Fig.20.6Homeostasisinthehypothalamus-pituitary-thyroidaxisandmechanismofactionofthyroidhormones.Secretionofthyroidhormones(T3andT4)iscontrolledbytrophicfactorssecretedbyboththehypothalamusandtheanteriorpituitarygland.DecreasedlevelsofT3andT4stimulatethereleaseofthyrotropin-releasinghormone(TRH)fromthehypothalamusandthyroid-stimulatinghormone(TSH)fromtheanteriorpituitary,causingT3andT4levelstorise.ElevatedT3andT4levels,inturn,suppressthesecretionofbothTRHandTSH.Thisrelationshipistermedanegative-feedback loop. TSHbindstotheTSHreceptoronthethyroidfollicularepithelium,whichcausesactivationofGproteins,releaseofcyclicAMP(cAMP),andcAMPmediatedsynthesisandreleaseofthyroidhormones(i.e.,T3andT4).Intheperiphery,T3andT4interactwiththethyroidhormonereceptor(TR)andformacomplexthattranslocatestothenucleusandbindstoso-called“thyroidresponseelements”(TREs)ontargetgenes,therebyinitiatingtranscription.
In the periphery, the majority of free T4 is deiodinated to T3; the latter binds to thyroid hormone nuclear receptors in target cells with 10-fold greater affinity than T4 and has proportionately greater activity. Binding of thyroid hormone to its nuclear thyroid hormone receptor (TR) creates a hormone-receptor complex that regulates the transcription of a subset of cellular genes. This produces diverse cellular effects, including increased carbohydrate and lipid catabolism and protein synthesis in a wide range of cell types. The net result of these processes is an increase in the basal metabolic rate.
Clinical recognition of diseases of the thyroid is important, because most are amenable to medical or surgical management. Such diseases include conditions associated with excessive release of thyroid hormones (hyperthyroidism), thyroid hormone deficiency (hypothyroidism), and mass lesions of the thyroid. Considered next are the clinical consequences of disturbed thyroid function, followed by an overview of the disorders that generate these problems.
Thyrotoxicosis is a hypermetabolic state caused by elevated circulating levels of free T3 and T4. Because it is caused most commonly by hyperfunction of the thyroid gland, thyrotoxicosis often is referred to as hyperthyroidism. In certain conditions, however, the oversupply either is related to excessive release of preformed thyroid hormone (e.g., in thyroiditis) or comes from an extrathyroidal source, rather than a hyperfunctioning gland (
Table 20.2 ). Thus, strictly speaking, hyperthyroidism is only one (albeit the most common) category of thyrotoxicosis. Despite this clear distinction, the following discussion adheres to the common practice of using the terms thyrotoxicosis and hyperthyroidism interchangeably.
The three most common causes of thyrotoxicosis are associated with hyperfunction of the gland:
Diffuse hyperplasia of the thyroid associated with Graves disease, a form of autoimmune thyroid disease (accounts for 85% of cases)
Hyperfunctional (“toxic”) adenoma of the thyroid
The clinical manifestations of thyrotoxicosis are protean and are mainly attributable to the hypermetabolic state induced by thyroid hormone and overactivity of the sympathetic nervous system:
Constitutional symptoms: The skin of thyrotoxic individuals tends to be soft, warm, and flushed because of increased blood flow and peripheral vasodilation to increase heat loss; heat intolerance and excessive sweating are common. Increased sympathetic activity and hypermetabolism result in weight loss despite increased appetite.
Gastrointestinal: Stimulation of the gut results in rapid transit time (hypermotility), which can cause fat malabsorption and steatorrhea.