- Euthyroid sick syndrome
- What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
- What Lab Results Are Absolutely Confirmatory?
- Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
- Euthyroid Sick Syndrome
- Euthyroid Sick Syndrome: Is It a Misnomer?
- Pathogenesis of the NTIS
- Clinical significance of NTIS
- Diagnosis of thyroid disease in NTI
- Low T3 / Euthyroid Sick Syndrome Causes & Treatment
- What is Low T3 or Euthyroid Sick Syndrome?
- Acute Illness
- Starvation and Fasting
- Chronic Conditions
- Effects of Low T3 Syndrome
- I. What every physician needs to know
- II. Diagnostic Confirmation: Are you sure your patient has Euthyroid Sick Syndrome?
- A. History Part I: Pattern Recognition:
- B. History Part 2: Prevalence:
- C. History Part 3: Competing diagnoses that can mimic Euthyroid Sick Syndrome
- D. Physical Examination Findings
- 1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- 2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
- F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis
- III. Default Management
- D. Long-term management
- A. Renal Insufficiency
- B. Liver Insufficiency
- C. Systolic and Diastolic Heart Failure
- D. Coronary Artery Disease or Peripheral Vascular Disease
- G. Immunosuppression (HIV, chronic steroids, etc)
- H. Primary Lung Disease (COPD, Asthma, ILD)
- I. Gastrointestinal or Nutrition Issues
- K. Dementia or Psychiatric Illness/Treatment
- C. When is the Patient Ready for Discharge
- D. Arranging for Clinic Follow-up
- 1. When should clinic follow up be arranged and with whom
- E. Placement Considerations
- F. Prognosis and Patient Counseling
Euthyroid sick syndrome
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Euthyroid sick syndrome is diagnosed in patients with low thyroid hormone levels suffering from some nonthyroidal systemic illness that may include nutritional deficits, kidney disease, liver disease, malignancy, trauma, or infection. This is commonly seen in the hospital setting and intensive care units, in particular. These patients are usually clinically euthyroid.
What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?
Laboratory tests that uncover suspected euthyroid sick syndrome in patients with nonthyroidal systemic illness include thyroid stimulating hormone (TSH), total triiodothyronine (T3), free T3 (fT3), total thyroxine (T4), and free thyroxine (fT4).
TSH is a glycoprotein with an alpha and beta subunit. TSH is secreted by the anterior pituitary gland as a result of a negative feedback loop involving T3 and T4. The most common early change in nonthyroidal illness is a decreased T3 or fT3 and a normal or mildly depressed TSH.
Total T4 may also be low, but fT4 will most often remain normal. During recovery from the illness, T4 will normalize first and TSH may rebound to slightly elevated levels.
Serum cortisol can also be obtained and should be elevated in euthyroid sick syndrome distinguishing this from hypothyroidism secondary to pituitary-hypothalamic disease. (Table 1)
|0.5 – 5.0 mclUnits/mL||14 mcg/dL (pm)|
Assessment of thyroid status can be difficult in acutely ill patients and, in general, should not be done. Hospitalized patients may have transiently low or high TSH.
TSH levels can be suppressed during treatment on glucocorticoid or dopamine therapy, whereas other drugs, such as amiodarone, can increase TSH levels.
Increases in T3 and T4 may occur with ingestion of large quantities of exogenous thyroid hormone.
What Lab Results Are Absolutely Confirmatory?
The pattern of normal TSH and reduced T3/T4 suggests a diagnosis of euthyroid sick syndrome.
Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?
The clinical setting must be considered when interpreting TSH, T3, and T4. Patients with euthyroid sick syndrome are clinically euthyroid but ly present with some other nonthyroidal systemic illness.
Critically ill euthyroid patients may be differentiated from hypothyroid patients, because the latter show very high TSH values, but, as previously mentioned, pharmacotherapeutics can inflate TSH levels, and this too should be considered when making the diagnosis of euthyroid sick syndrome.
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Euthyroid Sick Syndrome
The euthyroid sick syndrome, also known as nonthyroidal illness syndrome, refers to changes seen in patient thyroid function tests administered in the medical intensive care unit during episodes of critical illness.
It is not a true syndrome, and there are significant alterations in the hypothalamic-pituitary-thyroid axis in about 75% of the hospitalized patients. This condition often is seen in patients with severe critical illness, deprivation of calories, and following major surgeries.
The most common hormone pattern in sick euthyroid syndrome is a low total T3 and free T3 levels with normal T4 and thyroid-stimulating hormone levels.
Causes of euthyroid sick syndrome vary to include critical illness, pneumonia, starvation, anorexia nervosa, sepsis, stress, history of trauma, cardiopulmonary bypass, myocardial infarction, malignancies, congestive cardiac failure, hypothermia, inflammatory bowel disease, cirrhosis, major surgery, renal failure, and diabetic ketoacidosis.
