Primary Hypothyroid

[Mertie Oldow]

Yourthyroid gland controls the metabolism of your body. To stimulate your thyroid, your pituitary gland releases a hormone known as thyroid-stimulating hormone (TSH). Your thyroid then releases two hormones, T3 and T4. These hormones control your metabolism.

If you had hyperthyroidism (or overactive thyroid), your treatment may have left you with hypothyroidism. A common treatment for hyperthyroidism is radioactive iodine. This treatment destroys the thyroid. A less common treatment for hyperthyroidism involves the surgical removal of part or all of the thyroid. Both can result in hypothyroidism.

Your doctor will generally use a blood test to check your T4 and TSH levels. If your thyroid is malfunctioning, your pituitary gland will produce more TSH in an attempt to get your thyroid to produce more T3 and T4. An elevated TSH level can indicate to your doctor that you have a thyroid problem.

Treatment for hypothyroidism involves taking medication to replace the missing thyroid hormones. Your doctor will typically start you on a low dose and increase it gradually. The goal is for your levels of thyroid hormones to return to within the normal range.

Author disclosure: Birte Nygaard declares that she has received payment from MERCK-Sorono during 2012 as invited speaker on two occasions, and for writing an overview on the topic of the use of L-T4 + L-T3 in the treatment of hypothyroidism.

Primary hypothyroidism is defined as low levels of blood thyroid hormone due to destruction of the thyroid gland. This destruction is usually caused by autoimmunity or an intervention such as surgery, radioiodine, or radiation.

It can be classified as clinical (overt) when diagnosed by characteristic clinical features, raised levels of thyroid-stimulating hormone (TSH), and reduced levels of thyroxine (T4); or subclinical when serum TSH is raised, but serum T4 is normal, and there are no symptoms of thyroid dysfunction.

Hypothyroidism is characterized by low levels of blood thyroid hormone. Clinical (overt) hypothyroidism is diagnosed on the basis of characteristic clinical features (e.g., mental slowing, depression, dementia, weight gain, constipation, dry skin, hair loss, cold intolerance, hoarse voice, irregular menstruation, infertility, muscle stiffness and pain, bradycardia, hypercholesterolemia), a serum TSH above the reference range, and T4 (and/or triiodothyronine [T3]) below the reference range. A number of guidelines quote serum TSH of 5 to 10 mU per L as mild hypothyroidism, and greater than 10 mU per L as severe hypothyroidism. Subclinical hypothyroidism is a biochemical diagnosis with findings of a serum TSH above the reference range and serum T4 (and/or T3) within the reference range.

Primary hypothyroidism occurs after destruction of the thyroid gland because of autoimmunity (the most common cause) or medical intervention such as surgery, radioiodine, or radiation. Secondary hypothyroidism occurs after pituitary or hypothalamic damage and is caused by insufficient production due to pituitary or hypothalamic hypofunction. Secondary hypothyroidism is not covered in this review. Euthyroid sick syndrome is diagnosed when T3 levels are low, serum T4 is low, and TSH levels are normal or low. Euthyroid sick syndrome is not covered in this review.

Hypothyroidism is more common in women than in men (in the United Kingdom, female-to-male ratio of 6:1). One study (2,779 persons in the United Kingdom with a median age of 58 years) found that the incidence of clinical (overt) hypothyroidism was 40 in 10,000 women per year and six in 10,000 men per year. The prevalence was 9.3% in women and 1.3% in men. In areas with high iodine intake, the incidence of hypothyroidism can be higher than in areas with normal or low iodine intake. In Denmark, where there is moderate iodine insufficiency, the overall incidence of hypothyroidism is 1.4 per 10,000 per year, increasing to eight per 10,000 per year in persons older than 70 years. The incidence of subclinical hypothyroidism increases with age. Up to 10% of women older than 60 years have subclinical hypothyroidism (evaluated from data from the Netherlands and United States).

Primary thyroid gland failure can occur as a result of chronic autoimmune thyroiditis, radioactive iodine treatment, or thyroidectomy. Other causes include drug adverse effects (e.g., amiodarone, lithium), transient hypothyroidism due to silent thyroiditis, subacute thyroiditis, or postnatal thyroiditis.

