Three treatment options exist for Graves’ disease: antithyroid medications such as methimazole or propylthiouracil, radioactive iodine (RAI) ablation, and surgical thyroidectomy. One randomized clinical trial directly compared these three treatment modalities and concluded that they are all equally effective in eventually achieving a euthyroid state [6], although there are clinical situations when one treatment modality should be considered more or less strongly than the others. For example, RAI is contraindicated during pregnancy. The current published and accepted guidelines for the treatment of hyperthyroidism stress the importance of active discussion between patients and their providers before deciding on a treatment plan [7]. Those discussions should include details about the speed of recovery, risks and benefits, side effects and costs of each treatment, as well as discussions about certain clinical scenarios where one treatment is clearly favored.

Once a diagnosis of Graves’ disease is established through biochemical evidence of hyperthyroidism along with clinical extra-thyroidal manifestations, positive antibodies, or diffuse, or increased thyroid uptake on a radioiodine scan, treatment should be tailored to the individual patient’s clinical situation and his or her personal preferences and goals of therapy. No treatment yet exists that addresses the specific underlying autoimmune condition. Therefore, the goal of treatment for Graves’ disease is to correct the end-organ thyroid dysfunction. With rare exception, at the time of diagnosis, patients should be initiated on an antithyroid medication to restore euthyroidism [7]. This is usually achieved in 6–8 weeks, during which time more information can be gathered to help the patient and provider decide on a more definitive treatment plan. Antithyroid drugs pose long-term toxicities on the bone marrow and liver. For this reason, antithyroid medications cannot serve as a lifelong solution.

If palpable nodules are present on exam of a patient with newly diagnosed Graves’ disease, a formal ultrasound of the thyroid and lateral neck should be performed. Some groups advocate performing thyroid ultrasound in all patients newly diagnosed with Graves’ disease, since the incidence of differentiated thyroid cancer seems to be higher than in the general population [8, 9]. Newer data suggest that only patients with palpable nodules should undergo ultrasound imaging prior to definitive treatment [10], which may be more prudent in the current era where we are starting to recognize the economic effect of overdiagnosing and treating small thyroid cancers [11]. In some surgical practices, all patients referred for thyroid surgery undergo in-office surgeon-performed neck ultrasound for surgical planning, looking at gland size and anatomic position, vascularity, or presence of extra-thyroidal abnormalities that may need to be addressed, and incidental nodules may be found at this time. Whether palpable or incidentally discovered, fine needle aspiration should be performed for nodules according to the updated guidelines for the management of thyroid nodules, particularly if it will change management. The newest guidelines recommend biopsy of high or intermediate suspicion nodules based on ultrasound characteristics if the nodule is >1 cm, but for low suspicion waiting until the nodule is >1.5 cm, and very low suspicion nodules should be >2 cm [12]. One should keep in mind that the hyperplasia associated with hyperthyroidism may increase the likelihood for cytologic interpretation as follicular neoplasm or atypia due to the increased cellularity and inflammation.

Patients with Graves’ disease and nodules that are indeterminate or suspicious for thyroid cancer should be referred to an experienced thyroid surgeon for consideration of a total thyroidectomy for treatment of both conditions. Any patient with Graves’ disease and a nodule that is causing compressive symptoms, even if it is biopsy proven to be benign, should also be referred for surgical treatment, as neither antithyroid medications nor RAI will be effective in treating the symptomatic nodule, and RAI may make subsequent surgery more difficult. RAI leads to a fibrotic reaction similar to scar tissue that can increase operative difficulty and complications. Several surgical series have reported an increased incidence of thyroid cancer in Graves’ patients who underwent surgery, but this is most likely due to surgical series biases – more patients with suspicious nodules will be referred for surgery, so there will appear to be an increased incidence of cancer among those who have surgery. A recent series comparing cytology specimens to surgical specimens suggests that this is the case [13].

Regardless of this bias, patients with any suspicion of cancer at the time of diagnosis of nodular Graves’ disease should strongly consider thyroidectomy as their definitive treatment option, and such procedure should be performed by an experienced thyroid surgeon. Although the increased vascularity and inflammation of a Graves’ gland make the operation more challenging, the complication rate remains extremely low when done by high-volume centers [14].

