bubble_chart Overview

Toxic diffuse goiter is an autoimmune disease whose clinical manifestations are not limited to the thyroid but present as a multisystem syndrome, including hypermetabolic symptoms, diffuse thyroid enlargement, eye signs, skin lesions, and thyroid acropachy. Since most patients exhibit both hypermetabolism and thyroid enlargement, it is referred to as toxic diffuse goiter, also known as Graves' disease. Extrathyroidal manifestations, such as infiltrative endocrine exophthalmos, may occur independently without hypermetabolic symptoms.

bubble_chart Pathogenesis

This disease has been confirmed as an autoimmune disorder, but its pathogenesis is not yet fully understood. One of its characteristics is the presence of autoantibodies in the serum that can react with or stimulate thyroid tissue. These antibodies can stimulate the thyroid glands of rodents, enhance their function, and cause tissue hyperplasia, but their effects are slow and long-lasting. Initially, they were named long-acting thyroid stimulators (LATS). Later, due to the adoption of different measurement methods, they were given other names such as human thyroid stimulator (HTS), LATS protector (LATSP), TSH-displacing activity (TDA), thyroid-stimulating immunoglobulin (TSI), or thyroid-stimulating antibody (TSAb). Collectively, they are referred to as TSH receptor antibodies (TSAb). These are IgG secreted by lymphocytes in this disease, and their corresponding antigens are the TSH receptor or parts adjacent to the thyroid cell membrane. When TSI binds to thyroid cells, the TSH receptor is activated, leading to stimulation of thyroid function, causing hyperthyroidism and goiter. Their effects closely resemble those of TSH. It is now believed that the production of autoantibodies is primarily related to a decrease in the function of suppressor T lymphocytes (Ts) associated with a fundamental defect. The functional defect in Ts leads to inappropriate sensitization of helper T cells and, with the involvement of interleukin-1 and interleukin-2, prompts B cells to produce autoantibodies against the thyroid. Additionally, in this disease, the leukocyte migration inhibition test targeting thyroid tissue shows a positive reaction, and there is significant lymphocyte infiltration in both the thyroid and retrobulbar tissues, indicating the participation of cell-mediated immunity.

A defect in immune surveillance alone cannot explain certain specific immune abnormalities, which also need to be linked to the idiotype cascade mechanism. The variable regions of the heavy and light chains in immunoglobulin molecules contain antigenic determinants, and the specificity of the antibody is determined by the amino acid sequence in this region. Different specificities of the variable regions have different antigenic determinants or idiotypic determinants. For example, when rabbits are immunized with monoclonal human myeloma proteins, the resulting antiserum can specifically bind to the structural features in the variable region of the myeloma immunoglobulin. These structures are called idiotypes. Expanding the application of the idiotype/anti-idiotype principle can explain the formation of receptor antibodies in diseases such as Graves' disease and myasthenia gravis. For instance, in myasthenia gravis, the ligand (acetylcholine) can bind to both the cell surface receptor and its corresponding antibody (anti-acetylcholine, i.e., the idiotype), meaning the receptor and antibody share the same structure that binds the ligand. Similarly, Farid et al. immunized rabbits with anti-human TSH antibodies to obtain anti-idiotypic antibodies, which, in thyroid cell cultures, could both bind to TSH receptors and stimulate cAMP synthesis, behaving like LATS or TSAb in Graves' disease.

In Graves' disease, the autoantibodies against the TSH receptor (TRAb) are a group of polyclonal antibodies that act on different binding sites of the TSH receptor. TRAb can be divided into stimulating and blocking types. Among the stimulating type, one class binds to the TSH receptor and promotes the synthesis and release of thyroid hormones into the blood, while also stimulating thyroid cell proliferation. This is called TSAb (thyroid-stimulating antibody) and is the primary autoantibody in Graves' disease. Another class binds to the TSH receptor but only causes thyroid cell swelling without promoting hormone synthesis and release, known as thyroid growth immunoglobulin (TGI). The blocking type of autoantibodies, upon binding to the TSH receptor, inhibits and suppresses thyroid function, referred to as thyroid function-inhibiting antibody (TFIAb) and thyroid growth-blocking antibody (TGRAb). A small number of Graves' disease patients exhibit significant hypermetabolic symptoms but only mild thyroid enlargement, which may be due to the predominance of TRAb among the stimulating antibodies in their bodies.

Autoimmune surveillance defects are controlled by genetic factors. The disease exhibits a clear familial aggregation, with a 50% concordance rate in monozygotic twins for hyperthyroidism. The occurrence of the disease is associated with certain major histocompatibility complexes (MHC), such as DR₄ antigens or HLA-B₈, B₄₆, etc. Psychological factors, such as emotional trauma or intense anger, serve as significant triggers that can lead to decompensation of the Ts cell population and may also promote the production of cytotoxic effects.

