Mirna Bastos Marques

Endocrine, Metabolic, and Morphologic Alterations of Adipose Tissue During Critical Illness*

Objective:Observational studies report lower mortality in obese than in lean critically ill patients, an association referred to as the “obesity paradox.” This may suggest a possible protective role for adipose tissue during severe illness. Data Sources:Relevant publications were identified based on searches in PubMed and on secondary searches of their bibliographies. Data Synthesis:The endocrine functions of adipose tissue might play a role in the adaptation to critical illness. In the acute phase of illness, the anti-inflammatory adiponectin is reduced, whereas proinflammatory cytokine expression in adipose tissue is up-regulated. In the prolonged phase of critical illness, both adiponectin and anti-inflammatory cytokine production are increasing. Studies on the proinflammatory adipokine leptin during critical illness are inconsistent, possibly due to confounders such as gender, body mass index, and feeding. Morphologically, adipose tissue of critically ill patients reveals an increased number of newly differentiated, smaller adipocytes. Accentuated macrophage accumulation showing a phenotypic switch to M2-type suggests an adaptive response to the microenvironment of severe illness. Functionally, adipose tissue of critically ill patients develops an increased ability to store glucose and triglycerides. Conclusions:Endocrine, metabolic, and morphologic properties of adipose tissue change during critical illness. These alterations may suggest a possible adaptive, protective role in optimizing chances of survival. More research is needed to understand the exact role of adipose tissue in lean vs. obese critically ill patients, in order to understand how illness-associated alterations contribute to the obesity paradox.

Impact of Early Nutrient Restriction During Critical Illness on the Nonthyroidal Illness Syndrome and Its Relation With Outcome: A Randomized, Controlled Clinical Study

CONTEXT Both critical illness and fasting induce low circulating thyroid hormone levels in the absence of a rise in TSH, a constellation-labeled nonthyroidal illness syndrome (NTI). The contribution of restricted nutrition during critical illness in the pathophysiology of NTI remains unclear. OBJECTIVE The objective of the study was to investigate the impact of nutrient restriction early during critical illness on the NTI, in relation to outcome. DESIGN AND PATIENTS A preplanned subanalysis in a group of intensive care unit (ICU) patients admitted after complicated surgery and for whom enteral nutrition was contraindicated (n = 280) of a randomized controlled trial, which compared tolerating pronounced nutritional deficit for 1 week in the ICU [late parenteral nutrition (PN)] with early initiation of parenteral nutrition (early PN). MEASUREMENTS Circulating TSH, total T4, T3, rT3, and leptin levels were quantified upon admission and on ICU day 3 or the last day when patients were discharged earlier. After correction for baseline risk factors, the role of these changes from baseline in explaining the outcome benefit of late PN was assessed with the multivariable Cox proportional hazard analysis. RESULTS Late PN reduced complications and accelerated recovery. Circulating levels of TSH, total T4, T3, the T3 to rT3 ratio, and leptin levels were all further reduced by late PN. The further lowering of T4 appeared to reduce the outcome benefit of late PN, whereas the further reduction of T3 to rT3 ratio appeared to statistically explain part of the outcome benefit. CONCLUSIONS Tolerating nutrient restriction early during critical illness, shown to accelerate recovery, further aggravated the NTI. The statistical analyses suggested that the more pronounced peripheral inactivation of the thyroid hormone with nutrient restriction during critical illness could be a beneficial adaptation, whereas the lowering of T4 could be deleterious.

Critical illness induces nutrient-independent adipogenesis and accumulation of alternatively activated tissue macrophages

IntroductionWe previously reported that in artificially-fed critically ill patients, adipose tissue reveals an increase in small adipocytes and accumulation of M2-macrophages. We hypothesized that nutrient-independent factors of critical illness explain these findings, and that the M2-macrophage accumulation may not be limited to adipose tissue.MethodsIn a long-term cecal ligation and puncture (CLP) mouse model of sepsis, we compared the effect of parenteral nutrition (CLP-fed, n = 13) with nutrient restriction (CLP-restricted, n = 11) on body composition, adipocyte size and macrophage accumulation in adipose tissue, liver and lungs. Fed healthy mice (n = 11) were studied as controls. In a human study, in vivo adipose tissue biopsies were studied from ICU patients (n = 40) enrolled in a randomized control trial which compared early initiation of parenteral nutrition (PN) versus tolerating nutrient restriction during the first week of ICU stay. Adipose tissue morphology was compared with healthy human controls (n = 13).ResultsIrrespective of nutritional intake, critically ill mice lost weight, fat and fat-free mass. Adipocyte number, proliferation marker Proliferating Cell Nuclear Antigen (PCNA) and adipogenic markers PPARγ and CCAAT/enhancer binding protein-β (C/EBPβ) increased with illness, irrespective of nutritional intake. M2-macrophage accumulation was observed in adipose tissue, liver and lungs of critically ill mice. Macrophage M2-markers correlated with CCL2 expression. In adipose tissue biopsies of critically ill patients, increased adipogenic markers and M2 macrophage accumulation were present irrespective of nutritional intake.ConclusionsAdipogenesis and accumulation of tissue M2-macrophages are hallmarks of prolonged critical illness, irrespective of nutritional management. During critical illness, M2-macrophages accumulate not only in adipose tissue, but also in the liver and lungs.