Toxic diffuse goiter



OVERVIEW

Definition

Toxic diffuse goiter is an autoimmune disorder that is the leading cause of hyperthyroidism and can manifest as thyrotoxicosis, a diffuse enlargement of the thyroid gland.

Thyrotoxicosis is a group of clinical syndromes characterized by increased excitability of the nervous, circulatory, and digestive systems and hypermetabolism caused by overproduction of thyroid hormones in the blood circulation.

Morbidity

The results of a study conducted in China between 2015-2017 showed that the prevalence of toxic diffuse goiter was about 0.53%, with a significantly higher prevalence in women than in men [10].

Etiology

Causes of the disease

Immunologic factors

Toxic diffuse goiter is an organ-specific autoimmune disease, and the specific autoantibodies are thyroid-stimulating hormone receptor antibodies (TRAb), of which thyroid-stimulating antibodies (TSAb) are the pathogenic antibodies that cause hyperthyroidism and are present in more than 90% of patients.

Genetic factors

Studies of twins have found a higher concordance rate of 30% to 60% in identical twins and 3% to 9% in dizygotic twins, which is significantly higher than the general prevalence [2].

Environmental factors

Such as infections, environmental toxins, and stress are also associated with the development of the disease.

Predisposing factors

Toxic diffuse goiter is genetically linked and some patients have genes that predispose them to the disease, which can be triggered by the following factors.

Infection

Infectious diseases caused by bacteria, viruses, etc.

Mental stimulation

Severe mental stimulation, such as frequent anger, temper tantrums, rage, excessive stress, poor sleep.

Drugs

Such as taking interferon, amiodarone, etc.

Pathogenesis

Toxic diffuse goiter is mainly caused by an autoimmune abnormality, in which the body produces TSH receptor antibodies (TRAb) that bind to the TSH receptor, leading to the proliferation of thyroid follicular cells to produce excess thyroid hormones.

Symptoms

Main Symptoms

Thyrotoxicosis

The main symptoms include agitation, restlessness and insomnia, palpitations, fatigue, fear of heat, excessive sweating, loss of weight, hyperphagia, increased frequency of bowel movements or diarrhea, and scanty menstruation in women.

It may be accompanied by periodic paralysis (common in Asian, young adult males) and progressive weakness and atrophy of proximal muscles.

Myasthenia gravis occurs in 1% of cases.

Diffuse goiter

There may be diffuse, symmetrical enlargement of the thyroid gland, which is soft and may move up and down with swallowing.

Other symptoms

Thyroid-related eye disease

There may be protruding eyeballs, foreign body sensation in the eye, photophobia, tearing, diplopia, decreased visual acuity, and incomplete eyelid closure.

Anterior tibial mucous edema

Edema is commonly found in the lower 1/3 of the tibialis anterior (anterior side of the calf) of the lower leg, and occasionally in the dorsum of the foot and knee, upper limb or even head.

The lesions are mostly symmetrical and begin as dark purplish-red patches or nodules. The skin becomes thicker and thicker, and eventually becomes bark-like, with the lower limbs being thicker and resembling elephant-skinned legs.

Thickening of the fingertips

In a few patients, there is swelling of the soft tissues of the digits in the form of a pestle and mortar, formation of new bone under the metacarpophalangeal periosteum, and separation of the adjacent free marginal portion of the finger or toenail from the nail bed.

Complications

Thyroid crisis

Most often occurs in patients who have been untreated or inadequately treated for a long period of time.

Common triggers include infection, surgery, trauma, and mental stimulation.

There may be high or excessive fever, profuse sweating, tachycardia (>140 beats/min), irritability, anxiety, nausea, vomiting, diarrhea, etc. In severe cases, there may be heart failure, shock and coma.

Thyrotoxic heart disease

The main manifestations are severe arrhythmia, such as atrial fibrillation, atrial flutter, but also heart enlargement, heart failure, angina pectoris, myocardial infarction and so on.

Severe cases can lead to death.

Consultation

Department of Medicine

Endocrinology

It is recommended to consult a doctor when there is excessive eating, weight loss, easy to starve, frequent bowel movements, protruding eyeballs, or swelling of the neck.