In recent years, extensive research has been conducted on infectious agents and autoimmune thyroid diseases, proposing three possible mechanisms by which bacteria or viruses may initiate autoimmune thyroid disease: ① Molecular mimicry—where the infectious agent and the TSH receptor share highly similar molecular structures at antigenic determinant sites, leading to cross-reactivity of antibodies against the body's own TSH receptors. For example, Yersinia enterocolitica contains TSH receptor-like substances, and 72% of patients with this disease have Yersinia antibodies. ② Direct action of infectious agents on the thyroid and T lymphocytes, where cytokines induce the expression of class II MHC (HLA-DR) on thyroid cells, presenting autoantigens to T lymphocytes as targets for immune responses. ③ Infectious agents produce superantigen molecules that induce T lymphocytes to react against the body's own tissues.

bubble_chart Pathological Changes

(1) Thyroid Gland The thyroid gland shows diffuse enlargement with abundant and dilated blood vessels. The follicular epithelial cells are hyperplastic, forming papillary structures, and the follicular walls exhibit proliferative folds that protrude into the follicular lumen as papillary projections. The Golgi apparatus is hypertrophied, with numerous vesicles nearby, and the endoplasmic reticulum is well-developed, containing many ribosomes. The number of mitochondria is increased. The glandular tissue also displays diffuse lymphocyte infiltration, and even lymphoid tissue germinal centers may be present.

(2) Other Organs In patients with infiltrative exophthalmos, there is an increase in retrobulbar connective tissue and thickening of the extraocular muscles due to edema, caused by the deposition of increased mucopolysaccharides and hyaluronic acid, as well as infiltration by lymphocytes and plasma cells. Similar changes are observed in skeletal and cardiac muscles. In patients with prolonged disease, focal or diffuse necrosis of hepatocytes and periportal fibrosis may be seen. The adenohypophysis shows no specific pathological changes. In a few cases, symmetric localized pretibial myxedema may occur in the lower limbs, characterized by thickened skin and lymphocyte infiltration.

bubble_chart Clinical Manifestations

This disease is more common in women, with a male-to-female ratio of 1:4–6, and is most frequently seen in individuals aged 20–40. The onset is slow. In typical cases, the condition may be confused with functional neurosis if symptoms are mild. Some patients may present primarily with specific symptoms such as exophthalmos, cachexia, or myopathy (see later sections). The manifestations in elderly and pediatric patients are often atypical. In recent years, due to gradual improvements in diagnostic capabilities, the detection of mild and atypical cases has increased. Typical cases often exhibit the following manifestations.

(1) **Nervous System** Patients are prone to irritability, mental hypersensitivity, fine tremors in the tongue and hands when extended forward, talkativeness, hyperactivity, insomnia, tension, difficulty concentrating, anxiety, dysphoria, and indecisiveness. Some may experience hallucinations or even hypomania, while others may exhibit reticence or depression. Tendon reflexes are hyperactive, and reflex time is shortened.

(2) **Hypermetabolic Syndrome** Patients experience heat intolerance, profuse sweating, and flushed skin on the palms, face, neck, and armpits. Low-grade fever is common, and high fever may occur during a crisis. Patients often have tachycardia, palpitations, markedly increased appetite, weight loss, and fatigue.

(3) **Thyroid Gland Enlargement** A few patients primarily complain of thyroid enlargement. The thyroid is diffusely and symmetrically enlarged, soft, and moves downward during swallowing. In rare cases, the enlargement may be asymmetrical or pronounced. Due to increased blood flow in the thyroid, vascular murmurs and tremors may be auscultated or palpated, particularly in the upper lobes. Diffuse, symmetric thyroid enlargement accompanied by murmurs and tremors is a distinctive

sign of this disease and holds significant diagnostic value. However, it should be distinguished from venous hums and carotid bruits.

(4) **Eye Manifestations** Two special ocular signs are associated with this disease: 1. **Non-infiltrative Exophthalmos** (also called benign exophthalmos), which accounts for the majority of cases. It is generally symmetrical, though one eye may be more prominent than the other. It is primarily caused by sympathetic overstimulation of the extraocular muscles and increased tension in the levator palpebrae superioris (Müller’s muscle). The changes mainly involve the eyelids and external eye, with minimal alterations in retrobulbar tissues. The ocular signs include: - Widening of the palpebral fissure (Dalrymple’s sign). - Infrequent blinking and staring (Stellwag’s sign). - Impaired or absent convergence (Möbius’ sign). - Upper eyelid lag upon downward gaze (von Graefe’s sign). - Absence of forehead wrinkling upon upward gaze (Joffroy’s sign).

2. **Infiltrative Exophthalmos** (also called endocrine exophthalmos, ophthalmoplegic exophthalmos, or malignant exophthalmos) is less common and more severe. It may occur in patients with不明显 hyperthyroidism or no hypermetabolic symptoms. It is mainly caused by increased volume of extraocular muscles and retrobulbar tissues, lymphocyte infiltration, and edema (discussed in detail later).

(5) **Cardiovascular System** Patients report palpitations and shortness of breath, which worsen with minimal activity. Severe cases may present with arrhythmias, cardiomegaly, and heart failure.

1. **Tachycardia** is typically sinus, with a heart rate of 100–120 beats per minute. The persistence of tachycardia at rest or during sleep is a characteristic feature of this disease and serves as an important diagnostic and therapeutic parameter.

2. **Arrhythmias** are most commonly premature beats, but paroxysmal or persistent atrial fibrillation, atrial flutter, and atrioventricular block may also occur.

3. **Heart Sounds and Murmurs** The heartbeats are forceful, and the first heart sound at the apex is accentuated. A systolic murmur, similar to that of mitral regurgitation, is often heard. Occasionally, a diastolic murmur may be auscultated at the apex.

