Goiter

A goiter is a chronic enlargement of the thyroid gland due to nonneoplastic growth occurring in the setting of hypothyroidism, hyperthyroidism, or euthyroidism. Morphologically, thyroid enlargement can be diffuse (smooth consistency) or nodular (uninodular or multinodular). Hashimoto’s thyroiditis is associated with a benign hypothyroid goiter, while Graves’ disease produces a toxic or hyperthyroid goiter. Nontoxic goiter is euthyroid and is usually due to iodine deficiency (the most common cause of goiter). Diagnostic tests include thyroid function tests and measurement of thyroid antibodies. Ultrasound, CT, and/or MRI help if lab results are ambiguous and if worrisome features such as obstructive symptoms are present. Radioactive iodine uptake distinguishes hyperthyroid causes. Treatment depends on the underlying condition; options include observation, medication, surgery, and radioiodine ablation.

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Overview

Definition

  • Abnormal nonneoplastic enlargement of the thyroid, a highly vascular gland in the anterior neck region
  • Types according to morphology:
    • Uninodular or multinodular goiter: associated with 1 or more thyroid nodules, causing thyroid enlargement
    • Diffuse goiter: smooth and symmetrically enlarged thyroid gland
  • Types according to thyroid function:
    • Toxic goiter: associated with hyperthyroidism (↑ thyroid hormones)
    • Nontoxic goiter: associated with euthyroidism or normal amount of thyroid hormones
  • Hypothyroid goiter: associated with hypothyroidism (↓ thyroid hormones)

Etiology

  • Iodine deficiency: most common cause worldwide
  • Biosynthetic defects
  • Autoimmune:
    • Hashimoto’s thyroiditis
    • Subacute lymphocytic thyroiditis
    • Postpartum thyroiditis
    • Granulomatous thyroiditis
    • Graves’ disease
  • Infiltrative disease:
    • Riedel’s thyroiditis
    • Sarcoidosis
    • Histiocytosis
    • Cystinosis
    • Amyloid goiter
  • Radiation exposure
  • Goitrogen ingestion:
    • Lithium
    • Iodine
    • Food (cassava, millet)
  • Thyroid masses: cyst, adenoma, carcinoma

Epidemiology

  • About 200 million people affected in iodine-deficient areas
  • Women > men (4:1)
  • Incidence of goiter decreases with age.
  • Multinodular goiter:
    • More common in older adults
    • Carries up to 5% risk of thyroid cancer

Pathophysiology

Regulation of hormones

  • Hormones:
    • Thyrotropin-releasing hormone (TRH)
    • Thyroid-stimulating hormone (TSH)
    • Thyroid hormones (free and bound):
      • Thyroxine/tetraiodothyronine (T4): mostly a prohormone but with some hormonal activity
      • Triiodothyronine (T3): the more bioactive form, converted from T4
  • Hypothalamic–pituitary–thyroid axis:
    • Hypothalamus releases TRH → pituitary gland releases TSH (prolactin release is also stimulated) → thyroid gland produces T3/T4:
      • When there is level of free T3/free T4 (FT3/FT4) → ↓ TSH and TRH
      • When there is ↓ level of FT3/FT4 → ↑ TSH and TRH
Hypothalamic–pituitary–thyroid axis feedback loop

Hypothalamic–pituitary–thyroid axis feedback loop:
When the thyroid hormones are low, the hypothalamus releases TRH, and this triggers the pituitary gland to secrete TSH. This stimulates the thyroid gland to produce T4 and T3. Approximately ⅓ of the T4 produced is converted to the much more bioactive form T3.
Increase in free or unbound T3/T4 creates negative feedback, inhibiting the release of TRH and TSH.

Image by Lecturio.

