PATHOLOGY LAB V-DIFFUSE AND MULTINODULAR GOITER. Arben Santo. CASE OUTLINE. Case Presentation: Aina H.

Nontoxic goiter Dyshormonogenetic goiter Toxic multinodular goiter Endemic goiter OBJECTIVES. After completing this module the student will be able to: 1. Define goiter and explain the principles of classification of goiters into simple (nontoxic) and toxic, diffuse and multinodular 2. Explain the principle of classification of goiters into sporadic and endemic types 3. Describe the gross and histopathologic findings of diffuse and multinodular goiters 4. Describe the clinical and radiological findings in nontoxic goiters 5. Describe the pathogenesis of nontoxic goiters 6. Describe the etiology, pathogenesis, pathology and clinical characteristics of dyshormonogenetic goiter 7. Describe pathological and clinical features of toxic multinodular goiters REFERENCES. 1. Robbins and Cotran Pathologic Basis of Disease, 8th edition, p. 1116-1118 2. Loyd RV, Douglas BR, and Young WF, Atlas of nontumor pathology: Endocrine diseases. Armed Forces Institute of Pathology, Washington, DC, 2002

CASE PRESENTATION: AINA H. Aina, a 50-year-old female Cambodian refugee, presents with enlargement of a longstanding neck mass. Physical examination reveals a multinodular thyroid gland, all of which moves with swallowing. There is a dominant, left-lobe, 6-cm nodule, which the patient said had enlarged abruptly 10 days before. Her thyroid gland extends below the sternal notch into the anterior mediastinum, so the inferior portion is not palpable. A fine-needle aspiration smear of the leftlobe mass shows evidence of a hemorrhagic colloid cyst. The patient is taken to surgery because of her sensation oflaryngeal compression, and a total thyroidectomy is performed. The pathologist notes a multinodular goiter and confirms the large hemorrhagic cyst, but also finds a solid 2.5-cm nodule in the mediastinal portion of the thyroid gland. This mass is partially encapsulated, but enlarged follicular cells forming small follicles are seen to penetrate the capsuleand to invade vascular channels around the nodule. The cells have round, euchromatic nuclei without inclusions, grooves, or papillae. A definitive diagnosis of follicular thyroid carcinoma complicating a multinodular goiter was made. The patient does not return for follow-up visits until one year later, when she notes pain in her left humerus. On x-ray studies, a lytic lesion is found, as are several small nodules in the lungs. Her TSH (thyroid-stimulating hormone, thyrotropin) level is markedly elevated.

DEFINITIONS. 1. Goiter.

The term goiter is nonspecific and refers simply to an enlargement of the thyroid gland. Goiters have a variety of etiologies ranging from inflammatory diseases (thyroiditis), non-neoplastic enlargements (Graves disease), and neoplasms (thyroid adenoma or carcinoma). The presence of a goiter does not reflect the functional activity of the gland which can range from euthyroid to hyperthyroid and hypothyroid states. Thyroid function may be normal (simple or nontoxic goiter), overactive (toxic goiter), or underactive (hypothyroid goiter). A goiter may extend into the retrosternal space, with or without substantial anterior enlargement. Because of the anatomic relationship of the thyroid gland to the trachea, larynx, superior and inferior laryngeal nerves, and esophagus, abnormal growth may cause a variety of compressive syndromes. 2. Nontoxic goiter. Nontoxic or simple goiter may be defined as any thyroid enlargement that is not associated with hyperthyroidism or hypothyroidism and that does not result from inflammation (thyroiditis) or neoplasia (thyroid adenoma or carcinoma).The term is usually restricted to the form that occurs sporadically, i.e., in regions that are not the locus of endemic goiter. Although useful in indicating the presence of the characteristics just noted, the term simple goiter can be a result of different underlying abnormalities. The simple or nontoxic goiter may be diffuse or multinodular, but a diffuse goiter often evolves into a nodular goiter. Nontoxic goiters are characterized by diffuse hyperplasia of the thyroid gland and colloid accumulation. Thyroid hyperplasia often results from disturbances of the feedback system in which decreased production of thyroid hormone can lead to increased production of thyrotropinreleasing hormone (TRH) from the hypothalamus and thyroid stimulating hormone (TSH) from the pituitary. TSH stimulates hyperplasia of the thyroid gland, leading to enlargement of the gland. 3. Toxic goiter. Toxic goiter is a goiter that is associated with hyperthyroidism. Examples of toxic goiters include toxic multinodular goiter, and toxic thyroid adenoma. 4. Endemic goiter. Endemic goiter is defined as thyroid enlargement that occurs in more than 10% of a population, and sporadic goiter is a result of environmental or genetic factors that do not affect the general population. EPIDEMIOLOGY. Sporadic goiter is the most common cause of nontoxic goiter in the United States. The incidence of sporadic nontoxic goiter has been estimated in North America at approximately 5%. Sporadic diffuse nontoxic goiters are seen most frequently between 10 and 20 years of age. Nontoxic multinodular goiters are usually seen in persons after 30 years of age. Generally, the development of palpable thyroid nodules and goiter progressively increases with age. The prevalence of palpable nodules is approximately 5-6% in people aged 60 years, but on autopsy and ultrasonographic imaging findings, the incidence of small, nonpalpable nodules approaches 50% in people aged 60 years. Sporadic goiter is more common in women than in men. The female-to-male ratio is 4:1. ETIOLOGY.

