This patient presented with hyperthyroidism, which is seen in approximately 2% of women and 0.2% of men.

The etiology for hyperthyroidism may be divided into exogenous or endogenous causes. Exogenous hyperthyroidism is due to overtreatment with levothyroxine, which may be iatrogenic (unintentional over-treatment or therapeutic over-treatment such as in patients with thyroid cancer) or factitious (e.g. abuse for weight loss). Endogenous hyperthyroidism may be due to one of several conditions: Graves' disease, toxic multinodular goiter or solitary toxic adenoma. Thyrotoxicosis is also seen in the initial phase of thyroiditis, when the stored hormone is released into the circulation as a result of thyroid destruction. The typical symptoms of hyperthyroidism include fatigue, weight loss, anxiety, palpitations, and heat intolerance; women may have irregular menses. Common exam findings include tachycardia, tremor, enlarged thyroid and warm, moist skin. Elderly persons may have an atypical presentation with atrial fibrillation, weakness, unexplained weight loss, or congestive heart failure. Hyperthyroidism is diagnosed by the finding of a suppressed or undetectable TSH with elevated free T4 or free T3 (overt hyperthyroidism). In subclinical hyperthyroidism, the TSH is suppressed, but the free hormones are in the normal range. In general, thyroid function tests are not useful for establishing the etiology of hyperthyroidism, except in very rare cases, when the patient has an elevated TSH and elevated free T4 or T3; this is indicative of a thyrotropin-secreting tumor ("TSHoma") or resistance to thyroid hormone. Causes of hyperthyroidism Graves' disease is a relapsing/remitting condition that occurs predominantly in women, and has an autoimmune etiology (1). It is caused by thyroid-stimulating immunoglobulins (TSI), which stimulate the TSH receptor. In addition to the typical symptoms of hyperthyroidism, patients with Graves' disease may also have one or more the following findings: an audible bruit over the thyroid, pretibial myxedema (most commonly located on anterior shins), and ophthalmopathy. Possible eye findings in patients with Graves' disease include lid retraction (sclera can be seen above the iris as the patient looks straight ahead), lid lag (sclera can be seen above the iris as the patient looks downward), diploplia due to extraocular muscle dysfunction, and proptosis due to swelling of the retroorbital soft tissue. This may result in xeropthalmia and corneal damage. Inflammation of the extraocular muscles may lead to restriction of motion and diplopia on extreme gaze. With laboratory testing, subjects with Graves' disease will have a suppressed TSH, an elevated free T3 and usually an elevated free T4. Occasionally, only T3 is elevated, which is referred to as "T3 toxicosis". Additional testing in suspected Graves'disease will demonstrate the presence of thyroid-stimulating immunoglobulins (TSIs), which are elevated in 96% of patients with Graves' disease. The gold standard for diagnosis of Graves' disease is the I123scan and uptake, which shows homogenous symmetrical uptake in Graves' disease. Toxic multinodular goiter (Plummer's disease) is another common cause of hyperthyroidism and is a more common cause of hyperthyroidism in elderly. (2) Constitutive mutations of the TSH receptors on the surface of the nodules impart autonomy to these nodules. As with Graves' disease, the TSH will be suppressed with an elevated T3 and usually elevated T4 as well. However, T3 is generally less elevated compared to patients with Graves' disease. I123scan and uptake in Plummer's disease generally shows focal areas of increased uptake in the autonomous nodules, with suppression of the remaining gland. This condition is usually progressive and unlike Graves' disease, does not undergo spontaneous remission. Overt hyperthyroidism due to solitary toxic nodule generally occurs with large thyroid nodules (i.e. > 3 cm). The etiology of thyrotoxicosis in nodular disease is the constitutive activation of TSH-receptors on the nodules (3). Hence, the nodules continue to synthesize thyroid hormone.I123 