Emergency Department

When symptoms such as high fever, profuse sweating, irritability and unconsciousness appear, it is recommended to seek medical treatment immediately.

Preparation for medical treatment

Preparation for medical consultation: registration, preparation of documents, common problems

Tips for medical treatment

Do not wear make-up before going to the doctor as it may hide your condition.

In order to facilitate the doctor’s examination, try not to wear high-collared clothes or necklace jewelry.

If there is any weight change, it is recommended to record the time and result of weight measurement for the doctor’s reference.

Preparation Checklist for Medical Visit

In particular, you need to pay attention to the time of onset of symptoms, special performance, etc.

Is there irritability, panic, hunger, fear of heat and sweating, protruding eyes, goiter?

How long have the above symptoms lasted?

Has there been any change in weight in the last six months?

Are there any cases of exertion, mental tension, frequent anger, or stress?

Are you suffering from hypertension, diabetes, systemic lupus erythematosus, rheumatoid arthritis, etc.?

Is there any blood relative with thyroid disease?

Are there any allergies to drugs or food?

Test results in the last six months, which can be brought to the doctor’s office

Laboratory tests: blood test, thyroid function, thyroid autoantibodies, liver function, kidney function, etc.

Imaging tests: thyroid ultrasound, eye CT and eye magnetic resonance imaging (thyroid-related eye disease examination), etc.

Other tests: electrocardiogram, etc.

Medication in the last 3 months, if available in boxes or packages, bring with you to the doctor’s office

Anti-thyroid medication

Thyroid hormone: levothyroxine sodium tablets.

Beta-blockers: propranolol, metoprolol.

Iodine-containing drugs: amiodarone, compound iodine solution, iodine-containing contrast medium.

Glucocorticoids: hydrocortisone, prednisone acetate, methylprednisolone, dexamethasone.

Diagnosis

Diagnosis is based on

Medical history

There may be a family history of hyperthyroidism or other autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus.

There may be infections, mental stimulation, and medications such as interferon and amiodarone.

Clinical manifestations

There may be agitation, irritability and insomnia, palpitation, fatigue, fear of heat, excessive sweating, emaciation, hyperphagia, increased frequency of bowel movements or diarrhea, and scanty menstruation in women.

There may be protruding eyes, foreign body sensation in the eyes, photophobia, tearing, diplopia, loss of vision, and incomplete eyelid closure.

On examination, the doctor may find diffuse, symmetrical enlargement of the thyroid gland, which is soft and can move up and down with swallowing movements; vascular murmurs and palpable tremors may also be heard in the outer upper and lower lobes of the thyroid gland.

Laboratory tests

Thyroid function is determined by the levels of thyroid-stimulating hormone (TSH), serum total thyroxine (TT₄), serum total triiodothyronine (TT₃), serum free thyroxine (FT₄), and serum free triiodothyronine (FT₃), and the diagnosis of hyperthyroidism is made.

Serum free thyroid hormone is not affected by thyroxine-binding globulin, and is more directly reflective of thyroid function than TT₃ and TT₄, especially for patients with changes in thyroxine-binding globulin levels.

The test shows a decrease in thyrotropin and an increase in thyroid hormone levels.

Thyroid-stimulating hormone receptor antibody (TRAb) is the first line of diagnosis of diffuse toxic goiter and is useful in determining the activity of the disease and in evaluating the timing of drug discontinuation.

Thyroid Stimulating Antibody (TSAb): In contrast to TRAb, TSAb reflects the fact that this antibody not only binds to the TSH receptor but also produces a stimulatory function on thyroid cells.

Some patients may have mildly decreased white blood cell counts, hemoglobin, neutrophil and platelet counts.

The main focus is to check liver function, kidney function, electrolytes, etc., as well as any abnormalities in blood lipids.

Imaging

Ultrasound of the thyroid gland is performed to visualize thyroid nodules and the distribution of blood flow within the thyroid gland.

Extraocular muscle ultrasound can assess extraocular muscle involvement.

Ocular CT and magnetic resonance imaging can rule out other causes of ocular disease.

The size of the extraocular muscles and the position of the eye can be evaluated.

