Are you sure the patient has nonthyroidal illness?
Critical illness causes multiple nonspecific alterations in thyroid hormone concentrations that relate to the severity of the illness in patients who have no intrinsic thyroid disease. There is an ongoing debate whether such alterations are a physiologic adaptation or a pathologic perturbation. Due to the complexity of the sick euthyroid syndrome, it is likely that both physiologic and pathologic effects play a role.
Despite abnormalities in serum thyroid hormone parameters, there is little evidence that critically ill patients have clinically significant thyroid dysfunction. Thus, there is no current evidence to support thyroid hormone therapy in the management of the sick euthyroid patient. The sick euthyroid syndrome should not be viewed as an isolated pathologic event but as part of a coordinated systemic reaction to illness that involves both the immune and endocrine systems.
Free Hormone Concept
Essential to the understanding of the regulation of thyroid function and the alterations of circulating thyroid hormones seen in critical illness is the “free hormone” concept, that only the unbound hormone has metabolic activity. Overall thyroid function is regulated by the pituitary secretion of thyroid stimulating hormone (TSH) when there are any changes in free thyroid hormone concentrations. Changes in either the concentrations of binding proteins or the binding affinity of thyroid hormone to the serum binding proteins have significant effects on the total serum hormone levels due to the high degree of binding of T4 and T3 to these proteins. However, these changes may not necessarily be associated with thyroid dysfunction.
While the cause of the alterations in thyroid hormone economy in critical illness is largely unknown, cytokines, such as tumor necrosis factor alpha, interleukin 1 and interleukin 6, have been shown to reproduce many of the features of the sick euthyroid syndrome in both animal and human studies. Whether the sick euthyroid syndrome results from activation of the cytokine network or simply represents an endocrine response to systemic illness resulting from the same mediators that trigger the cytokine cascade remains to be determined.
The pathogenesis can be divided into three sections:
- Alterations in peripheral metabolic pathways of thyroid hormone
- Alterations in the pituitary-thyroid axis
- Alterations in serum binding proteins
Alterations in peripheral metabolic pathways of thyroid hormone
The major pathway of metabolism of T4 is by sequential monodeiodination by types 1 (D1) and 2 (D2) to generate T3 (activating pathway) or type 3 deiodinase (D3) to generate rT3 (inactivating pathway). One of the first alterations in acute illness is inhibition of D1 and D2 in peripheral tissues and subsequent impaired conversion of T4 to T3, causing serum and tissue T3 levels to fall soon after the onset of acute illness. D1 also deiodinates rT3, so degradation is impaired and levels of this inactive hormone rise in proportion to the fall in T3 levels. Recent studies have suggested that D3 may be increased in certain tissues, leading to increased T3 disposal within those tissues. Non-deiodinative pathways of metabolism, such as sulfoconjugation, are also increased in critical illness (see Table1).
Alterations in the pituitary-thyroid axis
While serum TSH levels are usually normal early in acute illness, levels often fall as the illness progresses due to the effects of a variety of inhibitory factors that are common in the treatment of the critically ill patient. The use of dopamine, increased levels of glucocorticoids, either endogeneous or exogenous, and inhibitory signals from higher cortical centers may also play a role in decreasing TSH secretion. Certain thyroid hormone metabolites that are increased in nonthyroidal illness may also play a role (See Table 2).
Alterations in serum binding proteins
Both T4 (99.97% bound) and T3 (99.7% bound) circulate in the serum bound primarily to thyronine-binding protein (TBG), and the binding of thyroid hormones to TBG is affected by a variety of factors in acute illness. Since only the unbound hormone has metabolic activity, changes in either the concentrations of, or binding to, TBG would have major effects on the total serum hormone levels but minimal changes in the free hormone concentrations, and, thus, overall thyroid function is maintained (See Table 3).
What are the stages of the sick euthyroid syndrome?
The sick euthyroid syndrome can be divided into four stages:
- Low T3
- High T4
- Low T4
While this is helpful in understanding the progression of abnormalities that leads to the sick euthyroid syndrome, it is important to realize that not all patients will progress through all of the stages. However, it does help in the distinction between the sick euthyroid syndrome and intrinsic thyroid dysfunction. For example, the patient presenting with an elevated TSH early in their intensive care unit (ICU) course is more likely to have significant hypothyroidism while the same TSH elevation late in the ICU course is more likely due to recovery from the underlying illness.
