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Thyroid peroxidase also catalyzes the binding of DITto another DIT, forming T4. Some DIT will also bind to an MIT, forming T3. These products remain linked tothe thyroglobulin (Tg). (5) The mature Tg, containing MIT, DIT, T4, and T3 (in order of greater to lesser abundance), is endocytosed back into the follicle cell and can be stored as colloid until secreted. (6) Proteolysisof the colloid is stimulated by TSH and releases the constituent molecules. MIT and DIT reenters the synthetic pool, and T3 and T4 exit the basolateral membrane into the blood.
TRH, thyrotropin-releasinghormone.323324Endocrine PhysiologyPropylthiouracil (PTU) is used to treat hyperthyroidism, because it blocks thyroid peroxidase and acts at allbiosynthetic steps of TH production, from organification ofiodine to conversion of T4 to T3 in the peripheral tissues.About one third of the iodine needed for T3 and T4 synthesiscomes from dietary sources. Although several tissues, including salivary glands, mammary glands, and stomach, can absorbiodine, oxidation can take place only in the thyroid gland,because of the presence of thyroid peroxidase.SYNTHESIS, RELEASE, AND UPTAKE OFTHYROID HORMONESThyroid Hormone Uptake at Target TissuesFree T4 and T3 diffuse into target cells, and within the cells theT4 is converted to T3 by 5′-deiodinase, producing approximately the same concentrations of T3 and rT3. The active T3then binds the intracellular thyroid hormone receptor in thenucleus, which forms a complex with the thyroid hormoneresponse element (TRE) in the nucleus and stimulates genetranscription (Fig.
27.4). TREs are found on a variety of genes,including the growth hormone receptor gene, cardiac andsarcoplasmic reticulum Ca2+-ATPase genes, and genes thatencode Na+/K+ ATPase subunits. Thus, TH can control diversefunctions like growth, heart rate, and general metabolic rate.In general, low to normal levels of TH have anabolic effectsand lead to synthesis of other hormones, and high levels ofTH have catabolic effects, causing breakdown of proteins andhormones.Synthesis and Release of Thyroid HormonesThe synthesis and release of TH is regulated by the secretionof TSH from the anterior pituitary gland (see Chapter 26).TSH binds to its G protein–coupled receptor on the thyroidgland, stimulating cAMP, which acts at each biosynthetic step(see Fig.
27.3). If TSH is elevated for extended periods of time,it can also exert a trophic effect on the thyrocytes, causinghypertrophy of the thyroid tissue and hyperthyroidism.■■TSH secretion is stimulated by thyroid-releasinghormone (TRH), estrogen, and low circulating T3 or T4.TSH secretion is inhibited by somatostatin, growthhormone, cortisol, and high circulating T3 or T4.ACTIONS OF THYROID HORMONESTH affects virtually all systems and can act at cellular andwhole tissue levels, generally to increase metabolism andgrowth processes (see Fig. 27.4).
Within cells, TH promotesproduction of proteins, enzymes, and other hormones;increases Na+/K+ ATPase; and increases the number of mitochondria, which increases O2 consumption. These actions ofTH are seen in:■■TSH ultimately releases T3 and T4 into the blood, with 20times the amount of T4 (thyroxine) secreted compared withT3. In the blood, most of the T3 and T4 is bound to proteinsincluding albumin and thyroxine-binding globulin (TBG).The TBG acts as a plasma reservoir for T4, because T4 will onlybe active when it is released from the plasma proteins andenters the target cells. Thus, because of the high affinity forbinding to plasma proteins, there is relatively little “free” circulating T3 and T4, but this is the fraction that is the physiologically and clinically relevant fraction.Circulating free T3 and T4 provides feedback to both the hypothalamus and pituitary gland to decrease TRH and TSH,respectively (see Fig.
27.3). This feedback system is critical tomaintaining appropriate levels of TH secretion.■■■■bone and tissues—contributing to normal growth anddevelopment; bone cell proliferationbrain and nervous system—contributing to normalgrowth and developmentlungs—increasing ventilationheart—increasing cardiac outputkidneys—increasing renal functionmetabolism—increasing food intake; increasing lipolytic effect on adipose cells, releasing free fatty acids intocirculation; decreasing adipose tissue; decreasing musclemass; increasing body temperatureThus, TH has major effects on metabolism and growth, anddisruptions in its normal secretion can have dramaticconsequences.Thyroid HormonesT4325Cell membraneCytoplasmDeiodinationT3Intracellular effectsNucleusMitochondriaNuclearreceptorDNARespiratory enzymesNa+-K+-ATPasemRNAOther proteinsand hormonesOther enzymesO2 consumptionMetabolic rateWhole Body EffectsNormal growthand developmentBonesCentral nervous systemCO2Cardiac outputVentilationFigure 27.4 Thyroid Hormone Action T4 is converted to active T3 at target tissue by 5′-deiodinaseaction.
The T3 binds to nuclear receptors, initiating transcription of a variety of proteins and enzymes. Theoverall effects of thyroid hormone are to increase metabolic rate and O2 consumption, and the generaleffects in target organs are illustrated.UreaRenal function326Endocrine PhysiologyCLINICAL CORRELATEDiseases of Thyroid Function: HypothyroidismHypothyroidism, or reduced TH, can result from lack of iodine,as well as autoimmune disease. Although there is dietary supplementation of iodine in the Western hemisphere, iodine deficiencyis a health problem in many countries. Iodine deficiency severelyreduces organification of Tg, and thus TH synthesis.
