Toxic Adenoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

A toxic adenoma is a benign tumor consisting of thyroid follicular cells, which produce excessive amounts of T3 and/or T4. In toxic adenoma, the excessive thyroid hormone autonomously produced can suppress the function of remaining thyroid tissue. Thus thyroid hormone production is no longer controlled by the hypothalamic-hypophyseal-thyroid axis, leading to thyroid hormone excess and the resulting clinical symptoms, signs, and potential complications. The most common cause of toxic adenoma is iodine deficiency. Alteration of the thyroid stimulation pathways by activation of germline or somatic mutations in the TSH receptor or cAMP signal transduction system is believed to be responsible for the development of autonomous thyroid gland growth and hormonogenesis. Patients with toxic adenomas typically present with signs and symptoms of thyrotoxicosis. If left untreated, thyrotoxicosis increases the risks of atrial fibrillation, heart failure, and decreased bone mineral density in postmenopausal women. Measurement of serum TSH is considered as the best initial test in the evaluation of thyroid disorders. The serum free T4 and free or total T3 levels are elevated or in the upper part of the normal range. The mainstay of treatment for most patients with toxic adenoma includes radioiodine, anti thyroid drugs.

In 1840, Adolph von Basedow from Germany was the first to coin the term toxic adenoma. In 1913, Henry Plummer was the first to give a detailed description of toxic adenoma.

Toxic Adenoma can be classified into asymptomatic and symptomatic toxic adenoma based upon the existence of symptoms.

Thyroid-stimulating hormone (TSH) binds to its receptor on the surface of thyroid follicular cells. When TSH binds to the TSH receptor, it stimulates adenylyl cyclase conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Activation of cyclic adenosine monophosphate (cAMP) results in thyroid hormone secretion. When TSH concentrations are five- to tenfold higher, TSH binding to its receptor leads to its interaction with Gq, activating phospholipase C, which in turn leads to increased intracellular calcium, diacylglycerol, and inositol phosphate. Activation of this pathway regulates iodination and thyroid hormone production. Alteration of the above pathway by activation of germline or somatic mutations in the TSH receptor or cAMP signal transduction system is believed to be responsible for the development of autonomous thyroid gland growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include somatic gain-of-function mutations in the TSH receptor or the stimulatory Gsα subunit. Both result in constitutive activation of the cAMP pathway, which results in enhanced proliferation and function of thyroid follicular cells.

The most common cause of toxic adenoma is iodine deficiency. Other causes include gene mutations of TSH receptor.

Toxic adenoma must be differentiated from other hyperthyroid diseases that cause anxiety, elevated blood pressure and insomnia such as essential hypertension, generalized anxiety disorder, and pheochromocytoma.

The prevalence rates of toxic adenoma is 5-7% and 1-2% of all hyperthyroid cases in women and men respectively. Toxic adenoma is more commonly seen in patients over 60 years. Similar to any thyroid disease females are more commonly affected by toxic adenoma than males. The female-to-male ratio is 5.9:1 for toxic adenoma.

Common risk factors in the development of toxic adenoma include iodine deficiency, young adult age, head and neck irradiation, family history of thyroid nodules, and female gender.

If left untreated, some of the patients with toxic adenoma may progress to develop thyrotoxicosis which increases the risks of atrial fibrillation, heart failure, and decreased bone mineral density in postmenopausal women. Common complications of toxic adenoma include atrial fibrillation, neck compression, bone mineral loss, thyroid storm, I-131-related hypothyroidism. Prognosis of toxic adenoma is generally good with treatment. About 45% to 75% of patients stay euthyroid following I-131 therapy.

Patients with toxic adenomas typically present with signs and symptoms of thyrotoxicosis. Common symptoms include fatigue, unintentional weight loss, heat intolerance, diaphoresis, palpitations, anxiety, and nervousness. Specific areas of focus when obtaining a history from the patient of toxic adenoma include the possibility of recent iodide exposure in any form that can provoke transient thyrotoxicosis in a pre-existing toxic nodule such as medication (e.g., amiodarone), radiocontrast dye, dietary supplements.

Patients with toxic adenoma usually appear fatigued and nervous. Physical examination of patients with toxic adenoma is usually remarkable for widened, palpebral fissures, tachycardia, hyperkinesis, moist, smooth skin, tremor, proximal muscle weakness, and brisk deep tendon reflexes.

