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

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).

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]

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

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]

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

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. 

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.