1Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India, 2Department of Statistics, University of Mumbai, India
Radioactive iodine uptake (RAIU) is a test used to differentiate hyperthyroidism from thyroiditis and to calculate the radioiodine dose for treatment of Graves’ disease. We aimed to evaluate the predictive role of 24h RAIU with respect to the outcome of radioiodine therapy in patients with diffuse toxic goiter (DTG). METHODS: Case records of patients with DTG treated with radioactive iodine were reviewed retrospectively. Patients were divided into two groups based on 24h RAIU (normal range: 15% - 35% at 24 h): the first group included patients with 24h RAIU values equal to or less than 50%, while the second group included patients with 24h RAIU values of over 50%. Gland size, duration of disease, treatment with antithyroid drugs (ATD) and its duration were the other factors considered. Success of the first dose of 131I was defined as a euthyroid or hypothyroid status at 12 months post-therapy without the need for additional radioiodine or ATD therapy. Data were analyzed with 95% power and 1% type I error (α=0.01). RESULTS: Six hundred thirty-three (633) consecutive patients with DTG were given a fixed-dose (5mCi) of radioiodine between January 1987 and December 2006. One hundred seventy-five patients (175) had an RAIU ≤50% and 458 patients had an RAIU >50%. First-dose success rate in the former group was 81.7% and in the second group 68.6% (p=0.001). The overall first-dose success was 72%. Multivariate analysis confirmed the significant role of 24h RAIU data to predict a successful outcome. CONCLUSION: A 24h RAIU value of ≤50% appears to be associated with a significantly better outcome compared to that of a 24h RAIU value of >50% in patients with DTG given as treatment a fixed dose of 185 MBq radioiodine.
Diffuse toxic goiter, First-dose success, Radioactive iodine uptake
INTRODUCTION
Diffuse
toxic goiter (DTG) is the most common etiology of hyperthyroidism, with
radioiodine therapy, ATD and surgery being the available modalities for
treatment of this condition. Radioiodine therapy is used as the preferred
modality of treatment due to its simplicity, cost-effectiveness and low
complication rates.1-3 In addition, it is the treatment of choice in
relapsed Graves' disease and hyperthyroidism due to toxic nodules.4
However, there is a lack of consensus regarding the ideal dosage of radioiodine
therapy. The regimens used include fixed activities (80, 185, 370, 555 MBq) as
well as activities calculated on the basis of gland size, radioactive iodine
uptake (RAIU), effective half-life of 131I and target dose.5-9
Multiple factors including use of ATD, age of onset of disease, gender,
etiology of the hyperthyroidism, radioiodine dose regimen, goiter size and RAIU
are among those investigated to determine response to radioiodine therapy.10
The
RAIU test is an old test and has been used for differentiating thyroiditis from
hyperthyroidism, calculation of 131I dose for thyroid ablation and
for prediction of the outcome of radioiodine treatment. The former two
indications are well established; however, the last is controversial. The
significance of RAIU in the success of the first dose of radioiodine remains
uncertain. Generally, high RAIU is widely considered as a favorable factor for
the success of radioiodine therapy.11 However, several studies have
suggested that there is no relationship between uptake and cure rate in the
range of RAIU varying from 30% to 100%.7 Recently, an inverse
correlation has been found between pre-treatment iodine uptake and a successful
outcome.12 Other authors have observed a poorer outcome in patients
with high 24h RAIU after radioiodine treatment for hyperthyroid disease when
the therapeutic dose was calculated on the basis of a 24h RAIU.13
The aim of our work was to evaluate this debatable issue by designing a
statistically sound study with alpha of 0.01 and power of 95% to determine
whether a 24h RAIU is useful in predicting the outcome of radioiodine therapy
in Graves' disease.
