Continuing Education Activity

Patients with goiter commonly present to outpatient facilities with a variety of complaints. Goiter encompasses many different causes and morbidities, and accurate diagnosis is essential for the proper treatment approach. Goiter, either simple or nodular, or either nontoxic or toxic can majorly impact a patient's quality of life and well-being and can have long-term physical and cosmetic health effects. This activity reviews the evaluation and management of goiter, reviews different causes and types, and highlights the role of the interprofessional team from various specialties in evaluating and treating goiter.

Objectives:

• Identify the etiology of goiter.
• Outline the evaluation of patients who present with a goiter.
• Describe the management options available for goiter.

Introduction

Goiter means enlargement of the thyroid gland and is a general term that conveys the information that the volume of the thyroid gland is larger than normal. The presence of goiter can be determined by inspection, palpation, or by an imaging study.

Normal thyroid gland measures 4 to 4.8 cm in sagittal, 1 to 1.8 cm in transverse, and 0.8 to 1.6 cm in anteroposterior dimensions. This corresponds to a volume of 7 to 10 mL on ultrasonography calculations and 10-20 grams in weight. Thyroid size increases with age and body size. It is larger in males as opposed to females. The size decreases with higher iodine intake.

The thyroid gland can enlarge due to a variety of physiological or pathological stimuli. Goiter during adolescence and pregnancy are two causes of a physiological goiter. Goiter can be associated with euthyroidism, hypothyroidism, or hyperthyroidism.[1] It can be diffuse, nodular, or multinodular. The thyroid gland usually grows anteriorly in the neck, because the enlarging thyroid is not constrained by the weak anterior cervical muscles, subcutaneous tissue, or the skin. The term goiter is usually used to denote cervical goiter. If the thyroid gland enlarges inferiorly and passes through the thoracic inlet, then it is called a substernal or retrosternal goiter.

Etiology

Several pathogenic mechanisms can cause goiter. It can be caused by iodine deficiency, which is often seen in countries that do not have a public health intervention to prevent iodine deficiency.[2] In this instance, the terminology is an endemic goiter. Inflammatory disorders of the thyroid gland such as autoimmune thyroiditis, postpartum thyroiditis, silent thyroiditis, radiation thyroiditis, subacute thyroiditis, and suppurative thyroiditis can cause thyroid enlargement, hence goiter.

As the enlargement of the thyroid is the consequence of the inflammatory process and abates after the inflammation resolves, the term "goiter" is not used to describe the disorder. Goiter is among the symptoms and signs of inflammatory thyroid disorder. Thyroid diseases that cause hyperthyroidism, such as Grave disease, toxic nodular goiter, and toxic multinodular goiter can cause goiter.[3] Goiter can include one or more nodules and is termed as nodular goiter or nontoxic multinodular goiter; in these entities, the enlarged thyroid is associated with euthyroidism. Other causes can be thyroid cancer and granulomatous and infiltrative diseases of the thyroid.[4]

Epidemiology

The most common cause of goiters worldwide is iodine deficiency that affects an estimated 2.2 billion people.[2] The prevalence and incidence of goiter are based on the degree of iodine deficiency. With mild iodine deficiency, the incidence of goiter is 5% to 20%. With a moderate deficiency, the prevalence increases to 20% to 30%, and with severe iodine deficiency, the incidence increases to greater than 30%. Even with the use of iodine, there has been an increase in the incidence of thyroid nodules. It is not clear the increase in prevalence represents a true increase or an increased detection. One of the causes of this could be the increased utilization of radiological imaging and more frequent screening with ultrasound.

