Diffuse toxic goiter: Graves' disease, a brief overview

Diffuse toxic goiter (Graves' disease) is an autoimmune disorder in which thyroid-stimulating hormone receptor antibodies (TRAb/TSI) stimulate the thyroid gland, causing hyperproduction of thyroxine and triiodothyronine. The result is thyrotoxicosis with multisystemic manifestations ranging from cardiovascular and neurological to cutaneous and ophthalmological. Unlike nodular toxic forms, Graves' disease involves diffuse enlargement of the gland and is often accompanied by sudden manifestations (ophthalmopathy, dermopathy). [1]

The key to the correct approach is to verify the immune mechanism: the presence of TRAb/TSI, typical scintigraphy with uniformly elevated radioiodine uptake, and characteristic vascular patterns on Doppler ultrasound. This allows us to differentiate Graves' disease from painless/subacute thyroiditis or toxic nodules, where the treatment and prognosis are different. Modern algorithms have shifted the emphasis toward highly accurate antibody tests and ultrasound features, and the thyrotropin-releasing hormone (TRH) test is no longer used to diagnose classic hyperthyroidism. [2]

Treatment is individually tailored from three basic strategies: antithyroid drugs, radioactive iodine, or thyroidectomy. In the presence of active ophthalmopathy, anti-inflammatory and immune-directed interventions are added to the treatment plan; since 2020, the targeted drug theoprotumumab (an IGF-1R inhibitor) has been added to the treatment arsenal, changing the approach to moderate to severe ophthalmopathy. The choice of treatment depends on age, pregnancy plans, the severity and activity of the eye disease, antibody levels, and the patient's preferences. [3]

Below is a systematic review with data on epidemiology, risk factors and pathogenesis, as well as detailed diagnosis and treatment, taking into account the latest recommendations (ETA 2018/2022, EUGOGO 2021, ATA 2016/2017) and recent reviews from 2020-2025. It is intended to replace outdated elements (e.g., "thyroid X-ray", TRG test) with valid tools for modern clinical practice. [4]

Epidemiology

Graves' disease is the most common cause of hyperthyroidism in iodine-supplemented countries. Globally, its prevalence is estimated at approximately 2-3% in women and ~0.5% in men; peak onset is between 30 and 60 years of age. Women are significantly more frequently affected (ratio 4-6:1). These estimates are supported by large reviews and population-based studies in recent years. [5]

The annual incidence in the population ranges from approximately 20 to 50 cases per 100,000 person-years, which is reproduced in modern registries (Denmark, UK, etc.). In a Danish analysis of 2024, the median age was ~44 years, and the female-to-male ratio was ~5:1. Such figures help to plan resources and estimate the burden of disease on the healthcare system. [6]

Graves' ophthalmopathy (GO) is the primary sudden manifestation. Its incidence among patients with Graves' disease in modern meta-analyses is approximately 25-30% (lower than in previous "pre-iodine" series). The annual incidence of GO in European registries is approximately 4-8 per 100,000, with a predominance in women. [7]

The COVID-19 pandemic has been associated with an increased incidence of new Graves' disease in some observational studies, likely due to immune triggers and changes in healthcare utilization, but the causal relationship remains under investigation. This means that clinicians should remain alert for symptoms of thyrotoxicosis after previous infections. [8]

Table 1. Epidemiological landmarks of Graves' disease

Indicator	Rating/Range	Sources
Women/Men	4-6: 1	[9]
Peak age	30-60 years old	[10]
Incidence (general)	20-50 per 100,000/year	[11]
Prevalence (women)	~2-3%	[12]
Ophthalmopathy (Graves lobe)	~25-30%	[13]

Reasons

The underlying cause is a loss of immune tolerance to thyroid antigens, resulting in the formation of stimulating antibodies to the TSH receptor (TRAb/TSI). These antibodies activate the TSH receptor, increase hormone synthesis and secretion, and trigger thyrocyte proliferation. The biological basis has been confirmed by both functional and immunogenetic studies. [14]

Genetic predisposition is a significant factor. Variations in the HLA complex (DRB1, DQA1, DQB1) and immunoregulatory genes (CTLA4, PTPN22, etc.) are associated with increased risk of development and relapse. However, genetics determines "predisposition" to the disease, and its development usually requires an external trigger. [15]

Environment and exposure are important: smoking, excess iodine, stress, the postpartum period, and certain medications and immunotherapies can trigger the clinical onset of ophthalmopathy in a pre-existing immune system. Smoking has been particularly proven to play a role in ophthalmopathy, increasing the risk and worsening the course. [16]