The most common abnormality, a T3 reduction, occurs in about 40% to 100% of cases, with about 10% of having low TSH. 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 four microg/dL, the probability of death is approximately 50%, and when serum T4 levels are below two microg/dL, the probability of death reaches 80%.
There are many proposed mechanisms regarding the pathogenesis of euthyroid sick syndrome. One cause is when the presence of thyroid binding hormone inhibitor in serum and body tissues inhibits the binding of thyroid hormone to thyroid-binding protein.
Euthyroid sick syndrome also is caused by cytokines such as interleukin 1, interleukin 6, tumor necrosis factor alpha, and interferon-beta affecting the hypothalamus and pituitary thus inhibiting TSH, thyroid-releasing hormone, thyroglobulin, T3, and thyroid-binding globulins production.
Cytokines also were thought to reduce the activity of type 1 deiodinase thus decreasing the binding capacity of T3 nuclear receptors.
Peripheral deiodinase activity type 1 is downregulated and 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 T3 in patients with a nonthyroidal illness such as high serum cortisol and exogenous corticosteroid therapy, amiodarone, and propranolol.
Serum albumin binds to fatty acids, which displaces thyroid hormones from thyroid binding globulin. The fall in serum albumin in euthyroid sick syndrome enhances the activity of competitors of T4 on thyroid binding globulin. Aspirin and heparin impair the protein binding of thyroid hormones, causing the reduction of total T3 and T4 and temporary elevation of free T3 and T4.
Histopathology of euthyroid sick syndrome is associated with 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 are associated with the reduction in volume and fibrosis of the thyroid gland.
History and physical examination findings are specific to the etiologic factors, with no typical findings specific to euthyroid sick syndrome. The condition may affect patients who have preexisting thyroid issues and coexisting euthyroid sick syndrome can mask the typical physical examination findings of hypothyroidism and hyperthyroidism.
Euthyroid sick syndrome has been classified as (1) low T4 syndrome, (2) low T3 -low T4 syndrome, (3) high T4 syndrome, and (4) other abnormalities. Low serum total T3 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 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 the T4 syndrome are observed in critically ill patients admitted to intensive care units. Low serum total T4 correlates with a bad prognosis; thyroid binding globulin is 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.
The free T4 level is reduced in euthyroid sick syndrome patients who had treatment with dopamine and steroids by decreasing TSH levels.
Serum thyroid binding globulin is increased in patients with acute intermittent porphyria and chronic hepatitis, causing normal free T4 and high serum total T4.
Total, as well as free T4 concentrations, are increased in patients who were treated with amiodarone and radiocontrast agents such as iopanoic acid.
These cause the decrease in hepatic uptake of T4 and 5' monodeiodination of T4 to T3 and precipitate hyperthyroidism in patients who have an autonomous thyroid nodule by accelerating Jod Basedow phenomenon. HIV patients have unusual variations of thyroid function causing an increase in T4 and TBG, decreases in reverse T3 and rT3/T4 ratio, and normal T3 and T3/T4 ratio.
Thyroid hormone replacement is not needed in patients with euthyroid sick syndrome. Treatment and management of underlying medical illness is the 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 six weeks after hospitalization to confirm overt thyroid dysfunction with persistent TSH abnormality or confirm euthyroid sick syndrome with normalization of TSH.
Differential diagnoses of euthyroid sick syndrome include Hashimoto thyroiditis, hyperthyroidism, thyrotoxicosis, panhypopituitarism, and thyroid dysfunction induced by amiodarone therapy.
Low serum T3 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 outcome in critically ill patients; values under three microg/dL have been associated with mortality rates in excess of 85%.
Two general guidelines are important in evaluating a critically ill patient.
First, measure TSH only if there is a high clinical suspicion of thyroid dysfunction. If TSH is abnormal, then further workup is done. If the TSH is greater than 20 microUnits/mL or is undetectable, euthyroid sick syndrome is less ly to be the cause, and overt thyroid dysfunction should be strongly considered.
When serum TSH is not elevated, euthyroid sick syndrome should be considered in patients with known thyroid disease and low serum-free T4.
Healthcare workers including nurse practitioners should be aware that the euthyroid sick syndrome is often seen in ill patients, especially after major surgery.
The key is to manage the primary illness and not the abnormalities seen in thyroid hormone levels.
The outlook for patients with euthyroid sick syndrome depends on the primary condition; as long as the primary disorder is being treated, patients will continue to show an aberration in the thyroid function tests.
