The American Journal of Surgery (2011) 201, 685– 691

Clinical Science

Determinants of postoperative hypocalcemia in vitamin

D– deficient Graves’ patients after total thyroidectomy
Yeşim Erbil, M.D.a*, Nese Colak Ozbey, M.D.b, Serkan Sari, M.D.a,
Haluk Recai Unalp, M.D.a, Orhan Agcaoglu, M.D.a, Feyzullah Ersöz, M.D.a,
Halim Issever, M.D.c, Selçuk Ozarmagan, M.D.a

a
Department of General Surgery, Istanbul University, 34093 Capa, Istanbul, Turkey; bDepartment of Endocrinology,
Istanbul University, Capa, Istanbul, Turkey; cDepartment of Public Health, Istanbul University, Capa, Istanbul, Turkey

KEYWORDS: Abstract
Graves disease; BACKGROUND: The etiology of postoperative hypocalcemia after total thyroidectomy appears to be
Hypothyroidism; multifactorial, that is, postoperative transient hypoparathyroidism, low 25-hydroxy vitamin D (25-
Hungry bone OHD) concentrations, aging, and hyperthyroidism with increased bone turnover. Our aim was to
syndrome; evaluate the factors responsible for postoperative hypocalcemia in euthyroid vitamin D– deficient/
Vitamin D insufficient Graves patients who underwent total thyroidectomy at our institution.
METHODS: Thirty-five consecutive patients with Graves disease treated by total thyroidectomy
were included in the present study. All patients were vitamin D deficient/insufficient (ie, 25-OHD
concentrations of ⬍20/⬍30 ng/mL, respectively). Patients were divided into 2 groups according to
postoperative serum albumin corrected calcium concentrations: group 1 (n ⫽ 13) patients had postop-
erative serum calcium concentrations of 8 mg/dL or less; group 2 (n ⫽ 22) patients had serum calcium
concentrations greater than 8 mg/dL. Bone turnover markers (deoxypiridinoline, bone-specific alkaline
phosphatase) and 25-OHD were determined the day before surgery.
RESULTS: In group 1 patients, disease duration was significantly longer, 25-OHD and postoperative
parathyroid hormone concentrations were significantly lower, and bone turnover markers were signif-
icantly higher. Logistic regression analysis revealed that a postoperative parathyroid hormone concen-
tration less than 10 pg/mL was the most powerful parameter to predict postoperative hypocalcemia
(odds ratio, 23; 95% confidence interval, 3.3–156).
CONCLUSIONS: In Graves patients with vitamin D deficiency/insufficiency, postoperative (tran-
sient) hypoparathyroidism is the most significant parameter to determine the development of postop-
erative hypocalcemia.
© 2011 Elsevier Inc. All rights reserved.

Transient postoperative hypocalcemia after thyroidec-
tomy for benign thyroid disorders leads to patient distress
and prolonged hospital stay.1 The etiology appears to be
* Corresponding author. Tel.: ⫹902124142000; fax: ⫹902125341605.
E-mail address: yerbil2003@yahoo.com
Manuscript received February 3, 2010; revised manuscript April 13,
2010
multifactorial, that is, postoperative transient iatrogenic hy-
poparathyroidism, preoperative low 25-hydroxy vitamin D
(25-OHD) concentrations, aging, and hyperthyroidism with
increased bone turnover leading to hungry bone syn-
drome.1,2
A previous study at our institution indicated that a low
preoperative 25-OHD level was the most significant predic-
tor for low postoperative serum calcium concentrations in

