Patterns of Euthyroid Sick Syndrome
Various patterns of thyroid hormone and TSH concentrations have been reported in euthyroid sick syndrome, reflecting the type and severity of illness.3 Chopra et al.7 have divided these patterns into following four major types:
1. Low T3 Syndrome
This is the most common abnormality, observed in about 70% of the hospitalized patients. Serum concentration of total triiodothyronine (T3) falls rapidly and progressively within 30 min to 24 hours of the onset of the causative illness. The degree of fall reflects the severity of disease process.8 Levels vary from undetectable to normal, and the mean value is approximately 40% of the normal level. Whenever measured, the concentration of serum free T3 (fT3) is low normal or slightly decreased.9 The daily production of T3 is decreased, while its clearance remains unchanged. The decreased conversion of thyroxine (T4) to T3 results from the inhibition of enzyme 1,5'-monodeiodinase (5'-MDI) activity, which catalyzes the deiodination of T4 to T3.10 Serum total T4 and free T4 (fT4) are normal in patients with low T3 syndrome.11
Generally serum TSH concentration and its response to thyrotropin releasing hormone (TRH) are normal. However TSH level may increase slightly, but returning to normal with recovery.12 The serum concentration of reverse T3 (rT3) is increased except in renal failure13 and traumatic brain injury.14 Daily production rate of rT3 is normal. The increase in the serum rT3 level is mainly due to its reduced metabolic clearance.15
2. Low T3 and T4 syndrome
The low T3 and T4 syndrome is observed in severely ill, moribund patients admitted to medical intensive care units. About 30-50% of patients have subnormal levels of T3 and T4. The T4 concentration falls over a period of 24-48 hours. However the fT4 values are frequently within normal limits. This disparity between low T4 values and normal fT4 levels is partly due to decreased T4 binding. Kinetic studies have shown reduced hepatic uptake and clearance of T4. The fall in circulating thyroid hormone concentration coupled with reduced clearance implies substantially low thyroidal production rates.16
Serum TSH concentration is frequently low, as measured with sensitive TSH assays and TRH responses are blunted.17 This blunted response is probably due to decrease in the enzyme activity responsible for TRH degradation, leading to impairment of TRH metabolism. TSH level rises with recovery, and may be transiently elevated until T3 and T4 levels are restored to normal.18 The rT3 synthesis diminishes due to the decreased availability of its precursor T4, but because of slow degradation rT3 concentrations are frequently increased.15
Several factors may contribute to low T3 and T4 levels. These include: (1) reduced binding proteins, e.g., thyroxine binding globulin (TBG), albumin and prealbumin especially in chronic liver disease19 and in renal dialysis20, (2) abnormal TBG due to altered sialylation21, (3) circulating competitive binding inhibitors of T4 to serum protein, including drugs22 (furosemide in high doses23), non-esterified fatty acids (NEFA) and metabolic products24 and (4) decreased serum TSH, especially in patients treated with dopamine.25
3. High T4 syndrome
This is an unusual variant of euthyroid sick syndrome, seen in approximately 1% of sick patients. High serum T4 level is seen in some systemic illnesses-notably acute intermittent porphyria26, liver diseases such as chronic active hepatitis and primary biliary cirrhosis27, acute psychiatric illness28, and patients on certain drugs such as amiodarone29, and radiocontrast agents like ipodate and iopanoic acid used for oral cholecystography.30 The serum concentration of fT4 remains normal. The high serum T4 level is usually the result of increased serum TBG. Serum T3 may be normal or increased, but fT3 concentration is typically decreased. The serum concentration of rT3 is also increased in such patients, a finding related to both a high TBG concentration and a decreased metabolism of rT3. The serum TSH is usually very low or undetectable, and TRH response is blunted to absent.16
4. Other abnormalities
Studies have shown that there is decreased nocturnal TSH surge, unrelated to ambient circulating T4 and T3 levels, but probably related to hypothalamic dysregulation.31 In addition, evidence suggests that TSH has reduced biological activity in euthyroid sick patients due to some structural abnormality.32 Euthyroid sick syndrome is also associated with low serum total protein. Low albumin33 and high sympathetic response like high cortisol and nor-epinephrine levels are also commonly seen in acutely ill patients.34
|Table. Conditions associated with Euthyroid Sick Syndrome. |
|1.. Medical |
Acute myocardial infarction.68
Acute renal failure.13
Alcoholic liver disease. 70
Lymphomas, leukemia and during their chemotherapy. 71
Obstructive chronic bronchopneumopathy with acute respiratory failure. 73
Acute cerebral vasculopathies.73
Chronic heart failure .75 2. Surgical
Acute and chronic spinal cord injury.76
After elective cholecystectomy. 78
During and after cardiopulmonary bypass.67 3. Infections
Viral hepatitis type A. 79
Advanced stages of HIV. 80
Patients receiving antituberculosis treatment.69
Premature and sick infants. 81
Bone marrow transplantation.82
Progressive systemic sclerosis. 83
Malignant Mediterranean spotted fever.73
Acute psychiatric illness.28
Acute intermittent porphyria.26 5. Drugs
a) Inhibitors of T4 to T3 conversion
Propranolol in high doses.19
Radiographic contrast agents.30
b) Augmentation of clearance of T4 (enzyme induction)
c) Inhibitors of TSH secretion
Somatostatin.22 d) Inhibitors of thyroid hormone synthesis or release
Lithium.22 e) Inhibitors of binding of T4/T3 to serum proteins
Nonsteroidal anti-inflammatory agents.22
Furosemide.23 f) Increasing concentration of T4 binding proteins22
Perphenazine. g) Stimulators of TSH secretion22
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