Download Secretory Capacity of the Parathyroid Glands after Total

ORIGINAL
ARTICLE
E n d o c r i n e
C a r e
Secretory Capacity of the Parathyroid Glands after
Total Thyroidectomy in Normocalcemic Subjects
Olympia E. Anastasiou, Maria P. Yavropoulou, Theodosis S. Papavramidis,
Chrysoula Tzouvara, Konstantina Triantafyllopoulou, Spiros Papavramidis,
and John G. Yovos.
Department of Endocrinology and Metabolism (O.E.A., M.P.Y., C.T., J.G.Y.) and Third Department of
Surgery (T.S.P., K.T., S.P.), American Hellenic Educational Progressive Association (AHEPA) University
Hospital, Aristotle University of Thessaloniki, Thessaloniki 54636, Greece
Context: Hypocalcemia, transient or permanent, represents a common complication after total
thyroidectomy, but data on the secretory capacity of the parathyroid glands in thyroidectomized
patients without clinical or biochemical hypocalcemia are limited.
Study Design: To address this issue, we studied the parathyroid response to acute hypocalcemia
induced by iv infusion of sodium bicarbonate in normocalcemic patients submitted to total thyroidectomy at the early postoperative period and 3 months later.
Patients and Methods: Sixty patients who underwent total thyroidectomy for benign thyroid
disease and did not develop clinical or biochemical hypocalcemia and hypoparathyroidism postoperatively and 50 healthy volunteers were included in the study. Patients (at 48 h and 3 months after
surgery) and controls (after overnight fast) were subjected to a sodium bicarbonate infusion test.
Results: In healthy volunteers plasma intact PTH increased significantly at 3 min after infusion
(4.42 ⫾ 0.15 ng/ml vs. 11.22 ⫾ 0.5 ng/ml, P ⬍ 0.001) and gradually returned to baseline values. In
the thyroidectomized patients, mean PTH levels were also increased after sodium bicarbonate
infusion but to a significantly lesser degree compared with healthy controls (1.77 mean fold increase vs. 2.57 mean fold increase, respectively, P ⬍ 0.001). Using as criterion the lowest fold
increase of plasma PTH levels at 3 min after infusion observed in healthy volunteers, 38% of the
thyroidectomized patients at 48 h after surgery and 6.6% of the patients at 3 months after surgery
demonstrated a diminished PTH response to acute hypocalcemia induced by sodium bicarbonate
infusion.
Conclusion: In thyroidectomized patients, normal postoperative calcium and PTH values do not
exclude a reduced secretory response of the parathyroids to hypocalcemic stimuli. (J Clin Endocrinol
Metab 97: 2341–2346, 2012)
T
ransient hypocalcemia is one of the most common
complications after total thyroidectomy with a reported incidence of 2–32% of cases (1–3). Underlying
mechanisms usually involve removal of the parathyroid
glands or disruption of the vascular supply of the remaining tissue (4). Permanent hypoparathyroidism, although
not as common, has also been reported in approximately
0.2–10% of cases, depending on the experience of the
center (1–3, 5).
Untreated hypocalcemia can be a serious complication
in the postoperative period, and several studies have focused on pre- and immediate postoperative parameters
that could predict the incidence of hypoparathyroidism
and subsequent hypocalcemia (6 –16). Preoperative fac-
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2012-1170 Received January 22, 2012. Accepted March 26, 2012.
First Published Online April 17, 2012
Abbreviation: SBI, Sodium bicarbonate infusion.
J Clin Endocrinol Metab, July 2012, 97(7):2341–2346
jcem.endojournals.org
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Anastasiou et al.
PTH Secretory Capacity after Thyroidectomy
J Clin Endocrinol Metab, July 2012, 97(7):2341–2346
Patients and Methods
A prospective study was performed of all patients who underwent total thyroidectomy at
the Third Department of Surgery of AHEPA
(American Hellenic Educational Progressive
Association) University Hospital of Thessaloniki within a period of 20 months (March
2008 to October 2009). A complete clinical
and biochemical thyroid workup was performed before surgery. Size and morphology
of the thyroid gland was evaluated by thyroid
ultrasound and a fine-needle aspiration was
performed where appropriate to assess the nature of thyroid nodules.
