Reduced Activation and Increased Inactivation of Thyroid Hormone in Tissues of Critically Ill Patients
Open accessAbstract
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.
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In disease states, particularly hypoxic states, D3 expression can be found ectopically in a wide range of tissues; the resultant increase in T3 clearance promotes tissue-specific and systemic lowering of T3 and has been implicated in the pathogenesis of nonthyroidal illness syndrome.
“In disease states, and particularly in hypoxic states, D3 expression can be found ectopically in a wide range of tissues (26); the resultant increase in T 3 clearance promotes both tissue-specific and systemic lowering of T3 and has been implicated in the pathogenesis of the ''nonthyroidal illness syndrome'' (27).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [26]
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Experimental — accuracy not yet measuredLiver DIO3 is differentially regulated during illness: acute inflammation in mice results in decreased DIO3 levels but prolonged critical illness, both in patients and in rabbits, increases DIO3.
“Liver DIO3 is differentially regulated during illness: acute inflammation in mice results in decreased DIO3 levels [15] but prolonged critical illness, both in patients and in rabbits, increases DIO3 [21, 22].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [22]
The Abstract and Discussion (pages unavailable) report induced liver D3 in critically ill patients, supporting the patient portion of the claim. The paper does not establish that the increase is specific to prolonged illness; the Discussion says the observed differences could not be explained by illness duration. It provides no rabbit evidence for the portion attributed jointly to [21, 22]. (LLM, conf=0.85)
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Self-citationInduction of Type 1 Iodothyronine Deiodinase to Prevent the Nonthyroidal Illness Syndrome in Mice
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Self-citationTissue thyroid hormone metabolism is differentially regulated during illness in mice
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Thyroid Hormone Transport into Cellular Tissue
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Self-citationNon-thyroidal Illness Syndrome (Euthyroid Sick Syndrome)
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- Authors
- Peeters, R. P., Wouters, P. J., Kaptein, E., van Toor, H., Visser, T. J., & Van den Berghe, G.
- Affiliations
- Erasmus MC (NL)
- KU Leuven (BE)
- ORCID
- Peeters, Robin P.
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2003-07
- Volume
- 88
- Issue
- 7
- Pages
- 3202-3211
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2165821124
- Cited by
- 452
- References
- 33
- Citations by year
- 2026: 11 · 2025: 22 · 2024: 12 · 2023: 15 · 2022: 21 · 2021: 29 · 2020: 19 · 2019: 21 · 2018: 23 · 2017: 18 · 2016: 18 · 2015: 19 · 2014: 21 · 2013: 24 · 2012: 19
- FWCI
- 10.78
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- critical illness, thyroid hormone metabolism, reverse T3, iodothyronine deiodinase, type I deiodinase, type 3 deiodinase, type 2 deiodinase, thyroid-stimulating hormone, liver, skeletal muscle, critically ill patients, acute kidney injury, sepsis, brain damage, cardiovascular collapse, insulin therapy, urea
- MeSH terms
- Aged, Aged, 80 and over, Biopsy, Humans, Hyperglycemia, Hypoglycemic Agents, Insulin, Liver, Middle Aged, Regression Analysis, Thyroid Hormones, Thyrotropin, Thyroxine, Triiodothyronine, Critical Illness, Muscle, Skeletal
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