The cause of sporadic goiter sporadic goiter is usually unknown. Causes of sporadic goiter development can be quite variable. 1. Iodine deficiency. Goiter formation occurs with moderately deficient iodine intake of less than 50 microgram/day. Severe iodine deficiency associated with intake of less than 25 microgram/day is associated with hypothyroidism and cretinism. 2. Goitrogens. Chemically-induced goiters may result from consumption of goitrogens. Goitrogens are substances that suppress the function of the thyroid gland by interfering with iodine uptake, which can, as a result, cause an enlargement of the thyroid, i.e., a goiter. There are various types of goitrogens. (A) Goitrogenic foods. There are two general categories of foods that interfere with thyroid gland function: soybeanrelated foods and cruciferous vegetables. Soybean-related foods. The soybean (Glycine max) is a species of legume native to Southeastern Asia. Included in the category of soybean-related foods are soybeans themselves as well as soy extracts, and foods made from soy, including soymilk, tofu and tempeh. It is the isoflavones in soy that have been associated with decreased thyroid hormone output. Isoflavones are naturallyoccurring substances that belong to the flavonoid family of nutrients. Isoflavones like genistein appear to reduce thyroid hormone output by blocking activity of the enzyme thyroid peroxidase (which is responsible for adding iodine onto the thyroid hormones). Cruciferous vegetables. A second category of foods associated with disrupted thyroid hormone production is the cruciferous food family. Foods belonging to this family are called "crucifers," and include broccoli, cauliflower, Brussels sprouts, cabbage, mustard, rutabagas, kohlrabi, and turnips. Isothiocyanates are the category of substances in crucifers that have been associated with decreased thyroid function. Like the isoflavones, isothiocyanates appear to reduce thyroid function by blocking thyroid peroxidase. Most goitrogens are inactivated with heat, but there is some evidence that isoflavones in soy are not heat inactivated. (B) Chemical goitrogens. Many drugs and environmental agents behave as goitrogens. The following drugs have goitrogenic effects: propylthiouracil (used to treat hyperthyroidism, including Graves disease), lithium (used to treat bipolar disorder), phenylbutazone (used as analgesic and antipyretic), aminoglutethimide (used to suppress adrenal function in Cushing syndrome), iodine-containing expectorants (used to reduce chest congestion). The following environmental agents have goitrogenic effects: phenolic and phthalate ester derivatives and resorcinol found downstream of coal and shale mines. 3. Dyshormonogenesis. Dyshormonogenetic goiter is a type of goiter resulting from enzyme defects in thyroid hormone synthesis. Most cases are familial and inherited as autosomal recessive conditions. 4. Childhood head and neck radiation. Radiation exposure during childhood results goiter. CLINICAL PRESENTATION. Sporadic goiters are generally asymptomatic and found either by a clinician's physical examination or by the patient's observation of neck enlargement (cosmetic disfigurement).

