Iodine, Radioactive
Amit Allahabadia
University of Sheffield, Sheffield, United Kingdom
Jayne A. Franklyn
University of Birmingham, Birmingham, United Kingdom
Glossary
differentiated thyroid cancer Papillary and follicular
thyroid carcinoma.
euthyroidism Normal thyroid function.
hyperthyroidism Overactivity of the thyroid gland
as determined by raised serum concentrations of free
thyroxine (T4) and triiodothyronine (T3) and a sup-
pressed serum thyrotropin (TSH) concentration.
hypothyroidism Insufficiency of the thyroid gland as
determined by reduced serum concentrations of free
thyroxine (T4) and triiodothyronine (T3) and an elevated
serum thyrotropin (TSH) concentration.
T he term ‘‘radioactive iodine’’ encompasses radioisotopes
of iodine that are used for the study of thyroid physiology and
pathology and for the ablation of thyroid tissue in the treat-
ment of patients with hyperthyroidism, nontoxic goiter, and
thyroid cancer.
INTRODUCTION
Iodine is essential for normal functioning of the thy-
roid and forms an integral part of the thyroid hor-
mones thyroxine (T4) and triiodothyronine (T3).
Iodine is actively transported into thyroid cells and
organified in the colloid, providing substrate for thy-
roid hormone production. During the late 1930s, it
was found that the thyroid takes up radioactive iodine
in the same manner as it does normal nonradioactive
iodine, an observation that led to the first trials of
radioactive iodine for the treatment of hyperthy-
roidism. After 1946, when 131I became routinely avail-
able from the Oak Ridge National Laboratory as a
by-product of atomic research, radioiodine became
widely adopted for the treatment of hyperthyroidism
and later for the postsurgical management of thyroid
100
cancer. Since then, radioiodine has also been
employed for uptake studies, scanning of thyroid
tissue, and (more recently) as an alternative treatment
for nontoxic goiter.
MECHANISM OF ACTION
Iodine Metabolism
Iodine is essential for thyroid homeostasis. The major
function of the thyroid is to produce thyroid hormone
and its formation requires availability of an adequate
amount of exogenous iodine. Iodine balance is main-
tained from diet that includes food and water, but
iodine may also enter the body from other sources
such as drugs, diagnostic agents, dietary supplements,
and food additives. Iodine is absorbed rapidly within
minutes of ingestion from the stomach as iodide (I )
into the bloodstream. Iodide uptake by thyroid cells
results from active transport by the sodium iodide
symporter (NIS), an iodide-concentrating mechanism
that provides iodide substrate for hormone formation.
Radiation Physics
There are more than 20 recognized radioactive iso-
topes of iodine in addition to the naturally occurring
stable isotope, 127I. Only 2 are currently used in clin-
ical practice, 131I for treatment and 123I for diagnostic
imaging, and they are typically administered as
sodium iodide. 125I is still in use for in vitro diagnostic
imaging.
131
I is ideal for ablative thyroid therapy by virtue of
its large beta particle emissions of moderate energy
(364 keV) and is associated with a moderate but suffi-
ciently long half-life of 8.1 days. The beta particles of
131
I are essentially nonpenetrating and so act locally,
delivering 90% of the radiation dose within a 1- to
2-mm zone to the thyroid follicular cells.
Encyclopedia of Endocrine Diseases, Volume 3. ß 2004 Elsevier Inc. All rights reserved.
Iodine, Radioactive
123
I is excellent for thyroid imaging because it de-
livers far less radiation to the thyroid than does 131I,
has a short half-life (13 h), and does not emit destruc-
tive beta radiation. Furthermore, its gamma radiation
emission energy (159 keV) is ideally suited to thyroid
scanning. The use of 123I has been superseded for
most routine thyroid imaging by Technetium-99m,
an isotope that is actively transported by the sodium
iodide symporter, with radiation characteristics simi-
lar to those of 123I but with the advantages of minimal
cost and ready availability due to its widespread use in
nuclear medicine.
131
Biological Effects of I 131
When 131
I is incorporated into thyroid tissue, the
emission of beta particles results in ionization of the
thyroid cell, leading directly to the damage of DNA
and essential proteins, such as enzymes, and indirectly
to the production of free radicals. The early effects of
131
I include necrosis of follicular cells and vascular
occlusion that fully develop over a period of weeks
to months. Long-term effects include shorter cell
survival, impaired replication of surviving thyroid
cells with atrophy and fibrosis, and a chronic inflam-
matory response resembling Hashimoto’s thyroiditis.
