Plummer Disease

Etiology

The enlargement of the thyroid gland may be due to a chronic low-grade intermittent stimulus or stimuli, which can be physiologic, pathologic, or a combination of the two. The chronic stimuli lead to diffuse hyperplasia of the gland and can form a nodule or multiple nodules followed by the autonomous activity of the nodules or part of the thyroid gland, independent of pituitary TSH feedback. These processes, in turn, lead to a toxic multinodular goiter. The hypothesis is that toxic multinodular goiter is developed from diffuse goiter, as seen in studies done by Taylor, in which the thyroid glands removed at surgery had initial diffuse lesions that, with time, developed into discrete nodules.[1] Many factors contribute to the development of this disease and are categorized as primary and secondary factors.  

Primary factors consist of functional heterogeneity of normal follicular cells, most probably due to genetic factors and the acquisition of new inheritable qualities by replicating thyroid cells. The incidence of Plummer disease increases when there is a family history of the disease. Multiple gene base substitution mutations occur on exon 10 of chromosome 14q31, leading to Plummer disease. Gender is an important factor, with females being at a higher risk.  

Secondary factors include elevated TSH, smoking, stress, certain drugs, other thyroid-stimulating factors (IGF-1 and others), and endogenous factors (gender). 

Iodine studies support the hypothesis of iodine deficiency, as described by David Marine, but it is considered circumstantial. The low levels of iodine cause hyperplasia of the thyroid gland due to the increased TSH levels, but when the iodine levels become normal, or there is a decreased demand of the gland for iodine, it goes into a resting phase. The alternation between these two phases leads to the development of diffuse hyperplasia, with the possible development of either one nodule or multiple nodules in the form of nontoxic multinodular goiter or even toxic multinodular goiter. Hence this disease is mostly seen later in life. The sequence of events from thyroid nodule to toxic MNG is not always uniform.

Epidemiology

Plummer disease (toxic multinodular goiter) is considered to be the second most common cause of hyperthyroidism (the first being Graves disease). It is more common among females. It is also prevalent in the 50 years and above age group, both in males and females. In comparison to Plummer disease, Graves disease occurs among younger age groups.[2] Thyrotoxicosis occurs in Plummer disease after long-standing goiter, and it peaks in the sixth or seventh decade of life, especially in patients with a family history of toxic multinodular goiter.[3][4]

Pathophysiology

Toxic multinodular goiter emerges from nontoxic multinodular goiter over a long duration. The hallmark of this disease is the presence of true functional autonomy with disordered, structural, and functional heterogeneity. The extent to which thyroid tissue has gained functional autonomy governs the transformation from nontoxic multinodular goiter to toxic multinodular goiter. Somatic point mutations in the TSH receptor (TSHR) gene are substitutions of amino acids that constitutively cause the activation of the TSH receptor in the absence of TSH. TSHR, therefore, appears as going from an off-state to an on-state.[5]

Somatic TSHR gene mutations and G protein mutations have been thought to cause this disease, but we see only about 60% TSHR gene mutations in the nodules and even fewer G protein mutations. Thus, many nodules have an undetermined cause of functional autonomy. Mutations in TSHR genes increase basal (TSH-induced) activation of cAMP, and IP cascades, which keeps TSHR in an inactive unliganded, but thyroid hormone-activated-like state. The hyperactive nodules in Plummer disease have these mutations. 

According to the two-state model, the TSH receptor has three states.[5] These are:

• Closed - inactive
• Opened - unliganded 
• Opened - hormone activated 

Radioiodine studies show localized concentration in one or more discrete nodules with a suppression of the rest of the gland. The thyroid gland in this disease state has areas of hyperfunctioning and hypo-functioning adenomas interspersed between normal suppressed tissue. The inactive tissue takes up iodine in the presence of TSH, indicating that suppression is due to low levels of TSH. If TSH suppression by autonomous nodules is not complete, the non-nodular part of the thyroid gland is not suppressed completely and is faintly or partially visible on thyroid scintigraphy.