Occasionally, the goiter may produce symptoms caused by pressure on anterior neck structures (neck discomfort). Large goiters may displace or compress the neck organs including the trachea (wheezing, cough), the esophagus (dysphagia), and the recurrent laryngeal nerve (hoarseness, although this sign is usually more diagnostic of a thyroid carcinoma).

Rarely, the obstruction can be dangerous because of narrowing of the trachea and the development of tracheitis with edema and tracheomalacia, leading to severe narrowing of the airway with serious obstruction resulting in a respiratory emergency. Sometimes, mechanical obstruction may result in superior vena cava syndrome, with engorgement of facial and neck veins from narrowing of the thoracic inlet. LABORATORY FINDINGS. Thyroid function tests should be obtained, though the results of these are usually normal. Initial screening should include TSH. Determination of serum TSH will distinguish nontoxic goiters from toxic goiters. In the absence of symptoms of hyper or hypothyroidism further testing is not required. If the TSH is low, measurement of serum free thyroxine (free T4) and total triiodothyronine (T3) is used to confirm the diagnosis of hyperthyroidism (i.e., toxic goiter). IMAGING. 1. Ultrasonography. High resolution ultrasonography is the imaging method of choice in the evaluation of thyroid gland morphology in goiters. This technique is capable of establishing goiter size and detecting nodules as small as 0.3 cm in diameter, which means that it can differentiate diffuse goiters from multinofular goiters. 2. CT scanning. CT scanning is more precise. It can be used to delineate size and goiter extent. CT scanning does a much better job than ultrasonography in determining the effect of the goitrous thyroid gland on nearby structures. 2. Scintigraphic thyroid scanning with (123iodine or 99m technetium). Thyroid scintigraphy is not routinely indicated in the assessment of diffuse goiter. The radioactive iodine uptake is usually normal in diffuse goiter. Thyroid scintigraphy allows the diagnosis of multinodular goiter and helps in the identifying the function of a thyroid nodule (hot nodule or cold nodule). MORPHOLOGY.

1. Gross findings. The normal thyroid gland weighs up to 40 g. Simple goiters usually weigh more than 40 g. Simple goiters are firm and diffusely enlarged. The cut surface shows a uniform amber color with a translucent appearance.

Multinodular goiters are of varying sizes and often weigh from 60 to 1000 g or more. The gland has a distorted shape and is nodular. Some nodules may be partially or completely separated from the gland, constituting sequestered or parasitic nodules. Cut sections of the multinodular goiter show areas with degenerative changes (such as scarred areas, fibrosis, old and recent hemorrhage, and calcification) along with hyperplastic areas (nodules). Extensive hemorrhage in these goiters as part of the degenerative or retrogressive process may lead to tracheal compression and present as a surgical emergency. Nodules with hyperplastic follicles can be quite variable in size and number and may be cystic. Some nodules contain a thickened fibrous connective tissue capsule and have the general appearance of follicular neoplasms.

2. Microscopic findings. The histologic appearance of diffuse nontoxic goiters consists of follicles of varying size that may be as large as a few millimeters in diameter. The follicles are lined by flattened epithelium with involutional changes. The histology of multinodular goiter parallels the macroscopic features, with nodules consisting of irregularly enlarged follicles of variable size with flattened epithelium and abundant colloid, adjacent to smaller follicles with a taller, more active epithelium.

Large distended follicles often coalesce to create cystic areas which may be several millimeters in diameter. Focal areas of papillary hyperplasia with Sanderson polster or a cluster of small follicles protruding into large dilated follicles may be seen. The polster is usually made up of taller, more columnar epithelium.

