Toxic multinodular goiter overview

# Overview
In 1913, Henry Plummer, an American physician was the first to describe toxic multinodular goiter or Plummer's disease. In 1947, Cope, Rawson, and McArthur were the first who described the usage of radioactive iodine to demonstrate a "hot" thyroid nodule.Toxic multinodular goiter is classified into three types- Primary, secondary, tertiary hyperthyroidism.The progression to Toxic multinodular goiter usually involves the somatic gain-of-function mutations in the TSH receptor in autonomousl, toxic adenoma.The incidence of toxic multinodular goiter is estimated to be 4.8 cases per 100,000 population per year. The prevalence of toxic multinodular goiter is 100 cases per 100,000 population and accounts for 5% of all patients with hyperthyroidism. Toxic multinodular goiter commonly affects individuals older than 60 years of age. The frequency of toxic multinodular goiter increases with age. Females are more commonly affected by toxic multinodular goiter than men. Common risk factors in the development of multinodular goiter include female sex,age over 50 years,areas with decreased iodine intake, iodine supplementation, natural goitrogens, vitamin A and iron deficiency,selenium deficiency.Toxic multinodular goiter is diagnosed with a physical examination which shows nodules in the throat and rapid heart rate, among other signs such as diaphoresis and tremors. Blood screening includes tests for elevated T3 and T4 hormone levels that indicate hyperthyroidism. TSH assays are the best initial screening tool for hyperthyroidism.If left untreated, toxic multinodular goiter may progress to develop hyperthyroidism. However, the progression of toxic multinodular goiter is quite slow. Untreated patients initially have a history of thyroid enlargement followed by a long period of subclinical hyperthyroidism. Overt hyperthyroidism occurs late in the course of toxic multinodular goiter. Common complications of toxic multinodular goiter include tachycardia, arrhythmia, atrial fibrillation, heart failure (dilated cardiomyopathy), pulmonary hypertension, facial plethora, inspiratory stridor, hoarseness, dysphagia, bone mineral loss and thyroid storm. Prognosis of toxic multinodular goiter is generally good with treatment. Both surgery and radioactive iodine therapy can confer a moderate long-term risk of hypothyroidism and such patients require lifelong hormone replacement therapy. Toxic multinodular goiter is commonly seen in elderly. The majority of patients with toxic multinodular goiter are asymptomatic. However, they can present with symptoms such as swelling or pain in front of the neck, cough, shortness of breath, hoarseness, Diaphoresis, skin flushing, increased appetite, restlessness, nervousness, ], tremors, palpitations, insomnia, anxiety, menstrual irregularities. Diagnosis of multinodular goiter is made by measurement of serum thyroid-stimulating hormone (TSH) , serum Free T4 test , total thyroxine (T4) and free triiodothyronine (T3).An ECG may be helpful in the diagnosis of hyperthyroidism due to toxic multinodular goiter. Findings on an ECG suggestive of hyperthyroidism due to include sinus tachycardia, higher voltage of P and T waves, elevated amplitude of QRS complex, prolonged P-Q and shortened Q-T intervals. Findings on an x-ray suggestive of multinodular goiter include anterior/superior mediastinal mass, that may be associated with deviation of the trachea and/or cervicothoracic sign.CT scan may be helpful in the diagnosis and fully characterizing the extent of substernal goitre. Findings on CT scan suggestive of multinodular goiter include enlarged and heterogeneous thyroid gland. CT scan is useful in defining the extent of tracheal deviation and compression.CT scanguided fine needle aspiration biopsy(FNAB) may be helpful. MRI may be helpful in the assessment of extent of substernal goiters. Findings on MRI suggestive of multinodular goiter include enlarged and heterogeneous thyroid gland. Thyroid ultrasonography is the imaging method of choice in the diagnosis of multinodular goiter. Findings on an ultrasonography suggestive of multinodular goiter include more than one nodule including the non-palpable nodules cysts with varying echogenicity. Thyroid ultrasonography helps in assessment of size and number of nodules. Assessment of vascular characteristics of a thyroid nodule with Doppler helps in screening thyroid nodules for malignancy. Radioidodine uptake may be helpful in the diagnosis of multinodular goiter. The mainstay of treatment for Toxic multinodular goiter is Surgery. Patients with symptomatic hyperthyroidism, sub-clinical hyperthyroid patients with expected compilations and patients refusing surgical therapy are treated with beta blockers and anti-thyroid pharmacological groups. Surgery is the mainstay of treatment for Toxic multinodular goiter. Usually, subtotal thyroidectomy is performed but unilateral thyroid lobectomy can also be performed in selected cases. Effective measures for the primary prevention of toxic multinodular goiter include mainly the adequate iodine intake, smoking cessation and also by maintaining normal intake of iron and vitamin A.