Low T3 State
Common to all of the abnormalities in thyroid hormone concentrations seen in critically ill patients is a substantial depression of serum T3 levels, which can occur as early as 24 hours after the onset of illness and affects the majority of the patients admitted to the medical service. This can be explained solely by inhibition of peripheral T4 to T3 conversion. This stage is common in patients with congestive heart failure and with acute cardiac injury. In patients with cardiac disease, serum T3 concentrations are a negative prognostic factor and inversely proportional to mortality.
High T3 State
Serum T4 levels may be elevated early in acute illness, mainly due to the acute inhibition of T4 to T3 conversion. As the duration of illness increases, non-deiodinative pathways of T4 degradation increase and return serum T4 levels to the normal range.
Low T4 State
As the severity and the duration of the illness increases, serum total T4 levels may decrease into the subnormal range as a result of a decrease in the binding of T4 to TBG, a decrease in serum TSH levels leading to decreased production of T4 and an increase in non-deiodinative pathways of T4 metabolism. The decline in serum T4 levels correlates with prognosis in non-cardiac ICU patients, with mortality increasing as serum T4 levels drop below 4 mcg/dl and approaching 80% in patients with serum T4 levels < 2 mcg/dl. Despite marked decreases in serum total T4 and T3 levels to the hypothyroid range, the free hormone levels are often normal; thus, the Low T4 State is more likely a marker of multi-system failure in these critically ill patients than a true hormone-deficient state.
The alterations in thyroid hormone concentrations resolve as the illness resolves. This stage may be prolonged and is characterized by modest increases in serum TSH levels. Full recovery, with restoration of thyroid hormone levels to the normal range, may take up to several months after the patient is discharged from the hospital.
What else could the patient have?
The differential diagnosis is simply the presence or absence of thyroid dysfunction (ie. hypothyroidism or hyperthyroidism).
Key laboratory and imaging tests
The routine screening of an ICU population for thyroid dysfunction is not recommended due to the high prevalence of abnormal thyroid function tests and low prevalence of true thyroid dysfunction. Whenever possible, it is best to defer evaluation of the thyroid-pituitary axis until the patient has recovered from the acute illness. No single test can definitively rule in the presence of intrinsic thyroid dysfunction.
By definition, the Sick Euthyroid Syndrome is the presence of abnormal thyroid function tests in the setting of non-thyroidal illness and in the absence of intrinsic thyroid dysfunction. The most common abnormality is low levels of T3, although this is not usually the first test performed. Abnormal levels of TSH usually lead to measurements of the free T4 (FT4) or free T4 index (FTI), which are often abnormal.
A reasonable initial approach is to obtain both free T4 index (FTI) (or less so, FT4) and TSH measurements in patients with a high clinical suspicion for intrinsic thyroid dysfunction. Assessment of these values in the context of the duration, severity and stage of illness of the patient will allow the correct diagnosis in most patients. If the diagnosis is still unclear, measurement of thyroid antibodies may be helpful as a marker of intrinsic thyroid disease. Only in the case of a suppressed TSH and a mid-normal to high FTI is measurement of serum T3 levels indicated.
Abnormal TSH values have been reported in up to 20% of hospitalized patients, over 80% of whom have no intrinsic thyroid dysfunction on followup testing when healthy. Abnormal TSH values require additional biochemical and clinical evaluation before a diagnosis of thyroid dysfunction can be made.
Total T4 measurements alone are of little use in the acutely ill patient since abnormalities in binding to serum proteins are commonplace. Measurement of true serum free T4 concentrations by equilibrium dialysis or ultrafiltration is time-consuming and expensive; thus, estimates of the free T4 concentrations are obtained by either the FTI or the FT4 by analog measurement.
There is no indication for the routine measurement of serum T3 levels in the initial evaluation of thyroid function in the critically ill patient, since serum T3 concentrations are affected to the greatest degree by the alterations in thyroid hormone economy resulting from acute illness. The only setting where serum T3 levels may be helpful is in the presence of a suppressed sensitive TSH value where an elevated or high normal serum T3 concentration will often help to differentiate between thyrotoxicosis and the Sick Euthyroid Syndrome.