4. **Cardiac Hypertrophy, Dilation, and Congestive Heart Failure** are more common in older male patients with severe disease. Concurrent infections or the use of β-blockers may predispose to heart failure.

5. Systolic stirred pulse Blood pressure increases, diastolic pressure is slightly lower or normal, and pulse pressure increases. This is due to the rich thyroid blood flow in this disease, increased stirred pulse anastomotic branches, and increased stroke volume and minute output.

(6) Digestive System Increased appetite with significant weight loss often suggests the possibility of this disease or diabetes. Excessive thyroid hormone can stimulate intestinal peristalsis, leading to increased frequency of bowel movements. Sometimes, malabsorption of fats may result in steatorrhea. Thyroid hormones can also have a direct toxic effect on the liver, causing hepatomegaly, BSP retention, and elevated GPT levels.

(7) Blood and Hematopoietic System In this disease, the total white blood cell count in peripheral blood is often low, with increased percentages and absolute values of lymphocytes and monocytes. Platelet lifespan is also shorter, and purpura may occasionally occur. Due to increased consumption, malnutrition, and impaired iron utilization, anemia may occasionally develop.

(8) Locomotor System The main manifestation is muscle weakness, and a few cases may present with thyrotoxic myopathy.

(9) Reproductive System Female patients often experience reduced menstruation, prolonged cycles, or even amenorrhea, though some may still conceive and give birth. Males often experience impotence, and occasionally gynecomastia.

(10) Skin and Extremities A small number of patients exhibit typical symmetrical myxedema, though this is not hypothyroidism, and it most commonly appears on the lower legs. Initially, the skin lesions are dark purplish-red, with thickened skin that later becomes scaly or nodular, eventually resembling tree bark, and may be accompanied by secondary infections and pigmentation. In rare cases, soft tissue swelling of the fingers (clubbing), subperiosteal new bone formation in the metacarpal and phalangeal bones, and separation of the nail from the nail bed at the distal edge (acropachy) may be observed.

(11) Endocrine System Excessive thyroid hormone can affect gonadal function. In the early stages of this disease, adrenal cortical function is often hyperactive, but in severe cases (such as crisis), it may become relatively impaired or even insufficient. Pituitary ACTH secretion increases, and while plasma cortisol levels remain normal, its clearance rate accelerates, indicating faster metabolism and utilization.

bubble_chart Auxiliary Examination

1. Measurement of serum total thyroxine (total T₄). If the patient's thyroxine-binding globulin (TBG) is estimated to be normal, an elevated T₄ (exceeding 12 ng/dl) suggests hyperthyroidism. If TBG abnormalities are suspected, the I¹²⁵-T₃ binding ratio should be measured (normal: 0.99 ± 0.1; hyperthyroidism: 0.74 ± 0.12) and multiplied by the T₄ value to correct for TBG abnormalities, calculating the free thyroxine index (FT₄I), which is elevated in patients with this condition. If normal, further testing should be pursued.

2. Serum total T₃ normal range is 100–150 mg/dl, which is elevated in this condition, often more significantly than total T₄.

3. Measurement of reverse T₃ (rT₃). The normal mean serum rT₃ is 50 ng/dl, which is significantly elevated in hyperthyroidism.

4. Free T₄ (FT₄) and free T₃ (FT₃). The measurement results of FT₄ and FT₃ are unaffected by the aforementioned TBG and can more accurately reflect the functional status of T₄ compared to total T₄ and T₃. Normal ranges: FT₄ is 10.3–25.7 pmol/L, and FT₃ is 2.2–6.8 pmol/L. Results in hyperthyroid patients are significantly higher than the upper limit of normal.

5. Thyroid ¹³¹I uptake. If iodine uptake is elevated—greater than 25% at 3 hours or greater than 45% at 24 hours (proximity method)—with an early peak, it may align with this condition. However, a T₃ suppression test should be performed to differentiate it from simple goiter.

6. T₃ suppression test. The method is as described earlier. In normal individuals and those with simple goiter, the second ¹³¹I uptake rate decreases significantly, by 50% or more. In this condition and in patients with infiltrative exophthalmos, TSH stimulation of the thyroid is replaced by TSAb and is not suppressed by T₃ or T₄. Therefore, after administering T₃ 20 μg every 8 hours for one week, the second ¹³¹I uptake rate is not suppressed or decreases by less than 50%. This method is not suitable for elderly patients with coronary heart disease to avoid arrhythmias or angina.

7. Thyrotropin-releasing hormone (TRH) stimulation test. A normal response indicates a healthy patient. If TSH is nearly zero or, using a highly sensitive immunometric assay, TSH is below normal and unresponsive to TRH stimulation, it may suggest hyperthyroidism (including T₃ hyperthyroidism). This test is similar in significance to the T₃ suppression test and avoids the drawbacks of T₃ intake affecting the heart or exacerbating symptoms. Unfortunately, reagent availability is not yet widespread.

8. TSAb or TSI The positive rate in patients with this disease is about 80-90%. After treatment and symptom relief, the activity of TSAb significantly decreases or returns to normal, which is beneficial for follow-up efficacy evaluation and assessing the possibility of recurrence after treatment. Clinically, this is also often used to determine the appropriate time to discontinue antithyroid drugs.