scan and uptake shows focal increased uptake limited to the autonomous nodule with suppression of the rest of the gland. In patients with Plummer's disease or solitary toxic adenoma, one or more nodules may be palpable. Thyroid function tests are generally similar to those seen in Plummer's disease. Thyroiditis (i.e. inflammation of the thyroid) may also result in hyperthyroidism. The inflammation may be due to an autoimmune process (e.g. painless thyroiditis, post-partum thyroiditis), viral infection (De Quervain's thyroiditis) or bacterial & fungal infection (suppurative thyroiditis). The mechanism of thyrotoxicosis in these conditions is the release of preformed hormone into the circulation from the injured follicles. Unlike other causes of thyrotoxicosis mentioned above, thyroiditis usually results in T4 toxicosis (since T4 is the main storage hormone within the gland). Hence, during this phase of thyroiditis, TSH will be suppressed or undetectable with elevated free T4. Usually, T3 is within the normal range. During the toxicosis phase, the patients have the usual manifestations of thyrotoxicosis. Treatment is mainly symptomatic. Anti-thyroid drugs are contraindicated, since the thyroid is not over-producing thyroid hormone (it is simply leaking preformed hormone due to injury). Beta-blockers are helpful in controlling palpitations. In patients with De Quervain's thyroiditis, NSAIDS are also of benefit. Sometimes, prednisone is needed to control inflammation. After the initial thyrotoxic phase (which may last for 2-3 months), the patients undergo a hypothyroid phase (generally lasting 2-4 months) due to damaged thyroid follicles. If symptomatic, patients should be treated with levothyroxine during this phase. The majority of the patients achieve euthyroidism upon recovery.

The diagnosis is made by the finding of an elevated (or inappropriately normal) TSH in the presence of elevated free hormones. therapy with octreotide may control tumor size and hyperthyroidism. Surgical treatment of hyperthyroidism is rare. retro-orbital pain and peripheral vision loss. subjects with TSH between 0. Subclinical hyperthyroidism is also associated with bone loss. Radioactive iodine ablation (I131 ablation)is another option for Graves' disease. subclinical hypothyroidism is also associatedwith increased left ventricular mass and diastolic dysfunction (9). many of these patients have subtle symptoms of hyperthyroidism on detailed history. such as headache. Magnetic resonance imaging (MRI) confirms the diagnosis. Similarly.Central hyperthyroidism due to a TSH secreting pituitary tumor is extremely rare. Subclinical hyperthyroidism is a biochemical diagnosis defined by the presence of a suppressed TSH and normal free T4 and T3. The choice of therapy depends on the etiology of hyperthyroidism and the patient's symptoms.4 mIU/ml were not at increased risk of arrhythmias. . Beta blockers are often used to treat the tremor. Data from the Framingham study showed that subjects aged 60 years or older with TSH <0. but they do not treat the underlying problem. Therapy is generally continued for 1218 months. In contrast to Graves' disease. Interestingly. which can be employed as the primary treatment modality or given to those who have a relapse after taking a course of antithyroid drugs. Methimazole is generally preferred since it is once-a-day drug compared to PTU. Patients with contraindications to anti-thyroid drugs and radioactive iodine are candidates for surgery. are also at increased risk for atrial fibrillation (8). radioactive iodine ablation and (rarely) surgery. which is taken three times daily.1-0. This rate is lower in patients with Graves' disease. a recent study showed that subjects > 65 years with low.e. The causes of subclinical hyperthyroidism are the same as that of overt hyperthyroidism. since hyperthyroidism in these conditions does not undergo spontaneous remission. Subclinical hyperthyroidism is a risk factor for atrial fibrillation. especially in postmenopausal women (10). The bone loss is mainly at the hip and forearm and a recent study showed that postmenopausal women with hyperthyroidism have a higher risk of fractures (13) Part 2 There are a number of treatment modalities for hyperthyroidism. including medication. The initial treatment is surgery. but still performed in some parts of the world like Asia and Latin America.g. but still detectable TSH. Despite its name and definition. If surgery is unsuccessful. 