ORIGINAL ARTICLE
ELEVATED PARATHYROID HORMONE LEVELS AFTER
PARATHYROIDECTOMY FOR PRIMARY
HYPERPARATHYROIDISM
Aviram Mizrachi, MD, Hanna Gilat, MD, Gideon Bachar, MD, Raphael Feinmesser, MD,
Thomas Shpitzer, MD
Department of Otorhinolaryngology-Head and Neck Surgery, Rabin Medical Center, Beilinson Campus,
Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. E-mail: thomas-s@zahav.net.il
Accepted 9 February 2009
Published online 29 April 2009 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/hed.21119
Abstract: Background. Curative parathyroidectomy is associated with elevated levels of parathyroid hormone (PTH) with
eucalcemia. This study sought to determine the frequency,
clinical significance, and risk factors of this finding.
Methods. Seventy-six consecutive patients surgically
treated for primary hyperparathyroidism due to a single parathyroid adenoma in 2006 to 2007 were monitored for 1 month
postoperatively; those with elevated PTH levels (>70 pg/mL)
were monitored for 18 months.
Results. Nineteen patients (25%) had high postoperative
PTH levels with normal calcium levels. Compared with the
remaining patients, this group had a significantly higher average preoperative PTH level (224.89 vs 156.86 pg/mL) and a
lesser intraoperative decrease in PTH.
Conclusions. About 25% of eucalcemic patients may have
elevated PTH levels after parathyroidectomy. A high preoperative PTH level (>225 pg/mL) may predict a persistently high
postoperative level. Evaluation of blood and urine calcium,
bone density, and cardiac function should be considered in
C 2009 Wiley Periodicals, Inc. Head Neck
affected patients. V
31: 1456–1460, 2009
Keywords: primary hyperparathyroidism; parathyroid hormone;
parathyroidectomy; calcium, bone turnover
Correspondence to: T. Shpitzer
C 2009 Wiley Periodicals, Inc.
V
1456
Elevated PTH Following Parathyroidectomy
Parathyroidectomy
for primary hyperparathyroidism is reportedly associated with elevated
postoperative parathyroid hormone (PTH) levels in the presence of normal calcium levels in
up to 40% of cases.1 Suggested reasons for this
finding include vitamin D deficiency,2,3 kidney
resistance to PTH-mediated 1-alpha hydroxylation of 25-hydroxyvitamin D(3) [25(OH)D(3)],4
and decreased renal and peripheral sensitivity
to PTH.5,6 Mittendorf et al7 proposed that a
persistent postoperative elevation in PTH most
likely represents a secondary response to cortical bone remineralization (‘‘bone hunger’’),
which causes compensatory secretion of PTH
in order to maintain a normal serum calcium
concentration. Westerdahl et al8 documented
higher preoperative serum alkaline phosphatase levels in patients with elevated postoperative PTH levels. They suggested that the
increase in PTH was a transient effect of
diminished calcium absorption and increased
bone turnover.8
The possibility of residual parathyroid disease due to incomplete adenoma excision has
been noted as well.9 The available data fail to
HEAD & NECK—DOI 10.1002/hed
November 2009
Table 1. Presenting symptoms of 76 patients with primary hyperparathyroidism due to a single parathyroid adenoma.
Symptom
Osteoporosis/bone pain
Nephrolithiasis/nephrocalcinosis
Weakness/fatigue
Peptic disease
Brown tumor
No symptoms*
Total, N ¼ 76
Elevated PTH, N ¼ 19
Normalized PTH, N ¼ 57
36
16
9
3
1
21
7 (36%)
2 (10%)
4 (21%)
–
1
5 (26%)
29 (50%)
14 (24.5%)
5 (8%)
3
–
16 (28%)
*Asymptomatic hypercalcemia.
support any one of these theories over the
others, and the issue remains controversial.
The purpose of this study was to determine
the frequency of occurrence of elevated PTH levels following curative parathyroidectomy at a
single major tertiary center and to evaluate its
clinical significance and risk factors.
PATIENTS AND METHODS
We reviewed the clinical data of all patients
with primary hyperparathyroidism who underwent parathyroidectomy at the Department of
Otorhinolaryngology and Head and Neck Surgery of Rabin Medical Center between January
2006 and January 2007. Only patients with a
solitary adenoma were included. All patients
were evaluated preoperatively by the same diagnostic routines, including laboratory measurement of serum calcium and PTH levels,
ultrasonography, and technetium 99m sestamibi
scan. Surgery was performed by a skilled and
experienced team with the aid of frozen-section
biopsy study. Intraoperative PTH was tested in
4 blood samples drawn before and after the
patient was anesthetized and 15 and 20 minutes
after adenoma excision. Resection was considered successful if the intraoperative PTH level
decreased by 50% or more and was within the
normal range (<70 pg/mL). Blood samples for
calcium levels were drawn routinely 1 day after
surgery and before discharge. Blood sampling
for PTH and calcium levels was repeated at the
outpatient follow-up evaluation performed 4 to
6 weeks later by the attending endocrinologist.
