ORIGINAL ARTICLE

The impact of vitamin D status and tumor sizeon the intraoperative parathyroid hormone dynamics in patientswith symptomatic primary hyperparathyroidism

Gaurav Agarwal • Dhalapathy Sadacharan •

Pooja Ramakant • Manoj Shukla • Saroj K. Mishra

Received: 1 June 2011 / Accepted: 27 September 2011 / Published online: 5 January 2012

� Springer 2011

Abstract

Purpose The intraoperative parathyroid hormone

(IOPTH) monitoring is a useful adjunct for predicting whe-

ther a cure has been obtained during parathyroidectomy. We

studied the influence of vitamin D status and parathyroid

tumor weight on the IOPTH dynamics for predicting a cure in

patients with symptomatic primary hyperparathyroidism.

Methods Fifty-nine primary hyperparathyroidism patients

with a single adenoma underwent curative surgery. Patients

were grouped according to their serum 25-hydroxy vitamin

D levels (deficient, insufficient and sufficient) and tumor

weights (small, large and giant). The IOPTH results in

patient groups were compared, and the percentage of the

IOPTH decrease was examined for a correlation with the

serum 25-hydroxy vitamin D level and tumor weight.

Results The sensitivity, specificity and overall accuracy of

IOPTH in predicting a cure of hyperparathyroidism were

94.8, 100 and 93.2%, respectively. The percentage decrease

in the IOTPH was significantly higher in the vitamin D

deficient, compared to the vitamin D sufficient patients

(p = 0.012); and in the patients with larger tumors, com-

pared to those with smaller parathyroid tumors (p = 0.02). A

statistically significant correlation was found between the

percentage decrease in the IOPTH at 10 min post-tumor

excision and the serum 25-hydroxy vitamin D level

(p = 0.037), but not with the tumor weight (p = 0.208).

Conclusions The IOPTH can accurately predict a cure in

patients with severe primary hyperparathyroidism. The

percentage of decrease in the IOPTH is steeper in patients

with lower serum 25-hydroxy vitamin D levels and larger

parathyroid tumors.

Keywords Symptomatic primary hyperparathyroidism �Parathyroidectomy � Intra-operative parathyroid hormone

monitoring � Serum 25-hydroxy vitamin D � Parathyroid

tumor weight

Introduction

The majority of patients with primary hyperparathyroidism

(PHPT) who are managed in India present with overtly

symptomatic disease, and many have severe musculoskel-

etal manifestations. A lack of screening for hypercalcemia,

late detection, vitamin D deficiency, and possibly some

genetic differences play major roles in such presentation of

PHPT in Indian patients [1, 2]. In spite of abundant sun-

shine, vitamin D deficiency is highly prevalent in India

because of nutritional deficiencies in pro-vitamin D, and

because of the dark skin of many Indians, as a longer

exposure to UVB light is needed for the synthesis of vitamin

D in subjects with darker skin. Serum 25-hydroxy vitamin

D (25-OH-D) levels are the best indicator of the vitamin D

nutritional status [3], and have negative correlations with

the serum intact parathyroid hormone (PTH) and alkaline

phosphatase levels, and the bone mineral density in PHPT

[4]. An inverse relationship exists between the serum

25-OH-D level and parathyroid gland weight [5]. The

parathyroid tumor weight in Indian PHPT patients is higher

compared to those reported from elsewhere, and is a sig-

nificant determinant of the severity of PHPT [2, 5].

G. Agarwal (&) � D. Sadacharan � P. Ramakant � M. Shukla �S. K. Mishra

The Departments of Endocrine and Breast Surgery,

Endocrine Sciences Centre, SGPGIMS, Raebareli Road,

Lucknow 226014, India

e-mail: gaurav@sgpgi.ac.in

123

Surg Today (2012) 42:1183–1188

DOI 10.1007/s00595-011-0113-5

Intraoperative calcium monitoring is not sufficient to

predict the success of parathyroidectomy for PHPT. [6]

Intraoperative PTH (IOPTH) monitoring is an important

adjunct used with modern day parathyroid surgery to pre-

dict the cure of PHPT with a high degree of accuracy [7, 8].

Certain conditions, including renal failure and multiglan-

dular parathyroid disease are known to result in inaccurate

IOPTH results. Vitamin D deficiency is also known to cause

persistently elevated serum PTH levels following parathy-

roidectomy, [9–11] and may affect the accuracy of IOPTH

monitoring. [12] Further, the role of IOPTH monitoring in

patients with overtly symptomatic PHPT, especially those

with large parathyroid tumors, has not been well studied.

