Download Severe Vitamin D Deficiency: A Significant Predictor of Early

Original Research—Endocrine Surgery
Severe Vitamin D Deficiency:
A Significant Predictor of Early
Hypocalcemia after Total Thyroidectomy
Otolaryngology–
Head and Neck Surgery
2015, Vol. 152(3) 424–431
Ó American Academy of
Otolaryngology—Head and Neck
Surgery Foundation 2014
Reprints and permission:
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DOI: 10.1177/0194599814561209
http://otojournal.org
Talal Al-Khatib, MD, FRCSC1, Abdulrahman M. Althubaiti, MBBS1,
Alaa Althubaiti, PhD2, Hala H. Mosli, FRCP(C), ABEM3,
Reem O. Alwasiah4, and Lojain M. Badawood4
No sponsorships or competing interests have been disclosed for this article.
Abstract
Objective. To assess the role of preoperative serum 25 hydroxyvitamin D as predictor of hypocalcemia after total thyroidectomy.
Study Design. Retrospective cohort study.
Setting. University teaching hospital.
Subjects and Methods. All consecutively performed total and
completion thyroidectomies from February 2007 to
December 2013 were reviewed through a hospital database
and patient charts. The relationship between postthyroidectomy laboratory hypocalcemia (serum calcium 2 mmol/
L), clinical hypocalcemia, and preoperative serum 25 hydroxyvitamin D level was evaluated.
Results. Two hundred thirteen patients were analyzed. The
incidence of postoperative laboratory and clinical hypocalcemia was 19.7% and 17.8%, respectively. The incidence of
laboratory and clinical hypocalcemia among severely deficient
(\25 nmol/L), deficient (\50 nmol/L), insufficient (\75
nmol/L), and sufficient (75 nmol/L) serum 25 hydroxyvitamin D levels was 54% versus 33.9%, 10% versus 18%, 2.9%
versus 11.6%, and 3.1% versus 0%, respectively. Multiple logistic regression analysis revealed preoperative severe vitamin D
deficiency as a significant independent predictor of postoperative hypocalcemia (odds ratio [OR], 7.3; 95% confidence
interval [CI], 2.3-22.9; P = .001). Parathyroid hormone level
was also found to be an independent predictor of postoperative hypocalcemia (OR, 0.6; 95% CI, 0.5-0.8; P = .002).
Received August 1, 2014; revised September 23, 2014; accepted
November 4, 2014.
T
he rate of operative procedures involving the thyroid
gland has undergone a rapid increase in recent years.1-4
Complications after thyroid surgery are well documented in the literature5,6; however, several studies have reported
trends in favor of performing total thyroidectomy for benign
and malignant thyroid disease.7-10 Postthyroidectomy hypocalcemia remains a common complication11,12 and presents an
obstacle to early hospital discharge.13 Intraoperative trauma to
the parathyroid glands, compromise of their blood supply, or
accidental parathyroid removal all contribute to disruptions in
parathyroid hormone (PTH) levels. Moreover, the lack of a
clear definition of postthyroidectomy hypocalcemia presents a
challenge to the study of this common complication.14
Considerable variation in the rate of hypocalcemia can result
from applying different reported definitions from the literature
to a single study.15 Another challenge is the multiplicity of
risk factors involved in developing postthyroidectomy hypocalcemia.16-18 The predictive role of several perioperative markers
including PTH, magnesium, and phosphate in developing this
complication has been examined.19-23 However, investigation
of these markers may be influenced by the interplay of a wide
variety of clinical and biochemical risk factors.
Vitamin D (25 hydroxyvitamin D; 25[OH]D) is an integral factor in calcium (Ca) homeostasis. Vitamin D deficiency (VDD) is a global condition and considered to be a
Conclusion. Postoperative clinical and laboratory hypocalcemia
is significantly associated with low levels of serum 25 hydroxyvitamin D. Our findings identify severe vitamin D deficiency
(\25 nmol/L) as an independent predictor of postoperative
laboratory hypocalcemia. Early identification and management
of patients at risk may reduce morbidity and costs.
