Toxic Adenoma overview

# Overview
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.

# Historical Perspective
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.

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

# Pathophysiology
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 Gs subunit. Both result in constitutive activation of the cAMP pathway, which results in enhanced proliferation and function of thyroid follicular cells.

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

# Differentiating Toxic adenoma from Other Diseases
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.

# Epidemiology and Demographics
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.

# Risk Factors
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.

# Natural History, Complications, and Prognosis
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.

# Diagnosis

## History and Symptoms
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.

## Physical Examination
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.

## Laboratory Findings
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
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.

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

## Ultrasound
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.

## CT scan
There are no CT findings associated with toxic adenoma.

## MRI
There are no MRI findings associated with toxic adenoma.

## Other Imaging Findings
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.

## Other Diagnostic Studies
There are no other diagnostic findings associated with toxic adenoma.

# Treatment

## Medical Therapy
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.

## Surgery
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.

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

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