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1.Lee YJ, Lee HY, Ahn MB, Kim SK, Cho WK, Lee JW, Chung NG, Cho B, Suh BK. Thyroid dysfunction in children with leukemia over the first year after hematopoietic stem cell transplantation. J. Pediatr. Endocrinol. Metab. 2018 Nov 27;31(11):1241-1247. [PubMed: 30325734]2.Akbaş T, Sahin İE, Ozturk A. Alterations in thyroid hormones in brain-dead patients are related to non-thyroidal illness syndrome. Endokrynol Pol. 2018;69(5):545-549. [PubMed: 30132587]3.Gutch M, Kumar S, Gupta KK. Prognostic Value of Thyroid Profile in Critical Care Condition. Indian J Endocrinol Metab. 2018 May-Jun;22(3):387-391. [PMC free article: PMC6063192] [PubMed: 30090732]4.El-Ella SSA, El-Mekkawy MS, El-Dihemey MA. [Prevalence and prognostic value of non-thyroidal illness syndrome among critically ill children]. An Pediatr (Barc). 2019 Apr;90(4):237-243. [PubMed: 29628400]5.Duyu A, Çıtak EC, Ak E, Küpeli S, Yağcı Küpeli B, Bayram İ, Sezgin G, Eskendari G, Sezer K. Prevalence and Related Factors of Euthyroid Sick Syndrome in Children with Untreated Cancer According to Two Different Criteria. J Clin Res Pediatr Endocrinol. 2018 Jul 31;10(3):198-205. [PMC free article: PMC6083463] [PubMed: 29553046]6.Wang B, Liu S, Li L, Yao Q, Song R, Shao X, Li Q, Shi X, Zhang JA. Non-thyroidal illness syndrome in patients with cardiovascular diseases: A systematic review and meta-analysis. Int. J. Cardiol. 2017 Jan 01;226:1-10. [PubMed: 27776249]7.Cho EB, Min JH, Cho HJ, Seok JM, Lee HL, Shin HY, Lee KH, Kim BJ. Low T3 syndrome in neuromyelitis optica spectrum disorder: Associations with disease activity and disability. J. Neurol. Sci. 2016 Nov 15;370:214-218. [PubMed: 27772762]8.Krysicki M, Jaworska M, Popowicz B, Jankiewicz-Wika J, Klencki M, Słowińska-Klencka D. [The incidence of hypothyroidism symptoms and risk factors for cardiovascular events in subclinical hypothyroidism]. Pol. Merkur. Lekarski. 2014 Jul;37(217):10-6. [PubMed: 25154193]9.Smallridge RC. Metabolic and anatomic thyroid emergencies: a review. Crit. Care Med. 1992 Feb;20(2):276-91. [PubMed: 1737461]
Euthyroid Sick Syndrome: Is It a Misnomer?
THE TERM euthyroid sick syndrome (ESS) identifies abnormalities in thyroid function tests observed in patients with systemic nonthyroidal illnesses (NTIs) and those undergoing surgery or fasting (1, 2). The term nonthyroidal illness syndrome (NTIS) has also been employed to describe these abnormalities (3).
These abnormalities result from variable, usually reversible, disturbances in the hypothalamo-pituitary-thyroid axis, thyroid hormone binding to serum proteins, tissue uptake of thyroid hormones, and/or thyroid hormone metabolism. Several recent reviews have addressed these issues (3–6).
I shall focus mainly on the clinical diagnosis, significance, and treatment of ESS.
Abnormalities of thyroid function in NTIS have been classified as 1) low T3 syndrome, 2) low T3-low T4 syndrome, 3) high T4 syndrome, and 4) other abnormalities (7).
Although serum concentrations of total T3 and T4 are now measured routinely by similar RIAs, several methods have been employed for measurement of the small, biologically active, free fraction of T3 and T4 (8–14). Most workers in the field view the measurement of free thyroid hormones by equilibrium dialysis as the gold standard, and the ultrafiltration method is comparable or a close second.
Until recently, tracer equilibrium dialysis was believed to be the most accurate procedure for measurement of free T3 or T4.
This is expected to be increasingly replaced by the newer, more accurate, equilibrium dialysis/RIA (12, 14); reasonably priced kits are available commercially for free T4 measurement by this procedure (Nichols Diagnostics, San Juan Capistrano, CA) and should be available soon for free T3 measurement.
A detailed discussion of methods of measurement of free thyroid hormones is beyond the scope of this minireview, and the reader is referred to several studies comparing available procedures (9, 10, 13). The analog methods for free thyroid hormone measurements are popular in several countries outside of the United States.
These methods yield free thyroid hormone readings in NTI that are similar to those from the index method and different from those by the tracer equilibrium dialysis or equilibrium dialysis/RIA procedures (9, 10, 13). For this review, I have relied mainly on free thyroid hormone levels measured by the newer equilibrium dialysis/RIA procedure when data are available, or those measured by tracer dialysis and/or ultrafiltration procedures.
Low serum total T3 is the most common abnormality in NTI. It is observed in about 70% of hospitalized patients. Serum total T3 may vary from undetectable to normal in patients with systemic illness, and the mean value is approximately 40% of the normal level.
The serum free T3 concentration as measured by direct equilibrium dialysis/RIA [free T3(D)] is also decreased, but less severely, and the mean value is approximately 60% that of normal (14). The serum free T3 concentration measured by ultrafiltration is either normal or reduced (11). Low values were observed in patients given dopamine.