0002-9610/$ - see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjsurg.2010.04.030
686
patients with euthyroid multinodular goiter who underwent
total thyroidectomy.1 However, the significant predictors of
postoperative hypocalcemia after thyroidectomy in patients
with hyperthyroidism could be different.
Hyperthyroidism has a significant impact on bone turn-
over even after restoration of euthyroidism.3 Pantazi and
Papapetrou3 showed ongoing increased bone turnover, de-
spite achievement of euthyroidism with antithyroid drugs.
In their study, parathyroid hormone (PTH) concentrations
remained increased during the first year of hyperthyroidism
treatment, suggesting a pivotal role for the relatively high
rate of bone turnover even in the euthyroid state. Increased
PTH concentrations lead to maintaining a positive calcium
balance by increased renal tubular and intestinal calcium
absorption (through stimulating renal 1␣-hydroxylase activ-
ity and formation of 1–25 dihydroxyvitamin D) and may
have anabolic effect on osteoblasts. Therefore, patients with
Graves hyperthyroidism who underwent thyroidectomy
should be more susceptible to hypocalcemia owing to iat-
rogenic transient hypoparathyroidism, which disrupts com-
pensatory increases in PTH concentrations.4 Patients with
Graves hyperthyroidism should be rendered euthyroid be-
fore planned surgical treatment. However, ongoing high-
turnover rate may contribute to postoperative hypocalcemia
even in patients with adequate 25-OHD concentrations and
undisturbed parathyroid function after surgery.
The aim of this study was to evaluate the factors respon-
sible for postoperative hypocalcemia, in particular the effect
of bone turnover parameters on postoperative hypocalce-
mia, in euthyroid vitamin D– deficient/insufficient Graves
patients who underwent total thyroidectomy at our institu-
tion.
Materials and Methods
Patients
In the Department of Surgery at the Istanbul Faculty of
Medicine 35 consecutive patients with Graves disease
treated by bilateral total thyroidectomy from January 2008
to September 2009 were included prospectively in the pres-
ent study. Patients still hyperthyroid on antithyroid drug
treatment, with substernal goiter or a previous thyroid or
neck surgery, and concomitant primary hyperparathyroid-
ism were excluded. None of the patients was on medications
known to affect serum calcium metabolism such as oral
calcium/vitamin D supplementation, antiresorptive agents,
hormone replacement therapy for postmenopausal women,
anabolic agents, thiazide-type diuretics, and antiepileptic
agents. Only 1 woman was postmenopausal. The indications
for surgical treatment were severe ophthalmopathy (n ⫽
17), large goiter (n ⫽ 7), suspicion of malignancy (n ⫽ 6),
and recurrence after antithyroid drug treatment (n ⫽ 5). The
study plan was reviewed and approved by our institutional
The American Journal of Surgery, Vol 201, No 5, May 2011
ethical committee, and informed consent was obtained from
all patients.
Vitamin D status was determined for all patients before
surgery. A 25-OHD level less than 20 ng/mL is considered
a deficiency; 20 to 30 ng/mL is considered insufficiency,
and greater than 30 ng/mL is considered a sufficient con-
centrations.5 A serum PTH concentration less than 10
pg/mL in association with serum albumin corrected calcium
concentrations less than 8 mg/dL was considered a marker
for postoperative hypoparathyroidism.
Transient iatrogenic hypoparathyroidism was defined as
postoperative hypocalcemia whether symptomatic or not, in
association with PTH concentrations less than 10 pg/mL,
treated with calcium and vitamin D at first presentation, and
recovered during follow-up evaluation with normal serum
calcium and PTH concentrations after cessation of vitamin
D and calcium replacement therapy.
Serum calcium, PTH, 25-OHD, deoxypiridinoline (DPD)
(a marker of osteoclast function), bone-specific alkaline
phosphatase (BALP) (a marker of osteoblast function), al-
kaline phosphatase, creatinine, and albumin levels were
determined the day before surgery. Serum calcium concen-
trations were measured 12 hours after surgery and repeated
at 24 hours. The lowest postoperative serum calcium level
was verified for all patients. Serum calcium concentration
was adjusted for serum albumin.
Total thyroidectomy was performed by experienced en-
docrine surgeons. Total thyroidectomy is defined as total
bilateral extracapsular thyroidectomy. Recurrent laryngeal
nerves carefully were identified and dissected. All parathy-
roid glands were preserved with meticulous dissection for
their blood supply. In the histopathologic examination of
the resected tissue no parathyroid gland was identified.
Hypocalcemia was defined as a serum albumin– cor-
rected calcium concentration of less than 8 mg/dL. Asymp-
tomatic hypocalcemia was a laboratory finding whereas
patients with symptomatic hypocalcemia had clinical symp-
toms (ie, paresthesia, in particular, perioral muscular
cramps and in advanced cases carpopedal spasm) besides
laboratory findings. Thirty-five patients were divided into 2
groups according to postoperative calcium concentrations.
Patients in group 1 (n ⫽ 13) had postoperative serum
calcium concentration less than 8 mg/dL, patients in group
2 (n ⫽ 22) had serum calcium concentration greater than 8
mg/dL. Serum calcium concentrations of hypocalcemic pa-
tients were measured every 12 hours until the serum cal-
cium levels stabilized. Symptomatic hypocalcemia was
treated with parenteral calcium and oral 1,25-dihydroxyvi-
tamin D3 (calcitriol, 1–1.5 ␮g/d) and calcium (2–3 g/d)
supplementation. Patients with symptomatic hypocalcemia
were discharged on oral calcium and calcitriol at doses
modified in relation to serum calcium concentration and
were followed up weekly until normalization of their serum
calcium and PTH levels. None of the patients had perma-
nent hypoparathyroidism after surgery.
Y. Erbil et al. Hypocalcemia in vitamin D– deficient Graves= patients 687

