Familial dysalbuminemic hyperthyroxinemia | |
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Specialty | Endocrinology |
Familial dysalbuminemic hyperthyroxinemia (FDH) rare genetic condition that is a common cause of euthyroid hyperthyroxinemia and is associated with mutations in the human serum albumin gene. [1] [2] It is an autosomal dominant condition that is often mistaken for resistance to thyroid hormone (RTH) syndromes or hyperthyroidism. [3] [4] FDH is characterized by high levels of thyroxine (T4) and normal levels of thyroid stimulating hormone (TSH). [3] Due to the mutations in the albumin gene, an abnormal albumin protein binds thyroid hormones with a high affinity than normal. [4] This explains why those with familial dysalbuminemic hyperthyroxinemia have increased T4 levels and normal TSH levels. [4]
Familial dysalbuminemic hyperthyroxinemia is usually asymptomatic. [4] The clinical features are not specific and vary from patient to patient. [3] In some cases, symptoms such as those seen in hyperthyroidism have been recorded like: palpitations, weight loss, tremors, and anxiety. [4] [5]
The mutations in the albumin gene cause an increase in T4 levels because the albumin now binds more readily to T4. Despite the increased levels of T4, TSH levels remain normal. [6] Because of genetic sequencing, the following albumin gene variants have been recorded in patients with FSH: p.Arg218His (R218H), p.Arg218Pro (R218P), p.Arg218Ser (R218S), p.Arg222Ile (R222I), and p.Leu66Pro (L66P). [5]
The pathophysiology of familial dysalbuminemic hyperthyroxinemia involves the mutation of the albumin gene, leading to increased binding of thyroid hormones, particularly T4, to albumin. This causes an elevation in total T4 levels without a corresponding increase in free T4, which is why those with this mutation have no clinical symptoms because their thyroid still functions normally. [7]
Due to patients generally being asymptomatic, diagnosis of familial dysalbuminemic hyperthyroxinemia is usually made incidentally when abnormal thyroxine levels are detected during routine testing such as a thyroid function test. [3] To be certain, gene sequencing could also be performed to confirm the diagnosis of FDH. This would also allow for the patient and providers to know which albumin gene variant that particular patient has. Protein electrophoresis can also be used to confirm a diagnosis of FDH. [8] This test measures specific proteins in the blood and in the case of testing for FDH, albumin would be the protein that is isolated.
Due to patients being asymptomatic and euthyroid, treatment is not required for those with familial dysalbuminemic hyperthyroxinemia. [2]
The prognosis of those with FDH is favorable due to the patients being asymptomatic and not requiring treatment. [2]
In the Caucasian population, the prevalence of familial dysalbuminemic hyperthyroxinemia is estimated at 1 in 10,000 individuals. The prevalence is higher in those of Hispanic origin compared to those in populations in Venezuela, France, and Denmark. [3]
Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidism. Some, however, use the terms interchangeably. Signs and symptoms vary between people and may include irritability, muscle weakness, sleeping problems, a fast heartbeat, heat intolerance, diarrhea, enlargement of the thyroid, hand tremor, and weight loss. Symptoms are typically less severe in the elderly and during pregnancy. An uncommon but life-threatening complication is thyroid storm in which an event such as an infection results in worsening symptoms such as confusion and a high temperature; this often results in death. The opposite is hypothyroidism, when the thyroid gland does not make enough thyroid hormone.
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans, it is a butterfly-shaped gland located in the neck below the Adam's apple. It consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the isthmus. Microscopically, the functional unit of the thyroid gland is the spherical thyroid follicle, lined with follicular cells (thyrocytes), and occasional parafollicular cells that surround a lumen containing colloid.
Graves' disease, also known as toxic diffuse goiter or Basedow’s disease, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyroid. Signs and symptoms of hyperthyroidism may include irritability, muscle weakness, sleeping problems, a fast heartbeat, poor tolerance of heat, diarrhea and unintentional weight loss. Other symptoms may include thickening of the skin on the shins, known as pretibial myxedema, and eye bulging, a condition caused by Graves' ophthalmopathy. About 25 to 30% of people with the condition develop eye problems.
Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.
Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.
Thyroxine-binding globulin (TBG) is a globulin protein encoded by the SERPINA7 gene in humans. TBG binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3 but is present in the lowest concentration relative to transthyretin and albumin, which also bind T3 and T4 in circulation. Despite its low concentration, TBG carries the majority of T4 in the blood plasma. Due to the very low concentration of T4 and T3 in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T4/T3. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.
Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.
Hashimoto's thyroiditis, also known as chronic lymphocytic thyroiditis, Hashimoto's disease, and autoimmune thyroiditis is an autoimmune disease in which the thyroid gland is gradually destroyed.
Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.
Thyroid storm is a rare but severe and life-threatening complication of hyperthyroidism. It occurs when an overactive thyroid leads to hypermetabolism, which can cause death from cardiac arrest or multiple organ failure.
Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.
Desiccated thyroid extract (DTE), is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism, but less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to three weeks to occur.
The thyrotropin receptor is a receptor that responds to thyroid-stimulating hormone and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.
The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.
An antithyroid agent is a hormone inhibitor acting upon thyroid hormones.
Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.
Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.
Hyperthyroxinemia is a thyroid disease where the serum levels of thyroxine are higher than expected. Thyroxine or tetraiodothyronine (T4) is produced by the thyroid gland.
Thyroid disease in pregnancy can affect the health of the mother as well as the child before and after delivery. Thyroid disorders are prevalent in women of child-bearing age and for this reason commonly present as a pre-existing disease in pregnancy, or after childbirth. Uncorrected thyroid dysfunction in pregnancy has adverse effects on fetal and maternal well-being. The deleterious effects of thyroid dysfunction can also extend beyond pregnancy and delivery to affect neurointellectual development in the early life of the child. Due to an increase in thyroxine binding globulin, an increase in placental type 3 deioidinase and the placental transfer of maternal thyroxine to the fetus, the demand for thyroid hormones is increased during pregnancy. The necessary increase in thyroid hormone production is facilitated by high human chorionic gonadotropin (hCG) concentrations, which bind the TSH receptor and stimulate the maternal thyroid to increase maternal thyroid hormone concentrations by roughly 50%. If the necessary increase in thyroid function cannot be met, this may cause a previously unnoticed (mild) thyroid disorder to worsen and become evident as gestational thyroid disease. Currently, there is not enough evidence to suggest that screening for thyroid dysfunction is beneficial, especially since treatment thyroid hormone supplementation may come with a risk of overtreatment. After women give birth, about 5% develop postpartum thyroiditis which can occur up to nine months afterwards. This is characterized by a short period of hyperthyroidism followed by a period of hypothyroidism; 20–40% remain permanently hypothyroid.
Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.