Measurement of serum TSH is considered as the best initial test in the evaluation of thyroid disorders. The serum free T4 and free or total T3 levels are elevated or in the upper part of the normal range. Findings of routine laboratory tests include elevated serum calcium, elevated alkaline phosphatase, elevated ferritin levels, low (LDL) cholesterol levels.

Electrocardiogram findings of toxic adenoma are mainly due to thyrotoxicosis. Common ECG changes seen with thyrotoxicosis are sinus tachycardia and atrial fibrillation with rapid ventricular response.

There are no x-ray findings associated with toxic adenoma.

Ultrasound is indicated only when adenoma presents as a nonpalpable nodule. Ultrasonography is helpful when correlated with nuclear scans to determine the functionality of nodules. Dominant cold nodules should be considered for fine-needle aspiration biopsy prior to definitive treatment of a TNG.

There are no CT findings associated with toxic adenoma.

There are no MRI findings associated with toxic adenoma.

Radionuclide imaging and quantitative radioisotopic uptake studies are always required to establish the diagnosis of toxic adenoma or toxic nodular goiter. Radionuclide imaging can be performed with radioactive iodine-123 or with technetium-99m. In patients with hyperthyroidism caused by a toxic adenoma, there is a characteristic restriction of radionuclide uptake to the responsible hyperfunctioning nodule with suppression of radionuclide uptake in the remainder of the gland.

There are no other diagnostic findings associated with toxic adenoma.

The mainstay of treatment for most patients with toxic adenoma includes radioiodine, anti thyroid drugs. In patients with overt thyrotoxicosis, beta blocker will alleviate the signs and symptoms mediated by the increased beta-adrenergic activity. Alternative treatment modalities include percutaneous ethanol injection, thermoablation, or radiofrequency ablation. Antithyroid drugs are not routinely employed in the management of toxic adenoma.

Subtotal thyroidectomy is the treatment of choice for patients that decline or are resistant to radioactive iodine. Subtotal thyroidectomy is an effective and prompt treatment for patients with toxic nodular goiter. Reduction of thyroid function is immediate, although recurrent hyperthyroidism or subsequent hypothyroidism is possible. Complications include rare recurrent laryngeal nerve damage and hypoparathyroidism.

There are no established measures for the primary prevention of toxic adenoma.

There are no established measures for the secondary prevention of toxic adenoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

In 1840, Adolph von Basedow from Germany was the first to coin the term toxic adenoma. In 1913, Henry Plummer was the first to give a detailed description of toxic adenoma.

• In 1840, Adolph von Basedow from Germany was the first to coin the term toxic adenoma.^[1]
• In 1913, Henry Plummer was the first to give a detailed description of toxic adenoma.

​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Toxic adenoma can be classified into asymptomatic and symptomatic toxic adenoma based upon the existence of symptoms.

Toxic adenoma can be classified into asymptomatic and symptomatic toxic adenoma based upon the existence of symptoms.^[1]

• About 40% of the times toxic adenoma presents a painless nodule without any symptoms.

• Toxic adenoma presents with signs and symptoms of hyperthyroidism.
• Also, can produce mass effects depending upon the size and anatomical location of the nodule in the thyroid.

​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Thyroid-stimulating hormone (TSH) binds to its receptor on the surface of thyroid follicular cells. When TSH binds to the TSH receptor, it stimulates adenylyl cyclase conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Activation of cyclic adenosine monophosphate (cAMP) results in thyroid hormone secretion. When TSH concentrations are five- to tenfold higher, TSH binding to its receptor leads to its interaction with Gq, activating phospholipase C, which in turn leads to increased intracellular calcium, diacylglycerol, and inositol phosphate. Activation of this pathway regulates iodination and thyroid hormone production. Alteration of the above pathway by activation of germline or somatic mutations in the TSH receptor or cAMP signal transduction system is believed to be responsible for the development of autonomous thyroid gland growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include somatic gain-of-function mutations in the TSH receptor or the stimulatory Gsα subunit. Both result in constitutive activation of the cAMP pathway, which results in enhanced proliferation and function of thyroid follicular cells.