9. Anti-thyroglobulin antibody (TGA) and anti-thyroid microsomal antibody (MCA)  In this disease, both TGA and MCA can be positive, but their titers are much lower than those in Hashimoto's thyroiditis.

bubble_chart Diagnosis

The diagnosis of typical cases is generally not difficult. For mild cases, or elderly and pediatric patients with minimal and atypical clinical manifestations, diagnosis often requires laboratory tests.

(1) Clinically significant manifestations Special attention should be paid to heat intolerance, profuse sweating, irritability, increased appetite with weight loss, tachycardia at rest, characteristic eye signs, and goiter. The presence of vascular murmurs or tremor over the thyroid gland further supports the diagnosis.

(2) Thyroid function tests For suspected cases with atypical presentations, the following tests may be selected in sequence (details refer to laboratory examinations) to aid diagnosis:

1. Serum total thyroxine (total T₄) measurement

2. Serum total T₃ and total T₄.

3. Reverse T₃ (rT3) measurement

4. Free T₄ (FT4) and free T₃ (FT₃)

5. Thyroid ¹³¹I uptake rate

6. T₃ suppression test

7. Thyrotropin-releasing hormone (TRH) stimulation test

8. TSAb or TSI

9. Anti-thyroglobulin antibody (TGA) and anti-thyroid microsomal antibody (MCA)

Under normal circumstances, hyperthyroid patients exhibit elevated serum concentrations of T₃, rT₃, and T₄, with FT₃ and FT₄ being more reliable indicators. The increase in T₃ is typically more pronounced than that of T₄. Thus, in early stages when T₄ has not yet exceeded normal levels, T₃ and rT₃ already show significant elevation. Subnormal TSH levels are only detectable through highly sensitive immunoradiometric assays. Thyroid ¹³¹I uptake rate is commonly used in T₃ suppression tests.

bubble_chart Treatment Measures

The cause of this disease is unknown, so there is currently no treatment targeting the disease cause. The primary focus is on controlling hypermetabolic symptoms and promoting the normalization of immune surveillance.

General Treatment

Eliminate factors detrimental to the disease, such as mental stress. During the initial stage of treatment, provide appropriate rest and various supportive therapies, supplementing sufficient calories and nutrients like sugars, proteins, and vitamins to correct the wasting caused by the disease.

Hyperfunction Treatment

The fundamental methods to control hyperthyroidism symptoms are: ① antithyroid drugs; ② radioactive iodine isotopes; ③ surgery. Among these, antithyroid drug therapy is the most convenient, safe, and widely used. Chinese medicine and Chinese medicinals also have some effect for mild cases: iodine preparations are only used for crisis and preoperative preparation; β-blockers are mainly used as adjuvant therapy or preoperative preparation, and are also used alone to treat this disease. The main treatment methods for hyperthyroidism are detailed below.

(1) Antithyroid Drug Therapy This group of drugs includes several types, with thioureas being the primary ones. The most commonly used are propylthiouracil (PTU), methimazole (Tapazole), and carbimazole. Others like thiocyanates or perchlorates are not used for treatment due to their inferior efficacy compared to thioureas and their potential to cause nephropathy and aplastic anemia. Lithium compounds, although they can block the effects of TSH and TRAbs on the thyroid, are rarely used due to severe side effects such as nephrogenic diabetes insipidus and mental depression. This chapter mainly discusses the application of thioureas. Their pharmacological action involves inhibiting the peroxidase system within the thyroid, preventing the conversion of iodide ions to nascent or active iodine, thereby hindering thyroid hormone synthesis. Propylthiouracil also blocks the conversion of T⁴ to T₃ and improves immune surveillance function, but it has no effect on already synthesized hormones, so it takes several days for the effects to become apparent after administration.

1. Indications for Antithyroid Drugs Suitable for: ① patients with mild symptoms and grade I to II thyroid enlargement; ② adolescents and children under 20, as well as elderly patients; ③ pregnant women; ④ patients with recurrence after subtotal thyroidectomy who are unsuitable for radioactive ¹³¹ iodine therapy; ⑤ preoperative preparation; ⑥ adjuvant therapy for radioactive ¹³¹ iodine treatment.

Antithyroid drugs are not suitable for patients with persistent peripheral blood white cell counts below 3,000/mm³ or those allergic to the drugs.

2. Dosage and Treatment Course The treatment course varies significantly among individuals. Recently, some reports suggest that single-dose short-term therapy (averaging only 3–5 months) can achieve similar results to long-term therapy. However, long-term therapy (2 years or more) yields better outcomes than short-term therapy. Long-term antithyroid drug therapy can restore suppressor T-lymphocyte function and reduce TSAb production, whereas short-term therapy has a higher relapse rate. The medication period can generally be divided into three stages.

(1) Initial Treatment Phase: The monthly dosage of propylthiouracil or methimazole is 300–400mg or 30–40mg, respectively. For more severe cases, higher doses may be used, divided into three doses taken every 8 hours. If no clinical improvement is observed after 2–3 weeks, the dose may be increased, but generally should not exceed 60mg per day. The initial phase typically lasts 1–3 months, with an average daily reduction in BMR of about 1%. If symptoms remain significant after 3 months of medication, check for interfering factors such as irregular dosing, iodine intake, or stressors like mental or infectious stress.