This study was conducted to evaluate the accuracy and

utility of IOPTH in such patients, and to investigate the

relationships between the IOPTH dynamics and the serum

25-OH-D levels and parathyroid tumor weights.

Methods

This retrospective case–control study was conducted at

Sanjay Gandhi Post Graduate Institute of Medical Sciences,

Lucknow, India, which is a tertiary care referral institute,

from 2001 to 2009. Data for 59 sporadic, symptomatic

PHPT patients who underwent parathyroidectomy for single

parathyroid adenoma, diagnosed based on classical histol-

ogy, were retrieved from a prospectively maintained para-

thyroid disease database. Patients with multi-gland

parathyroid disease, parathyroid cancer, and those with

renal failure were excluded from the study. All patients

were managed using a uniform protocol, including esti-

mation of the serum 25-OH-D level using a radioimmuno

assay (RIA) kit (Incstar, Stillwater, MN, USA). The PHPT

patients with concordant parathyroid localization on neck

ultrasonography and 99mTc-sestamibi scans were offered

minimally invasive parathyroidectomy (MIP); the rest were

managed with standard bilateral neck exploration (BNE).

During parathyroid surgery, peripheral blood samples were

collected preoperatively, just before adenoma excision, and

5, 10 and 15 min after adenoma excision for serum PTH

estimations using an immunoradiometric assay (IRMA)

iPTH kit (DSL Inc, Webster, TX, USA) in a central labo-

ratory. The IOPTH results were not available to the surgeon

intraoperatively, and their interpretations were not used for

intraoperative decision making. A cure was defined as a

[50% drop in the PTH levels at 10 min post-excision,

compared to the peak pre-excision PTH value.

Ex vivo, the parathyroid tumor was trimmed of all fibro-

fatty tissue, measured, and weighed using an electronic

scale in the operating room. Postoperatively, the patients

were monitored for manifestations of hypocalcemia with

daily serum calcium estimations. Those with hypocalcemia

were managed with vitamin D supplements, and oral (and

if needed, intravenous) calcium supplements. During the

follow-up period, the serum calcium level was estimated at

1 and 3 weeks, and then every 3 months. A cure of PHPT

was defined by documenting normal serum calcium levels,

against which the true and false positive and negative

results of IOPTH were evaluated.

Based on the serum 25-OH-D levels, patients were cate-

gorized into three groups: normal s-25-OH-D ([30 ng/mL),

insufficient (15–30 ng/mL) and deficient (\15 ng/mL).

Patients were also grouped into three groups based on their

tumor weights: small (\1000 mg), large (1000–3000 mg)

and giant ([3000 mg). The results of IOPTH were compared

in these groups, and the percentage drop in IOPTH at 10 min

post-excision were examined for correlations with the serum

25-OH-D levels and tumor weights.

The statistical analyses were done using the SPSS 17.0

software program (SPSS Inc, Chicago, IL, USA) employ-

ing a one-way ANOVA (Bonferroni post hoc test) for

comparisons of the means between groups; and the

Spearman correlation coefficient was determined. p values

\0.05 were considered to be significant.

Results

The mean age of the 59 PHPT patients was 36.3 years

(range 24–78), and 41 were females. All of the patients had

overtly symptomatic PHPT, with almost 20% being crip-

pled due to severe musculoskeletal complications and 37%

having a palpable parathyroid tumor at presentation. The

clinical, biochemical and radiologic features of the patients

are summarized in Table 1. Thirty-six patients underwent

MIP, and the remaining 23 underwent classical BNE. The

mean serum 25-OH-D levels in the overall patient cohort

were 23 ± 14.6 ng/mL (range 7–76). Twenty-two (37.3%)

were vitamin D deficient (s-25-OH-D \15 mg/mL), 19

(32.2%) were vitamin D insufficient (s-25-OH-D

15–30 ng/mL) and 18 (30.5%) were vitamin D sufficient or

normal (s-25-OH-D [30 ng/mL). The mean tumor weight

was 3543.9 ± 6123.3 mg (range 160–36, 400). The small

tumor (\1000 mg) group included 12 patients (20.3%), 34

patients had large tumors (1000–3000 mg) (57.6%), and 13

had giant tumors ([3000 mg) (22%). The serum 25-OH-D

levels had a highly significant inverse correlation with the

tumor weight (Spearman correlation coefficient -0.723,

p \ 0.0001). The histological results of the tumors in all

patients were indicative of parathyroid adenoma.