At this time, ultrasonography can detect even the smallest of nodules, causing the incidence of nodules to be 60% to 70% in adults. However, imaging and screening are not the sole causes of the increase in incidence. It has been thought that obesity, insulin resistance, and metabolic syndrome may be factors that have caused an increased incidence of goiter.[4] Females are approximately four times more likely to develop goiter as compared to males. There is no racial difference in goiter prevalence.[5]

Pathophysiology

Enlargement of thyroid, i.e. goiter is an adaptive reaction of thyroid follicular cells to any process that blocks thyroid hormone production. The most common cause of goiter is iodine deficiency. In countries that use iodized salt and in others where iodine deficiency is not a problem, Hashimoto thyroiditis is an important cause of goiter. However, iodine deficiency still remains the most common cause worldwide. Goiters have various morphological, hormonal, and clinical presentations and not all causes of goiter can be attributed to iodine deficiency. Genetic, demographic, and environmental factors are also responsible for the development of goiter. Other causes include Graves disease, inborn errors of thyroid hormone synthesis, congenital hypothyroidism, inflammatory thyroid diseases like postpartum thyroiditis, infiltrative diseases of thyroid like sarcoidosis, and amyloidosis, TSH secreting pituitary adenomas, and others.[6]

Pathophysiology of Diffuse Nontoxic Goiter

Iodine deficiency: Iodine deficiency leads to subtle decreases in thyroid hormone production with T4 and T3 levels remaining in the reference range. The decrease of thyroid hormone levels from baseline increases TSH secretion from the pituitary gland. Increased demand for thyroid hormones due to physiological requirements like adolescence or pregnancy also leads to pituitary stimulation and increased TSH secretion. The increased TSH causes increased cellularity and hyperplasia of the thyroid gland. The thyroid follicular cells are stimulated and contribute to follicular hyperplasia and thyroid enlargement.[6] Sodium-iodide symporter (NIS) functions to uptake circulating iodide to follicular thyroid cells. The source for circulating iodide is oral intake and turnover of previously synthesized thyroid hormones and iodothyronines. Iodide is transferred to colloid, oxidized by thyroid peroxidase, and T4 and T3 are synthesized. Medications like lithium, dietary goitrogens, or endocrine disruptors may block any of these steps, cause a decrease in thyroid hormone synthesis and increase TSH stimulation, although TSH levels may not go above the reference range for the TSH assay but may be higher than baseline. The end result would be goiter formation to attempt to restore thyroid hormone synthesis and secretion to baseline. Diet is the most important source of iodine. The level of iodide in the extracellular fluid is about 10 to 15 µg/L and the peripheral pool of iodine is about 250 µg. Thyroid contains 8000 µg of iodine. The recommended dietary iodine intake for adults is 150 µg/day, during pregnancy 220 µg/day, and for children 90 to 120 µg/day.

Autoimmune thyroid disorders: Goiter can be the initial symptom of autoimmune thyroid disease. In Hashimoto’s thyroiditis thyroid enlarges gradually and can be detected by inspection, palpation, or ultrasonography. Occasionally it may enlarge rapidly and gives the impression of subacute thyroiditis. Elevated TSH levels due to hypothyroidism may also contribute to goiter in autoimmune thyroid disease. As Hashimoto’s thyroiditis progresses and follicular cells are destroyed by inflammation and fibrosis component increases, the thyroid volume decreases and the gland becomes atrophic with chronic atrophic thyroiditis. There are several variations in the clinical course and heterogeneity in presentation for Hashimoto’s thyroiditis and also other autoimmune thyroid disorders. The most common cause of diffuse toxic goiter is Graves’ disease, an autoimmune thyroid disease. Patients with diffuse toxic goiter have a diffusely enlarged, vascular gland. The follicular cells are hypertrophic and hyperplastic, and lymphocytes and plasma cells infiltrate into the gland and group into lymphoid follicles. Antibodies (TSI: thyroid-stimulating immunoglobulin) are directed towards the thyroid-stimulating hormone receptors that are present on follicular cells. This stimulation of the receptors leads to the production of increased T4 and T3. Eventually, the thyroid gland becomes enlarged leading to the development of a goiter.[7]

Hereditary factors: Goiter is common in some families. In iodine deficiency areas, after iodine is supplemented, the goiter incidence does not drop to zero and there is the persistence of goiter in some families. The concordance of goiter is higher in monozygotic twins than dizygotic. Mutations in sodium iodide symporter, thyroid peroxidase, dual oxidase 2, pendrin, and TSH receptor gene have been identified responsible for the development of goiter.

