Graves Disease

In Graves disease, B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known thyroid antigens: thyroglobulin, thyroid peroxidase, sodium-iodide symporter and the TSH receptor. However, the TSH receptor itself is the primary autoantigen of Graves disease and is responsible for the manifestation of hyperthyroidism. In this disease, the antibody and cell-mediated thyroid antigen-specific immune responses are well defined. Direct proof of an autoimmune disorder that is mediated by autoantibodies is the development of hyperthyroidism in healthy subjects by transferring TSH-receptor antibodies in serum from patients with Graves disease and the passive transfer of TSH-receptor antibodies to the fetus in pregnant women.

The thyroid gland is under continuous stimulation by circulating autoantibodies against the TSH receptor, and pituitary TSH secretion is suppressed because of the increased production of thyroid hormones. The stimulating activity of TSH-receptor antibodies is found mostly in the immunoglobulin G1 subclass. These thyroid-stimulating antibodies cause release of thyroid hormone and thyroglobulin that is mediated by 3,'5'-cyclic adenosine monophosphate (cyclic AMP), and they also stimulate iodine uptake, protein synthesis, and thyroid gland growth.

The anti-sodium-iodide symporter, antithyroglobulin, and antithyroid peroxidase antibodies appear to have little role in the etiology of hyperthyroidism in Graves disease. However, they are markers of autoimmune disease against the thyroid. Intrathyroidal lymphocytic infiltration is the initial histologic abnormality in persons with autoimmune thyroid disease and can be correlated with the titer of thyroid antibodies. Besides being the source of autoantigens, the thyroid cells express molecules that mediate T cell adhesion and complement regulation (Fas and cytokines) that participate and interact with the immune system. In these patients, the proportion of CD4 lymphocytes is lower in the thyroid than in the peripheral blood. The increased Fas expression in intrathyroidal CD4 T lymphocytes may be the cause of CD4 lymphocyte reduction in these individuals.

Viral infection is an environmental factor linked to Graves disease. The prevalence of enteroviral proteins, the upregulation of human leukocyte antigen (HLA) class I expression, and co-localization with antiviral response proteins such as Stat1, VP1, and PKR all indicate an association between Graves disease and viral infection.[6]  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has also been linked to the development of subacute thyroiditis and Graves disease.[7, 8]

Several autoimmune thyroid disease susceptibility genes are considered to be linked to Graves disease, including CD40, CTLA-4, the thyroglobulin gene (TG), the TSH-receptor gene (TSHR), PTPN22, FOXP3, CD25, and VDR. The RNASET2-FGFR1OP-CCR6 region at 6q27 and an intergenic region at 4p14 have also been associated with the disorder.[9, 10, 11, 12, 13, 13]  Similarly, in a genome-wide association study of more than 1500 patients with Graves disease and 1500 controls, six susceptibility loci were found to be related to the condition: the major histocompatibility complex (MHC), TSHR, CTLA-4, FCRL3, the RNASET2-FGFR1OP-CCR6 region at 6q27, and the intergenic region at 4p14.[14]

A genetic predisposition to thyroid autoimmunity may interact with environmental factors or events to precipitate the onset of Graves disease. Moreover, TSHR and MHC class II variants were found to be strongly associated with persistently TSH receptor autoantibody (TRAb)–positive Graves disease.[15]  In terms of epigenetic regulation, non-coding RNA molecules such as miR-23a-3p and lncRNA MEG3 may participate in the pathophysiology of Graves disease by disrupting Th17/Treg cell balance.[16]

Gut microbiota have been shown to be associated with autoimmune thyroid diseases.[17]  Decreases in Bifidobacterium and Lactobacillus may be linked to such disorders, but microbiome data in Graves disease are still limited.[17, 16]

Graves disease patients have a higher rate of peripheral blood mononuclear cell conversion into CD34+ fibrocytes compared with healthy controls. These cells may contribute to the pathophysiology of ophthalmopathy by accumulating in orbital tissues and producing inflammatory cytokines, including tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6).[18]

The TSH receptor is detectable in orbital tissues, but whether it has a pathogenetic role in Graves ophthalmopathy is unclear. The insulin-like growth factor-1 (IGF1) receptor is overexpressed in orbital fibroblasts, B cells, and T cells of patients with Graves ophthalmopathy, and patients with this eye disorder may have circulating immunoglobulins that bind to IGF1 receptors. Activation of IGF1R will increase hyaluronan synthesis and cytokine release. Using monoclonal antibodies to block IGF1R can reduce the expression levels of TSHR and IGF1R on fibrocytes and antagonize TSH-induced expression of inflammation genes (IL6, IL8, and TNFA).

Pathophysiologic mechanisms are shown in the image below.

Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating immunoglobulins to hyperthyroidism and ophthalmopathy. T4 is levothyroxine. T3 is triiodothyronine.

Frequency

United States

Graves disease is the most common cause of hyperthyroidism in the United States. A study conducted in Olmstead County, Minnesota estimated the incidence to be approximately 30 cases per 100,000 persons per year.[19] The prevalence of maternal thyrotoxicosis is approximately 1 case per 500 persons, with maternal Graves disease being the most common etiology. Commonly, patients have a family history involving a wide spectrum of autoimmune thyroid diseases, such as Graves disease, Hashimoto thyroiditis, or postpartum thyroiditis, among others.

International

Among the causes of spontaneous thyrotoxicosis, Graves disease is the most common. Graves disease represents 60-90% of all causes of thyrotoxicosis in different regions of the world. In the Wickham Study in the United Kingdom, the incidence was reported to be 100-200 cases per 100,000 population per year.[20] The incidence in women in the UK has been reported to be 80 cases 100,000 per year.[21]

Mortality/Morbidity

If left untreated, Graves disease can cause severe thyrotoxicosis. A life-threatening thyrotoxic crisis (ie, thyroid storm) can occur. Long-standing severe thyrotoxicosis leads to severe weight loss with catabolism of bone and muscle.[22] Cardiac complications and psychocognitive complications can cause significant morbidity. Graves disease is also associated with ophthalmopathy, dermopathy, and acropachy.

Thyroid storm is an exaggerated state of thyrotoxicosis.[23] It occurs in patients who have unrecognized or inadequately treated thyrotoxicosis and a superimposed precipitating event such as thyroid surgery, nonthyroidal surgery, infection, or trauma. When thyroid storm was first described, the acute mortality rate was nearly 100%. In current practice, with aggressive therapy and early recognition of the syndrome, the mortality rate is approximately 20%.[24]

Long-term excess of thyroid hormone can lead to osteoporosis in men and women. The effect can be particularly devastating in women, in whom the disease may compound the bone loss secondary to chronic anovulation or menopause. Bone loss is accelerated in patients with hyperthyroidism. The increase in bone loss can be demonstrated by increased urinary pyridinoline cross-link excretion. Serum calcium and phosphate, plasma FGF-23 were significantly higher in the patients with Graves disease than in healthy control subjects, suggesting that FGF-23 is physiologically related to serum phosphate homeostasis in untreated Graves disease.[25]

Hyperthyroidism increases muscular energy expenditure and muscle protein breakdown. These abnormalities may explain the sarcopenia and myopathy observed in patients with hyperthyroid Graves disease.

Cardiac hypertrophy has been reported in thyrotoxicosis of different etiologies. Rhythm disturbances such as extrasystolic arrhythmia, atrial fibrillation, and flutter are common. Cardiomyopathy and congestive heart failure can occur.[26]

Psychiatric manifestations such as mood and anxiety disorders are common.[27] Subjective cognitive dysfunction is often reported by Graves disease patients and may be due to affective and somatic manifestations of thyrotoxicosis, which remit after treatment of Graves thyrotoxicosis.[28]

A study by Folkestad et al reported Graves disease and toxic nodular goiter to be a risk factors for dementia. The investigators found that every 6 months of reduced TSH was linked to a 16% rise in dementia risk in hyperthyroid individuals.[29]

Nonpitting edema is the most prevalent form of dermopathy (about 40%) and are primarily in the pretibial area. The nearly all (>95%) patients with dermopathy had ophthalmopathy.[30] Advanced forms of dermopathy are elephantiasis or thyroid acropachy. Severe acropachy can be disabling and can lead to total loss of hand function.

