OVERVIEW: What every practitioner needs to know
“Sick-euthyroid syndrome” occurs most commonly in acutely ill infants or children admitted to intensive care units, and is characterized by changes in serum thyroid hormone and TSH levels not caused by an intrinsic abnormality of thyroid function.
Sick-euthyroid syndrome also can occur with starvation or with essentially any acute or chronic illness.
The most consistent changes in thyroid tests are a decrease in serum T3 and an increase in reverse T3 (rT3) levels. With more severe acute illness, serum T4 levels also fall. Changes in serum free T4 (and, to a lesser extent, serum free T3) are more assay-dependent. Serum freeT4 levels measured by the most common (analogue) methods are low, whereas if free T4 is measured by equilibrium dialysis or ultrafiltration, levels typically are normal or even high. Serum TSH levels remain normal or low. With recovery from sick-euthyroid syndrome, serum TSH levels may transiently rise above the normal range, and serum T3 (and T4 and free T4) levels return to normal.
Acutely or chronically ill children manifest clinical features that overlap with hypothyroidism, including lethargy, hypothermia, bradycardia, hypotension, hypoventilation, and hypotonia. There is controversy about treatment of patients with sick-euthryroid syndrome. Most experts consider the changes in thyroid function to be an “adaptive response” and therefore do not recommend thyroid hormone treatment. However, in certain situations, others believe that these changes are “maladaptive” and might be improved by thyroid hormone treatment.
Are you sure your patient has sick-euthyroid syndrome? What are the typical findings for this disease?
The most common symptoms and signs occur in acutely ill patients, and include bradycardia, hypotension, hypoventilation, hypotonia, and altered mental status. These features may also occur with hypothyroidism.
The defining feature of sick-euthyroid syndrome is a normal serum TSH level, despite low T3 and T4 levels, in acutely ill patients.
Common conditions or situations complicated by sick-euthyroid syndrome include hypothyroxinemia of prematurity, cardiac surgery in infants and children, and chronic renal insufficiency. There is disagreement about whether these patients are truly euthyroid; most experts therefore now refer to sick-euthyroid syndrome as “non-thyroidal illness syndrome.”
“Sick-euthyroid syndrome” is the term used to describe changes in serum thyroid hormone and thyroid stimulating hormone (TSH) levels with acute illness not caused by an intrinsic abnormality of thyroid function. Sick-euthyroid syndrome occurs most commonly in acutely ill infants or children admitted to intensive care units, but it can occur with starvation or any acute or chronic illness.
The first changes in thyroid function tests are a decrease in triiodothyronine (T3) and an increase in reverse T3 (rT3) levels (another name for this condition is “low T3 syndrome”). With increasing severity of illness, serum total T4 levels also decrease. Changes in serum free T4 and free T3 are less certain. When free T4 is measured by the most common “analogue” immunoassay methods, levels appear to decrease. However, if free T4 is measured by equilibrium dialysis or ultrafiltration methods, levels are normal or even increased. The same results are seen with free T3 measurements, although levels tend to be low even with dialysis methods. Serum TSH levels generally are in the normal range, although TSH may fall below normal in some patients.
Thus, some acutely ill patients will manifest low serum T3, T4 and free T4 levels with normal or low serum TSH levels, a pattern identical with central (hypopituitary) hypothyoidism. Serum rT3 levels, however, tend to be normal or low with central hypothyroidism, in contrast to the elevated levels seen with sick-euthyroid syndrome.
What other disease/condition shares some of these symptoms?
Patients with central (hypopituitary) hypothyroidism manifest low serum T4, free T4, and low or “inappropriately normal’ serum TSH levels, findings identical to patients with sick-euthyroid syndrome.