Toxic goiter

  • ↓ TSH, ↑ FT3/FT4
  • Seen in Graves’ disease: TSH receptor antibodies (TRAbs) stimulate the TSH receptor → thyroid growth + ↑ thyroid hormones
  • Also noted in multinodular goiter, where nodules become autonomous, leading to ↑ T3/T4

Nontoxic goiter

  • Normal thyroid function: 
    • The thyroid overcompensates to maintain the euthyroid state.
    • Small TSH elevation seen leading to growth of the thyroid:
      • Hyperplastic phase: ↑ follicle epithelium
      • Involutional phase: when demand for thyroid hormone declines, follicle epithelium involutes and colloid accumulates (“colloid goiter”)
    • May start as diffuse goiter → cycles of hyperplasia and involution → irregularity in growths (nodularities) → diffuse type turns into a multinodular goiter
  • Seen in:
    • Endemic goiter (in iodine-poor areas)
    • Sporadic goiter (in iodine-sufficient areas)
      • Exact mechanism unknown
      • Growth factors like TSH may affect follicular cells with unique growth potentials.
    • Biosynthetic defects of thyroid hormones
    • Goiter in pregnancy: ↑ hCG → thyroid stimulation
    • Physiologic goiter (puberty: ↑ thyroid size as body grows and develops)
    • Goitrogens
    • Radiation exposure

Hypothyroid goiter

  • ↑ TSH, ↓ FT3/FT4
  • Most commonly seen in Hashimoto’s thyroiditis
  • ↓ Thyroid hormones → ↑ TSH levels → ↑ cellularity and hyperplasia of the thyroid gland → goiter

Clinical Presentation

Signs and symptoms

  • Initially asymptomatic, as most goiters grow slowly
  • Presentation associated with thyroid dysfunction:
    • Hypothyroidism: fatigue, cold intolerance, swelling, constipation
    • Hyperthyroidism: weight loss, palpitations, dyspnea, tremors
  • Presentation associated with mass/obstructive effect:
    • Exertional dyspnea:
      • Most common obstructive symptom
      • Compression of trachea
      • Tracheal diameter of < 5 mm → stridor or wheezing occurs
    • Neck discomfort (from the enlarging mass)
    • Hoarse voice from recurrent laryngeal nerve compression
    • Dysphagia or difficulty swallowing from compression of the esophagus
    • Phrenic nerve paralysis
    • Horner’s syndrome from compression of cervical sympathetic chain
    • Jugular vein compression
    • Superior vena cava syndrome

Disease-specific manifestations

  • Tenderness/pain (granulomatous thyroiditis)
  • Accompanying orbitopathy, dermopathy (Graves’ disease)
  • Hard thyroid gland with extensive fibrosis beyond thyroid area (Riedel’s thyroiditis)
Patient from South Sudan with a goiter

Patient from South Sudan with a goiter:
In rural areas of South Sudan, iodine deficiency is a major public health problem.

Image: “Iodine deficiency among goiter patients in rural South Sudan” by Chuot CC, Galukande M, Ibingira C, Kisa N, Fualal JO. License: CC BY 2.0

Diagnosis

Initial assessment

  • Determine history of:
    • Autoimmune disease
    • Iodine intake
    • Medications
    • Head and neck radiation
    • Thyroid disease and associated syndromes in family members
  • Palpation of the thyroid gland:
    • Determine morphology, consistency, size, and tenderness and search for signs of malignancy
    • Severity of goiter graded 0–2 by the World Health Organization (WHO)
  • Pemberton maneuver (worsens obstructive symptoms):
    • Have the patient hold the arms above the head for 1 minute.
    • This maneuver pushes the thyroid gland into the thoracic inlet.
    • The results are considered positive if the patient’s neck veins distend or if facial plethora, cyanosis, or difficulty in swallowing occurs.
WHO classification of goiter
GradeSeverity of goiter
0No goiter
1
  • Palpable goiter but not visible when the neck is in the normal position (i.e., the thyroid gland is not visibly enlarged)
  • Nodules in a thyroid that is otherwise not enlarged
2Clearly visible swelling in the neck when the neck is in a normal position and is consistent with an enlarged thyroid gland when the neck is palpated