Progression of ophthalmopathy can lead to compromised vision and blindness. Visual loss due to corneal lesions or optic nerve compression can be seen in severe Graves ophthalmopathy.

In a study of 1128 patients with Graves ophthalmopathy, Kim et al found the prevalence of ocular hypertension (OHT) to be 6.8% and the prevalence of open-angle glaucoma (OAG) to be 1.6%. The prevalences were higher in patients over age 40 years, being 9.5% and 3.4%, respectively. The investigators also reported the prevalence of OHT in Graves ophthalmopathy to be associated with male sex, duration of the ophthalmopathy, a clinical activity score of 3 or above, extraocular muscle involvement, and lid retraction. Male sex and duration of the ophthalmopathy were associated with the prevalence of OAG in Graves ophthalmopathy.[31]

Maternal Graves disease can lead to neonatal hyperthyroidism by transplacental transfer of thyroid-stimulating antibodies. Approximately 1-5% of children of mothers with Graves disease (usually with high TSI titer) are affected. Usually, the TSI titer falls during pregnancy.

Elderly individuals may develop apathetic hyperthyroidism, and the only presenting features may be unexplained weight loss or cardiac symptoms such as atrial fibrillation and congestive heart failure.

Boelaert et al investigated the prevalence of and relative risks for coexisting autoimmune diseases in patients with Graves disease (2791 patients) or Hashimoto thyroiditis (495 patients). The authors found coexisting disorders in 9.7% of patients with Graves disease and in 14.3% of those with Hashimoto thyroiditis, with rheumatoid arthritis being the most common of these (prevalence = 3.15% and 4.24% in Graves disease and Hashimoto thyroiditis, respectively). Relative risks of greater than 10 were found for pernicious anemia, systemic lupus erythematosus, Addison disease, celiac disease, and vitiligo. The authors also reported a tendency for parents of patients with Graves disease or Hashimoto thyroiditis to have a history of hyperthyroidism or hypothyroidism, respectively.[32]

Race

In whites, autoimmune thyroid diseases are, based on linkage analysis, linked with the following loci: AITD1, CTLA4, GD1, GD2, GD3, HT1, and HT2. Different loci have been reported to be linked with autoimmune thyroid diseases in persons of other races.

Susceptibility is influenced by genes in the human leukocyte antigen (HLA) region on chromosome 6 and in CTLA4 on band 2q33. Association with specific HLA haplotypes has been observed and is found to vary with ethnicity.

Sex

As with most autoimmune diseases, susceptibility is increased in females. Hyperthyroidism due to Graves disease has a female-to-male ratio of 7-8:1.

The female-to-male ratio for pretibial myxedema is 3.5:1. Only 7% of patients with localized myxedema have thyroid acropachy.

Unlike the other manifestations of Graves disease, the female-to-male ratio for thyroid acropachy is 1:1.

Age

Typically, Graves disease is a disease of young women, but it may occur in persons of any age.

The typical age range is 20-40 years.

Most affected women are aged 30-60 years.

Although pediatric cases are rare, Beliard et al reported on Graves disease in a 12-month-old infant.[33]

The natural history of Graves disease is that most patients become hypothyroid and require replacement. Similarly, the ophthalmopathy generally becomes quiescent. On occasion, hyperthyroidism returns because of persisting thyroid tissue after ablation and high antibody titers of anti-TSI. Further therapy may be necessary in the form of surgery or radioactive iodine ablation.

A study by Tun et al indicated that in patients with Graves disease receiving thionamide therapy, high TSH receptor–stimulating antibody (TRab) levels at diagnosis of the disease and/or high TRab levels at treatment cessation are risk factors for relapse, particularly within the first two years. The study included 266 patients.[34]

A retrospective study by Rabon et al indicated that in children with Graves disease, antithyroid drugs usually do not induce remission, although most children who do achieve remission through these agents do not relapse. Of 268 children who were started on an antithyroid drug, 57 (21%) experienced remission, with 16 of them (28%) relapsing.[35]

A study by Song et al indicated that in patients with long-standing Graves disease, following a 2-year course of antithyroid drugs, the risk of developing diabetes mellitus is 1.18 times higher than that of controls. More specifically, the investigators reported that in patients who, following a 2-year course of antithyroid drugs, continued on such medications for at least 1 more year, with no radioactive iodine ablation, the risk for diabetes was 1.17 times higher. For those who at some point after the initial 24-month drug course underwent radioactive iodine ablation, the risk was 1.88 times higher. It was also found that the diabetes risk rose as the duration of antithyroid drug treatment increased.[36]

Awareness of the symptoms related to hyperthyroidism and hypothyroidism is important, especially in the titration of antithyroid agents and in replacement therapy for hypothyroidism.

Patients also should be aware of the potential adverse effects of these medicines. They should watch for fever, sore throat, and throat ulcers.

Patients also must be instructed to avoid cold medicines that contain alpha-adrenergic agonists such as ephedrine or pseudoephedrine.

Because Graves disease is an autoimmune disorder that also affects other organ systems, taking a careful patient history is essential to establishing the diagnosis.

In some cases, the history may suggest a triggering factor such as trauma to the thyroid, including surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma. Other factors can include immunotherapy for cancer (such as the use of interferon [eg, interferon beta-1b], IL-4, and immune checkpoint inhibitors [anti–CTLA-4, anti–PD-1, and anti–PD-L1 antibodies]).

Patients usually present with symptoms typical of thyrotoxicosis. Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation.[37] Tachycardia and palpitation are very common symptoms.

Not all patients present with such classic features. In fact, a subset of patients with euthyroid Graves disease is described.

In elderly individuals, fewer symptoms are apparent to the patient. Clues may include unexplained weight loss, hyperhidrosis, or rapid heart beat.

Young adults of Southeast Asian descent may complain of sudden paralysis thought to be related to thyrotoxic periodic paralysis. There is an association of polymorphisms of the calcium channel alpha1-subunit gene with thyrotoxic periodic paralysis.[38] One third of patients with thyrotoxic hypokalemic periodic paralysis were found to have mutations in the inwardly rectifying potassium channel (Kir2.6).[39]

The signs and symptoms of Graves disease, organized by systems, are as follows:

• General - Fatigue, general weakness

• Dermatologic - Warm, moist, fine skin; sweating; fine hair; onycholysis; vitiligo; alopecia; pretibial myxedema

• Neuromuscular - Tremors, proximal muscle weakness, easy fatigability, periodic paralysis in persons of susceptible ethnic groups

• Skeletal - Back pain, increased risk for fractures

• Cardiovascular - Palpitations, dyspnea on exertion, chest pain, edema

• Respiratory - Dyspnea

• Gastrointestinal - Increased bowel motility with increased frequency of bowel movements

• Ophthalmologic - Tearing, gritty sensation in the eye, photophobia, eye pain, protruding eye, diplopia, visual loss

• Renal - Polyuria, polydipsia

• Hematologic - Easy bruising

• Metabolic - Heat intolerance, weight loss despite increase or similar appetite, worsening diabetes control

• Endocrine/reproductive - Irregular menstrual periods, decreased menstrual volume, secondary amenorrhea, gynecomastia, impotence

• Psychiatric - Restlessness, anxiety, irritability, insomnia

Most of the physical findings are related to thyrotoxicosis.

Physical findings that are unique to Graves disease but not associated with other causes of hyperthyroidism include ophthalmopathy and dermopathy. Myxedematous changes of the skin (usually in the pretibial areas) are described as resembling an orange peel in color and texture. Onycholysis can be seen usually in the fourth and fifth fingernails.

The presence of a diffusely enlarged thyroid gland, thyrotoxic signs and symptoms, together with evidence of ophthalmopathy or dermopathy, can establish the diagnosis.