Some clinical features of acute illness overlap with symptoms and signs of hypothyroidism; these include decreased body temperature, bradycardia, hypotension, hypoventilation, hypotonia, and altered mental status. In general, laboratory testing will clearly separate primary hypothyroidism from sick-euthyroid syndrome. While serum T4 or free T4 levels may be low in both conditions, serum TSH levels are elevated with primary hypothyroidism and normal or low in patients with sick-euthyroid syndrome. It is possible that serum TSH levels will be lower in patients with a combination of primary hypothyroidism and sick-euthyroid syndrome, but it would be unlikely that they would fall into the normal range.
What caused this disease to develop at this time?
Sick-euthyroid syndrome may occur with starvation, trauma, surgery, or any severe acute or chronic illness. In general, there are no predisposing genetic or seasonal risk factors.
Starvation and acute illness result in diminished TRH production and TSH secretion. Certain drugs commonly used to treat patients with acute illness, including dopamine and glucocorticoids, also inhibit TSH secretion. The initial decrease in serum T3 levels is the result of both decreased production of T3 by the thyroid gland and decreased extra-thyroidal conversion of T4 to T3. This latter process is the result of decreased function of the activating type 1 deiodinase (D1) and type 2 deiodinase (D2), the enzymes working in extra-thyroidal tissues to convert T4 to T3. Increased function of the inactivating type 3 deiodinase (D3) results in increased conversion of T4 to reverse T3.
Severe acute illness further results in decreased production of T4 by the thyroid gland. Decreased levels of total T4 and total T3 are also the result of decreased thyroid hormone binding proteins (thyroxine binding globulin [TBG], transthyretin, and albumin). (A fall in TBG appears to be an “acute phase response.”) Circulating inhibitors of T4 and T3 binding to their binding proteins also appear to contribute to low serum total T4 and T3 levels. Examples of inhibitors include non-esterified fatty acids produced with sick-euthyroid syndrome and certain drugs used to treat patients, including furosemide and salicylate.
History and physical examination help to separate sick-euthyroid sydrome from true hypothyroidism. Children with true hypothyroidism likely have been previously diagnosed and are on thyroid hormone replacement. In cases of undiagnosed hypothyroidism, there may be clues on history and physical examination.
Because the most common cause of acquired hypothroidism in children is autoimmune thyroiditis, there may be a family history of some type of autoimmune thyroid disease (e.g., Hashimoto’s or Graves’ disease). Other potential causes of hypothyroidism may be revealed by history, including radiation for head and neck tumors or excess iodine ingestion. On neck exam, a goiter supports underlying thyroid disease; a neck scar could be a sign of previous thyroidectomy.
Many features of hypothyroidism, including low body temperature, bradycardia, hypotension, hypoventilation, hypotonia, and altered mental status, may also be seen with acute illness.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Patients with sick-euthyroid syndrome manifest a low serum T3, elevated rT3, and normal-to-low TSH level. Depending on the assay method, serum free T4 and free T3 may be low (analogue method) or normal-to-elevated (equilibrium dialysis method). As patients recover from sick-euthyrod syndrome, serum TSH will rise, and transiently may even increase above the normal range. Serum T3 and T4 levels (and free T3 and free T4 levels) rise into the normal range, while rT3 levels fall into the normal range. If there is clinical suspicion of thyroid dysfunction, first-line tests include measurement of serum free T4 and TSH.
Patients with central (hypopituitary) hypothyroidism will have a low serum free T4 level and low or “inappropriately normal” TSH level, findings also seen in sick-euthyroid syndrome. To separate sick-euthyroid sydrome from true central hypothyroidism, we recommend measurement of free T4 by equilibrium dialysis along with measurement of serum rT3. Patients with sick-euthyroid syndrome typically manifest a normal (or even high) free T4 by equilibrium dialysis and a high rT3 level, while patients with true central hypothyroidism manifest a low free T4 by equilibriium dialysis and a normal (or low) rT3 level.