Biochemical analysis considered as 10 ng/mL for statistical purposes. Logistic

Thyroid hormones and thyroid antibody concentrations
were determined by a chemiluminescent assay using the
DPP Modular System (Roche Diagnostics, F. Hoffmann-La
Roche, Ltd, Basel, Switzerland). Serum 25-OHD and PTH
levels were determined by immunoradiometric assay using
commercially available kits: the PTH 120-minute IRMA kit
and the 25-OHD RIA CT kit, respectively (BioSource, Eu-
rope S.a, Nivelles, Belgium). Serum DPD and BALP levels
were determined by high-performance liquid chromatogra-
phy and enzyme-linked immunosorbent assay using Bio-
grad and Mikrovue Quidal kits, respectively (BioSource,
Europe S.a, Nivelles, Belgium). Normal ranges of the mea-
sured parameters were as follows: PTH, 0 to 65 pg/mL;
tri-iodothyronine, .8 to 2 ng/mL; free-tri-iodothyronine, 2.6
to 5.7 pmol/L; thyroxine, 5.1 to 14.1 mg/dL; free-thyroxine,
12 to 22 pmol/L; thyrotropin, .3 to 4.9 mIU/L; anti–thyroid
peroxidase, 0 to 35 IU/mL; antithyroglobulin, 0 to 115
IU/mL; and thyrotropin receptor antibody (TRAb), 9 to 14
ng/mL; ALP, 30 to 135 U/L; and BALP, 15 to 41.3 U/L;
DPD premenopausal female, 0 to 0.57 mg/mL; postmeno-
pausal female, 0 to 1 mg/mL; 20 to 49 year old male, 0 to
0.58 mg/mL; 50 to 59 year old male, 0 to 0.70 mg/mL; more
than 50 year old male, 0 to 0.85 mg/mL.
Statistical analysis
Data are reported as the mean ⫾ standard deviation.
Analysis was performed with the statistical package SPSS
10.1 (SPSS, Chicago, IL). Differences between parameters
were compared with the t test, Mann–Whitney U test, Wil-
coxon test, and chi-square test. Correlation analyses were
performed using the nonparametric Spearman correlation
test. A serum PTH concentration less than 10 pg/mL was
regression analysis was performed to determine significant
variables to predict postoperative hypocalcemia.
Results
The mean age ⫾ standard deviation of the whole study
group was 38.7 ⫾ 14 years (range, 19 –73 y). The female/
male ratio was 4/1 (n ⫽ 28/7). The duration of disease
according to antithyroid treatment length was 31.4 ⫾ 28.5
months. Of 35 patients, 15 were treated with propylthioura-
cil and 20 were treated with methimazole. Clinical findings
of ophthalmopathy were evident in 17 patients. There was
no surgical mortality. The incidence of transient vocal cord
paralysis was 5.7% (2 of 35).
Postoperative hypocalcemia
In 13 (37.1%) patients in group 1 (13 of 35) the serum
calcium level was found to be less than 8 mg/dL postoper-
atively. No significant difference was observed with respect
to frequency of ophthalmopathy, the choice of antithyroid
drug, serum thyroid hormone, thyroid antibodies, or preop-
erative PTH concentrations (Table 1). In group 1, the du-
ration of disease, serum alkaline phosphatase level, BALP
level, and DPD level were found to be significantly higher
and 25-OHD and postoperative PTH concentrations were
significantly lower.
In the whole group, only 4 male patients had serum
25-OHD concentrations greater than 20 ng/mL but less than
30 ng/mL (vitamin D insufficiency). The remaining patients
(men and women) had 25-OHD concentrations less than 20
ng/mL (vitamin D deficiency). Therefore, all study patients
were vitamin D deficient/insufficient. One of 4 male patients