Common physical findings, organized by anatomic region, are as follows:

• General - Increased basal metabolic rate, weight loss despite increased or similar appetite (in pediatrics, poor weight gain with a hyperdynamic state)

• Skin - Warm, most, fine skin; increased sweating; fine hair; vitiligo; alopecia; pretibial myxedema

• Head, eyes, ears, nose, and throat - Chemosis, conjunctival irritation, widening of the palpebral fissures, lid lag, lid retraction, proptosis, impairment of extraocular motion, visual loss in severe optic nerve involvement, periorbital edema

• Neck - Upon careful examination, the thyroid gland generally is diffusely enlarged and smooth; a well-delineated pyramidal lobe may be appreciated upon careful palpation; thyroid bruits and, rarely, thrills may be appreciated; thyroid nodules may be palpable.

• Chest - Gynecomastia; tachypnea; tachycardia; murmur; hyperdynamic precordium; S3, S4 heart sounds; ectopic beats; irregular heart rate and rhythm

• Abdomen - Hyperactive bowel sound

• Extremities - Edema, acropachy, onycholysis

• Neurologic - Hand tremor (fine and usually bilateral), hyperactive deep tendon reflexes

• Musculoskeletal - Kyphosis, lordosis, loss of height (in pediatrics, craniosynostosis and increased height for age), proximal muscle weakness, hypokalemic periodic paralysis in persons of susceptible ethnic groups

• Psychiatric - Restlessness, anxiety, irritability, insomnia, depression

Ophthalmopathy is a hallmark of Graves disease. Approximately 25-30% of patients with Graves disease have clinical evidence of Graves ophthalmopathy. Progression from mild to moderate/severe ophthalmopathy occurs in about 3% of cases.[40] TSH receptor is highly expressed in the fat and connective tissue of patients with Graves ophthalmopathy. Measuring diplopia fields, eyelid fissures, range of extraocular muscles, visual acuity, and proptosis provides quantitative assessment to follow the course of ophthalmopathy. Signs of corneal or conjunctival irritation include conjunctival injection and chemosis. A complete ophthalmologic examination, including retinal examination and slit-lamp examination by an ophthalmologist, is indicated if the patient is symptomatic.

Although thyroid nodule(s) may be present, excluding multinodular toxic goiter (especially in older patients) as the cause of thyrotoxicosis is essential. The approach to treatment may be different. Excluding thyroid neoplasia is also important in these patients because reports have indicated that differentiated thyroid cancer is probably more common in patients with Graves disease and may also have a more aggressive course in these patients.[41]

Similarly, mortality has been reported to be increased in patients with Graves disease and differentiated thyroid carcinoma compared with euthyroid control patients with differentiated thyroid carcinoma.[42] Graves disease patients had also higher mortality rates compared with general population, with a particular increase in mortality due to cardiovascular and lung disorders, while hyperthyroid patients had increased mortality secondary to toxic nodules had increased mortality associated with malignancies.[43]

Graves disease is autoimmune in etiology, and the immune mechanisms involved may be one of the following:

• Expression of a viral antigen (self-antigen) or a previously hidden antigen

• The specificity crossover between different cell antigens with an infectious agent or a superantigen

• Alteration of the T cell repertoire, idiotypic antibodies becoming pathogenic antibodies

• New expression of HLA class II antigens on thyroid epithelial cells (eg, HLA-DR antigen)

The autoimmune process in Graves disease is influenced by a combination of environmental and genetic factors.

Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, TG, TSHR, and PTPN22.[10] Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. HLA-DRB1 and HLA-DQB1 also appear to be associated with Graves disease susceptibility. Genetic factors contribute approximately 20-30% of overall disease susceptibility.

• Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4) is a major thyroid autoantibody susceptibility gene,[44, 45] and it is a negative regulator of T-cell activation and may play an important role in the pathogenesis of Graves disease. The G allele of exon1 +49 A/G single nucleotide polymorphism (SNP) of the CTLA-4 gene influences higher TPOAb and TgAb production in patients who are newly diagnosed with Graves disease.[44] This SNP of the CTLA-4 gene can also predict recurrence of Graves disease after cessation of thionamide treatment.[46]

• There is an association of a C/T SNP in the Kozak sequence of CD40 with Graves disease.[10, 47]

• The association of SNPs in PTPN22 varies among autoimmune diseases individually or as part of a haplotype, and the mechanisms by which PTPN22 confers susceptibility to Graves disease may differ from other autoimmune diseases.[48]

• Alleles of intron 7 of the TSH-receptor gene (TSHR) have also been shown to contribute to susceptibility to Graves disease.

• Inhibitory antibodies directed against insulinlike growth factor receptor-1 (IGFR-1) were seen in 14% of patients with Graves ophthalmopathy, but there was no activation of IGFR-1 in association with these antibodies.[49]

Environmental factors associated with susceptibility are largely unproven. Other factors include infection, iodide intake, stress, female sex, steroids, and toxins. Smoking has been implicated in the worsening of Graves ophthalmopathy.

• Graves disease has been associated with a variety of infectious agents such as Yersinia enterocolitica and Borrelia burgdorferi. Homologies have been shown between proteins of these organisms and thyroid autoantigens.[50, 51]  Graves disease has also been linked to viral infections, including with SARS-CoV-2 (the pathogen for coronavirus disease 2019 [COVID-19]).[6, 7, 8]

• Stress can be a factor for thyroid autoimmunity. Acute stress-induced immunosuppression may be followed by immune system hyperactivity, which could precipitate autoimmune thyroid disease. This may occur during the postpartum period, in which Graves disease may occur 3-9 months after delivery. Estrogen may influence the immune system, particularly the B-cell repertoire. Both T- and B-cell function are diminished during pregnancy, and the rebound from this immunosuppression is thought to contribute to the development of postpartum thyroid syndrome.

• Immune checkpoint inhibitors (eg, anti–CTLA-4 antibody [ipilimumab], anti–PD-1 antibodies [nivolumab, pembrolizumab, cemiplimab], anti–PD-L1 antibodies [avelumab, atezolizumab, durvalumab]), interferon beta-1b, and IL-4, when used therapeutically, may cause Graves disease.

• Trauma to the thyroid has also been reported to be associated with Graves disease. This may include surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma.

Ultrasensitive (third-generation) TSH assays remain the best screening test for thyroid disorders.

• With the exception of TSH-induced hyperthyroidism, subnormal or suppressed TSH levels are seen in most patients with thyrotoxicosis.

• Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index. Subclinical hyperthyroidism, defined as a free T4 or free T3 level within the reference range with suppressed TSH, also can be seen.

• On occasion, only the free T3 level is elevated, a syndrome known as T3 toxicosis. This may be associated with toxic nodular goiter or the ingestion of T3. Elevated T3 levels are often seen in early phase Graves disease as well.

• Assays for TSH-receptor antibodies (particularly TSIs) almost always are positive.

• Detection of TSIs is diagnostic for Graves disease.

• The presence of TSIs is particularly useful in reaching the diagnosis in pregnant women, in whom the use of radioisotopes is contraindicated.

• Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroidal peroxidase antibodies, are usually present.

• Other autoantibodies that may be present include TSH receptor–blocking antibodies and anti–sodium-iodide symporter antibody.

• The presence of these antibodies supports the diagnosis of an autoimmune thyroid disease.

Liver function test results should be obtained to monitor for liver toxicity caused by thioamides (antithyroid medications).

A CBC with differential should be obtained at baseline and with the development of fever or symptoms of infection. Graves disease may be associated with normocytic anemia, low-normal to slightly depressed total WBC count with relative lymphocytosis and monocytosis, and low-normal to slightly depressed platelet count. Thioamides may rarely cause severe hematologic side effects, but routine screening for these rare events is not cost-effective.

Investigation of gynecomastia associated with Graves disease may reveal increased sex hormone–binding globulin levels and decreased free testosterone levels.

