Keywords Cold solid thyroid nodule - radioactive iodine therapy - retinoic acid
Introduction
Nodules in the thyroid gland, whether solitary or multiple, are very common in clinical
practice. According to several epidemiologic studies, there is approximately 5% prevalence
in women and 1% in men who live in iodine-sufficient parts of the world.[1 ],[2 ] Radioactive iodine (RAI) (NaI-131) has been used for over 50 years to treat clinical
or subclinical hyperthyroidism due to Graves' disease or autonomously functioning
thyroid nodules (either toxic or nontoxic).[3 ] The sodium iodide (Na +/I -) symporter (NIS), which was identified in 1996, is responsible
for active iodine trapping to the thyroid follicular cell.[4 ] Cold thyroid nodules (CTNs) are characterized as nodules with less iodide uptake
than normal thyroid tissue.[5 ] NIS expression in cold nodules is similar to nonnodular tissue due to TSH. Hot nodules
have about 1.5 fold NIS expression compared to CTNs.[6 ],[7 ]
Oral retinoic acid (RA) is a synthetic derivative of Vitamin A. It is an important
regulator of a diverse spectrum of physiological processes, including cell proliferation,
differentiation, morphogenesis, angiogenesis, and apoptosis.[8 ] RA can induce several re-differentiating effects such as induction of 5'-deiodinase
(D1)[9 ],[10 ] and increased expression of NIS mRNA.[11 ] In 2009, Handkiewicz-Junak et al. showed that RA increased RAI uptake in thyroid
tissue in 17% of the 53 epithelial cell thyroid carcinoma patients studied, whose
previous posttherapeutic I-131 scans were negative.[12 ] However, Schmutzler et al. showed that RA suppresses NIS expressions in normal thyroid
tissue.[11 ]
The aim of this study is to evaluate the effect of RA to the uptake value of RAI in
cold solid thyroid nodule.
Materials and Methods
Subject
Between September 2017 and November 2017, a total of 10 patients were included in
this study. Two participants were dropped off due to side effects of RA. Patients'
characteristics are summarized in [Table 1 ].
Table 1 Patient characteristics
Inclusion criteria
Individuals with solid thyroid nodule based on ultrasonographic examination were evaluated
for the thyroid nodule characteristics. Individuals with cold nodule were included
in this study.
Exclusion criteria
Individuals with liver dysfunction, smokers, and pregnancy patients were excluded
from this study.
Thyroid nodule characteristic determination
To determine the characteristic of the thyroid nodule, each participant underwent
thyroid scintigraphy. A 1 mCi (37 MBq) of NaI-131 was administered orally, and 24
h later, the thyroid scintigraphy was performed.
Retinoic acid administration
A 1 mg/kg body weight (BW) of RA was taken by the participants for 2 weeks, followed
by a 1.5 mg/kg BW for 4 weeks. Liver function test was performed before consuming
RA and also 2 and 6 weeks after consuming.
Thyroid uptake calculation
The baseline uptake imaging values of the thyroid gland and nodule were collected
before consuming RA. The imaging was performed at 24 h after administration of 1 mCi
(37 MBq) of NaI-131. And 6 weeks after consuming RA, another uptake was repeated.
The uptake was calculated using the following formula:[13 ]
where
Pthyroid : decay-corrected total thyroid counts
Pbackground : decay-corrected background counts
Precount: decay-corrected counts of the preinjection syringe image
Postcount: decay-corrected counts of the postinjection syringe image.
Decay correction is calculated by multiplying the image counts by the factor as follows:
exp = (−0.693t)/T1/2
where
t: the time that elapses between preparation of the radiopharmaceutical and image
acquisition
T1/2 : half-life time of the tracer
A standard syringe was used to determine the exact t value.
Statistical analysis
A Wilcoxon test was used to analyze sample distribution. Unpaired t-test was used
to analyze the significance of the alteration in the uptake value of the nodules and
normal thyroid tissues. P <0.05 was considered statistically significant.
