Continuing Education Activity

Euthyroid sick syndrome is also known as nonthyroidal illness syndrome and refers to changes in thyroid function tests that were administered in the inpatient or intensive care setting during critical illness. It is not a true syndrome, and transient alterations in the hypothalamic-pituitary-thyroid axis are present in about 75 percent of hospitalized patients. This condition is often seen in patients with severe critical illness, deprivation of calories, and following major surgeries. The most common hormone pattern in euthyroid sick syndrome is a low total T3 and free T3 levels with low or normal T4 and thyroid-stimulating hormone (TSH) levels. This activity reviews when to consider euthyroid sick syndrome and how to evaluate and manage the condition while emphasizing the critical role of the interprofessional care team in caring for patients with euthyroid sick syndrome.

Objectives:

• Describe the pathophysiology of euthyroid syndrome.
• Explain how to distinguish euthyroid sick syndrome from true pathology affecting the thyroid.
• Identify when euthyroid sick syndrome should receive further evaluation.
• Outline the need for an interprofessional team approach to caring for a patient with euthyroid sick syndrome.

Introduction

The euthyroid sick syndrome, also known as nonthyroidal illness syndrome, refers to changes seen in the patient thyroid function tests administered in the medical intensive care unit during episodes of critical illness. It is not a true syndrome, but it represents significant alterations in the hypothalamic-pituitary-thyroid axis in about 75% of hospitalized patients. This condition is often seen in patients with severe critical illness, deprivation of calories, and following major surgeries. The most common hormone pattern in euthyroid sick syndrome is a low total T3 and free T3 levels with low or normal T4 and thyroid-stimulating hormone levels.[1][2][3]

Etiology

Causes of euthyroid sick syndrome vary to include several critical illnesses of different etiology. Pneumonia, starvation, anorexia nervosa, sepsis, stress, history of trauma like, for example, hip fracture[4][5], cardiopulmonary bypass, myocardial infarction, malignancies, burns, organ transplantations, congestive cardiac failure[6], hypothermia, inflammatory bowel disease, cirrhosis, major surgery, renal failure, and diabetic ketoacidosis have all been correlated with this condition.[7] The latest addition to this long list has been the reports about euthyroid sick presentation after Covid-19 infection.[8][9] The discovery of low T3 levels in Covid-19 patients was also a predictive marker for poor prognosis, even in the early stages of the disease.[10]

Epidemiology

The most common abnormality, a total T3 level reduction, occurs in about 40% to 100% of cases. In hospitalized patients, 10% are found to have low TSH levels measured, an abnormality unrelated to thyroid pathology. The highest incidence occurs in the most severely ill group. The probability of death correlates with the level of serum total T4. When total T4 levels drop below 4 mcg/dL, the probability of death is approximately 50%, and when serum T4 levels are measured below 2 mcg/dL, the probability of death reaches over 80%.[11][12]

Pathophysiology

There are many proposed mechanisms regarding the pathogenesis of euthyroid sick syndrome. One cause suggested is when the presence of thyroid-binding hormone inhibitors in the serum and different body tissues inhibits the binding of the thyroid hormone to the thyroid-binding protein. The euthyroid sick syndrome is also caused by cytokines such as interleukin 1, interleukin 6, tumor necrosis factor-alpha, and interferon-beta affecting the hypothalamus and pituitary glands, thus inhibiting TSH, thyroid-releasing hormone (TRH), thyroglobulin (TG), T3, and the thyroid-binding globulins (TBG) production. Cytokines were also thought to reduce the activity of type 1 deiodinase and decrease the binding capacity of the T3 nuclear receptors.

The peripheral deiodinase activity type 1 is downregulated, and the central type 2 and type 3 deiodinase activities are up-regulated in critically ill patients. Several other mechanisms can contribute to the inhibition of 5'-monodeiodination, causing a decrease in the concentration of serum total T3 levels in patients with a nonthyroidal illness, such as high serum cortisol and the use of exogenous corticosteroid therapy, as well as other medications like amiodarone and propranolol.

