Graves’ Disease

Graves’ disease is the most frequent cause of hyperthyroidism, accounting for more than 70% of cases in iodine- sufficient areas, where its prevalence may be as high as 2% in women. In Graves’ disease, hyperthyroidism is caused by an autoimmune reaction to the thyroid, leading to the production of autoantibodies to the TSH receptor (TSHR autoantibodies). These antibodies mimic the action of TSH in stimulating the TSH receptor on thyroid follicular cells (TSHR- S autoantibodies).

As the effect of TSHR- S autoantibodies is exerted on all follicular cells, a diffusely enlarged thyroid is the hallmark of the disease, but in some cases thyroid nodules can develop. Graves’ ophthalmopathy and, rarely, pretibial myxoedema are other typical physical findings. On careful physical exam, 30– 45% of patients with Graves’ disease have some signs of Graves’ ophthalmopathy. When obviously pre sent, Graves’ ophthalmopathy is extremely useful in supporting Graves’ disease as the cause of thyrotoxicosis. Pretibial myxoedema is only rarely observed in Graves’ disease, but almost never observed without it.

Toxic Adenoma and Multinodular Toxic Goitre

Toxic adenoma and multinodular toxic goitre are frequent causes of hyperthyroidism, especially in iodine- deficient areas. Toxic adenomas are monoclonal benign encapsulated tumours that synthesize thyroid hormones independently of TSH stimulation. They are characterized by heterozygous gain- of- function mutations involving the TSHR or the Gsα protein genes which induce a permanent and TSH- independent activation of the adenylate- cyclase pathway. Somatic mutations of the TSHR gene, which cause amino acid changes leading to constitutive activation of the TSHR, are the cause of 20– 80% of toxic adenomas, while the rate of mutations of the Gsα protein range from 8% to 75%. The natural history of toxic adenoma is characterized by one autonomous adenoma developing in an otherwise normal thyroid, slowly growing over many years. The coexistence or two or more toxic adenomas (multiple adenomatosis) is uncommon. In the early phases, the amount of secreted thyroid hormones is not sufficient to completely suppress TSH secretion (partial autonomy) and the function of the extranodular tissue. With further growth of the nodule, TSH suppression becomes complete, while circulating thyroid hormones are in the upper range of normal values (complete autonomy). Eventually, overt thyrotoxicosis ensues, with frankly elevated thyroid hormone levels (hyperthyroidism). The rate of progression is quite slow. The risk of overt hyperthyroidism is higher for adenomas greater than 3 cm in size.

Multinodular toxic goitre is also often detected in iodine- deficient countries, in which accounts for up to 60% of cases of thyrotoxicosis. The prevalence of multinodular toxic goitre in these iodine- deficient areas has been reduced by iodine prophylaxis. The same somatic activating mutations of the TSHR demonstrated in toxic adenoma have been observed in toxic multinodular goitre as well. However, in many nodules neither TSHR nor Gsα protein mutations have been observed. The clonal development of follicles with high replicative capacity will induce the onset of non- functioning (cold) or hyperfunctioning (hot) nodules, in which the uptake and thyroid hormone synthesis is independent from TSH stimulation. The natural history of multinodular toxic goitre is similar to that of toxic adenoma, with the slow formation of multiple autonomously functioning nodular areas in the setting of an overall nodular goitre. The only known mechanism inducing sub clinical hyperthyroidism and overt thyrotoxicosis is the administration of excessive amount of iodine. Because of the slow progression through several degrees of thyrotoxicosis and of their advanced age, patients with multinodular toxic goitre may report few symptoms.

Thyroid- Stimulating Hormone- Secreting Adenoma

TSH secretion by a benign pituitary adenoma, which is characterized by a partial or complete loss of the feedback regulation by thyroid hormones (central hyperthyroidism), causes a sustained stimulation of the thyroid gland, with the subsequent development of goitre and hyperthyroidism. An increased prevalence has been reported, probably as a consequence of the introduction of ultra- sensitive assays for TSH measurement, that enables an earlier detection of an inappropriate secretion of TSH.

hCG- Dependent Hyperthyroidism

Due to its partial homology with TSH, hCG can act as a weak (about 1/ 10 00th less potent) TSH agonist. When present in large amounts in the bloodstream, it can overstimulate the thyroid gland, inducing hyperthyroidism. Human chorionic gonadotropin (hCG) is secreted in large amounts by placental tissue in normal pregnancy and also by trophoblastic tumours.