Graves disease may worsen diabetes control and may be reflected by an increase in hemoglobin A1C in diabetic patients.

A fasting lipid profile may show decreased total cholesterol levels and decreased triglyceride levels.

TSH-releasing hormone testing has largely been replaced by third-generation TSH assays.

A high titer of serum antibodies to collagen XIII is associated with active Graves ophthalmopathy.[52]

Radioactive iodine scanning and measurements of iodine uptake are useful in differentiating the causes of hyperthyroidism. In Graves disease, the radioactive iodine uptake is increased, and the uptake is diffusely distributed over the entire gland.[4]

Ultrasounds with color-Doppler evaluation have been found to be cost-effective in hyperthyroid patients.[41, 53] A prospective trial showed that thyroid ultrasound findings are predictive of radioiodine treatment outcome, and, in patients with Graves disease, normoechogenic and large glands are associated with increased radioresistance.[54]

Computed tomography scanning or magnetic resonance imaging (of the orbits) may be necessary in the evaluation of proptosis. If routinely performed, most patients have evidence of ophthalmopathy, such as an increased volume of extraocular muscles and/or retrobulbar connective tissue. These techniques are useful to monitor changes over time or to ascertain the effects of treatment. Careful monitoring is required after using iodinated contrast agents as they may affect ongoing treatment plans.

In select cases in which thyroidectomy was performed for the treatment of severe hyperthyroidism, the thyroid glands from patients with Graves disease show lymphocytic infiltrates and follicular hypertrophy, with little colloid present.

Treatment involves alleviation of symptoms and correction of the thyrotoxic state. Adrenergic hyperfunction is treated with beta-adrenergic blockade. Correcting the high thyroid hormone levels can be achieved with antithyroid medications that block the synthesis of thyroid hormones or by treatment with radioactive iodine.

A study by Yasuda et al of pediatric patients with Graves disease found that a greater incidence and variety of adverse events occurred in those on a high dose of the antithyroid drug methimazole (0.7 or more mg/kg/day) than in those on a low dose (< 0.7 mg/kg/day), with the frequencies of adverse events being 50% and 20%, respectively. However, neutropenia and rash were found to manifest independently of dose.[55]

Radioactive iodine

The most commonly used therapy for Graves disease is radioactive iodine. Indications for radioactive iodine over antithyroid agents include a large thyroid gland, multiple symptoms of thyrotoxicosis, high levels of thyroxine, and high titers of TSI. Information and guidelines are as follows:

• Many physicians in the United States prefer to use radioactive iodine as first-line therapy, especially in younger patients, because of the high relapse rate (>50%) associated with antithyroid therapy.

• Radioiodine treatment can be performed in an outpatient setting.

• The usual dose ranges from 5-15 mCi, determined either by using various formulas that take into account the estimated thyroid weight and radioiodine uptake or by using fixed dosages of iodine-131 (131I); detailed kinetic studies of 131I are not essential and do not lead to better treatment results. A fixed dose of 7 mCi has been advocated by some researchers as the first empirical dose in the treatment of hyperthyroidism. In general, higher dosages are required for patients who have large goiters, have low radioiodine uptake, or who have been pretreated with antithyroid drugs.

• Patients currently taking antithyroid drugs must discontinue the medication at least 2 days prior to taking the radiopharmaceutical.[56] In one study, withholding antithyroid drugs for just over 2 weeks before radioiodine treatment resulted in the lowest failure rate. Pretreatment with thioamides reduces the cure rate of radioiodine therapy in hyperthyroid diseases.[57]

• Thyroid function test results generally improve within 6-8 weeks of therapy, but this can be highly variable.

• With radioactive iodine, the desired result is hypothyroidism due to destruction of the gland, which usually occurs 2-3 months after administration.

• Following up with the patient and monitoring thyroid function monthly or as the clinical condition dictates is important.

• When patients become hypothyroid, they require lifelong replacement with thyroid hormone.

• The possibility exists that radioactive iodine can precipitate thyroid storm by releasing thyroid hormones. This risk is higher in elderly and debilitated patients. This problem can be addressed by pretherapy administration with antithyroidal medication such as propylthiouracil (PTU) or methimazole, but antithyroid medication also may decrease the effectiveness of radioiodine.

• If thyroid function does not normalize within 6-12 months of treatment, a second course at a similar or higher dose can be given. Third courses are rarely needed.

• Hypothyroidism may ensue in the first year in up to 90% of patients given higher doses of radioiodine.

• Approximately one third of patients develop transient hypothyroidism. Unless a patient is highly symptomatic, thyroxine replacement may be withheld if hypothyroidism occurs within the first 2 months of therapy. If it persists for longer than 2 months, permanent hypothyroidism is likely, and replacement with T4 should be initiated.

• Radiation thyroiditis is rare, but it may occur and exacerbate thyrotoxicosis.

• Long-term follow-up is mandatory for all patients.

• One concern with the use of radioiodine in persons with Graves disease is its controversial potential for exacerbating existing Graves ophthalmopathy. However, the presence of ophthalmopathy should not influence the choice of therapy for hyperthyroidism. If possible in patients with mild progressive ophthalmopathy, institute a course of steroids (prednisone up to 1 mg/kg) for 2-3 months, tapering a few days before radioiodine therapy. For those with no obvious ophthalmopathy, the chances of exacerbation are much lower. In patients with severe Graves ophthalmopathy, treatment of hyperthyroidism and ophthalmopathy should proceed concurrently and independently of each other.

• The absolute contraindication for radioiodine is pregnancy. No evidence of germ-line mutations has been demonstrated from gonadal exposure. The incidence of birth defects or abnormal pregnancies has not increased after radioiodine treatments.[58] After radioiodine therapy, germinal epithelium and Leydig cell function may change marginally, which may have some clinical significance in male patients with preexisting fertility impairment.[59]

• Long-term side effects are observed mainly in pediatric Graves disease patients treated with radioactive iodine doses administered to achieve euthyroidism.[60] Low-dose thyroid radiation therapy in children with Graves disease increases the risk for thyroid cancer later in life, because it can leave behind thyroid cells with gene mutations that may eventually transform to become malignant.[61] In patients aged 6-10 years, ablative doses of 131I (100-150 mCi/g of thyroid tissue) may be used. In a national database analysis, Graves disease patients had increased risk for developing malignancies, especially breast and thyroid cancer, compared with controls, particularly within the first 3 years of diagnosis.[62] Detection bias because of Graves disease diagnosis could be a factor for this epidemiologic association. Exactly what the risk for cancer from radioactive iodine therapy itself is in patients with Graves disease remains a subject of controversy.[63]

Graves ophthalmopathy

Graves ophthalmopathy can be divided into two clinical phases: the inflammatory stage and the fibrotic stage. The inflammatory stage is marked by edema and deposition of glycosaminoglycan in the extraocular muscles. This results in the clinical manifestations of orbital swelling, stare, diplopia, periorbital edema, and, at times, pain. The fibrotic stage is a convalescent phase and may result in further diplopia and lid retraction.

In a longitudinal cohort of 8404 adults with newly diagnosed Graves disease, 740 (8.8%) developed ophthalmopathy.[64] Graves ophthalmopathy improves spontaneously in 64% of patients. Approximately 10-20% of patients have gradual progression of disease over many years, followed by clinical stability. Approximately 2-5% have progressive worsening of the disease, with visual impairment in some.

Radioactive iodine therapy for Graves disease is a risk factor for Graves ophthalmopathy, while cholesterol-lowering drugs of the hydroxymethylglutarate-coenzyme A reductase inhibitor (statin) class have been associated with a reduced risk of ophthalmopathy.[64, 65]  For example, a randomized clinical trial showed that the addition of oral atorvastatin to intravenous (IV) pulse glucocorticoid therapy can improve clinical outcomes in patients with moderate to severe Graves ophthalmopathy.[66] Ethnic factors are also important for Graves ophthalmopathy after radioactive iodine treatment; Japanese patients are less prone to Graves ophthalmopathy after radioactive iodine.[67]

Smoking is a risk factor for Graves ophthalmopathy, and smoking cessation is advised.