50% of patients undergo remission. Recent studies have shown that these women lose bone at a rate of 2% per year (11) and the bone loss is attenuated once euthyroidism is restored (12). one focus of uptake with suppression of the rest of the gland in solitary toxic adenoma and decreased uptake with thyroiditis). Based on this observation. anxiety and palpitations that can occur with thyrotoxicosis. Usually these tumors are macroadenomas (> 1 cm) and the patients manifest symptoms of mass effects. The prevalence of suppressed TSH in the population is between 1-3% (4. In addition to arrhythmias.1 mIU/ml were three times more likely to develop atrial fibrillation compared to subjects with a normal TSH (7). The progression rate from subclinical hyperthyroidism to overt hypothyroidism is 5% per year in subjects with Plummer's disease (6). Antithyroid drugs (i. Antithyroid drugs can be used to control toxicosis while the patient is being prepared for ablation. Usually in subclinical hyperthyroidism these hormones are at the upper limit of the normal range of the general population. 5).. PTU is the drug of choice since the use of methimazole has been associated with birth defects in the newborn. the term "subclinical" has been considered a misnomer and some have suggested the term "mild hyperthyroidism". high T3 levels and elevated titers of TSIs are considered by some to be predictors of relapse. the treatment of choice for toxic multinodular goiter and solitary hot nodule is I131ablation. However. raised homogenous uptake with Graves' disease. Subclinical hyperthyroidism is a state of mild hyperthyroidism that is enough to cause TSH suppression but no clinical features of hyperthyroidism. methimazole or propylthiouracil (PTU)) are a treatment option for Graves' disease. hyperthyroid patients with large compressive nodular goiters (often associated with symptoms of mass effects like dysphagia. while the disease relapses in the remaining subjects. during pregnancy. They are especially useful for symptom relief while the patient is undergoing diagnostic evaluation. multiple foci of uptake indicating nodules in Plummer's disease. However. After discontinuation of the drug. I123 scan and uptake will confirm the diagnosis (e. Large goiter. dyspnea and dysphonia) are candidates for surgery since radioactive iodine therapy only results in a 50% decrease in size of the goiter at 12 months.

Similarly. Testing for hypothyroidism Hypothyroidism may be classified on the basis of its time of onset (congenital or acquired).Treatment of Subclinical Hyperthyroidism Based on the available evidence. measurement of free T4 then helps to confirm the diagnosis and differentiate overt hypothyroidism (low free T4) from "subclinical" or mild hypothyroidism (normal free T4) However. It was described by Dr. Though hypothyroidism is mild. Hence the autoimmunity is indeed familial. sallow discoloration of the skin. this diagnosis should be entertained in a patient with known disease who presents with a sudden enlargement of neck with compressive symptoms. depression. A minotiry of women with significant hypothyroidism may have elevation of serum prolactin. and premature ovarian failure. Anti-thyroid peroxidase antibodies (formerly called anti-microsomal antibodies) may also have some role in destruction of thyroid cells via complement system. history of previous head and neck irradiation. It is important to note that thyroid lymphoma is a rare complication in patients with history of Hashimoto's thyroiditis. or of autoimmune conditions like Addison's disease. Confirmation of the diagnosis of Hashimoto's thyroiditis can be done by checking anti-thyroid peroxidase antibodies or by FNA. serum thyrotropin (TSH) is elevated. the management of subclinical hypothyroidism is controversial. adrenal