It is mainly used in the differential diagnosis of hyperthyroidism to help clarify the cause.

Concentration of large amounts of nuclides in some tissues within the thyroid gland and no nuclide uptake in other thyroid tissues and the contralateral thyroid gland suggests that it may be an autonomous high-functioning adenoma of the thyroid gland.

Very low or even no iodine uptake by the thyroid gland suggests thyrotoxicosis due to inflammation of the thyroid gland, for example.

It can be used to identify the cause of hyperthyroidism.

Patients with diffuse toxic goiter may have an elevated iodine 131 uptake rate, mostly with an anterior shift of the peak.

Patients with multinodular goiter and autonomous high-functioning adenomas of the thyroid gland may have elevated or normal iodine 131 uptake rates.

Patients with iodine hyperthyroidism and non-hyperthyrotoxic thyrotoxicosis may have normal or decreased iodine 131 uptake rates.

Other tests

Cardiac function can be visualized.

Electrocardiogram may show sinus tachycardia or atrial fibrillation.

Differential Diagnosis

Inflammatory thyrotoxicosis

Similarities: Both have hypermetabolic symptoms, such as polyphagia, emaciation, pyrexia, hyperhidrosis, palpitations, and agitation.

Differences: Inflammatory thyrotoxicosis is caused by the destruction of thyroid follicles by inflammation, and the excessive amount of thyroid hormone stored in the follicles enters the circulation. It can be differentiated by thyroid function, thyroid autoantibody test, ultrasonography, and thyroid iodine uptake rate.

Simple goiter

Similarities: Both are characterized by enlargement of the thyroid gland.

Difference: Simple goiter has no hypermetabolic symptoms and can be differentiated by thyroid function tests.

Thyroid cancer

Similarity: Both can have enlargement of the neck.

Difference: Thyroid cancer is visible as a lesion on ultrasound, and cancer cells are visible on cytopathologic and histopathologic examination.

Treatment

Aim of treatment: Reduce the level of thyroid hormone in blood, improve the symptoms, and improve the quality of life of patients.

Treatment principle: mainly adopt drug treatment, radioactive iodine 131 treatment and surgical treatment, supplemented by lifestyle management.

Drug treatment

Drugs: Commonly used antithyroid drugs, such as imidazole and thiouracil; in the early stage of treatment, β-blockers (propranolol) can be used to control the clinical symptoms of hyperthyroidism, and discontinued within 2 to 6 weeks.

Effects: The application of antithyroid drugs can reduce the synthesis of thyroid hormones and relieve the symptoms of hyperthyroidism.

Advantages: The medication is safer and the dosage is controllable, and the effect is reversible and does not permanently lead to hypothyroidism.

Disadvantages: The treatment period is long (1-2 years), the effect is slow (4-8 weeks), the recurrence rate is high (40%-60%), and there are adverse reactions.

Indications

Mild and moderate conditions.

Mild to moderate enlargement of the thyroid gland.

Pregnant women, advanced age, or those who are unfit for surgery due to other serious illnesses.

Pre-surgical preparation.

Those who have relapsed after surgery and are unfit for ¹³¹I treatment.

Patients with moderately to severely active thyroid-related eye disease.

Dosage and Course of Treatment

During the treatment, the medication should be taken according to the doctor’s prescription, dosage and course of treatment, and should not be reduced or stopped at will.

The dosage depends on the severity of the disease. Thyroid function, blood test and liver function should be rechecked according to the doctor’s instructions.

After 4 to 12 weeks of medication, most patients’ thyroid function can be improved or normalized, after which the dosage can be gradually reduced.

Follow-up examinations of thyroid function once every 4 to 6 weeks and monitoring of blood and liver functions are required.

The maintenance dose varies from person to person and is usually maintained for 12 to 18 months.

Thyroid function is checked every 1~3 months during the maintenance period.

Treatment effect

Remission after antithyroid drug treatment: 1 year after stopping the drug, serum TSH and thyroid hormone are normal.

Optimal discontinuation index of antithyroid drugs: normal thyroid function and negative TRAb.