Patients found to have an elevated PTH level at
that time (>70 pg/mL) underwent further monitoring for 12 months.
The following data were collected from the
medical files for purposes of the study: patient
age and sex, preoperative serum creatinine and
bone mineral density, preoperative and postoperative calcium, alkaline phosphatase, 25(OH)
Elevated PTH Following Parathyroidectomy
D, and PTH levels, presenting symptoms, intraoperative PTH levels, and postoperative
complications.
The study was approved by the Institutional
Review Board.
For statistical analysis, continuous variables
were expressed as means standard deviations.
Between-group differences were assessed by
paired t test. The significance level was set at p
< .05. Data were analyzed with SPSS software,
version 16.
RESULTS
Eighty-six patients were treated by parathyroidectomy for primary hyperparathyroidism during the study period. Of these, 10 were excluded
from the present analysis because they had a
double adenoma (n ¼ 6, 8.1%) or 3 or 4 hyperplastic glands (n ¼ 4, 4.6%).
Of the 76 patients with a single adenoma, 19
(25%) had an elevated PTH level at 1 month after surgery (mean, 107.74 pg/mL; range, 70–226
pg/mL) and 57 had a normal PTH value (p <
.0001).
Calcium levels measured 1 day after surgery
were normal in all patients, with no significant
difference between the elevated and normalized
PTH groups (p ¼ .131). No changes were noted
in calcium levels at 1 month follow-up.
During the 12-month follow-up of the 19 elevated PTH group, PTH levels remained high in
16 patients and decreased to normal range in 3.
At an average of 18 months’ follow-up, PTH levels remained high in 13 patients and decreased
to normal range in 6. There was no change in
serum calcium levels for all 19 patients.
Table 1 shows the presenting symptoms in
the patients with elevated and normalized PTH
levels postoperatively.
Analysis of the preoperative PTH levels
showed that the mean (SEM) peak PTH was
significantly higher in the patients who had
HEAD & NECK—DOI 10.1002/hed
November 2009
1457
Table 2. Comparison of patients with elevated or normalized PTH following parathyroidectomy.
Feature
Elevated PTH, N ¼ 19
Normalized PTH, N ¼ 57
54.7
56.3
2 (10.5%)
17 (89.5%)
26%
14 (24.5%)
43 (75.5%)
28%
11.71
86.15
224.89
0.86
1.24
11.45
93.78
156.86
0.74
1.62
Age, y
Sex
Male (%)
Female (%)
Asymptomatic, %
Preoperative laboratory
Calcium, mg/dL
Alkaline phosphatase, IU/L
PTH, pg/mL
Serum creatinine, mg/dL
Bone mineral density*
Intraoperative PTH
Endpoint, pg/mL
Decline, %†
Postoperative laboratory findings‡
Calcium, mg/dL
Alkaline phosphatase, IU/L
25(OH)D, mmol/L
PTH, pg/mL
30.16
83.73%
9.25
70.31
22.53
107.74
p value
.131
.222
.005
.261
.357
21.51
87.84%
.037
.044
9.14
71.11
22.49
43.88
.402
.46
.49
<.0001
*T-score of femoral neck PTH-parathyroid hormone.
†
Percentage in decline in intraoperative PTH level between the first and endpoint measurements.
‡
Taken 1 month after surgery.
elevated PTH levels postoperatively than in the
patients in whom PTH normalized (224.89 16.39 pg/mL vs 156.86 12.61 pg/mL, p ¼ .005)
(Table 2). Eighty-five percent of the patients in
the normalized-PTH group had a preoperative
PTH level lower than 225 pg/mL.
Intraoperatively, PTH level decreased to a
lesser degree in the patients with elevated levels
postoperatively than in the patients in whom
PTH normalized (87.8% vs 83.7%, p ¼ .044)
(Table 2). The patients with high postoperative
values also had higher values of PTH at
20 minutes after adenoma excision (21.51 pg/mL
vs 30.16 pg/mL, p ¼ .037).
Alkaline phosphatase levels were similar in
both groups before and after surgery (Table 2).
There was no significant difference in alkaline
phosphatase levels between the transient and
the persistent PTH group.
The average 25(OH)D levels after surgery
were 22.49 mmol/L in the normalized PTH
group versus 22.53 mmol/L in the persistent
PTH group (p ¼ .49). There was no significant
difference in 25(OH)D levels between the group
with transient postoperative hyperparathyroidism and the group with persistent PTH. Two
patients in the normalized-PTH group (3.5%)
and 1 in the elevated-PTH group (5.2%) had
25(OH) D values below the normal range.