(2) Dose reduction phase: When symptoms are significantly relieved, body weight increases, heart rate decreases to 80-90 beats per minute, and T₃ or T₄ levels approach normal, the dosage can be gradually reduced every 2-3 weeks based on the patient's condition, with each reduction being 5mg. During the dose reduction process, regular follow-ups should be conducted to monitor clinical manifestations, basal heart rate, body weight, white blood cell count, as well as T₄ and TSH levels when necessary. The dose reduction should not be too rapid, and efforts should be made to maintain normal and stable thyroid function, gradually transitioning to the maintenance phase, which generally takes about 2-3 months.

(3) Maintenance phase: The daily dosage is 5-10 mg, which can be further reduced to 2.5-5.0 mg before discontinuation, lasting approximately 1-1.5 years. For unstable patients unwilling to adopt other treatment plans, the maintenance phase may be extended to 2-3 years or longer.

Throughout the course of treatment, it is essential to avoid intermittent medication. At any stage, if stress factors such as infection or psychological issues arise, the dosage should be adjusted as needed and then gradually reduced once stability is restored. With the above treatment, about 50% of patients with this condition can achieve a full recovery.

3. Drug reactions: The types and incidence rates of toxic reactions from various antithyroid drugs are generally similar. The main reactions include:

(1) Leukopenia: In severe cases, agranulocytosis may occur, with methylthiouracil being the most common cause and propylthiouracil the least. This typically occurs within the first 2-3 months of medication but can happen at any time during the treatment. Therefore, during the initial treatment phase, total white blood cell count and differential should be monitored every 1-2 weeks, and during the dose-reduction and maintenance phases, every 2-4 weeks. If the white blood cell count falls below 4,000/mm³, close observation is required. If it recovers, another antithyroid drug may be substituted under close monitoring. Alternatively, the medication may be continued temporarily with a short-term increase in prednisone (10 mg, three times daily). Sudden agranulocytosis is primarily an allergic reaction to the drug, often accompanied by symptoms such as sore throat, fever, lack of strength, and joint pain, requiring emergency treatment. Thus, if these symptoms appear during medication, the total white blood cell count and differential should be checked immediately. Additionally, some patients may already have leukopenia (below 4,000/mm³) before starting medication. In such cases, antithyroid drugs may be tried under close observation, and sometimes the white blood cell count may even increase.

(2) Drug rash: Most cases are mild, with severe exfoliative dermatitis being extremely rare. For general drug rashes, antihistamines may be administered, or another antithyroid drug may be substituted. If signs of exfoliative dermatitis appear, the drug should be discontinued immediately, and adrenal corticosteroids should be administered.

(3) Others: Some patients may experience elevated serum alanine aminotransferase (ALT) levels after taking antithyroid drugs. In such cases, liver-protecting drugs may be added, and the medication may be continued under close observation or switched to another antithyroid drug. If jaundice occurs, extra caution is required. Other possible side effects include headache, vertigo, arthralgia, and gastrointestinal symptoms.

(B) Adjuvant drug therapy: Antithyroid drugs do not rapidly control the various symptoms of patients, especially those related to increased sympathetic nervous system activity. Therefore, during the first 1-2 months of antithyroid drug therapy, a beta-blocker such as propranolol (10-20 mg, three times daily) may be used in combination to improve symptoms such as palpitations, tachycardia, nervousness, tremor, and profuse sweating. Propranolol can also be used for rapid preparation before thyroid crisis, emergency thyroid surgery, or radioactive ¹³¹ iodine therapy, and it has some efficacy in acute and chronic thyrotoxic myopathy. However, it is contraindicated in patients with bronchial asthma, atrioventricular block, heart failure, or during childbirth, and should be used cautiously in insulin-dependent diabetes.

At the beginning of the dose-reduction phase, a small dose of thyroid extract tablets (0.03-0.06 g daily) or levothyroxine (50-100 μg daily) may be added to stabilize the hypothalamic-pituitary-thyroid axis, prevent thyroid enlargement and worsening of exophthalmos. Some reports suggest that thyroid hormone therapy, whether combined with antithyroid drugs or continued alone after discontinuation of antithyroid drugs, may reduce thyroid autoantibodies and decrease the recurrence rate of hyperthyroidism.

Iodides inhibit the synthesis of thyroid hormones (Wolff-Chaikoff effect), as discussed in the physiology section. However, both normal individuals and patients with hyperthyroidism soon develop an escape phenomenon from this inhibitory effect due to the weakening of the thyroid's active transport of iodides, rendering the inhibition clinically ineffective after a few weeks. Since iodides also suppress the release of thyroid hormones, leading to an accumulation of hormones within the thyroid gland, the subsequent use of antithyroid drugs would significantly prolong the treatment course, increase dosage requirements, and reduce remission rates to 50%. Therefore, antithyroid drugs must be administered before iodides. Long-term use of iodine preparations may also cause hypothyroidism or hyperthyroidism, which is why they are currently reserved for managing thyroid storm or preoperative preparation for hyperthyroidism surgery, as well as for reducing side effects after radioactive ¹³¹ iodine therapy.

After determining the dose, it is administered orally once on an empty stomach, which is the method adopted by most domestic institutions. Some advocate small divided doses, believing it can reduce treatment reactions, observe individual sensitivity, and allow dose adjustments. However, this method prolongs the treatment course, making it difficult to control the patient's hyperthyroid state for an extended period. It is only considered when the condition is severe or the total single dose is too large (exceeding 740MBq [20mCi]). Initially, two-thirds of the total dose is given, followed by observation for 1.5 to 2 months before deciding whether to administer the second treatment (the remaining one-third of the dose).