# Historical Perspective
In the year 40 BC, Pliny, Vitruvius, and Juvenal were the first who documented the prevalence of goiter in the Alps. In 1500, Leonardo da Vinci was the first who recognized and drew the thyroid gland.  In 1913, Henry Plummer, an American physician was the first to describe toxic multinodular goiter also known as Plummer's disease. In 1947, Cope, Rawson, and McArthur were the first who described the usage of radioactive iodine to demonstrate a "hot" thyroid nodule.

# Classification
Toxic multinodular goiter is classified into three types namely primary, secondary and tertiary hyperthyroidism. Primary hyperthyroidism is further divided into graves disease, toxic thyroid nodule, thyroid adenoma, multinodular goiter. Secondary hyperthyroidism is divided into pituitary adenoma, intracranial tumors pressing pituitary gland. Tertiary hyperthyroidism is divided into intracranial tumors or masses involving hypothalamus.

# Pathophysiology
The progression to toxic multinodular goiter usually involves the somatic gain-of-function mutations in the TSH receptor in autonomously functioning thyroid nodules.

# Causes
The progression to Toxic multinodular goiter usually involves the somatic gain-of-function mutations in the TSH receptor gene.

# Differentiating Toxic multinodular goiter from Other Diseases
Toxic multinodular goiter may be differentiated from other thyroid disorders. The most common differentials include grave's disease, thyrotoxic phase of subacute thyroiditis and toxic adenoma.

# Epidemiology and Demographics
The incidence of toxic multinodular goiter is estimated to be 4.8 cases per 100,000 population per year. The prevalence of toxic multinodular goiter is 100 cases per 100,000 population and accounts for 5% of all patients with hyperthyroidism. Toxic multinodular goiter commonly affects individuals older than 60 years of age. The frequency of toxic multinodular goiter increases with age. Females are more commonly affected by toxic multinodular goiter than men.

# Risk Factors
Common risk factors in the development of multinodular goiter include female sex,age over 50 years,areas with decreased iodine intake,iodine supplementation, natural goitrogens, vitamin A deficiency, iron deficiency and selenium deficiency.

# Screening
Toxic multinodular goiter is diagnosed by a physical examination which reveals nodules in the throat, rapid heart rate, diaphoresis, and tremors. Screening includes testing for elevated T3 and T4 hormone levels that indicate hyperthyroidism. TSH assays are the best initial screening tool for hyperthyroidism.

# Natural History, Complications, and Prognosis
If left untreated, toxic multinodular goiter may progress to develop hyperthyroidism. However, the progression of toxic multinodular goiter is quite slow. Untreated patients initially have a history of thyroid enlargement followed by a long period of subclinical hyperthyroidism. Overt hyperthyroidism occurs late in the course of  toxic multinodular goiter. Common complications of toxic multinodular goiter include tachycardia, arrhythmia, atrial fibrillation, heart failure (dilated cardiomyopathy), pulmonary hypertension, facial plethora, inspiratory stridor, hoarseness, dysphagia, bone mineral loss and thyroid storm. Prognosis of toxic multinodular goiter is generally good with treatment. Both surgery and radioactive iodine therapy can confer a moderate long-term risk of hypothyroidism and such patients require lifelong hormone replacement therapy. Toxic multinodular goiter is commonly seen in elderly. Therefore, in elderly, presence of other conditions may influence the outcome of toxic multinodular goiter.

