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Iodine Research

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                       Iodine and Disease

Thyroid - Nodules

ABRAHAM
The concept of orthoiodosupplementation and its clinical implications.
Abraham, GE
The Original Internist, 11(2):29-38, 2004

Elevated TSH induces hypertrophy, whereas intrathyroidal iodine deficiency induced thyroid
hyperplasia. In iodine-deficient goiter, iodine supplementation abolishes not only hypertrophy, but
also hyperplasia of the thyroid gland. On the other hand, suppression of TSH with T4 abolishes
hypertrophy, not hyperplasia if there is intrathyroidal iodine deficiency. Therefore, administration of
T4 to iodine-deficient patients does not decrease their risk for thyroid cancer, an effect expected
with iodine supplementation.


A Rebuttal of Dr. Gaby's Editorial on Iodine
Guy E. Abraham, MD and David Brownstein, MD
Townsend Letter for Doctors & Patients, October 2005

One of the most satisfying effects of orthoiodosupplementation has been in the treatment of
fibrocystic breasts and thyroid nodules. The treatment of fibrocystic breasts with iodine has been
reported for over 100 years. Iodine/iodide supplementation has resulted in significant improvement
in fibrocystic breast illness for nearly every patient treated. Thyroid nodules also respond
positively to iodine/iodide supplementation. Serial ultrasounds usually show decrease in the size of
the thyroid cysts and nodules and eventual resolution of the lesions. When
orthoiodosupplementation is combined with a complete nutritional program, it is rare not to see
improvement in the palpation and radiological examination of thyroid nodules and cysts following
iodine/iodide therapy as described here.


ENDOCRINEWEB
Thyroid Nodules
EndocrineWeb

Simply put, thyroid nodules are lumps which commonly arise within an otherwise normal thyroid
gland. Often these abnormal growths of thyroid tissue are located at the edge of the thyroid gland
so they can be felt as a lump in the throat. When they are large or when they occur in very thin
individuals, they can even sometimes be seen as a lump in the front of the neck. The following is a
list of facts regarding thyroid nodules:
  • One in 12 to 15 young women has a thyroid nodule
  • One in 40 young men has a thyroid nodule
  • More than 95 percent of all thyroid nodules are benign (non-cancerous growths)
  • Some are actually cysts which are filled with fluid rather than thyroid tissue
  • Most people will develop a thyroid nodule by the time they are 50 years old

The incidence of thyroid nodules increases with age
  • 50% of 50 year olds will have at least one thyroid nodule
  • 60% of 60 year olds will have at least one thyroid nodule
  • 70% of 70 year olds will have at least one thyroid nodule

Three questions that should be answered about all thyroid nodules:
  • Is the nodule one of the few that are cancerous ?
  • Is the nodule causing trouble by pressing on other structures in the neck ?
  • Is the nodule making too much thyroid hormone?

After an appropriate work-up, most thyroid nodules will yield an answer of NO to all of the above
questions. In this most common situation, there is a small to moderate sized nodule which is simply
an overgrowth of "normal" thyroid tissue, or even a sign that there is too little hormone being
produced. Patients with a diffusely enlarged thyroid (called a goiter) will present with what is
perceived at first to be a nodule, but later found to be only one of many benign enlarged growths
within the thyroid (a goiter). Usually a fine needle aspiration biopsy (FNA) will tell if the nodule is
cancerous or benign. This one test can get right to the bottom of the issue (covered in detail on
another page). Often an Ultrasound examination is necessary to determine the characteristics of a
thyroid nodule (ultrasound is covered in detail on another page).

Symptoms of thyroid nodules.Most thyroid nodules cause no symptoms at all. They are usually
found by patients who feel a lump in their throat or see it in the mirror. Occasionally, a family
member or friend will notice a strange lump in the neck of someone with a thyroid nodule. Another
common way in which thyroid nodules are found is during a routine examination by a physician.

Occasionally, nodules may cause pain, and even rarer still are those patients who complain of
difficulty swallowing when a nodule is large enough and positioned in such a way that it impedes
the normal passage of food through the esophagus (which lies behind the trachea and thyroid).