Thyroid-stimulating hormone (TSH) binds to its receptor on the surface of thyroid follicular cells. When TSH binds to the TSH receptor, it stimulates adenylyl cyclase conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP). Activation of this pathway leads to cell growth and thyroid hormone secretion. When TSH concentrations are five- to tenfold higher, TSH binding to its receptor leads to its interaction with Gq, activating phospholipase C, which in turn leads to increased intracellular calcium, diacylglycerol, and inositol phosphate. Activation of this pathway regulates iodination and thyroid hormone production. Alteration of the above pathway by activation of germline or somatic mutations in the TSH receptor or cAMP signal transduction system is believed to be responsible for the development of autonomous thyroid gland growth and hormonogenesis. The molecular alterations responsible for toxic adenomas include somatic gain-of-function mutations in the TSH receptor or the stimulatory Gsα subunit. Both result in constitutive activation of the cAMP pathway, which results in enhanced proliferation and function of thyroid follicular cells.^{[1][2][3][4][5]}

• Toxic adenomas represent a clone of proliferating follicular epithelial cells that grow and produce thyroid hormone autonomously.
• The first mutations identified in toxic adenomas were somatic activating point mutations in Gs alpha, which were identified after similar mutations were found in pituitary somatotroph adenomas.^[6][7]
• Mutations located at arginine 201 and glutamine 227 lead to constitutive activation of the G protein, with consequent stimulation of the cAMP signaling cascade.
• Gain-of-function mutations in Gsα impair the hydrolysis of guanine triphosphate (GTP) to guanine diphosphate (GDP), resulting in persistent activation of adenylyl cyclase.
• Mosaicism for Gsα mutations with onset during blastocyst development causes McCune-Albright syndrome, which can also be associated with toxic adenomas in which there is a sporadic activating mutation in arginine 201.^[8]
• In addition to thyrotoxicosis, which occurs in 33% of these patients, constitutive activation of the cAMP cascade in other tissues can cause polyostotic fibrous dysplasia (98%), cafe-au-lait skin hyperpigmentation (85%), and other endocrine gland hyperfunction, including gonadotropin-independent precocious puberty (62%), acromegaly (27%), and adrenocortical hyperfunction (6%).

• Somatic mutations in the TSH receptor in toxic adenomas were among the first discovered naturally occurring G protein–coupled receptor (GPCR) mutations.^[9]
• Somatic activating thyroid-stimulating hormone receptor mutations increase basal cAMP levels, and also activate the phospholipase C cascade in a constitutive manner.
• The prevalence of TSH receptor mutations in toxic adenomas varies widely from 8% to 80%.
• Somatic activating TSH receptor mutations are more commonly responsible in the pathogenesis of toxic adenoma than Gsα mutations.

• Germline mutations that activate the TSH receptor are rare.^[10]
• Germline mutations are more commonly associated with diffuse gland involvement and present with more severe thyrotoxicosis.
• Affected individuals develop a toxic multinodular goiter that can have its onset from infancy to adult.
• Transmission is usually autosomal dominant.^[11]

Growth factors play an important role in the pathogenesis of toxic adenoma of thyroid. The following table summarizes the role of growth factors in the pathogenesis of toxic adenoma.^{[12][13][14][15][16][17][18][19][20]}

Growth Factors (GF)	Role of Growth Factors on TSH[21]
Transforming GF-β1	Counteracts the stimulatory roles of TSH and other growth factors Blocks uptake and organification of iodine Inhibits thyroglobulin expression, and thyroid follicular cell proliferation
Insulin-like GF-1	Works synergistically with TSH in thyroid growth
Insulin-like GF–Binding proteins	Binds to IGF-1 and control its availability by stimulating IGF-I action Mechanisms of their stimulatory effects include Enhancing IGF-1 binding to its receptor and prolonging its intracellular half-life. Insulin and epidermal growth factor (EGF) increase the productions of binding proteins
Fibroblast GF and their receptors	Fibroblasts with the help of proteases become active mitogens Control TSH production similar to that of IGF BPs and IGF-1
Vascular endothelial growth factor (VEGF)	VEGF stimulates growth of blood vessels supplying thyroid follicular cells Production of VEGF receptors on endothelial cells, but not follicular cells, is stimulated by TSH VEGF then activates the VEGF receptors on endothelial cells in a paracrine fashion Responsible for thyroid cell proliferation and hypervascularity Iodide can inhibit TSH-induced expression of the angiogenic factors
Atrial natriuretic peptide	ANP decreases the production of VEGF  Mutation in ANP producing results uncontrolled VEGF production Finally TSH and hyperplasia of thyroid

• On macroscopic examination, a solitary toxic nodule is red and surrounded by normal thyroid tissue that is functionally suppressed and is pale in color.