Goitrogens or endocrine disruptors: Lithium can cause hypothyroidism and goiter. Amiodarone, interleukin-2, sunitinib, sorafenib, ipilimumab, pembrolizumab, and nivolumab can cause thyroiditis and hence goiter. Thiocyanate, perchlorate, and NO3- inhibit transport of iodide to the thyroid gland and decrease iodide uptake and thyroid hormone formation. Perchlorate has a pharmacological use, but these monovalent anions are not accepted as widespread causes of goiter, although in theory, they may cause goiter if ingested over prolonged periods of time in small quantities. Phthalates, isoflavones and organochlorides, certain foods containing cyanogenic glucosides like cassava, sorghum, maize, millets or containing thioglucosides like cabbage, kale, Brussels sprouts, cauliflower, kohlrabi, rutabaga, mustard, and horseradish were suggested as goitrogens but they are not proven conclusively as major etiological factors of goiter formation.

Rare causes

• Nonautoimmune autosomal dominant hyperthyroidism
• TSH secreting pituitary adenoma
• Thyroid hormone resistance syndrome
• Tumors secreting human chorionic gonadotropin

Pathophysiology of Nodular Goiter

Diffuse nontoxic goiter is considered to be the precursor of euthyroid thyroid nodules and nontoxic multinodular goiter. So the pathophysiology of diffuse nontoxic goiter also applies to nodular goiter. In addition, the following mechanisms can be considered:

Radiation: Accidental or medical radiation, by external ionizing radiation or radioactive iodine, causes thyroid abnormalities. Individuals exposed to radiation under the age of 20 years have an increase in the incidence of thyroid nodules in early years and papillary thyroid cancer as they age.

Genetic factors, mutations: SPOP, ZNF148, and EZH1 in benign nodules and PAX8/PPARg, RET/PTC, BRAF, and RAS in papillary thyroid cancer.

Insulin resistance, metabolic syndrome, stimulation of MAPK cascade by insulin signaling while showing insulin resistance in other pathways like the phosphoinositide-3 kinase pathway, and activation of the IGF receptor pathway.[4]

Pathophysiology of Toxic Adenoma

Up to 70% of toxic adenomas harbor a somatic point mutation in the TSH receptor gene. These mutations cause constitutive activation of the TSH receptor without TSH stimulation. A minority of toxic adenomas has a mutation in the G protein genes. EZH1 gene mutation has been found in toxic adenomas that have a TSH receptor activating mutation suggesting a second hit.

Pathophysiology of Toxic Nodular Goiter

Nontoxic multinodular goiter and/or single toxic adenomas are considered as precursors of toxic multinodular goiter (Plummer’s Disease). When a nodule or several nodules in nontoxic multinodular goiter gain autonomy, they secrete excess thyroid hormones and lower TSH levels causing the development of toxic multinodular goiter. During the transition from nontoxic to toxic goiter, pathophysiological and morphological alterations occur. Histology of toxic multinodular goiter shows nodules well demarcated from the rest of the thyroid gland. Some of these nodules may be hot whereas some of these nodules may be cold or somewhere in between (cool, warm, or normoactive) with the remaining of the non-nodular thyroid tissue either partially or completely suppressed. Microscopically nodules have large follicles with epithelial hyperplasia. The non-nodular tissue is not hyperplastic and may contain areas of degeneration and is functionally less active or inactive as seen in the nuclear medicine radioiodine scan.

As in toxic adenomas up to 60% of toxic multinodular goiters carry a TSH receptor mutation, few have G protein mutations and the rest is still unknown and understudy.

In summary toxic multinodular goiter contains single or multiple solitary hyperfunctioning nodules with or without single or multiple hyperfunctioning adenomas on the background of suppressed non-nodular tissue.

History and Physical

Thyroid hormonal function and the growth rate of the thyroid gland reflect the clinical presentation of a goiter. If the patient has hypothyroidism or hyperthyroidism, he or she will have the signs or symptoms of hypothyroidism or hyperthyroidism. The vast majority of patients will be euthyroid. The growth rate is usually slow and patients accommodate the enlarging thyroid at is a usual anatomic place very well without any sign or symptoms except for esthetical complaints or if the thyroid grows inferiorly to the thoracic cavity.