Rarely, Graves' hyperthyroidism is triggered by medications or immunotherapy (e.g., checkpoint inhibitors), but more often they cause painless thyroiditis. It is important to distinguish between these two conditions: in Graves' disease, TRAb/TSI is positive and radioiodine uptake is increased, while in destructive thyroiditis, the opposite is true. [17]

Risk factors

The most powerful modifiable factor is smoking: it increases the risk of developing Graves' disease and especially ophthalmopathy (up to a 3-5-fold increase in risk), worsens the response to treatment, and increases the risk of progression after radioactive iodine. Smoking cessation is a mandatory part of management. [18]

Female gender and age 30–60 years are non-modifiable factors. The postpartum period and stressful events are also considered triggers for manifestation in predisposed individuals. Finally, high TRAb titers are associated with a more severe course and risk of ophthalmopathy. [19]

Excessive iodine intake (contrast media, antiseptics, amiodarone) can trigger clinical decompensation and a shift in the immune response, especially in the context of a subclinical autoimmune process. "Hidden" sources of iodine must also be considered. [20]

A family history of autoimmune diseases (including autoimmune thyroiditis, type 1 diabetes, and vitiligo) increases the likelihood of Graves' disease, reflecting a shared genetic background of immune regulation. This does not determine the diagnosis, but it increases the pretest probability in the presence of typical symptoms. [21]

Table 2. Risk factors for Graves' disease

Factor	Level of influence	Comment
Smoking	high	↑ risk and severity of ophthalmopathy, worse response to treatment
Female, ages 30-60	moderate	non-modifiable
Postpartum period/stress	moderate	manifestation triggers
Excess iodine (including amiodarone)	moderate	provocation of thyrotoxicosis
High TRAb	high	marker of activity and risk of OH

Pathogenesis

The trigger is the activation of B cells with the production of TRAb/TSI, which bind to the TSH receptor on thyrocytes. This activates intracellular cascades (cAMP, etc.), enhancing iodide uptake, organification, thyroglobulin synthesis, and hormone exocytosis. The result is diffuse hyperfunction and hypertrophy of the gland. [22]

Tissue-specific autoantigens and HLA presentation pattern characteristics support chronic activation of adaptive immunity. Genetic variations in CTLA4/PTPN22 lower the tolerance threshold, while external factors (smoking, iodine) increase oxidative stress and antigen modification, enhancing their immunogenicity. [23]

Ophthalmopathy is associated with an autoimmune reaction against ophthalmic fibroblasts/adipocyte precursors expressing TSHR and IGF-1R. Activation of these pathways causes swelling, infiltration, and fibrosis of the retrobulbar tissues, which clinically manifests as exophthalmos, diplopia, and pain symptoms. This has led to the targeting of IGF-1R (teoprotumumab). [24]

Thyroid autonomy in Graves' disease is secondary: the gland remains "under control" of immune stimuli, so remission is possible when the autoimmune response subsides (TRAb decreases). This explains the role of long-term drug therapy and the use of TRAb levels to stratify the risk of relapse. [25]

Table 3. Key links in pathogenesis

Link	What's happening	Clinical investigation
TRAb/TSI → TSHR	receptor stimulation	thyrotoxicosis, diffuse hyperplasia
HLA/CTLA4/PTPN22	decreased tolerance	chronicization of autoimmunity
Ophthalmic fibroblasts (TSHR/IGF-1R)	edema, remodeling	exophthalmos, diplopia
High TRAb	activity persistence	↑ risk of relapse, OG

Symptoms

Common manifestations include unintentional weight loss despite a good appetite, heat intolerance, sweating, tremors, muscle weakness, irritability, and insomnia. Warm, clammy skin, thin, brittle hair, and increased reflexes are often noted. In the elderly, an "apathetic" variant with predominant weakness and cardiac symptoms is possible. [26]

Cardiac manifestations include sinus tachycardia, increased pulse pressure, and extrasystole; in the elderly and with concomitant pathology, atrial fibrillation with a risk of thromboembolism. Nocturnal palpitations and decreased exercise tolerance are typical reasons for initial consultation with a cardiologist. [27]

Neuromuscular signs include fine postural tremor, proximal myopathy (difficulty climbing stairs, rising from a chair), and emotional lability. Sleep disturbances and anxiety often mask the diagnosis as "stress/neurosis," which delays referral. [28]

Ophthalmologic symptoms range from a feeling of "wide-open stare," lacrimation, and photophobia to overt ophthalmopathy with exophthalmos, diplopia, and pain behind the eye. Signs of optic nerve compression (decreased visual acuity, "fog") require urgent evaluation and treatment according to EUGOGO guidelines. [29]

