Hyperthyroidism refers to a group of clinical syndromes in which the thyroid gland itself produces too much thyroid hormone, resulting in increased excitability and hyper-metabolism of the nervous, circulatory and digestive systems. Common symptoms include fatigue and weakness, fear of heat and sweating, damp skin, excessive food and hunger, significant weight loss, talkativeness, nervousness and anxiety, agitation, insomnia, lack of concentration, memory loss, hand and eyelid tremors, palpitations and shortness of breath, tachycardia, etc. Patients commonly have abnormally elevated serum total thyroxine (TT4), serum total triiodothyronine (TT3), serum free thyroxine (FT4), and free triiodothyronine (FT3). In recent years, it has been found that the development of Graves’ disease is mainly related to autoimmunity, while other lesions causing hyperthyroidism have their own characteristics or are still unclear in their development. They are described as follows.
1, immune factors
In 1956, Adams et al. discovered that long-acting thyroid-stimulating hormone (LATS), which is similar to TSH, is an immunoglobulin (IgG) produced by B lymphocytes and is an autoantibody against the thyroid gland, which can bind to thyroid subcellular components and excite the thyroid follicular epithelium to secrete thyroid hormone and cause hyperthyroidism. LATS is increased in 60% to 90% of hyperthyroid patients. LATS-P substance, also an IgG, has since been found to excite only human thyroid tissue and is also known as human thyroid-stimulated immunoglobulin (HTSI), which is positive in more than 90% of hyperthyroid patients. Direct evidence of immune mechanisms in the pathogenesis of hyperthyroidism include
In humoral immunity: a variety of antibodies against thyroid cell components are known, such as thyroid-stimulating antibodies (TISI) against TSH receptors, or TSH receptor antibodies (TRAb), which bind to TSH receptors or their associated tissues, further activating cAMP and enhancing thyroid function. Such antibodies can pass through placental tissue and cause neonatal hyperthyroidism, or incompletely treated hyperthyroidism, and The antibodies continue to be positive, leading to recurrence of hyperthyroidism;1,2 cellular immune aspects: it is confirmed that these antibodies are produced due to B lymphocytes. The presence of sensitized T lymphocytes against thyroid antigens in the blood of hyperthyroid patients and the activation of phytohemagglutinin (PHA) by lymphocytes in hyperthyroidism can produce LATS. PHA excites T lymphocytes and then stimulates B lymphocytes, thus producing immunoglobulins that can excite thyroid action, such as TSI, and trigger hyperthyroidism.
Organ-specific autoimmune diseases are caused by immune dysregulation due to defective function of suppressor T lymphocytes (Ts), therefore, the immune response is a complex result involving the interaction of T and B lymphocytes and phagocytes. It is now believed to be mainly associated with genetic defects related to reduced suppressor T lymphocyte function, and defective Ts function can lead to T cell sensitization, causing B cells to produce TRAb and cause hyperthyroidism. Indirect evidence includes.
(i) A large infiltration of lymphocytes and plasma cells in the thyroid gland and behind the eyes.
(ii) Increased number of lymphocytes in the peripheral blood circulation, which may be accompanied by proliferation of reticuloendothelial tissue in the lymph nodes, liver and spleen.
(iii) Some other autoimmune diseases may occur simultaneously or sequentially between the patient and his relatives.
(iv) Positive blood antithyroid antibodies, TRAb and anti-gastric lining cell antibodies and anti-cardiac antibodies in the patient and his relatives.
⑤ Elevated IgG, IgA and IgM in the thyroid and blood.
The cause of the initiation of Graves’ disease is thought to be due to a genetic defect in the immune guardianship and regulation of the patient’s Ts cells, and when there are factors such as external trauma or infection, the immune system is destroyed and the “forbidden” cells are out of control. The disease is caused by the secretion of a large number of TSI autoantibodies under the action of Ts cells. The disease is caused by a large number of TSI autoantibodies secreted by Ts cells. In recent years, it has been found that HLA-B8 is two times higher than normal in Caucasians, HLA-BW35 is higher in Asian Japanese, and HIA-BW46 positive susceptibility is higher in foreign Chinese, and B13 and B40 are more obvious, which have drawn attention.
2, genetic factors
Clinically, familial Graves’ disease is not uncommon, with up to 30% to 60% of identical twins successively suffering from Graves’ disease and only 3% to 9% of heterozygotes. In addition to hyperthyroidism, the family history may also include other thyroid diseases such as hypothyroidism, or TSI positivity in family relatives, indicating a familial predisposition to Graves’ disease. The mode of inheritance may be autosomal recessive, autosomal dominant, or polygenic.
3. Other causes of pathogenesis
(1) Hyperfunctional nodular goiter or adenoma
In 1988, it was reported that serum thyroglobulin antibodies and microsomal antibodies were detected in single nodules with a positive rate of 16.9% (62/383) and 54.7% (104/190) in multiple nodules. The hyperplastic thyroid tissue in these nodules is not regulated by TSI and becomes autonomously hyperactive or hyperfunctioning thyroid nodules or adenomas. The pathogenesis of thyroid adenomas and carcinomas is also currently thought to be due to oncogenes.
(2) Increased TSH secretion by pituitary tumors causes pituitary hyperthyroidism, such as TSH-secreting tumors or hyperthyroidism associated with acromegaly.
(3) Subacute thyroiditis, chronic lymphocytic thyroiditis, and painless thyroiditis can be associated with hyperthyroidism.
(4) Hyperthyroidism caused by increased exogenous iodine is called iodine hyperthyroidism. For example, patients with goiter who take too much iodine, excessive thyroid tablets or levothyroxine sodium (L-T4) can cause hyperthyroidism, and a few patients taking amiodarone drugs can also cause hyperthyroidism.