Patients with primary hypothyroidism will have a low serum free T4 level (by both analogue and equilibrium dialysis methods). However, serum TSH levels will be elevated in patients with primary hypothyroidism, differentiating them from sick-euthyroid syndrome. As patients recover from euthyroid-sick syndrome, serum TSH levels may transiently rise into the 10-20 mU/L range. A TSH >20 mU/L would almost always indicate true primary hypothyroidism. As autoimmune thyroid disease is the most common cause of primary hypothyroidism in children, measurement of antithyroid antibodies (anti-thyroglobulin and anti-thyroid peroxidase) may provide supportive evidence for primary hypothyroidism.
Rarely, an elevated serum free T4 level (by equilibrium dialysis) and a low serum TSH level may generate suspicion for hyperthyroidism. While TSH may be low, in the range of .01-.30 mU/L, with sick-euthyroid syndrome, patients with true hyperthyroidism will typically have an unmeasurable TSH, <.01 mU/L. Further thyroid testing should help to differentiate these two possibilities. Patients with sick-euthyroid syndrome manifest a low serum total T3 and a high rT3 level, while patients with true hyperthyroidism manifest a high total T3 and a normal rT3 level. Because Graves’ disease is the most common cause of hyperthyroidism in children, some measurement of the thyrotropin receptor stimulating antibody, such as thyroid stimulating immunoglobulin (TSI) will support the diagnosis of true hyperthyroidism.
Would imaging studies be helpful? If so, which ones?
Ultrasonography of the neck may help separate true thyroid disease from sick-euthyroid syndrome. Generally, the appearance of the thyroid gland is normal in sick-euthyroid syndrome. Patients with primary hypothyroidism may manifest enlargement of the thyroid (goiter); patients with autoimmune thyroiditis typically have heterogeneous echogenicity.
If central hypothyroidism is suspected, an MRI of the brain may be useful. Patients with sick-euthyroid syndrome appear normal, while patients with central hypothyroidism may manifest abnormal appearance of the hypothalamus or pituitary gland.
Confirming the diagnosis
Table I provides a comparative list of laboratory test results to help differentiate sick-euthyroid syndrome from other thyroid disorders.
|Thyroid Disorder/Thyroid Test||Sick-Euthyroid Syndrome||Secondary (Central) Hypothyroidism||Primary Hypothyroidism||Hyperthyroidism|
|Free T4(analogue method)||↓||↓||↓||↑|
|Free T4(equilibrium dialysis)||normal or ↑||↓||↓||↑|
|Free T3||↓ or normal or ↑||normal or↓||normal or ↓||↑|
|Total T3||↓||normal or ↓||normal or ↓||↑|
|Reverse T3||↑||normal or ↓||normal or ↓||normal|
|TSH||normal or ↓||normal or ↓||↑||↓|
|Anti-Tg and anti-TPOantibodies||negative||negative||positive with autoimmunethyroiditis||positive with Graves’disease|
positive with Graves’disease
If you are able to confirm that the patient has sick-euthyroid syndrome, what treatment should be initiated?
Priority should be given to diagnosis and treatment of the underlying acute illness associated with the sick-euthyroid syndrome. Most experts consider the thyroid hormone and TSH changes in sick-euthyroid syndrome to be an “adaptive response” and therefore do not recommend thyroid hormone treatment. However, in certain situations others believe that these changes are “maladaptive” and might be improved by thyroid hormone treatment. The evidence for treatment in specific clinical situations is summarized as follows:
Preterm infants with hypothyroxinemia: Serum T4 levels are decreased in infants born preterm; the degree of decrease has a positive correlation with gestational age and birth weight. Clinical trials using either l-T3 or l-T4 treatment have not shown differences in measured outcome variables, including level of inspired oxygen, duration of mechanical ventilation, enteral fluid intake, weight gain, CNS ischemia or hemorrhage, or mortality.