There may be evidence of old and recent hemorrhage with hemosiderin-laden macrophages, and ischemic necrosis with lipid-laden macrophages. Cholesterol clefts are usually evident along with extensive irregular fibrosis, variable dystrophic calcification, and ossification. Colloid nodules usually refer to the dilated follicles lined by flattened epithelium. Hyperplastic nodules are often seen. These nodules are encapsulated which differentiates them from thyroid adenomas. They are often referred to as adenomatous or adenomatoid nodules and the goiter as adenomatous goiter. PRINCIPLES OF TREATMENT AND PROGNOSIS. Nontoxic goiters usually grow very slowly over decades without causing symptoms. Without evidence of rapid growth, obstructive symptoms (e.g. dysphagia stridor, and cough), or thyrotoxicosis, no treatment is necessary. Therapy is considered if compressive symptoms or thyrotoxicosis are present. The currently available therapies include thyroidectomy, thyroxine therapy and radioactive iodine therapy. Surgery is probably the most definitive method of treating multinodular nontoxic goiter in symptomatic patients, although they recur in 10 to 20 % of patients. The rate of postoperative hypothyroidism depends on the extent of the surgical resection. Treatment with thyroxine is an effective way of reducing the size of diffuse simple goiters, although this is less effective with multinodular goiters. Radioactive iodine treatment of nontoxic multinodular goiter is usually effective and safe. One complication, especially in younger patients, is the increasing incidence of hypothyroidism in a time-dependent manner. PATHOGENESIS. 1. Pathogenesis of diffuse goiter. The traditional theory about the pathogenesis suggests that gaiter is a response to any of several factors that impair hormone synthesis. A deficiency in thyroid hormone synthesis or intake leads to increased TSH production. Increased TSH causes increased cellularity and hyperplasia of the thyroid gland in an attempt to normalize thyroid hormone levels. If this process is sustained, a goiter is established. As a consequence of the increase in thyroid mass and functional activity, a normal rate of hormone secretion is restored, and the patient is goitrous but euthyroid. This sequence is evident in some patients with iodine deficiency and in others who develop goiter in response to specific agents. For example, lithium administration can cause goiter with or without

hypothyroidism. Goiter (if early) regresses when iodine is administered (if iodine deficiency is the cause), when lithium or another offending agent is withdrawn, or if suppressive doses of exogenous thyroid hormone are administered. In most patients with diffuse nontoxic goiter, however, no extrinsic goitrogenic factor can be identified. As a consequence, the cause may be some intrinsic, probably inborn, abnormality in thyroid hormone synthesis akin to those that produce goitrous hypothyroidism. This concept of the pathogenesis of nontoxic goiter is inconsistent with the fact that the serum TSH concentration is normal in most patients with nontoxic goiter. This can be explained with the fact that goitrogenic stimulus has been present in the past but may no longer be detectable at the time of study, so the residual normal TSH concentration can maintain but not initiate the goiter. A second possibility is that the increase in serum TSH concentration is significant but too small to be detected by the immunoassay methods now available. 2. Pathogenesis of multinodular goiter. (A) Why a long-standing nontoxic goiter becomes nodular? The concept of areas of hyperplasia coupled with areas of involution. In the pathogenesis of simple and multinodular goiters, it is assumed that there is initially diffuse hyperplasia which becomes nodular with increasing size, fibrosis, and distortion of the vascular supply of the thyroid gland. But we dont know why a long-standing nontoxic goiter becomes nodular and develops anatomic and functional heterogeneity and functional autonomy. These characteristics have been assumed to result from either prolonged hyperstimulation by TSH or repeated cycles of hyperstimulation and involution. Hyperstimulation or cycles of hyperstimulation and involution could lead to the emergence of areas of hyperplasia, possibly associated with functional autonomy, coupled with areas of involution (exhaustion atrophy), the whole made more heterogeneous by localized hemorrhage, fibrosis, and sometimes calcification. (B) Microheterogeneity of structure and function within the goitrous thyroid gland. Another pathogenetic concept is the microheterogeneity of structure and function within the goitrous thyroid gland. Heterogeneity may result from clonal differences among the cells that give rise to thyroid follicles, some being more and some less responsive to external stimulation by TSH and some being autonomous at the outset. This concept implies that the anatomic and functional heterogeneity within the thyroid at the outset of the disease is exaggerated by prolonged stimulation. (C) Polyclonality. Studies involving X-chromosome inactivation analysis have revealed that both monoclonal and polyclonal nodules coexist within the same gland. Polyclonality implies multicellular origin due to the proliferation of a group of cells, whereas a monoclonal tumor is thought to be formed by an expansion of a single cell. In multinodular glands, one or more than one nodule could be monoclonal, the remainder of nodules being polyclonal. (D) The biologic continuum between hyperplastic nodules and follicular adenomas. Hyperplastic nodules can evolve into follicular adenomas. There is a biologic continuum between hyperplastic nodules and follicular adenomas. Monoclonal adenomas within hyperplastic thyroid glands may reflect a stage in progression along the hyperplasia-neoplasia spectrum; accumulation of multiple somatic mutations may subsequently confer a selective growth advantage to this single cell. (E) Autonomous hyperfunction leads to thyrotoxicosis. Ultimately, autonomous hyperfunction may be sufficient to produce thyrotoxicosis, or thyrotoxicosis may supervene when the patient is exposed to an iodine load. For this reason, patients with nontoxic multinodular goiter should not be given medications that contain iodine and should be observed after radiologic procedures that involve administration of iodinated contrast media