Occasionally a thyroid nodule is found because the patient is undergoing a CT scan, MRI scan, or
ultrasound scan of the neck for some other reason (parathyroid disease, carotid artery disease,
cervical spine pain, etc). Thyroid nodules found this way (by accident) are cancerous far less than
1% of the time. If this is you, then please stop worrying.



FLECHAS
Iodine Insufficiency FAQ
Flechas JD

Most people over age 60 are becoming depleted of iodine due to the lack of iodine in the diet and
that this particular group of individuals is also the group with the highest occurrence of thyroid
nodules and goiters. Also of interest is that 25% of the people in this age category will become
senile as a result of low thyroid (hypothyroidism). Iodine supplementation may alleviate these
iodine-related maladies, but iodine testing and thyroid studies such as a thyroid ultrasound and
thyroid lab tests should be conducted prior to beginning iodine supplementation therapy.

Traditional medical literature indicates that patients who have thyroid nodules or thyroid goiter may
have the potential to develop hyperthyroidism when supplementing with iodine. Hence, before
commencing iodine supplementation, it would be advantageous for a person to have their primary
care doctor order a thyroid ultrasound to rule out the possibility of pre-existing goiter or thyroid
nodules. The primary care doctor should also order thyroid lab work (to be used as a baseline)
before prescribing iodine therapy and this lab work should be repeated and followed at regular
intervals during the patient's iodine therapy. For iodine therapy patients not also on thyroid
hormone replacement therapy, adjustments to the iodine therapy should be made if signs of
hyperthyroidism should occur. Should signs of hyperthyroidism occur in patients who are taking
thyroid hormone replacement therapy as well as taking iodine supplementation, the physician
should first recommend an adjustment in the thyroid hormone therapy rather than in the iodine
supplementation. This adjustment in therapy is recommended because iodine is required not only
by the thyroid but is required for the proper functioning of many other tissues. The presence of
pre-existing thyroid nodules or goiter does not preclude the patient from iodine supplementation
therapy. In fact, in the extensive research with iodine therapy done in my office, I have seen many
case of pre-existing thyroid nodules and goiter shrink in the presence of iodine therapy.



MAIER, KROHN, PASCHKE
Iodine deficiency activates antioxidant genes and causes DNA damage in the thyroid gland of rats
and mice.
Maier J, van Steeg H, van Oostrom C, Paschke R, Weiss RE, Krohn K.
Biochim Biophys Acta. 2007 Mar 24; [Epub ahead of print]
[abstract only]

Because thyroid nodules are frequent in areas with iodine deficiency the aim of this study was to
characterise molecular events during iodine deficiency that could explain mutagenesis and nodule
formation. We therefore studied gene expression of catalytic enzymes prominent for H(2)O(2)
detoxification and antioxidative defence, quantified DNA oxidation and damage as well as
spontaneous mutation rates (SMR) in mice and rats fed an iodine controlled diet. Antioxidative
enzymes such as superoxide dismutase 3, glutathione peroxidase 4 and the peroxiredoxins 3 and
5 showed increased mRNA expression, which indicates increased radical burden that could be the
cause of additional oxidized base adducts found in thyroidal genomic DNA in our experiments of
iodine deficiency. Furthermore, the uracil content of thyroid DNA was significantly higher in the
iodine-deficient compared to the control group. While SMR is very high in the normal thyroid gland
it is not changed in experimental iodine deficiency. Our data suggest that iodine restriction causes
oxidative stress and DNA modifications. A higher uracil content of the thyroid DNA could be a
precondition for C-->T transitions often detected as somatic mutations in nodular thyroid tissue.
However, the absence of increased SMR would argue for more efficient DNA repair in response to
iodine restriction.