On histological examination, toxic adenomas demonstrate following findings:

• Uniform hypertrophy and hyperplasia of the acinar cells.
• Some papillary infolding
• Nodules can be encapsulated follicular neoplasms or adenomatous nodules without a capsule.^[22]
• Hemorrhage, calcifications, and cystic degeneration can also be demonstrated.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

The most common cause of toxic adenoma is iodine deficiency. Other causes include gene mutations of TSH receptor.

The most common cause of toxic adenoma is iodine deficiency. Other causes include gene mutations of TSH receptor.^[1]

​​

[[Image:Home_logo1.png|right|250px|link=https://www.wikidoc.org/index.php/Toxic_Adenoma] Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Toxic adenoma must be differentiated from other hyperthyroidism diseases that cause anxiety, elevated blood pressure and insomnia such as essential hypertension, generalized anxiety disorder, and pheochromocytoma.

Toxic adenoma must be differentiated from other hyperthyroidism diseases that cause anxiety, elevated blood pressure and insomnia such as essential hypertension, generalized anxiety disorder, and pheochromocytoma.

Cause of thyrotoxicosis	TSH receptor Antibodies	Thyroid US	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves’ disease	+	Hypoechoic pattern	↑	↑	Ophthalmopathy, dermopathy, acropachy
Toxic nodular goiter	–	Multiple nodules	–	Hot nodules at thyroid scan	–
Toxic adenoma	–	Single nodule	–	Hot nodule	–
Subacute thyroiditis	–	Heterogeneous hypoechoic areas	Reduced/absent flow	↓	Neck pain, fever, and elevated inflammatory index
Painless thyroiditis	–	Hypoechoic pattern	Reduced/absent flow	↓	–
Amiodarone induced thyroiditis-Type 1	–	Diffuse or nodular goiter	↓/Normal/↑	↓ but higher than in Type 2	High urinary iodine
Amiodarone induced thyroiditis-Type 2	–	Normal	Absent	↓/absent	High urinary iodine
Central hyperthyroidism	–	Diffuse or nodular goiter	Normal/↑	↑	Inappropriately normal or high TSH
Trophoblastic disease	–	Diffuse or nodular goiter	Normal/↑	↑	–
Factitious thyrotoxicosis	–	Variable	Reduced/absent flow	↓	↓ serum thyroglobulin
Struma ovarii	–	Variable	Reduced/absent flow	↓	Abdominal RAIU

Disease		Findings
Thyroiditis	Direct chemical toxicity with inflammation	Amiodarone, sunitinib, pazopanib, axitinib, and other tyrosine kinase inhibitors may also be associated with a destructive thyroiditis.[1][2]
	Radiation thyroiditis	Patients treated with radioiodine may develop thyroid pain and tenderness 5 to 10 days later, due to radiation-induced injury and necrosis of thyroid follicular cells and associated inflammation.
	Drugs that interfere with the immune system	Interferon-alfa is a well-known cause of thyroid abnormality. It mostly leads to the development of de novo antithyroid antibodies.[3]
	Lithium	Patients treated with lithium are at a high risk of developing painless thyroiditis and Graves’ disease.
	Palpation thyroiditis	Manipulation of the thyroid gland during thyroid biopsy or neck surgery and vigorous palpation during the physical examination may cause transient hyperthyroidism.
Exogenous and ectopic hyperthyroidism	Factitious ingestion of thyroid hormone	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.[4]
	Acute hyperthyroidism from a levothyroxine overdose	The diagnosis is based on the clinical features, laboratory findings, and 24-hour radioiodine uptake.[5]
	Struma ovarii	Functioning thyroid tissue is present in an ovarian neoplasm.
	Functional thyroid cancer metastases	Large bony metastases from widely metastatic follicular thyroid cancer cause symptomatic hyperthyroidism.
Hashitoxicosis		It is an autoimmune thyroid disease that initially presents with hyperthyroidism and a high radioiodine uptake caused by TSH-receptor antibodies similar to Graves’ disease. It is then followed by the development of hypothyroidism due to the infiltration of the thyroid gland with lymphocytes and the resultant autoimmune-mediated destruction of thyroid tissue, similar to chronic lymphocytic thyroiditis.[6]
Toxic adenoma and toxic multinodular goiter		Toxic adenoma and toxic multinodular goiter are results of focal/diffuse hyperplasia of thyroid follicular cells independent of TSH regulation. Findings of single or multiple nodules are seen on physical examination or thyroid scan.[7]
Iodine-induced hyperthyroidism		It is uncommon but can develop after an iodine load, such as administration of contrast agents used for angiography or computed tomography (CT), or iodine-rich drugs such as amiodarone.
Trophoblastic disease and germ cell tumors		Thyroid-stimulating hormone and HCG have a common alpha-subunit and a beta-subunit with considerable homology. As a result, HCG has weak thyroid-stimulating activity and high titer HCG may mimic hyperthyroidism.[8]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