All patients underwent successful parathyroidectomy,

and all had biochemical hypocalcemia. Symptomatic

hypocalcemia occurred in 36 (61%) patients. None of the

patients had persistent hyperparathyroidism or permanent

hypoparathyroidism. During the mean follow-up of

1184 Surg Today (2012) 42:1183–1188

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43 months (range 22–90), recurrent PHPT was detected in

1 patient. The IOPTH correctly predicted a cure in 55/59

patients (true positivity: 93.2%) and identified failure in

one patient who underwent MIP (true negativity: 1.7%).

The IOPTH results were false negative in 3 patients (5.2%,

two in the BNE group and one in the MIP group) and false

positive in none of the patients. Thus, the sensitivity,

specificity, positive predictive value, negative predictive

value and overall accuracy of IOPTH in predicting a cure

were 94.8, 100, 100, 25, and 93.2%, respectively.

The patient groups with deficient, insufficient and

sufficient serum 25-OH-D levels had significant differ-

ences (p value = 0.012, Table 2) in their percentage of

the decrease in IOPTH and the accuracy of predicting a

cure of hyperparathyroidism with the IOPTH. The serum

25-OH-D level and percentage decrease in the IOPTH

exhibited an inverse correlation, with a Spearman corre-

lation coefficient of -0.272 (p = 0.037, Fig. 1). Simi-

larly, significant differences were found during the

comparison of the percentage decrease in the IOPTH and

the accuracy of predicting a cure of hyperparathyroidism

by patient groups based on the parathyroid tumor weight

(p value = 0.02, Table 3). The parathyroid tumor weight

and percentage decrease in the IOPTH also had an inverse

correlation, although it was not statistically significant,

with a Pearson correlation coefficient of 0.166

(p = 0.208, Fig. 2).

Table 1 The clinical, biochemical and radiological features of the

primary hyperparathyroidism patients

Mean duration of symptoms in years (range) 3.5 (0.5–26)

Crippling [number (%)] 18 (30.5%)

Palpable parathyroid tumor [number (%)] 22 (37.3%)

Mean serum calcium level (normal 8.5–10.2) 13.6

Mean serum alkaline phosphatase level

(normal \135 IU/L)

1789.3

Mean serum intact parathyroid hormone level

(normal 9–55 pg/mL)

683

Mean serum 25-hydroxy vitamin D level

(normal 15–52 ng/dL)

23.05

Mean bone mineral density at the distal radius

(gm/cm2/z-score)

0.426/-3.8

Osteitis fibrosa cystica [number (%)] 43 (72.9%)

Pathological fractures [number (%)] 30 (50.8%)

Brown tumors [number (%)] 26 (44.1%)

Syndrome of disappearing bones [number (%)] 4 (6.8%)

Table 2 A comparison of the percentage decrease in the IOPTH in patient groups according to their vitamin D status

Vitamin D status

(serum 25-OH-D

levels in ng/ml)

N Mean percent

decrease

in IOPTH

SD 95% Confidence

interval for mean

Minimum Maximum

Lower bound Upper bound

Deficient (\15) 22 71.63 11.2 66.6 76.6 55.0 93.0

Insufficient (15.1–30) 19 72.47 10.9 67.2 77.7 54.0 92.0

Sufficient ([30) 18 61.33 14.6 54.0 68.6 37.0 89.0

Total 59 68.76 13.0 65.3 72.1 37.0 93.0

p value between groups = 0.012 (one-way ANOVA)

25-OH-D = 25-hydroxy vitamin D

Fig. 1 The correlation between

the percent decrease in the

serum parathyroid hormone

levels at 10 min after tumor

excision and the serum

25-hydroxy vitamin D levels

Surg Today (2012) 42:1183–1188 1185

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Discussion

IOPTH monitoring is currently used as a standard adjunct

during parathyroid surgery for PHPT, and can reliably

predict a cure in patients with single parathyroid adenomas

[7]. IOPTH monitoring is based on the short half-life of

circulating PTH and its intraoperative decay kinetics.