Serum albumin binds to fatty acids, which displaces thyroid hormones from the thyroid-binding globulin. The fall in serum albumin level in euthyroid sick syndrome enhances the activity of different competitors of T4 on thyroid-binding globulin. Aspirin and heparin drugs impair the protein binding of the thyroid hormones, causing the reduction of total T3 and T4 levels and, subsequently, temporary elevation of free T3 and T4 levels.

Histopathology

Histopathology of the euthyroid sick syndrome is associated with a reduced follicular size and weight of the thyroid gland in chronically ill patients. Acute liver disease and chronic kidney disease are associated with an increase in the volume of the thyroid gland. Patients with a history of chronic alcoholism have been found to have a reduction in the volume of the thyroid and also the development of fibrosis in the gland.

History and Physical

History and physical examination findings are specific to the etiologic factors, with no typical findings seen due to euthyroid sick syndrome per se. The condition may also affect patients who have preexisting thyroid issues, and coexisting euthyroid sick syndrome can mask the typical physical examination findings of hypothyroidism and hyperthyroidism, so ultimately, special attention is required to differentiate a purely thyroid-related pathology from a euthyroid sick effect.

Evaluation

Euthyroid sick syndrome has been classified as (1) low T4 syndrome, (2) low T3 and low T4 syndrome, (3) high T4 syndrome, and (4) other abnormalities of the thyroid.

Low serum total T3 level is the most common abnormality in euthyroid sick syndrome, and it is seen in about 70% of hospitalized patients. The serum level of reverse T3 (rT3) is increased in euthyroid sick syndrome, except in renal failure. Elevated rT3 level is predominantly due to decreased activity of the type I iodothyronine 5'-monodeiodinase (deiodination of T4 to T3 as well as rT3 to 3,3'-diiodothyronine).

Both low T3 and low T4 syndrome are usually observed in the most critically ill patients admitted to intensive care units. Low serum total T4 correlates with a bad prognosis; thyroid binding globulin level is usually within normal, and the free T4 index is low in those patients. This combination of findings in euthyroid sick syndrome has been explained by the presence in the circulation of a thyroid-binding hormone inhibitor.[13][14]

The free T4 level is reduced in euthyroid sick syndrome patients who had received treatment with drugs like dopamine and steroids that promote decreased TSH levels. Serum thyroid binding globulin level is increased in patients with acute intermittent porphyria and chronic hepatitis, causing normal free T4 and high serum total T4 levels. Total, as well as free T4 concentrations, are increased in patients who have been treated or exposed to amiodarone and radiocontrast agents such as iopanoic acid. These substances cause a decrease in the hepatic uptake of T4 and 5' monodeiodination of T4 to T3, and they can potentially precipitate hyperthyroidism in patients with an autonomous thyroid nodule by accelerating the Jod Basedow phenomenon.

HIV patients have unusual variations of thyroid function, causing an increase in the T4 and TBG levels, decreases in the reverse T3 and rT3/T4 ratio, and normal T3 and T3/T4 ratio.

No imaging studies or thyroid biopsy are necessary or play any role in evaluating and managing the euthyroid sick syndrome.

Treatment / Management

Thyroid hormone replacement is generally not needed in patients with euthyroid sick syndrome. Treatment and management of underlying medical illness is the main focus; however, periodic monitoring of thyroid function should be done while the patient is in the hospital. After discharge from the hospital, thyroid function abnormalities may persist for several weeks. In a clinically euthyroid patient, thyroid function tests should be repeated no earlier than six weeks after hospitalization to confirm either overt thyroid dysfunction when there is a persistent TSH abnormality or euthyroid sick syndrome when there is a normalization of the TSH and the T3 levels.[15] If the thyroid labwork is ordered at any earlier time, the TSH level might be found to be elevated, reflecting the recovery phase of the axis, and this can be confusing and mixed up with overt hypothyroidism.