1
Department of Otolaryngology–Head and Neck Surgery, Faculty of
Medicine, King Abdulaziz University, Jeddah University, Jeddah, Saudi Arabia
2
Department of Basic Medical Sciences, College of Medicine, King Saud bin
Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
3
Department of Medicine, Endocrinology and Metabolism Division, King
Abdulaziz University, Jeddah, Saudi Arabia
4
Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
Keywords
vitamin D deficiency,
hypocalcemia
Corresponding Author:
Abdulrahman M. Althubaiti, Department of Otolaryngology–Head and
Neck Surgery, Faculty of Medicine, Jeddah University, PO Box 15183,
Jeddah 21444, Saudi Arabia.
Email: [email protected]
low
25(OH)D,
thyroidectomy,
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Al-Khatib et al
425
key factor in several clinical outcomes.24 Several trials have
investigated the role of vitamin D supplementation in the prevention of postthyroidectomy hypocalcemia and demonstrated
reduced incidence rates and severity.25-27 Nevertheless, the
reliability of using preoperative vitamin D status as a predictor
of postthyroidectomy hypocalcemia risk remains unclear.
Results reported by several studies concluded that VDD
did not affect postthyroidectomy hypocalcemia rates.19,21,28-32
However, the serum vitamin D level has been established as
a risk factor and significant predictor of postthyroidectomy
hypocalcemia in several other studies.23,33-36
The aim of this study was to investigate the controversial
role of serum 25(OH)D in the development of early hypocalcemia after total thyroidectomy.
Materials and Methods
Study Subjects
The research ethics committee at the Unit of Biomedical Ethics
approved this study (Reference No. 1254-13). This was a retrospective chart review of all consecutively performed total thyroidectomy and completion thyroidectomy procedures from
February 2007 to December 2013. The study was conducted at
the Department of Otolaryngology–Head and Neck Surgery
(ORLHNS), Faculty of Medicine, King Abdulaziz University,
Jeddah, Saudi Arabia. Our study reviewed registered patients
from the operating room database at King Abdulaziz University
Hospital. Surgeons from both the Departments of ORLHNS and
General Surgery performed the procedures.
Method
Data were collected from the hospital database and patients’
charts. Four hundred ninety-one records of registered total
or completion thyroidectomies were reviewed. Standard surgical technique involved careful identification and conservation of parathyroid glands together with the recurrent
laryngeal nerve.
Exclusion criteria included the following: records with
missing data, substernal goiter, simultaneous neck dissection,
reported parathyroid gland from the histopathologic analysis
of the resected specimen, and documented parathyroid gland
autotransplantation; comorbidities affecting Ca homeostasis,
including hyperthyroidism, parathyroid disease, solid tumors,
granulomatous disease, and chronic kidney disease; and
patients on medication that affect Ca levels, including calcium/vitamin D supplements, steroids, thiazide diuretics, antiepileptic agents, and hormone replacement therapy.
Patients’ charts, operative notes, and histopathology
reports were reviewed in detail. Demographic data were collected, including age, gender, and histopathology diagnosis.
Operative notes were examined for surgical technique as well
as documented preservation of any adherent parathyroid
gland to the thyroid capsule with mention of the integrity of
its blood supply and/or documented intraoperative identification of at least 3 parathyroid glands. Histopathology reports
were reviewed for the diagnosis and reported parathyroid
tissue to rule out incidental removal.