Subclinical hypothyroidism is associated with depression. Persons with subclinical hypothyroidism may have depression that is refractory to antidepressant drugs and thyroid hormone alone. Memory impairment, hysteria, anxiety, somatic complaints, and depressive features without depression have been described in persons with subclinical hypothyroidism.

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Congenital hypothyroidism is a partial or complete loss of function of the thyroid gland (hypothyroidism) that affects infants from birth (congenital). The thyroid gland is a butterfly-shaped tissue in the lower neck. It makes iodine-containing hormones that play an important role in regulating growth, brain development, and the rate of chemical reactions in the body (metabolism). People with congenital hypothyroidism have lower-than-normal levels of these important hormones.

Congenital hypothyroidism occurs when the thyroid gland fails to develop or function properly. In 80 to 85 percent of cases, the thyroid gland is absent, severely reduced in size (hypoplastic), or abnormally located. These cases are classified as thyroid dysgenesis. In the remainder of cases, a normal-sized or enlarged thyroid gland (goiter) is present, but production of thyroid hormones is decreased or absent. Most of these cases occur when one of several steps in the hormone synthesis process is impaired; these cases are classified as thyroid dyshormonogenesis. Less commonly, reduction or absence of thyroid hormone production is caused by impaired stimulation of the production process (which is normally done by a structure at the base of the brain called the pituitary gland), even though the process itself is unimpaired. These cases are classified as central (or pituitary) hypothyroidism.

Signs and symptoms of congenital hypothyroidism result from the shortage of thyroid hormones. Affected babies may show no features of the condition, although some babies with congenital hypothyroidism are less active and sleep more than normal. They may have difficulty feeding and experience constipation. If untreated, congenital hypothyroidism can lead to intellectual disability and slow growth. In the United States and many other countries, all hospitals test newborns for congenital hypothyroidism. If treatment begins in the first two weeks after birth, infants usually develop normally.

Congenital hypothyroidism can also occur as part of syndromes that affect other organs and tissues in the body. These forms of the condition are described as syndromic. Some common forms of syndromic hypothyroidism include Pendred syndrome, Bamforth-Lazarus syndrome, and brain-lung-thyroid syndrome.

Congenital hypothyroidism can be caused by a variety of factors, only some of which are genetic. The most common cause worldwide is a shortage of iodine in the diet of the mother and the affected infant. Iodine is essential for the production of thyroid hormones. Genetic causes account for about 15 to 20 percent of cases of congenital hypothyroidism.

The cause of the most common type of congenital hypothyroidism, thyroid dysgenesis, is usually unknown. Studies suggest that 2 to 5 percent of cases are inherited. Two of the genes involved in this form of the condition are PAX8 and TSHR. These genes play roles in the proper growth and development of the thyroid gland. Mutations in these genes prevent or disrupt normal development of the gland. The abnormal or missing gland cannot produce normal amounts of thyroid hormones.

Thyroid dyshormonogenesis results from mutations in one of several genes involved in the production of thyroid hormones. These genes include DUOX2, SLC5A5, TG, and TPO. Mutations in each of these genes disrupt a step in thyroid hormone synthesis, leading to abnormally low levels of these hormones. Mutations in the TSHB gene disrupt the synthesis of thyroid hormones by impairing the stimulation of hormone production. Changes in this gene are the primary cause of central hypothyroidism. The resulting shortage of thyroid hormones disrupts normal growth, brain development, and metabolism, leading to the features of congenital hypothyroidism.

When inherited, the condition usually has an autosomal recessive inheritance pattern, which means both copies of the gene in each cell have mutations. Typically, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they do not show signs and symptoms of the condition.

When congenital hypothyroidism results from mutations in the PAX8 gene or from certain mutations in the TSHR or DUOX2 gene, the condition has an autosomal dominant pattern of inheritance, which means one copy of the altered gene in each cell is sufficient to cause the disorder. In some of these cases, an affected person inherits the mutation from one affected parent. Other cases result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family.

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