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Diffuse Toxic Goiter


Diffuse Toxic Goiter

Article Author:
Gauri Singh
Article Editor:
Ricardo Correa
Updated:
10/12/2020 10:22:59 AM
For CME on this topic:
Diffuse Toxic Goiter CME
PubMed Link:
Diffuse Toxic Goiter

Introduction

Goiter simply refers to the enlargement of the thyroid gland. It can be due to various causes, dietary iodine deficiency being the most common cause worldwide. In the United States, however, Graves disease and Hashimoto disease are more common. Goiter has been classified as per different categories, morphology (nodular/diffuse), functional status (hyper/hypo/euthyroid), malignancy, etc. By definition, a 'diffuse, toxic" Goiter refers to a diffusely hyperplastic thyroid gland that is excessively overproducing the thyroid hormones.

Etiology

The following are common causes of goiter:

  • Iodine deficiency[1]
  • Autoimmune disorders[2]
  • Smoking
  • Heredity[3]
  • Medications ex. lithium, iodides, interferon-alpha[4]
  • Radiation therapy[5]
  • Inflammation ex. infections 

Diffuse, toxic goiter is most commonly caused by autoimmune disorders like Graves disease in the United States.

Epidemiology

The most common cause of diffuse, toxic goiter, is Graves disease. It is the most common cause of hyperthyroidism in the United States and affects 1 in 200 people.

It usually affects people between 30 and 50 years of age, but can occur in any age group. It is 7 to 10 times more common in females than in males. A marked increase in familial incidence has been observed, as well.

Pathophysiology

Diffuse, toxic goiter consists of a diffusely enlarged, vascular gland with rubber-like consistency. Microscopically, the follicular cells are hypertrophic and hyperplastic with little colloid in them. Lymphocytes and plasma cells infiltrate into the gland and can ultimately aggregate into lymphoid follicles.

All cases of diffuse, toxic goiter are not Graves disease and may have various non-autoimmune causative processes. But the majority of cases are auto-immune in nature. In Graves disease, antibodies are directed towards the thyroid-stimulating hormone receptor (TSHr) present on follicular cells. The chronic stimulation of these receptors results in the production of excess amounts of T3, T4, and the eventual enlargement of the thyroid gland resulting in a goiter.[6]

Histopathology

This disease has the following histological characteristics[7]:

  • Diffuse non-nodular enlargement of the gland with a smooth capsule and increased vascularity.
  • Hyperplasia of both follicular and papillary cells with lymphocytic infiltration into the stroma of the thyroid gland
  • Follicular cells can also be enlarged and, in extreme cases, have enlarged nuclei mimicking that of papillar thyroid carcinoma. In Graves disease, however, they tend to maintain their rounded shape and have minimal clearing.

Due to the last point above, there have been controversies regarding the association between Graves disease and papillary thyroid carcinoma, and whether the coexistence of the two affects the prognosis. On systematic review of various studies, it has been seen that if a papillary carcinoma is discovered after surgical removal of the gland the prognosis is excellent, whereas on discovering a tumor in a patient of Graves disease, the local characteristics of the tumor (size, extent, margins, functionality, etc.) decide the prognosis.[8]

History and Physical

History [9]

  • Patients may present with a history of one or more consequences of a hyperthyroid state. These include weight loss, heat intolerance (with other heat-related symptoms like polydipsia, sweating), tremor, nervousness, anxiety, fatigue, palpitations, shortness of breath, frequent defecation, diarrhea, nausea, vomiting, etc. 
  • Patients may also complain of an obvious neck swelling or sensation of a lump in the neck, globus, swallowing difficulty, orthopnea, etc.
  • Patients with Graves disease may present with additional features like:
  1. Ophthalmopathy/Graves orbitopathy (seen in 25% of patients): proptosis, diplopia, periorbital edema, excessive lacrimation, etc.
  2. Thyroid dermatopathy (rare, seen in 4% of patients and usually concurrent with orbitopathy): Slightly thickened pigmented skin, especially over the pretibial area.
  3. Reproductive system- irregular menstruation

Physical Examination

The common findings in a patient with the diffuse, toxic goiter on physical exam are as follows:

  • Constitutional- weight loss
  • Head, eyes, ears, neck- neck swelling, proptosis, lid lag, periorbital edema
  • Cardiovascular system: tachycardia, irregular heartbeat, systolic hypertension
  • Neuromuscular: tremor of extremities, hyperreflexia, hyperactivity, muscle weakness
  • Respiratory system- tachypnea
  • Skin and extremities- moist, warm skin, pretibial myxedema

Evaluation

The primary evaluation consists of a complete thyroid profile, including serum T3, T4, TSH levels.