Deoxyribonucleic acid damage and spontaneous mutagenesis in the thyroid gland of rats and mice.
Maier J, van Steeg H, van Oostrom C, Karger S, Paschke R, Krohn K.
Endocrinology. 2006 Jul;147(7):3391-7. Epub 2006 Apr 20.
[abstract only]

Thyroid tumors are a frequent finding not only in iodine-deficient regions. They are predominantly
characterized by somatic genetic changes (e.g. point mutations or rearrangements). Because slow
thyroid proliferation is a apparent contradiction to a high frequency of tumor initiation, we
characterized mutational events in thyroid. First we studied the frequency of certain base
exchanges in somatic TSH receptor (TSHR) mutations and determined the spontaneous mutation
rate in thyroid and liver. Then we applied different protocols of the comet assay to quantify
genomic DNA damage and conducted immunohistochemistry for 8-oxoguanine as a molecular
marker for oxidative stress. Among 184 somatic mutations of the human TSHR found in thyroid
tumors, C-->T transitions had a unexpectedly high frequency (>32%). The mutation rate in thyroid
is 8-10 times higher than in other organs. The comet assay detected increased levels of oxidized
pyrimidine (2- to 3-fold) and purine (2- to 4-fold) in thyroid, compared with liver and lung, and a 1.6-
fold increase of oxidized purine, compared with spleen. Immunohistochemistry revealed high levels
of 8-oxoguanine in thyroid epithelial cells. We have shown a strikingly high mutation rate in the
thyroid. Furthermore, results of the comet assay as well as immunohistochemistry suggest that
oxidative DNA modifications are a likely cause of the higher mutation rate. It is possible that free
radicals resulting from reactive oxygen species in the thyroid generate mutations more frequently.
This is also supported by the spectrum of somatic mutations in the TSHR because more frequent
base changes could stem from oxidized base adducts that we detected in the comet assay and
with immunohistochemistry.


Similar prevalence of somatic TSH receptor and Gsalpha mutations in toxic thyroid nodules in
geographical regions with different iodine supply in Turkey.
Gozu HI, Bircan R, Krohn K, Muller S, Vural S, Gezen C, Sargin H, Yavuzer D, Sargin M, Cirakoglu
B, Paschke R.
Eur J Endocrinol. 2006 Oct;155(4):535-45.
[abstract only]

OBJECTIVE: Differences in iodine intake could account for the variable prevalences reported for
somatic TSH receptor (TSHR) mutations in toxic thyroid nodules (TTNs). However, this question
has not been settled, since no study has yet determined the TSHR mutation prevalence in regions
with different iodine supplies in the same population using the same methodology. Therefore, we
studied the prevalence of somatic TSHR mutations in TTNs from patients living in iodine-deficient
or -sufficient regions in Turkey.

DESIGN AND METHODS: We screened 74 TTNs for somatic TSHR mutations. Exons 9 and 10 of
the TSHR and 7 and 8 of the Gsalpha were screened by denaturing gradient gel electrophoresis.
Determination of X-chromosome inactivation was used for clonality analysis.

RESULTS: TSHR mutations were identified in 52 (70.2%) of 74 TTNs. A Gsalpha mutation was
identified in one TTN. Three new TSHR mutations were detected (A627V, I640K, I486N). No
significant difference between frequencies of TSHR mutations in iodine deficient/sufficient regions
was found. The frequency of non-random X-chromosome inactivation was similar in iodine-
sufficient or -deficient regions and in TSHR mutation positive or negative hot nodules.

CONCLUSIONS: These findings suggest that TTNs in iodine deficient/sufficient areas
predominantly arise from aberrant growth of a single cell. Our results suggest that neither the
prevalence of TSHR mutations nor that of monoclonal TTNs is related to iodine supply.


Cold thyroid nodules show a marked increase in proliferation markers.
Krohn K, Stricker I, Emmrich P, Paschke R.
Thyroid. 2003 Jun;13(6):569-75.
[abstract only]

Thyroid follicular adenomas and adenomatous thyroid nodules are a frequent finding in
geographical areas with iodine deficiency. They occur as hypofunctioning (scintigraphically cold)
or hyperfunctioning (scintigraphically hot) nodules. Their predominant clonal origin suggests that
they result from clonal expansion of a single cell, which is very likely the result of a prolonged
increase in proliferation compared with non-affected surrounding cells.

To test whether increased cell proliferation is detectable in cold thyroid nodules, we studied
paraffin-embedded tissue from 40 cold thyroid nodules and their surrounding normal thyroid tissue
for the occurrence of the proliferating cell nuclear antigen (PCNA) and Ki-67 (MIB-1 antibody)
epitopes as markers for cell proliferation. All 40 thyroid nodules were histologically well
characterized and have been studied for molecular characteristics before. The labeling index
(number of labeled cells versus total cell number) for nodular and surrounding tissue was
calculated.