Patient characteristics
Only patients with benign thyroid disease were included in the study. Exclusion
criteria were participation in other clinical
trials within 3 months from the initial recruitment period, known parathyroid disease, other diseases or medications known
to affect bone metabolism and calcium homeostasis (i.e. bisphosphonates, calcimimetics, glucocorticoids), vitamin D deficiency (assessed as 25-hydroxyvitamin D
levels ⱕ 20 ng/ml), and abnormal liver or
FIG. 1. Flow chart of the patients recruited for the study.
renal function. All patients were euthyroid
for at least 2 months before surgery. Patients who developed postoperative hytors include an advanced age, the preexistence of second- pocalcemia (serum calcium ⱕ 8.00 mg/dl) and hypoparathyroidary hyperparathyroidism due to vitamin D deficiency, and ism (PTH ⱕ 0.6 pmol/liter) were excluded from the study and
hyperthyroidism (6, 7). Low PTH in the early postoper- were supplemented with calcium and vitamin D. In patients with
ative period is considered the most reliable marker, with a borderline calcium (between 8.10 and 8.50 mg/dl) or PTH levels
(between 1.0 and 2.0 pmol/liter), we evaluated the response to
cutoff point of 85–90%, in identifying those patients at
Trousseau and Chovsteck signs for latent hypocalcemia. Rehigh risk of hypocalcemia after thyroidectomy (8 –10).
sponse was assessed by two independent endocrinologists and
Besides the overt postoperative hypoparathyroidism, patients who did not show any clinical signs of hypocalcemia
cases of latent hypoparathyroidism after cervical sur- were subjected to sodium bicarbonate infusion test the second
gery or radiotherapy that develop severe hypocalcemia day after surgery and were included in the final analysis. Patients
during treatment with agents that alter calcium homeo- with postsurgical histological findings of thyroid carcinoma
were also excluded from the study.
stasis, such as bisphosphonates, have also been deFifty healthy volunteers matched for age and body mass index
scribed (17–19). However, data are scarce regarding the were recruited from the personnel of AHEPA University Hospisecretory capacity of the parathyroid glands in thyroid- tal. Informed consent was obtained from all the participants
ectomized patients without postoperative clinical or enrolled and the research protocol was approved by the Ethics
Committee of the Aristotle University of Thessaloniki. The study
biochemical hypocalcemia.
To address this issue we evaluated the secretory re- was registered with www.clinicaltrials.gov with registration
number NCT 00793689.
sponse of PTH to hypocalcemic stimulus induced by an iv
One hundred twenty-seven patients underwent total thyroidinfusion of sodium bicarbonate in normocalcemic patients ectomy over the study period and from those, 70 were considered
in the early postoperative period and 3 months after total eligible for the study according to the inclusion criteria used (Fig.
thyroidectomy. A sodium bicarbonate infusion (SBI) test 1). Seven patients also excluded from the analysis due to posthas been recently introduced in clinical practice for the operative clinical and/or biochemical hypocalcemia, and three
quick evaluation of parathyroid response to acute hy- patients were excluded due to postsurgical histological findings
of thyroid carcinoma (two patients with papillary and one papocalcemia (20, 21), as a simple and more safe and effectient with follicular thyroid carcinoma) (Fig. 1). None of the
tive test, compared with EDTA and sodium citrate infu- patients developed permanent hypoparathyroidism. From the 60
sion tests that have been previously used to differentiate patients who were included in the final analysis, 44 had euthybetween parathyroid adenomas and hyperplasia (22–24). roid nodular or multinodular goiters, six patients had Grave’s
J Clin Endocrinol Metab, July 2012, 97(7):2341–2346
disease, and 10 patients had hyperfunctioning adenoma or toxic
multinodular goiters.
jcem.endojournals.org
2343
to be significant. The statistical software packages SPSS version
20.0 for OsX (SPSS Inc., Chicago, IL) and GraphPad Prism 4
(GraphPad Software, Inc., La Jolla, CA) were used.
Research protocol
Blood samples were collected preoperatively and 4 h, 48 h,
and 3 months postoperatively. Circulating levels of calcium, albumin, magnesium, phosphate, 25-hydroxyvitamin D, and intact PTH were assessed. A sodium bicarbonate infusion test was
performed 48 h after surgery for the evaluation of the secretory
capacity of the parathyroids, as has been previously described
(20). In brief, after an overnight fast, 35 ml/m2 of body surface
of 8.4% sodium bicarbonate solution was infused in about 2 min
into the antecubital vein, and blood samples for the measurement
of PTH and calcium levels were drawn at 0, 3, 5, 10, 30, and 60
min after the infusion from the antecubital vein of the other arm.