Trophoblastic Tumours

Hyperthyroidism may ensue in patients with a hydatidiform mola or a choriocarcinoma as well as with chorionic tumour of the testes, as a consequence of the large quantities of hCG produced by the tumour. Thyrotoxicosis is common in trophoblastic tumours and 200– 400 IU/ ml of hCG are associated with high fT4 and fT3. However, clinical overt thyrotoxicosis is observed in a minority (10%) of patients, when hCG is extraordinarily high (>3000 IU/ ml). The routine use of ultrasonography during pregnancy has led to earlier diagnosis of hydatidiform mola, when the tumour mass is smaller and the thyrotoxicosis less likely.

Hyperemesis Gravidarum

 Hyperemesis gravidarum is characterized by prominent nausea and vomiting, weight loss, ketosis, and electrolyte abnormalities. It occurs in 1.5% of pregnancy and is more common in twin pregnancies because of the higher serum hCG concentrations. In 25% to 75% of cases have been reported increased levels of fT4 and fT3, which correlates with serum hCG concentrations. A minority of women with hyperemesis gravidarum experience a clinically evident thyrotoxicosis (gestational hyperthyroidism). It resolves spontaneously within the first 3 to 4 months of gestation.

Familial Gestational Hyperthyroidism

 Two families with recurrent hyperemesis gravidarum and gestational hyperthyroidism due to a mutation in the TSHR gene causing increased responsiveness to hCG have been reported [7, 8]. Hyperthyroidism only manifests during pregnancy and recurs every time an affected woman becomes pregnant.

Fetal and Neonatal Autoimmune Hyperthyroidism

 TSHR- S autoantibodies in the serum of mothers with Graves’ dis ease can cross the placenta and cause fetal and neonatal hyperthyroidism, through direct stimulation of the fetal and neonatal thyroid. Usually the mother is affected by Graves’ disease, in the majority of cases presenting with hyperthyroidism, but sometimes with hypothyroidism after thyroidectomy or 131I treatment. Transplacental passage of TSHR- S autoantibodies from maternal to fetal circulation increases from low levels at 15 weeks to reach maternal levels by 30 weeks of gestation. Hyperthyroid fetus presents with tachycardia, hyperactivity, poor growth, and occasionally acceleration of skeletal maturation. Fetal goitre may occur. In severe and untreated hyperthyroidism intrauterine death has been reported.

Neonatal hyperthyroidism can be very severe and is characterized by tachycardia, jaundice, heart failure, failure to thrive. A goitre is usually present. The disease is transient and resolves within 3 to 12 weeks after birth, when TSHR- S autoantibodies disappear.

Non- Autoimmune Congenital and Familial Hyperthyroidism

After the first report of congenital hyperthyroidism caused by a germline activating mutation of the TSHR gene, only few cases of non- autoimmune neonatal hyperthyroidism have been described. The diagnosis should be suspected when a neonate presents with severe hyperthyroidism and goitre and the mother has no history of Graves’ disease.

Familial hyperthyroidism due to autosomal dominant activating germline mutations of the TSHR has been described. In the few cases reported, hyperthyroidism and goitre developed in adulthood because the effect of the mutation is mild. Germline mutations of the TSHR gene are uncommon in juvenile thyrotoxicosis.

Cases of congenital hyperthyroidism from mutations of the Gsα protein have been also reported, associated with McCune– Albright syndrome.

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المزيد

مواضيع ذات صلة

Causes of Destructive (Low RAIU) Thyrotoxicosis

Hypothalamic-Pituitary-Testes Axis: Hormonal Control of the Testis

Sex Hormone-binding Globulin

Modification of Testosterone in Target Tissues

Clinical Aspects of Hormones of the Adrenal Medulla: Chronic Stress

Biological Responses to Epinephrine

Adrenergic Receptors

Pharmacology of Catecholamines

Regulation of Catecholamine Synthesis and Secretion

Feedback Effects of Glucocorticoids

Glucocorticoids and Stress

Transport of Glucocorticoids in the Blood (CBG)