These later effects account for the development of
hypothyroidism even years after treatment. The
extent of loss of thyroid function, and therefore of
the disease state, can be controlled to some extent by
the amount of 131I administered.
RADIOACTIVE IODINE UPTAKE IN
THYROID FUNCTION TESTING
AND IMAGING
In the past, measurement of radioactive iodine uptake
by the thyroid was commonly used to assess thyroid
function. The development of sensitive in vitro thy-
roid function tests and the decrease in normal values
for thyroidal radioiodine uptake consequent to an
increase in dietary iodine intake have largely rendered
this technique obsolete.
Radioiodine uptake measurement, however,
remains an important technique in evaluating the
hyperthyroid patient. Its main roles are to distinguish
subacute or silent thyroiditis from Graves’ disease,
to provide information regarding the feasibility of
radioiodine therapy, and to aid in dose calculation at
centers using calculated doses of 131I.
Thyroid scanning (scintigraphy) allows visual-
ization of the thyroid gland and functioning tissue
elsewhere in the body. Therefore, it is valuable in
101
many clinical situations, including identifying the
cause of hyperthyroidism, evaluating thyroid enlarge-
ment, the functionality of thyroid nodules, postopera-
tive evaluation of differentiated thyroid cancer, and
localization of ectopic thyroid tissue.
HYPERTHYROIDISM
131
I is increasingly used as first-line therapy for
Graves’ hyperthyroidism and is the treatment of
choice for patients with relapsed hyperthyroidism
after antithyroid drug treatment and toxic nodular
goiter. Because adequate thyroidal iodine (and hence
I) uptake is a prerequisite for 131I therapy, it is not
an appropriate treatment modality for thyroid-stimu-
lating hormone (TSH)-dependent hyperthyroidism
and for other causes of hyperthyroidism with low
iodine uptakes such as thyroiditis. The objective of
131
I therapy is to destroy sufficient tissue to cure
hyperthyroidism. This may be achieved by rendering
the patient either euthyroid or hypothyroid.
131
I typically takes 6 to 8 weeks to produce its effects,
and euthyroidism is expected 3 to 6 months after
131
I administration. If this is not achieved, a second
dose of 131I is usually administered. The degree of
lasting remission is close to 100% after one or more
doses, and there is much more predictable shrinkage
of goiter, often with complete disappearance, than can
be achieved with antithyroid drugs.
Much attention has focused on achieving euthyr-
oidism by adjusting the dose of 131I, but there is little
consensus regarding the most appropriate dose regi-
men. The regimens include repeated low doses
(80 MBq), fixed doses of 200 or 400 MBq, and doses
calculated on the basis of the size of the thyroid, the
uptake of radioiodine, or the turnover of radioiodine.
There is no evidence that giving a calculated dose of
131
I will achieve euthyroidism but not hypothyroid-
ism, and calculated doses have the disadvantages of
inconvenience (> 1 hospital visit required) and higher
cost, so many centers use a single fixed dose. The
lifetime chance of becoming hypothyroid following
131
I is at least 50% with a lifelong requirement for
thyroxine replacement.
THYROID CANCER
The affinity of differentiated thyroid cancer for iodine
is the basis for the use of 131I for both the detection
and the treatment of recurrent thyroid cancer in pa-
tients following initial surgical treatment (thyroidect-
omy). The main indications for 131I therapy are the
102
ablation of residual thyroid tissue after thyroidectomy,
the treatment of locoregional recurrence, and distant
metastases that involve the lung and bones almost
exclusively. The precise protocols for 131I scanning
and treatment are complex and controversial and
have been reviewed extensively elsewhere.
NONTOXIC GOITER
Although thyroidectomy remains the standard treat-
ment for large nontoxic goiters that compress the
trachea, it may be contraindicated in the elderly or
in goiter recurrence after previous thyroid surgery. In
such cases, 131I represents an effective alternative to
surgery. Studies have shown that 131I, administered in
doses similar to those used in hyperthyroidism, is
effective in reducing goiter size by approximately
40% in patients with nontoxic goiter. Initial con-
cerns that 131I treatment may lead to thyroid enlarge-
ment and worsening of airways obstruction in the
short term have proved to be groundless. However,
hypothyroidism may occur, as may the development
of Graves’ disease, which has been described in 5% of
cases.
