The Journal of Clinical Endocrinology & Metabolism 92(6):21822189, 2007

Effect of Lugol Solution on

Thyroid Gland Blood Flow
and
Microvessel Density in
the Patients with Graves Disease
Yes im Erbil, Yasemin Ozluk, Murat Giris , Artur Salmasloglu, Halim Issever, Umut
Barbaros, Yersu Kapran, Selc uk O zarmag an, and Serdar Tezelman
Departments of General Surgery (Y.E., U.B., S.O., S.T.), Pathology (Y.O., Y.K.), Biochemistry (M.G.), Radiology (A.S.),
and
Public Health (H.I.), Istanbul Medical Faculty, Istanbul University, 34093 Capa/Istanbul, Turkey

By:
Raymond Adiwicaksana

Abstract
Context: Some endocrine surgeons administer Lugol solution to decrease thyroid gland
vascularity, there is still not an agreement on its effectiveness.
Objective: To evaluate thyroid blood flow and microvessel density in patients with Graves
disease who received Lugol solution treatment preoperatively.
Design: a prospective clinical trial.
Setting: tertiary referral center.
Method: Thirty-six patients were randomly assigned to receive either preoperative
treatment with Lugol solution (group 1, n =17) or no preoperative treatment with Lugol
solution (group 2, n=19).
Main Outcome Measures: Blood flow through the thyroid arteries of patients with Graves
disease was measured by color flow Doppler ultrasonography. The microvessel density
(MVD) was assessed by immunohistochemical and Western blot analysis of the level of
expression of CD-34 in thyroid tissue. The weight and blood loss of the thyroid gland were
measured in all patients.
Results: The mean blood flow, MVD, CD-34 expression, and blood loss in group 1 patients
were significantly lower than those in group 2 patients. There was a negative correlation
between Lugol solution treatment and blood flow (rs = -0.629; P =0.0001), blood loss (rs =
-0.621; P = 0.0001), MVD (rs = -0.865; P = 0.0001), and CD-34 expression (rs = -0.865; P
=.0001). According to logistic regression analysis, Lugol solution treatment resulted in a
9.33-fold decreased rate of intraoperative blood loss.
Conclusion: Preoperative Lugol solution treatment decreased the rate of blood flow,
thyroid vascularity, and intraoperative blood loss during thyroidectomy.
(J Clin Endocrinol Metab 92: 21822189, 2007)

Introduction
GRAVES DISEASE (GD) genetically determined
autoimmune disorder characterized by hyperthyroidism
Treatment : medically, radioiodine, surgery
Preoperative preparation of the patient crucial
Avoid thyrotoxicosis at the time of surgery
reduce intraoperative and postoperative
complications related to anesthesia or surgery

 Preoperative treatment with Lugol solution

for 10 days blocks the release of thyroid
hormone decreasing the vascularity of
the thyroid gland.
Lugol solution causes :
a decrease in thyroidal iodide uptake,
a decrease in iodide oxidation and organification
a block in the release of thyroid hormones

 Lugol : still not an agreement on its effectiveness

Study
: empirical or indirect evaluations, such as the
impression of the surgeon, objective results are
difficult to achieve
Color flow Doppler ultrasonography (CFDS): rapid,
informative, non-invasive allowed direct measurement
of intrathyroidal blood flow and thyroid artery blood flow
Several studies revealed that thyroid vascularity increased
in patients with GD .

 Angiogenesis : the development of new blood

vessels, and it is observed in various physiologic
and pathologic conditions.
Measurement of microvessel density (MVD) has
been used to investigate angiogenesis in various
tissues.
Immunohistochemistry (CD 34)
Western blot analysis.

this is the first study to evaluate the effect of Lugol solution treatment using
immunohistochemistry and Western blot analysis.