Rapid growth may be due to hemorrhage into a nodule, inflammatory thyroid disorders, or malignancy. Hemorrhage into a nodule causing sudden enlargement and subacute thyroiditis can cause pain on the lower neck at the thyroid area. Large goiters or rapidly enlarging goiters can cause obstructive or compressive symptoms. Obstructive symptoms are choking sensation, cough, exertional dyspnea, and stridor due to compression of the trachea, hoarseness due to compression of the recurrent laryngeal nerve, and difficulty in swallowing due compression of the esophagus. These symptoms are subjective and patients with large goiters may not have any obstructive symptoms. Tracheal diameter can be assessed by CT scan and needs to be over 10 mm.[8] 

Rarely, compression of nervous structures such as Horner’s syndrome due to compression of the cervical sympathetic chain, compression of venous structures especially jugular vein compression, compression of arterial structures with cerebrovascular steal syndrome can occur.

History

Prior history of thyroid disease or surgery in the patient, family history of thyroid disease, the geographic area where the patient spent most of his life to determine if the patient is from an endemic goiter area, information about iodine deficiency, medication history, prior exposure to head and neck irradiation, and history of accidental radioactivity exposure should be sought. The presence of dyspnea, cough, pressure sensation on the anterior neck, and hoarseness should be inquired. Patients should be asked if the appearance of goiter is bothersome esthetically.

Physical Examination

A comprehensive physical examination should be done to detect signs and symptoms of hypo- or hyperthyroidism. Thyroid should be inspected visually by standing anterior to the patient and asking him or her to swallow. An enlarged thyroid and asymmetry can be obvious to the plain eye. Then the thyroid needs to be palpated either from the front with both thumbs or from behind with index, 2, and/or 3 fingers and the patient is asked to swallow. A glass of water helps the patient to swallow. With swallowing, the thyroid moves up and down facilitating palpation. The examiner should orient themself by identifying thyroid cartilage, bilateral sternocleidomastoid muscles, and sternal notch. These anatomical structures border the thyroid gland.

The examiner compresses the thyroid against posterior structures to better feel its size, texture, consistency, tenderness, and feel any nodules. The lower border of goiter should be determined. The patient should lie down and hyperextend his or her neck by placing a pillow under the shoulder if the lower border cannot be felt when upright. The inability to palpate the lower border indicates the presence of substernal goiter. Pemberton’s sign is employed to assess the substernal extension. The patient is asked to raise both arms until medial parts touch to lateral sides of the head for at least one minute. If the patient develops facial congestion, bulging of neck veins, hoarseness, or dyspnea, then Pemberton sign is positive, indicating compression at the thoracic inlet due to substernal goiter. Arm elevation spirometry with flow volume loops has been suggested to increase the sensitivity to detect upper airway obstruction and also as an objective assessment of Pemberton sign.[9]

“Corking” of the thyroid at the thoracic inlet is believed to cause compression of surrounding anatomical structures and a positive Pemberton sign. The size of the thyroid should be determined by palpation. Palpation of a thrill and auscultation of a bruit over the thyroid area suggests Grave’s disease and are due to increased vasculature. One or more nodules can be palpable in uni- or multinodular goiter, respectively. Then the rest of the neck should be examined for enlarged lymph nodes and other masses.

Evaluation

Patients with goiter can be euthyroid, hypothyroid, or hyperthyroid. The vast majority of the patients with simple goiter (diffuse enlargement of thyroid without any nodules) are euthyroid. This is also the case with a solitary thyroid nodule and a multinodular goiter. Nodular goiters can be asymptomatic and having normal TSH levels or being associated with thyrotoxic symptoms having low TSH levels.[10] 

Most of the time, goiters are found during a physical examination or can be an incidental finding on imaging such as carotid Doppler, neck CT, cervical MRI, or PET-CT. In order to evaluate patients with simple goiters, biochemical testing and imaging studies need to be performed. Imagining studies can help assess the size and extent of goiter, the relationship with surrounding anatomical structures, help assess for compression and presence of nodules. For nodular goiters, fine needle aspiration biopsy may be required if indications are met for a cold nodule.  