DEFINITION. These familial goiters develop because of an inherited defect in the metabolism of thyroid hormone. There are several major biodefects which lead to decreased thyroid hormone synthesis. The resultant alterations in thyroid gland homeostasis, disturbance of the feedback system, and chronic TSH stimulation lead to enlarged thyroid glands or goiters. The defect is usually transmitted as an autosomal recessive trait and is a cause of cretinism and hypothyroidism. The goiter is usually not present at birth but appears later in life. EPIDEMIOLOGY. Dyshormonogenetic goiters are rare, with a prevalence of 1 in 30,000 to 50,000 live births in North America and Europe. It is the second most frequent cause of permanent congenital hypothyroidism after thyroid dysgenesis (i.e. thyroid aplasia and hypoplasia). ETIOLOGY. The following is a short list of possible inherited anomalies: (a) TSH receptor abnormalities associated with lack of responsiveness to TSH, (b) impaired ability to uptake iodide, (c) organification defect, i.e. inability to add iodine to thyroglobulin which is a critical step in generating thyroid hormone, (d) Pendred syndrome which is a familial organification defect associated with congenital deafness, (e) thyroglobulin defect which is inability to form or degrade thyroglobulin, and (f) deiodinase defect which leads to impairment in the activation of thyroid hormones. CLINICAL FINDINGS. The clinical presentation depends on the severity of the inborn error. A severe defect will lead to neonatal or congenital hypothyroidism, goiter, mental retardation, and growth abnormalities (cretinism). Milder defects will present later in life (adolescence or young adulthood) as goiter and minimal (if any) thyroid dysfunction. Laboratory evaluation for inborn errors of thyroid metabolism is complex and extensive.

MORPHOLOGY. 1. Gross findings. Grossly the thyroid appears as a multinodular goiter. The gland is enlarged asymmetrically and may weigh up to 600 g. Areas of cystic change, fibrosis, and old and recent hemorrhage are present. The cut surface is firm and tan with nodules of varying size, which may be up to a few centimeters in diameter. 2. Microscopic findings. The histological pattern varies depending on site of enzymatic block. Histologically, the process is diffuse, without normal thyroid tissue. Hypercellular thyroid nodules are composed of epithelial cells arranged in trabeculae, or cords, solid masses or microfollicules with reduced amounts of colloid. The follicular cells typically exhibit severe cytologicatypia, including bizarre and markedly enlarged, hyperchromatic nuclei. These nuclear changes are most common in the internodular areas. 3. Differential diagnosis: The two most significant differential diagnoses include (a) thyroid carcinoma and (b) sporadic multinodular goiters. Because of the severe cytologicatypia, dyshormonogenetic goiters may be misdiagnosed as carcinomas. However, to make a diagnosis of carcinoma, there must be convincing vascular invasion, or distant metastasis, or the architectural and cytologic features of papillary carcinomas. Distinction of dyshormonogenetic goiter from sporadic multinodular goiter may be difficult, since both lesions may have extensive hyperplasia. In dyshormonogenetic goiter there is a marked decrease in colloid and absence of normal internodular tissue. PRINCIPLES OF TREATMENT AND PROGNOSIS. The mainstay in the treatment of dyshormonogenetic goiters is early diagnosis and thyroid hormone replacement. The optimal care includes early diagnosis. If the diagnosis of dyshormonogenetic goiter is made before age 13 days it will take about three weeks to normalize the thyroid hormone blood levels. Early treatment is particularly important to avoid or diminish mental retardation and growth abnormalities. The prognosis is excellent with treatment.