The preoperative biochemical markers reviewed were serum
25(OH)D, Ca, phosphate, albumin, magnesium, creatinine, thyroid stimulating hormone (TSH), and alkaline phosphatase
(ALP). The postoperative biochemical markers included 3 Ca
measurements: the first, second, and third measurements were
taken at 6 to 12 hours, 18 to 24 hours, and 48 to 72 hours postoperation, respectively. All Ca measurements were corrected
using the following formula: corrected Ca = (40-serum albumin)
3 0.02 1 serum Ca.37 Laboratory hypocalcemia was defined
as any single corrected postoperative Ca level of 2 mmol/L or
less (to convert to ng/mL, divide by 0.25), which is a frequently
used definition.17,25,28,29,35 Patients were grouped into 2 categories according to postoperative Ca levels. Group 1 consisted
of patients with serum Ca level of 2 mmol/L or less, and group
2 was composed of patients with a serum Ca level greater than
2 mmol/L. Laboratory hypocalcemia was managed with oral
calcium (calcium carbonate 600 mg orally twice a day up to a
maximum of 1200 mg orally 3 times a day) and vitamin D supplementation (one alpha 0.25 mg orally twice a day up to 1 mg
orally twice a day, the only available form in the hospital pharmacy). Records were reviewed for physician-documented symptoms of clinical hypocalcemia during the hospital stay, which
included cramping, numbness, paresthesia, and/or positive
Chvostek or Trousseau signs that required intravenous Ca gluconate administration. The PTH levels were measured 6 to 12
hours postsurgery.
Serum 25(OH)D and PTH levels were measured using an
electrochemiluminescence immunoassay on a Roche Modular
analytics E170 (Elecsys module) immunoassay analyzer. Serum
25(OH)D levels were grouped into 4 reference ranges as follows:
sufficient (75 nmol/L), insufficient (75 nmol/L . 25(OH)D 50 nmol), VDD (50 nmol/L . 25(OH)D 25 nmol/L), and
severe VDD (\25 nmol/L; to convert to ng/mL, divide by 2.5).38
Other reference ranges used were Ca (2.12-2.52 mmol/L), PTH
(1.6-6.9 pmol/L), phosphate (0.81-1.58 mmol/L), albumin (40.247.6 g/L), magnesium (0.7-1 mmol/L), creatinine (53-115 mmol/
L), TSH (0.27-4.2 mIU/L), and ALP (50-136 U/L).
Statistical Analysis
Data are presented as the mean 6 standard deviation (SD)
for continuous variables and percentages for categorical
variables. The x2 test or Fisher exact test was used to compare categorical data. An independent sample t test, MannWhitney test, or 1-way analysis of variance was used to
compare continuous data. A multiple logistic regression was
used to determine independent significant predictors of
hypocalcemia. Odds ratios (ORs) with 95% confidence
intervals (CIs) were expressed relative to a reference baseline category. A P value \.05 was considered to be statistically significant. Data were analyzed using the SPSS
database (IBM SPSS Statistics, SPSS Inc, Chicago, Illinois).
Results
Subject Characteristics
The data review revealed that of 491 charts reviewed, 189
patients had missing perioperative markers but were otherwise
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Otolaryngology–Head and Neck Surgery 152(3)
Table 1. Biochemical Parameters.a
Preoperative serum albumin, g/L
Preoperative creatinine, umol/L
Preoperative phosphate, mmol/L
Preoperative serum Ca, mmol/L
Preoperative alkaline phosphatase, u/L
Preoperative serum 25(OH)D, nmol/L
Sufficient serum 25(OH)D, 75 nmol/L
Insufficient serum 25(OH)D, \75 nmol/L
Deficient serum 25(OH)D, \50 nmol/L
Severely deficient serum 25(OH)D, \25 nmol/L
Preoperative TSH, mIU/L
Preoperative magnesium, mmol/L
First postoperative serum Ca, mmol/L
Second postoperative serum Ca, mmol/L
Third postoperative serum Ca, mmol/L
Postoperative PTH, pmol/L
Mean 6 SD or n (%)
Range
33.0 6 4.2
62.4 6 17.9
1.1 6 0.3
2.3 6 0.1
71.6 6 24.6
45.8 6 21.6
32 (15.0)
69 (32.4)
50 (23.5)
62 (29.1)
3.7 6 9.4
0.6 6 0.1
2.2 6 0.1
2.1 6 0.1
2.1 6 0.2
3.1 6 2.1
17.0-43.0
18.0-131.0
0.2-2.4
2.0-2.7
27.0-133.0
7.0-137.4
0.2-96.3
0.3-0.9
1.7-2.7
1.0-2.5
1.1-2.6
0.1-7.5
Abbreviations: 25(OH)D, 25 hydroxyvitamin D; Ca, calcium; NTMNG, nontoxic multinodular goiter; PTH, parathyroid hormone; TSH, thyroid-stimulating
hormone.