Correction of both hyperthyroidism and hypothyroidism is important for the ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may exacerbate preexisting ophthalmopathy but can be prevented by glucocorticoids. However, Japanese patients may not respond well to prophylactic use of low-dose glucocorticosteroids.[67] No beneficial effect of glucocorticoid prophylaxis was found in patients without preexisting clinical evidence of ophthalmopathy.[68] In the long term, thyroid ablation may be beneficial for ophthalmopathy because of the decrease in antigens shared by the thyroid and the orbit in the autoimmune reactions. In general, treatment of hyperthyroidism is associated with an improvement of ophthalmopathy, but hypothyroidism must be avoided because it worsens ophthalmopathy.[69, 70, 71]

For mild to moderate ophthalmopathy, local therapeutic measures (eg, artificial tears and ointments, sunglasses, eye patches, nocturnal taping of the eyes, prisms, elevating the head at night) can control symptoms and signs. 

For severe or progressive disease, high-dose pulse IV methylprednisolone (cumulative dose of 4.5 g in 12 weekly infusions) may be used as a first-line treatment. Mycophenolate mofetil (a potent, selective, noncompetitive, and reversible inhibitor of inosine-5'-monophosphate dehydrogenase) can suppress the immune system by depleting guanosine and deoxyguanosine nucleotides in T and B cells. Real-world, retrospective data support mycophenolate as an effective and safe second-line agent for moderate, severe, or sight-threatening Graves ophthalmopathy, to maintain remission after first-line IV glucocorticoid therapy.[72]  The 2021 European Group on Graves’ Orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ ophthalmopathy recommend high-dose pulse IV methylprednisolone combined with mycophenolate as first-line treatment, or alternatively, a higher cumulative dose (7.5 g) of pulse IV methylprednisolone monotherapy for the most severe cases.[73]

Second-line treatments for moderate to severe and active Graves ophthalmopathy include the following[73] :

• High–cumulative-dose (7.5 g) pulse IV methylprednisolone - The treatment starts with 0.75 g IV methylprednisolone once weekly x6, followed by 0.5 g once weekly x6
• Oral prednisone/prednisolone in combination with either cyclosporine or azathioprine - Glucocorticoids at prednisone equivalent 40 mg/d (usual dose) may be tried; the drug should be continued until evidence of improvement and disease stability is observed; the dosage is then tapered over 4-12 weeks; a meta-analysis showed that a 3-month course of prednisone (0.4-0.5 mg/kg) reduced the progression of preexisting mild to moderate ophthalmopathy ^[68]
• Combination of orbital radiotherapy and oral or IV glucocorticoids - This is an effective second-line treatment for moderate to severe and active disease, especially when diplopia or extraocular movement defects are present; a meta-analysis found that combining steroids with radiotherapy produced better outcomes than did steroid therapy alone; ^[74]  a study by Wakelkamp et al found that orbital radiotherapy did not increase the risk for radiation-induced tumors or retinopathy (except in patients with diabetes, in whom a greater risk for possible or definite retinopathy was reported); ^[75]  low-dose radiation from various sources (even if not aimed at the eyes) is linked to cataracts, which may be detected only after long-term follow-up ^[76]
• Teprotumumab - Teprotumumab (an inhibitory IGF1 receptor monoclonal antibody) was approved by the US Food and Drug Administration (FDA) for Graves ophthalmopathy in 2020, with patients who received teprotumumab having shown a better response (over placebo) with regard to reduction in clinical activity score and the severity of proptosis; teprotumumab (10 mg/kg initial dose, then 20 mg/kg) is given intravenously every 3 weeks. ^[77]
• Rituximab - An anti-CD20 monoclonal antibody, rituximab may transiently deplete B lymphocytes and may suppress the active inflammatory phase of Graves ophthalmopathy; ^[78]  however, clinical data concerning rituximab are still conflicting and controversial; ^{[79, 80]}  a prospective, multicentered pilot study suggested that periocular injection of triamcinolone may reduce diplopia and the size of extraocular muscles in patients with Graves ophthalmopathy of recent onset; ^[81]
• Pentoxifylline - In a prospective, randomized trial, pentoxifylline, a hemorrheologic agent, improved symptoms and proptosis in the inactive phase of Graves ophthalmopathy ^[82]
• Tocilizumab - A monoclonal antibody against IL-6, tocilizumab can be used as a second-line therapy in the setting of glucocorticoid resistance

Sight-threatening Graves ophthalmopathy with optic nerve compression is treated immediately with pulse dosing of high-dose methylprednisolone (typically 0.5-1 g IV daily for 3 consecutive days). If there is no response within 2 weeks or the response is poor, urgent surgical orbital decompression is indicated.  Severe corneal exposure requires urgent medical or surgical management to avoid corneal breakdown.[73]

Gamma knife radiosurgery has been attempted with success in a limited number of patients, but further studies are needed to validate this approach.

Infliximab, an anti–tumor necrosis factor alpha (anti-TNF-α) antibody, has reportedly been used to successfully treat a case of sight-threatening Graves ophthalmopathy.[83]

Pretibial myxedema

Some degree of pretibial (localized dermopathy) myxedema is observed in 5-10% of patients, with 1-2% having cosmetically significant lesions. Affected patients tend to have more severe ophthalmopathy than those who are not affected.

It usually manifests as elevated, firm, nonpitting, localized thickening over the lateral aspect of the lower leg, with bilateral involvement. It also may involve the upper extremities.

Milder cases do not require therapy other than treatment of the thyrotoxicosis.

Therapy with topical steroids applied under an occlusive plastic dressing film (eg, Saran Wrap) for 3-10 weeks has been helpful. In severe cases, pulse glucocorticoid therapy may be tried.

Acropachy

Clubbing of fingers with osteoarthropathy, including periosteal new bone formation, may occur. This almost always occurs in association with ophthalmopathy and dermopathy. No therapy has been proven to be effective.

Inpatient Care

With the exception of thyroid storm, Graves disease generally is managed in an outpatient setting.

On occasion, patients may present with thyrotoxic heart disease, including congestive heart failure, atrial fibrillation, or other tachyarrhythmia, which requires inpatient management. Prompt recognition of thyrotoxicosis is required for optimal therapy. In certain cases, the patient may have to be admitted to the intensive care unit or critical care unit. Appropriate subspecialty consultations (eg, endocrinologist, cardiologist) are needed. Once patients' conditions are stabilized, they can be transferred to a regular room or discharged from the hospital.

In certain cases (ie, noncompliant patients, those who develop severe reactions to antithyroid drugs), radioiodine ablation therapy may be given in an inpatient setting.

Indications and outcomes are as follows:

• Thyroidectomy is not the recommended first-line therapy for hyperthyroid Graves disease in the United States. However, a retrospective cohort study[84] showed that one third of all patients electing surgery as definitive management did so without a specific indication, and the patient satisfaction with the decision for surgery as definitive management of Graves disease was high. In certain Asian health-care systems, thyroidectomy may play a larger role as a first-line treatment for Graves disease.[85]

• Surgery is a safe alternative therapeutic option in patients who are noncompliant with or cannot tolerate antithyroid drugs, have moderate to severe ophthalmopathy, have large goiters, or refuse or cannot undergo radioiodine therapy. Also, surgical treatment has been found to be more effective than radioiodine therapy to achieve cure and reduce recurrence.[86]

• Thyroidectomy may be appropriate in the presence of a thyroid nodule that is suggestive of carcinoma.

• In certain cases (eg, in pregnant patients with severe hyperthyroidism), thyroidectomy may be indicated because radioactive iodine and antithyroid medications may be contraindicated.

• It generally is reserved for patients with large goiters with or without compressive symptoms.

• It also may be indicated in patients who refuse radioiodine as definitive therapy or in those in whom the use of antithyroid drugs and/or radioiodine does not control hyperthyroidism.