Initial tests

Identify thyroid function and possible underlying cause:

  • Thyroid function tests:
    • TSH followed by FT3/FT4
    • Scenarios:
      • Toxic goiter: low TSH, ↑ T3/T4 
      • Nontoxic goiter: normal TSH
      • Hypothyroid goiter: Elevated TSH, ↓ FT3/FT4
  • Thyroid peroxidase (TPO) antibodies:
    • For clear-cut hypothyroidism (in the United States), obtaining TPO antibodies is not routine, since Hashimoto’s thyroiditis is the most common etiology.
    • In some cases with an unclear picture (e.g., normal TSH):
      •  TPO antibody measurements are obtained.
      • Presence of TPO antibodies is suggestive of Hashimoto’s thyroiditis.
  • TRAbs: measured in hyperthyroidism

Subsequent tests

Identify goiter size and presence of nodule with its characteristics and obstructive effect:

  • Ultrasound (US):
    •  Indications: 
      • Thyroid asymmetry, firm consistency or tenderness
      • Rapid growth
      • Nodule(s)
      • Nondiagnostic exam and lab findings
    • An option to assess thyroid vascularity when radioactive iodine uptake (RAIU) scan is contraindicated
  • RAIU: 
    • Assessment of hyperthyroidism or subclinical hyperthyroidism
    • Can help differentiate hyperthyroid states (e.g., Graves’ disease versus multinodular goiter with autonomy)
  • CT or MRI:
    • In patients with obstructive or substernal goiter
    • In those with features suspicious for malignancy
    • Assessment of the thyroid gland, masses or nodules, and the surrounding structures

Biopsy

Evaluate worrisome features (suspected malignancy) with fine-needle aspiration biopsy:

  • Suspicious nodule findings on US
  • Prominent nodules (≥ 1.5 cm)
  • Firm thyroid gland
  • Risk factors for malignancy:
    • Young age
    • History of radiation to the head or neck
    • Family history of thyroid cancer
    • Familial adenomatous polyposis (FAP) or other associated syndromes
    • Firm, solid, and/or cold nodules

Management

Toxic goiter

  • Surgery or radioiodine ablation 
  • Thionamides are an option in those who decline radioiodine ablation or surgery.
  • Beta-blockers for symptomatic relief

Nontoxic goiter

  • Observation: 
    • Indicated for asymptomatic euthyroid nonobstructive goiters
    • Regular neck exam, with thyroid function tests and US
  • Suppression (levothyroxine) therapy for euthyroid goiter:
    • Controversial
    • Associated with angina, atrial fibrillation, and ↓ bone density
  • Iodine replacement if needed
  • Surgery (total or near-total thyroidectomy) for: 
    • Large (> 80–100 mL), growing goiters
    • Goiters causing obstruction
  • Radioiodine ablation: 
    • For those with growing goiters who are poor surgical candidates or who decline surgery
    • Goiter reduction by 50%

Hypothyroid goiter

  • Levothyroxine: 
    • For hypothyroid nonobstructive goiters
    • Goiter size may decrease, but with less efficacy.
  • Surgery if goiter causes obstruction

