Euthyroid sick syndrome

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Euthyroid sick syndrome
Other namesSick euthyroid syndrome (SES); thyroid allostasis in critical illness, tumours, uremia and starvation (TACITUS); nonthyroidal illness syndrome (NTIS); low T3 low T4 syndrome
Specialty Endocrinology   OOjs UI icon edit-ltr-progressive.svg

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control [1] wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences, and impaired assay characteristics in critical illness.

Contents

The classical phenotype of this condition is often seen in starvation, critical illness, or patients in the intensive care unit. Similar endocrine phenotypes are observed in fetal life and in hibernating mammals. [2] The most common hormone pattern in nonthyroidal illness syndrome is low total and free T3, elevated rT3, and normal T4 and TSH levels, although T4 and TSH suppression may occur in more severe or chronic illness. [3] This classical pattern results from type 1 allostatic load, i.e. a stress response resulting from lacking energy, oxygen, and glutathione. [2]

An alternative phenotype with a largely inverse hormonal pattern is seen in several physiological and pathological conditions, including pregnancy, obesity, endurance training, and psychiatric diseases. It is typically associated with high-T3 syndrome, increased plasma protein binding of thyroid hormones, and an elevated set point of the homeostatic system. It represents a response to type-2 allostatic load. [2]

Classical phenotype (type 1 thyroid allostasis)

Causes

Causes of classical euthyroid sick syndrome include a number of acute and chronic conditions, including pneumonia, fasting, starvation, anorexia nervosa, sepsis, trauma, [4] cardiopulmonary bypass, malignancy, stress, heart failure, hypothermia, myocardial infarction, kidney failure, cirrhosis, diabetic ketoacidosis, [1] surgery, infection, brain injury, shock, cancer, [5] and HIV. [6]

Outside the hospital setting, euthyroid sick syndrome (nonthyroidal illness syndrome - NTIS) has been assumed closely related with a series of chronic diseases, such as inflammatory bowel disease, [7] chronic fatigue syndrome, [8] and autoimmune diseases. [5]

Additionally, an NTIS-like phenotype can be present in major depressive disorder, [5] as well as overexercise. [2]

Pathophysiology

In critical illness, the activity of different deiodinases is altered. Humoral and neuronal inputs at the level of the hypothalamus may adjust the set point of thyroid homeostasis. This may play an important role in the pathogenesis of the central component of thyroid allostasis in critical illness, tumors, uremia and starvation (TACITUS). [9] In addition, both illness and medication (e.g. salicylates and heparin) may impair plasma protein binding of thyroid hormones, resulting in reduced levels of total hormones, while free hormone concentrations may be temporarily elevated.[ citation needed ]

Euthyroid sick syndrome probably represents an overlap of an allostatic response with pathologic reactions and drug interferences. [2] Allostatic overload may result in wasting syndrome and myxedema coma. Thyroid storm, though, represents allostatic failure, where the organism is unable to develop NTIS in the situation of thyrotoxicosis. [2]

Deiodinases

D1, D2, and D3 regulate the levels of T4, T3, and rT3. Iodothyronine deiodinase.jpg
D1, D2, and D3 regulate the levels of T4, T3, and rT3.

Three primary deiodinases are responsible for thyroid hormone conversion and breakdown. Type 1 (D1) deiodinates T4 to the biologically active T3, as well as the hormonally inactive and possibly inhibitory rT3. [3] [5] Type 2 (D2) converts T4 into T3, and breaks down rT3. D3 produces rT3 from T4, and breaks down T3. The balance of D2 and D3 is important for overall T3/rT3 balance. [5] [10]

In NTIS, the concentrations of these deiodinases are altered, although whether NTIS is the cause or effect of this in peripheral tissues is unclear; in some studies, the alterations in thyroid hormone concentrations occurred before the changes in deiodinase activity. [5] Typically, peripheral D1 and D2 are downregulated, while peripheral D3 is upregulated; this is associated with lower T4 and increased rT3. [3] [5]

Hypothalamic-pituitary-thyroid axis downregulation

Thyrotropin releasing hormone (TRH) neurons in the hypothalamus integrate global signals about the body's energy state. They may be stimulated by signals such as leptin, alpha-MSH, and catecholamines; and inhibited by glucocorticoids, neuropeptide Y, and agouti-related peptide. [2]

The HPT Axis. Thyroid system.png
The HPT Axis.