The largest randomized controlled trial (RCT) to evaluate the effect of thyroid hormone treatment on neurocognitive outcome was undertaken in the Netherlands in 200 preterm infants <30 weeks gestation. One hundred infants were treated with l-T4 8 mcg/kg/day for the 1st 6 weeks of life, while 100 infants received a placebo. Psychometric testing was carried out at intervals from 6 months to age 10 years. An initial report at 24 months of age showed no difference in IQ between the two groups. A subgroup analysis showed that infants <27 weeks gestation receiving l-T4 had a mean IQ 18 points higher, while the infants >27 weeks gestation receiving l-T4 had a mean IQ 10 points lower compared with the placebo group. These changes have diminished with IQ testing at older ages.
A Cochrane review concluded that there is insufficient evidence to determine whether or not the use of thyroid hormone improves measures of morbidity, mortality, or neurodevelopmental outcome in preterm infants with hypothyroxinemia.
Acute ill children: Acutely ill children manifest lower serum T3 and T4 levels and elevated rT3 levels, with normal TSH levels. There are no RCTs of thyroid hormone treatment in acutely ill children admitted to intensive care units (ICU). RCTs in adults admitted to an ICU treated with l-T4 and in burn patients treated with l-T3 have not shown benefit.
Cardiac surgery: Children undergoing cardiac surgery experience a fall in total and free T3 levels, with free T3 falling as much as 80% from pre-operative levels by 12 -48 hrs postoperatively. In addition to the factors described above (see “What caused this disease to develop at this time?”), hypothermia and hemodilution during cardiopulmonary bypass contribute to the decrease in serum T3 levels.
Studies show a correlation between decreased serum T3 levels and decreased cardiac function, including decreased cardiac output, left ventricular dysfunction, increased vascular resistance, and impaired ventilatory drive. It therefore would seem logical to carry out studies investigating the effects of T3 treatment in children undergoing cardiac surgery. Studies have been carried out using once daily T3 dosing (0.4 to 2.0 mcg/kg) or continuous T3 infusion (0.05 to 0.15 mcg/kg/hr), some starting pre-op, but most treating for a period of time post-operatively. In addition, some studies targeted treatment to patients with low serum T3 levels (<40 ng/dL in neonates, <60 ng/dL in infants).
Various studies have reported benefit on one or more outcome measures, such as improved cardiac index, a shorter time to extubation, a more rapid negative fluid balance, improvement in a measure of severity of illness (therapeutic intervention scoring system = TISS), or a trend toward a shorter hospital stay. No study reports an effect on mortality. A Cochrane review concluded that there was insufficient evidence to support a positive effect of T3 intervention in infants undergoing cardiac surgery.
Chronic renal insufficiency (CRI): Studies in children with CRI report low serum total and free T3 levels and low total and free T4 levels, whereas serum TSH levels usually are normal. These changes are compatible with either sick-euthyroid syndrome or central hypothyroidism. Serum rT3 levels usually are normal, in contrast to the elevation seen in sick-euthyroid syndrome.
CRI is associated with decreased metabolic clearance of iodine, thyroid hormone, and TSH; in addition, there is decreased conversion of T4 to T3 in the kidney. Uremic factors appear to inhibit binding of T4 and T3 to their binding hormones.
Drugs commonly used to treat patients after kidney transplant, such as glucocorticoids, lower serum TSH levels. Thus, the changes in thyroid function tests seen in patients with CRI may be more a result of the effects of renal failure than sick-euthyroid syndrome.
Studies of T4 or T3 treatment in adults with acute renal failure have not shown any benefit. No studies have been carried out in children with CRF. The fact that most of the changes described above revert to normal following hemodialysis argues for treatment to correct renal failure rather than thyroid hormone treatment.
Sick-euthyroid syndrome typically is precipitated by an acute illness, lasting a few days or weeks. Thus, longer term treatment with thyroid hormone (if administered) does not appear indicated and has not been studied.
As described for the common conditions associated with sick-euthyroid syndrome, for most patients the changes in thyroid function appear to be “adaptive” and are not improved by thyroid hormone treatment. There do appear to be some unique situations, e.g., hypothyroxinemia in preterm infants <27 weeks gestation and in some infants undergoing cardiac surgery, where RCTs demonstrate benefit of thyroid hormone treatment (see above for T4 or T3 dosing). Expert consensus, however, does not support thyroid hormone treatment as standard of care; such treatment, therefore, is best carried out in the context of a randomized controlled trial.
