The Role of Levothyroxine on Goiter With Atypia of Undetermined Significance
The Role of Levothyroxine on Goiter With Atypia of Undetermined Significance
1. To elucidate the therapeutic role of levothyroxine on the patient with atypia of
 undetermined significance (AUS) goiter, we would design a prospective, open label and
 non-randomized trial to verify the therapeutic effects on goiter with AUS by means of
 TSH (Thyrotropin; Thyroid-Stimulating Hormone) suppression related reduction of goiter
 volume with subsequent alleviation of previous cytological malignant tendency. During
 following for 1-2 years after therapy with simultaneous monitor of possible adverse
 effects of levothyroxine (eltroxin), we collected blood samples and gathered all
 necessary data as well as performed thyroid sonography with fine-needle aspiration (FNA)
 for the subjects. Furthermore, we would finish our individual study for each enrolled
 subject if his/her condition exhibited the criteria of primary end point: reduced goiter
 volume under sono >15% or cytology: benign for 2 times; operation for thyroidectomy, CAD
 attack, refractory arrhythmia, newly DM (Diabetes Mellitus), etc.

 2. To re-evaluate the current prevalence of goiter within Taiwanese adults, we recruited
 all patients who presented possible thyroid related symptoms, such as unexplained body
 weight loss with increased appetite, palpitation, hand tremors, neck swelling,
 hoarseness and abnormal sensation over throat. Only the patients with goiter proven by
 thyroid sono in euthyroid status without other preexisting major disorders can be
 enrolled in our trial to undergo open label, non-randomized study.
The prevalence of goiter in Taiwanese adults was found to be 19.4% in males, 33.6% in females
 and 25% in total about 20 years ago even though there was no iodine-deficient area reported
 in Taiwan. The result implied that goiter not only became a quite common disorder, but also
 deserved further investigation, particularly since 0.7% of goiter would be diagnosed as
 thyroid cancers by means of fine-needle aspiration (FNA). However, the recent research
 indicated 5-15% of results after fine-needle aspiration directly disclosed malignant
 cytology. On the other hand, about 80% of initial results of FNA would appear non-malignant
 cytology. The most common feature of them was found to be indeterminate cytology, which
 refers to 15-30% of FNA specimens. The indeterminate cytology included follicular or Hurthle
 cell neoplasm as well as atypia of undetermined significance (AUS). Based on the revised
 American Thyroid Association Management Guidelines for Patients with Thyroid Nodules, people
 would be referred to visit surgeons for surgical intervention if their reports of FNA
 demonstrated either Hurthle cell neoplasm or follicular neoplasm without autonomously
 functioning nodules; instead, population with AUS goiter only received observation for a
 period of time for following. Otherwise, they would be arranged to undergo surgical
 manipulations if any evidence of malignancy was suspected. There has been lack of sufficient
 studies to offer therapeutic options for the patient with AUS goiter around the world up to
 the present, especially in Taiwan. Therefore, in order to avoid unnecessary operation
 performed upon the patient with AUS goiter and provide another effective treatment for them,
 a well-designed, prospective clinical trial will be warranted on the patient with AUS goiter.

 To achieve the goal, the pathophysiology of goiter required to be understood at first.
 Although the actual etiology of goiter was uncertain, TSH (thyrotropin) has been regarded as
 a major factor to induce its formation up to now. To attenuate the growth-tropic effects of
 TSH, levothyroxine suppression therapy had been administered in the past to treat goiter,
 particularly about the goiter with colloid nodules. Successful reduction of goiter volume was
 found in some published papers while others did not verify the therapeutic effects of
 levothyroxine. However, the fact that goiter with size under thyroid sonogram more than 1cm
 required to be further examined indicated reduced volume of goiter may offer benefits
 including amelioration of previous malignant tendency especially in AUS goiter through TSH
 suppression therapy though some studies indicated routine suppression therapy of benign
 thyroid nodules in iodine sufficient populations is not recommended At first, patients who
 aged 20 to 70 with thyroid dysfunction related manifestations as goiter, palpitation or hand
 tremors would be recruited while they visited MET OPD (Out-Patient Department) and then they
 would be arranged to undergo thyroid sono as well as receive thyroid functional tests during
 screening periods before the study. The patients would be eligible for the interventional
 trial if their thyroid sonography demonstrated goiter and their thyroidal function revealed
 euthyroid status. After careful investigations of subjects' associated histories as family
 histories, drug histories and diet habits, the patients would be actually recruited for the
 clinical trial with the signed informed consent. Initially, the enrolled subjects would be
 classified into two major groups as solitary nodular goiter and multiple nodular goiter.
 Subsequently, two subgroups would be identified from each major group by presence of
 autoantibody of thyroglobulin or not. Thereafter, the patients would be asked to comply with
 the guidelines of ATA (American Thyroid Association) for advanced evaluation , fine needle
 aspiration and following if they indeed present with either goiter with more than 1 cm in
 size or less than 1 cm with regard to typical malignant characteristics under thyroid
 sonography, such as heterogeneous, hypoechoic, increased peri-vascularization, tall than
 wide. Furthermore, patients with history of family MTC (Medullary Thyroid Cancer) or contact
 of radiation or radiation therapy would be arranged to under FNA, too. The patients with
 first FNA disclosing AUS (atypia of undetermined significance) would be arranged to receive
 FNA again for confirmatory examination one month later and soon later those patients with
 positive findings of AUS twice would be allowed to take eltroxin for TSH suppression therapy.
 On the contrary, the patients would be assigned to the groups who will receive traditional
 observation and following of thyroid sonography as well as thyroid functional tests. These
 observed patients would receive surgical interventions if their FNA showed malignant
 potentials as NUCLEAR GROOVING， MICROFOLLICULAR FOCI，Hurthle cell, etc.

 As to the studied patients with consecutive FNA reports indicating AUS twice would be
 arranged to take levothyroxine (eltroxin, 0.1 mg) for therapy and its dosage would be
 adjusted carefully after 2 weeks per each OPD visiting. Optimal therapeutic goals would be
 regarded as subclinical hyperthyroidism and constant concentrations or dosages of eltroxin
 would be achieved in 2 months. Thereafter, the studied subjects would be arranged to receive
 thyroid sonography and FNA 3 months later and other necessary blood biochemistry studies for
 following. All following information would be recorded well and completely. The primary
 endpoint means: reduced goiter volume under sono >15% or cytology: benign*2 times; operation
 for thyroidectomy; CAD attack; refractory arrhythmia; newly DM. The pathology of all FNA
 during the clinical trial would be judged by the Bethesda System for Reporting Thyroid
 Cytopathology.
Inclusion Criteria:

 -  all patients who presented with goiter proven by thyroid sono in euthyroid status
 without other preexisting major disorders and possible thyroid related symptoms, such
 as unexplained body weight loss with increased appetite, palpitation, hand tremors,
 neck swelling, hoarseness and abnormal sensation over throat.

 Exclusion Criteria:

 -  all patients without definite goiter

 -  all patients with major illness as CAD, DM or CVA (CerebroVascular Accident)

 -  all patients with pregnancy or malignancy