SAFETY AND SIDE EFFECTS
131
I treatment has been shown to be safe. Concerns
about increased cancer risk are largely unfounded,
with population studies showing no overall increase
in the incidence of cancer or cancer mortality except
for a small increase in the absolute risk of small bowel
and thyroid cancer. Furthermore, there is no evidence
to suggest any reduction in fertility or any problems in
the offspring of women treated before pregnancy. The
only absolute contraindications are pregnancy and
breast-feeding. Pregnancy should be excluded before
131
I administration and should be delayed for 4
months after therapy. Relative contraindications in-
clude the use of 131I in patients under 20 years of
age, in whom it should be used with caution, and the
presence of thyroid eye disease, which can potentially
be worsened by 131I but easily prevented by the use of
corticosteroids.
Permanent hypothyroidism is the only common
complication of 131I treatment, occurring in at least
50% of patients given high doses ( 400 MBq) by 1
year and in at least 50% of those given lower doses
( 200 MBq) by 25 years. It is dose dependent, and its
Iodine, Radioactive
incidence remains at 2 to 3% per year many years after
therapy. Rarer complications include radiation thyr-
oiditis, thyrotoxic crisis, and early paradoxical in-
crease in goiter size.
See Also the Following Articles
Graves’ Disease, Hyperthyroidism in . Iodine . Iodine De-
ficiency . Irradiation, Thyroid and . Nontoxic Goiter .
Thyroid Carcinoma
Further Reading
Bartalena, L., Marcocci, C., Bogazzi, F., Manetti, L., Tanda, M. L.,
Dell’Unto, E., Bruno-Bossio, G., Nardi, M., Bartolomei, M. P.,
Lepri, A., Rossi, G., Martino, E., and Pinchera, A. (1998).
Relation between therapy for hyperthyroidism and the course
of Graves’ ophthalmopathy. N. Engl. J. Med. 338, 73–78.
Bonnema, S. J., Bertelsen, H., Mortensen, J., Andersen, P. B.,
Knudsen, D. U., Bastholt, L., and Hegedus, L. (1999). The
feasibility of high dose iodine 131 treatment as an alternative
to surgery in patients with a very large goiter: Effect on thyroid
function and size and pulmonary function. J. Clin. Endocrinol.
Metab. 84, 3636–3641.
Cavalieri, R. R. (1996). Nuclear imaging in the management of
thyroid carcinoma. Thyroid 6, 485–492.
Franklyn, J. A., Maisonneuve, P., Sheppard, M., Betteridge, J., and
Boyle, P. (1999). Cancer incidence and mortality after radio-
iodine treatment for hyperthyroidism: A population-based
cohort study. Lancet 353, 2111–2115.
Glinoer, D. (1994). Radioiodine therapy of non-toxic multinodular
goitre. Clin. Endocrin. (Oxf.) 41, 715–718.
Kaplan, M. M., Meier, D. A., and Dworkin, H. J. (1998). Treatment
of hyperthyroidism with radioactive iodine. Endocrinol. Metab.
Clinics North America 27, 205–223.
Lazarus, J. H. (1995). Guidelines for the use of radioiodine in the
treatment of hyperthyroidism: A summary. J. Royal College Phys-
icians London 29, 464–469.
Maurer, A. H., and Charkes, N. D. (1999). Radioiodine treat-
ment for nontoxic multinodular goiter. J. Nuclear Med. 40,
1313–1316.
Mazzaferri, E. L., and Kloos, R. T. (2001). Current approaches to
the primary therapy for papillary and follicular thyroid cancer.
J. Clin. Endocrinol. Metab. 86, 1447–1463.
Meier, D. A., and Kaplan, M. M. (2001). Radioiodine uptake and
thyroid scintiscanning. Endocrinol. Metab. Clinics North America
30, 291–313.
Nygaard, B., Knudsen, J. H., Hegedus, L., Scient, A. V. C., and
Hansen, J. E. M. (1997). Thyrotropin receptor antibodies and
Graves’ disease: A side-effect of 131I treatment in patients with
non-toxic goiter. J. Clin. Endocrin. Metab. 82, 2926–2930.
Spitzweg, C., Heufelder, A. E., and Morris, J. C. (2000). Thyroid
iodine transport. Thyroid 10, 321–330.
Wartofsky, L., Sherman, S. I., Gopal, J., Schlumberger, M., and
Hay, I. D. (1998). The use of radioactive iodine in patients with
papillary and follicular thyroid cancer. J. Clin. Endocrinol. Metab.
83, 4195–4203.