Patients and Methods

Patients
This prospective study included 36 consecutive patients undergoing
surgical therapy for GD at the Department of General Surgery,
Istanbul Medical Faculty, between September 2005 and September
2006. Patients were randomly assigned to preoperative treatment
with Lugol solution.
Patients in group 1 (n =17) received Lugol solution for 10 d before
surgical intervention,
Patients in group 2 (n=19) did not receive it.
Lugol solution was administrated at 10 drops per day orally three
times a day for 10 d. The patients in group 1 immediately underwent
operations after these 10 d..

Total and near total thyroidectomies

The volume of blood loss,
histopathological examination.
Randomization and administration of
Lugol solution
the same surgeons

Vascular studies
CFDS was performed before treatment of
group 1 patients with Lugol solution.
Vascular studies were also performed on all
patients 24 h before surgery.
Thyroid volume was measured
A mean thyroid the resistance index RI and
blood flow rate were calculated from 12
measurements, with four for each artery.

Western blot analysis

The use of fresh tissue homogenates in Western blot
analysis results in a higher confidence in the results
compared with other methods

Biochemical analysis
free T3 (FT3)

2.65.7 pmol/liter

freeT4 (FT4)

918 pmol/liter

TSH

0.34.9 mIU/liter

anti-thyroid peroxidase (TPO)

035 IU/ml

TSH receptor antibody (TRAb)

less than 10 IU/ml

Immunohistochemistry
Consecutive 5-mm sections were recut from each block. One section from each case
was stained with hematoxylin and eosin, and additional sections were immunostained
for CD-34.
The primary monoclonal antibody was a monoclonal mouse anti-CD-34
Vessel counting was performed using x4,x10, x20, and x40 achrometric objectives
and x10/20 left oculars on an Olympus Optical (Tokyo, Japan) BX51 microscope.

Statistical analysis

Analysis was performed with the statistical

package SPSS 10.1

Results

FIG. 4. Positive immunoreactivity of endothelial cells between thyroid follicular

structures in two cases displaying low (A, Lugol treatment thyroid) and high (B, nonLugol treatment thyroid) MVD, respectively (anti-CD-34, x200).

Correlations
FIG. 5.
Relationship
between
preoperative
Lugol solution
treatment and
blood flow (A),
MVD (B), CD-34
expression (C),
and
intraoperative
blood loss (D) in
GD

Evaluation of the cutoff values of

the study parameters
Lugol solution treatment resulted in a 15.5-fold [odds ratio (OR), 15.5;
95% confidence interval (CI), 2.691.5] decrease in the rate of
blood flow, a 21-fold (OR, 21; 95% CI, 3.4126.32) decrease
in the rate of blood loss, a 44.8-fold (OR, 44.8; 95% CI, 4.65
430.90) decrease in the rate of MVD, and a 60-fold (OR, 60;
95% CI, 6.0599.49) decrease in the level of CD-34 expression.

Stepwise regression analysis

When age, gender, thyroid hormone, thyroid antibodies,
blood flow, MVD, CD-34 expression, and Lugol solution
treatment were included as independent variables, Lugol
solution treatment (OR, 9.33; 95% CI, 1.1376.67; P 0.03)
was found to be the only significant independent determinant
of intraoperative blood loss.
Lugol solution treatment resulted in a 9.33-fold decrease in
the rate of intraoperative blood loss.

FIG. 6.
Relationship
between
intraoperative
blood loss and
thyroid gland
volume (A), blood
flow (B), MVD (C),
and CD-34
expression (D) in
GD.

Discussion
Lugol solution treatment before surgery is significantly associated with thyroid vascularity and
intraoperative blood loss.
Negative correlations were found between Lugol solution treatment and blood flow, thyroid
vascularity, and intraoperative blood loss. Lugol solution treatment resulted in 15.5-fold, 21-fold,
44.8-fold, and 60-fold decreases in the rates of blood flow, blood loss, MVD, and CD-34
expression, respectively.
According to logistic regression analysis, Lugol solution treatment before surgery was the only
significant independent determinant of intraoperative blood loss.
GD is one of the most common causes of hyperthyroidism . Hyperthyroidism is associated with
hemodynamic changes, including high output state, increased heart rate and cardiac
contractility, and decreased peripheral resistance that are related to both direct
cardiostimulatory effects of thyroid hormone and increased peripheral oxygen consumption .