In 33 cold thyroid nodules a significant (p < or = 0.05) increase in the labeling index for PCNA was
detectable. In 19 cold thyroid nodules a significant (p < or = 0.05) increase in the labeling index for
Ki-67 was detectable. Moreover, surrounding tissues with lymphocyte infiltration showed a
significantly higher labeling index for both PCNA and Ki-67 compared with normal surrounding
tissue.

These findings are first evidence that an increased thyroid epithelial cell proliferation is a uniform
feature common to most cold nodules. However, the increase of proliferation markers shows a
heterogeneity that is not correlated with histopathologic, molecular, or clinical characteristics.


Somatic mutations in thyroid nodular disease.
Krohn K, Paschke R.
Mol Genet Metab. 2002 Mar;75(3):202-8. Review.
[abstract only]

Thyroid nodules can be found in up to 50% of inhabitants of iodine-deficient areas and are
classified as hot or cold thyroid nodules according to their scintigraphic characteristics. Studies of
hot thyroid nodules with comparable mutation detection methods and screening at least exon 10 of
the TSH receptor reported frequencies for somatic TSH-receptor mutations ranging from 20 to
82% in patients with similar iodine supply. We have recently screened 75 hot thyroid nodules for
somatic TSH-receptor mutations with the more sensitive DGGE method and found somatic TSH-
receptor mutations in 57% and Gsalpha mutations in 3%. As 50% of the mutation-negative nodules
from female patients are of monoclonal origin when tested for X-chromosome inactivation somatic
mutations in other genes are likely to cause the development of hot thyroid nodules.
Scintigraphically nonsuppressible areas have been identified in up to 40% of euthyroid goiters in
iodine-deficient areas. We recently identified somatic TSH-receptor mutations in microscopic
autonomous areas with increased 125T uptake in euthyroid goiters studied by autoradiography 20
years ago. These constitutively activating somatic TSH-receptor mutations in minute
autoradiographically hot areas of euthyroid goiters are very likely starting foci which most likely
lead to toxic thyroid nodules in iodine-deficient goiters. Therefore iodine deficiency does not only
lead to euthyroid goiters but also to thyroid autonomy. The latter is also suggested by
epidemiologic studies. Similar mechanisms induced by iodine deficiency and the subsequent
hyperplasia, mutagenesis, and selection of cell clones could also lead to cold thyroid nodules by
somatic mutations that only initiate growth but not hyperfunction of the affected thyroid epithelial
cell. Somatic ras mutations have frequently been detected in histologically characterized thyroid
adenomas or adenomatous nodules. However, they seem to be rare in cold thyroid nodules. Since
the majority of these latter nodules and 60% of the cold thyroid nodules are monoclonal other
somatic mutations are likely in these nodules.


Growth factor expression in cold and hot thyroid nodules.
Eszlinger M, Krohn K, Kratzsch J, Voigt C, Paschke R.
Thyroid. 2001 Feb;11(2):125-35.
[abstract only]

Hot thyroid nodules (HTNs) are predominantly caused by constitutively activating thyrotropin
receptor (TSHR) mutations leading to an activation of the cyclic adenosine monophosphate (cAMP)
-cascade that stimulates growth and function of thyroid epithelial cells and confers growth
advantage. In contrast to HTNs, the molecular etiology of scintigraphically cold thyroid nodules
(CTNs) is largely unknown. An increased prevalence of toxic multinodular goiters in iodine-deficient
regions has been reported. Growth factors increase during early stages of iodine deficiency in
rats. These growth factors could modulate the proliferation of thyrocytes.

In order to determine if and which growth factors could modulate the increase in thyroid epithelial
cell proliferation in late stages of CTNs and HTNs we investigated epidermal growth factor (EGF),
transforming growth factor-alpha (TGF-alpha), and TGF-beta1 concentrations by enzyme-linked
immunosorbant assay (ELISA) in CTNs (n = 7), HTNs (n = 9), and their normal surrounding tissue
(ST). Insulin-like growth factor-1 (IGF-1) was determined in CTNs (n = 5) and HTNs (n = 10) and
their surrounding tissues by radioimmunoassay (RIA).