METERIALS AND METHODS
Our
population was composed of patients presenting to our Thyroid Clinic and found
to be suffering from diffuse toxic goiter. These patients were given as
treatment a fixed-dose of 185 MBq radioiodine between January 1987 and December
2006. Inclusion criteria were: a) patients with diffuse goiter on palpation
and/or thyroid scan, b) off ATD for at least three days prior to the 24h RAIU test,
c) no history of intake of other medications potentially interfering with the
24h RAIU test and d) 24h RAIU values which excluded subacute thyroiditis or
extrathyroidal thyrotoxicosis. Patients excluded from this study were those
having: a) multinodular goiter, b) solitary autonomously functioning nodule, c)
history of intake of other medications potentially interfering with the RAIU
test. RAIU was performed in our Department of Nuclear Medicine at 2h and 24h
after oral administration of 185-370kBq (5-10 µCi) 131I with normal
laboratory values being 5-15% at 2h and 15-35% at 24h. Clinical examination,
RAIU, thyroid profile and detailed history relevant to the disease were
reviewed. As per our Institutional Protocol, the gland size had been graded
from 0-3 (0-not palpable/normal, 1-mildly enlarged, 2-moderately enlarged,
3-grossly enlarged) before therapy. According to RAIU, the patients were
classified into two groups: 1) a low uptake group with a 24h RAIU equal to or
less than 50% and 2) a high uptake group with 24h RAIU of more than 50%. Age,
sex, duration of disease, treatment with ATD and its duration were also
reviewed. Post-therapy follow-up was performed every three months via clinical,
biochemical and RAIU examination for a period of one year. Our patients were
classified into persistent hyperthyroid, euthyroid and hypothyroid groups based
on the follow-up biochemical and clinical assessment. First-dose success was
defined as euthyroidism or hypothyroidism and no requirement for repeat
radioiodine/ATD therapy during the year-long follow-up period, while first-dose
failure was defined as persistent hyperthyroidism necessitating further
treatment with radioiodine/ATD.
For
our statistical analysis SPSS software was used. We performed the Chi-square test
to check the dependence of individual explanatory variable and outcome variable
in the absence of other explanatory variables. However, since univariate
analysis does not give any indication of the significance of an explanatory
variable in the presence of other such variables, we used multivariate
analysis. In our analysis, we have used the dichotomous logistic regression
method. The beta coefficients were calculated using maximum likelihood
estimation (Table 4). The goal of the analysis using this method was to find
the best fitting yet biologically most reasonable model to describe the
relationship between an outcome and a set of explanatory variables. We have
also calculated odds ratio for each significant explanatory variable.
RESULTS
A
total of 633 patients (449 female, 184 male) with diffuse toxic goiter were
included in our study. Mean age of our patients was 38.2yr (range 14 - 75yrs).
As for age, 488 patients were ≤45yrs
at the time of radioiodine ablation while the remaining 145 were > 45yrs.
According to 24h RAIU, there were 175 patients in the low uptake group and 458
in the high uptake group. Four hundred fifty-five patients (455) achieved cure
with a single dose of 131I and the remaining 178 patients needed
more than one dose. Table 1 compares different patient variables between the
groups of patients successfully treated with the first dose of radioiodine and
the patients who had persistent hyperthyroidism after the first dose of
radioiodine. Table 2 compares different variables between the patients with
high and low radioiodine uptake. Thus, the overall first-dose success was 72%.
Success rate in females (449) was 73.9% and in males (184) it was 66.8% (p-value
= 0.07). The success rates were comparable between the younger and older
patient groups (73.3% in ≤45yrs
group and 66.9% in the >45yrs group; p = 0.13). First-dose success rate was
81.7% in the low uptake group and 68.1% in the high uptake group, a difference
which was significant (p = 0.001).
For
post-hoc univariate analysis considering the influence of duration of disease,
patients were divided into two groups: group 1 with ≤12 months duration and group 2 with >12 months
duration of disease. First-dose success rate in the two groups was 75.9% and
68.3%, respectively (p = 0.03). In the assessment of the effect of ATD, 505
patients had already taken an ATD and the remaining 128 patients were drug
naive at the time of radioiodine therapy. The former population had a success
rate of 69.7% as against the latter population with a success rate of 80.5%.