Immunesystem dysfunction accounts for most cases of thyroid disease inthe Western hemisphere. The most common cause of low TH isproduction of antibodies to thyroglobulin or thyroid peroxidase(TPO) (Hashimoto’s thyroiditis). These antibodies act at thethyroid gland to inhibit the production and secretion of TH, andeventually destroy the gland.■■■In children, untreated congenital hypothyroidism can result incretinism, which is associated with stunted growth, mentalretardation, impaired motor neuron function, andconstipation.In adults, hypothyroidism results in myxedema, which is associated with increased fat deposition, nonpitting edema, coldintolerance, constipation, hypotension, fatigue, and depression,among other symptoms.Whether hypothyroidism is caused by iodine deficiency orimmune cells, the low circulating TH feeds back to the pituitaryand hypothalamus, causing high levels of circulating TSH.
Treatment of hypothyroidism is with synthetic thyroxine.Appearance of thyroid gland“Spillage” ofthyroglobulinAntigenMicroscopy of Hashimoto. Mixture of hyperplasticand atrophic follicles with lymphofollicular infiltrationAntibodiesLymph nodeAntibodies may be identifiedin serum by laboratory proceduresHashimoto’s Thyroiditis Hashimoto’s thyroiditis is a common form of hypothyroidism and is causedby autoimmune antibodies directed against thyroglobulin or thyroid peroxidase.
This results in low TH production (and high circulating TSH) and eventual destruction of the thyroid gland.Thyroid HormonesCLINICAL CORRELATEDiseases of Thyroid Function: HyperthyroidismHyperthyroidism, or overproduction of TH, is associated withhigh metabolic rate (30% to 60% above normal), weight loss,increased appetite, tachycardia, hyper-reactive bowels, and muscleweakness.
Again, the most common cause is from immune cellstargeting the thyrocytes.■■Thyroid-stimulating immunoglobulins can bind to the TSHreceptors on the thyroid gland and produce the same biologicactions as TSH. However, while the elevated circulating THsuppresses pituitary TSH, there is no feedback regulation of thethyroid-stimulating immunoglobulins, so synthesis and releaseof TH continues. The gland becomes hypertrophied, forming agoiter, due to the trophic effect of immunoglobulin on thethyrocytes.
These immunoglobulins are the cause of hyperthyroidism in Graves’ disease, which is characterized by elevatedcirculating TH but reduced TSH. Exophthalmus (protrudingeyes) is a symptom of Graves’ disease and is caused by deposition of glycoproteins and water behind the eyes.In contrast to Graves’ disease, the hyperthyroidism resultingfrom a TSH-secreting pituitary tumor is characterized by ele-vated TH and TSH. Although rare, thyroid storms can occurwhen TH levels increase to toxic levels, creating acute awarenessof discomfort in the patient. These symptoms can includetachycardia, sleeplessness, dramatic mood swings, and hyperkinesis.
If untreated, it can rapidly (within days) progress tocongestive heart failure, circulatory collapse, and death. Treatment of hyperthyroidism is by propylthiouracil (PTU), radiation, or thyroidectomy and then thyroxine replacement.Many people with autoimmune thyroid disease have antibodiesto both the TSH receptor and thyroid peroxidase and have a mixof Graves’ disease and Hashimoto’s thyroiditis. Initially, thepatient will be hyperthyroid, and then hypothyroid. Approximately 70% of people with Graves’ disease have Hashimoto’s.Goiter (enlarged thyroid gland) can occur in hypothyroid andhyperthyroid conditions.
For example, in both iodine deficiencyand TSH-secreting tumor, elevated TSH levels stimulate thyroidgrowth. This is because, in both cases, elevated TSH has a growtheffect on the thyrocytes. In each case, it takes years to developgoiter.NervousnessExcitabilityRestlessnessEmotional instabilityInsomniaA. PerspirationFacial flushingAge 12 to 50 years(usually)ExophthalmosPalpable lymph nodesGoiter(may have thrill and bruit)Muscle wastingWarm, velvety skinShortness of breathPalpitation, tachycardia,poor response to digitalisBreast enlargement,gynecomastia in maleIncreased appetiteDiarrhea (occasional)Loss of weightTremorRapid pulseClubbing of fingers(in some patients withsevere exophthalmos)Warm, moist palmsOligomenorrheaor amenorrheaMuscular weakness,fatigabilityLocalized myxedemaSymphysis mentiB.Hyoid boneScintigramDiffuse goiter of moderate size327Suprasternal notchDiffuse enlargement and engorgementof thyroid gland (broken line indicatesnormal size of gland)Clinical Symptoms of Hyperthyroidism A, Hyperthyroidism, such as is seen in Graves’ disease,affects most physiologic systems and can increase metabolic rate by 30% to 60% over normal.
The elevatedthyroid hormone causes a wide variety of symptoms as illustrated above. B, Goiter. Enlargement of thethyroid gland (goiter) can be caused by both hypothyroid and hyperthyroid conditions and results from TSH,or immunoglobulin-mediated stimulation of hyperplastic growth of the thyrocytes.This page intentionally left blank329CHAPTER28Adrenal HormonesThe paired adrenal glands are also known as the suprarenalglands, due to their location above the kidneys in the retroperitoneal space (Fig. 28.1).
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