Patients with goiter because of iodine deficiency, Graves disease, toxic multinodular goiter, and some thyroid adenomas can experience iodine-induced hyperthyroidism (Jod-Basedow phenomenon) when a patient is made iodine replete whether in the form of iodine supplementation in diet, iodine contrast for imaging, or in the case of amiodarone use.[6] Multinodular goiter can be monoclonal, polyclonal, or a mixture of both.[1]

Histopathology

The gross appearance of MNG is an enlarged thyroid gland with multiple nodules exhibiting fibrosis, dystrophic calcification, and old and new hemorrhage. Microscopically hyperplastic nodules with a discrete fibrous capsule, composed of follicles with papillary hyperplasia and tall columnar cells, are present. The nonfunctioning nodules may appear inactive and have degenerative changes of calcification, fibrosis, and old and new hemorrhage.[7]

In electron microscopic analysis, there is increased production of secretory granules in the epithelial cells of the thyroid follicles in the hyperactive nodules and varied development of general cytoplasmic organelles with the presence of fenestrated capillaries.[8]

History and Physical

The history should focus on age, gender, demographics (geographic area where the patient spent most of his life to determine if the patient is from an endemic goiter area), information of iodine deficiency, medical history (that should include medication use, exposure to head and neck irradiation), history of accidental or work-related radioactivity exposure, symptoms of hyperthyroidism and symptoms of goiter.  

Symptoms caused by the effect of hyperthyroidism are the following:

Common Presentation 

• Heat intolerance 
• Weight loss 
• Tremors 
• Palpitations, tachycardia 
• Increased bowel frequency 
• Menstrual irregularity 
• Sweaty palms, excessive sweating

Less Commonly Presentation

• Symptoms of muscle wasting and proximal myopathies like difficulty in rising from squatting or climbing stairs 
• Atrial fibrillation
• Frequent fractures (due to osteoporosis) 
• Lid lag and stare 
• Decreased libido 
• Enuresis in children 

Presentation Due to Neck Mass 

• Dyspnea 
• Dysphagia 
• Hoarseness of voice 
• Tracheal compression (less common)

Physical exam findings in these patients secondary to the enlarged thyroid gland are multiple soft, smooth, mobile nodules. Findings due to hyperthyroidism are flushing, diaphoresis, thin and moist skin, thinning of hair, stare, lid lag, tremor, irritability, hyperkinesis, nervousness, psychiatric disturbances, normal or exaggerated deep tendon reflexes, and proximal myopathy. 

Patients with Plummer disease have fewer signs and symptoms than those with Graves disease.[2]

Evaluation

Evaluation is done through laboratory studies and imaging studies.  

Laboratory Findings

• Thyroid Function Tests:  TSH levels are suppressed, and T3 and T4 are elevated. 
• Complete Blood Count, Liver Function Tests are required, especially if one plans to start methimazole or PTU (propylthiouracil)
• Antithyroid peroxidase (anti-TPO) and antithyroglobulin antibodies
• Thyroid Stimulating Immunoglobulin

Imaging Studies

• Ultrasonography: Ultrasound is used to determine the number of nodules and their sizes. Color Doppler helps in assessing nodule vascularity.[9]
• Thyroid scintigraphy: It is done by nuclear medicine using radioactive iodine-123 or technetium-99m. Plummer disease has a patchy uptake of radioactive substance.[10] Scans show localized iodine uptake in one or more nodules and decreased uptake in the background of thyroid tissue due to decreased TSH. Background isotope uptake may vary depending on the degree of hyperthyroidism, TSH suppression, and activity of the non-nodular areas. Thyroid scintigraphy is crucial in differentiating Plummer disease from other causes of hyperthyroidism.[11]
• FNAC: Fine needle aspiration cytology is used to exclude malignancy on cold nodules on thyroid scintigraphy. 
• CT and MRI: These investigations give anatomical detail of thyroid enlargement but are not first-line investigations. They are useful in the assessment of retrosternal and recurrent thyroid enlargement.  
• Laryngoscopy: It is used to check the trachea's patency and mobility of vocal cords for medicolegal reasons more than clinical use. It is done or ordered by surgeons to document the presurgery status of vocal cords if surgery is planned.

Treatment / Management

Patients at the stage of subclinical hyperthyroidism can be monitored without intervention and with the recommendation to avoid excessive iodine intake in the form of supplements and medications and avoid iodinated contrast media for radiological studies if possible. Patients with risk factors for atrial fibrillation or with atrial fibrillation, patients with osteoporosis, and women with osteopenia should be treated, even if they have subclinical hyperthyroidism due to toxic multinodular goiter.