(3) Radioactive ¹³¹Iodine Therapy

1. Principle The thyroid gland has a highly selective ability to concentrate ¹³¹iodine. During the decay of ¹³¹iodine, it emits β and γ rays (99% β rays and only 1% γ rays). The range of β rays in tissue is only about 2mm, so the ionization radiation is limited to the thyroid locally without affecting adjacent tissues (such as the parathyroid glands). The effective half-life of ¹³¹iodine in the thyroid averages 3 to 4 days, allowing ionization radiation to destroy most thyroid follicular epithelial cells, thereby reducing thyroid hormone production and achieving therapeutic effects similar to surgical resection.

2. Indications and Contraindications Opinions vary regarding the indications and contraindications for ¹³¹iodine therapy for this condition. We advocate the rational selection of radioactive ¹³¹iodine therapy, carefully considering its indications and contraindications, especially long-term effects.

⑴ Indications: ① Age 25 or older; ② Patients allergic to antithyroid drugs who cannot continue treatment, or those with long-term treatment failure or relapse after discontinuation; ③ Patients with recurrence after subtotal thyroidectomy; ④ Patients with comorbid heart disease, diabetes, or severe liver or kidney disease who are contraindicated for surgical resection; ⑤ Hyperthyroidism with exophthalmos; ⑥ Patients with an effective half-life of ¹³¹I conversion in the thyroid of no less than 3 days.

⑵ Radioactive ¹³¹iodine therapy is not suitable for the following situations: ① Pregnancy or breastfeeding women; ② Age under 25 (antithyroid drug therapy is preferred); ③ Patients with severe or active liver or kidney disease; ④ Peripheral blood leukocyte count less than 3000/mm³ (but may still be considered if the neutrophil count exceeds 2000/mm³ or improves after treatment); ⑤ Grade III hyperthyroidism patients; ⑥ Nodular goiter with hyperfunction, showing "cold nodules" on scan.

3. Treatment Methods and Dose   The treatment dose has a decisive impact on efficacy and long-term complications. The dose of ¹³¹ iodine depends on the size of the thyroid gland, the maximum uptake of ¹³¹ iodine in the thyroid, the effective half-life of the thyroid, and the sensitivity of the thyroid to ionizing radiation. However, the latter is difficult to estimate, so the weight of the thyroid and the maximum absorption rate of ¹³¹ iodine are usually used as references for determining the dose. There are three methods for estimating thyroid weight: ① Palpation diagnostic method; ② X-ray examination; ③ Thyroid imaging. The combination of the palpation diagnostic method and thyroid imaging is considered more reliable for physiological estimation and mutual correction, though some margin of error remains. Most authors recommend administering 2.6–3.7 MBq (70–100 μCi) of ¹³¹ iodine per gram of thyroid tissue in a single dose, with the average absorbed radiation dose for the entire thyroid being 50–70 Gy (5000–7000 rad). The calculation is generally based on the following formula, with appropriate adjustments to the dose according to the effective half-life of ¹³¹ iodine in the thyroid.

4. Precautions Before and After Treatment The calculated dose based on the above formula must not be applied mechanically. It should be comprehensively considered based on factors such as the severity of the condition, previous treatment history, age, the effective half-life of ¹³¹ iodine in the thyroid, and the presence of thyroid nodules. Avoid iodine-containing agents, foods, or medications 2–4 weeks before taking ¹³¹ iodine. For patients with severe conditions before ¹³¹ iodine treatment, such as a heart rate exceeding 120 beats per minute or significantly elevated serum T₃ and T₄ levels, it is advisable to first use antithyroid drugs or propranolol to alleviate symptoms before proceeding with radioactive ¹³¹ iodine treatment. Opinions vary on how long patients taking antithyroid drugs should discontinue them before ¹³¹ iodine treatment. We recommend that antithyroid drugs can be taken until 2–3 days before administering ¹³¹ iodine, followed by a ¹³¹ iodine uptake test, and then proceeding with ¹³¹ iodine treatment. Since the therapeutic effect of ¹³¹ iodine is slow to manifest, patients who previously used antithyroid drugs may resume such treatment early (1–2 weeks) after taking ¹³¹ iodine to urgently control the condition.

5. Efficacy and Complications The efficacy of ¹³¹ iodine treatment for this condition is generally over 90%. The effects typically appear around the 3rd–4th week after taking ¹³¹ iodine, with symptoms gradually improving month by month; the thyroid shrinks, weight increases, and most patients achieve normal thyroid function levels within 3–4 months. In a minority of patients, the effect of ¹³¹ iodine is slower, with symptoms only gradually improving after 6 months of treatment. Statistics show that two-thirds of cases are cured with a single dose, while about one-third require a second treatment, of which one-third may need a third or more courses to achieve full recovery. Generally, repeat treatments should be spaced at least 6 months apart. If symptoms are mild or only involve autonomic dysfunction, a longer observation period is advisable before considering repeat treatment. Such cases often respond satisfactorily to supplementary low-dose antithyroid drug therapy. ¹³¹ iodine treatment usually causes mild short-term reactions, with slight swelling in the thyroid area. Due to radioactive thyroiditis, the release of thyroid hormones into the bloodstream increases, potentially causing a slight worsening of hyperthyroidism symptoms in the first week after treatment. Therefore, palpation or compression of the thyroid should be avoided in the first week after taking ¹³¹ iodine. In rare severe cases where antithyroid drugs were not used before treatment, thyroid storm is more likely to occur, so close monitoring is recommended post-treatment, with care to avoid emotional stress or infection.