Other tests that may prove helpful diagnostically
Thyroid autoantibodies are secondary tests that add to the specificity of abnormal TSH and FTI values in diagnosing intrinsic thyroid disease.
Predictors of mortality
In most critical medical and surgical illnesses that result in the sick euthyroid syndrome, serum T4 levels serve as predictors of mortality, with mortality increasing with decreasing serum T4 levels. However, in patients hospitalized with complications of AIDS, serum T3 levels are better predictors of mortality, as serum T3 levels are higher in these patients than in the non-AIDS patient with an equivalent degree of illness. Serum T3 levels are inversely associated with prognosis in patients with congestive heart failure.
Management and treatment of the disease
Emergent therapy is aimed only at the underlying, non-thyroidal disorder. Treatment with thyroid hormone has not been shown to be effective and is not indicated in any patient with the sick euthyroid syndrome.
The question of whether the sick euthyroid syndrome in critically ill patients represents pathologic alterations in thyroid function that negatively impacts these patients or simply reflects the multisystem failure (ie. respiratory, cardiac, renal, hepatic failure) that occurs in critically ill patients is still debatable. What is not debatable is that thyroid hormone replacement therapy has not been shown to be of benefit in the vast majority of these patients in published studies to date. Evidence does suggest a beneficial effect on L-T3 on increasing organ survival harvested from brain-dead organ donors.
While L-T3 appears to slightly improve hemodynamic and neurohumoral parameters in patients with congestive heart failure, these benefits may represent a pharmacologic effect of T3 rather than a physiologic replacement hormonal effect. Further, the studies involving patients with congestive heart failure treated with T3 do not have a deleterious effect of L-T3 treatment but do not appear to have any sustained clinical benefit. However, future studies do appear to be warranted in this patient population. At the present time, in the absence of any clinical evidence of hypothyroidism, there does not appear to be any compelling evidence for the use of thyroid hormone therapy in any patient with decreased thyroid hormone parameters due to the sick euthyroid syndrome.
- L-T3 treatment results in increased protein breakdown and increased nitrogen excretion in fasting normal and obese patients.
General ICU patients
- No benefit of L-T4 on general medical patients, burn patients, patients with acute renal failure or renal transplant.
- No benefit of L-T4 on developmental indices of premature infants at 26-28 weeks gestation.
- Possible beneficial effect of L-T4 on infants of at 25-26 weeks gestation but possible deleterious effects on infants of 27-30 weeks gestation.
- No benefit of L-T3
- Meta-analysis shows no significant effects of thyroid hormone treatment of premature infants.
Cardiac Surgery patients
- Small studies suggest improved hemodynamic parameters with L-T3
- Large trials show no benefit of L-T3 noted in patients undergoing cardiac bypass.
- Possible improvement in hemodynamic parameters and hospital stay with L-T3 in children undergoing cardiac surgery.
- Variable results (helpful, no benefit) on the effects of L-T3 in preserving function of normal hearts in brain-dead cardiac donors prior to transplantation.
- Possible benefits of L-T3 in improving function of impaired hearts prior to transplant, potentially increasing the pool of organs available for transplantation.
- Consensus conferences recommend the use of L-T3 as part of the hormonal resuscitation in donors whose cardiac ejection fraction is <45%.
Congestive Heart Failure
- Small uncontrolled study suggested short term L-T4 therapy increased cardiac output and functional capacity and decreased systemic vascular resistance.
- Improved hemodynamic parameters and neurohumoral profiles with short-term intravenous L-T3 infusion, possibly requiring supraphysiologic concentrations.
Thyroid hormone concentrations should return to the normal range once the patient has fully recovered from their underlying illness. Repeating a FT4/FTI and TSH in 2-3 months after the acute hospitalization has ended is reasonable.
What’s the Evidence?/References
Adler, SM, Wartofsky, L. “The nonthyroidal illness syndrome”. Endocrinol Metab Clin North Am. vol. 36. 2007. pp. 657-72. (Recent review with details of the points discussed in this chapter with extensive references.)
Peeters, RP, Wouters, PJ, Kaptein, E, van Toor, H, Visser, TJ, Van den Berghe, G. “Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients”. J Clin Endocrinol Metab. vol. 88. 2003. pp. 3202-11. (Seminal article measuring changes in tissue thyroid hormone metabolism in critically ill humans.)