a
Total number of patients, N = 213.
demographically similar to the included patients, which would
make selection bias less likely; 20 patients had concomitant
neck dissection; 13 patients had substernal goiter; 25 patients
had parathyroid glands in resected specimens; and 31 patients
had hyperthyroidism. These patients were excluded from our
study. The remaining 213 patients who underwent a total or
completion thyroidectomy were included. Indications for surgery
included goiter with compressive symptoms, clinically or radiologically evident suspicious nodule, or fine-needle aspiration
biopsy reported as malignant, suspicious for malignancy, or
undetermined in high-risk patients.
The mean 6 SD age of patients was 44.9 6 15.14 years
(range, 13-86 years). Of the 213 patients, 43 (20.2%) were
male and 170 (79.8%) were female. Parathyroid glands
were identified intraoperatively in 160 patients (75.1%).
Benign lesions were identified in 121 patients (56.8%),
including 8 (6.6%) with a hyperplastic thyroid nodule, 7
(5.7%) with follicular adenoma, 22 (18.1%) with
Hashimoto’s thyroiditis, and 84 (69.4%) with nontoxic multinodular goiter. Well-differentiated thyroid carcinoma was
identified in 84 patients (91.3%) and, additionally, 4 (4.3%)
had medullary thyroid carcinoma, 3 (3.2%) lymphoma, and
1 (1.08%) poorly differentiated thyroid carcinoma.
Patients’ biochemical parameters are shown in Table 1.
The mean 6 SD preoperative levels of serum albumin, creatinine, Ca, phosphate, magnesium, TSH, and ALP were 33.0 6
4.22 g/L, 62.42 6 17.94 mmol/L, 2.35 6 0.14 mmol/L, 1.12
6 0.35 mmol/L, 0.68 6 0.12 mmol/L, 3.77 6 9.44 mIU/L,
and 71.64 6 24.63 m/L, respectively.
The mean 6 SD preoperative level of 25(OH)D was 45.8
6 21.6 nmol/L (range, 7.0-137.4 nmol/L). Thirty-two patients
(15.0%) had sufficient levels of 25(OH)D, 69 patients
(32.4%) had insufficient levels, 50 patients (23.5%) had
deficient levels, and 62 patients (29.1%) had severely deficient levels.
The mean 6 SD postoperative serum Ca concentrations
at the first, second, and third measurements were 2.22 6
0.15, 2.18 6 0.18, and 2.19 6 0.21 mmol/L, respectively.
The mean 6 SD PTH postoperative level was 3.10 6 2.10.
All postoperative serum Ca levels were significantly lower
than preoperative serum Ca levels (P \ .001).
