eMedicine Specialties > Endocrinology > Thyroid

Euthyroid Sick Syndrome: Differential Diagnoses & Workup

Author: Serhat Aytug, MD, Staff Physician, Division of Endocrinology, Diabetes and Metabolism, CrystalRun Healthcare
Coauthor(s): Lawrence E Shapiro, MD, Chief, Division of Endocrinology and Metabolism, Professor of Medicine, Department of Medicine, Winthrop University Hospital
Contributor Information and Disclosures

Updated: Aug 13, 2009

Differential Diagnoses

Hypopituitarism (Panhypopituitarism)
Hypothyroidism

Other Problems to Be Considered

Drugs that influence thyroid function include the following:

Drugs that decrease thyroid-stimulating hormone secretion

Dopamine
Glucocorticoids
Octreotide

Drugs that decrease thyroid hormone secretion

Lithium
Iodide
Amiodarone
Aminoglutethimide

Drugs that increase thyroid hormone secretion

Iodide
Amiodarone

Drugs that decrease thyroxine absorption

Colestipol
Cholestyramine
Aluminum hydroxide
Ferrous sulphate
Sucralfate

Drugs that alter thyroxine and triiodothyronine transport in serum (increased serum thyroxine-binding globulin concentration)

Estrogens
Tamoxifen
Heroin
Methadone
Mitotane
Fluorouracil

Drugs that alter thyroxine and triiodothyronine transport in serum (decreased serum thyroxine-binding globulin concentration)

Androgens
Anabolic steroids
Slow-release nicotinic acid
Glucocorticoids

Drugs that alter thyroxine and triiodothyronine transport in serum (displacement from protein-binding sites)

Furosemide
Fenclofenac
Mefenamic acid
Salicylates

Drugs that alter thyroxine and triiodothyronine metabolism (increased hepatic metabolism)

Phenobarbital
Rifampin
Phenytoin
Carbamazepine

Drugs that alter thyroxine and triiodothyronine metabolism (decreased thyroxine 5'-deiodinase activity)

Propylthiouracil
Amiodarone
Beta-adrenergic antagonist drugs

Conditions that affect thyroid function tests

Certain thyroid function test result abnormalities also have been characterized in the conditions and NTIs discussed as follows:

• Effect of heat: Induction of increased temperature in patients with primary hypothyroidism results in demonstrable decreases in serum TSH, and thyroid hormone secretion may be less in summer than winter. Acute exposure to heat decreases serum T3 and causes reciprocal elevation of rT3. Both total T3 and free T3 commonly are decreased in patients who are hyperpyrexic.
• Thermal injury: Patients with significant burns exhibit typical euthyroid sick profile values, ie, low T3 and FT3 with increased rT3; total T4 and free T4 levels may be slightly decreased acutely but normalize after a few days. Basal TSH secretion is unchanged.
  
  In a study of euthyroid sick syndrome in burn patients, Gangemi et al found significantly lower FT3 and TSH levels in patients who did not survive their injuries than in those who did.⁵ A significant correlation was also found between FT3 concentrations and the severity of patients' burns. However, there was no significant difference in FT4 levels between survivors and nonsurvivors. The authors suggested that assessment of FT3 levels might be used in determining prognosis in burn patients.
• Effects of cold: After acute cold exposure, rats have demonstrated increased serum levels of TSH and thyroid hormone; similar changes have been more difficult to demonstrate in humans. Cold exposure is associated with increased rates of deiodination of T4 and T3, enhanced hepatic binding and biliary and fecal clearance of the iodothyronines, and increased conversion of T4 to T3. A transient increase in TSH also occurs after exposure to cold.
• Fasting and/or starvation: Total T4 usually remains unchanged, but thyroidal secretion might be diminished. Free T4 may remain unchanged, or it may elevate due to decreased binding of T4 secondary to an increase in free fatty acids, which elevate during starvation. Serum total T3 and free T3 levels decrease dramatically. rT3 generally is elevated, and basal TSH secretion is diminished. TSH response to TRH also is diminished.
• Protein/calorie malnutrition: Starvation alters the results of thyroid function tests. Total T4 is reduced, free T4 is unchanged, total T3 is reduced significantly, free T3 is reduced, and rT3 is elevated significantly. Basal TSH either is unchanged or elevated. A delay of TSH to TRH stimulation is exaggerated.
• Obesity: Obesity affects thyroid function only minimally. Total T3 might be elevated.
• Surgery⁶ : Total T3 falls dramatically on the day of surgery and remains significantly decreased postoperatively. The degree of the fall is related to the severity of surgical trauma. An absolute percent increase of free T3 also occurs on the day of the surgery. The free T3 concentration rapidly falls to low levels postoperatively, paralleling the decline in total T3. T4 usually is not altered on the day of surgery. One study demonstrated that total T4 decreased during surgery with epidural anesthesia but increased with general anesthesia. The percent of free T4 increases during surgery and decreases postoperatively.
  