insufficiency. Hence the term "mild hypothyroidism" has been suggested as an alternative (14). In addition to these indications.e. dry skin. Some patients may experience weight gain or complain of failure to lose weight. The gland in classic Hashimoto's thyroiditis is enlarged. subclinical hypothyroidism Though there is general agreement that overt hypothyroidism should be treated. lithium and interferon can also result in hypothyroidism. raspy voice. Hence. In patients with primary hypothyroidism. goiter or both. and the degree of dysfunction (overt or subclinical). Antithyroglobulin antibodies are positive in 60% of the patients while anti-thyroid peroxidase antibodies are detected in 95% of the cases. Hence. Physical findings of hypothyroidism include goiter. The etiology of subclinical hyperthyroidism dictates the choice of treatment (as discussed above). Populations at higher risk of developing hypothyroidism include subjects with family history of thyroid disorders. cold intolerance. Treatment of hypothyroidism secondary to Hashimoto's thyroiditis is the same as for any other cause of hypothyroidism i. firm. It is unclear whether therapy with beta-blockers alone will prevent the development of arrhythmias in subjects with subclinical hyperthyroidism. pernicious anemia. since thyrotropin releasing hormone (TRH) is a stimulus for prolactin secretion. As with subclinical hyperthyroidism. Half of the patients with Hashimoto's thyroiditis have 1st degree relatives with positive antibodies. In severe hypothyroidism. vitiligo. women with hypothyroidism may present with amenorrhea/galactorrhea. patients may develop psychosis. menstrual irregularity and infertility. dry skin. type 1 diabetes mellitus. These cells are cytotoxic and destroy thyroid parenchyma. Certain drugs like amiodarone. The most common etiology of hypothyroidism is Hashimoto's thyroiditis (also known as Hashimoto's disease and chronic lymphocytic thyroiditis). if TSH is abnormal. The prevalence of Hashimoto's thyroiditis is higher in countries with sufficient iodine intake (such as the US). Overt vs. By far the most common cause of hypothyroidism is Hashimoto's thyroiditis (also known as chronic lymphocytic thyroiditis). many physicians order free T4 along with TSH. the anatomic location of dysfunction (primary or secondary). constipation. postmenopausal women should also be treated to prevent the worsening of bone health. Myxedema coma is the extreme presentation of severe hypothyroidism. Symptoms and signs of hypothyroidism Symptoms of hypothyroidism include fatigue. Hashimoto in 1912 in Japan. proximal muscle weakness and delayed relaxation phase of reflexes (most appreciated in the Achilles reflex). with levothyroxine. Normalization of TSH results in decrease in the size of the gland in >50% of the patients. thyroid surgery. subjects over 60 years old with suppressed TSH should be treated to prevent cardiac arrhythmias. Patients may present with hypothyroidism (mild or overt). TSH levels are low or inappropriately normal. These patients should get FNA with flow cytometry to confirm the diagnosis. It used to be known as "struma lymphomatosa" indicating the fact that the thyroid is replaced by lymphoid tissue. thinning of the eye brows. subclinical hypothyroidism is a biochemical diagnosis defined by the presence of an elevated TSH and normal free T4 and T3. Part 3 Hypothyroidism is a common condition that occurs more often in women and its incidence increases with age. . bosselated (grainy feel) and has a palpable pyramidal lobe. Serum TSH is the best initial test for the diagnosis (and for monitoring response to treatment) of hypothyroidism. symptomatic patients should also be considered for treatment. whereas in subjects with secondary (central) hypothyroidism. some patients do have subtle clinical features of hypothyroidism on history and physical examination. Biochemical diagnosis of hypothyroidism is the same as mentioned before. The pathophysiology of Hashimoto's thyroiditis involves activation of CD4 T cells which in turn recruit cytotoxic CD8 lymphocytes. which is also known as "myxedema madness".

