Peeters Robin P, Wouters Pieter J, Kaptein Ellen, van Toor Hans, Visser Theo J, Van den Berghe Greet
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE Rotterdam, The Netherlands.
J Clin Endocrinol Metab. 2003 Jul;88(7):3202-11. doi: 10.1210/jc.2002-022013.
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.
危重病常伴有促甲状腺激素（TSH）和甲状腺激素分泌减少以及外周甲状腺激素代谢的显著变化，导致血清三碘甲状腺原氨酸（T3）水平降低和反三碘甲状腺原氨酸（rT3）水平升高。为研究后者变化的机制，我们测定了已故重症监护患者肝脏和骨骼肌中血清甲状腺激素水平以及1型、2型和3型碘甲状腺原氨酸脱碘酶（D1、D2和D3）的表达。为研究这些变化的潜在机制，在80例接受强化或常规胰岛素治疗的重症监护病房患者死亡后数分钟内，获取了65份血液样本、65份肝脏组织和66份骨骼肌活检样本。测定了血清甲状腺参数和组织D1 - D3的表达。与正常受试者相比，血清TSH、T4、T3以及T3/rT3比值较低，而血清rT3较高（P < 0.0001）。肝脏D1活性下调，肝脏和骨骼肌中D3活性被诱导。血清T3/rT3比值与肝脏D1活性呈正相关（P < 0.001），与肝脏D3活性呈负相关（无统计学意义）。这些参数与胰岛素治疗类型无关。死于严重脑损伤的患者肝脏D1和血清T3/rT3最高，死于脓毒症或过度炎症的患者次之，死于心血管衰竭的患者最低（P < 0.01）。肝脏D3呈现相反的关系。需要透析的急性肾衰竭以及需要使用血管活性药物与肝脏D1活性低（P < 0.01和P = 0.06）以及肝脏D3（P < 0.01）和骨骼肌D3（P < 0.05）活性高有关。肝脏D1活性与血浆尿素（P = 0.002）、肌酐（P = 0.06）和胆红素（P < 0.0001）呈负相关。D1和D3 mRNA水平与酶活性相符（均P < 0.001），提示两种脱碘酶的表达在翻译前水平受到调控。这是第一项在一大群危重病患者中将组织脱碘酶活性与血清甲状腺激素水平及临床参数相关联的研究。肝脏D1下调，D3（健康个体肝脏和骨骼肌中不存在）被诱导，特别是在与组织灌注不良相关的疾病状态下。这些观察到的变化，与低T3/rT3比值相关，可能代表细胞缺氧期间降低甲状腺激素生物活性的组织特异性方式，并导致重症患者的低T3综合征。