All patients were routinely checked for blood
creatinine levels throughout the follow-up pe-
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Elevated PTH Following Parathyroidectomy
riod and none had evidence of impaired renal
function. A decline in bone mineral density was
evident in both groups without significant
difference.
All patients with persistently elevated PTH
underwent repeated ultrasonography, with no
pathological findings.
DISCUSSION
Curative parathyroidectomy is a well-established
and highly successful approach to the treatment of
primary hyperparathyroidism worldwide.10,11 However, the definition of cure in these cases is still controversial because in a considerable percentage of
patients, serum PTH levels remain high after surgery despite normal serum calcium levels.12,13 A frequency of 25% was demonstrated in this study, and
up to 40% was reported by others.14 Several studies
have documented the importance of an isolated elevation of PTH and its association with high rates of
osteoporosis, and consequent high risk of bone fractures,15 even in the earliest form of primary hyperparathyroidism, which presents as elevated PTH
levels with normocalcemia.16 Furthermore, recent
reports showed evidence of a direct adverse influence of high PTH levels on myocardial structure,
leading to heart failure and increased cardiac morbidity and mortality.17,18
Since parathyroidectomy is currently a focused, minimally invasive procedure, preoperative
HEAD & NECK—DOI 10.1002/hed
November 2009
imaging and intraoperative PTH monitoring have
become important aids.19 All patients in this
study underwent preoperative evaluation with
ultrasonography and technetium 99m sestamibi
scan, which proved to be accurate tools in this
setting.20,21
We found no significant differences between
patients with elevated postoperative PTH levels
and patients in whom PTH normalized in demographic features, preoperative signs, and symptoms, or preoperative and postoperative calcium
levels (Tables 1 and 2). However, patients who
had persistently high PTH levels after surgery
had significantly higher PTH levels before surgery than patients in whom PTH normalized (p
¼ .005). In addition, the rate of decline in their
intraoperative PTH levels was lower (p ¼ .044)
and their endpoint intraoperative PTH value
was higher, though still within normal range (p
¼ .037).
Wang et al22 attributed elevated postoperative PTH levels to either mild hypocalcaemia
caused by vitamin D deficiency or to a persistent
hyperparathyroidism. In this study, we found no
difference in vitamin D level between the 2
groups. Furthermore, we found no difference in
vitamin D level between the group with transient postoperative hyperparathyroidism and
the group with persistent PTH. Most of the
patients had a normal vitamin D level.
The differences in intraoperative PTH reduction in our series were too small to be clinically
applicable. The outcome of treatment in terms
of intraoperative PTH, postoperative calcium
levels, and repeated ultrasonography findings
appeared to be satisfactory.
The only factor identified in this study that
might serve as a clinical predictor of high postoperative PTH was the preoperative PTH level.
According to our measurements, a preoperative
PTH level of more than 225 pg/mL could be considered a risk factor for persistently high postoperative PTH.
Mittendorf et al7 suggested that the transient short-term elevation of PTH could be due
to cortical bone remineralization. These authors
noted that in about half their patients with an
elevated PTH soon after surgery, levels dropped
to normal within an average of 16 months. In
this study, the elevated levels normalized in 6 of
19 patients during an average follow-up of
18 months. Our findings support the theory of
cortical bone remineralization. The fact that
patients in the elevated PTH group had higher
Elevated PTH Following Parathyroidectomy
preoperative PTH levels and a slower tendency
to lower their PTH intraoperatively could suggest a longer-standing disease resulting in more
severe bone hunger and peripheral resistance to
PTH.
Nevertheless, serum alkaline phosphatase levels, which might serve as a marker for bone remineralization,8 were normal in these patients and
the decline in bone mineral density was evident
in both groups without significant difference.
In patients in whom PTH elevation persists
for more than 1 year, another explanation, such
as residual hyperfunctioning parathyroid tissue,
should be sought. However, we found no pathology on repeated ultrasonography scans in any of
our patients in whom PTH failed to normalize.23
In conclusion, this study indicates that 25%
of eucalcemic patients may have elevated PTH
levels after parathyroidectomy. A high preoperative PTH level may predict a persistently high
postoperative PTH level. A preoperative PTH
level of more than 225 pg/mL could be considered a risk factor. The importance of the lesser
decrease in intraoperative PTH in affected
patients remains unclear. Cortical bone remineralization may explain short-term postoperative
elevation in PTH level, but for longer-term
cases, residual hyperfunctioning parathyroid tissue should be considered. Repeated imaging
scans (ultrasound and/or Tc99m sestamibi scan)
should be obtained if the elevation in PTH persists for more than 1 year. Because of the possible risk of high bone turnover and cardiac
morbidity in the presence of high PTH levels,
evaluation of blood and urine calcium, bone density, and cardiac function should be considered
in all affected patients.
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