Factors associated with relapse: smoking, significant thyroid enlargement, persistent high titers of TRAb

Adverse drug reactions

Can cause granulocyte deficiency, rash, toxic liver disease, vasculitis.

Blood routine and liver function need to be checked before treatment, and blood routine and liver function should be monitored regularly after treatment.

Radioactive Iodine 131 Treatment

Treatment purpose: destroying thyroid tissue and reducing thyroid hormone production.

Treatment mechanism: Destroying thyroid tissue cells by using beta rays released after 131 iodine is ingested by the thyroid gland.

Advantages: shorter time required for definitive control of thyrotoxicosis; avoids risk of surgery; avoids potential adverse effects of applied ATD therapy.

Disadvantages: may cause hypothyroidism and require lifelong medication.

Allergy to antithyroid medications.

Poor efficacy of antithyroid medication or multiple relapses.

Have contraindications to surgery or high risk of surgery.

History of neck surgery or external irradiation.

Long duration of disease.

Elderly patients (especially those with concomitant cardiovascular disease).

Combined hepatic impairment.

Combined leukopenia or thrombocytopenia.

Combined periodic paralysis of skeletal muscle.

Combined atrial fibrillation [4].

Pregnant patients.

Combined suspected or confirmed thyroid cancer in patients with diffuse goiter [4].

Hypothyroidism.

Radiation thyroiditis

Induced thyroid crisis

Occurs mainly in patients with severe hyperthyroidism with uncontrolled symptoms.

Aggravation of active thyroid-related ophthalmopathy

May be characterized by a marked worsening of ocular discomfort.

Surgery

Advantages: rapid and definitive control of thyrotoxicosis; avoids radiation exposure; avoids potential adverse effects of antithyroid drug therapy.

Disadvantages: destructive treatment of the thyroid gland; hypothyroidism may occur after treatment, requiring lifelong thyroid hormone replacement therapy; surgery itself may be potentially risky.

Those with more than moderate diffuse toxic goiter.

Those with large glands with symptoms of compression.

Those who have adverse reactions to antithyroid medications.

Those for whom 131I therapy is contraindicated or for whom 131I therapy is ineffective.

Combined with malignant tumor of the thyroid gland.

Patients with moderate to severe Graves’ ophthalmopathy.

Patients who wish to undergo surgery to shorten the course of treatment and rapidly improve the symptoms of hyperthyroidism [5].

Poor general condition, such as severe cardiac, hepatic, renal and other organic lesions, or combined with malignant diseases such as end-stage consumptive diseases, who can not tolerate surgery.

Early or late pregnancy.

Appropriate surgical procedures need to be selected under the supervision of a physician, and current guidelines recommend the preferred surgical procedure of subtotal or total thyroidectomy [5].

Postoperative dyspnea and asphyxia: It is the most critical postoperative complication, mostly occurring within 48 hours after surgery. If not detected in time and treated appropriately, asphyxia can occur and become life-threatening.

Laryngeal recurrent nerve injury: it is a direct injury of surgery, such as the nerve being cut, ligated, squeezed and pulled. A few are caused by postoperative hematoma compression or scar tissue pulling.

Superior laryngeal nerve injury: it is caused by cutting off the superior thyroid artery and vein without close to the thyroid gland, or cluster ligation of the superior thyroid artery and vein.

Hypoparathyroidism: It is caused by the parathyroid glands being mistakenly cut, contused or impaired blood supply during surgery, and its incidence is directly related to the scope of thyroid surgery and the experience of previous surgeons.

Thyroid crisis: one of the life-threatening complications after hyperthyroid surgery.

Treatment of Graves’ ophthalmopathy

Intravenous glucocorticoids combined with oral mycophenolate mofetil therapy is used as first-line treatment for most patients with moderate-to-severe, active Graves’ ophthalmopathy.

Second-line treatment options for Graves’ ophthalmopathy include glucocorticoids combined with orbital radiation therapy, rituximab, and azathioprine combined with oral glucocorticoids.

Medication selection needs to be made under the guidance of a physician, and medication should be administered as prescribed.

Prognosis

Cure

The disease has a long course. After active treatment, most of them have a good prognosis, and some of them can be relieved by medication without affecting life expectancy.