It is curious that free T3 was often low in NTI when measured by equilibrium dialysis (14) and typically normal when measured by ultrafiltration (11). The discrepancy is possibly explained by the lower total T3 and more severe NTI in patients determined by equilibrium dialysis than by ultrafiltration.
Free T3 in systemic illness has also been measured by a variety of other techniques and has been found to be low, but the accuracy of these procedures is questionable in NTI patients (8, 10, 15). When measured, the daily production rate (PR) of T3 is decreased in NTI (16, 17), which supports the finding in NTI of low free T3(D).
Serum total T4 and free T4(D) and, when measured, daily PR-T4 are normal in the low T3 syndrome (12, 16, 18, 19). A decreased serum free T3(D) concentration and PR-T3 at a time when the serum free T4(D) concentration and PR-T4 are normal reflect decreased conversion of T4 to T3 in NTI (12, 16, 18, 19). The serum concentration of rT3 is increased in NTI, except in renal failure (20).
However, daily PR-rT3 is normal, and the increase in the serum rT3 level is related mainly to the delayed MCR of rT3, which is predominantly due to decreased activity of the type I iodothyronine 5′-monodeiodinase (5′-MDI) in tissues (16); 5′-MDI deiodinates T4 to T3 and rT3 to 3,3′-diiodothyronine (T2) (21).
The low T3 and low T4 syndrome is observed in severely ill, frequently moribund, patients, usually admitted to medical intensive care units. Low serum total T4 correlates with a bad prognosis (22). The serum concentration of free T4, as measured by equilibrium dialysis/RIA [free T4(D)], is normal in most NTI patients with low total T4 (12).
Interestingly, total T4 is often low in NTI patients even when their serum concentration of immunoassayable T4-binding globulin (TBG) is clearly normal (8). However, the free T4 index is frequently low in these patients (7, 9, 10).
This combination of findings in NTI has been explained by the presence in the circulation of an inhibitor of serum (and resin) binding of thyroid hormones (15, 23). The nature of the inhibitor is not known. We and others have considered a role for nonesterified fatty acids in some cases, especially when serum albumin is low (15, 24, 25).
An inhibitor of serum binding of thyroid hormones is present in tissues (26), and its nature or its leakage into the circulation are not known. Some investigators do not agree with the existence of such an inhibitor in the sera of NTI patients (27). On the basis of experiments involving mixing of normal sera with NTI sera, Mendel et al.
(27) were unable to document the existence of an inhibitor in NTI. They suggested that diminished serum binding of T4 in NTI patients with normal immunoassayable TBG is a result of high level of desialylated TBG (27). This may indeed be the case, but direct measurements of desialylated TBG were not performed.
Interestingly, however, the researchers observed that desialylated TBG has markedly decreased avidity for T4, but its avidity for T3 remains unchanged (27).
Therefore, the finding of clearly decreased serum binding of T3, evidenced by a markedly elevated dialyzable fraction of T3, in several NTI patients with normal immunoassayable TBG (8) supports the possibility of a thyroid hormone binding inhibitor in NTI.
When present, a decreased serum concentration and/or affinity of thyroid hormone binding proteins, especially TBG, can explain the findings of low total T4 and normal free T4(D) in NTI. Decreased serum binding of T4 in NTI is associated with an increased MCR, which, too, contributes to a decreased serum concentration of total T4. Interestingly, however, the increase in the MCR of T4 in NTI is not as much as expected from the degree of reduction in serum binding of thyroid hormones (4).
The serum free T4 concentration is low in NTI patients treated with dopamine and corticosteroids, which decrease serum TSH levels (11, 28–30). Besides low TSH, factors that may contribute to the low T4 of NTI include abnormalities in TSH secretion, decreased biological activity of TSH, and diminished thyroidal response to TSH (31, 32).
High serum total T4 is seen in some NTI patients, who have elevated serum concentrations of TBG. Serum TBG is elevated in acute intermittent porphyria (33) and several liver diseases, including chronic hepatitis and primary biliary cirrhosis (34).
The serum concentration of free T4(D) is normal in these patients in the absence of thyroid disease. Serum total T3 may be normal, but free T3(D) or the free T3 index is low normal or low as in other patients with NTI.
The serum concentration of rT3 is elevated in NTI patients with high T4.
Both serum total and free T4(D) concentrations are often increased in NTI patients treated with amiodarone and iodinated radiocontrast agents, e.g. iopanoic acid and ipodate used for oral cholecystography (13, 35, 36).
These agents decrease hepatic uptake of T4 and 5′-monodeiodination of T4 (to T3) and, in addition, may precipitate hyperthyroidism in patients with autonomous thyroid nodules by invoking the Jod Basedow phenomenon (37, 38).
The effect of a single dose of oral cholecystography agents on serum T4 typically lasts less than 24 h (36, 37, 39). NTI patients with high total and free T4(D), especially those who have ingested iodine-containing agents, should be followed carefully for the appearance of typical hyperthyroidism (38).