Results
A total of 12 cold solid thyroid nodules from eight participants were evaluated. The
mean percentage values of the nodule uptake pre- and post-intervention were 1.11%
and 0.62% with a median of 0.65% and 0.32%, respectively (P = 0.004). The mean percentage uptake value of the normal thyroid tissue was 27.57%
in preinterventional evaluation and 13.40% in postinterventional evaluation with a
median of 28.42% and 14.45%, respectively (P = 0.002) [Figure 1 ].
Figure 1 Comparison of the normal thyroid tissue and cold thyroid nodule to take up NaI-131
pre- and post-intervention
The mean alteration percentage uptake of the nodules and the normal thyroid tissues
were 42.4% and 51.5% with a median of 35.4% and 50.8%, respectively,
(P = 0.354). The comparison of the uptake values pre- and post-intervention is shown
in [Table 2 ].
Table 2 Comparison of the uptake values pre- and post-intervention
Discussion
Thyroid nodules can be detected in <5% of individuals screened by cervical palpation,
but autopsy data have shown a 50% prevalence of nodular lesions in clinically normal
thyroid glands.[1 ],[2 ],[14 ] According to a recent study (1999–2002), the use of ultrasonography by endocrinologists
in the management of thyroid disease is increasing.[15 ],[16 ],[17 ],[18 ] That trend makes the unexpected detection of nonpalpable thyroid nodules <10–15
mm in diameter more frequent in clinical practice.[19 ] Most of these nodules are benign, at most only 5% were found to be malignant.[20 ] The first step in the management of a patient with nodular thyroid disease is to
exclude the presence of malignancy. There are several approaches that can be applied
to benign thyroid nodules such as surgery, iodine supplementation, levothyroxine,
RAI (NaI-131), percutaneous ethanol injection, and percutaneous laser ablation.[21 ]
RAI has been used for over 50 years to treat clinical or subclinical hyperthyroidism
due to Graves' disease or autonomously functioning thyroid nodules (either toxic or
nontoxic).[3 ] The effectiveness of RAI in reducing the size of the thyroid gland is widely recognized.[22 ],[23 ] Uptake of RAI may be reduced in patients with multinodular goiters, especially the
nontoxic forms, so in these cases, higher doses of RAI should be given.[21 ] The risk of hypothyroidism is approximately 10% after 5 years and unrelated to RAI
dose.[24 ]
The NIS, which was identified in 1996, is responsible for active iodine trapping to
the thyroid follicular cell.[4 ] High level of NIS in benign thyroid nodule may be taken as one of the indicators
of the success of RAI therapy in decreasing nodular size. The highest NIS expression
is in hot nodules, followed by warm nodules and then cold nodules. In cold nodules,
NIS expression is similar to the surrounding nonnodular tissue.[7 ]
RA is a biologically active metabolite of Vitamin A. It is essential for morphogenesis,
differentiation, and homeostasis.[25 ],[26 ] It is an effective therapeutic and chemopreventive agent for treating several cancers.[27 ],[28 ],[29 ] RA regulates thyroid-specific differentiation markers, such as type I D1, thyroperoxidase,
and NIS.[30 ] In 1997, Schmutzler et al. showed that RA suppresses the expression of NIS in the
normal thyroid cell line FRTL-5.[11 ]
This study showed a mean of 42.4% decrease in the capability of the nodule to take
up RAI after administration of RA and also 51.5% decrease in the normal thyroid tissue.
Nygaard et al. found that hypothyroidism occurred in 6%–20% (P < 0.005) of 130 multinodular toxic goiter patients after a median of 42 months (range:
3–60 months) and within 5 years of treatment, the hypothyroidism frequency was 14%,[23 ] while Adamali et al. found that in toxic nodular goiter group, hypothyroidism occurred
in 22.7% of the patients (P < 0.001).[31 ]
From this study, it was observed that the RAI uptake in the surrounding normal thyroid
tissue was decreased more than the uptake in the nodule. It may be postulated that
the use of RA will be useful in the RAI therapy for functional nodule in reducing
the incidence of hypothyroidism. A further study with larger population with functional
nodule is required to confirm the result of this study.
Conclusion
This study showed that RA reduces the ability of cold solid thyroid nodule, as well
as normal thyroid tissue, to take up RAI.