  TSH has been found to be unchanged during surgery, except with hypothermic surgery, where TSH increased. In a 2001 study by Michalaki, in patients who underwent abdominal surgery, the decline of serum T3 was not correlated with the increase of serum IL-6 or TNF-alpha levels; rather, brisk cortisol response to surgery was postulated to explain, in part, the early decrease in serum T3 levels in sick euthyroid syndrome.⁷
• Myocardial infarction⁸ : In 1-3 days postinfarction, total T3 is low, rT3 is elevated, and basal TSH might be elevated.
• Renal disease⁹ : The thyroid hormones may be affected by renal function in a variety of ways considering the heterogeneity of renal dysfunction and variations in renal function, which may have profound effects on thyroidal economy. Variation in thyroid function test findings also depends on the severity and duration of the disease. In chronic renal failure, total T4 and free T4 can be either normal or elevated, total T3 is reduced significantly, free T3 is reduced, rT3 is unchanged, basal TSH can be unchanged or elevated, and TSH response to TRH stimulation is decreased or delayed. Many of these abnormalities are reversed with kidney transplantation.
  
  In nephrotic syndrome, clinical presentation and thyroid function test findings mimic hypothyroidism. Total T4 and free T4 levels can be normal or reduced (significant proteinuria or loss of TBG and concomitant steroid administration can explain reduced T4). Total T3 is reduced significantly, free T3 is reduced, and rT3 is unchanged. In contrast to primary hypothyroidism, basal TSH either is unchanged or increased slightly, while TSH response to TRH is decreased and delayed.
• Liver disease: Abnormalities of thyroid function test results are common in patients with liver disease. These abnormalities vary depending on the type and severity of the liver disease. The liver probably is the most important site for conversion of T4 to T3; decreases in T3 generation may reflect a direct effect of liver disease on the deiodinative process rather than an indirect effect of systemic illness. Liver disease affects thyroid hormone transport in blood significantly because synthesis of all 3 of the binding proteins, ie, TBG, TBPA, and albumin, occurs in the liver. In cirrhosis, thyroid function test result abnormalities depend on the amount of residual functional liver tissue. Generally, total T4 is unchanged or reduced, free T4 is unchanged or elevated, free T3 is reduced or unchanged, and rT3 is elevated. In contrast to most of the other low T3 syndrome categories, basal TSH may be elevated.
• Infectious hepatitis: In infectious hepatitis, the abnormalities are not the common ones. Total T4 often is unchanged. Total T4 is elevated when TBG is increased. Free T4 may be reduced, total T3 is increased, free T3 is decreased, rT3 is unchanged, and basal TSH is increased. TSH response to TRH is exaggerated.
• Chronic active hepatitis and primary biliary cirrhosis: In these cases, serum levels of TBG are increased, resulting in increased levels of total T4 and T3 and decreased T3 resin uptake. In contrast to patients with cirrhosis, decreased free T4 and free T3 levels, elevated basal TSH, and unchanged rT3 levels are present. TSH response to TRH stimulation is exaggerated.
• Infection: In humans, serum T4 and T3 levels fall shortly after the onset of clinical infection. This reflects decreased TSH stimulation of the thyroid, decreased thyroidal secretion, accelerated T4 disappearance, and inhibited hormone binding to transport proteins. With recovery, TSH release resumes, and T4 and T3 levels progressively rise.
• Human immunodeficiency virus infection¹⁰ : Patients with asymptomatic HIV infection, or AIDS, and without opportunistic infections or hepatic dysfunction have serum T4 and T3 concentrations within the reference range. Their FTI values and free T4 concentrations also are within the reference range or are slightly low. Some patients may have slightly elevated TBG concentrations, which tend to be inversely related to the percentage of CD4 cells. Some patients may have small increases in serum TSH concentrations. Patients with AIDS complicated with Pneumocystis carinii infection or other serious infections have thyroid function alterations typical of other severe NTI.