Postoperative Hypocalcemia
The incidence of postoperative laboratory and clinical hypocalcemia was 19.7% (42 patients) and 17.8% (38 patients),
respectively. Postoperative PTH levels and preoperative
25(OH)D levels were significantly lower in patients with hypocalcemia compared with patients with normocalcemia (1.4 6
0.6 vs 3.8 6 1.9 pmol/L, P \ .001, and 21.7 6 19.3 vs 51.8
6 24.1 nmol/L, P \ .001, respectively). Postoperative PTH
levels and preoperative 25(OH)D levels were also significantly
lower in patients with clinical hypocalcemia compared with
patients without clinical hypocalcemia (1.8 6 1.0 vs 3.7 6
1.9 pmol/L, P \ .001, and 30.7 6 19.4 vs 46.4 6 26.0
nmol/L, P = .001, respectively). There was no significant
association between hypocalcemia and age, gender, histopathology, preoperative serum Ca concentration, or magnesium levels (P . .05; Table 2). There was also no
significant difference in mean postoperative Ca levels
between gender and histopathology groups and no significant
difference between benign and malignant groups with respect
to preoperative 25(OH)D and postoperative PTH levels.
We calculated the incidence of postoperative laboratory
and clinical hypocalcemia according to the different
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Table 2. Comparison of Demographics and Laboratory Measurements in Patients with Hypocalcemia (Laboratory or Clinical) and Patients
with Normocalcemia.a
Laboratorial Hypocalcemia
Variable
Gender, n (%)
Male
Female
Age, mean 6 SD, y
Histopathology, n (%)
Benign
Cancer
Preoperative serum Ca,
mean 6 SD, mmol/L
Preoperative serum 25(OH)D,
mean 6 SD, nmol/L
Postoperative serum PTH,
mean 6 SD, pmol/L
Magnesium, mean 6 SD, mmol/L
Normocalcemia (n = 171)
Hypocalcemia (n = 42)
35 (20.5)
136 (79.5)
44.9 6 15.3
8 (19.0)
34 (81.0)
44.8 6 14.3
85 (55.6)
68 (44.4)
2.36 6 0.14
21 (61.8)
13 (38.2)
2.30 6 0.1
51.8 6 24.1
21.7 6 19.3
3.8 6 1.9
0.7 6 0.1
Clinical Hypocalcemia
P Value
No (n = 175)
Yes (n = 38)
34 (19.4)
141 (80.6)
43.7 6 14.1
9 (23.7)
29 (76.3)
47.4 6 15.9
92 (58.6)
65 (41.4)
2.3 6 0.1
14 (46.7)
16 (53.3)
2.4 6 0.1
.109
\.001
46.4 6 30.7
30.7 6 19.4
.001
1.4 6 0.6
\.001
3.7 6 1.9
1.8 6 1.0
\.001
0.6 6 0.1
.149
0.7 6 0.1
0.6 6 0.1
.358
.999
.969
P Value
.650
.569
.494
.153
.236
Abbreviations: 25(OH)D, 25 hydroxyvitamin D; Ca, calcium; PTH, parathyroid hormone.
a
Total number of patients, N = 213.
Table 3. Study Outcomes (Laboratory and Clinical Hypocalcemia) and Postoperative PTH by Preoperative Serum 25(OH)D Categories.a
Preoperative Serum 25(OH)D, nmol/L
Sufficient (n = 32)
Study outcomes, n (%)
Laboratorial hypocalcemia
Clinical hypocalcemia
Variable, mean 6 SD
Postoperative PTH, pmol/L
Insufficient (n = 69)
1 (3.1)
0
4.4 6 1.2
Deficient (n = 50)
Severely Deficient (n = 62)
2 (2.9)
8 (11.6)
5 (10.0)
9 (18.0)
34 (54.8)
21 (33.9)
4.4 6 1.7
3.5 6 1.9
1.9 6 0.9
Abbreviations: 25(OH)D, 25 hydroxyvitamin D; PTH, parathyroid hormone.
a
Total number of patients, N = 213.
categories of preoperative serum 25(OH)D concentrations
(Table 3). Of the patients with severely deficient preoperative serum 25(OH)D levels, 34 (54.8%) and 21 (33.9%)
developed laboratory and clinical hypocalcemia, respectively. Of the patients with deficient serum 25(OH)D levels,
5 (10.0%) and 9 (18.0%) patients developed laboratory and
clinical hypocalcemia, respectively. Two patients (2.9%)
with insufficient serum 25(OH)D levels developed laboratory hypocalcemia, while 8 patients (11.6%) developed clinical hypocalcemia. Only 1 patient (3.1%) with sufficient
serum 25(OH)D levels developed laboratory hypocalcemia,
and none developed clinical hypocalcemia.