TSH needs to be measured first to assess the thyroid status of a patient. Free T4, total T3, antithyroglobulin and thyroid peroxidase antibodies can also be obtained for additional evaluation. Following this, ultrasound of the thyroid should be performed to assess the size of the thyroid gland, for the presence of the nodules for the extent of thyroid enlargement, relationship with surrounding anatomic structures, and for the presence of any suspicious findings.

Ultrasound findings showing hypoechogenicity, microcalcification, irregular borders, taller than wide, a protrusion from the nodule capsule, and size greater than 1 cm make nodules more suspicious and in this case, fine-needle aspiration biopsy is warranted if the size is 1 cm or larger. For those that show malignant cytology, surgery is the next step. Chest x-ray, computerized tomography, or magnetic resonance imaging can also be obtained if compression symptoms are suspected to better assess tracheal deviation, airway compression, and retrosternal extension. Pulmonary function tests and rarely if there is dysphagia barium swallow studies are useful in these instances.

Treatment / Management

The aim of goiter treatment is to relieve compression and to restore euthyroidism. By definition patients with nontoxic goiters are euthyroid or in lower frequency hypothyroid. If there is any coexistent hypothyroidism, treatment includes thyroid hormone administration. Patients with toxic goiter require modalities that address thyroid enlargement and thyrotoxicosis.

Treatment of Nontoxic Goiter

Today the main treatment options include monitoring without any treatment and thyroidectomy. Levothyroxine suppression therapy is no longer recommended.

Monitoring and observation are recommended initially if there are no compressive symptoms, as certain goiters can spontaneously regress with time. Monitoring includes obtaining yearly TSH levels, thyroid ultrasound, and regular physical examinations. However, at other times, goiters can increase in size and cause compressive symptoms and cosmetic problems. Compressive symptoms include choking sensation, dysphagia, or hoarseness. For patients that fall into this latter category, the treatment of choice is surgery. Surgery is also indicated when malignancy is suspected or diagnosed. When surgery is the treatment option, total or near-total thyroidectomy is preferred over subtotal thyroidectomy. For patients that need a treatment option besides monitoring, however, cannot undergo surgery due to personal preference or being poor surgical candidates, radioiodine therapy is the treatment of choice.[10] In the United States, radioiodine treatment is used relatively less compared to other countries.

Use of levothyroxine for thyroid hormone suppressive therapy is another treatment option used in the past, however, due to its limited efficacy and side effects, it is no longer recommended. Side effects of hormone suppressive therapy include atrial arrhythmias, decreased bone density, and overt hyperthyroidism. Using levothyroxine can help goiters regress at times if patients have hypothyroidism but there is no guarantee as there are some patients showing an increase in goiter size despite being on levothyroxine. 

Regular follow up with neck palpation and thyroid ultrasound is recommended, no matter the treatment option the patient chooses.[11][12]

Treatment of Toxic Goiter

In patients with toxic goiters, treatment options include surgery, radioiodine therapy, or antithyroid drugs.[12] Symptomatic control with beta-blockers is also recommended to help alleviate symptoms of hyperthyroidism as well as for cardioprotection. If the patient has a toxic goiter with subclinical hyperthyroidism (normal T3/T4 and low TSH level with no hyperthyroid symptoms), monitoring and proceeding to a treatment modality if hyperthyroid symptoms depend on age, etiology, and clinical comorbid conditions. The most effective and preferred treatment option is radioiodine therapy for toxic goiters.

Thionamides do decrease thyroid hormone production but discontinuation usually results in recurrence of hyperthyroidism. Therefore antithyroid drugs should mostly be used in patients preparing for definitive treatment with surgery or radioiodine therapy. It can also be used long term in patients who cannot or prefer not to undergo surgery or radioiodine therapy. Antithyroid drugs can be used with a beta-blocker such as propranolol or atenolol as well. The initial dosage of antithyroid drugs is based on the extent of the disease with the methimazole dose ranging from 5 mg to 60 mg daily. Propylthiouracil is not used because of the risk of hepatotoxicity.[13] If used, Propylthiouracil dose ranges from 50 mg to 600 mg daily, doses higher than 50 mg should be given in two to three divided doses. TSH and free T4 should be measured every one to six weeks and the dose of thionamide can be tapered with the goal being to maintain euthyroidism. After euthyroidism is achieved, thyroid function tests can be obtained every 3-6 months. Women desiring pregnancy should also be aware of the teratogenic effects of thionamides.