Table 4. Symptom groups (for initial examination)

Group	Examples	What to look out for
Metabolic	↓ weight, heat, sweating	"apathetic" variant in the elderly
Cardiac	tachycardia, AF	risk of TEO in AF
Neuromuscular	tremor, weakness, insomnia	masquerading as anxiety disorders
Ophthalmological	photophobia, exophthalmos, diplopia	signs of nerve compression

Forms and stages

Thyrotoxicosis is classified into mild, moderate, and severe forms based on clinical presentation and hormone levels, which determines the choice of initial therapy and the need for hospitalization in the event of threatening complications. The presence of nodules does not rule out Graves' disease (a "mixed" goiter is possible), but requires an assessment for toxic autonomy. [30]

Ophthalmopathy is classified by activity (active/inactive) and severity (mild, moderate-severe, vision-threatening). Activity is assessed using the CAS clinical score, while severity is assessed using the EUGOGO scale (including VISA/NO SPECS in a historical context). This directly influences the choice of anti-inflammatory/targeted therapy. [31]

Special clinical situations include pregnancy, childhood, and old age, as well as combinations with other autoimmune pathologies. In these groups, the choice of antithyroid drugs, the volume and timing of radical interventions, and the goals of monitoring and control vary. For children, the 2022 ETA recommends longer courses of MMI and a balanced approach to radioactive iodine. [32]

Rare, sudden manifestations include pretibial dermopathy and acropachia; they are more common in cases of high autoimmune activity and severe ophthalmopathy. Their presence clarifies the immune "load" and indirectly indicates a high TRAb titer. [33]

Table 5. Classification of ophthalmopathy (EUGOGO 2021, brief)

Parameter	Criteria	Clinical tactics
Activity	CAS ≥ 3/7 - active	anti-inflammatory/immune-targeted therapy
Severity: light	irritation, moderate exophthalmos, without diplopia	observation, selenium in deficient/borderline
Moderate to severe	functional disorders, diplopia	IV methylprednisolone + mycophenolate as 1st line
Vision-threatening	optic neuropathy, keratopathy	emergency steroids ± surgical decompression

Complications and consequences

Cardiovascular complications (AF, heart failure), osteopenia/osteoporosis, and sarcopenia are the main systemic consequences of uncompensated thyrotoxicosis. The risk is higher in the elderly and with long-term progression, so early compensation is key to prevention. [34]

Endocrine and metabolic effects include impaired glucose tolerance, weight loss, and vitamin D/calcium deficiency. In women, menstrual and fertility disturbances are possible, while in men, decreased libido and asthenic symptoms are reversible upon achieving euthyroidism. [35]

Ophthalmopathy can lead to persistent functional defects: diplopia, limited ocular motility, chronic discomfort, and, in severe cases, optic neuropathy. Smoking and high TRAb are risk factors for progression and poorer response. [36]

Thyrotoxic crisis is a rare but life-threatening complication with fever, delirium, and multiple organ dysfunction. It requires intensive care (beta-blockade, antithyroid drugs, iodine, steroids, cholestyramine, and treatment of the trigger). Timely recognition and hospitalization are critical. [37]

Table 6. Common complications and what to do about them

Complication	Risk factors	Prevention/management
Atrial fibrillation	age, severity of thyrotoxicosis	early compensation, beta-blockers, anticoagulation according to CHA₂DS₂-VASc
Osteoporosis/fractures	prolonged thyrotoxicosis	correction of hormones, vitamin D/Ca, assessment of BMD
Ophthalmopathy	smoking, high TRAb, steroid-free RT	smoking cessation, euthyroidism, steroid prophylaxis in rheumatoid arthritis
Thyrotoxic crisis	infection, discontinuation of therapy	intensive care according to ATA/EUGOGO

Diagnostics

Primary laboratory panel: suppressed TSH + elevated free T4 and/or T3. In "T3 toxicosis," free T4 may be normal; free T3 is used as a guide. In modern algorithms, low TSH is the most sensitive screening marker for thyroid dysfunction. [38]

Confirmation of an autoimmune nature: TRAb/TSI are the preferred markers; they help both in the differential diagnosis with thyroiditis/nodular toxic forms and in the prognosis of relapse. In recent years, the use of TSI/TRAb has increased, while scintigraphy is used less frequently, reserved for ambiguous cases. [39]

Instrumentally: Color Doppler ultrasound shows diffuse hypoechogenicity and "thyroid inferno" (rich vascularization). Scintigraphy/radioiodine uptake test demonstrates diffusely increased uptake in Graves' disease and low uptake in destructive thyroiditis; the method is contraindicated in pregnancy. [40]

