Thyroid disorders

Regulation

Synthesis and secretion of thyroid hormone is under the control of the anterior pituitary hormone thyrotropin (or thyroid-stimulating hormone [TSH]). Consistent with a classic negative feedback system, TSH secretion increases when serum thyroid hormone levels fall and decreases when they rise ( Fig. 137.1 ). TSH secretion is also under the regulation of the hypothalamic hormone thyrotropin-releasing hormone (TRH). The negative feedback of thyroid hormone is targeted mainly at the pituitary level, but also likely affects TRH release from the hypothalamus. In addition, input from higher cortical centers can affect hypothalamic TRH secretion.

Under the influence of TSH, the thyroid gland synthesizes and releases thyroid hormone. Thyroxine (3,5,3′,5′-tetraiodothyronine, or T ₄ , which is 65% iodine by weight) is the principal secretory product of the thyroid gland, comprising about 90% of secreted thyroid hormone under normal conditions. Although T ₄ may have direct actions in some tissues, it primarily functions as a hormone precursor that is metabolized in peripheral tissues to the transcriptionally active 3,5,3′-triiodothyronine (T ₃ , which is 59% iodine by weight).

Metabolic pathways

The major pathway of metabolism of T ₄ is by sequential monodeiodination. At least three deiodinases, each with its unique expression in different organs, catalyze deiodination reactions involved in the metabolism of T ₄ . Removal of the 5′-, or outer ring, iodine by type I iodothyronine 5′-deiodinase (D1) or type II iodothyronine 5′-deiodinase (D2) is the “activating” metabolic pathway leading to the formation of T ₃ . Removal of the 5′-, or inner ring, iodine by type III iodothyronine deiodinase (D3) is the “inactivating” pathway that produces the metabolically inactive thyroid hormone 3,3′,5′-triiodothyronine (reverse T ₃ or rT ₃ ). D1 is found most abundantly in the liver, kidneys, and thyroid. It is up-regulated in hyperthyroidism and down-regulated in hypothyroidism. D2 is found primarily in the brain, pituitary, and skeletal muscle and is down-regulated in hyperthyroidism and up-regulated in hypothyroidism. D3 is expressed primarily in the brain, skin, and placental and chorionic membranes. The actions of D3 also include inactivation of T ₃ to form T ₂ , another inactive metabolite. Under normal conditions, about 41% of T ₄ is converted to T ₃ , about 38% is converted to rT ₃ , and about 21% is metabolized via other pathways, such as conjugation in the liver and excretion in the bile. ^,

T ₃ is the metabolically active thyroid hormone and exerts its actions via binding to chromatin-bound nuclear receptors and regulating gene transcription in responsive tissues. It is important to note that only around 10% of circulating T ₃ is secreted directly by the thyroid gland, whereas more than 80% of T ₃ is derived from the conversion of T ₄ in peripheral tissues. ^, Thus factors that affect peripheral T ₄ -to-T ₃ conversion will have significant effects on circulating T ₃ levels. Serum levels of T ₃ are approximately 100-fold less than those of T ₄ , and like T ₄ , T ₃ is metabolized by deiodination to form diiodothyronine (T ₂ ) and by conjugation in the liver. The half-lives of circulating T ₄ and T ₃ are 5–8 days and 1.3–3 days, respectively.

Serum binding proteins

Both T ₄ and T ₃ circulate in the serum as hormones bound to several proteins synthesized by the liver. Thyroid-binding globulin (TBG) is the predominant transport protein and binds to approximately 80% of the circulating serum thyroid hormones. The affinity of T ₄ for TBG is about 10-fold greater than that of T ₃ , which accounts in part for the higher circulating T ₄ levels as compared with T ₃ levels. Other serum binding proteins include transthyretin, which binds about 15% of T ₄ but little, if any, T ₃ ; and albumin, which has a low affinity but a very large binding capacity for T ₄ and T ₃ . Overall, 99.97% of circulating T ₄ and 99.7% of circulating T ₃ are bound to plasma proteins.

Role of the free thyroid hormones

Essential to an understanding of the regulation of thyroid function and the alterations of circulating thyroid hormones seen in critical illness is the “free hormone” concept, which is that only the unbound hormone has metabolic activity. Although overall thyroid hormone production is regulated by the pituitary, serum thyroid function is affected by changes in the free thyroid hormone concentrations. Alterations in either the concentrations of binding proteins or the binding affinity of thyroid hormones to their serum binding proteins have significant effects on total serum hormone levels, owing to the high degree of binding of T ₄ and T ₃ to these proteins. However, despite these changes, binding effects do not necessarily translate into clinically significant thyroid dysfunction.

Peripheral metabolic pathways

There is considerable variation in the transcriptional and translational activities of genes important for thyroid hormone metabolism during acute illness. One of the initial alterations in thyroid hormone metabolism in acute illness is the acute inhibition of D1, which results in the impairment of T ₄ -to-T ₃ conversion in peripheral tissues. D1 is inhibited by a wide variety of factors, including acute illness ( Box 137.1 ), resulting in the acute decrease in T ₃ production in critically ill patients. In contrast, inner ring deiodination by D3 may be increased by acute illness, resulting in increased levels of rT ₃ . Additionally, because rT ₃ is subsequently deiodinated by D1, degradation of rT ₃ decreases, and levels of this inactive hormone rise in proportion to the fall in T ₃ levels. There may also be potential roles of other T ₄ metabolites like 3,5-diiodothyronine (3,5-T2) and 3-iodothyronamine (3-T1AM) in critical illness, but this remains unclear.