Serum T3 may be normal or even low initially because of the effects of the drug and/or NTI on peripheral conversion of T4 to T3, and it may increase dramatically during follow-up.
The serum concentration of free T4(D) is elevated in NTI patients given heparin (40). This is an in vitro artifact explained by displacement of T4 from binding proteins by fatty acids generated from the action of lipase(s) on plasma triglycerides. Total T4 and the free T4 index are normal in these patients, who are clinically euthyroid.
Infection with human immunodeficiency virus (HIV) produces unusual alterations in thyroid function, including increases in T4 and TBG, paradoxical decreases in rT3 and the rT3/T4 ratio, and the maintenance of a normal T3 and T3/T4 ratio even in severely ill patients. Serum T3 decreases, however, in critically ill patients with HIV and pneumocystis infection (41). The basis for the differences in thyroid hormone abnormalities in HIV compared to those in other NTIs is not known.
Pathogenesis of the NTIS
Some factors that may contribute to major abnormalities of the NTIS are listed in Fig. 1. They have recently been critically reviewed (3–6).
There is evidence for decreased conversion of T4 to T3 in extrathyroidal tissues in the NTIS (16–19), and this may, in turn, be related to decreased activity and/or concentration of 5′-MDI (42).
5′-MDI has now been cloned in the rat and man, and it turns out that it belongs to a small group of selenocysteine-containing proteins (43, 44). No data are available on the tissue content of the 5′-MDI protein or its messenger ribonucleic acid in human NTIS.
However, the hepatic content of 5′-MDI protein was decreased in the fasting rat, studied as a model of NTIS (42). Diminution in the uptake of T4 by tissues can also explain the decreased generation of T3 in tissues (5).
However, this abnormality should be associated with an elevated serum concentration of free T4(D), which is clearly not the case (see above) (45). One could argue that decreased T4 to T3 conversion in NTI should also be associated with increased free T4(D). However, T4 is metabolized not just by 5′-MDI, but also by type III iodothyronine deiodinase, conjugation and side-chain alteration (21, 46); these alternate routes of T4 metabolism are not known to be impaired in NTI and may compensate for T4 not metabolized by 5′-MDI.
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Some factors that may contribute to major abnormalities of NTIS. The reader is referred to previous reviews (3–6) for detailed discussion of these factors.
Alterations in serum binding of thyroid hormones is clearly an important factor contributing to changes in thyroid hormone levels in NTI (see above). Serum albumin binds compounds, e.g. fatty acids, that are capable of displacing thyroid hormones from TBG.
The fall in serum albumin in NTI enhances the activity of such low affinity competitors of T4 on TBG (15, 24, 25).
Additionally, much has been written on abnormalities in the synthesis, secretion, structure, regulation, and effectiveness of TSH in NTI (3–6, 31, 32).
There has been much interest recently in the roles of cytokines in the pathogenesis of the NTI (3). However, their significance remains unclear. Proinflammatory cytokines [tumor necrosis factor-α (TNFα), interleukins (e.g.
IL-1 and IL-6), and interferon-γ], when administered to man or experimental animals, have caused changes in thyroid function tests that resemble NTIS (47–50).
However, humans or animals so treated manifest substantial systemic illness, and it is unclear whether the thyroid hormone changes observed are due to the sickness induced by cytokines or the cytokines per se.
In this respect, it is curious that lipopolysaccharide-induced NTIS in mice, although associated with increases in circulating TNFα and IL-6, was not prevented by immunoneutralization of IL-1 receptor, TNFα, IL-6, or interferon-γ (51) (Wiersinga, W. M., personal communication).
Clinical significance of NTIS
Abnormal thyroid function tests are observed at least as frequently in systemic NTIS as in thyroid diseases (4, 52, 53). Thyroid function abnormalities in NTI may at times mimic and at other times mask the biochemical abnormalities observed in true thyroid disease.
Furthermore, the severity and the nature of changes in thyroid function test have implications for the prognosis of the systemic illness. Thus, a low serum T3 level predicts increased mortality form liver cirrhosis, advanced congestive heart failure (54, 55), and possibly several other systemic illnesses.
Similarly, low total T4 is associated with increased mortality from systemic illness, and those patients with low T4 who have very low serum T3 levels have the worst prognosis (22, 55, 56).
Previous studies have suggested that there exist tissue factors that can inhibit the binding of thyroid hormones to serum proteins and the ability of polymorphonuclear leukocytes to phagocytose Escherichia coli (26, 57).
However, it is not known whether the two effects are due to the same or even similar factors and whether the thyroid hormone binding inhibitor considered above in serum is similar to that extracted from tissues. In any case, leakage of tissue elements in the circulation in systemic illnesses may explain the correlation between the fall in serum T4 and the increased mortality in NTI; this requires further study.
Diagnosis of thyroid disease in NTI
It can be challenging to establish the diagnosis of thyroid disease in patients manifesting NTIS. The difficulty exists in hyperthyroid patients who may exhibit normal total T4 and T3 on account of a diminution in serum binding of thyroid hormones.