Table 1 Comparison of demographic features, thyroid hormones, and thyroid antibodies in hypocalcemic and normocalcemic
patients

Hypocalcemic patients Normocalcemic patients

(n ⫽ 13) (n ⫽ 22) P
Age, y 36.1 ⫾ 16 40.2 ⫾ 3.8 NS
Female/male 12/1 16/6 NS
Duration of disease, mo 67.1 ⫾ 10 10.4 ⫾ 3.8 .001
Presence of ophthalmopathy, n 7 10 NS
Ratio of treatment with PTU/MMI 5/8 10/12 NS
Preoperative serum T3 level, ng/mL 1.2 ⫾ .5 1.2 ⫾ .6 NS
Preoperative serum FT3 level, pmol/L 5 ⫾ 1 4.2 ⫾ 1 NS
Preoperative serum T4 level, mg/dL 6.2 ⫾ 3.6 6.1 ⫾ 1 NS
Preoperative serum FT4 level, pmol/L 13 ⫾ 8.1 12.7 ⫾ 3.8 NS
Preoperative serum TSH level, mIU/L* (range) 1.2 ⫾ 2.3 (.001–4.4) .9 ⫾ 1.8 (.001–3.2) NS
Preoperative serum anti-TPO leve, IU/L* (range) 332.08 ⫾ 174 (57–600) 324.61 ⫾ 181 (90–600) NS
Preoperative serum anti-Tg level, IU/L* (range) 108.46 ⫾ 148 (10–450) 222.25 ⫾ 343 (10–1010) NS
Preoperative serum TRAb level, ng/mL* (range) 17.9 ⫾ 20 (.15–368) 24.5 ⫾ 16 (.01–440) NS
PTU ⫽ propylthiouracil; MMI ⫽ methimazole; T3 ⫽ tri-iodothyronine; FT3 ⫽ free-tri-iodothyronine; T4 ⫽ thyroxine; FT4 ⫽ free-thyroxine; TSH ⫽
thyrotropin; TPO ⫽ thyroid peroxidase; Tg ⫽ thyroglobulin.
*The Mann–Whitney U test was used because of non-normal distribution.
688 The American Journal of Surgery, Vol 201, No 5, May 2011

Table 2 Comparison of laboratory parameters in hypocalcemic and normocalcemic patients

Hypocalcemic patients Normocalcemic patients

(n ⫽ 13) (n ⫽ 22) P
Preoperative serum calcium level, mg/dL 9.2 ⫾ .3 9.1 ⫾ .3 NS
Postoperative serum calcium level, mg/dL 7.2 ⫾ .3 8.9 ⫾ .4 .001
Preoperative serum PTH level, pg/mL 37.5 ⫾ 7.5 38.4 ⫾ 7.4 NS
Postoperative PTH level, pg/mL 5.3 ⫾ 1.7 42.6 ⫾ 6 .001
Preoperative serum ALP level, U/L* (range) 220.33 ⫾ 90 (122–401) 222.87 ⫾ 114 (50–446) NS
Preoperative serum 25-OHD level, ng/mL* (range) 9.7 ⫾ 6.2 (5–17.8) 13.2 ⫾ 5.4 (6.3–16) .01
Patient with vitamin D insufficiency/deficiency, n 1/11 3/19 NS
Preoperative serum DPD level, mg/mL* (range) 20.7 ⫾ 14 (.6–48) 9.2 ⫾ 13 (.3–33) .001
Preoperative serum BALP level, U/L* (range) 50.6 ⫾ 17 (33–97) 12.6 ⫾ 3.8 (5.5–22.6) .001
*The Mann–Whitney U test was performed because of non-normal distribution.