In critical illness, inflammation increases tanycyte D2 in the paraventricular nucleus (PVN) of the hypothalamus, leading to local tissue hyperthyroidism. There may also be decreased central D3. [3] [5] This causes negative feedback on the HPT axis, and therefore reduced TRH gene expression in the PVN. This is exemplified by the common NTIS phenotype of low TSH even in the face of peripheral hypothyroidism. [3] [5] [10] [2]

Cytokines

Illness can cause inflammation, which often involves an increase in cytokines such as TNFa, IL-1, and IL-6. Cytokines are implicated in NTIS. [10] [3] IL-1β has been shown to decrease liver D1, [10] as well as thyroid hormone receptor (THR) levels. IL-6 and TNFa downregulate D1 and suppress TSH, are negatively correlated with fT3, and are positively correlated with rT3. [3] NF-κB also inhibits D1, and decreases the expression of Thyroid receptors α and β. [3] IFNy inhibits thyroid and Tg release, and also inhibits the upregulation of TSH receptors. [11]

Thyroid hormone receptors

In chronic liver and renal (kidney) failure, increased THR expression occurs. In contrast, in acute illness such as sepsis and trauma, decreased THR expression occurs. [5]

Thyroid hormone transporters

During NTIS, alterations arise in the concentrations of thyroid hormone transporters such as MCT8 and MCT10, although whether the levels are increased or decreased depends on the study. The altered concentrations are thought to be a result of NTIS, rather than a cause; a study in rabbits showed that administering thyroid hormones normalized transporter expression. [5]

Binding proteins

Decreased thyroxine-binding globulin (TBG) occurs following bypass surgery, and in chronic illness, a less effective form of TBG with lower affinity for thyroxine is synthesized. Reduced quantities of bound thyroid result, leading to decreased total thyroid measurements. Decreases in total thyroid may be more severe than alternations in free hormone levels. [5]

Drugs

Dopamine and corticosteroids, commonly given in the hospital setting, can suppress TSH and suppress conversion of T4 to T3. [3] [5] Other drugs such as estrogen, contraceptives, salicylates, and phenytoin can alter the binding of TBG to TH, resulting in different TH concentrations. [3] Additionally, lithium disrupts thyroid function, [2] and thyromimetic endocrine disrupters may downregulate the HPT axis. [2]

Fasting

Fasting is a common response in inflammation and critical illness. Originally, selenium deficiency as a result of malnutrition was thought to reduce D1 catalytic activity, but this theory has not been supported as a cause of NTIS. [3] [5]

A fasting response is common in critical illness. Symptoms-lost-appetite.jpg
A fasting response is common in critical illness.

NTIS as a result of fasting may be regarded as a healthy and adaptive mechanism that reduces energy expenditure. [10] Fasting in healthy, euthyroid people causes reduced T3 and elevated rT3, although TSH is usually unchanged. [3] [5] [10] Even moderate weight loss can lower T3. [2]

This may be primarily via reduced levels of leptin (the satisfaction hormone). Low leptin levels can downregulate hypothalamic TRH neurons and cause a reduction in TSH. [5] [10] Ιn fasting animals, administering leptin reverses NTIS symptoms and restores thyroid hormone concentrations. [5] In obesity, increased leptin increases TSH and T3, and lowers rT3, possibly as an attempt to increase energy expenditure and return to weight set point. [2]

Other signals associated with hunger also affect the HPT axis. Insulin and bile acids, which are elevated after a meal, lead to increased D2 activity, [2] therefore increasing T3 and reducing rT3. Low leptin increases NPY and AGRP (associated with appetite), which inhibit TRH gene expression; this effect is enhanced by ghrelin (the hunger hormone). [5] a-MSH stimulates TRH gene expression in the PVN. This is enhanced by leptin, and inhibited by low leptin. a-MSH is also antagonized by AGRP. [5]

Alternative phenotype (type 2 thyroid allostasis)