We found lower concentrations of all investigated growth factors and iodine in CTNs compared to
surrounding normal tissues (ST). Only iodine showed a significant difference. Furthermore, we
found significantly lower concentrations of EGF and TGF-beta1 concentration in HTNs compared
to their STs. Differences of TGF-alpha and IGF-1 were not significant.

In conclusion, low EGF, TGF-alpha, and IGF-1 concentrations in most CTNs in spite of low iodine
concentrations argue against a pathophysiologic role of EGF, TGF-alpha, or IGF-1 in late stages
of CTNs. The low EGF, TGF-alpha, and IGF-1 concentrations in HTNs irrespective of their clonal
origin or the presence or absence of activating mutations argue for increased cAMP as the primary
cause for thyroid epithelial cell proliferation in established HTNs. However, the pathophysiologic
significance of low TGF-beta1 concentrations in CTNs and HTNs remains to be elucidated. It might
be possible that growth factors like EGF, TGF-alpha, TGF-beta1, and IGF-1 play a more
prominent role during early clonal expansion and that aberrant intrinsic signaling through a
somatic mutation (e.g., TSHR for HTNs) confers the predominant selective growth advantage in
later stages of HTNs or CTNs.



ROSS
Patient information: Thyroid nodules
Ross DS

Thyroid nodules feel round or oval-shaped, and differ from the surrounding normal thyroid tissue.
In some cases a person notices a nodule in their own neck, while in other cases a healthcare
provider will feel a nodule during a routine examination of the neck. Nodules can also be
discovered during tests for an unrelated condition.

Thyroid nodules are very common; up to half of all people have at least one thyroid nodule,
although most do not know about it. Thyroid nodules can be caused many different conditions.
Reassuringly, about 95 percent of all thyroid nodules are caused by benign (non-cancerous)
conditions.

    Benign nodules — These nodules usually develop as a result of overgrowth of normal
    components of the thyroid gland. Surgery is not usually recommended, and the nodule can
    usually be monitored over time. If the nodule grows, a repeat biopsy or surgery may be
    recommended.

    Malignant nodules (thyroid cancer) — Only about 5 percent of all thyroid nodules are
    malignant. The majority of thyroid cancers are papillary thyroid cancer. Most patients with
    thyroid cancer have an excellent chance for cure or long-term survival.  The treatment of
    thyroid cancer will depend on the type of cancer. Thyroid cancers require surgical removal
    of the thyroid gland and one or more treatments with radioiodine, followed by thyroid
    hormone (T4) suppressive therapy.

    Indeterminate or suspicious nodules — These nodules are not officially classified as
    malignant nodules, but they share many features with thyroid cancer. With time, they may
    invade surrounding tissues, at which point they are classified as cancer.  Surgical removal of
    these nodules is generally recommended. At the time of surgery, about 10 to 20 percent of
    suspicious nodules have become invasive and are classified as cancers. Occasionally,
    synthetic thyroid hormone (T4) treatment may be recommended to slow the growth of a
    microfollicular nodule. Close monitoring is also recommended.

    Autonomous nodules — Some nodules produce thyroid hormone, similar to the thyroid
    gland, but fail to respond to the body's hormonal controls. These nodules are called
    autonomous nodules. They are almost always benign, but they can lead to excess thyroid
    hormone production and hyperthyroidism. Patients with an autonomous nodule and marked
    hyperthyroidism usually undergo surgery to remove the nodule, or undergo radioactive
    iodine treatment to destroy the nodule.

If there is an autonomous nodule and normal thyroid function or minimal hyperthyroidism, the
appropriate treatment will depend on the patient's age and other health factors. This type of
nodule may be monitored in young adults. However, high thyroid hormone levels pose a risk of an
abnormal heart rhythm (atrial fibrillation) and bone loss (osteoporosis) with advancing age, and
radioactive iodine treatment may be recommended for older adults.

Cystic nodules — Cystic nodules are usually benign nodules that have filled with fluid. These
nodules may simply collapse when the fluid is removed. Cystic nodules are usually monitored for
changes; some symptoms, such as recurrent bleeding or cyst reformation require that the nodules
are surgically removed.
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