Long-term complications include:

⑴ Hypothyroidism: This is a relatively prominent complication after ¹³¹ iodine treatment. According to a series of studies abroad, in the standard dosage group, where 3.7 MBq (100 μCi) of ¹³¹ iodine is administered per gram of thyroid tissue, the incidence of hypothyroidism in the first year after treatment is approximately 5–10%, increasing by 2–3% annually thereafter. After more than 10 years of treatment, the incidence can reach 30–70%. In recent years, domestic long-term follow-up data also show a significant increase in the incidence of hypothyroidism, which is attributed to the improved diagnostic sensitivity of serum TSH radioimmunoassays. Based on our hospital’s follow-up of 64 cases between 1958 and 1980, the incidence of ¹³¹ iodine treatment-induced late-stage [third-stage] hypothyroidism was 25% at 2–5 years, 50% at 6–10 years, and 83.5% at 16–20 years, with an overall incidence of 52.08%.

There are three possible hypotheses for the causes of hypothyroidism: First, ¹³¹Iodine treatment dose is too high, destroying excessive thyroid tissue. The second hypothesis suggests that ionizing radiation may cause injury to cell nuclei, preventing division and regeneration, leading to progressively worsening thyroid function over time. The third hypothesis attributes it to autoimmune reactions.

⑵ Carcinogenic concerns: Over approximately 30 years of clinical application of this therapy, the incidence rates of leukemia and stony goiter (thyroid carcinoma) have not increased compared to their natural occurrence rates. An analysis of stony goiter (thyroid carcinoma) incidence across three treatment methods showed: ¹³¹Iodine treatment group (22,714 cases) at 0.1%, surgical group (11,732 cases) at 0.5%, and antithyroid drug group (1,238 cases) at 0.3%. Another report noted 18 cases of leukemia among 60,000 ¹³¹Iodine-treated patients, a rate no higher than the natural incidence in the general population. Domestically, over 50,000 cases of hyperthyroidism have been treated with ¹³¹Iodine, with only 2 reported leukemia cases—again, no higher than the general population’s natural incidence. Moreover, both cases occurred about a year after ¹³¹Iodine treatment, with a relatively short onset time, leaving doubt as to whether they were directly related to the treatment. Since younger patients are more sensitive to ionizing radiation, some reports indicate a higher incidence of stony goiter (thyroid carcinoma) in infants and children who received neck X-ray therapy. Therefore, as a precaution, patients under 25 years old should opt for alternative treatments.

⑶ Genetic effects: Hyperthyroidism patients treated with ¹³¹Iodine show no impact on fertility, with no increased rates of congenital malformations, dead fetus, or premature labor in offspring. The incidence of infertility does not differ significantly from the general population. Data from domestic and international sources confirm that many ¹³¹Iodine-treated patients have had healthy children, including some female patients who previously suffered from infertility due to endocrine disorders caused by hyperthyroidism but later conceived after treatment. While some have observed chromosomal variations post-{119|}131Iodine treatment, these tend to normalize over time. Thus, the biological and clinical significance of such variations requires further study. Although current genetic perspectives suggest that ¹³¹Iodine treatment poses minimal risk for gene mutations and chromosomal aberrations, the long-term effects of ionizing radiation necessitate extended follow-up to draw definitive conclusions. To safeguard the health of future generations, pregnancy is reasonably listed as a contraindication for ¹³¹Iodine treatment.

⑷ Worsening exophthalmos: This occurs in only a small fraction of patients. Most experience varying degrees of improvement post-treatment.

（四）Surgical treatment: Subtotal thyroidectomy achieves remission in over 90% of patients, with postoperative TRAbs levels declining—though the mechanism remains unclear.

1. Preoperative Preparation Generally, antithyroid drugs are first used to control the condition, bringing the heart rate down to below 80–90 beats per minute and restoring T₃ and T₄ blood levels to normal. Then, compound formula iodine solution is added to prevent relapse. Initially, it is administered three times daily, 3–5 drops each time, gradually increasing to 10 drops per dose over several days. This regimen is maintained for two weeks before surgery. By this time, thyroid congestion and edema are significantly reduced, and the tissue becomes firmer, facilitating the surgical procedure and minimizing bleeding. In recent years, propranolol or propranolol combined with iodides has been used for preoperative preparation, yielding rapid results. The heart rate typically drops noticeably within 2–3 days. The usual protocol involves taking 40mg every 6–8 hours for one week before surgery, followed by an additional week of consolidation postoperatively.

2. Indications and Contraindications Surgical indications include: ① Significant thyroid enlargement with compression of adjacent organs; ② Large thyroid gland with ineffective antithyroid drug therapy or recurrence after discontinuation; ③ Nodular goiter with hyperthyroidism; ④ Substernal thyroid; ⑤ Patients unable to adhere to long-term medication and seeking rapid disease control.