The incidence of laboratory hypocalcemia was significantly
higher in patients with severely deficient serum 25(OH)D than
in patients with a serum 25(OH)D levels of 25 nmol/L or
greater (34 of 62 vs 8 of 151, respectively; P \ .001).
Similarly, the incidence of clinical hypocalcemia was significantly higher in patients with severely deficient serum
25(OH)D levels than in those with 25 nmol/L serum 25(OH)D
or greater (21 of 62 vs 17 of 151, respectively; P = .001).
Patients with serum 25(OH)D levels less than 50 nmol/L
had a higher incidence of laboratory hypocalcemia than
patients with serum 25(OH)D levels of 50 nmol/L or greater
(39 of 112 vs 3 of 101, respectively; P \ .001). Similarly,
the incidence of clinical hypocalcemia was higher in the
patients with serum 25(OH)D levels less than 50 nmol/L
than in the patients with serum 25(OH)D levels of 50 nmol/
L or greater (30 of 112 vs 8 of 101, respectively; P \ .001).
An analysis of subgroups showed no significant difference in the incidence of laboratory (P =.12) or clinical (P =
.59) hypocalcemia between the patients with deficient levels
of serum 25(OH)D and the patients with serum 25(OH)D
levels of 50 nmol/L or higher. Moreover, the incidence of
laboratory hypocalcemia was significantly higher in the
patients with severely deficient serum 25(OH)D than in the
patients with deficient levels of serum 25(OH)D (34 of 62
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Otolaryngology–Head and Neck Surgery 152(3)
Table 4. Multiple Logistic Regression Analysis for Predicting Hypocalcemia after Thyroidectomy.a
Variable
OR
95% CI
P Value
Postoperative serum PTH, pmol/L
Preoperative serum 25(OH)D, \25 nmol/L
0.6
7.3
0.5-0.8
2.3-22.9
.002
.001
Abbreviations: 25(OH)D, 25 hydroxyvitamin D; PTH, parathyroid hormone
a
N = 213. The dependent variable is postoperative hypocalcemia. Reference category for dependent variable (normocalcemia) and preoperative serum
25(OH)D (25 nmol/L).
vs 5 of 50, respectively; P \ .001). However, no significant
difference was observed in the incidence of clinical hypocalcemia (P = .08) between the patients with severely deficient and deficient levels of serum 25(OH)D.
Mean postoperative PTH levels are reported in Table 3
according to the 4 categories of preoperative serum 25(OH)D
levels. Postoperative PTH levels in patients with severely
deficient preoperative serum 25(OH)D levels (\25 nmol/L)
were significantly lower than those of patients with deficient,
insufficient, and sufficient serum 25(OH)D levels (1.9 6 0.9
vs 3.5 6 1.9, 4.4 6 1.7, and 4.4 6 1.2 pmol/L, respectively;
P \ .001).
Multiple logistic regression analysis was performed to
assess patients’ preoperative serum 25(OH)D levels (using
the cutoff value of 25 nmol/L) and postoperative PTH
levels (Table 4). We found that both preoperative serum
25(OH)D levels and postoperative PTH levels were significant, independent predictors of postoperative hypocalcemia
(P \ .05). Patients with a preoperative serum 25(OH)D
level less than 25 nmol/L had a 7.3-fold increased risk of
developing postoperative laboratory hypocalcemia (OR, 7.3;
95% CI, 2.3-22.9; P = .001). Moreover, there was a reduced
risk of developing postoperative laboratory hypocalcemia in
patients with increased PTH levels (OR, 0.6; 95% CI, 0.50.8; P = .002).