  • The serum TSH is the best screening test for evaluating thyroid hormone excess or deficiency.[10]
  • In the case of diffuse, toxic goiter, the above tests usually result in low or normal TSH levels with elevated serum thyroid levels.
  • Based on preferences in accordance with population characteristics, socioeconomic reasons, and cultural backgrounds, the modalities of evaluation of the cause of thyrotoxicosis can either be radioactive iodide uptake or a combination of thyroid ultrasound with TSH-receptor antibodies.[9]
  • A high radioactive iodine uptake diffusely depicts Graves disease, as does an enlarged gland with positive TSH-receptor antibodies (TRAb).

Treatment / Management

The treatment modalities for diffuse toxic goiter include:

Antithyroidthyroid Drugs (ATD)  

  1. The antithyroid drug options are propylthiouracil, thiamazole, and carbimazole.
  2. The American Thyroid Association (ATA) and American Association of Clinical Endocrinology recommend thiamazole as a preferred drug for Graves disease, except in patients with adverse reactions to the drug or patients in the first trimester of pregnancy. It is preferred over propylthiouracil due to better efficacy, longer half-life and duration of action, and once-daily dosing.
  3. There are two regimens to administer ATD, and the first is titration, where the dose of ATD is tapered to the lowest possible dose when the euthyroid state is achieved. The next regimen is block-and-replace, where a high dose of ATD is given adjunct with thyroxine to maintain a euthyroid state.[11]
  4. A drawback of ATD therapy is the risk of recurrence, especially in the first year after stopping therapy. Studies prove a risk of 50% to 55% risk of recurrence, with poor prognostic factors like severe hyperthyroidism, large goiter, high T3: T4 ratios, persistently suppressed TSH, and high baseline concentrations of TRAb.[12]
  5. Rare but major side effects of ATD therapy include agranulocytosis, hepatotoxicity, vasculitis, etc.

Radio-iodine Therapy (I-31, RAI) [12]

  1. RAI is the commonest modality to treat Graves disease in the United States and is a safe and effective form of treatment.
  2. The absolute contraindications of this therapy are pregnancy, breastfeeding, and severe uncontrolled thyrotoxicosis.
  3. It can be administered in liquid or capsule forms, and fixed-dose therapy is as effective as calculated dose therapy based on the volume of the gland, iodine uptake, etc.
  4. Patients must discontinue all iodine-containing medication and be on iodine restricted diet to ensure effective uptake of RAI.
  5. ATD therapy is to be discontinued before the use of RAI and can be resumed after a week of administering RAI if needed.
  6. Potential side effects include the risk of developing hypothyroidism, and rarely transient radiation hyperthyroidism or worsening of thyroid-associated ophthalmopathy (TAO).
  7. While hypothyroidism is actively screened as subsequent follow-ups, prednisone is known to prevent the progression of mild TAO.
  8. Patients have to be counseled about lifelong follow up for disease recurrence or development of hypothyroidism and need prompt treatment if diagnosed with the same. 

Surgery

  1. Thyroidectomy is the most successful form of therapy for diffuse, toxic goiter, with total thyroidectomy being more successful than sub-total with equivalent side effects.
  2. Due to the side effects associated with the use of general anesthesia, recurrent laryngeal nerve palsy, hypothyroidism, etc. it is usually the last line of treatment. 
  3. It is preferred in patients who are unable to tolerate antithyroid medications or RAI, or in patients with compressive symptoms.[13]

Differential Diagnosis

Although diagnosed with the various forms of evaluation, as mentioned above, the differential diagnosis of diffuse, toxic goiter include:

  • Thyrotoxicosis factitia- over prescription/consumption of thyroid hormones
  • Subacute thyroiditis
  • Multinodular goiter
  • TSH secreting pituitary adenoma
  • Iatrogenic iodine supplementation

Prognosis

Patients with diffuse toxic goiter, especially due to Graves disease, are expected to become hypothyroid during the natural course of their disease regardless of treatment. Prolonged thyrotoxicosis may cause ventricular thickening and, therefore, an increased risk of cardiac mortality.