However, serum free T4 and free T3 determinations by equilibrium dialysis/RIA (12) or ultrafiltration (45) should yield appropriately diagnostic elevated values. The free T4 index and analog methods for free T4 determination frequently yield low values in NTI and should be interpreted with caution.
Serum TSH measured by the ultrasensitive RIA is typically undetectable (
Low T3 / Euthyroid Sick Syndrome Causes & Treatment
Low T3 syndrome is a common condition in patients who are critically ill. Those with chronic conditions, such as an autoimmune disease, may also experience low T3 syndrome. However, there is some debate on the effects of low T3 syndrome and how to treat it. Read on to learn about the causes of low T3 syndrome and if treatment is warranted.
What is Low T3 or Euthyroid Sick Syndrome?
The thyroid gland releases the thyroid hormones T3 and T4, which play an important role in metabolism in the body. Problems in the thyroid gland can lead to an overproduction of thyroid hormones (hyperthyroidism) or underproduction of thyroid hormones (hypothyroidism).
Low T3 syndrome, also known as euthyroid sick syndrome or non-thyroidal illness syndrome, is a condition where T3 and/or T4 levels are lower than normal, but the thyroid gland is functioning properly .
The most common lab results in those with low T3 syndrome are :
- Low T3 (total and free)
- High rT3
- Normal TSH (may be low in some cases)
- Normal T4 (may be low in some cases)
Many conditions may cause low T3 syndrome, including starvation, trauma, pneumonia, heart attack, kidney failure, cancer, chronic fatigue syndrome, and autoimmune diseases .
The consequences of low T3 syndrome are unclear and there is some debate on whether the condition is beneficial or harmful for the body. A popular theory is that low T3 syndrome is the body’s natural protective response to acute and severe illness [1, 3].
Critically ill hospitalized patients often present with low T3 syndrome. Some examples of acute conditions that may cause low T3 syndrome include [2, 4]:
- Severe infections (pneumonia, sepsis)
- Heart attack
- Diabetic ketoacidosis
According to research, there are several reasons why these acute conditions may lead to low T3 syndrome.
One possible mechanism is an imbalance in deiodinases, which are the enzymes that are responsible for converting and breaking down thyroid hormones. During times of extreme stress, such as during critical illness, the balance of deiodinases is disturbed, which can change the levels of thyroid hormones [4, 5].
Other potential causes of low T3 syndrome during acute illness include :
- Increase in cytokines (TNF, IL-1, IL-6)
- Decrease in thyroid hormone receptors (THR)
- Decrease in thyroxine-binding globulin (TBG)
- Certain medications (such as corticosteroids)
Starvation and Fasting
Low T3 syndrome is often seen in people who are fasting or experiencing starvation.
According to research, this effect may be due to a reduction in leptin levels. Leptin is a hormone that plays a role in regulating energy and hunger. During starvation, leptin levels are decreased. This leads to a reduction in thyroid hormone receptors and TSH, which ultimately may decrease levels of T3 and T4 [1, 5].
This mechanism may be tied to acute illness and chronic conditions as well. For example, starvation is commonly seen in critically ill patients. Chronic inflammation may also lead to a fasting response by the body [1, 2, 6].
A number of chronic conditions are associated with low T3 syndrome, including :
- Chronic fatigue syndrome
- Inflammatory bowel disease
- Autoimmune diseases
- Kidney failure
- Heart failure
It’s not completely understood how these conditions contribute to low T3 syndrome. According to some researchers, one major mechanism may be an increase in cytokines (TNF, IL-1, IL-6) due to inflammation. These cytokines can alter the activity of deiodinases and TSH, leading to changes in thyroid hormone levels [6, 7].
Effects of Low T3 Syndrome
The effects of low T3 syndrome are not well studied. According to some researchers, low T3 syndrome may be an adaptive response by the body to preserve energy during times of great stress. By lowering thyroid hormone levels, the metabolism of the body slows and less energy is used, which may be beneficial during malnutrition or critical illness .
However, clinical research also suggests that low T3 levels and high rT3 levels during critical illness are associated with poor prognosis .
For example, studies suggest that low T3 syndrome in patients with end-stage kidney disease is associated with higher rates of death [8, 9].
Similar associations have been found in patients with heart failure, liver disease, and in patients in the ICU. In all these cases, low T3 syndrome was associated with worse outcomes or higher rates of death .
For patients who are not critically ill, the research on low T3 syndrome is very limited. Theoretically, low T3 syndrome may cause symptoms similar to hypothyroidism, which includes tiredness, constipation, and weight gain .
There is some debate on how to treat low T3 syndrome, or if it should be treated at all. In most cases, treatment should be focused on the underlying cause rather than correcting thyroid hormone levels [1, 6].
Some studies do suggest that there may be some benefit to directly treating low T3 syndrome. For example, a randomized placebo-controlled trial of 20 patients with chronic heart failure found that T3 replacement therapy may improve heart function [1, 10].