Surgical contraindications include: ① Second thyroid surgery with extensive adhesions; ② Severe exophthalmos with potential postoperative worsening; ③ Patients with other serious illnesses or conditions unsuitable for surgery, such as elderly or frail patients, active heart, liver, or kidney diseases, and pregnancy.

3. Surgical Complications ① Local bleeding, with vigilance for potential asphyxia; tracheotomy may be necessary; ② Injury to the recurrent laryngeal nerve or superior laryngeal nerve, leading to hoarseness (approximately 0.5%); ③ Injury or removal of parathyroid glands, causing temporary or permanent hand and foot convulsions; ④ Worsening of exophthalmos; ⑤ Permanent hypothyroidism, with an incidence of approximately 10–15% after 10 years post-surgery; ⑥ Local wound infection.

（5）Traditional Chinese Medicine Treatment This condition is often classified in TCM as yin deficiency liver depression or ascendant hyperactivity of liver yang, with subduing yang as the treatment principle. Herbs such as Unprocessed Rehmannia Root, Peony Root, Asparagus Root, Ophiopogon Tuber, Prunella, turtle carapace, Tortoise Carapace, oyster shell, and Nacre may be used, with modifications based on symptoms as adjunctive therapy. For adenomas, add sun euphorbia, Appendiculate Cremastra Pseudobulb, and Xiaojin tablets. When combined with Western medicine, ensure the iodine content in herbs is not excessively high to avoid compromising efficacy.

（6）Selection of Treatment for Diffuse Hyperthyroidism and Efficacy Evaluation Although the three basic therapies mentioned above can effectively control the disease, the most suitable treatment plan should be selected based on a comprehensive analysis of the patient's age, size and nature of the thyroid gland, disease severity, and other relevant factors (refer to Table 15-24 for treatment selection).

Table 15-24 Treatment Options for Toxic Diffuse Goiter

Factors such as age	Treatment selection
（1）Age	Antithyroid drugs (ATD)
Newborns and children	1. First-line ATD; 2. If ATD is ineffective or recurs, and thyroid enlargement is significant, consider surgery.
<20歲	1. Consider radioactive 131 iodine; 2. If ATD is ineffective or recurs, or adverse reactions prevent continued use, prioritize surgery, then consider radioactive 131 iodine (RAI) therapy.
<40歲	1. Mild cases: ATD; 2. Grade II or higher with significant thyroid enlargement, if ATD is expected to be ineffective or adverse reactions prevent continued use, prioritize RAI therapy, then consider surgery.
>40 years
（2）Factors other than age
Thyroid nodules or suspected malignancy	First-line surgical treatment
Severe diffuse thyroid enlargement	First-line surgical treatment
Recurrence Postoperative recurrence	ATD or RAI treatment for those >20 years old
Recurrence after ATD	Surgery or ATD treatment, RAI treatment is also an option for those >20 years old
Not cured after RAI	ATD or second RAI treatment
Complicated with pregnancy	ATD is the first choice, surgery should be performed during the 4th to 6th month of pregnancy
Complicated with severe conditions such as heart disease	First choice is ATD or RAI treatment
Allergic to ATD	After propranolol preparation,<20歲者手術，>consider surgery or RAI for those >20 years old
Accompanied by leukopenia (<3000/mm3)	Continue ATD with short-term prednisone use; if ineffective, switch to other options. For those >20 years old, consider RAI if prednisone is ineffective, or surgery after propranolol and iodine preparation
Accompanied by infiltrative exophthalmos	First choice is ATD, try RAI for those >20 years old

In recent years, the normalization of the patient's hypothalamic-pituitary-thyroid axis and the disappearance of TRAbs in the serum have been used to estimate whether the disease has been relieved. If the TRH stimulation test, T₃ suppression test return to normal, and serum TRAbs decrease or disappear, with T₃, T₄, and TSH returning to normal, it indicates the axis has normalized, and most patients can expect lasting remission. Otherwise, treatment should continue to prevent relapse. Due to significant individual differences among patients, the required treatment duration varies—some achieve satisfactory remission in just 3–4 months, while others may require 2–3 years and still relapse after stopping medication. Therefore, it is necessary to make judgments based on specific conditions, considering the hypothalamic-pituitary-thyroid axis relationship and serum TRAbs.

bubble_chart Differentiation

During differential diagnosis, the following conditions should be considered: ① Simple goiter. Apart from thyroid enlargement, there are no aforementioned symptoms or signs. Although 131I uptake may sometimes be increased, the T3 suppression test mostly shows suppressibility. Serum T3 and rT3 levels are normal. ② Neuro Guanneng disorder. ③ Autonomous hyperfunctioning thyroid nodule, where scanning shows radioactivity concentrated in the nodule: upon TSH stimulation and repeat scanning, increased radioactivity in the nodule can be observed. ④ Others. Subcutaneous node disease and Bi disease often present with low-grade fever, profuse sweating, tachycardia, etc. Cases primarily manifesting as diarrhea are often misdiagnosed as chronic colitis. Hyperthyroidism in the elderly often presents atypically, with symptoms such as apathy, anorexia, and significant weight loss, easily misdiagnosed as cancer. Unilateral infiltrative exophthalmos needs to be differentiated from intraorbital and cranial base tumors. Hyperthyroidism accompanied by myopathy requires differentiation from familial periodic paralysis and myasthenia gravis.