The acute infusion of sodium bicarbonate causes a transient increase in blood pH and a subsequent decrease in ionized calcium
due to transport of calcium ions from the extracellular to intracellular space. In turn, release of PTH from the parathyroids is
potently stimulated. Patients were then followed for the next 3
months and at the end of the third month, a second sodium
bicarbonate infusion test was performed.
Fifty healthy individuals were also subjected to sodium bicarbonate infusion test after an overnight fast.
The reproducibility of the SBI test was evaluated in a separate
group of four healthy volunteers (two males and two females
aged between 46 and 50 yr), who were subjected to sodium
bicarbonate infusion three consecutive times. Each infusion was
performed 2 d apart from the previous infusion. The average
intraassay coefficient of variation of fold increase in PTH levels
at 3 min after SBI was 2.8% (range between 0.4 and 4.7%).
The test was well tolerated from all the participants, and no
serious complications were recorded except for a transient paresthesia of the digits, metallic taste, and mild discomfort in the
infusion arm.
Results
Demographic characteristics and baseline values of all
participants are depicted in Table 1.
There were no significant differences in the baseline
PTH, total and corrected calcium, and 25-hydroxyvitamin D levels between the control group and the patients
submitted to total thyroidectomy (Table 1).
Plasma PTH levels were significantly decreased from
the baseline values at 4 and 48 h after total thyroidectomy
(4.9 ⫾ 0.2 vs. 3.26 ⫾ 0.25 and 3.6 ⫾ 0.3, pmol/liter,
respectively P ⬍ 0.001) and were restored at 3 months
postoperatively (Fig. 2A). Similarly, serum calcium levels
significantly decreased after surgery but remained within
normal limits at all time points measured (Fig. 2B).
Sodium bicarbonate infusion test
In the healthy volunteers, plasma PTH levels were immediately increased at 3 min after the infusion (4.42 ⫾
0.15 vs. 11.22 ⫾ 0.5 ng/ml, P ⬍ 0.001) and then rapidly
returned to baseline values (Fig. 3). At 48 h postoperatively, thyroidectomized patients also increased mean
PTH levels at 3 min after sodium bicarbonate infusion but
TABLE 1. Demographic characteristics and baseline
values of patient and control group
Assays
Serum levels of total calcium, albumin, phosphate, and magnesium, were routinely measured in the Department of Biochemistry of AHEPA University Hospital.
Plasma 25-hydroxyvitamin D levels (nanograms per milliliter) were measured by a RIA (RIA; DiaSorin, Sallugia, Italy),
according to the manufacturer’s instructions. The minimum detectable concentration is 1.5 ng/ml, and the within-run and total
run assay coefficients of variation are between 8.6 –12.5 and
1–9.4%, respectively.
Plasma PTH levels (picomoles per liter) were measured by an
electrochemiluminescence immunoassay (ECLIA, Cobas; Roche,
West Sussex, UK), according to the manufacturer’s instructions.
The minimum detectable concentration is 0.127 pmol/liter, and the
within-run and total run assay coefficients of variation are between
0.6 –2.8 and 1.6 –3.4%, respectively. No cross-reactions were detected with osteocalcin, PTH fragment 1–37, PTH-related protein,
bone-specific alkaline phosphatase, or ␤-CrossLaps.