Before starting antithyroid drugs, a complete blood count and liver function tests are recommended (for safety), followed by monitoring free T4/T3 every 4-8 weeks until euthyroidism. TRH testing and thyroid X-rays are not considered modern diagnostic standards for hyperthyroidism (the TRH test retains niche value when central forms are suspected). [41]

Table 7. Diagnostic "ladder" for suspected Graves' disease

Step	What are we doing?	For what
1	TSH, free T4/T3	we are recording thyrotoxicosis
2	TRAb/TSI	we confirm autoimmune genesis
3	Ultrasound + Doppler	diffuse hypoechogenicity, "inferno"
4	RAIU/scintigraphy*	differentiate from thyroiditis/nodes
*Pregnancy/lactation	contraindication to RAIU/RY	choosing alternatives

Differential diagnosis

Painless/subacute thyroiditis: clinically - recent infection/neck pain (in subacute cases); laboratory findings - low radioiodine uptake, negative TRAb. It is important not to prescribe radioactive iodine for thyroiditis - hyperthyroidism there is "not from synthesis," but from destruction. [42]

Toxic nodular goiter and toxic adenoma are autonomous nodules with "hot" spots on scintigraphy and a heterogeneous pattern on ultrasound; TRAb is usually negative. Treatment is usually radical (radiation/surgery) due to the low probability of remission with antithyroid drugs. [43]

Rare causes: actual thyrotoxicosis (hormonal administration), thyrotropinoma (unsuppressed/high TSH with high hormones, no positive TRH response), gestational thyrotoxicosis. These scenarios require targeted laboratory and imaging verification. [44]

Amiodarone-induced thyrotoxicosis (AIT) is classified into type 1 (iodine-induced hyperfunction, sometimes associated with autonomic dysfunction) and type 2 (destructive thyroiditis); treatment approaches differ (antithyroid drugs vs. steroids). Correct classification is critical. [45]

Table 8. Key differences in the differential diagnosis of thyrotoxicosis

State	TRAb	RAI capture	Ultrasound/Doppler	Tactics
Graves	+	↑ (diffuse)	thyroid inferno	TS, RY or surgery
Painless/subacute thyroiditis	-	↓	hypoecho, low blood flow	symptomatic/steroids
Toxic adenoma/TOX	-	hot spot(s)	local hypervasc.	RY/operation
Thyrotropinoma	-	norm./↑	-	neuroendocrine tactics

Treatment

Antithyroid drugs (ATDs). Methimazole/carbimazole are the drugs of choice in adults (except during the first trimester of pregnancy and thyroid storm), propylthiouracil - in the first trimester and during crisis. Starting doses depend on the severity of thyrotoxicosis, then titration by free T4/T3 every 4-8 weeks. A 12-18-month course provides a chance for remission; TRAb assessment at the end of the course helps decide on discontinuation/extension of therapy. Long courses (>24 months) as a "long-ATD" strategy are increasingly being considered. [46]

Titration vs. block-and-replace regimens. In titration, the ATD dose is gradually reduced to a maintenance dose; in block-and-replace, a fixed, high dose of ATD plus levothyroxine is used. According to the Cochrane review and new studies, relapse rates are similar, but side effects are more frequent with block-and-replace; this regimen may be useful in certain cases for biochemical stability (especially in children according to ETA-2022 – the choice is individual). [47]

Radioactive iodine (RI) therapy. Effective and minimally invasive, especially in cases of relapse after ATD or contraindications. Risk: transient worsening of ophthalmopathy, so steroid supplementation is recommended for patients with risk factors (smoking, high TRAb, pre-existing ophthalmopathy). Contraindicated during pregnancy and lactation. Achieving euthyroidism before RI improves safety. [48]

Thyroidectomy. Indicated for large, compressed goiters, suspected cancer, intolerance/ineffectiveness of ATD, or planning a pregnancy in the near future with high TRAb. Preparation is required (euthyroidism, β-blockers ± potassium iodide), and it should be performed by an experienced team to minimize the risk of hypoparathyroidism and nerve damage. [49]

Symptomatic therapy and adjuvants. Beta-blockers reduce tachycardia and tremor; cholestyramine as an adjunct accelerates the reduction of hormones in severe thyrotoxicosis/crisis; during crisis, glucocorticoids and iodides are added. In patients with mild active ophthalmopathy in regions with deficient/borderline selenium status, 6-month selenium supplementation is indicated. [50]

Treatment of ophthalmopathy. For moderate-severe active OH, EUGOGO recommends first-line: iv methylprednisolone (4.5 g cumulatively over 12 weeks) + mycophenolate; alternatives/escalation: theoprotumumab (anti-IGF-1R, FDA 2020) if available, rituximab/tocilizumab in refractory cases and as indicated. In case of vision threat: emergency pulse steroids ± orbital decompression; strabismus/eyelid surgery is possible in the stable phase. Mandatory: smoking cessation, euthyroidism control, eye protection. [51]

Special groups.