Surgery: Surgical treatment is the mainstay therapy for toxic MNG. It provides rapid resolution with low morbidity and mortality.[4][12] A selective strategy is used to avoid remnant nodules and preserve a normal functional remnant. It led to low morbidity and increased recurrence compared to radical resection, which is associated with increased morbidity but less recurrence.[13] Clinical recurrence may occur in some patients after surgery, but it is rare after ten years.[14] Patients are expected to have post-treatment hypothyroidism after surgery.[15] Total, near-total, or subtotal thyroidectomy may be done according to the disease state. Surgical treatment may lead to complications, including: (A1)

• Unilateral or bilateral vocal cord paralysis 
• Hypoparathyroidism  
• Significant post-operative bleeding or infection
• Tracheostomy   

Radioactive iodine ablation (RIA): RIA (sodium iodide-131) is indicated in the treatment of Plummer disease.[16] It has no absolute contraindication except for pregnancy. A single dose is usually required, and recent studies suggest customized dose calculation and not using fixed-dose formula. RAI is a safe and effective treatment but does not entirely resolve the disease, and the results are delayed.[12] There is also an increased risk for the development of secondary cancers because of radioactive iodine treatment.[17] Complications of RAI include: (B2)

• Hypothyroidism 
• Mild thyrotoxic symptoms 
• Exacerbation of congestive cardiac failure and atrial fibrillation  
• Tracheal compression  
• Thyroid storm (rare) 

Antithyroid drugs: Propylthiouracil and methimazole are used in the time period of waiting until RAI is given and for surgery preparation.[17] Propylthiouracil is preferred over methimazole in pregnant patients during the first trimester. Long-term methimazole therapy has been shown to be safe in patients with Plummer disease.[13] Methimazole therapy converts the hot thyroid nodule to hypofunctioning nodule over time, according to studies using scintigrams.[18] (A1)

Ethanol ablation: Percutaneous ethanol ablation is a minimally invasive procedure used to treat hyperfunctioning nodules. It can be performed in the outpatient department. Before careful ultrasound assessment, thyroid scintigraphy and thyroid FNA cytology for cold nodules should rule out malignancy before ethanol injection of hot nodules.[19] Ethanol ablation is favorable for patients who are unfit to undergo surgery. It should be noted that this is not a routine treatment as this must be done weekly for several sessions. This treatment shows good short-term outcomes, but the long-term outcomes are unsatisfactory. (B3)

Other drugs: Cardiovascular effects such as hypertension and tachycardia should be treated with beta-blockers.[17]

Differential Diagnosis

Differential diagnoses include:

• Diffuse toxic goiter (Graves disease)
• Subacute thyroiditis
• Hashimoto's thyroiditis at the Hashitoxicosis stage 
• Nontoxic goiter
• Thyroid nodule 
• Nontoxic (euthyroid) multinodular goiter
• Papillary thyroid carcinoma 
• Riedel thyroiditis  
• Struma ovarii

Prognosis

Some toxic multinodular goiters do not need treatment if they are not causing any symptoms or if the degree of hyperthyroidism is at the subclinical level (normal T4, T3, and low TSH). Symptomatic multinodular goiters need surgical resection or radioactive ablation. Disease recurrence is very low after surgery. Overall, Plummer disease has a good prognosis.

Complications

Plummer disease may lead to a variety of complications, including: 

• Progression of hyperthyroidism with hyperthyroid signs and symptoms. Toxic MNG may cause osteoporosis, bone fractures, tachycardia, arrhythmia, atrial fibrillation, or heart failure.[20] Thyrotoxicosis may exacerbate underlying coronary heart disease by increasing the oxygen demand and may also cause worsening asthma symptoms, COPD, atherosclerotic cardiovascular disease, and congestive heart failure.
• A decrease in bone density, hypercalciuria, hypercalcemia, and accelerated bone loss may occur. Studies show variable results regarding the reversibility of bone changes. Plummer disease also increases the risk of fractures.[21] 
• The thyroid gland in Plummer disease may harbor malignancy. Hyperthyroidism, along with malignancy, has been reported in 1.2% to 13.3% of surgeries for both causes.[22]
• Pain over the thyroid area can occur if there is any hemorrhage, especially in one of the cystic nodules if coincidentally present in a toxic multinodular goiter.
• A thyroid storm may be precipitated by triggering factors like infection or stress, causing the worsening of symptoms, fever, abdominal pain, and decreased mental alertness. The frequency of thyroid storm is lower in toxic multinodular goiter than in Graves disease.
• An increase in the size of the thyroid gland due to Plummer disease may compress the trachea and esophagus, causing dyspnea, voice hoarseness (due to compression of the recurrent laryngeal nerve), dysphagia, tracheomalacia, and asphyxiation.