Preoperative preparation of the patient is crucial to avoid intraoperative or

postoperative thyroid storms and to decrease the vascularity of the gland.

Inorganic iodide (Lugol solution) decreases the synthesis of thyroid hormone

and release of hormone from the thyroid in the short term. It is used to treat
patients with thyroid storm or, more commonly, to reduce thyroid vascularity
before thyroidectomy.

Iodine also reduces thyroid cellularity and vascularity and therefore is used in
the preparation of patients for thyroidectomy. This effect transiently blocks
thyroid hormone generation, with thyroid hormone synthesis recovering in a few
days or weeks. There is no consensus that reductions in vascularity, glandular
friability, and blood loss are obtained preoperatively.
Most studies related to the effects of Lugol solution are based on indirect
evaluations, such as the impression of the surgeon.

Doppler techniques seem to be the best method to evaluate blood flow in the thyroid
gland, because thyroid vascularity has been quantitatively assessed by counting the
number of by measuring volumetric blood flow in the thyroid artery.
Higher intrathyroidal blood flow and increased peak systolic velocity have been
documented in GD. In this study, the blood flow of thyroid arteries was higher than the
values obtained in control subjects. Ansaldo et al. aimed to evaluate the effects of Lugol
solution therapy in a series of patients with GD through analysis of the RI of thyroid
arteries.
After Lugol solution treatment, RI reached a mean value similar to that of the normal
subjects reported our results. RI is a semiquantitative, easy-to-obtain, and reproducible
measurement reflecting the vascular impedance within the vascular bed distal to the site
of sampling.
Changes in vascular impedance after drug administration have been widely studied using
this method. Chang et al demonstrated a reduction of blood volume flow within the
superior thyroid arteries after Lugol solution treatment in patients with Graves
hyperthyroidism.

In our study, Lugol solution treatment resulted in a significant decrease of the mean basal
blood flow in patients with GD relative to values obtained before treatment.

Thyroid vascularity in GD patients can be evaluated by monitoring CD-34 expression

using immunohistochemistry and Western blot analysis as well as by CFDS.

The vascular density of different tissues has been assessed by counting vessels labeled
using immunohistochemistry with antibodies against different endothelial markers on both
frozen and paraffin-embedded sections. Antibodies that are most commonly used are
directed against the endothelial antigens factor eight-related antigen, CD-31 (platelet
endothelial cell adhesion molecule), CD-34, and the lectin ulex europaeus agglutinin 1.

CD-34 is the most sensitive and specific marker currently available for the detection of
angiogenesis. The use of these markers reflects total vascular density.

Yamada et al. show that iodide inhibits vascular

endothelial growth factor-A expression in cultured
human thyroid follicles, and, consequently, they
suggest that proangiogenic and antiangiogenic
factors may at least partly account for the iodideinduced decrease in thyroid blood flow.

Currently, there are not any published reports on

the effect of Lugol solution on patients with GD
using MVD and West- ern blot analysis.

The main aim of our study was to investigate the effect of

Lugol solution on vascular density in GD.
We hypothesized that Lugol solution might act through two
mechanisms. It probably decreases both angiogenic stimuli
and blood flow in GD. Decreased angiogenesis and blood flow
resulted in a significantly decreased number of vessels.
Therefore, it is reasonable to presume that increased vascular
density could reflect increased angiogenic stimuli in this
disease.

Conclusion
Preoperative Lugol solution treatment, blood flow, MVD, and
CD-34 expression were found to be significant independent
determinants of intraoperative blood loss.
Moreover, preoperative Lugol solution treatment decreased the
rate of blood flow, thyroid vascularity, and intraoperative blood
loss during thyroidectomy.
The reduction of intraoperative bleeding allows better
visualization and preservation of the surrounding nerves,
vasculature, and parathyroid glands.