The prevalence rates of toxic adenoma is 5-7% and 1-2% of all hyperthyroidism cases in women and men respectively. Toxic adenoma is more commonly seen in patients over 60 years. Similar to any thyroid disease females are more commonly affected by toxic adenoma than males. The female-to-male ratio is 5.9:1 for toxic adenoma.

• Toxic adenoma prevalence is inversely related to a population’s dietary iodine sufficiency.
• In women and men, the prevalence rate of toxic adenoma is 5-7% and 1-2%, respectively.

• The incidence of toxic adenoma increases with age; the median age at diagnosis is 50 years.^[1]
• Toxic adenoma is more commonly seen in patients over 60 years.

There is no racial predilection to toxic adenoma.

• Similar to any thyroid disease females are more commonly affected by toxic adenoma than males.
• In women and men, the prevalence rate of palpable nodules is 5-7% and 1-2%, respectively.
• The female-to-male ratio is 5.9:1 for toxic adenoma.

​​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Common risk factors in the development of toxic adenoma include iodine deficiency, young adult age, head and neck irradiation, family history of thyroid nodules, and female gender.

Common risk factors in the development of toxic adenoma include:

• Iodine deficiency
• Young adult age^[1][2][3]
• Head and neck irradiation^[4]
• Family history of thyroid nodules^[5][1]
• Female gender

​ ​

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

According to USPSTF, screening for thyroid cancer is not recommended and there is insufficient evidence to recommend routine screening for toxic adenoma.

According to USPSTF, screening for thyroid cancer is not recommended and there is insufficient evidence to recommend routine screening for toxic adenoma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] ; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

If left untreated, some of the patients with toxic adenoma may progress to develop thyrotoxicosis which increases the risks of atrial fibrillation, heart failure, and decreased bone mineral density in postmenopausal women (osteoporosis). Common complications of toxic adenoma include atrial fibrillation, neck compression, bone mineral loss, thyroid storm, I-131-related hypothyroidism. Prognosis of toxic adenoma is generally good with treatment. About 45% to 75% of patients stay euthyroid following I-131 therapy.

• If left untreated, some of the patients with toxic adenoma may progress to develop thyrotoxicosis.^[1][2]
• Nodule size is a strong predictor of whether thyrotoxicosis will develop in solitary adenomas.
• Most autonomously functioning thyroid nodules that become thyrotoxic are larger than 2.5 to 3 cm in diameter.
• Consequences of untreated toxic multinodular goiter are due to hyperthyroidism or thyrotoxicosis which includes increased risks of atrial fibrillation, heart failure, and decreased bone mineral density in postmenopausal women.
• Spontaneous resolution of a toxic adenoma can occur very rarely because of hemorrhage, cystic degeneration, and loss of autonomous function.

Complications of toxic adenoma are mainly due thyrotoxicosis which includes a constellation of symptoms and signs caused by excess circulating and tissue free triiodothyronine (T3 ), free thyroxine (T4 ), or both. These result in hypermetabolism and other excessive tissue-specific thyroid hormone effects. Common complications of toxic adenoma include:^[3]

• Atrial fibrillation
• Heart failure
• Facial plethora
• Inspiratory stridor
• Hoarseness
• Dysphagia
• Bone mineral loss
• Thyroid storm
• I-131-related hypothyroidism
• Surgery-related
  • Hypothyroidism
  • Recurrent laryngeal nerve damage
  • Hypoparathyroidism
• Antithyroid drug-related agranulocytosis

• Prognosis of toxic adenoma is generally good with treatment.
• About 45% to 75% of patients stay euthyroid following I-131 therapy.
• Both surgery and radioactive iodine therapy can confer a moderate long-term risk of hypothyroidism.^[4][5]