• Surgery provides rapid treatment of Graves disease and permanent cure of hyperthyroidism in most patients, and it has "negligible mortality and acceptable morbidity" by experienced surgeons.[87]

Procedures and preparations are as follows:

• Preoperative preparation to render the patient euthyroid is essential in order to prevent thyrotoxic crisis (thyroid storm). The hyperthyroid state can be rapidly corrected using a combination of iopanoic acid, dexamethasone, beta blockers, and thioamides.[88, 89]  These antithyroid drugs are used for approximately 6 weeks, with or without concomitant beta blockade. Most surgeons administer iodine (as Lugol solution or saturated solution of potassium iodide to provide ≥30 mg of iodine/d) for 10 days before surgery, to decrease thyroid gland vascularity, the rate of blood flow, and intraoperative blood loss during thyroidectomy.[90, 91, 92]

• Preparation can also be accomplished using therapeutic plasma exchange, which can quickly and effectively reduce serum thyroid hormones and TSIs; the technique is especially useful for patients who are intolerant of antithyroid drugs.[93]

• With experienced surgeons, vocal cord paralysis due to superior or recurrent laryngeal nerve injury and hypoparathyroidism are rare adverse events, occurring in less than 1% of patients.

• Subtotal thyroidectomy is usually used with the intention of leaving enough thyroid remnants behind to avoid hypothyroidism.

• Importantly, keep in mind that the risk of recurrent hyperthyroidism potentially increases with larger remnant sizes. However, many studies have shown that the size of the remnant is not the only determinant of the risk of recurrence.

• Iodine uptake and immunologic activity (eg, level of TSI) are just 2 of the other factors that influence the risk of recurrent hyperthyroidism.

• If the goal of surgery is to avoid recurrent hyperthyroidism, near-total thyroidectomy has been advocated as the procedure of choice.

• Regardless of the extent of surgery, all patients require long-term follow-up.

A literature review by Zhang et al comparing endoscopic with conventional open thyroidectomy for Graves disease reported that the endoscopic technique offers better cosmetic satisfaction and less blood loss, while open surgery is associated with reduced operation time. Complication rates for the two techniques with regard to transient recurrent laryngeal nerve palsy, recurrent hyperthyroidism, hypothyroidism, and transient hypocalcemia were equivalent.[94]

Graves ophthalmopathy

Near-total thyroidectomy has little, if any, effect on the course of ophthalmopathy.

Reducing proptosis and decompressing the optic nerve can be achieved using transantral orbital decompression.

If sight-threatening Graves ophthalmopathy with optic nerve compression does not respond to high-dose IV methylprednisolone therapy within 2 weeks, urgent surgical orbital decompression is needed. Recent eyeball subluxation also requires urgent surgery. Severe corneal exposure may need increasingly invasive surgical procedures to avoid corneal breakdown, which would then become a surgical emergency. Non-urgent surgical management is generally performed in the fibrotic phase, when the patient is euthyroid.

A study by Liao and Huang indicated that decompression by resecting orbital fat can decrease proptosis in patients with disfiguring Graves ophthalmopathy.[95] Rehabilitative surgery, including eyelid surgery (eg, severance of the Müller muscle, scleral or palatal graft insertion) and extraocular muscle surgery, are indicated for inactive residual manifestations of Graves ophthalmopathy or to improve exposure keratitis.

A study by Alsuhaibani et al found that in patients with Graves ophthalmopathy who undergo orbital bony wall decompression, volume change in the medial rectus muscle may help to explain the variability in proptosis reduction.[96]

The major adverse effect of orbital decompression is postoperative diplopia, which may necessitate a second surgery, on the extraocular muscles, to correct the problem.

Consultation with an endocrinologist may be necessary for the management and regulation of thyroid hormone levels in atypical presentations, as follows:

• Graves disease in pregnancy

• Neonatal Graves disease management

• Graves disease complicated by a nodular thyroid gland unresponsive to usual medical therapy or in older adults

Consultation with an ophthalmologist may be needed in the following situations:

• Unilateral or bilateral proptosis

• Workup of other etiologies for eye findings besides Graves disease

• Follow-up of visual acuity, corneal disease prevention, and eye muscle function

Consultation with a dermatologist may be needed in patients with localized myxedema that is unresponsive to topical corticosteroids.

The amount of iodine in the diet can influence the hormone synthesis activity in the thyroid gland.

Iodine-containing food has different effects on thyroid uptake of 131I and technetium-99m (99mTc) . Iodine-rich food decreases 131I uptake but increases 99mTc in most patients. However, the diagnostic value of a radioiodine uptake test to differentiate Graves disease from silent thyroiditis is not affected by dietary iodine intake.[97] Iodine restriction before a radioiodine uptake test is unnecessary.

Dietary iodine intake may influence the remission rate after antithyroid drug therapy. This is based on the observation that the outcome of antithyroid therapy in the older literature showed lower remission rates than it did in later studies and that the average dietary iodine content has been decreasing over the years. However, a direct causal relationship has not been established by clinical trials.

In addition, the use of antithyroid drug therapy for more than 2 years is a good predictor of Graves disease.[98] In pediatric patients with Graves disease, no difference was noted in remission rates between methimazole and PTU, while minor adverse effects were significantly increased in patients receiving PTU doses of 7.5 mg/kg or higher.[99]

Dietary/nutritional selenium supplementation is generally believed to be beneficial for mild Graves ophthalmopathy, although the real effectiveness of selenium remains controversial.[100]

Given the high-output state of the heart, strenuous exercise may be detrimental. The patient should be advised to avoid severe fatigue from exercise. Patients can use their pulse as a guide to activity.

Agranulocytosis is an idiosyncratic reaction to antithyroid drugs. The role of serial CBC counts to predict who will develop this serious adverse reaction is not well established.

In contrast to patients with Graves disease, preoperative iodine treatment should not be given to patients with toxic nodular goiters because it can exacerbate hyperthyroidism.

Prevention is difficult because of the lack of knowledge regarding the pathogenesis of this condition.

Hyperthyroidism represents a continuum of thyroid dysfunction. In the case of thyroid storm, decompensated patients with hyperthyroidism should be cared for in an institution with personnel familiar with this disease.

All patients should receive long-term follow-up, regardless of the mode of therapy (ie, surgery, radioiodine, antithyroid drugs).

Close follow-up visits with monitoring of examination findings, thyroid hormone levels, and TSH levels are required.

If the patient is on antithyroidal medication (eg, thioamides), liver function tests and CBC counts with differentials should be monitored based on the clinical situation.

Examination of the eyes should be a routine part of follow-up of these patients, given the lack of predictability of ophthalmopathy.

Smoking cessation techniques should be continued.

American Thyroid Association

In 2016, the American Thyroid Association updated the 2011 hyperthyroidism/thyrotoxicosis guidelines it had codeveloped with the American Association of Clinical Endocrinologists. The following is a sampling of the 124 evidence-based recommendations included in the guideline update[101] :