with vitamin D insufficiency had postoperative hypocalce- Logistic regression analysis

mia.
No statistically significant difference was observed with
respect to the frequency of vitamin D insufficiency/defi-
ciency between patients with postoperative hypocalcemia
and normocalcemia (1 of 11 vs 3 of 19; P ⬎ .05) (Table 2).
In group 1, all patients (male and female) had PTH
concentrations less than 10 ng/mL in association with hy-
pocalcemia. Therefore, all patients had postoperative (tran-
sient) hypoparathyroidism. In group 2, none of the patients
had PTH concentrations less than 10 ng/mL. In our study
group all female patients were vitamin D deficient (ie,
25-OHD was ⬍20 ng/mL). 25-OHD concentrations of fe-
male patients with hypocalcemia and normocalcemia were
8.2 ⫾ 3.4 ng/mL and 10.7 ⫾ 3.3 ng/mL, respectively (P ⫽
.06). Postoperative PTH concentrations of female patients
with hypocalcemia and normocalcemia were 5.5 ⫾ 1.9
pg/mL and 39.8 ⫾ 7 pg/mL, respectively (P ⫽ .001). All the
female patients in the hypocalcemia group (n ⫽ 12) had
PTH concentrations less than 10 pg/mL. None of 16 females
in the normocalcemia group had PTH concentrations less
than 10 pg/mL.
All the patients with hypocalcemia developed symptoms.
Hospital stay was significantly longer in group 1 (3.6 ⫾
1.1 d; range, 2–7 d) compared with group 2 (1.3 ⫾ .4 d;
range, 1–2 d) (P ⫽ .001). During the follow-up evaluation,
all patients were able to stop oral vitamin D and calcium
supplementation.
The most significant parameter to predict postoperative
hypocalcemia was postoperative PTH concentrations. Post-
operative PTH concentrations less than 10 pg/mL increased
the risk of hypocalcemia 23-fold (odds ratio, 23; 95% con-
fidence interval, 3.3–156) (Table 3). When male patients
were excluded from the analysis, the odds ratio of female
patients was similar to the whole group (Table 4).
Correlations
Negative correlations were found between the postoper-
ative serum calcium level and the BALP (r ⫽ ⫺.607; P ⫽
.0001), the DPD level (r ⫽ ⫺.688; P ⫽ .0001), the duration
of disease (r ⫽ ⫺.778; P ⫽ .0001), and being female (r ⫽
⫺.344; P ⫽ .04), whereas significant positive correlations
were observed between the postoperative serum calcium
and the 25-OHD level (r ⫽ .401; P ⫽ .01) (Fig. 1).
Comments
Hyperthyroidism has significant effects on bone metab-
olism, even in the subclinical stage.3,6 – 8 Triiodothyronine
nuclear receptors are found on osteoblasts.6 Accelerated
bone turnover caused by direct stimulation of bone cells
triggers bone loss in hyperthyroidism. In the hyperthyroid

Table 3 Significant parameters to predict postoperative

hypocalcemia for the whole group Table 4 Significant parameters to predict postoperative
hypocalcemia for female patients
Odds 95% confidence
Parameter ratio interval Odds 95% confidence
Parameter ratio interval
Postoperative PTH ⬍10 ng/mL 23 3.3–156.0
25-OHD ⬍11 ng/mL 9 2.0–50.0 Postoperative PTH ⬍10 ng/mL 17 2.5–113.0
DPD ⬎1 mg/mL 7.9 1.4–44.8 25-OHD ⬍11 ng/mL 8.3 1.4–50.0
BALP ⬎15 U/L 3.6 1.7–7.5 DPD ⬎1 mg/mL 6.4 1.0–39.3
Disease duration ⬎12 mo 5.3 1.9–14.7 BALP ⬎15 U/L 5 1.8–3.7
Age ⬎40 y 4.5 .4–42.5 Disease duration ⬎12 mo 5 1.8–13.7
Females 2.5 .5–9.0 Age ⬎40 y 4.5 3.7–42.9
Y. Erbil et al. Hypocalcemia in vitamin D– deficient Graves= patients 689

Figure 1 Relationship between the postoperative serum calcium level and the (A) BALP and (B) OPD level and the (C) duration of
disease and (D) 25-OHD level in Graves disease.