Spencer, C, Elgen, A, Shen, D, Duda, M, Qualls, S, Weiss, S, Nicoloff, J. “Specificity of sensitive assays of thyrotropin (TSH) used to screen for thyroid disease in hospitalized patients”. Clin Chem. vol. 33. 1987. pp. 1391-6. (Classic article documenting the development and use of sensitive TSH assays by the investigators who developed these assays.)
Van den Berghe, G, de Zegher, F, Lauwers, P. “Dopamine and the sick euthyroid syndrome in critical illness”. Clin Endocrinol (Oxf). vol. 41. 1994. pp. 731-7. (Documents the effects of dopamine on TSH secretion, a major mediator of abnormal thyroid function tests in the ICU.)
Kaptein, EM, Weiner, JM, Robinson, WJ, Wheeler, WS, Nicoloff, JT. “Relationship of altered thyroid hormone indices to survival in nonthyroidal illness”. Clin Endocrinol (Oxf). vol. 16. 1982. pp. 565-574. (Describes the various thyroid hormone indices in nonthyroidal illness.)
Pingitore, A, Landi, P, Taddei, MC, Ripoli, A, L’Abbate, A, Iervasi, G. “Triiodothyronine levels for risk stratification of patients with chronic heart failure”. Am J Med. vol. 118. 2005. pp. 132-6. (Classic articles on the use of thyroid hormone indices as predictors of mortality in the critically ill patient.)
DeGroot, LJ. “”Non-thyroidal illness syndrome” is functional central hypothyroidism, and if severe, hormone replacement is appropriate in light of present knowledge”. J Endocrinol Invest. vol. 26. 2003. pp. 1163-70. (Lead investigator suggesting that the use of thyroid hormone therapy in the sick euthyroid syndrome should be re-evaluated.)
Farwell, AP. “Treatment of the sick euthyroid syndrome with thyroid hormone is not indicated”. Endocr Practice. vol. 14. 2008. pp. 1180-7. (Recent review of the trials of thyroid hormone therapy in the sick euthyroid syndrome.)
Klemperer, JD, Klein, I, Gomez, M, Helm, RE, Ojamaa, K, Thomas, SJ, Isom, OW, Kreiger, K. “Thyroid hormone treatment after coronary artery bypass surgery”. N Engl J Med. vol. 333. 1995. pp. 1522-7. (Examines the role of thyroid hormone replacement therapy in the sick euthyroid syndrome produced after coronary artery bypass surgery.)
Novitzky, D, Cooper, DK, Rosendale, JD, Kauffman, HM. “Hormonal therapy of the brain-dead organ donor: experimental and clinical studies”. Transplantation. vol. 82. 2006. pp. 1396-401. (Examines the role of T3 therapy in the “resuscitation” of impaired hearts.)
Osborn, DA. “Thyroid hormones for preventing neurodevelopmental impairment in preterm infants”. Cochrane Database Syst Rev. 2001. pp. CD001070(Meta-analysis of the effects of thyroid hormone treatment in premature infants.)
Pingitore, A, Galli, E, Barison, A, Iervasi, A, Scarlattini, M, Nucci, D, L’Abbate, A, Mariotti, R, Iervasi, G. “Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study”. J Clin Endocrinol Metab. vol. 93. 2008. pp. 1351-8. (Recent study suggesting a possible role for L-T3 in patients with CHF.)
Boelen, A, Kwakkel, J, Fliers, E. “Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection”. Endocrine Reviews. vol. 32. 2011. pp. 670-93. (A comprehensive review of the effects of the cellular and immunologic states of acute illness in different organs.)
Gourin, CG, Johnson, JT, Randolph, G. “Postoperative complications”. Thyroid and Parathyroid Surgery. 2003. pp. 433-43.
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- Are you sure the patient has nonthyroidal illness?
- Alterations in peripheral metabolic pathways of thyroid hormone
- Alterations in the pituitary-thyroid axis
- Alterations in serum binding proteins
- What are the stages of the sick euthyroid syndrome?
- What else could the patient have?
- Key laboratory and imaging tests
- Other tests that may prove helpful diagnostically
- Management and treatment of the disease
- What’s the Evidence?/References