DEFINITION. This is a condition in which hyperthyroidism arises in a multinodular goiter, usually of longstanding duration. One or several nodules in a multinodular goiter develop autonomous function. Toxic multinodular goiter represents a spectrum of disease ranging from a single hyperfunctioning nodule (toxic adenoma) within a multinodular thyroid to a gland with multiple areas of hyperfunction. Autonomous hyperactivity is conferred by somatic mutations of the TSH receptor in some nodules of multinodular goiters. Autonomously functioning nodules may become toxic., especially when nodules are larger than 2.5 cm in diameter. Signs and symptoms of toxic nodular goiter are similar to those of other types of hyperthyroidism. EPIDEMIOLOGY. Toxic multinodular goiter accounts for approximately 15-30% of cases of hyperthyroidism in the United States, second only to Graves disease. Most patients with toxic nodular goiter are older than 50 years. Toxic multinodular goiter occurs 3 to 4 times more commonly in women than in men. PATHOGENESIS. Increased thyroid cell replication in longstanding multinodular goiters predisposes single cells to somatic mutations of the TSH receptor. Constitutive activation of the TSH receptor may generate autocrine factors that promote further growth, resulting in clonal proliferation. Cell clones then produce multiple nodules.

The TSH receptor is a member of the G protein-coupled receptor superfamily of membrane proteins and is coupled to the GS alpha protein. Somatic mutations of the TSH receptors and GS alpha protein confer constitutive activation to the cyclic adenosine monophosphate (cAMP) cascade of the inositol phosphate pathways. These mutations may be responsible for functional autonomy of the thyroid in 20-80% of cases. These mutations are found in autonomously functioning solitary thyroid nodules within a multinodular gland. Nonfunctioning thyroid nodules within the same gland lack these mutations. The reported frequency of these mutations varies widely, ranging from 10-80%. CLINICAL PRESENTATION. Most patients with toxic multinodular goiter present with symptoms typical of hyperthyroidism, including heat intolerance, atrial fibrillation or tachycardia, tremor, weight loss, hunger, and frequent bowel movements. Some patients are asymptomatic or have minimal symptoms and are incidentally found to have hyperthyroidism during routine screening. The most common laboratory finding is a suppressed TSH with normal free thyroxine (T4) levels. Signs found on physical examination include tachycardia, hyperkinesis, moist, smooth skin, tremor, proximal muscle weakness and brisk deep tendon reflexes.

LABORATORY STUDIES. Thyroid function tests. Evidence of hyperthyroidism must be present in order to consider a diagnosis of toxic nodular goiter. TSH assays are generally the best initial screening tool for hyperthyroidism. Patients with toxic multinodular goiter will have suppressed TSH levels. The overproduction of thyroid hormone in toxic multinodular goiter is usually less than in Graves disease. The serum T3 and T4 concentrations may be only slightly increased while suppressed TSH may be the only early manifestation of this condition. Free T4 levels may be elevated or within the reference range. Note that even when the total T3 and T4 levels are within the reference range they are higher than the normal range for a particular individual. IMAGING. 1. Nuclear scintigraphy. Nuclear scans should be performed on patients with biochemical hyperthyroidism. Nuclear medicine scans can be performed with radioactive iodine (123 I) or with technetium-99m (99m Tc). In patients with toxic nodular goiter, the scan results usually reveal patchy uptake, with areas of increased uptake (hot nodules) and decreased uptake (cold nodules). 2. Ultrasonography. Ultrasonography is able delineate discrete nodules that are not palpable during thyroid examination. Ultrasonography is helpful when correlated with nuclear scans to determine the functionality of nodules. Cold nodules should be considered for fine-needle aspiration biopsy prior to definitive treatment of a toxic multinodular goiter.