However, a number of other clinical trials have found that thyroid hormone replacement therapy may offer no benefit, such as in ICU patients, premature infants, and patients undergoing heart surgery .
Thyroid hormone levels may naturally return to normal within a few months once the underlying cause is treated in critically ill patients .
It’s even less clear if low T3 syndrome associated with chronic conditions should be treated. In general, thyroid hormone replacement in these patients is not recommended .
I. What every physician needs to know
Patients hospitalized with acute, severe illness are frequently found to have low triiodothyronine (T3) levels with normal or low normal thyroxine (T4) and thyroid stimulating hormone (TSH) levels.
This constellation of findings is known by several names: euthyroid sick syndrome, low T3 syndrome, and non-thyroidal illness syndrome. Non-thyroidal illness syndrome (NTIS) is the preferred name at this time.
The most prevalent form of thyroid hormone is T4. This is converted in the peripheral tissues to the more potent and principally active thyroid hormone, T3, by deiodination. There are three iodothyroxine deiodinases: D1, D2, and D3.
The conversion of T4 to T3 and reverse T3 (rT3), and the clearance of rT3 which is biologically inert, is mediated by hepatic D1. Starvation or cytokines interleukin 1 (IL-1) suppress hepatic D1 causing decreased conversion of T4 to T3 and decreased clearance of reverse T3 (rT3).
Deiodinase D2 is found in skeletal muscles, central nervous system, thyroid and the pituitary. Deiodinase D3, particularly induced by tissue hypoperfusion, is the major deactivating enzyme which causes conversion of T4 to rT3.
Initially, the result is low T3 and normal T4 and TSH concentrations; most experts view this as an adaptive response to stress and illness. With prolonged critical illness, T4 and TSH may decline as well.
Thyroid levels should not be measured during critical illness unless there is a strong suspicion of underlying thyroid disorder.
II. Diagnostic Confirmation: Are you sure your patient has Euthyroid Sick Syndrome?
Low serum T3. Low pulsatile measurement of TSH. Low or normal serum concentrations of T4 and TSH, but TSH is usually not undetectable. Transient upsurge of TSH, generally less than 20 milliunits/liter (mU/L), may be seen with recovery.
A. History Part I: Pattern Recognition:
Typical case with NTIS is a hospitalized patient with severe acute illness. At first, the patient has low serum T3 levels with normal T4 and TSH levels. During prolonged illness, T4 and TSH levels may decrease.
Most recent evidence suggests that central hypothyroidism and altered peripheral metabolism of T4 and T3 combine to produce a state marked by diminished serum and tissue supplies of thyroid hormones.
Post-mortem brain samples of chronic critically ill patients show reduced hypothalamic messenger ribonucleic acid (mRNA) for thyrotropin releasing hormone (TRH) and lower TSH.
These data indicate that production of thyroid hormone declines due to reduced hypothalamic stimulation of the thyrotropes, in turn leading to diminished stimulation of the thyroid gland. Rise in TSH levels preceding onset of recovery from severe illness supports this theory. Factors triggering hypothalamic suppression during prolonged critical illness are not completely known.
B. History Part 2: Prevalence:
In non-selected hospitalized patients the prevalence of NTIS is 11-18%. In the intensive care unit (ICU), it may be seen in upwards of 70-75% of patients.
In congestive heart failure, the prevalence is 18- 23%. In a study looking at elderly patients in Italy, the prevalence was 31.9%. NTIS in the elderly was found to be predictive of mortality at 17.
7%, compared to 3.9% in those who were euthyroid.
C. History Part 3: Competing diagnoses that can mimic Euthyroid Sick Syndrome
Primary hypothyroidism: Primary hypothyroidism is characterized by an elevated TSH, low T4, and low or normal T3 and Free T3 (FT3).
Central hypothyroidism: Central hypothyroidism is characterized by low T4, low or normal T3, and low TSH or normal single measure of TSH. Central hypothyroidism, NTIS, displays low pulsatile secretion of TSH versus elevated pulsatile secretion of TSH in primary hypothyroidism.
D. Physical Examination Findings
The presence of NTIS does not correspond with any specific physical exam finding.
1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
Serum TSH, free T4 (FT4), FT3, and total T3.
– Elevated TSH could be diagnostic of very early or recovery phase of NTIS or may be diagnostic of hypothyroidism.
– Low or normal T4, low or normal TSH, low T3 in the critically ill patient is diagnostic of NTIS.
2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?
There is no role for imaging tests in the diagnosis or management of NTIS.
F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis
Thyroid levels should not be measured during critical illness unless there is a strong suspicion of underlying thyroid disorder.
III. Default Management
Management is usually conservative and aimed at treating the underlying illness.
D. Long-term management
Thyroid function may take several months to recover after critical illness; outpatient monitoring is recommended.
A. Renal Insufficiency
In animal models, treatment with thyroid hormone helped to reduce or reverse ischemic injury and toxic acute renal failure. These effects have not been verified in humans.