• Pregnancy: in the first trimester - PTSD; after 12-16 weeks, switching to methimazole is preferable due to the hepatotoxicity of PTSD. RI is contraindicated; surgery - in the second trimester if necessary. Planning pregnancy - after stabilization of function. [52]
• Children: according to ETA-2022 - preference is given to long courses of MMI (24-36 months), RI and surgery - according to strict indications taking into account age. [53]

Table 9. Comparison of treatment strategies for Graves' disease

Method	Pros	Cons/risks	Who is it suitable for?
ATD (MMI/KMB, PTU)	chance of remission, avoiding hypothyroidism	skin reactions, agranulocytosis (rare), PTU - hepatotoxicity	first choice for many adults; vocational school - first trimester
RY	reliable ablation, outpatient	risk of worsening of OH, subsequent hypothyroidism	relapses, contraindications to ATD
Thyroidectomy	quick control, removes goiter	surgical risks	large goiter, compression, pregnancy plans
OG therapy (IV MP + MMF; theoprotumumab)	improvement of CAS/exophthalmos	steroid/immune risks; cost	moderate to severe active OH

Prevention

Smoking cessation is key: it reduces the risk of ophthalmopathy onset and progression, improves response to therapy, and reduces the likelihood of worsening ocular symptoms after RI treatment. Patients should be encouraged to quit completely and offered evidence-based support programs. [54]

Maintaining euthyroidism and controlling triggers: avoid excess iodine (contrast agents, dietary supplements), promptly treat intercurrent infections, plan pregnancy while maintaining stable thyroid function, inform doctors of the diagnosis when prescribing potentially influencing drugs (e.g., amiodarone). [55]

Forecast

With timely and appropriate therapy, the prognosis is favorable: most patients achieve symptom control and marker normalization. The risk of relapse after a course of ATD is assessed based on clinical evaluation and TRAb: low/negative TRAb indicate a higher likelihood of sustained remission; if antibodies persist, rhinosinophilic leukemia (RI) or surgery or long-term maintenance ATD therapy are more often considered. [56]

Ophthalmopathy has variable outcomes: mild forms often stabilize with euthyroidism and smoking cessation; in moderately severe active forms, modern regimens (IV steroids + mycophenolate, theoprotumumab when available) significantly improve function and quality of life. Optic neuropathy is an emergency with the risk of irreversible vision loss. [57]

FAQ

1) How is Graves' different from "just hyperthyroidism"?

Graves' disease is a specific autoimmune cause of hyperthyroidism. It is confirmed by TRAb/TSI, a characteristic ultrasound blood flow pattern, and diffusely increased radioiodine uptake. This is important because treatment (including the approach to ophthalmopathy) differs from that of thyroiditis and toxic nodules. [58]

2) Does everyone need scintigraphy?

No. The trend is to use high-precision antibody tests and ultrasound more often; RAIU/scintigraphy is reserved for differential diagnosis, doubts, or planning of RI. It is contraindicated in pregnant women. [59]

3) How long should I take antithyroid medications and how do I know when I can stop taking them?

The typical course is 12–18 months with dose titration; at the end of the course, TRAb is assessed: with normal TSH and low/negative TRAb, the chance of remission is higher. A “long-term ATD” strategy (>24 months) is possible depending on the indications and preferences. [60]

4) Is it possible to be treated with radioactive iodine if there are eye problems?

It is possible, but in cases of active/risky ophthalmopathy, steroid supplementation and mandatory smoking cessation are recommended. In some cases, another strategy (ATD/surgery) is preferable; this is decided individually by the ophthalmological and endocrine team. [61]

5) What's new in eye treatment for Graves' disease?

The targeted drug theoprotumumab (anti-IGF-1R), which has been shown to reduce exophthalmos and diplopia in RCTs, has been approved by the FDA (2020) for the treatment of OH. Availability and cost vary between countries; alternatives include standard steroid regimens, mycophenolate, and, in resistant cases, other immunotherapy agents and/or surgery. [62]

6) Pregnancy and Graves' Disease: What's Important to Know?

In the first trimester, propylthiouracil is preferred; after 12-16 weeks, switch to methimazole. RI is contraindicated; surgery is an option in the second trimester if necessary. It is best to plan pregnancy while maintaining euthyroidism. [63]