What are the adverse effects associated with each treatment option?
The Dutch study (see above) reported that preterm infants with hypothyroxinemia >27 weeks gestation treated with l-T4 had a mean IQ 10 points lower than the placebo group. There is some evidence that hyperthyroxinemia may have untoward effects on brain development.
Adults admitted to a medical ICU treated with l-T4 had a delayed rise in serum T3 levels, which normally occurs as patients recover from sick-euthyroid syndrome. The investigators speculated that this might delay recovery from the sick-euthyroid syndrome.
Infants or children undergoing cardiac surgery treated with l-T3 could be at risk for arrhythmias or high-output cardiac failure.
Adults with acute renal failure treated with l-T4 had a higher mortality than the placebo group (43% vs. 13%).
What are the possible outcomes of sick-euthyroid syndrome?
The changes in thyroid function that occur with sick-euthyroid syndrome will revert to normal with recovery from the underlying acute (or chronic) illness. Thus, the overall prognosis is determined more by the underlying acute (or chronic) illness than sick-euthyroid syndrome.
Most experts consider the changes in thyroid function in sick-euthyroid syndrome to be an “adaptive response” and therefore do not recommend thyroid hormone treatment. However, in certain situations others believe that these changes are “maladaptive” and might be improved by thyroid hormone treatment. A discussion of the risks/benefits therefore depends on each patient’s specific medical circumstances.
The safest course is to monitor thyroid function tests without treatment; this would avoid any of the risks of thyroid hormone treatment noted above. In the unique situations where it appears a patient might benefit from thyroid hormone treatment, monitoring thyroid function tests will reduce the risk of overtreatment. However, physicians should counsel parents that even restoration of a “euthyroid” state may pose some of the risks described above.
What causes this disease and how frequent is it?
Incidence: In adult patients admitted to a medical service, 50% develop a low serum T3 level, 15%-20% develop a low T4 level, and 10% have an abnormal TSH level (either low or high); similar data for children do not exist. There is no seasonal variation. Any age, from preterm newborns on, may develop sick-euthyroid syndrome.
Genetics: There does not appear to be a genetic predisposition toward sick-euthyroid syndrome.
How do these pathogens/genes/exposures cause the disease?
N/A (except as a cause of the underlying acute illness).
Other clinical manifestations that might help with diagnosis and management
What complications might you expect from the disease or treatment of the disease?
Are additional laboratory studies available; even some that are not widely available?
How can this be prevented?
What is the evidence?
Warner, MH, Beckett, GJ. “Mechanisms behind the non-thyroidal illness syndrome: an update”. J Endocrinol. vol. 205. 2010. pp. 1-13. (Excellent current review of the pathogenesis of sick-euthyroid syndrome).
Wiersinga, WM, Braverman, LE, Utiger, Rd. “Nonthyroidal illness”. 2005. pp. 246-63. (Excellent review of thyroid hormone changes, diagnosis, and risk/benefit of thyroid hormone treatment of sick-euthyroid syndrome.)
Baloch, Z, Carayon, P, Conte-Devolx, B. “Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease”. Thyroid. vol. 13. 2003. pp. 3-126. (Includes a summary of the natural history of thyroid function tests during the course of sick-euthyroid syndrome.)
Fisher, DA. “Thyroid function and dysfunction in premature infants”. Pediatr Endocrinol Rev. vol. 4. 2007. pp. 317-28. (An excellent summary of hypothyroxinemia of prematurity, including RCTs of thyroid hormone treatment.)