Statistical analysis
All data are presented as mean values ⫾ SEM or mean ⫾ SD, when
indicated. A Student’s t test or ANOVA for repeated measures was
used as applicable, and Pearson analysis was performed for correlations between measured parameters. Categorical data were analyzed using Pearson ␹2 test. For all values, P ⬍ 0.01 was considered
n
Age (yr)
BMI (kg/cm2)
Men (%)
iPTH (pmol/liter)
(RR. 1.6 – 6.9)
Total calcium (mg/dl)
(RR. 8.2–10.6)
Corrected calcium
Phosphate (mg/dl)
(RR. 2.7– 4.5)
Magnesium (mg/dl)
(RR. 1.58 –2.55)
25-Hydroxyvitamin D
(ng/ml)
Urea (mg/dl)
(RR. 10 –50)
Creatinine (mg/dl)
(RR. 0.4 –1.10)
Control group
50
47.58 ⫾ 14.2
27.1 ⫾ 3.9
10
4.5 ⫾ 1.2
Patients’
groupa
P value
60
NA
48.3 ⫾ 11.5 0.763
27.6 ⫾ 5.5
0.124
10
NA
4.9 ⫾ 1.3
0.059
9.8 ⫾ 0.6
9.4 ⫾ 0.5
0.336
9.5 ⫾ 0.34
3.4 ⫾ 0.55
9.3 ⫾ 0.27
3.5 ⫾ 0.8
0.445
0.450
2.1 ⫾ 0.25
2.1 ⫾ 0.36
0.991
36.56 ⫾ 4.4
38.31 ⫾ 6.5
0.170
20.23 ⫾ 1.4
25.6 ⫾ 1.5
0.446
1.1 ⫾ 0.1
0.714
0.9 ⫾ 0.06
BMI, Body mass index; iPTH, intact PTH; NA, Not applicable; RR,
reference range.
Values are presented as mean ⫾ SD.
a
Preoperative values.
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Anastasiou et al.
PTH Secretory Capacity after Thyroidectomy
J Clin Endocrinol Metab, July 2012, 97(7):2341–2346
standardized for evaluation of parathyroid gland function in large clinical trials, we arbitrarily used as a cutoff value the lowest fold increase of
plasma PTH levels at 3 min after the
infusion observed in the healthy volunteers (1.5-fold increase). According to this criterion, 38% of the patients (n ⫽ 24) demonstrated a
diminished PTH response at 48 h after
surgery, suggestive of a partial subclinical postoperative hypoparathyroidism (Fig. 4). These patients
showed a significant decrease in calcium and PTH levels at 4 and 48 h
after thyroidectomy (Fig. 2). However, when they were compared with
patients who had increased PTH levels at 3 min after sodium bicarbonate
infusion more than 1.5-fold (n ⫽ 36),
there was no significant difference in
the absolute decline of calcium levels
at 4 or 48 h postoperatively (0.78 ⫾
0.1 vs. 0.66 ⫾ 0.1 mg/dl at 4 h and
0.84 ⫾ 0.09 vs. 0.73 ⫾ 0.08 mg/dl at
48
h, respectively, P ⬎ 0.05).
FIG. 2. Changes in serum calcium (A) and plasma PTH (B) levels after total thyroidectomy.
Values are presented as mean ⫾ SEM. **, P ⬍ 0.001 post-op (postoperatively).
PTH response at 3 min after the SBI
test was significantly correlated only
to a significantly lesser degree compared with controls with PTH levels at 4 h postoperatively (r ⫽ 0.408, P ⫽
(mean fold increase 1.77 ⫾ 0.07 vs. 2.57 ⫾ 0.1, respec- 0.002) (Fig. 5) but not with serum calcium at 4 or 48 h.
tively, P ⬍ 0.001). At 3 months after surgery, an SBI test
During the follow-up period, none of the patients rewas repeated in the thyroidectomized patients. Mean quired calcium or vitamin D supplementation. At 3
plasma PTH levels were significantly increased at 3 min
after the infusion (5.2 ⫾ 0.22 vs. 12.1 ⫾ 0.68 ng/ml, respectively, P ⬍ 0.001, mean fold increase 2.36 ⫾ 0.1).
Because the sodium bicarbonate test has not yet been
FIG. 3. Plasma PTH levels after sodium bicarbonate infusion. Values
are presented as mean ⫾ SEM.
FIG. 4. PTH response at 3 min after sodium bicarbonate infusion in
patients and controls. Transverse lines indicate mean ⫾ SD. CMR,
Control Minimum Response.
J Clin Endocrinol Metab, July 2012, 97(7):2341–2346
FIG. 5. Relationship between plasma PTH at 4 h after surgery and PTH
response at 3 min after the sodium bicarbonate infusion 48 h after
surgery. Patients are classified according to PTH fold increase at 3 min
after sodium bicarbonate infusion.
months after surgery, the great majority of patients significantly increased PTH levels 3 min after the infusion
(⬎1.5-fold increase), but 6.6% (n ⫽ 4) persisted in showing a diminished response (Fig. 4).
