Reduced Activation and Increased Inactivation of Thyroid Hormone in Tissues of Critically Ill Patients

Abstract

Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T(3) and high rT(3) levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment. Serum thyroid parameters and the expression of tissue D1-D3 were determined. Serum TSH, T(4), T(3), and the T(3)/rT(3) ratio were lower, whereas serum rT(3) was higher than in normal subjects (P < 0.0001). Liver D1 activity was down-regulated and D3 activity was induced in liver and skeletal muscle. Serum T(3)/rT(3) ratio correlated positively with liver D1 activity (P < 0.001) and negatively with liver D3 activity (ns). These parameters were independent of the type of insulin treatment. Liver D1 and serum T(3)/rT(3) were highest in patients who died from severe brain damage, intermediate in those who died from sepsis or excessive inflammation, and lowest in patients who died from cardiovascular collapse (P < 0.01). Liver D3 showed an opposite relationship. Acute renal failure requiring dialysis and need of inotropes were associated with low liver D1 activity (P < 0.01 and P = 0.06) and high liver D3 (P < 0.01) and skeletal muscle D3 (P < 0.05) activity. Liver D1 activity was negatively correlated with plasma urea (P = 0.002), creatinine (P = 0.06), and bilirubin (P < 0.0001). D1 and D3 mRNA levels corresponded with enzyme activities (both P < 0.001), suggesting regulation of the expression of both deiodinases at the pretranslational level. This is the first study relating tissue deiodinase activities with serum thyroid hormone levels and clinical parameters in a large group of critically ill patients. Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion. These observed changes, in correlation with a low T(3)/rT(3) ratio, may represent tissue-specific ways to reduce thyroid hormone bioactivity during cellular hypoxia and contribute to the low T(3) syndrome of severe illness.

Thyroid abnormalities in term infants with fungal sepsis

“…[4][5][6][7][8] NTIS has been used as an interesting parameter of severity, since it has been verified that more severe patients have more prolonged alterations and a later recovery, and that the prognosis in adults is poor, and may even lead to death. [9][10][11][12] However, there are still no reports of there being a worse prognosis in infants, let alone those presenting fungal sepsis.…”

“…All of these hormones decrease within 24 hours, remaining at higher levels than those of the cord blood for 2 to 3 days. [4][5][6][7][8][9] In the same manner as the thyroid hormones, there is a rapid increase in cortisol in term infants at birth, which can reach 20 μg/dL. This hormone stimulates the increase in serum T3, which is essential for activation of type 1 deiodinase (D1) enzyme between 4 and 6 hours after birth, and very low levels of reverse T3.…”

“…[19][20][21][22][23][24][25][26][27][28] Currently, four stages of NTIS are recognized in adults and children, known as low T3 syndrome, low T3-T4 syndrome, high T4 syndrome, and mixed syndromes. [4][5][6][7][8][9][10][20][21][22][23][24][25][26][27][28] Low T3 syndrome This is characterized by low serum levels of T3, normal or slightly increased TSH, and normal free T4 and T4. The level of reverse T3 may be normal or increased.…”

“…This change is due to inhibition of the activity of the D1 enzyme, which is responsible for both peripheral degradation of T4 to T3 as well as lower clearance of reverse T3. [6][7][8][9][10][11][12] The decline in T3 levels appears to occur a few hours after the onset of sepsis. 6,10,[23][24][25][26][27][28] Recovery occurs in parallel with the improvement of the underlying disease.…”

“…It is currently believed that a mechanism occurs in this type of NTIS related to the effects of cytokines in the hypothalamic-pituitary axis, associated with reduced peripheral T4 action. [4][5][6][7][8][9][10][11][12][19][20][21][22][23][24][25][26][27][28] The response of TSH to thyrotropin-releasing hormone (TRH) seems to be reduced in patients in critical clinical condition. There is evidence that in certain periods of severe disease there may be genuine central and transient hypothyroidism, in which there is not a nighttime peak in TSH, as well as evidence of changes in the glycosylation process regulated by TRH.…”