MORPHOLOGY. The gross and histologic appearance of a toxic multinodular goiter and a nontoxic multinodular goiter overlap. Distinguishing these two entities without clinical correlation and imaging studies may be difficult. PRICIPLES OF TREATMENT AND PROGNOSIS. Patients with toxic multinodular goiter who have autonomously functioning nodules should be treated definitely with radioactive iodine or surgery. The treatment of choice is radioactive iodine. Patients with obstructive syndromes are usually treated with surgery, especially when there is danger of further obstruction from the temporary thyroid enlargement that radioactive iodine treatment sometimes produces.

DEFINITION. Goiter is conveniently referred to as endemic when it occurs in more than 10% of the population in a defined area with iodine-poor soil. It is the chief consequence of iodine deficiency, resulting from either low iodine intake. AREAS OF IODINE DEFICIENCY. 1. Worldwide. Worldwide, the soil in large geographic areas is deficient in iodine. About 29% of the worlds population, living in approximately 130 countries, is estimated to live in areas of deficiency Historically, endemic goiters have developed in geographic areas such as the mountainous regions of South America (Andes), Europe (Alps) and Asia (Himalayas). The use of the term iodine deficiency disorder emphasizes the results of iodine deficiency on mental and physical

development. The incidence of endemic goiter and cretinism decreases markedly when iodine is introduced into the diet as a supplement. 2. United States. Normal dietary iodine intake is 100-150 microgram/day. In the United States, iodine has been voluntarily supplemented in table salt (70 microgram/g). In the early 1900s, the Great Lakes, Appalachian, and northwestern regions of the United States were endemic regions for iodine deficiency disorder, but since the iodization of salt and other foods in the 1920s, dietary iodine levels generally have been adequate.

CLINCAL MANIFESTATIONS. Affected patients from geographic regions where iodine deficiency disorders are endemic manifest with goiter, symptoms and signs of hypothyroidism. Cretinism and mental retardation as the most extreme manifestation of iodine deficiency disorders are frequent in the endemic areas. MORPHOLOGY. The macroscopic and microscopic findings in endemic goiters are similar to those of multinodular goiters, with multiple nodules in a background of degenerative changes including fibrosis, old and recent hemorrhage, and dystrophic calcification. The histologic picture is variable-sized follicles, with thin follicular cells in dilated colloid follicles admixed with smaller follicles lined by columnar epithelium. PRINCIPLES OF TREATEMENT. Long-term dietary iodine replacement at levels recommended by the Institute of Medicine and WHO may decrease the size of iodine-deficient goiters in very young children and pregnant women and is indicated for all patients with iodine deficiency. Generally, long-standing goiters associated with iodine deficiency disorder respond with only small amounts of shrinkage after iodine supplementation, and patients are at risk for developing hyperthyroidism. Patients do not routinely require specific therapy unless the goiter is large enough to cause compressive symptoms.

1. A 34-year-old woman, gravida 3, para 2, presented with polyhydramnios and premature labor during the 32nd week of gestation. Her thyroid function and thyroid antibodies were normal, her history revealed no exposure to goitrogens. Fetal ultrasound demonstrated a bilobed symmetric anterior neck mass measuring 4.0 x 8.0 cm. It caused hyperextension of the head and polyhydramnios, making spontaneous delivery impossible. Fetal blood sampling revealed severe hypothyroidism with a serum total thyroxine (T4) of 2.4 mcg/dL (normal: 316) and a thyroid-stimulating hormone (TSH) of 200 micro-U/mL (normal: 3-14) so that 250 micro-g L-thyroxine were injected intraamniotically. Hypothyroidism had improved at 36 weeks with a total thyroxineof 4.3 mcg/dL and a TSH of 80 micro-U/mL. At this time 200 mg L-thyroxine were injected into the umbilical vein. The procedure was repeated at 37 weeks with another 100 micro-g L-thyroxine. Thyroid function had improved further. Total thyroxine was 6.3 mcg/dL, and TSH was 36.6 micro-U/mL. The goiter was reduced to 4.2 x 5.1 cm so that a male infant with a small goiter was born by uncomplicated vaginal delivery at 39 weeks and 6 days. Molecular genetic studies revealed that the infant had a homozygous mutation of the thyroid peroxidase gene. Thyroid peroxidase gene abnormalities are known to give rise to organification defects, i.e. inability to add iodine to thyroglobulin which is a critical step in generating thyroid hormone. This infants goiter can most likely classified as: Dyshormonogenetic