Discussion
Predictors of postthyroidectomy hypocalcemia have been
widely investigated in several studies, and the drive to identify these predictors may reflect a growing trend toward
shorter and more cost-effective hospital stays.
Vitamin D is a fat-soluble vitamin. It is derived from
cholesterol and then activated in the liver into 25(OH)D. It
is then converted into 1,25(OH)2 vitamin D in a PTHdependent manner. In the active form, vitamin D permits
increased gastrointestinal absorption of Ca and increased Ca
and phosphate resorption by the kidney, which ultimately
contributes to Ca homeostasis.39
Very few studies to date have examined the relationship
between VDD and the incidence of postthyroidectomy
hypocalcemia; the studies that have explored this relationship have shown diverse results, and thus a consensus has
not yet been reached regarding the role of this potentially
significant risk factor. A study conducted by Griffin et al29
of 121 patients who underwent total or completion thyroidectomy found no significant differences in the incidence
rate of postthyroidectomy clinical or laboratory hypocalcemia
among different vitamin D categories. However, their study
included patients who underwent concomitant central compartment neck dissection, patients with hyperthyroidism, and
patients with parathyroid glands in histopathologic analysis.
Although they did not report any significant effect of these
factors on postoperative hypocalcemia rates, they remain
widely reported risk factors in the literature for developing
hypocalcemia.17,18,40-42 Salinger and Moore31 reported similar
results as well, yet the study population was considerably
variable and included patients who underwent central compartment neck dissection and patients with parathyroid glands
in resected specimens. They also included patients with
Graves’ disease and toxic multinodular goiter (15%) and did
not conduct any subanalysis to establish the risk of developing hypocalcemia in this particular group. These conditions
may lead to Ca accumulation in bones and reversal of thyrotoxic osteodystrophy postoperatively, which may subsequently lead to higher hypocalcemia rates.43 Moreover, other
studies have suggested that low serum 25(OH)D levels may
play an insignificant role in this condition.28,19,21,30,32
In the present study, we investigated the relationship
between the development of postoperative hypocalcemia
and serum 25(OH)D levels in 213 patients who underwent
total thyroidectomy. Since the purpose of this study was to
accurately investigate the role of low serum 25(OH)D levels
in developing this complication, we aimed to reduce the
number of confounders as much as possible by implementing a strict exclusion criteria.
Overall, the incidence rate of laboratory and clinical hypocalcemia was 19.7% and 17.8%, respectively. Importantly,
these results are in agreement with similar rates ranging from
15.8% to 37% found in previous studies using the same definition for hypocalcemia.17,23,25,29,34
Our data indicate that gender, age, and preoperative
serum Ca and magnesium levels as well as histopathologic
diagnosis were not significantly associated with hypocalcemia (Table 2). Results from a previous systematic review
and meta-analysis44 are in agreement with our data in
terms of age and preoperative serum Ca and magnesium
levels but differ with the results pertaining to gender as they
found that the incidence of hypocalcemia was significantly
higher in females. Although we found the incidence of hypocalcemia slightly higher in females (20% vs 18.6%), this
result was not statistically significant. The diagnosis of malignant versus benign thyroid disease also did not reveal any
significant difference in our results, which is consistent with
a prospective analysis by Asari et al.45
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429
We also found that serum 25(OH)D levels were significantly lower in patients with laboratory or clinical hypocalcemia compared with normocalcemic patients (P .001).