If the disease is recurrent and drug treatment is not effective, radioactive iodine 131 treatment or surgical treatment is needed. After the surgery, there will be different degrees of hypothyroidism and long-term thyroid hormone replacement therapy is needed to maintain normal metabolism.

Patients with more severe disease without timely treatment, or insufficient treatment may develop thyroid crisis, which may lead to death, and most of the causes of death are high fever and weakness, heart failure, pulmonary edema, and severe water and electrolyte metabolic disorders.

Hazards

The disease can affect multiple systems throughout the body, such as the mental system, cardiovascular system, digestive system, musculoskeletal, and skin.

The disease may affect bone decalcification and osteoporosis may occur.

Pre-tibial mucous edema may occur, which can thicken the skin of the lower legs and cause orange peel and bark-like changes.

It may lead to thyrotoxic heart disease, which can cause heart failure, angina pectoris, myocardial infarction, and heart failure.

The appearance of thyroid crisis untreated may be life-threatening.

Daily

Daily Management

Dietary management

A high-calorie, high-protein, high-vitamin, low-iodine, low-fiber diet should be adopted, and attention should be paid to hydration.

Staple foods should be adequate to meet the body’s ability to metabolize faster.

High-quality proteins such as milk, eggs, lean meat (beef, etc.) and soybean products can be increased to correct the negative nitrogen balance in the body and alleviate body wasting, etc.

Consume more fresh vegetables and fruits, especially foods rich in B vitamins and vitamin C, such as unrefined coarse grains, animal liver, nuts, strawberries and oranges.

Low iodine, avoid iodine-rich seafood such as kelp and nori.

Reduce the intake of foods with high fiber content such as celery and sweet potatoes to reduce the frequency of bowel movements.

Eat more food rich in calcium, phosphorus and other minerals such as yogurt, cheese, nuts, etc. as appropriate, and get more sunshine to prevent osteoporosis; for those with low blood potassium, eat more bananas and so on.

Drink more water, drink 2000~3000 ml of water per day to replenish the water lost from sweating, diarrhea, accelerated respiration, etc. However, those with concurrent heart disease should avoid drinking a lot of water to prevent aggravating edema and causing heart failure.

Exercise management

When thyroid function is not well controlled, choose walking, playing tai chi, yoga, etc. Avoid strenuous exercise.

Those with heart failure or severe infection should take bed rest and should not exercise.

Others

Avoid iodine-containing drugs and iodine-containing contrast media, etc.

Avoid smoking, including second-hand smoke.

Strengthen self-protection, the collar of the upper garment should be loose to avoid compressing the thyroid gland, and squeezing the thyroid gland with hands is strictly prohibited.

Increase rest time appropriately, maintain sufficient sleep, and avoid staying up late to prevent aggravation of the condition.

Learn ways to control emotions and reduce stress, and correctly handle unexpected events in life.

Avoid infection, severe mental stimulation, trauma and other factors that trigger thyroid crisis.

Check your pulse every morning before getting up and measure your weight regularly.

Follow-up and review

Long-term follow-up examinations should be conducted after treatment in order to observe the effect of treatment and detect complications in time.

Regularly check thyroid function, liver function, blood routine, etc. as directed by your doctor.

Pay attention to your own physical condition. If you develop high fever, nausea, vomiting, unexplained diarrhea, etc., be alert to the possibility of thyroid crisis and consult a doctor promptly.

Prevention

Reasonable diet

Eat a balanced diet with plenty of fruits and vegetables to replenish vitamins.

It is not advisable to consume large quantities of high iodine foods such as kelp for a long period of time.

Emotion regulation

Keep an optimistic mindset, don’t put too much pressure on yourself, and learn to resolve the unhappiness in your heart.

Don’t let yourself be under extreme busyness and high pressure for a long time.

If you can’t solve the psychological problems by yourself, seek help from a psychiatrist in time.

Regular work and rest

Stick to a regular routine, get up early and go to bed early, don’t stay up late.

Regular medical checkups

Patients with a family history of hyperthyroidism need to have regular medical checkups.

Patients with other diseases, such as systemic lupus erythematosus and diabetes mellitus, should also have regular medical checkups.