An anti-NTIS phenotype is observed in some circumstances, wherein TSH, T3, and T4 are generally elevated rather than suppressed. This can occur during pregnancy, obesity, cold adaptation, stay in high altitudes, endurance exercise, acute psychosis, and post-traumatic stress disorder. [2] [12]

According to newer theories, [2] elevated concentrations of TSH and thyroid hormones in type 2 allostasis result from an up-regulated set point of the feedback loop, which ensues from increased TRH expression in the basolateral amygdala and the paraventricular nucleus of the hypothalamus in response to stress. [13] [14]

High-T3 syndrome in thyroid carcinoma may result from autonomous thyroid hormone secretion or overexpression of type 2 deiodinase in cancer cells rather than from type 2 allostasis. [15] [16] [17] [18]

Conditions with mixed phenotypes

Psychiatry

Stress suppresses TSH, [5] and alterations in thyroid hormone levels may arise in psychiatric illness. In major depressive disorder, an NTIS-like phenotype may be observed, with reduced T3 and increased rT3. T4 may be elevated, and TSH is usually normal, although TSH's normal circadian rhythm may be disrupted. [2] Bipolar 1 and PTSD can exemplify an anti-NTIS phenotype, with upregulation of the HPT axis and increased T3. This may also occur during acute schizophrenic episodes. [2]

Exercise

After exercise, a transient increase occurs in TSH, T4, and T3, but this is thought to be due to increased blood concentration as a result of dehydration. [2] The effects normalize after rest. After long-term heavy strain, levels of thyroid hormones decrease. [2] This is exacerbated by other stressors such as undernutrition and lack of sleep, such as in a military training setting. During endurance exercise, before exhaustion, elevated thyroid hormone levels may happen due to increased expected energy demand (type 2 allostatic load). [2]

Environmental conditions

Cold exposure and stay at high altitude may lead to type 1 or type 2 phenotype, depending on duration and other boundary conditions (which determine whether or not stress is associated with energy deprivation). [12] [19]

Diagnosis

Affected patients may have normal, low, or slightly elevated TSH depending on the spectrum and phase of illness. Total T4 and T3 levels may be altered by binding protein abnormalities, and medications. Reverse T3 levels are generally increased, while FT3 is decreased. FT4 levels may have a transient increase, before becoming subnormal during severe illness. Correspondingly, in the majority of cases calculated sum activity of peripheral deiodinases (SPINA-GD) is reduced. [7] [20] [21] [22] Generally the levels of free T3 will be lowered, followed by the lowering of free T4 in more severe disease. Several studies described elevated concentrations of 3,5-T2, an active thyroid hormone, in NTIS. [22] [23] 3,5-T2 levels were also observed to correlate with concentrations of rT3 (reverse T3) [22] in patients with euthyroid sick syndrome.

NTIS is a component of a complex endocrine adaptation process, so affected patients might also have hyperprolactinemia and elevated levels of corticosteroids (especially cortisol) and growth hormone.[ citation needed ] NTIS can be difficult to distinguish from other forms of thyroid dysfunction in the hospital setting. Both NTIS and primary hypothyroidism may have reduced fT3 and fT4, and elevated TSH (which is common in the hospital, during the recovery phase of NTIS). [2] Prescribing thyroxine to treat this may lead to lifelong thyroid overtreatment. [2]

Hyperthyroidism may be assumed due to decreased TSH and a transient fT4 increase. In some cases, this can be distinguished from NTIS by a thyroid ultrasound, which is commonly available in the hospital intensive care unit. [2]

NTIS looks similar to central hypopituitarism; both frequently have reduced TSH and thyroid hormone levels. [2]

Treatment

Debate is ongoing as to whether NTIS is an adaptive or maladaptive mechanism in response to physiological stress. [3] [5] [10] Some sources indicate that NTIS is beneficial as an acute-phase response, but detrimental during the chronic phase of illness. [2] Several trials have investigated a possible therapy for NTIS, but they yielded inconsistent and partly contradictory results. This may be due to the heterogeneity of investigated populations, and to the lack of a consistent definition of NTIS. [24]

Administering exogenous T3 and T4 has variable results, [3] [10] but overall seems to confer no improvements to health outcome. [5] Administering TRH to patients with chronic illness, however, seems to normalize thyroid levels and improve catabolic function. [5]