• Beta-adrenergic blockade is recommended in all patients with symptomatic thyrotoxicosis, especially elderly patients and thyrotoxic patients with resting heart rates in excess of 90 beats per minute or coexistent cardiovascular disease
• Patients with overt Graves hyperthyroidism should be treated with any of the following modalities: radioactive iodine therapy, antithyroid drugs, or thyroidectomy
• If methimazole is chosen as the primary therapy for Graves disease, the medication should be continued for approximately 12-18 months and then discontinued if the serum TSH and TSH-receptor antibody levels are normal at that time
• If surgery is chosen as the primary therapy for Graves disease, near-total or total thyroidectomy is the procedure of choice
• If surgery is chosen as treatment for toxic multinodular goiter, near-total or total thyroidectomy should be performed
• If surgery is chosen as the treatment for toxic adenoma, a thyroid sonogram should be done to evaluate the entire thyroid gland; an ipsilateral thyroid lobectomy (or isthmusectomy, if the adenoma is in the thyroid isthmus), should be performed for isolated toxic adenomas
• Children with Graves disease should be treated with methimazole, radioactive iodine therapy, or thyroidectomy; radioactive iodine therapy should be avoided in very young children (< 5 years); radioactive iodine therapy in children is acceptable if the activity is over 150 μCi/g (5.55 MBq/g) of thyroid tissue and for children between ages 5 and 10 years if the calculated radioactive iodine administered activity is under 10 mCi (< 473 MBq); thyroidectomy should be chosen when definitive therapy is required, the child is too young for radioactive iodine, and surgery can be performed by a high-volume thyroid surgeon
• If methimazole is chosen as the first-line treatment for Graves disease in children, it may be tapered in those children requiring low doses after 1-2 years to determine if a spontaneous remission has occurred, or it may be continued until the child and caretakers are ready to consider definitive therapy, if needed
• If surgery is chosen as therapy for Graves disease in children, total or near-total thyroidectomy should be performed
• Euthyroidism should be expeditiously achieved and maintained in hyperthyroid patients with Graves ophthalmopathy or risk factors for the development of ophthalmopathy
• In patients with Graves hyperthyroidism who have mild active ophthalmopathy and no risk factors for deterioration of their eye disease, radioactive iodine therapy, antithyroid drugs, and thyroidectomy should be considered equally acceptable therapeutic options
• In Graves disease patients with mild Graves ophthalmopathy who are treated with radioactive iodine, steroid coverage is recommended if there are concomitant risk factors for Graves ophthalmopathy deterioration

European Group on Graves' Orbitopathy

In 2021, the European Group on Graves' Orbitopathy (EUGOGO) published clinical practice guidelines for the medical management of Graves ophthalmopathy.[73]  Some highlights are as follows:

• Standardized criteria should be used to assess the clinical activity and severity of Graves ophthalmopathy, with the condition classified as active or inactive, and mild, moderate to severe, or sight threatening; the EUGOGO quality-of-life questionnaire for Graves ophthalmopathy is a recommended tool
• Smoking cessation should be urged
• All patients should be rendered euthyroid
• Oral glucocorticoid prophylaxis should be prescribed to radioactive iodine–treated patients at risk of progression or new ophthalmopathy (smokers, patients with severe/unstable hyperthyroidism, individuals with high TSI); patients with inactive ophthalmopathy can receive radioactive iodine without prophylactic glucocorticoid if the above risk factors are absent; the high-risk regimen is 0.3-0.5 mg/kg, tapered off over 3 months; the low-risk regimen is 0.1-0.2 mg/kg, tapered off over 6 weeks 
• Moderate to severe and active cases - intermediate dose IV methylprednisolone (0.5 g once weekly x6, then 0.25 g once weekly x6, totaling 4.5 g); more severe cases (eg, diplopia, severe proptosis): high-dose IV methylprednisolone (0.75 g once weekly x6, then 0.5 g once weekly x6, totaling 7.5 g).
• Local subconjunctival/periocular injections of triamcinolone acetate may be one alternative if systemic glucocorticoids are contraindicated
• Hyperthyroidism should be treated with anti-thyroid drugs until the ophthalmopathy therapy is finished

First-line treatment for moderate to severe and active ophthalmopathy

First-line treatment for moderate to severe and active ophthalmopathy includes the following:

• IV methylprednisolone in combination with oral mycophenolate
• In the more severe forms (such as those characterized by diplopia [constant or not], exophthalmos >25 mm, and severe inflammatory signs), monotherapy with IV methylprednisolone, the cumulative dose being 7.5 g per cycle

Second-line treatment for moderate to severe and active ophthalmopathy

Second-line treatments for moderate to severe and active ophthalmopathy are used If response to primary/first-line treatment is poor. The following second-line treatments should be considered after careful eye examination and measurement of liver enzymes:

• Monotherapy with a second course of IV methylprednisolone, commencing with high, single doses (0.75 g), the maximal cumulative dose being 8 g per cycle
• Radiotherapy to the orbit (in combination with glucocorticoids), particularly in patients with diplopia and/or extraocular motion defect
• Cyclosporine plus oral glucocorticoids
• Azathioprine plus oral glucocorticoids 
• Tocilizumab
• Teprotumumab - Very promising drug with a strong beneficial response; currently used in second-line treatment pending the availability of more clinical data
• Rituximab - A second-line treatment for patients with moderate to severe and active ophthalmopathy of onset within less than 12 months and refractory to IV glucocorticoids; for use when no optic neuropathy is present

Sight-threatening Graves ophthalmopathy

Guidelines for managing sight-threatening Graves ophthalmopathy include the following:

• Urgent treatment should be provided for severe corneal exposure, either medically or via increasingly more invasive surgeries, so that there is no progression to corneal breakdown; corneal breakdown should immediately be managed surgically

Thyroid treatment in patients with Graves ophthalmopathy

Thyroid treatment in patients with Graves ophthalmopathy includes the following:

• Mild and inactive Graves ophthalmopathy - The preferred management is with antithyroid drugs or thyroidectomy; if radioactive iodine is employed, prophylaxis with prednisone/prednisolone should be used
• Moderate to severe, but long-standing and inactive, ophthalmopathy - Treatment should be the same as for mild and inactive Graves ophthalmopathy, but consider prednisone/prednisolone prophylaxis if choosing radioactive iodine treatment, especially in patients with risk factors for ophthalmopathy (smoking, high TSH-receptor antibodies)

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Class Summary

Thioamides function as antithyroid agents mainly by inhibiting iodide organification and coupling processes, thereby preventing synthesis of thyroid hormones. Half-life of T4 is 7 d in persons who are euthyroid and somewhat shorter in patients who are thyrotoxic. This accounts for a several-week delay in onset of clinical improvement in most patients. Agents have been reported to alter intrathyroidal immunoregulatory mechanisms. Only oral preparations are available, but they have been used as retention enemas in patients in whom oral intake is not possible or is contraindicated.

Although these agents fall under pregnancy category D, they have been used safely in many pregnant patients. Retrospective study indicates rate of major congenital malformations with PTU (3%) or methimazole (2.7%) was not significantly different from normal background rate (2-5%). Duration of treatment ranged from 0-23 wk, with doses ranging from 100-600 mg/d of PTU or 10-60 mg/d of methimazole.

Concentrations of methimazole are higher in breast milk; therefore, PTU is preferred in this patient population.

Risk of agranulocytosis is similar (0.2-0.5%) in members of this class. In general, PTU is associated with transaminase elevation in susceptible individuals, while methimazole may cause a cholestatic effect.[102]

The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, radioactive iodine, or surgery.

Medically treated Graves disease has a significant risk of relapse (23% within 6 months of discontinuation of antithyroid medication and 42% within 5 years). The presence of goiter is associated with an increased risk of relapse after medical therapy.[103]

The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community.

The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death).

PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU (for more information, see the FDA Safety Alert):

- Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole.

- Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy.

- For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care.

- PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole and no other treatment options are available.

- Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Propylthiouracil

Derivative of thiourea that inhibits organification of iodine by thyroid gland. Blocks oxidation of iodine in thyroid gland, thereby inhibiting thyroid hormone synthesis; inhibits T4-to-T3 conversion by blocking type I deiodinase (advantage over other agents). Usual course/duration of therapy is 1-2 y; sustained remission more likely after 1-2 y vs 3-6 mo of therapy.

Methimazole (Tapazole)

Inhibits thyroid hormone by blocking oxidation of iodine in thyroid gland; however, not known to inhibit peripheral conversion of thyroid hormone. Considerable debate surrounds optimal dosage/duration.

Class Summary

Both cardioselective and noncardioselective types are important adjuncts in treating hyperthyroidism. Beta-blockade provides rapid relief of hyperadrenergic symptoms and signs of thyrotoxicosis (eg, palpitations, tremors, anxiety, heat intolerance, various eyelid signs) before any decrease in thyroid hormone levels demonstrated. Also useful in preventing episodes of hypokalemic periodic paralysis in susceptible individuals. DOC for thyroiditis, which is self-limiting. High-dose propranolol can inhibit peripheral T4-to-T3 conversion. Also useful in preparing thyrotoxic patients for surgery.