In one study, over 80% of acute kidney injury patients were noted to have abnormal thyroid function test, most commonly NTIS; spontaneous resolution was observed with improvement of renal function.
In a small randomized trial of 59 patients with acute renal failure, treatment with T4 did not reverse renal injury, suppression of TSH was observed, and there was association with increased mortality.
In another study of 54 patients undergoing renal transplant, treatment with T4 did not change the primary outcome of graft function in patients with delayed graft function.
In chronic kidney disease, inflammatory cytokines and oxidative stress may play a pivotal role in pathogenesis of NTIS. Treatment remains controversial. In a study of hemodialysis patients, low T3 was a frequent finding and did not predict outcome. However, FT3 was found inversely linked to mortality, possibly due to its association with suboptimal nutritional state and inflammation.
B. Liver Insufficiency
In cirrhosis, the most common thyroid abnormalities are decreased free T3, T3, and elevated rT3. Some studies have suggested that low T4 and / or low T3 in cirrhosis may be indicative of disease severity and may correlate with decreased short- and long-term survival.
C. Systolic and Diastolic Heart Failure
Low T3 has been implicated as an independent predictor of cardiac and all-cause mortality among critically ill patients.
Thyroid hormone increases inoptropy, chronotropy, blood volume, and decreases systemic vascular resistance. In dilated cardiomyopathy, T3 has been shown to increase left ventricular end systolic volume, increase stroke volume, and decrease heart rate.
D. Coronary Artery Disease or Peripheral Vascular Disease
In coronary artery bypass, thyroid hormone increases cardiac output and decreases systolic vascular resistance.
In some small nonrandomized open heart surgery trials, T3 showed benefit when administered to those with poor myocardial function despite inotropic and intra-aortic balloon pump support.
Some experts advocate use of thyroid hormone therapy in patients with NTIS and myocardial depression, studies showing improvement in myocardial function in three conditions: transient regional myocardial ischemia and reperfusion, transient global myocardial ischemia in patients undergoing cardiac surgery or coronary artery bypass grafting, and transient inadequate myocardial perfusion in brain dead potential organ donors.
G. Immunosuppression (HIV, chronic steroids, etc)
Prior to the use of highly active antiretroviral therapy (HAART), nonthyroidal illness was a common feature of patients with terminal acquired immunodeficiency syndrome (AIDS).
NTIS may affect up to 16% of those with human immunodeficiency virus (HIV). They characteristically have increased resting energy expenditure, poor oral intake, and increased prevalence of weight loss and wasting.
Patients with nonthyroidal illness do not need therapy as it is a normal adaptive mechanism.
H. Primary Lung Disease (COPD, Asthma, ILD)
NTIS may be associated with prolonged weaning in intubated chronic obstructive pulmonary disease (COPD) patients.
I. Gastrointestinal or Nutrition Issues
Thyroid function test was monitored in the EPaNIC trial, a large randomized controlled trial studying early versus late parenteral nutrition in critically ill adults.
Findings suggested that tolerating macronutrient deficiency during the first week in ICU improved outcomes by reducing incidence of nosocomial infection, and was associated with faster recovery with fewer complications. Acute fasting induced NTIS phenotype, not seen in the group receiving parenteral nutrition.
Possible benefits of acute NTIS include reduction in energy expenditure with low T3 levels, and also increased D3 activity locally in granulocytes enhancing bacterial killing.
K. Dementia or Psychiatric Illness/Treatment
Up to one-third of psychiatric patients may show thyroid function abnormalities consistent with NTIS. These resolve spontaneously and treatment is not recommended.
C. When is the Patient Ready for Discharge
Discharge planning is determined by the status of the underlying disease process, not resolution of NTIS.
D. Arranging for Clinic Follow-up
Patient should have thyroid function tested as an outpatient and may benefit from Endocrinology follow up in cases where there is significant derangement in thyroid tests.
1. When should clinic follow up be arranged and with whom
The patient should follow up with their primary care provider within 1 – 2 weeks of discharge. Depending on the degree of derangement in thyroid studies, referral to an Endocrinologist may be warranted. Due to the time required for recovery on normal thyroid function, 4 weeks would be a reasonable time frame.
E. Placement Considerations
Since NTIS is seen in seriously ill patients and its presence is predictive of increased mortality, it is ly that patients who have NTIS during their hospital admission will require discharge to a skilled nursing facility for subacute rehabilitation.
F. Prognosis and Patient Counseling
The presence of NTIS in a population of elderly patients admitted to a hospital in Italy was associated with mortality of 17.7% versus 3.9 %, when compared to patients without NTIS.
The probability of death is 50% when free T4 is less than 4 microgram per deciliter and 80% when free T4 is less than 2 microgram per deciliter.
In a study of ICU patients, overall mortality was 12.7% compared to 17.6% p=0.396 for NTIS. However, NTIS with low T4 resulted in a mortality of 45.8%, p