Delahunty, C, Falconer, S, Hume, R. “Levels of neonatal thyroid hormone in preterm infants and neurodevelopmental outcome at 5 ½ years: millennium cohort study”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 4898-908.
van Wassenaer, AG, Kok, JH, de Vijlder, JJ. “Effects of thyroxine supplementation on neurologic development in infants born at less than 30 weeks' gestation”. N Engl J Med. vol. 336. 1997. pp. 21-6. (The Dutch RCT of thyroid hormone vs. placebo treatment and neurodevelopmental outcome in preterm infants)
Osborn, DA, Hunt, RW. “Postnatal thyroid hormones for preterm infants with transient hypothyroxinaemia”. Cochrane Database Syst Rev. vol. 2007. pp. CDC005945(Cochrane review of thyroid hormone treatment in preterm infants.)
Bettendorf, M, Schmidt, KG, Grulich-Henn, J. “Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study”. Lancet. vol. 356. 2000. pp. 529-34.
Portman, MA, Fearneyhough, C, Ning, X-H. “Triiodothyronine repletion in infants during cardiopulmonary bypass for congenital heart disease”. J Thorac Cardiovasc Surg. vol. 120. 2000. pp. 604-8.
Mackie, AS, Booth, KL, Newburger, JW. “A randomized, double-blind, placebo-controlled pilot trial of triiodothyronine in neonatal heart surgery”. J Thorac Cardiovasc Surg. vol. 130. 2005. pp. 810-6.
Dimmick, SJ, Badawi, N, Randell, T. “Thyroid hormone supplementation for the prevention of morbidity and mortality in infants undergoing cardiac surgery”. Cochrane Database Syst Rev. 2004. pp. CD004220(Cochrane review of thyroid hormone treatment in infants undergoing cardiac surgery.)
Kaptein, EM. “Thyroid hormone metabolism and thyroid diseases in chronic renal failure”. Endocr Rev. vol. 17. 1996. pp. 45-63.
Ongoing controversies regarding etiology, diagnosis, treatment
The “etiology” of sick-euthyroid syndrome is essentially the pathophysiologic alterations in acute illness that lead to the changes in thyroid function (as summarized above – see “What caused this disease to develop at this time?”).
There is some controversy about whether some of the pathogenetic changes are a cause of sick-euthyroid syndrome or a result of the thyroid function abnormalities which occur with sick-euthyroid syndrome. For example, studies in D1/D2 and D3 knockout mice report that the changes in serum T3 and T4 with induced illness are similar to wild-type animals, suggesting that the changes in the deiodinase enzymes are a consequence, not a cause of the sick-euthyroid syndrome.
There is also some controversy as to whether the cells mirror the low serum thyroid hormone levels. Studies in an animal model of sick-euthyroid syndrome show an increase in tanycyte D2 activity. The tanycyte is a unique glial cell with processes that extend from the portal circulation into the hypothalamus. Increased D2 activity could increase T4 to T3 conversion, resulting in “intracellular hyperthyroidism” in the hypothalamus, thus suppressing TRH and TSH secretion.
There is general agreement about the diagnosis of sick-euthyroid syndrome, confirmed by finding the typical pattern of T3, T4, rT3, and TSH levels. As summarized above, most experts consider the changes in thyroid function in sick-euthyroid syndrome to be an “adaptive response” and therefore do not recommend thyroid hormone treatment. However, in certain situations others believe that these changes are “maladaptive” and might be improved by thyroid hormone treatment.
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- OVERVIEW: What every practitioner needs to know
- Are you sure your patient has sick-euthyroid syndrome? What are the typical findings for this disease?
- What other disease/condition shares some of these symptoms?
- What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
- Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
- If you are able to confirm that the patient has sick-euthyroid syndrome, what treatment should be initiated?
- What are the adverse effects associated with each treatment option?
- What are the possible outcomes of sick-euthyroid syndrome?
- What causes this disease and how frequent is it?
- How do these pathogens/genes/exposures cause the disease?
- Other clinical manifestations that might help with diagnosis and management
- What complications might you expect from the disease or treatment of the disease?
- Are additional laboratory studies available; even some that are not widely available?
- How can this be prevented?
- What is the evidence?
- Ongoing controversies regarding etiology, diagnosis, treatment