Euthyroid sick syndrome overview

# Overview
Euthyroid sick syndrome is a thyroid hormone disorder in which the levels of T3 (triiodothyronine) and/or T4 (thyroxine) are at abnormal levels, in the setting of a severe underlying illness. The thyroid gland itself is normal. Euthyroid sick syndrome is seen in conditions of starvation and critical illness such as sepsis, surgery, severe trauma, burns, metabolic disorders, bone marrow transplantation, and malignancy. During these stressful conditions, hypermetabolism, increased energy expenditure, hyperglycemia, and muscle loss takes place. It is speculated, that the body in order to contain this hypermetabolism induces some degree of hypothyroidism by inhibiting deiodination of T4 to T3 by the enzyme 5-monodeiodinase. This is an adaptive process by which the body prevents further muscle and calorie loss. In euthyroid sick syndrome the symptoms of the underlying condition may overlap with features of hypothyroidism. Generally it takes atleast 2-3 weeks for thyroid hormone levels to decline and symptoms of hypothyroidism take even longer to be visible. Common symptoms of hypothyroidism are fatigue, cold intolerance, decreased sweating, hypothermia, coarse skin, weight gain, depression, emotional lability, and attention deficit. The diagnosis of euthyroid sick syndrome is based on clinical presentation and thyroid function tests. Thyroid function tests helps to differentiate between other causes of hypothyroidism and euthyroid sick syndrome. Management of euthyroid sick syndrome includes rapid correction of the underlying disease. Replacement of thyroid hormones in euthyroid sick syndrome is controversial and generally not recommended.

# Historical Perspective
In 1960s, the first scientific descriptions on transient alterations in thyroid hormones metabolism were given by several authors who described altered half life of thyroid hormones in athletes under training and with adaptation to cold. In the early 1970s, German and US researchers simultaneously described low T3 syndrome in starvation and shortly thereafter reduced T3 concentrations were observed in critical illnesses requiring intensive care such as in patient's with tumor or uremia.

# Classification
Euthyroid sick syndrome may be classified according to the level of thyroid hormones and the severity of the underlying disease into mild, moderate, severe, and recovery phase.

# Pathophysiology
Euthyroid sick syndrome is not a primary thyroid disorder but instead results from changes induced by the nonthyroidal illness. The pathophyisology of euthyroid sick syndrome is multifactorial. It is believed that euthyroid sick syndrome is the result of severe illness and inflammation. During these stress conditions, there occurs hypermetabolism, increased energy expenditure, hyperglycemia, and muscle loss. It is speculated, that the body in order to contain this hypermetabolism induces some degree of hypothyroidism by inhibiting deiodination of T4 to T3 by the enzyme 5-monodeiodinase. This is an adaptive process by which the body prevents further muscle and calorie loss. Inflammation leads to increased production of cytokines that severely affect genes involved in the production and release of T4 and T3. There is also downregulation of TRH and TSH release from the hypothalamus and pituitary gland respectively. It may be signalled by a decrease in leptin caused by malnutrition. On gross pathology, euthyroid sick syndrome does not appear to be dysfunctional. On microscopic histopathological analysis, euthyroid sick syndrome presents with normal thyroid histology.

# Causes
Euthyroid sick syndrome can be caused by any serious illness which leads to increased level of cytokines, decreased level of leptin, hyper-metabolism, decreased protein synthesis and decreased level of thyroid-binding globulin. The conditions include sepsis, malignancy, trauma, surgery, burns, bone marrow transplantation, metabolic disorders, and other inflammatory conditions.

# Differentiating Euthyroid sick syndrome from Other Diseases
Euthyroid sick syndrome must be differentiated from other causes of hypothyroidism on the basis of clinical features and laboratory findings. In euthyroid sick syndrome, serum T3 is decreased more than T4, the T3RU (T3 resin uptake) is high, and TSH is normal or mildly decreased. Various causes of hypothyroidism include primary hypothyroidism, transient hypothyroidism, sub-clinical hypothyroidism, central hypothyroidism (pituitary or hypothaalmic) and peripheral resistance to TSH/TRH.

# Epidemiology and Demographics
The incidence of euthyroid sick syndrome in intensive care unit (ICU) is approximately 70,000 per 100,000 cases of nonthyroidal illness. The prevalence of euthyroid sick syndrome is estimated to be 40,000 per 100,000 cases of nonthyroidal illness. Euthyroid sick syndrome is more commonly seen in elderly population. There is no racial predilection for euthyroid sick syndrome and both men and women are affected equally.

# Risk Factors
Common risk factors in the development of euthyroid sick syndrome include iodine deficiency, female gender, pregnancy, radiation exposure, elderly, family history of thyroid disease, primary pulmonary hypertension, and infiltrative disease. Less common risk factors are excessive intake of iodine, textile workers, and diabetes mellitus type I.