# Diagnosis

## History and Symptoms
The majority of patients with toxic multinodular goiter are asymptomatic. However, they can present with symptoms such as swelling or pain in front of the neck, cough, shortness of breath, hoarseness, diaphoresis, skin flushing, increased appetite, restlessness, nervousness, heat intolerance, tremors, palpitations, insomnia, anxiety, menstrual irregularities.

## Physical Examination
The clinical features of toxic multinodular hyperthyroidism includes flushing,diaphoresis, smooth skin, onycholysis, hyperpigmentation, thinning of the hair, thyromegaly,lymphadenopathy, lid lag, shortness of breath on exertion, hypoxemia, hypercapnia, tachycardia, atrial fibrillation, weight loss, increased appetite anorexia, dysphagia, increased urinary frequency, enuresis, gynecomastia, reduced libido, erectile dysfunction, psychosis, agitation, and depression,anxiety, restlessness, irritability, and emotional lability, insomnia, confusion, poor orientation and immediate recall, amnesia, and constructional difficulties, peripheral neuropathy, carpal tunnel syndrome, tremors, myopathy, muscle weakness, proximal and distal weakness, deep tendon reflexes are usually normal or increased, osteoporosis and an increased fracture probability.

## Laboratory Findings
Diagnosis of multinodular goiter is made by measurement of serum thyroid-stimulating hormone (TSH) , serum Free T4 test , total thyroxine (T4) and free triiodothyronine (T3).

## Electrocardiogram
An ECG may be helpful in the diagnosis of hyperthyroidism due to toxic multinodular goiter. Findings on an ECG suggestive of hyperthyroidism due to toxic multinodular goiter include sinus tachycardia, higher voltage of P and T waves, elevated amplitude of QRS complex, prolonged P-Q and shortened Q-T intervals.

## X-ray
An x-ray may be helpful in the diagnosis of multinodular goiter. Findings on an x-ray suggestive of multinodular goiter include anterior/superior mediastinal mass, that may be associated with deviation of the trachea and/or cervicothoracic sign.

## CT scan
CT scan may be helpful in the diagnosis and fully characterizing the extent of substernal goitre. Findings on CT scan suggestive of multinodular goiter include enlarged and heterogeneous thyroid gland.CT scan is useful in defining the extent of tracheal deviation and compression.CT scanguided fine needle aspiration biopsy(FNAB) may be helpful.

## MRI
MRI is not routinely performed for the diagnosis of multinodular goiter. MRI can help in the assessment of extent of substernal goiters.Findings on MRI suggestive of multinodular goiter include enlarged and heterogeneous thyroid gland.

## Ultrasound
Thyroid ultrasonography is the imaging method of choice in the diagnosis of multinodular goiter. Findings on an ultrasonography suggestive of multinodular goiter include more than one nodule including the non-palpable nodules cysts with varying echogenicity. Thyroid ultrasonography helps in assessment of size and number of nodules.Assessment of vascular characteristics of a thyroid nodule with Doppler helps in screening thyroid nodules for malignancy.

## Other Imaging Findings
Radioidodine uptake may be helpful in the diagnosis of multinodular goiter. Patchy pattern of increased radionuclide uptake in more than one nodule associated with decreased uptake in the surrounding extranodular thyroid tissue is characteristic of toxic multinodular goiter.

## Other Diagnostic Studies
The most important diagnostic test to differentiate thyroid nodules from each other is fine needle aspiration (FNA).

# Treatment

## Medical Therapy
The mainstay of treatment for Toxic multinodular goiter is Surgery. Patients with symptomatic hyperthyroidism, sub-clinical hyperthyroid patients with expected compilations and patients refusing surgical therapy are treated with beta blockers and anti-thyroid pharmacological groups.

## Surgery
Surgery is the mainstay of treatment for Toxic multinodular goiter. Almost all multinodular goiters can be surgically removed through a collar incision. Usually, subtotal thyroidectomy is performed but unilateral thyroid lobectomy can also be performed in selected cases.

## Primary Prevention
Effective measures for the primary prevention of toxic multinodular goiter include mainly the adequate iodine intake, smoking cessation and also by maintaining normal intake of iron and vitamin A.

## Secondary Prevention
Surgery is recommended for the secondary prevention of toxic multinodular goiter.