(5) Ectopic endocrine tumors can cause hyperthyroidism, such as ovarian tumors, choriocarcinoma, digestive system tumors, respiratory system tumors and breast cancer, etc. The secretion of thyroid stimulating hormones can cause clinical hyperthyroidism.
(6) Albright syndrome is clinically manifested by multiple bone fibrous dysplasia, skin pigmentation and elevated AKP in blood, which may be accompanied by hyperthyroidism.
(7) Familial hyperglobulinemia (TBG) can cause hyperthyroidism, which can be due to a familial genetic defect or related to the use of medication.
Hyperthyroidism is a common disease, what are the classifications of hyperthyroidism?
1. Thyroid hyperthyroidism: The thyroid gland itself is hyperfunctioning and the synthesis and secretion of hormones are increased.
(1) Diffuse goiter with hyperthyroidism: also known as toxic diffuse goiter, proptosis goiter, Graves’ disease, Basedow’s disease, etc. This type is the most common form of hyperthyroidism, accounting for about 90% of cases. It is mainly due to autoimmune mechanisms, and thyroid-stimulating hormone (TSH) receptor antibodies (TRAb) can often be detected in patients. Typical clinical symptoms include hypermetabolic syndrome, proptosis, and diffuse enlargement of the thyroid gland.
(2) Multinodular goiter with hyperthyroidism: also known as toxic multinodular goiter. The cause of this type is unknown, and it is common in patients who have had thyroid nodules for many years. It is common in middle-aged and elderly patients, with a slow onset, mild symptoms, and rare protrusions. TSH or exogenous thyroid hormones do not alter the iodine-absorbing function of the thyroid gland.
(3) Autonomous hyperfunctional thyroid adenoma or nodule: The etiology of this type is unknown, and the majority of patients have a solitary adenoma, or occasionally multiple nodules. The onset of the disease is slow, with mild symptoms and no protrusions, and T3 hyperthyroidism is more common in middle-aged women. The thyroid gland may appear as a single “hot nodule” (nodule with concentrated nuclei) or occasionally as multiple “hot nodules”, and the rest of the gland may have reduced or absent iodine uptake; these nodules are not regulated by TSH and are therefore called autonomously hyperactive. These nodules are not regulated by TSH, so they are called autonomic hyperfunctional adenomas or nodules or Plummer’s disease.
(4) Neonatal hyperthyroidism: Infants delivered by pregnant women with hyperthyroidism can develop hyperthyroidism, and the incidence is closely related to the concentration of TRAb in the mother. Very few children are born to mothers with no history of hyperthyroidism, which may be related to the child’s own immune disorder.
(5) Iodine-derived hyperthyroidism (referred to as iodine hyperthyroidism): This is caused by long-term excessive iodine intake. It is mostly seen in areas with endemic goiter and occasionally in areas with non-endemic multinodular goiter. Long-term use of iodine-containing medications such as amiodarone (acetaminophen iodofurazone) is also a common cause of this condition. The thyroid gland may already be defective in patients with this disease, and excessive iodine intake is only a causative factor. Clinical symptoms of hyperthyroidism are mild, proptosis is rare, and nodules in the thyroid gland are common.
(6) Primary thyroid cancer causes hyperthyroidism: Some primary thyroid cancers can secrete large amounts of thyroxine, which leads to hyperthyroidism.
2. Secondary hyperthyroidism: Various causes lead to increased concentration of TSH in the blood, which in turn leads to hyperthyroidism.
(1) Pituitary hyperthyroidism: caused by pituitary tumors secreting large amounts of TSH, which is extremely rare. Many patients also have hyperprolactinemia or acromegaly.
(2) Ectopic TSH secretion syndrome: extremely rare. It is occasionally seen in women with choriocarcinoma or staphyloma, or men with testicular choriocarcinoma; sometimes bronchial cancer and digestive tract cancer can also cause it, because the above cancer tissues can secrete TSH-like substances, thus leading to hyperthyroidism.
Heterogenous hyperthyroidism: There are tissues that secrete thyroid hormone in other parts of the body, but there is no lesion in the thyroid gland itself.
(1) Hyperthyroidism due to ovarian goiter: When some ovarian teratomas are mainly or entirely composed of thyroid tissue, they are called ovarian goiters. When ovarian goiter secretes too much hormone, it can cause hyperthyroidism, but it is very rare. Strictly speaking, this disease should be called ectopic thyroid hormone hypersecretion disorder.
(2) Hyperthyroidism caused by metastatic tumors of the thyroid gland.
4. Drug-induced hyperthyroidism.
(1) Thyroxine (artificial): caused by taking too much thyroid hormone, but the thyroid gland itself does not function abnormally.
(2) Iodine hyperthyroidism: seen in patients who have been taking iodine-containing drugs such as amiodarone (acetaminophen iodofuran) for a long time.
5. Thyroiditis with hyperthyroidism.
In the early stage of subacute thyroiditis, chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis), and after radioactive iodine treatment, the thyroid follicles are destroyed and thyroid hormones overflow into the blood circulation, which can cause hyperthyroidism, but the function of the gland is not high and may even be lower than normal. Sometimes, Hashimotos toxiccosis can be accompanied by Graves’ disease, which is called Hashimoto’s hyperthyroidism, but most of this hyperthyroidism is temporary and can be converted to hypothyroidism later. Strictly speaking, the above conditions cannot be classified as hyperthyroidism, but they are usually classified as this condition due to the presence of transient hyperthyroid symptoms.
Among the above-mentioned types of hyperthyroidism, Graves’ disease is the most common.