thyroid nodules are incidentally picked up on physical examination by the patientÙs primary provider. Once a patient has achieved biochemical euthyroidism on a particular dose of levothyroxine.). Serum TSH>10 mIU/ml (since these patients benefit the most with regard to symptoms and lipids). a 30 percent increase in thyroxine dose may be required during pregnancy due to increase in throxine-binding globulin (as a result of elevated estradiol) (26). The majority of patients with subclinical hypothyroidism have mild elevation of TSH (5-10 mIU/ml). follow up monitoring T4 levels is not necessary. etc. the approximate dose would be 100 mcg/day. The effect of treatment of subclinical hypothyroidism on hyperlipidemia remains controversial. Contrary to popular belief. congestive heart failure and myocardial infarction. In women with elevated TSH and anti-TPO antibodies. It is more common in women. another study from Netherlands (The Rotterdam Study). subclinical hypothyroidism does not result in significant weight gain. Significant hypothyroid symptoms. thyroid nodules are more common in women. and increases with age in both sexes.6 mcg/kg/day (0. Thyroid nodules are one of the most common reasons for referral to an endocrinologist. normalization of TSH only decreases total cholesterol by less than 1 mg/dl. Presence of goiter. angina. the progression rate from subclinical to overt hypothyroidism is 4. with the prevalence approaching 20% in women over 60 years old (15). iron. cholestyramine. Other medications may affect thyroxine by decreasing its absorption. in elderly patients or those with known heart disease. However. found increased prevalence of aortic calcification on chest x-ray when compared to euthyroid women and a tendency toward increase risk of myocardial infarction (that was not statistically significant) (20). Studies from Europe and the United States have shown the prevalence of thyroid nodules to be 5-6% in women and 1-1. most of the placebo-controlled trials have shown improvement in these symptoms once TSH is normalized. including: phenytoin. In fact. carotid dopplers). this issue remains unresolved.(27) Thyroid nodules may be solitary in some individuals. However. treatment should begin with a low dose of 12. Hence for a 60 kg adult. Solid nodules may be further classified as functional or non-functional. indications of treatment in patients with subclinical hypothyroidism include [adapted from Cooper DS (23)]:      Positive Anti-TPO antibodies (since subjects are at a higher risk of developing overt hypothyroidism). Women with ovulatory dysfunction and infertility. The effect of subclinical hypothyroidism on cardiovascular mortality is also controversial. For decades. Levoxyl. calcium. Likewise. with dose increments at four to six weeks to avoid development of dysrhythmias. Acohort from UK followed prospectively for 2 decades did not show any increase in cardiovascular mortality compared to euthyroid individuals (19). the usual starting dose for otherwise healthy adults aged 60 or younger has been 1. One of the most common causes of subclinical hypothyroidism is intermittent noncompliance with thyroxine therapy. Part 4 All patients with overt hypothyroidism should be treated with thyroxine (T4). including: proton pump inhibitors. complex or solid.3% per year (16). The etiologies of subclinical hypothyroidism are the same as overt hypothyroidism. The prevalence of thyroid nodules increases with advancing age (28). or are found on head and neck imaging performed for unrelated reasons (e. however. respectively (17). Furthermore. patients who have total cholesterol levels > 240 mg/dl or TSH > 10 mIU/ml benefit the most (18). TSH can be checked on an annual basis. Many endocrinologists favor maintaining TSH levels between 1-2 mIU/ml.5% in men . There are a number of drugs which may increase clearance of thyroxine. with subjects with TSH >10 mIU/ml showing the most benefit (21).g. resulting in decreased bioavailability of thyroxine. Thyroid nodules are further classified as cystic.8 mcg/lb/day). In terms of hypothyroid symptoms. if a patient's cholesterol is < 240 mg/dl. There is no evidence that a combination of T4 and T3 is more effective than T4 alone (24). aluminum hydroxide and sucralfate. while others may have multinodular goiters. In most instances. (25) TSH should be rechecked in 6 weeks and the dose of thyroxine should be adjusted to normalize serum TSH levels. In summary. The most common cause is Hashimoto's thyroiditis with positive anti-TPO antibodies. In women. The generic formulation of thyroxine has been shown to be as effective as brand name products (Synthroid. resulting in normal free hormones but elevated TSH. phenobarbital and rifampin. hypothyroid women who are prescribed estrogen may need increase in dosage due to increasing throxine-binding globulin. carbamazepine. a placebo-controlled study showed that treatment of subclinical hypothyroidism does not result in significant weight loss (22).5 to 25 µg daily.The prevalence of subclinical hypothyroidism is between 1-10% of the population. Hence. A recent meta-analysis found that treating subclinical hypothyroidism decreases total cholesterol and LDL levels by 8 and 10 mg/dl.