We do not have a good estimate of the number of patients with Graves’ disease and nodules who undergo RAI treatment only to have their nodule turn out to be cancer and require further treatment. One study performed over 30 years ago reported on 11 patients who had previously undergone RAI for hyperthyroidism and then subsequently presented with thyroid cancer [15]. All of these 11 patients had their cancer diagnosis made more than 1 year after RAI, but there was no way of knowing whether the cancer was present prior to or as a result of the treatment. They did not report an increased number of surgical complications when operating on these patients with previous RAI therapy, though surgeons may find operating on a previously irradiated thyroid gland to be challenging due to the increased fibrosis and scarring as mentioned earlier. In the modern era where many patients undergo thyroid ultrasound or other imaging, we may be better at selecting patients with Graves’ disease and nodules who may be better suited for surgery over the other treatment options.

Historically, surgeons would perform subtotal thyroidectomy for Graves’ disease, with the goal of leaving enough thyroid tissue behind to render the patient euthyroid. Such approach is associated with unacceptably high recurrence risks and potentially more dangerous repeat surgery. Surgery for Graves’ disease today consists of a total thyroidectomy followed by lifelong levothyroxine administration [16, 17]. One recent meta-analysis of 3,242 patients found that subtotal thyroidectomy was associated with a tenfold higher risk of recurrence, although subtotal thyroidectomy did have lower rates of postoperative hypoparathyroidism [18]. Because Graves’ disease itself plays a role in a patient’s metabolism of calcium, even temporary hypoparathyroidism is not an insignificant complication, sometimes manifesting in very low calcium levels causing severe symptoms. One recent study suggests that pretreatment with calcium carbonate can decrease these symptoms in the postoperative period for patients with Graves’ disease [19], and this low-cost intervention may be something that surgeons should consider adding to their regimen for preparing patients for the operating room.

The treatment for thyroid cancer is also total thyroidectomy, so any patient with suspicious nodules and Graves’ disease is well suited to this treatment modality. With any suspicious nodule, a preoperative ultrasound including an examination of the lateral compartment lymph nodes should be performed [20], and this recommendation holds true for patients with Graves’ disease and nodules. Any abnormal appearing lymph nodes that are amenable to FNA biopsy should be sampled prior to surgery to determine the extent of surgery. The first surgical procedure is always the best time to do a complete nodal basin dissection, and the underlying diagnosis of Graves’ disease should not distract a surgeon from doing a thorough workup of coexisting nodules.

The technical aspects of thyroidectomy for Graves’ disease are no different than thyroidectomy for other indications, but the vascularity and friability of the gland can make it challenging [21]. Adding large or adherent nodules to an already challenging operation can increase the complexity. It is important that a surgeon remember a few important pearls when operating on patients with Graves’ disease in an attempt to reduce both surgical complications and recurrence rates. The surgeon and anesthesiologist must communicate frequently regarding the possibility and manifestations of thyroid storm (such as tachycardia or fever) and be able to appropriately manage this condition should it occur. It is best to have medications immediately available (beta-blockers – specifically esmolol due to its rapid onset and steroids) in case they are needed, but thoughtful preoperative preparation is the best way to prevent this. In any patient with hyperthyroidism or suspicious nodules, a surgeon must be vigilant about the presence of a pyramidal lobe and to entirely resect it to reduce recurrence risk. Finally, the inflammation of the gland and the possible presence of reactive lymph nodes can make parathyroids difficult to identify, and they can be densely adherent to the thyroid gland. The large surface vessels and overall vascularity of a Graves’ thyroid gland may make it additionally challenging to identify and preserve the blood supply to the parathyroid glands. A close capsular dissection is important to preserve the parathyroid glands. After the thyroid gland has been removed, the surgeon should carefully examine it to be sure that no parathyroid glands were inadvertently removed with the specimen. This is a step many surgeons may forget, particularly if the dissection was difficult and lengthy, but this step may prove critical in preventing long-term hypocalcemia. If a parathyroid gland is seen on the specimen or its blood supply is compromised, then the parathyroid gland should be placed in cold saline and autotransplanted at the end of the case. One recent study found that parathyroid tissue identified by the pathologist was associated with a higher incidence of temporary and permanent hypoparathyroidism [22].