1. 
   

   How does one interpret thyroid function tests in the inpatient setting?

   
   
2. 
   

   How can one distinguish nonthyroidal illness from other thyroid conditions?

   
   
3. 
   

   How does myxedema coma differ from a normal hypothyroid state and how is it treated?

   
   
4. 
   

   What characterizes thyroid storm and how is it distinct from thyrotoxicosis?

   
   
5. 
   

   How is thyroid storm treated?

Thyroid disease is important to hospitalists for two reasons. Rarely, patients are admitted to the hospital with myxedema coma or thyrotoxicosis, conditions that must be recognized early as prompt diagnosis and treatment reduce patient morbidity and mortality. More often, patients have thyroid function tests performed in the hospital because of nonspecific symptoms such as fatigue, weight loss, and palpitations, and the hospitalist has to distinguish between true thyroid disease and nonthyroidal illness syndrome (euthyroid sick syndrome). To understand the diagnosis and treatment of thyroid disease, it is necessary to review the normal physiology of thyroid hormone.

Thyroid hormone usually refers to both thyroxine (T4) and triiodothyronine (T3). The thyroid synthesizes primarily T4, but can also synthesize T3. T3 is felt to be the biologically active form of the hormone; T4, which has a longer half-life, functions as a prohormone. Eighty percent of T3 is produced by deiodination of the tyrosine rings of T4 by a family of deiodinases, which are expressed in a variety of tissues. Both the type 1 and 2 deiodinases convert T4 to T3. In contrast, the type 3 deiodinase converts T4 to inactive reverse T3 (rT3) and also inactivates T3.

Both T4 and T3 likely gain access to cells by a variety of transporters that are still being elucidated. T3 acts mainly in the nucleus, binding to thyroid hormone receptors (TRs) to regulate gene expression. This genomic action accounts for many of T3‘s physiologic effects including thermogenesis, decreased systemic vascular resistance, and increased cardiac chronotropy and inotropy. T3 and the TR may also act directly in the cytoplasm on other cell signaling pathways that influence physiologic function.

T3 feeds back at the level of the hypothalamus and pituitary to regulate thyrotropin-releasing hormone (TRH) and thyroid stimulating hormone (TSH) synthesis and secretion respectively. TSH governs the amount of thyroid hormone synthesized by the thyroid gland. TSH is a heterodimeric glycoprotein hormone that can be measured by rapid, sensitive, and reliable immunoassays in the laboratory. A suppressed TSH demonstrates excessive thyroid hormone and hyperthyroidism, while an elevated TSH indicates inadequate thyroid hormone and hypothyroidism (Figure 150-1).

In certain clinical situations, including patients with central hypothyroidism (secondary hypothyroidism) due to hypothalamic-pituitary dysfunction, those treated with medications such as dopamine and glucocorticoids, and critically ill patients, the TSH is not able to reliably determine thyroid status and should not be used as a screening test (Table 150-1).

Thyroid status can also be assessed by measuring circulating T4 and T3 levels. Because thyroid hormones are protein bound, the most common test used to measure peripheral thyroid hormone is an analogue free T4 (fT4) assay. While this assay is usually reliable, the indirect methodology used may make it difficult to interpret in severe illness or pregnancy. In these circumstances, measurement of total T4 (TT4) and total T3 (TT3), together with an index of protein binding such as thyroxine binding globulin (TBG) or resin uptake, is the preferred method. Also available, but rarely used due to limited availability and cost, is direct measurement of fT4 by equilibrium dialysis. Free T3 levels can also be measured, but have limited clinical utility. In the hospital or outpatient setting, once thyroid disease is clinically suspected, it is usual to screen with a TSH and if abnormal proceed to determine circulating thyroid hormone levels by measuring fT4 and potentially TT3. However, in the critically ill patient suspected of having thyroid dysfunction, it is reasonable to obtain a full panel of thyroid tests, including TSH, fT4, TT4, and TT3.