Surgery is a definitive treatment option and indications include goiters that are obstructive or large, malignancy, coexistent primary hyperparathyroidism, or need for immediate or definitive correction of hyperthyroidism. Surgery consists of total or partial thyroidectomy.[14][15] Patients should be treated with an antithyroid drug such as methimazole to achieve euthyroidism prior to surgery. Methimazole should be discontinued immediately post-surgery. Beta-blockers should also be slowly discontinued after surgery. Laryngeal nerve function and calcium should be assessed pre- and postoperatively. After a total thyroidectomy, thyroid hormone replacement should be initiated. In those that underwent a hemithyroidectomy, TSH and free T4 should be checked 4-6 weeks post-surgery and thyroid hormone replacement should be initiated if needed.

The radioactive iodine dose is based on the size of the thyroid nodule, the size of the thyroid gland, thyroid function tests, and the radioactive iodine uptake on a thyroid scan.[16] Patients biochemically hyperthyroid who had older, symptomatic, or have heart disease are usually pretreated with a thionamide prior to radioiodine therapy. The thionamide, which is preferably methimazole, should be discontinued five days prior to receiving radioiodine. It can be restarted three to seven days after radioiodine and can be stopped when radioiodine therapy has shown to work which can take up to six months. At times, patients require subsequent radioiodine treatments to achieve a euthyroid state.[17] Those that are pregnant, breastfeeding, or plan on being pregnant within the next six months should not receive radioiodine treatment.[10] In most cases, the American Thyroid Association prefers radioactive iodine treatment as the first line of treatment for graves disease or toxic nodular disease.

Differential Diagnosis

• Branchial cleft cyst
• Carotid artery aneurysm
• Lymphatic malformation (cystic hygroma)
• Fibroma
• Lipoma
• Lymphadenopathy (common)
• Parathyroid adenoma
• Parathyroid cyst
• Pseudogoiter (common)
• Thyroglossal duct cyst
• Thyroid abscess
• Thyroid lymphoma

Prognosis

Simple goiter has good prognosis. If thyroid continues to enlarge it may compress the surrounding structures and may cause difficulty in breathing, difficulty in swallowing, and hoarseness. It is important to differentiate between benign and malignant causes of thyroid enlargement. If the goiter continues to enlarge, surgical treatment should be considered. If the goiter is a sign of another thyroid disease like Graves disease or Hashimoto thyroiditis, the prognosis depends on the underlying cause of thyroid enlargement.

Complications

Consequences of goiter with having hypothyroidism, hyperthyroidism, further goiter enlargement, retrosternal extension, nodule formation and thyroid cancer detection are mentioned above and can be regarded as goiter associated presentations or clinical entities and do not count as complications. Potential complications of simple goiter include:

• Compression of the trachea with tracheomalacia
• Iodo-Basedow phenomenon, which is the development of hyperthyroidism if exposed to iodine intake
• Intra-nodular hemorrhage or necrosis

Deterrence and Patient Education

A sufficient daily intake of iodine is needed to prevent goiter. The recommended daily intake (RDI) of iodine is 90 µg/day for children aged 2 to 5 years, 120 µg/day for children aged 6 to 9 years, and 150 µg/day for children from 10 years of age, adolescents, and adults. In pregnancy, the RDI is 250 µg/day and for lactating women, an extra 50 µg/day is recommended to provide sufficient iodine in breast milk.[18]

Avoiding goitrogens and radiation exposure are other ways one could prevent goiter.

Enhancing Healthcare Team Outcomes

The patient with goiter can be managed by a family physician, internist, endocrinologist, ENT specialist, general or endocrine surgeon. If there is an indication for surgery, it should ideally be performed by experienced high-thyroid-volume surgeons.