Sporadic Endemic Toxic 2. All of the following clinical findings are correct concerning simple non-toxic goiter except: Neck discomfort Venous engorgement Dysphagia Male predominance Peak incidence during adolescence and early adult years 3. A 22year old woman was referred by her family physician to the Department of Endocrinology because of a large thyroid, but no clinical or biochemical signs of thyroid dysfunction. The patient had no major focal, nor major cosmetic problems. The thyroid enlargement appeared at her first pregnancy. At the time of referral TSH was 2.23 micro-U/L (normal: 210) and thus TSH was not suppressed, total thyroxine (T4) was 8 mcg/dL (normal: 5-12) and total triiodothyronine (T3) was 163 ng/dL (normal: 70205). A nuclear thyroid scintigraphy showed a diffuse, homogenous and equal uptake in both lobes. Both the right and the left lobe were considerably enlarged, measuring 6 x 10 cm. No hypo-functioning cold nodules were identified and thus no fine needle aspiration was performed. Which of the following is the most likely diagnosis?

Papillary carcinoma of thyroid Normal thyroid Hashimoto thyroiditis Diffuse non-toxic goiter Graves disease 4. An 86-year-old man presents with large goiter on April 2009. He reported weight loss of 10 pounds over the last year, fatigue, and an irregular heart rate over the last 2 years. Physical examination showed a bilaterally enlarged 100 g, asymmetric and nodular thyroid gland. A review of his records from the past 15 years shows that on January 1995 he had a diffuse goiter that was only slightly enlarged, at 40 g. He denies a history of head and neck radiation. His free thyroxine (T4) index has been increasing slowly, and his thyroidstimulating hormone (TSH) level has fallen progressively from 2.5 U/mL 15 years ago to his recent value of 0.4 U/mL (reference range is 0.5-5.5 U/mL). Which of the following is the most likely diagnosis? Nontoxic multinodular goiter Papillary carcinoma of the thyroid Graves disease Toxic multinodular goiter Diffuse nontoxic goiter 5. All of the following elements of the traditional theory about the pathogenesis of simple non-toxic goiter are correct except:

Hyperplastic thyroid produces hormone in excess leading to symptoms of thyrotoxicosis. Thyroid hyperplasia restores hormone secretion to the normal level. Insufficient iodine intake is at the root of the problem. Insufficient iodine intake brings about increased production of thyroid stimulating hormone (TSH). Increased TSH induces hyperplasia and enlargement of the thyroid gland with increase in functional activity. 6. Endemic goiter is an enlargement of the thyroid gland that occurs in more than 10% of a population of a geographic region secondary to iodine deficiency. False True 7. The term goiter refers to: Any enlargement of the thyroid associated with inflammatory diseases Any enlargement of the thyroid regardless of etiology Enlargement of the thyroid secondary to Graves disease Any enlargement of the thyroid associated with neoplastic diseases Enlargement of the thyroid secondary to the ingestion of goitrogens

8. A 55-year-old woman who reports shortness of breath on exertion is referred to Policlinico Di Monza (Torino, Italy) for evaluation of a neck mass. She was born and raised in northern Italy, an area of endemic goiter. She has been in good health until he noted recent shortness of breath, stridor, and cough on climbing stairs; she reports difficulty swallowing solid food because it sticks in his mid neck during a swallow. On physical examination, she has no cyanosis, no cough, and no wheezing. Her respiratory rate is 15 breaths per minute. The trachea is deviated to the left, with an enlarged thyroid about 6 times normal size. The thyroid is firm, with an irregular surface and with evidence of nodules. Upon raising her

arms, her face turns red and her external jugular veins fill with blood. Laboratory studies show a reference range thyroid-stimulating hormone (TSH) and free thyroxine (T4) level. Which of the following is the most likely diagnosis? Papillary carcinoma of the thyroid Thyroid adenoma Diffuse nontoxic goiter Toxic multinodular goiter Non-toxic multinodular goiter