A recent study showed that in children undergoing cardiac surgery, using thyroid hormone preoperatively to prevent euthyroid sick syndrome helped decrease some cardiac complications, especially those related to ischemia.[16][17]

Differential Diagnosis

Differential diagnoses of euthyroid sick syndrome include:

• Hashimoto thyroiditis or hypothyroidism
• Hyperthyroidism or thyrotoxicosis
• Panhypopituitarism
• Thyroid dysfunction is induced by the use of different drugs through various mechanisms; the list of these medications is long, and some examples include but are not limited to, amiodarone therapy, dopamine, steroids, lithium, iodide, estrogen or androgen use, as well as antiseizure or opioid meds

Prognosis

Low serum T3 level is correlated with an increased length of hospital stay, intensive care unit admission, and the need for mechanical ventilation in patients with acute heart failure. The serum T4 value also correlates with the outcomes in critically ill patients; values under 2 microg/dL have been associated with mortality rates in excess of 80%.

In a recent study from China, an increased rT3 level was associated with worse outcomes, and it was mostly observed in the most severely ill patients.[18]

In other recent reports of Covid-19 infected patients, the presence of euthyroid sick picture was associated with poor prognosis and worse outcomes even in the early stages of the disease.[10][19]

In patients with hip fractures, the presence of euthyroid sick syndrome was associated with an increased need for blood transfusions and the development of anemia after a surgical repair.[5]

Complications

Complications of euthyroid sick syndrome are mostly associated with the underlying cause of the problem and not related to the malfunction of the thyroid gland per se. After the initial medical problem that caused the euthyroid sick syndrome presentation is treated, the expectation is for the thyroid tests to become normal again without any remnant thyroid function issues. If the patient has a known thyroid problem, every effort must be placed into clarifying the current status of the thyroid function based on symptomatology and physical examination findings so that it can be treated accordingly. 

Consultations

Depending on the underline disease that might have been the triggering factor for the presentation of euthyroid sick syndrome, different specialists will need to treat the patients to help them recover and resolve the initial problem. If in doubt, the thyroid function tests should be evaluated by an endocrine team that can also make arrangements for potential patient follow-up after they are discharged from the hospital to secure complete resolution of the thyroid test abnormalities without missing the possibility of the presence of a real thyroid-related issue that will require further specialized and timely treatment.

Deterrence and Patient Education

Patients need to be notified of the abnormal thyroid test findings and advised to follow up with their primary care physician to retest their thyroid levels later when they have completely recovered from the acute illness. The recommended timing is usually at least six weeks after hospitalization. If the patients present with persistently abnormal thyroid hormone levels after the initial medical disease has been resolved, further workup of the thyroid function is warranted to clarify and recognize any purely thyroid-related problems that need special evaluation and appropriate treatment. 

Pearls and Other Issues

Two general guidelines are important in evaluating critically ill patients:

1. First, measure TSH level only if there is a high clinical suspicion of thyroid dysfunction. If the TSH level is abnormal, then further workup should be done. If the TSH level is greater than 20 microUnits/mL, or if it is undetectable, euthyroid sick syndrome is less likely to cause abnormal lab results, and overt thyroid dysfunction should be strongly considered. 
2. Second, when serum TSH is not elevated, euthyroid sick syndrome should be considered even in patients with known thyroid disease and low serum free T3 or T4 levels.

Enhancing Healthcare Team Outcomes

Healthcare workers, including family clinicians and various specialists, should be aware of euthyroid sick syndrome, which often presents in hospitalized patients, especially after major surgery or other serious illness. The key is to manage the primary illness and not the abnormalities seen in the thyroid hormone levels. The outlook for patients with euthyroid sick syndrome depends on the underlying primary condition; as long as the primary disorder is unresolved, patients will continue to show an aberration in the thyroid function tests until full resolution is achieved. This requires the efforts of an interprofessional healthcare team that includes all clinicians (including surgeons in those cases), and nursing staff, where everyone involved in the patient's care is in open communication with the rest of the team, leading to prompt recognition of the condition and appropriate management. This interprofessional approach will result in the best patient outcomes. [Level 5]