalcemia.
In other series as well, hypercalcemia has not occurred in this subset of
patients. McHenry and colleagues10 reported
that patients with elevated postoperative PTH levels and low or normal serum
calcium levels responded to oral calcium load tests exactly as normal control
patients responded, distinguishing postoperative secondary hyperparathyroidism
from persistent hyperparathyroidism. Westerdahl and colleagues7
recently reported that patients who had an elevated PTH level 2 weeks after
surgery had initially experienced a decline in PTH (as measured within four
days after adenoma excision) comparable with patients who had normal PTH levels
2 weeks postoperatively. This finding, combined with the fact that the 2 groups
did not vary in relative PTH suppressibility during an oral calcium load test,
led the authors to conclude that increased postoperative PTH levels were not
likely due to persistent hyperparathyroidism.7
IMPAIRED RENAL FUNCTION
Another proposed cause for persistent elevation of PTH is impaired renal
function. Duh and colleagues1 reported that
their patients with elevated PTH levels postoperatively had significantly
higher serum urea nitrogen and serum creatinine levels than patients with
normal PTH levels. Bergenfelz et al4 reported
that 6 of 13 patients with normal calcium levels and increased PTH levels
1 year following parathyroidectomy for primary hyperparathyroidism had mildly
to moderately decreased renal function. It has also been shown that serum
levels of intact PTH correlate with serum creatinine levels.3
No patient in our series had impaired renal function, and no differences were
observed in serum urea nitrogen and serum creatinine levels between patients
with elevated PTH levels and those with normal PTH levels following curative
parathyroidectomy (Table 2). A
recent study by Westerdahl and colleagues7
showed no difference in renal function, estimated by glomerular filtration
rate and serum creatinine levels, for patients with or without elevated PTH
levels 8 weeks after surgery, suggesting that the PTH levels cannot be explained
by impaired renal function.
BONE REMINERALIZATION
Risk factors for developing postoperative PTH level elevation are also
unclear. Other authors have suggested that it is more likely to occur in elderly
patients with more severe or advanced hyperparathyroidism.4-6
For this reason, we performed a multivariate analysis looking at age, sex,
race, symptomatology, biochemical markers, and gland weight to identify variables
that might be predictive of persistent postoperative PTH level elevation.
In performing this analysis, we found that 85% of our patients had symptoms
that could be attributed to hyperparathyroidism, including 47% with musculoskeletal
symptoms. In our series, we had 8 patients with osteoporosis, 4 patients with
pathologic fractures, and 4 with radiographic evidence of osteopenia. Although
severe musculoskeletal disease is uncommon, multiple studies have shown that
the bone mineral content in patients with primary hyperparathyroidism is consistently
lower than the average for age-, sex-, and race-matched controls.11-13 Although we do not
routinely determine bone mineral content, 5 of our patients had been referred
to us for surgical evaluation because of low bone mineral content.
When we completed our multivariate analysis, we found that the presence
of musculoskeletal symptoms and black race were the only factors associated
with a persistently elevated postoperative PTH level. Other variables accepted
as markers for severity of hyperparathyroidism, such as preoperative calcium
and PTH levels and weight of the resected parathyroid tissue, although higher
in patients with elevated postoperative PTH levels, were not significantly
different from patients with normal postoperative PTH levels (Table 2). We believe that patients with musculoskeletal symptoms
are likely to have significant bone turnover with cortical bone remineralization
in the postoperative period. This results in a compensatory increase in their
PTH secretion to maintain a normal extracellular concentration of ionized
calcium. Westerdahl and colleagues7 documented
decreased bone mineral content and higher serum alkaline phosphatase levels
preoperatively and higher serum levels of osteocalcin and propeptide of type
I collagen in patients with elevated postoperative PTH levels and normal calcium
levels. This finding, along with a significant increase in bone mineral content
postoperatively, suggests that increased bone turnover with cortical bone
remineralization is the cause of this phenomenon.7
The explanation for the higher frequency of postoperative PTH elevation
in blacks is unknown. Of interest is the fact that black subjects are generally
thought to have a higher bone mineral content than age- and sex-matched whites.
In one study addressing bone density in hyperparathyroidism, the control value
for bone density in black subjects was considered to be 110% of the corresponding
value for white control subjects.12 In white
patients with hyperparathyroidism, the initial bone density was below percentile
2.5 of the value for control subjects in 32% of patients and below the mean
in 80% of control patients. In black subjects, the initial bone density was
below percentile 2.5 of the estimated control value in 18% and below the mean
for control patients in 82%.12 The finding
that black race is associated with postoperative PTH elevation cannot be readily
explained by bone remineralization and warrants further investigation.
The elevation in postoperative PTH levels observed in our patients with
normal calcium levels was usually a transient phenomenon. After an average
follow-up of 16 months, PTH levels had normalized in 13 patients, decreased
in 5, and increased or remained unchanged in 2. In a study by Leppla et al,12 bone density was shown to have declined during the
years immediately preceding surgery for hyperparathyroidism and then risen
by 6.4% during the year following surgery, after which it stabilized. Mautalen
and colleagues11 confirmed that the incremental
increase in bone density postoperatively is a limited phenomenon.11 They reported that the average increase in bone mineral
content 9 to 26 months after surgery was 9.9%. No gain was observed 2 years
after parathyroidectomy except in 1 patient with extremely severe bone loss.
Remineralization of bone seemed to reach its near-maximum point within the
first 3 months following curative parathyroidectomy in the study by Mautalen
et al and then stabilized, with very little increase in bone mineral content
after the first year.14 However, Silverberg
et al15 have documented that increases in bone
mineral content can continue for up to 4 years, and compensatory increases
in PTH levels postoperatively have been documented to persist even for 15
years.3
We suspect that the increase in bone mineral content occurs over a limited
time, probably not exceeding 1 to 2 years after surgery. After that point,
further cortical bone remineralization is likely to be minimal; therefore,
an increased need for extracellular calcium no longer exists, and stimulation
of remaining parathyroid glands may decrease, which would correspond to normalization
of PTH levels. This process likely occurs at different intervals postoperatively
in different patients based on the severity of their preoperative bone disease.
However, we were unable to identify any definite factors that would help predict
normalization of PTH levels. Theoretically, oral calcium supplementation may
help resolve this phenomenon by providing the additional calcium necessary
for active bone remineralization.
In conclusion, we have demonstrated that persistently elevated PTH levels
occur in 27% of patients following curative parathyroidectomy. This seems
to be a compensatory response to remineralization of cortical bone. This phenomenon
occurs most commonly in blacks and in patients with associated musculoskeletal
symptoms. It is transient in most patients, resolving within 5 months of surgery.
The time of resolution of postoperative PTH level elevation corresponds to
the period during which the near-maximum increases in bone mineral content
occur in patients with bone disease of hyperparathyroidism. The higher incidence
of musculoskeletal symptoms observed in these patients also supports the notion
that cortical bone remineralization is the cause for the increases in PTH
levels seen in patients with normal calcium levels following parathyroidectomy.
AUTHOR INFORMATION
Accepted for publication August 24, 2001.
This study was presented at the annual meeting of the American Head
and Neck Society, Palm Desert, Calif, May 14-16, 2001.
Corresponding author and reprints: Christopher R. McHenry, MD, Department
of Surgery, MetroHealth Medical Center, 2500 MetroHealth Dr, H920, Cleveland,
OH 44109-1998 (e-mail: cmchenry{at}metrohealth.org).
From the Department of Surgery, MetroHealth Medical Center, Case Western
Reserve University School of Medicine, Cleveland, Ohio.
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