However, the IOPTH kinetics can be affected by factors

that contribute to calcium-PTH-vitamin D homeostasis,

and include the renal function, parathyroid pathology and

vitamin D status of the patient [13]. The complex effects of

vitamin D on IOPTH kinetics remain largely unstudied

[13]. This issue is of paramount importance for countries

with widely prevalent vitamin D deficiency, including

India, as vitamin D deficiency is known to influence the

clinical profile of PHPT patients, and result in severely

symptomatic disease and large parathyroid tumors [1, 2, 4].

Varying definitions of vitamin D deficiency and cut offs

of serum 25-OH-D levels have been used by different

researchers. We have been following the WHO classifica-

tion of vitamin D deficiency, insufficiency and sufficiency.

We undertook this study to clarify the IOPTH kinetics in

patients with symptomatic PHPT and to study the influence

of the vitamin D nutritional status and parathyroid tumor

size and weight on the IOPTH decay.

Our present PHPT patients were young, severely

symptomatic, had a high prevalence of vitamin D defi-

ciency and had large parathyroid tumors. These patients

had much higher preoperative serum calcium and PTH

levels compared to PHPT patients managed in other

countries. In the past, we have reported the unique

demographic, clinical and investigative features of our

PHPT patients, and the inter-relationship of the serum

25-OH-D levels, parathyroid tumor weights and serum

PTH levels [2, 4]. Using the Miami criterion of a [50%

decrease in the PTH level at 10 min post-excision com-

pared to the peak pre-excision PTH level, the sensitivity,

specificity and overall accuracy of IOPTH monitoring in

our patients with severely symptomatic PHPT were sim-

ilar to those reported elsewhere [7, 8]. Almost all of the

PHPT patients managed in the industrialized world are

asymptomatic or minimally symptomatic, and are gener-

ally detected during a biochemical screening for hyper-

calcemia. Our study therefore appears to be the first report

on the utility of IOPTH monitoring in overtly symptom-

atic PHPT patients.

Table 3 A comparison of the

percentage decrease in the

IOPTH level in the patient

groups according to the

parathyroid tumor weight

p value between groups = 0.02

(one-way ANOVA)

Parathyroid tumor

(weight in g)

N Mean percent decrease

in IOPTH

SD 95% Confidence

interval for mean

Minimum Maximum

Lower

bound

Upper

bound

Small tumor (\1000) 12 59.91 13.4 51.3 68.4 39.0 78.0

Large tumor

(1001–3000)

34 71.91 12.7 67.4 76.3 37.0 93.0

Giant tumor ([3000) 13 68.69 10.1 62.5 74.8 54.0 87.0

Total 59 68.76 13.0 65.3 72.1 37.0 93.0

Fig. 2 The correlation between

the percent decrease in the

serum parathyroid hormone

levels at 10 min after tumor

excision and the parathyroid

tumor weight

1186 Surg Today (2012) 42:1183–1188

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Our results suggest that IOPTH monitoring can be used

reliably even in overtly symptomatic patients with severe

hyperparathyroidism. Three (5%) patients in our study had

a false negative result, with a\50% decrease in IOPTH at

10 min, even though they were cured of PHPT. One patient

had a true negative result, who after almost 1 year of

normocalcemia presented with recurrent PHPT due to

metachronous multi-gland disease. All four of these

patients with true negative or false negative IOPTH results

had vitamin D deficiency or insufficiency, and none of the

vitamin D sufficient patients had false negative results. One

possible explanation for the false negative IOPTH results

in vitamin D deficient patients is the high probability of

secondary and possible tertiary hyperparathyroidism due to

vitamin D deficiency. A non-significant trend for there to

be more frequent multiple gland disease in vitamin D

deficient patients was previously reported by Uncht et al.

[14], who also commented that following adenoma exci-

sion and the cure of PHPT, vitamin D deficient patients

may subsequently manifest with multi-gland disease if the

vitamin D deficiency is not corrected. Similar views have

been expressed by others [11, 15, 16].

Vitamin D deficiency is a stimulus for parathyroid

hyperplasia, and may result in persistently high postoper-

ative serum PTH levels in spite of eucalcemia [11, 15, 16,

17]. As an extension of this physiological relationship, low

vitamin D levels may result in a slower decay of PTH

following parathyroidectomy, and a smaller decrease in the

IOPTH, possibly leading to false negative results. How-

ever, the results of our present study, as well as those of

other studies that correlated the IOPTH level with the

vitamin D nutritional status do not support this notion, and

found that the overall accuracy of IOPTH monitoring for

predicting a cure in vitamin D deficient PHPT patients is

similar to that of subjects with vitamin D sufficient status.