Nondeiodinative pathways may play an important role in critical illness, as sulfoconjugation and alanine side chain deamination/decarboxylation are increased, resulting in increased levels of T ₃ -sulfate and Triac, respectively, although thyroid hormone hypermetabolism may not entirely be the result of these processes in critical illness. Triac, which binds to the thyroid hormone receptor and has weak thyromimetic activity, increases locally during illness and fasting. An increase in Triac production in the pituitary may be a factor in decreasing TSH levels during illness.

Finally, in critical illness, there is impaired transport of T ₄ to peripheral tissues, such as the liver and kidney, where much of the circulating T ₃ is produced. This further contributes to the decrease in the production of T ₃ . ^, Interestingly, increased expression of the thyroid hormone transporters OATP1C1 and MCT8 in animal models and increased expression of MCT8 and MCT1 in the liver and muscle in human studies involving critical illness have been observed. The mechanisms underlying the decrease in tissue transport during critical illness has yet to be more fully elucidated.

Thyrotropin regulation

It has long been recognized that serum TSH levels are usually normal in the early phases of acute illness. ^, Decreased TRH secretion caused by inhibitory signals from higher cortical centers, impaired TRH metabolism, alteration of pulsatile TSH, and the decrease or absence of a nocturnal TSH surge ^, may all further lower TSH levels. Serum levels of leptin, the ob gene product that has been shown to vary directly with thyroid hormone levels, also falls as illness progresses and hypothalamic TRH secretion falls, which in turn lead to lowered TSH levels. The decrease of hypothalamic TRH gene expression in animal models, however, is not associated with increased serum T ₄ and T ₃ levels. Finally, certain thyroid hormone metabolites that are increased during acute nonthyroidal illness may play a role in the inhibition of TSH and TRH secretion.

Common medications used in the treatment of critically ill patients may also have inhibitory effects on serum TSH levels ( Box 137.2 ). Van den Berghe and colleagues reported that intravenous (IV) administration of dopamine for 15–21 hours can acutely decrease TSH, whereas its withdrawal results in a 10-fold increase in serum TSH levels. Other medications that can inhibit TSH secretion include glucocorticoids, rexinoids, and somatostatin.

Serum binding proteins

The affinity of thyroid hormones binding to transport proteins and the concentration of serum binding proteins are altered with acute illness ( Table 137.1 ). Serum levels of transthyretin and albumin decrease, especially during prolonged illness, malnutrition, and in high catabolic states. TBG levels may be increased, as seen with liver dysfunction, or decreased, as seen with severe or prolonged illness.

An acquired binding defect of T ₄ to TBG is commonly seen in patients with critical illness. This is thought to result from the release of some as yet unidentified factor from injured tissues that has the characteristics of unsaturated nonesterified fatty acids (NEFAs), which also inhibit T ₄ -to-T ₃ conversion. In systemically ill patients, NEFA levels rise in parallel with the severity of the illness, and drugs such as heparin stimulate the generation of NEFA. Many drugs, including high-dose furosemide, antiseizure medications, and salicylates, also alter the binding of T ₄ to TBG. The alteration in serum binding proteins in critical illness makes estimating free hormone concentrations challenging.

Diagnostic tests

Diagnosis

Routine serum thyroid function screening of an ICU population is not recommended because of the high prevalence of abnormal thyroid function tests and low prevalence of true thyroid dysfunction. When thyroid function tests are ordered in hospitalized patients, they should only be done if there is a high clinical index of suspicion for thyroid dysfunction. Whenever possible, it is best to defer evaluation of the thyroid-pituitary axis until patients have recovered from the acute illness. Because every test of thyroid hormone function can be altered in critically ill patients, no single test can definitively rule in or rule out the presence of intrinsic thyroid dysfunction.

If there is a high clinical suspicion for intrinsic thyroid dysfunction in critically ill patients, reasonable initial tests should include either serum free T ₄ index or free T ₄ and TSH measurements. Assessment of these values in the context of the duration, severity, and stage of illness will allow the correct diagnosis in most patients. For example, a mildly elevated TSH coupled with a low FT4I or free T ₄ is more likely to indicate primary hypothyroidism early in an acute illness, as opposed to the same values obtained during the recovery phase of the illness. Similarly, the combination of an elevated TSH and low-normal FT4I or free T ₄ is more likely to indicate thyroid dysfunction in hypothermic, bradycardic patients than the tachycardic, normothermic individuals. If both the FT4I or free T ₄ and TSH are normal, thyroid dysfunction is effectively eliminated as a significant contributing factor. If the diagnosis is still unclear, measurement of thyroid antibodies is helpful as a marker of intrinsic thyroid disease and increases the sensitivity of both the FT4I or free T ₄ and the TSH. Only in the case of a suppressed TSH and a mid- to high-normal FT4I or free T ₄ are measurements of serum T ₃ levels indicated.