(15. Other risk factors for thyroid nodules include a history of head and neck radiation or malignancies and exposure to nuclear radiation (as in the Chernobyl disaster) (30).The following algorithm illustrates this approach to the thyroid nodule: Evaluation of multiple nodules In a euthyroid subject with multiple nodules that are > 1 cm. since the chance of malignancy is negligible. When a thyroid nodule is suspected. A hard nodule in a multinodular goiter should also be biopsied. some parts of western Europe. the thyroid nodule is often found on physical exam. fine punctate calcifications (2 mm in size). if a subject is hypothyroid. Features associated with malignancy include: hypoechogenecity. TSH should be normalized first with treatment with levothyroxine before further evaluation of the thyroid nodule. then one should concentrate on management of hyperthyroidism. 32). On the other hand. If the TSH is undetectable or suppressed. Ultrasound is the best imaging modality to detect and evaluate thyroid nodules. Furthermore. Worldwide. irregular margins and increased nodular blood flow (34. Since hot nodules are almost always benign. the American Thyroid Association (ATA) recommends preferentially aspirating those with suspicious features (33). I123scan and uptake would be the next step. the ultrasound is very helpful in delineating certain characteristics in the nodule that increase the suspicion for malignancy (discussed below). 29). even if it is not a dominant nodule. then biopsy should be performed….e. In the United States. mountainous regions of the Indian subcontinent). the single most common cause of thyroid nodules is iodine deficiency and nodules are more common in regions of the world where iodine intake is insufficient (i. Genetic factors and some growth factors may be responsible in the development of nodules in those without iodine deficiency. effectively eradicating iodine deficiency as a cause of thyroid nodules in the US. If after treatment of hypothyroidism the nodule is still palpable. or incidentally when the neck is imaged for another reason. but also serves as a guide to fine-needle aspiration of the nodule (if indicated). The serum TSH is important in evaluating the thyroid nodule. The ATA guidelines also state “If none of the nodules has a suspicious . Evaluation of the thyroid nodule As mentioned above. it is possible that the nodule(s) in question may be functioning (“hot”). If the nodule in question is hot. one should proceed with FNA to determine whether or not malignancy is present. 35). which not only can determine the presence of one or more nodules. the next step is to image the thyroid and check serum TSH. iodized salt was introduced more than half a century ago. If the TSH is normal. (31.

A diagnosis of malignancy should be followed by total thyroidectomy. the patients are followed conservatively and watched for post-surgical hypothyroidism. often lobectomy is performed. the aspiration is also not completely benign. etc) or follicular carcinomas (hypercellular material.” Thyroid biopsy results The results of the FNA may show one of four results: benign. Approximately 50% of the subjects who have undergone lobectomy will develop post-surgical hypothyroidism. . with surgical intervention done only if the nodule is not functional. This result simply indicates that although clear-cut features of malignancy are not seen. The last result may be avoided with the presence of on-site pathologist to confirm specimen adequacy. however. When the FNA is characterized as suspicious (also called indeterminate or follicular neoplasm/lesion). psommoma bodies.sonographic appearance and multiple sonographically similar coalescent nodules with no intervening normal parenchyma are present. If the pathology is benign. their size should be evaluated by serial ultrasounds and should only be re-aspirated if they show a significant growth during follow-up (36). Benign nodules are followed conservatively. suspicious (indeterminate) or inadequate material. nuclear inclusions. etc). Some suggest performing I123scan and uptake. completion thyroidectomy is performed in a few weeks. the chance of malignancy in that nodule is about 20%. scant colloid. If surgical pathology shows cancer. the likelihood of malignancy is low and it is reasonable to aspirate the largest nodules only and observe the others with serial US examinations. malignant. Hence. The reports of "colloid nodule" or "adenomatoid nodule" are included in the benign category. in these patients. for definitive diagnosis. microfollicles. The FNA reports suggestive of malignancy usually mention features of papillary thyroid cancer (nuclear grooves.

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