Propranolol (Inderal, Inderal LA)

DOC in treating cardiac arrhythmias resulting from hyperthyroidism. Controls cardiac and psychomotor manifestations within minutes.

Drug completely absorbed from GI tract; because of extensive first-pass metabolism in liver, systemic bioavailability affected by hepatic blood flow, intrinsic clearance in liver, and genetic and age differences in individuals.

Dosage prediction for IV from prior PO difficult; therefore, careful titration of IV dose necessary.

Atenolol (Tenormin)

Selectively blocks beta1 receptors with little or no effect on beta2 types. Useful in treating cardiac arrhythmias resulting from hyperthyroidism.

Metoprolol (Lopressor, Toprol-XL)

Selective beta1-adrenergic receptor blocker that decreases automaticity of contractions. Useful in treating cardiac arrhythmias resulting from hyperthyroidism. During IV administration, carefully monitor BP, heart rate, and ECG.

Class Summary

Have long been used to treat thyrotoxicosis and are still important adjunctive therapy for hyperthyroidism in modern medicine. In pharmacologic concentrations (100-times normal plasma level), decrease activity of thyroid gland. Action involves decreasing thyroidal iodide uptake, decreasing iodide oxidation and organification, and blocking release of thyroid hormones (Wolff-Chaikoff effect).

Oral contrast agents ipodate or iopanoic acid also shown to be potent inhibitors of T4-to-T3 conversion, making them ideal for severe or decompensated thyrotoxicosis. Generally administered after thioamide is started. Also used as preoperative preparation for thyroid surgery for Graves disease.

In combination with thioamides and/or propranolol, iodines are used routinely before thyroidectomy. Iodines are given for 2-3 weeks before surgery and decrease vascularity of hyperthyroid gland. Making patient euthyroid before surgery prevents intraoperative and postoperative complications.

Potassium iodide (SSKI, Pima)

Inhibits thyroid hormone secretion.

Contains 5% iodine and 10% potassium iodide. Contains 8 mg of iodide per drop. May be mixed with juice or water for intake.

Diatrizoate (Hypaque sodium)

Blocks release of thyroid hormones.

Iopanoic acid (Telepaque)

Oral contrast agent for rapid and significant inhibition of peripheral T4-to-T3 conversion. Inorganic iodide released also blocks release of thyroid hormones.

Class Summary

Based on the observation that a small portion of L-thyroxine is usually reabsorbed in the bowel and recycled in the enterohepatic circulation, exchange resins have been used to bind thyroid hormones in the GI tract. Enterohepatic circulation of thyroxine is increased in cases of hyperthyroidism.

Cholestyramine (Questran)

Can be used to lower serum thyroid hormone levels. This cholesterol-lowering resin has been used as adjunctive therapy in management of hyperthyroid Graves disease. Proved to be effective and well-tolerated adjunctive therapy, leading to a more rapid reduction of thyroid hormone levels.

Class Summary

Act in a manner similar to iodine but is not routinely used because of transient effect and risk of potentially serious adverse effects. Now primarily used as a backup agent when other first-line agents are contraindicated because of hypersensitivity or toxicity.

Lithium (Lithotabs, Eskalith, Lithobid)

Patients intolerant to iodine can be treated with lithium, which also impairs thyroid hormone release. Can be used in patients who cannot take PTU or MMI. Use of iodine alone is debatable.

Class Summary

Amiodarone, an iodinated benzofuran, is an important antiarrhythmic medication that also alters thyroid hormone metabolism. High iodine content of this molecule (37.5%) is responsible for hypothyroidism. On the other hand, amiodarone can lead to hyperthyroidism through 2 complex mechanisms. Type I amiodarone-induced thyrotoxicosis is due to increased thyroid hormone synthesis and release in patients with multinodular goiter or Graves disease, while type II amiodarone-induced thyrotoxicosis is a destructive thyroiditis with release of preformed thyroid hormone.

Amiodarone (Cordarone)

Case report described successful normalization of thyroid hormone level in a patient with Graves disease who had fulminant PTU-induced hepatitis. However, experience and information in treatment of Graves disease is scant.

Class Summary

Graves disease is an autoimmune disease. Although glucocorticoids have been shown to decrease T4-to-T3 conversion and decrease thyroid hormones by yet undiscovered mechanisms, the adverse effect profile of long-term glucocorticoid therapy makes it unattractive for long-term management of Graves hyperthyroidism. However, glucocorticoids may have a role in rapidly lowering thyroid hormone levels in the clinical setting of thyroid storm. With regard to Graves ophthalmopathy, current evidence indicates that glucocorticoids represent the only class of drug therapy that, either alone or combined with other therapies, has an unequivocal role in management.

Prednisone (Sterapred)

Has been customarily used in management of Graves ophthalmopathy. Other oral glucocorticoids at equipotent doses may also be effective.

Methylprednisolone (Solu-Medrol)

Has been customarily used for high-dose pulse steroid therapy in management of Graves ophthalmopathy. Other glucocorticoids at equipotent doses may also be effective. Intravenous high dose glucocorticoid therapy may be more effective and better tolerated than oral steroid therapy in the management of Graves ophthalmopathy (Aktaran, 2007).

Dexamethasone (Decadron)

In healthy persons, induces decrease in serum T3 levels without a change in serum T4 levels, suggesting an effect of dexamethasone on peripheral T3-to-T4 conversion.

In patients with Graves hyperthyroidism, induces rapid fall in serum thyroid hormone levels. Changes are too rapid to be explained by a steroid-induced fall in the level of a circulating IgG thyroid stimulator (TSI). Mechanism for this observation is unclear.

Class Summary

Biologic agents are derived from living organisms or their products. Antibodies, interleukins, and vaccines are included in this group. Monoclonal antibody biologics are used in the treatment of Graves ophthalmopathy.

Teprotumumab (Teprotumumab-trbw, Tepezza)

Teprotumumab, a monoclonal antibody against insulin-like growth factor-1 receptor (IGF1R), is indicated for the treatment of Graves ophthalmopathy. This agent may exacerbate inflammatory bowel disease. In two thirds of patients with preexisting diabetes or impaired glucose tolerance, this drug increased blood glucose, causing hyperglycemia.

Tocilizumab (Actemra)

Tocilizumab is a monoclonal antibody that selectively binds to the interleukin-6 receptor (IL-6R), antagonizing the binding of IL-6 to both soluble and membrane-bound IL-6R and thus impacting IL-6 signaling. This agent may be useful in the treatment of Graves ophthalmopathy. 

Rituximab (Rituximab-abbs, Riabni, Rituxan)

Rituximab is a monoclonal antibody that binds to CD20 on the surface of pre-B cells and mature B lymphocytes, triggering the lysis and death of these cells. Rituximab may be used as a second-line treatment for Graves ophthalmopathy, especially in refractory cases. Rituximab may induce sustained remission of Graves ophthalmopathy in patients with relatively low TSH-receptor antibody (thyroid-stimulating immunoglobulin [TSI]) levels.

Class Summary

These agents inhibit key steps in immune reactions.

Azathioprine (Azasan, Imuran)

The metabolites of azathioprine, an imidazolyl derivative of mercaptopurine, are incorporated into replicating DNA. The metabolites block DNA replication and also inhibit purine synthesis. Therefore, this drug has immunosuppressive and antiproliferative effects and is used in the treatment of Graves ophthalmopathy.  

Mycophenolate (CellCept, MMF, Myfortic)

Mycophenolate mofetil is a pro-drug that is converted in the liver to its active form, mycophenolic acid. Mycophenolate reversibly inhibits inosine monophosphate dehydrogenase. It inhibits the synthesis of guanine monophosphate in de novo purine synthesis, that is needed for B- and T-lymphocyte proliferation. This agent is used in the management of Graves ophthalmopathy.