Treatment with RAI is done with the aim of permanent hypothyroidism, thus making the patient dependant on life long thyroid hormone supplementation. ATDs have an average remission rate of 50% but an excellent prognosis after 4 years, devoid of relapse.[14]

Complications

  • Hyperthyroidism, or thyroid storm due to prolonged untreated excess of thyroid hormone
  • Dermatopathy, associated with Graves disease
  • Graves ophthalmopathy

Deterrence and Patient Education

Diffuse, toxic goiter may present with the usual hypermetabolic(ex. heat intolerance, sweating, weight loss, etc.) and adrenergic symptoms(ex. palpitations, tremors, emotional lability, etc.) of hyperthyroidism, along with the swelling of the goiter. But elderly patients may not present with adrenergic symptoms, rather with apathy, atrial fibrillation, etc. which might also be presentations for depression, malignancy, or cardiac abnormalities. 

Enhancing Healthcare Team Outcomes

Diagnosing diffuse, toxic goiter is an amalgamation of clinical signs and investigations. Evaluating radiological and blood investigations are important to reach a conclusion to the underlying cause of the disease. Once diagnosed, it is the physician's responsibility to help the patient pick the best treatment option based on their profile, and with a thorough understanding of potential side effects. Women need to be especially careful and well informed as being pregnant or breastfeeding requires them to change their form of therapy if contraindicated. Since this condition can also lead to cosmetic concerns (ex. bulging eyes,etc.) physicians, need to be sensitive and perceptive to them and counsel patients about treatment options available, along with having a realistic approach to the treatment response.



(Click Image to Enlarge)
toxic nodular goiter
toxic nodular goiter
Image courtesy S Bhimji MD

(Click Image to Enlarge)
goiter in a female
goiter in a female
Image courtesy S Bhimji MD

References

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[3] Knobel M, Etiopathology, clinical features, and treatment of diffuse and multinodular nontoxic goiters. Journal of endocrinological investigation. 2016 Apr;     [PubMed PMID: 26392367]
[4] Dong BJ, How medications affect thyroid function. The Western journal of medicine. 2000 Feb;     [PubMed PMID: 10693372]
[5] Jereczek-Fossa BA,Alterio D,Jassem J,Gibelli B,Tradati N,Orecchia R, Radiotherapy-induced thyroid disorders. Cancer treatment reviews. 2004 Jun;     [PubMed PMID: 15145511]
[6] Prabhakar BS,Bahn RS,Smith TJ, Current perspective on the pathogenesis of Graves' disease and ophthalmopathy. Endocrine reviews. 2003 Dec;     [PubMed PMID: 14671007]
[7] LiVolsi VA,Baloch ZW, The Pathology of Hyperthyroidism. Frontiers in endocrinology. 2018;     [PubMed PMID: 30559722]
[8] Oertli D,Harder F,Oberholzer M,Staub JJ, [Hyperthyroidism and thyroid carcinoma--coincidence or association?]. Schweizerische medizinische Wochenschrift. 1998 Nov 28;     [PubMed PMID: 9879620]
[9] De Leo S,Lee SY,Braverman LE, Hyperthyroidism. Lancet (London, England). 2016 Aug 27;     [PubMed PMID: 27038492]
[10] Baskin HJ,Cobin RH,Duick DS,Gharib H,Guttler RB,Kaplan MM,Segal RL, American Association of Clinical Endocrinologists medical guidelines for clinical practice for the evaluation and treatment of hyperthyroidism and hypothyroidism. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2002 Nov-Dec;     [PubMed PMID: 15260011]
[11] Allannic H,Fauchet R,Orgiazzi J,Madec AM,Genetet B,Lorcy Y,Le Guerrier AM,Delambre C,Derennes V, Antithyroid drugs and Graves' disease: a prospective randomized evaluation of the efficacy of treatment duration. The Journal of clinical endocrinology and metabolism. 1990 Mar;     [PubMed PMID: 1689737]
[12] Abraham P,Avenell A,McGeoch SC,Clark LF,Bevan JS, Antithyroid drug regimen for treating Graves' hyperthyroidism. The Cochrane database of systematic reviews. 2010 Jan 20;     [PubMed PMID: 20091544]
[13] Girgis CM,Champion BL,Wall JR, Current concepts in graves' disease. Therapeutic advances in endocrinology and metabolism. 2011 Jun     [PubMed PMID: 23148179]
[14] Wiersinga WM, Graves' Disease: Can It Be Cured? Endocrinology and metabolism (Seoul, Korea). 2019 Mar     [PubMed PMID: 30912336]