Furthermore, we assessed the occurrence of hypocalcemia
according to established categories of serum 25(OH)D
levels.38 The incidence of laboratory hypocalcemia in vitamin D sufficient (n = 32), insufficient (n = 69), deficient
(n = 50), and severely deficient (n = 62) subjects was
found to be 3.1%, 2.9%, 10%, and 54.8%, respectively
(Table 3). We also noted that patients with severe VDD
had the highest incidence rate of laboratory and clinical
hypocalcemia among the other categories. Further analysis revealed a significantly higher incidence of hypocalcemia in severely deficient 25(OH)D levels compared with
levels of 25 nmol/L or greater (P .001). Similarly,
25(OH)D levels less than 50 nmol/L had a significantly
higher incidence of hypocalcemia when compared with
levels of 50 nmol/L or higher (P \ .001). Although the
subgroup analysis did not reveal any statistical significance between patients labeled as VDD and the insufficient/sufficient group in terms of laboratory (P = .12) or
clinical (P = .59) hypocalcemia, we did note a statistically significant increase in the incidence of laboratory
hypocalcemia in severe VDD patients compared with
VDD patients (P \ .001). However, this was not the case
for clinical hypocalcemia (P = .08). Another study also
reported a significant difference in hypocalcemia rates
between severe VDD patients (35.5%) and subjects with
VDD (28%).35
Multiple logistic regression analysis was conducted to
evaluate preoperative severe VDD (Table 4). This particular group was chosen because it significantly deferred from
other categories in terms of higher incidence of hypocalcemia. Our results confirmed that severe VDD is an independent risk factor for the development of postthyroidectomy
hypocalcemia (P \ .05), which was consistent with the
findings of Erbil et al.23 That study found that patients with
25(OH)D levels \37.5 nmol/L had a 558.5-fold increase in
the risk for hypocalcemia compared with a 7.3-fold increase
in risk for patients with levels \25 nmol/L in our study.
Although several other studies23,33-36 also support our
results pertaining to the role of low serum 25(OH)D levels
in developing postoperative hypocalcemia, the results may
differ because of different serum 25(OH)D cutoff values as
well as clinical parameters used by other authors.
Lower vitamin D levels have been implicated in the
development of secondary hyperparathyroidism and subsequently higher serum PTH levels.46 However, there is no
cutoff value for vitamin D below which PTH levels are
expected to rise.47 Our subjects did not display higher PTH
levels postoperatively, including patients who did not
develop hypocalcemia. One study reported that postoperative
PTH was unreliable in the prediction of postthyroidectomy
hypocalcemia in patients with VDD.48 Interestingly, our
results showed significantly lower serum PTH levels among
subjects with severe VDD when compared with other vitamin
D categories. Our results also revealed serum PTH level as a
significant independent predictor of postoperative hypocalcemia.
Our study was limited by the lack of long-term follow-up of
serum Ca levels and preoperative serum PTH levels, which
might have aided in determining the incidence of transient and
permanent hypocalcemia as well as further study of serum PTH
levels in patients with VDD.
Conclusion
In conclusion, we found that serum 25(OH)D is a marker of
postoperative hypocalcemia. Our analysis revealed severe
VDD as an independent predictor of postoperative laboratory
hypocalcemia. This may permit a more cost-effective approach
regarding this specific category of VDD and allow early recognition and prevention of hypocalcemia. Prospective multicenter
studies may be useful in future studies.
Acknowledgments
We would like to acknowledge thyroid surgeons in our hospital
who performed the procedures.
Author Contributions
Talal Al-Khatib, contributed to the writing of the Discussion section, the design, data interpretation, and revised the manuscript
with major adjustments to the structure; Abdulrahman M.
Althubaiti, contributed to the writing of the Introduction,
Discussion section, and references and critically revised the manuscript; Alaa Althubaiti, wrote the Results section, performed data
analysis, and participated extensively in data interpretation; Hala H.
Mosli, outlined the initial study design, revised the Results and
Conclusion sections, and contributed extensively to the Methods section; Reem O. Alwasiah, contributed to data collection and interpretation, cowrote the Methods section, and revised the references;
Lojain M. Badawood, contributed to data collection, interpretation,
and cowrote the Methods section.
Disclosures
Competing interests: None.
Sponsorships: None.
Funding source: None.
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