When NTIS is caused by the normal fasting response to illness, early parenteral nutrition has been shown to attenuate alterations in thyroid hormone (TSH, T3, T4, rT3) levels, whereas late parenteral nutrition exacerbates it. [10] Late parenteral nutrition, though, also reduced complications and accelerated recovery in one study. [10]

History

In 1968, a reduced T4 half-life in athletes was discovered. This was the first awareness of thyroid hormone concentration alterations that were not a result of thyroid gland or pituitary dysfunction. In 1971, they also found a transient increase in T4 during bicycle training. [2]

In 1973, Rothenbuchner et al. discovered that starvation is correlated with reduced T3 concentration. Following this, a similar phenotype was noted in patients with critical illness, tumors, and uremia. [2]

The alternative phenotype of type-2 thyroid allostasis was first predicted in 1968, when John W. Mason expected the concentrations of thyroid hormones to rise in situations of psychosocial stress. [25] Mason's postulate was later confirmed by numerous studies. [26] [27] [28] [29] [30] [31] [32] [ excessive citations ]

See also

Related Research Articles

<span class="mw-page-title-main">Endocrine system</span> Hormone-producing glands of a body

The endocrine system is a messenger system in an organism comprising feedback loops of hormones that are released by internal glands directly into the circulatory system and that target and regulate distant organs. In vertebrates, the hypothalamus is the neural control center for all endocrine systems.

<span class="mw-page-title-main">Hypothyroidism</span> Insufficient production of thyroid hormones by the thyroid gland

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormones. It can cause a number of symptoms, such as poor ability to tolerate cold, extreme fatigue, muscle aches, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goitre. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

<span class="mw-page-title-main">Iodothyronine deiodinase</span> Class of enzymes

Iodothyronine deiodinases (EC 1.21.99.4 and EC 1.21.99.3) are a subfamily of deiodinase enzymes important in the activation and deactivation of thyroid hormones. Thyroxine (T4), the precursor of 3,5,3'-triiodothyronine (T3) is transformed into T3 by deiodinase activity. T3, through binding a nuclear thyroid hormone receptor, influences the expression of genes in practically every vertebrate cell. Iodothyronine deiodinases are unusual in that these enzymes contain selenium, in the form of an otherwise rare amino acid selenocysteine.

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

<span class="mw-page-title-main">Triiodothyronine</span> Chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

<span class="mw-page-title-main">Thyroid hormone resistance</span> Medical condition

Thyroid hormone resistance (also resistance to thyroid hormone (RTH), and sometimes Refetoff syndrome) describes a rare syndrome in which the thyroid hormone levels are elevated but the thyroid stimulating hormone (TSH) level is not suppressed, or not completely suppressed as would be expected. The first report of the condition appeared in 1967. Essentially this is decreased end organ responsiveness to thyroid hormones. A new term "impaired sensitivity to thyroid hormone" has been suggested in March 2014 by Refetoff et al.

<span class="mw-page-title-main">Levothyroxine</span> Thyroid hormone

Levothyroxine, also known as L-thyroxine, is a synthetic form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency (hypothyroidism), including a severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken orally (by mouth) or given by intravenous injection. Levothyroxine has a half-life of 7.5 days when taken daily, so about six weeks is required for it to reach a steady level in the blood.

<span class="mw-page-title-main">Thyroid disease</span> Medical condition

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

Thyroid storm is a rare but severe and life-threatening complication of hyperthyroidism. It occurs when an overactive thyroid leads to hypermetabolism, which can cause death from cardiac arrest or multiple organ failure.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

<span class="mw-page-title-main">Hypothalamic–pituitary–thyroid axis</span> Part of the neuroendocrine system

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

<span class="mw-page-title-main">Reverse triiodothyronine</span> Chemical compound

Reverse triiodothyronine (3,3′,5′-triiodothyronine, reverse T3, or rT3) is an isomer of triiodothyronine (3,5,3′ triiodothyronine, T3).