Clinical Relevance

  • Thyroid nodule: disordered growth of thyroid cells, producing a mass in the thyroid gland: The majority of nodules are detected on examination or found incidentally in radiologic images. Workup includes TSH and US, followed by a RAIU/thyroid scan if hyperthyroidism is present. Biopsy is recommended in those with suspicious US findings, cold nodules on thyroid scan, large-sized nodules (generally > 1.5 cm), and risk factors for malignancy. Treatment is dictated by pathology findings.
  • Hypothyroidism: condition characterized by the deficiency of thyroid hormones: Iodine deficiency and Hashimoto’s thyroiditis are the 2 leading etiologies Clinical features reflect the effects of slowed organ function/decreased metabolic rate. Lab tests show elevated TSH and low FT4. Treatment is with levothyroxine.
  • Hyperthyroidism: condition caused by sustained overproduction and release of the thyroid hormones T3 and T4: Graves’ disease is the most common cause of hyperthyroidism. Manifestations are mostly due to the increased metabolic rate and overactivity of the sympathetic nervous system. Lab tests show low TSH and elevated FT4. Treatment depends on the underlying condition.
  • Hashimoto’s thyroiditis: also called chronic lymphocytic thyroiditis: Hashimoto’s thyroiditis is the most common cause of hypothyroidism in iodine-sufficient regions. It is an autoimmune disorder that leads to destruction of the thyroid cells and thyroid failure. Presentation can be a painless goiter (in later/“burned-out” stages, the gland is atrophic). Lab tests show elevated TSH and low FT4 and are positive for antibodies against thyroglobulin and thyroid peroxidase. Treatment is lifelong thyroid replacement therapy.
  • Graves’ disease: autoimmune disorder characterized by the presence of circulating antibodies against the TSH receptors, causing the thyroid gland to hyperfunction: Clinical features include hyperthyroidism, orbitopathy, goiter, and dermopathy/pretibial myxedema. Laboratory tests show low TSH, elevated T4, and thyrotropin-receptor antibodies (particularly the thyroid-stimulating immunoglobulins). Treatment options include thionamides, radioiodine ablation, and surgery.
  • Thyroid cancer: most common endocrine system cancer: Malignancy arises from the cell types of the gland: thyroid follicular cells, calcitonin-producing C cells, lymphocytes, and stromal and vascular elements. Metastasis from other malignancies can occur in the thyroid gland. Patients can present with a growing thyroid mass, thyroid asymmetry, or gland enlargement/swelling. Diagnosis is by biopsy. Treatment varies by type and stage. Options include surgery, radioactive iodine, targeted therapy, and radiation therapy.
  • Metastases from other malignancies can occur in the thyroid gland. Patients can present with a growing thyroid mass, thyroid asymmetry, or gland enlargement/swelling. Diagnosis is by biopsy. Treatment varies by type and stage. Options include surgery, radioactive iodine, targeted therapy, and radiation therapy.

References

  1. Alkabban F, Patel B. (2020). Nontoxic goiter. StatPearls. Retrieved February 13, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK482274/
  2. Fitzgerald PA. (2021). Thyroid nodules & multinodular goiter. In Papadakis MA, McPhee SJ, Rabow MW (Eds.). Current Medical Diagnosis & Treatment 2021. New York: McGraw-Hill.
  3. Jameson J, Mandel SJ, Weetman AP. (2018). Thyroid nodular disease and thyroid cancer. In Jameson JL, et al. (Eds.) Harrison’s Principles of Internal Medicine, 20th ed., vol. 2, pp 2710–2714.
  4. Kuo LE, Cho NL. (2020). Thyroid & parathyroid. In: Doherty GM (Ed.), Current Diagnosis & Treatment: Surgery, 15th ed. New York: McGraw-Hill.
  5. Mulinda J, Khardori R. (2020). Goiter. Medscape. Retrieved February 12, 2021, from https://emedicine.medscape.com/article/120034-overview#a6
  6. Ross D. (2020). Clinical presentation and evaluation of goiter in adults. UpToDate. Retrieved February 14, 2021, from https://www.uptodate.com/contents/clinical-presentation-and-evaluation-of-goiter-in-adults
  7. Ross, D. (2019). Treatment of nontoxic, nonobstructive goiter. UpToDate. Retrieved February 14, 2021, from https://www.uptodate.com/contents/treatment-of-nontoxic-nonobstructive-goiter
  8. Peeters RP, Visser TJ. (2000). Metabolism of thyroid hormone. In Feingold KR, Anawalt B, Boyce A, et al. (Eds.), Endotext. MDText.com, Inc. http://www.ncbi.nlm.nih.gov/books/NBK285545/

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