• Bone marrow transplantation: Thyroid dysfunction is observed usually as a late complication after bone marrow transplantation. In an interesting 2001 study by Kami, transient thyrotoxicosis was observed in 7 of 52 patients at a median time of 111 days. Six months after bone marrow transplantation, 24 patients had developed euthyroid sick syndrome. After 1 year, 8 patients were diagnosed with hypothyroidism and 9 patients were diagnosed with euthyroid sick syndrome.¹¹
• Malignancy: The severity, the type, and the stage of malignancy affect a thyroid function test in various ways. Effects on thyroid function test results also are associated with nutritional status, medications, and treatment types. Generally, total T4 is unchanged, free T4 is increased or unchanged, total T3 is decreased, free T3 is unchanged, rT3 is elevated, basal TSH is unchanged, and TSH response to TRH is unchanged.
• Subarachnoid hemorrhage: In a study in Brazil, subarachnoid hemorrhage due to ruptured intracranial aneurysm was demonstrated to cause changes in the thyroid hormone profile, particularly causing a reduction in serum T3 and free T4. No significant difference was noted in the serum levels of total T4 and TSH levels. The control group included patients who underwent surgery for benign spine disease.¹²
• Psychiatric illness: The alterations in thyroid function test results are varied and confusing. The factors that cause alterations in thyroid function test results, such as the specific psychiatric illness, age of the patient, stage of the patient's illness, concomitant medications, and the presence of other thyroidal illnesses and NTIs, are variable. In primary depression, total T4 can be elevated or unchanged, free T4 can be elevated or unchanged, total T3 is unchanged, free T3 is unchanged, rT3 is elevated, basal TSH is unchanged, and TSH response to TRH is decreased. One of the most common abnormality in thyroid function test findings in acute psychiatric admissions is an elevation of FTI (7-9% of patients). This is secondary to a transient increase in T4, which is rare in other diseases. Elevated total T4 and FTI normalize after treatment.
  
  The TRH response is blunted in depression but not in schizophrenia. In a 2006 study, out of 250 subjects with major psychiatric  depression, 6.4% exhibited low T3 syndrome and these were not ascribed to malnutrition or any other illness and the metabolic parameters were all normal.¹³
• Anorexia nervosa: This disease has aspects similar to starvation and hypothyroidism. Dry skin, bradycardia, hypothermia, constipation, and amenorrhea can be signs and symptoms. A hypothalamic defect in TRH release is present. In this disorder, total T4 is decreased, and free T4 usually is not changed. Total T3 is reduced significantly, but free T3 usually is unchanged. rT3 is elevated, and basal TSH is not changed, but a late peak of TSH in response to TRH occurs.

Workup

Laboratory Studies

• Typical NTI findings are T4 level within the reference range, low T3 level, slightly reduced or reference range level of TSH, elevated rT3 level, and a free T4 level that is within the reference range or is elevated.
• In severe NTI, the findings are low T4, low T3, reduced TSH, elevated rT3, and free T4 that is within the reference range or is diminished.
• Recommended tests include the following:
  • Total T4
  • Total T3
  • TSH
  • Free T4
  • rT3
  • Free T3
• Refer to specific nonthyroidal diseases for particular alterations in thyroid function test results.

Imaging Studies

• No specific imaging study can be used to diagnose an NTI.
• Thyroid sonogram, thyroid uptake and scan, and other radiological studies have no role in the diagnosis of NTI.

Procedures

Thyroid biopsy has no role in the diagnosis of NTI.

Histologic Findings

No typical histological findings of thyroid biopsies in NTI exist.

Staging

No established clinical staging of NTI exists; abnormalities of thyroid function test findings are proportional to the severity and duration of NTI.

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