When we compared the percentage decrease in the

IOPTH in patient groups with normal serum 25-OH-D

levels with those having vitamin D deficiency or insuffi-

ciency, we found that the percentage decrease was signif-

icantly lower in the vitamin D sufficient patients. The mean

preoperative serum PTH levels were also higher, although

not significantly so (data not shown) in patients with lower

serum 25-OH-D levels. We found a significant inverse

relationship between the serum 25-OH-D levels and the

percentage decrease in the IOPTH when they were com-

pared as continuous variables. However, patients in all

three groups had comparable sensitivity and accuracy in

predicting a cure of hyperparathyroidism based on a[50%

drop in the IOPTH level at 10 min post-excision. These

results are in agreement with other studies that have shown

that IOPTH monitoring is equally informative in patients

with vitamin D deficiency [14, 18]. A few other studies

have shown an inverse correlation of the decrease in the

IOPTH with vitamin D levels, and none have reported a

converse or positive correlation between the two. In a study

on 351 patients, 56% of whom were vitamin D deficient

(serum 25-OH-D\25 ng/mL), Adler et al. [18] reported an

inverse correlation between the serum 25–OH-D and

IOPTH levels, but found that vitamin D deficiency did not

affect the sensitivity and accuracy of IOPTH monitoring.

Uncht et al. [14] found an inverse correlation between the

serum 25-OH-D levels and percentage decrease in IOPTH

at 5 min post-excision, but not at 10 min post-excision.

Contrary to our results that suggest a robust prediction of a

cure based on IOPTH monitoring in vitamin D deficient

patients, Wang et al. [9] have reported that the MIP based

on the IOPTH levels might not be as effective in patients

with pre-existing Vitamin D insufficiency, as they found

that patients with vitamin D levels in the low tertile of the

reference range were likely to have elevated postoperative

PTH levels.

The parathyroid tumor weight is the most reliable

indicator of parathyroid cell mass, [16, 19] and correlates

directly with the disease severity, serum calcium, PTH and

alkaline phosphatase levels, and inversely with the serum

25-OH-D levels [2, 4, 5, 19]. The study cohort in our study

had large, but benign tumors, with 37% being palpable. As

expected, these patients had very high serum PTH levels,

and the parathyroid tumor weight had a strong inverse

correlation with the serum 25-OH-D levels. However, the

sensitivity and the overall accuracy of IOPTH monitoring

were not significantly different between the patient groups

with small (parathyroid tumor weight \1000 mg), large

(1000–3000 mg) and giant ([3000 mg) adenomas. The

percentage decrease in the IOPTH at 10 min post-excision

was significantly higher in the patient groups with large

and giant tumors, compared to those with small tumors,

even though when correlated as continuous variables, the

percent decrease in the IOPTH and the tumor weight were

not found to have a significant correlation. Our results are

in agreement with those of Untch et al. [14], who reported

that the intraoperative PTH assay kinetics were not dif-

ferent in patients with large adenomas, who also had

vitamin D deficiency and more severe biochemical disease,

even though their patients had asymptomatic disease and a

mean tumor weight of about 1 g, in contrast to the mean

tumor weight of about 3.5 g in our study. Contrary to our

finding of a positive correlation between the decrease in

IOPTH and tumor weight, Gannage-Yared et al. [20], have

reported that the parathyroid adenoma weight is a negative

predictor of the decrease in IOPTH in a multivariate

analysis.

Our study is constrained by the limitations of its retro-

spective nature and the small sample size. The patient

numbers were small due to the fact that all of the patients

were overtly symptomatic, and had severe

Surg Today (2012) 42:1183–1188 1187

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hyperparathyroidism with large benign tumors. In this

unique patient cohort, our results emphasize the fact that

the IOPTH dynamics are influenced, at least somewhat, by

the vitamin D status and the parathyroid tumor weight. The

serum 25-OH-D levels had a negative correlation, and the

parathyroid tumor weight had a positive correlation with

the decrease in the IOPTH at 10 min post-excision. How-

ever, the sensitivity and overall accuracy of predicting a

cure based on a [50% decrease in the IOPTH level at

10 min were not significantly influenced by the vitamin D

status or parathyroid tumor weight. The IOPTH is therefore

a sensitive adjunct during parathyroid surgery even in

overtly symptomatic PHPT patients with vitamin D defi-

ciency and large parathyroid tumors.

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