All patients who showed a diminished response in PTH
secretory capacity at 3 months had also shown a reduced
response at 48 h after surgery. In addition, we found no
association between the underlying thyroid disease and
the occurrence of a deficient PTH response to the SBI test.
Discussion
Decreased secretory capacity of the parathyroid glands
after total thyroidectomy is an underrecognized condition
due to lack of clinical symptoms. In our study we have
shown that within thyroidectomized patients who are normocalcemic and with normal PTH levels postoperatively,
PTH response to hypocalcemic stimulus can still be impaired. This diminished response of the parathyroid
glands to acute hypocalcemia is mostly evident during the
early postoperative period (48 h after thyroidectomy) and
attenuates during time, and although in a small percentage
of patients, it persists even at 3 month after surgery.
A sodium bicarbonate infusion test was introduced by
Iwasaki and colleagues (20, 21) as a safer, easier, and
reliable test for the evaluation of the secretory capacity of
parathyroid glands compared with previous tests with
EDTA and sodium citrate infusion (22–24). In the study by
Iwasaki et al. (20), the infusion of sodium bicarbonate in
eight healthy volunteers demonstrated an average of 4.3-
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fold increase in plasma PTH levels at 3 min after the start
of the infusion, whereas patients diagnosed with hypoparathyroidism have shown diminished or no response. In
our study the mean PTH increase in healthy subjects was
lower (2.5-fold increase). We do not have an explanation
for this discrepancy between results, but differences in age
of the population or the size of the sample could mostly
contribute.
Postoperative hypoparathyroidism can be caused by
injury, devascularization, stretching, compression, or
ischemia and unintentional excision of parathyroid
glands. The relatively quick recovery of the parathyroid
glands shows that in case of injury or devascularization,
they can regain their function and in the case of inadvertent excision of one or more parathyroid glands, the remaining tissue can, over time, compensate the functional
postoperative deficit through the development of hyperplasia. Spontaneous delayed recovery of the parathyroid
function after 2 yr of total thyroidectomy has also been
described (25), and thus, a longer follow-up of these patients is needed. In addition, even in the absence of occult
hypocalcemia, cases of latent hypoparathyroidsm have
been described in patients with a history of previous surgery in the cervical region (26). The identification of such
cases can be useful in preventing incidents of acute hypocalcemia after drug administration, such as bisphosphonates, that interfere with calcium homeostasis and can
alter the compensatory mechanisms of the parathyroid
glands.
This is the first study evaluating the secretory capacity
of the parathyroid glands after total thyroidectomy in patients with normal calcium and PTH levels. Despite the
limitations that this study has, mainly due to the use of a
PTH provocation test that has not yet been standardized
in large clinical trials and the relatively short follow-up
period of our patients, it has clearly shown that parathyroid response can be impaired after total thyroidectomy,
even in normocalcemic subjects. In addition, low, but
within normal range, plasma PTH levels at 4 h after surgery appear to be a valuable predicting tool for the functional status of parathyroid glands and should not be neglected. Significant decrease of PTH values at the early
postoperative period (3 h after surgery) has been reported,
even in patients with normal calcium levels (27). However,
in this study (27), researchers did not look for a potential
parathyroid dysfunction in hypocalcemic stimuli in these
patients. The use of an SBI test in everyday clinical practice
is probably limited, but it could be of value in cases with
significant decrease of PTH levels in the early postoperative period, even without the development of hypocalcemia. The possibility of an asymptomatic impaired parathyroid function in patients with a previous history of total
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Anastasiou et al.
PTH Secretory Capacity after Thyroidectomy
thyroidectomy should be taken into consideration when
prescribing medications that could potentially impair the
parathyroid gland compensatory mechanisms and result
in an unexplained hypocalcemia.
J Clin Endocrinol Metab, July 2012, 97(7):2341–2346
11.
12.
Acknowledgments
Address all correspondence and requests for reprints to: Maria P.
Yavropoulou, M.D., Ph.D., Department of Endocrinology and
Metabolism, Aristotle University of Thessaloniki, AHEPA University Hospital, 1 Stilponos Kyriakidi Street, 54636 Thessaloniki, Greece. E-mail: [email protected].
Disclosure Summary: The authors have nothing to disclose.
13.
14.
15.
16.
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