Alterated Thyroid Function in Nonthyroidal Illness Syndrome

Ideally, routine laboratory testing of thyroid function is best done outside the hospital. In severe illness, changes in thyroid function make it difficult to determine whether thyroid disease is present. Studies show abnormalities in thyroid function testing in 40–70% of intensive care unit (ICU) patients. Nonthyroidal illness syndrome, known as the “euthyroid sick syndrome” or “low T3 syndrome,” is characterized by low serum T3, high rT3, normal-low T4, and normal-low TSH. As these changes somewhat resemble central hypothyroidism, the clinical scenario must be taken into consideration when interpreting thyroid testing. The nonthyroidal illness syndrome is due to a complex interplay of changes in the hypothalamic-pituitary-thyroid axis and in the peripheral metabolism of thyroid hormone. There is controversy over whether these changes are maladaptive or are adaptive, but it is likely that they are an effort to decrease energy utilization during extreme stress and illness.

Low T3 and High rT3 in Nonthyroidal Illness

Nonthyroidal illness syndrome is sometimes termed “low T3 syndrome,” as this is the earliest and most persistent abnormality. Uniformly, T3 is low and rT3 is high, with the T3 level bearing an inverse relationship to the severity of disease. In acute illness, these changes may occur within hours. Alterations in deiodinase activity appear to be responsible. Type 1 deiodinase is inhibited, leading to diminished conversion of T4 to T3. Action of type 3 deiodinase is increased, which metabolizes T4 to inactive rT3, and also lowers T3 by increasing its degradation. Thus, T3 levels are rapidly lowered and rT3 levels are elevated.

T4 and TSH in Nonthyroidal Illness

TSH and T4 levels may be normal in nonthyroidal illness. However, a normal TSH in nonthyroidal illness may be inappropriate in the face of an already low T3 level. In a healthy individual with an intact hypothalamic-pituitary-thyroid axis, this would lead to an increase in TSH. As the patient’s underlying illness worsens, changes in hypothalamic and pituitary action also occur, leading to low TSH levels. TSH is usually detectable in this setting (> 0.05 μU/mL), whereas in clinical thyrotoxicosis it is completely suppressed. Once TSH falls, serum T4 usually follows suit. However, severe illness can also cause decreased binding of T4 to its serum binding proteins. As a result, fT4 concentrations can be low, normal, or high in nonthyroidal illness depending on the assay used. When TSH is low, the possibility of secondary hypothyroidism should also be considered. Production of other pituitary hormones is usually also affected, and it is important to remember that both gonadotropins and growth hormone can be suppressed in acute illness.

In recovery from nonthyroidal illness, the axis tends to reset from the top down. TSH rises, sometimes above the normal range in the initial period of the recovery, though typically not above 20 μU/mL, in order to allow for the recovery of T4. However, T3 may still remain low in this setting. The TSH eventually returns to its physiologic normal level as the recovery continues. If TSH concentrations rise above 20 μU/mL in presumed nonthyroidal illness, primary hypothyroidism should be considered. Outpatient thyroid function tests prior to hospitalization may be very helpful, as this may establish a previous baseline.

When interpreting thyroid testing in hospitalized patients, it should be borne in mind that dopamine, glucocorticoids, amiodarone, and other medications often administered to the critically ill, may affect the results of thyroid function testing (Table 150-1).

Should Nonthyroidal Illness Syndrome Be Treated?

In patients with a persistently low T3 from nonthyroidal illness, the T3 level is an independent predictor of morbidity and mortality. Does replacement of thyroid hormone to normal levels in such patients lead to lower morbidity and mortality? Treatment of nonthyroidal illness with T4 therapy has not shown to be of clinical benefit. In one study of ICU patients with nonthyroidal illness, those treated with T4 to normalize serum T4 values did not have a significant rise in their T3 levels. Furthermore, the T4-treated group had the same mortality rate as the untreated control group.

Thyroid hormone replacement with T3 has been tried in patients with low T3 in a variety of clinical settings, including renal failure, congestive heart failure, and coronary artery bypass graft (CABG). T3 replacement has not been found to be beneficial in the majority of studies. Although T3 supplementation appears to temporarily improve hemodynamics in critically ill patients with cardiac disease, there is no evidence of a mortality benefit. Because of the potential for morbidity and harm with both T4 and T3 replacement, we do not believe that there is adequate evidence to treat patients who have nonthyroidal illness with thyroid hormone.