Patients not treated with ATD had a significantly better outcome compared to
those with prior ATD treatment (p = 0.004). In the assessment of the effect of
duration of ATD intake, it was observed that 292 patients who had taken the
drug for a period of more than one year had a success rate of 68.5%, whereas
213 patients who had taken ATD for a period of less than one year had a success
rate of 70.4% (p = 0.55).
Out
of 631 patients (gland size of two patients was not recorded in the chart), 82
did not have goiter and their success rate was 90.2%. Two hundred eighty-eight
(288) patients had mild goiter and their success rate was 79.5%. Two hundred
forty-four (244) patients had moderate goiter and their success rate was 58.6%.
Finally, 17 patients had severe goiter and their success rate was 41.2% (Table
3). Gland size and success rate of ablation were thus inversely related
(p<0.001). To summarize, univariate analysis revealed gland size, 24h RAIU,
treatment with ATD and duration of disease as statistically significant
variables affecting outcome of radioiodine therapy. Multiple logistic
regression analysis was applied. Since two observations were missing on gland
size, 631 sample observations were taken into consideration for multivariate
analysis. The 24h uptake and gland size remained significant. On the basis of
the Wald test statistic, the most important variable affecting the success rate
was gland size (41.5) and followed by 24 hour uptake (4.1).
DISCUSION
A
large number of studies have addressed the issue of the response of radioiodine
therapy in relation to 24h RAIU. Several studies have described a favorable
outcome of radioiodine therapy in patients with high 24h RAIU,7,14
while most published reports yield contradictory results.15,16 These
contradictory results notwithstanding, high 24h RAIU is still regarded as an
important factor in the success of radioiodine therapy.11 Decreasing
the iodide pool by a low iodine diet17 or increasing the retention
of iodine in the thyroid gland by administering lithium carbonate have
previously been proposed by several studies.18 However, the use of
lithium is not a generally accepted option as adjuvant to increase the first-dose
success of radioiodine therapy.19 A recent study found an inverse
relationship between pretreatment iodine uptake and post-treatment outcome.12
Patients with the lowest RAIU showed highest success at 18 months after
therapy; the cure rate decreased with increasing pretreatment uptake. Another
study suggested poorer outcome in patients with high 24h RAIU after radioiodine
treatment for hyperthyroid disease when the therapeutic dose was calculated on
the basis of 24h RAIU.13 In their study of radioiodine therapy of
diffuse goiter, Catargi et al. found that mean uptake of a group of
patients that remained hyperthyroid after one year follow-up was significantly
higher compared to that of the euthyroid group.20
The
significance of our study is that our patients with diffuse toxic goiter
received exactly the same dose. The data, therefore, reflect a homogenous
treatment modality. Our sample size is large enough for acceptance or rejection
of the hypothesis that lower RAIU leads to a better outcome after 131I
therapy with 95% power and 1% type 1 error (alpha = 0.01). However, the
duration of disease, ATD and their duration and gland size are potentially
important factors which could affect the outcome. Increasing gland size would
be expected to lead to high uptakes. Hence, the major issue here was whether
the high uptake group had more patients with grade 2 and 3 goiter as compared
to the low uptake group, thus leading to lower cure rates when a fixed dose of
185 MBq 131I was used. We did a logistic regression analysis taking
all these factors into account. The success rate in the low uptake group was
still significantly better than the high uptake group. Out of 455 patients with
a first-dose success, we found that 249 (54.7%) were euthyroid and 206 (45.3%)
were hypothyroid at 12 months after therapy. Thus, there was a higher rate of
euthyroidism with fixed dose 185 MBq (5 mCi) radioiodine therapy. Physicians
who advocate high dose radioiodine ablation of Graves' disease put forth the
argument that leaving behind thyroid tissue partially damaged by radiation has