state increased bone resorption leads to increased serum
calcium concentrations and suppression of circulating
PTH.7–9 After treatment of hyperthyroidism, either with
surgery or antithyroid drugs, serum calcium concentrations
tend to decline.2,3 At this stage increased PTH concentra-
tions seem to play a compensatory role for positive calcium
balance and deposition of calcium to bone.3
Yamashita et al2 reported that preoperative serum cal-
cium levels were significantly lower and preoperative PTH
levels were higher in Graves patients with tetany compared
with patients who did not develop tetany despite undetect-
able PTH concentrations after surgery. They concluded that,
apart from surgery-induced transient hypoparathyroidism,
postoperative tetany occurred in patients with preoperative
secondary hyperparathyroidism caused by calcium and vi-
tamin D deficiency. Therefore, preoperative sufficiency of
calcium and vitamin D may overcome the deleterious ef-
fects of postoperative hypoparathyroidism on serum cal-
690
cium concentrations. In a more recent report, Yamashita et
al10 also indicated that female Graves patients with vitamin
D deficiency and higher alkaline phosphatase concentra-
tions were at the greatest risk for tetany after subtotal
thyroidectomy. The present study did not support those
conclusions. Our patients, in particular females, were a
relatively homogenous group with respect to vitamin D
concentrations. Our female patients with postoperative hy-
pocalcemia had similar 25-OHD concentrations compared
with postoperative normocalcemic females. With a status of
vitamin D deficiency/insufficiency, postoperative hypopara-
thyroidism had the most important impact on the develop-
ment of postoperative hypocalcemia. Bone-turnover par-
ameters also significantly predicted the development of
postoperative hypocalcemia although having less strong an
effect compared with postoperative hypoparathyroidism. In
addition, being female had significant impact on postoper-
ative hypocalcemia. It previously was reported that women
with Graves disease were more susceptible to postoperative
hypocalcemia because a higher percentage of women had
vitamin D deficiency.11
In the present study, patients with postoperative hypocal-
cemia had a longer duration of hyperthyroidism. Kumeda at
al7 showed that TRAb could be used as a sensitive marker
for bone turnover; increased TRAb concentrations corre-
lated significantly and positively with BALP and urinary
pyridinoline and deoxypyridinoline concentrations. In the
present study, TRAb concentrations did not differ signifi-
cantly between patients with and without postoperative hy-
pocalcemia, but a longer duration of disease may indicate
more serious influence of hyperthyroidism on bone metab-
olism.
As a whole group, all of our patients had vitamin D
deficiency or insufficiency. Vitamin D deficiency and insuf-
ficiency is common in our population.12,13 Low levels of
25-OHD also were reported in patients with Graves dis-
ease.14,15 In hyperthyroidism, increased metabolic clearance
of 25-OHD could contribute or potentiate the low vitamin D
status.2
Our vitamin D– deficient/insufficient patients had serum
PTH concentrations within normal limits before the surgery;
this is not appropriate for the vitamin D deficiency states.
Increased bone turnover and increased calcium influx from
bone may prevent development of secondary hyperparathy-
roidism of vitamin D– deficiency states in Graves disease.
Chernobilski et al16 reported suppressed PTH and 1,25-
dihydroxyvitamin D3 concentrations in Graves patients
compared with toxic multinodular goiter cases. This obser-
vation could be caused by a more severe degree of hyper-
thyroidism in Graves patients or profoundly decreased 1,25-
dihydroxyvitamin D3 concentrations might be secondary to
an immune-mediated event.16
In the present study, aging also had a significant influ-
ence on postoperative hypocalcemia. Aging contributed to a
negative calcium balance via decreased intestinal calcium
absorption, decreased renal 1-␣ hydroxylase activity, and
The American Journal of Surgery, Vol 201, No 5, May 2011
decreased dermal synthesis of vitamin D under sunlight.17,18
Therefore, aging is associated with a decrease in defense
mechanisms against hypocalcemia.
In conclusion, in vitamin D– deficiency/insufficiency
states, in particular for female patients, postoperative tran-
sient hypoparathyroidism is the most significant parameter
to determine the development of postoperative hypocalce-
mia. Duration of hyperthyroidism, increased bone turnover,
and having vitamin D concentrations less than 11 ng/mL
also have significant effects on postoperative hypocalcemia.
Adequate status of vitamin D and calcium during medical
treatment of hyperthyroidism may help to deal with post-
operative hypocalcemia owing to hungry bone syndrome.
However, meticulous dissection and preservation of para-
thyroid function are of the utmost importance to prevent the
development of postoperative hypocalcemia in patients al-
ready deficient for vitamin D.
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