Myxedema coma is an extreme or decompensated form of hypothyroidism and while uncommon, is potentially lethal. A person may have laboratory values identical to a "normal" hypothyroid state, but a stressful event precipitates the myxedema coma state, usually in the elderly. Primary symptoms of myxedema coma are altered mental status and low body temperature. Low blood sugar, low blood pressure, hyponatremia, hypercapnia, hypoxia, slowed heart rate, and hypoventilation may also occur. Myxedema, although included in the name, is not necessarily seen in myxedema coma. Coma is also not necessarily seen in myxedema coma, as patients may be obtunded without being comatose.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are any hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine, derived from food. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

Deiodinase (monodeiodinase) is a peroxidase enzyme that is involved in the activation or deactivation of thyroid hormones.

<span class="mw-page-title-main">Thyroid's secretory capacity</span>

Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.

The sum activity of peripheral deiodinases is the maximum amount of triiodothyronine produced per time-unit under conditions of substrate saturation. It is assumed to reflect the activity of deiodinases outside the central nervous system and other isolated compartments. GD is therefore expected to reflect predominantly the activity of type I deiodinase.

<span class="mw-page-title-main">Jostel's TSH index</span>

Jostel's TSH index, also referred to as Jostel's thyrotropin index or Thyroid Function index (TFI), is a method for estimating the thyrotropic function of the anterior pituitary lobe in a quantitative way. The equation has been derived from the logarithmic standard model of thyroid homeostasis. In a paper from 2014 further study was suggested to show if it is useful, but the 2018 guideline by the European Thyroid Association for the diagnosis of uncertain cases of central hypothyroidism regarded it as beneficial. It is also recommended for purposes of differential diagnosis in the sociomedical expert assessment.

The Thyrotroph Thyroid Hormone Sensitivity Index is a calculated structure parameter of thyroid homeostasis. It was originally developed to deliver a method for fast screening for resistance to thyroid hormone. Today it is also used to get an estimate for the set point of thyroid homeostasis, especially to assess dynamic thyrotropic adaptation of the anterior pituitary gland, including non-thyroidal illnesses.

The Thyroid Feedback Quantile-based Index (TFQI) is a calculated parameter for thyrotropic pituitary function. It was defined to be more robust to distorted data than established markers including Jostel's TSH index (JTI) and the thyrotroph thyroid hormone sensitivity index (TTSI).

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  28. ↑ Chopra, IJ; Solomon, DH; Huang, TS (May 1990). "Serum thyrotropin in hospitalized psychiatric patients: evidence for hyperthyrotropinemia as measured by an ultrasensitive thyrotropin assay". Metabolism: Clinical and Experimental. 39 (5): 538–43. doi:10.1016/0026-0495(90)90014-4. PMID   2336036.
  29. ↑ Wang, S; Mason, J; Southwick, S; Johnson, D; Lubin, H; Charney, D (July–August 1995). "Relationships between thyroid hormones and symptoms in combat-related posttraumatic stress disorder". Psychosomatic Medicine. 57 (4): 398–402. doi:10.1097/00006842-199507000-00012. PMID   7480570. S2CID   20905167.
  30. ↑ Friedman, MJ; Wang, S; Jalowiec, JE; McHugo, GJ; McDonagh-Coyle, A (15 May 2005). "Thyroid hormone alterations among women with posttraumatic stress disorder due to childhood sexual abuse". Biological Psychiatry. 57 (10): 1186–92. doi:10.1016/j.biopsych.2005.01.019. PMID   15866559. S2CID   23455036.
  31. ↑ Mason, J; Southwick, S; Yehuda, R; Wang, S; Riney, S; Bremner, D; Johnson, D; Lubin, H; Blake, D; Zhou, G (August 1994). "Elevation of serum free triiodothyronine, total triiodothyronine, thyroxine-binding globulin, and total thyroxine levels in combat-related posttraumatic stress disorder". Archives of General Psychiatry. 51 (8): 629–41. doi:10.1001/archpsyc.1994.03950080041006. PMID   8042912.
  32. ↑ Karlović, D; Marusić, S; Martinac, M (30 June 2004). "Increase of serum triiodothyronine concentration in soldiers with combat-related chronic post-traumatic stress disorder with or without alcohol dependence". Wiener klinische Wochenschrift. 116 (11–12): 385–90. doi:10.1007/BF03040918. PMID   15291291. S2CID   26011489.

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