potential risk of malignancy. The long-term risk of malignancy developing in
such a gland, particularly in adults, is negligible. However, in pediatric
Graves' disease the risk of malignancy in radiation injured residual thyroid
tissue is not well established. A recent review by Verburg et al concluded that
the risk of malignancies after radioiodine therapy of benign thyroid disease is
not increased.21
Duration
of disease and treatment with ATD were found to be significant in the
univariate analysis but not significant in multivariate analysis, indicating
that these may be secondarily related to other factors like the aggressiveness
of the disease which necessitates initial antithyroid drug treatment. It is also
known that patients with severe hyperthyroidism may not respond to a single
fixed low dose of radioiodine. Odds ratio for 24h uptake was 1.6
(CI=1.02-2.56), which indicates that if 24h uptake changes from >50% to ≤50%, the probability of
success increases 1.6-fold. Thus, we can conclude that as uptake decreases,
probability of success increases. Odds ratio for gland size was 13.7
(CI=3.97-47.46), implying that if gland size changes from severely enlarged to
not enlarged, probability of success increases 13.7-fold. When gland size
changes from severely enlarged to mildly enlarged, probability of success
increased 5.0-fold. Thus, as gland size decreases, probability of success
appears to increase. In other words, larger glands need higher radioiodine
therapy dose for a successful outcome with single dose.
Several
hypotheses may be proposed to explain this apparently paradoxical observation,
i.e. that lower 24h RAIU produces higher success rate with a fixed dose of radioiodine.
Firstly, there could be a biologically different response of the follicular
cells in the form of decreased radiosensitivity in response to higher RAIU.22
A two-compartmental model suggesting less possibility of cure in patients with
high RAIU in comparison with the low 24h RAIU group has been postulated if the
same target dose is delivered.23 Also, altered iodine kinetics in
the subsequent 131I therapy has been described after using 131I
for 24h RAIU. This could be due to stunning of the thyroid following low dose
of 131I used for 24h RAIU, although this is extremely rare. Studies
have shown the phenomenon of stunning in thyroid cancer, but the radioiodine
dose used in the whole body scan was almost one thousand times the 24h RAIU
dose.24-26 Another hypothesis could be that high uptake values lead
to lower effective intrathyroidal half-life of radioiodine, but this is
speculative and needs to be confirmed by further studies. In addition, our
findings may have been influenced by the short duration of follow-up, i.e. one
year, and longer follow-up is needed to confirm these. Moreover, there seem to
be three shortcomings in our study that deserve mention. Firstly, the gradation
of gland size was not done using neck ultrasound, which would have been a fully
objective method. Secondly, whether the patients were iodine deficient or
iodine-sufficient was not known, but there may be a similar proportion of
patients of both types in the high as well as the low uptake group. Lastly, the
success rate of radioiodine may change on prolonged follow-up as detection of
delayed hypothyroidism increases with longer follow-up. Nevertheless, our data
suggest that the hypothesis that we sought to verify may be correct and high
uptake may in fact be an adverse factor as far as outcome of the first dose of
radioiodine therapy is concerned, and that low 24h RAIU may not be a
contraindicating factor as is commonly perceived. The data also highlight the
fact that a fixed dose of 185 MBq (5 mCi) produces satisfactory and comparable
results in glands with an RAIU less than or equal to 50% and smaller glands.
However, its routine use in glands showing more than 50% uptake and larger
gland size may not achieve equally good results and may need higher
administered activity of 131I to achieve higher first-dose success
rate.
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Address for correspondence:
Dr. Nishikant A. Damle, MD, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
110029, Tel.: 91-11-26593530, Fax: 91-11-26588663, E-mail: nishikant_damle@yahoo.com
Received 07-12-11, Revised 3-04-12, Accepted 01-06-12