# Screening
There is insufficient evidence to recommend routine screening for euthyroid sick syndrome.

# Natural History, Complications, and Prognosis
If left untreated, patients with euthyroid sick syndrome may progress to develop hypothyroidism or resolve spontaneously with correction of underlying condition. If underlying condition is not treated, the thyroid hormone levels starts to drop after 2-3 weeks of initial illness. The symptoms of hypothyroidism may take some additional weeks to appear. The complications of euthyroid sick syndrome depends upon other organ systems involved and underlying disease(s). The general complications of hypothyroidism as seen in euthyroid sick syndrome include hypothermia, bradycardia, heart failure, dyspnea, myopathy, confusion, apathy and psychosis. Laboratory finding will show increased levels of cholesterol and triglycerides. In addition, patients will have features of organs system involved. The prognosis varies and depends upon extent of the underlying disease at the time of diagnosis. Patients with low T3 (< 2.3 pg/ml) levels may have a longer hospital stay. Mortality rate is as high as 80% when serum T4 value is <3 mcg/dL.

# Diagnosis

## Diagnostic Criteria
The diagnosis of euthyroid sick syndrome is based on clinical presentation and thyroid function tests. An important part in diagnosing euthyroid sick syndrome is to be able to differentiate between other causes of hypothyroidism and euthyroid sick syndrome. Although  the diagnosis of hypothyroidism is mainly a laboratory diagnosis, the coexisting conditions and wide variation in clinical presentation may make the diagnosis difficult. The best initial test is TSH, which in euthyroid sick syndrome can be low, normal, or elevated but not as high as it would be in hypothyroidism. Serum reverse T3 is elevated from inhibition of 5' monodeiodinase (type I). Patient having severe underlying illness, as in euthyroid sick syndrome, have elevated levels of serum cortisol from underlying stress whereas, patients of hypothyroidism have low serum cortisol from associated hypothalmic/pituitary abnormality.

## History and Symptoms
Obtaining a thorough history contributes in making a diagnosis of euthyroid sick syndrome. Complete history should be obtained  regarding past and any newly diagnosed medical conditions, previous history of thyroid disease and current medications. Patients of euthyroid sick syndrome present with serious illness and are febrile with hypermetabolism. In euthyroid sick syndrome the symptoms of the underlying condition may overlap with features of hypothyroidism. Generally it takes atleast 2-3 weeks for thyroid hormone levels to decline and symptoms of hypothyroidism takes even longer period for expression. The common symptoms of hypothyroidism are fatigue, cold intolerance, decreased sweating, hypothermia, coarse skin, weight gain, depression, emotional lability, and attention deficit.

## Physical Examination
There are no specific physical examination findings associated with euthyroid sick syndrome. The physical examination findings in each patient depends upon the underlying cause of euthyroid sick syndrome such as sepsis, myocardial infarction, pneumonia, chronic renal failure and cirrhosis.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of euthyroid sick syndrome include low T3, increased reverse T3 and variable proportions of T4 depending upon the severity of the disease. Patients having reduced concentration of T4 suggests progression of the underlying nonthyroidal illness. Complete thyroid function tests should be done which includes TSH, free T3, total T3, reverse T3, free T4, and total T4.

## Electrocardiogram
There are no specific ECG findings associated with euthyroid sick syndrome. However, euthyroid sick syndrome leads to hypothyroidism. The decrease in the levels of thyroid hormones causes decreased activity of the sympathetic nervous system. There can also be deposition of myxoedematous material within the myocardium. ECG in hypothyroidism will present with QT prolongation, first degree AV block, interventricular conduction delay. Severe cases of hypothyroidism will have bradycardia and low QRS voltage.

## X-ray
There are no x-ray findings associated with euthyroid sick syndrome.

## CT scan
There are no CT scan findings associated with euthyroid sick syndrome. However, a CT scan may be helpful in the diagnosis of complications associated with the underlying condition.

## MRI
There are no MRI findings associated with euthyroid sick syndrome. However, a MRI may be helpful in the diagnosis of complications associated with the underlying condition.

## Ultrasound
In euthyroid sick syndrome the thyroid gland appears normal. Therefore, there is no role of thyroid ultrasound in euthyroid sick syndrome.

## Other Imaging Findings
There are no other imaging findings associated with euthyroid sick syndrome.

## Other Diagnostic Studies
There are no other diagnostic studies associated with euthyroid sick syndrome.

# Treatment

## Medical Therapy
In euthyroid sick syndrome emphasis is on rapid correction of the underlying disease. Many seriously ill patients have low levels of thyroid hormones but are not clinically hypothyroid and do not require thyroid hormone supplementation. Replacement of thyroid hormones in euthyroid sick syndrome is controversial except, in patients of congestive heart failure where liothyronine (LT3) or levothyroxine (LT4) may be recommended, to improve ventricular performance. Therefore, thyroid hormone therapy is generally not recommended for patients with euthyroid sick syndrome, except possibly those with chronic heart failure.

## Surgery
Surgical intervention is not recommended for the management of euthyroid sick syndrome.

## Primary Prevention
There are no established measures for the primary prevention of euthyroid sick syndrome.

## Secondary Prevention
There are no established measures for the secondary prevention of euthyroid sick syndrome.