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Muscle mass vs. adipose tissue to predict outcome in cirrhosis: Which matters and in which patients?

2018; Elsevier BV; Volume: 69; Issue: 3 Linguagem: Inglês

10.1016/j.jhep.2018.06.005

1600-0641

Manuela Merli, François Durand,

Liver Disease and Transplantation

Low subcutaneous adiposity associates with higher mortality in female patients with cirrhosisJournal of HepatologyVol. 69Issue 3PreviewDifferences in body composition between the sexes exist in healthy subjects,1,2 and populations with cancer3 and cirrhosis,4–6 with females having higher adipose tissue mass (adiposity) and males having greater muscularity. Body composition of people with cirrhosis has been assessed using approaches such as air displacement plethysmography, bioelectrical impedance analysis, and dual-energy X-ray absorptiometry.4,7 However, the ability of these techniques to differentiate between two major body compartments, muscle and adipose tissue, as well as their capability to provide a specific measure of adipose tissue depots (i.e. Full-Text PDF Body composition is definitely different in men and women. For a similar body mass index, women have a higher proportion of adipose tissue and men have a higher proportion of lean (muscle) mass. Major changes in body composition can be observed in patients with advanced cirrhosis: the depletion of adipose tissue is more frequent in females while muscle loss is more characteristic of males.1Nutritional status in cirrhosis. Italian multicentre cooperative project on nutrition in liver cirrhosis.J Hepatol. 1994; 21: 317-325Abstract Full Text PDF PubMed Scopus (262) Google Scholar, 2Alberino F. Gatta A. Amodio P. Merkel C. Di Pascoli L. Boffo G. et al.Nutrition and survival in patients with liver cirrhosis.Nutrition. 2001; 17: 445-450Crossref PubMed Scopus (416) Google Scholar The causes of the dissimilarity in terms of distribution of adipose tissue and lean mass between men and women are likely to depend upon differences in fatty acid storage, mobilization and oxidation.[3]Blaak E. Gender differences in fat metabolism.Curr Opin Clin Nutr Metab Care. 2001; 4: 499-502Crossref PubMed Scopus (430) Google Scholar Differences in hormone profiles, play a major role in body fat distribution although the exact mechanisms have not been not completely elucidated. Estrogens have been found to improve insulin sensitivity while too low or excess androgens have been linked to insulin resistance in some conditions. Energy expenditure and substrate oxidation are also potentially involved.[4]Geer E.B. Shen W. Gender differences in insulin resistance, body composition, and energy balance.Gend Med. 2009; 6: 60-75Abstract Full Text PDF PubMed Scopus (561) Google Scholar The anatomical site of fat deposits is another well-known difference between men and women. In women adipose tissue is more frequently located in the gluteal-femoral region (gynoid obesity) while men more often have increased body fat in the abdomen (android obesity). As a consequence, fat accumulation mainly translates into increased subcutaneous adipose tissue (SAT) in women and in increased visceral adipose tissue (VAT) in men. Adipose tissue has been mainly considered as a means of energy storage but in recent years this view has been largely modified due to the recognition that adipose tissue is able to release proteins, hormones, cytokines and growth factors.[5]Kershaw E.E. Flier J.S. Adipose tissue as an endocrine organ.J Clin Endocrinol Metab. 2004; 89: 2548-2556Crossref PubMed Scopus (3678) Google Scholar These substances, also known as adipokines, may act with an autocrine mechanism regulating lipid accumulation and adipocyte differentiation. Furthermore, adipokines may modulate insulin action and secretion, control food intake and energy metabolism. Adipokines have been involved as pro-inflammatory (leptin) or anti-inflammatory (adiponectin) mediators/agents and have raised recent interest for their possible involvement in liver fibrogenesis in non-alcoholic steatohepatitis (NASH).[6]Buechler C. Haberl E.M. Rein-Fischboeck L. Aslanidis C. Adipokines in liver cirrhosis.Int J Mol Sci. 2017; 18Crossref Scopus (53) Google Scholar Differences in metabolic changes associated with VAT and SAT are well known. The deleterious effects of obesity, including NASH, are strongly correlated to VAT. VAT compared with SAT is more cellular, with a greater percentage of large adipocytes, metabolically active, more sensitive to lipolysis and more insulin‐resistant. VAT is more vascularized and innervated and contains a larger number of inflammatory and immune cells. Glucocorticoid and androgen receptors are higher in VAT than in SAT. Lipolysis from VAT generates free fatty acids delivered directly to the liver. SAT is more avid in absorption of circulating free fatty acids and triglycerides.[7]Ibrahim M.M. Subcutaneous and visceral adipose tissue: structural and functional differences.Obes Rev. 2010; 11: 11-18Crossref PubMed Scopus (1178) Google Scholar From a pathophysiology viewpoint, it is therefore important to differentiate these two components, which has become possible by the analysis of cross-sectional CT scan images.[8]Shen W. Punyanitya M. Wang Z. Gallagher D. St-Onge M.P. Albu J. et al.Visceral adipose tissue: relations between single-slice areas and total volume.Am J Clin Nutr. 2004; 80: 271-278Crossref PubMed Scopus (258) Google Scholar As CT scan images are also utilized in cirrhotic patients for the assessment of sarcopenia, considering VAT and SAT to assess their prognostic role is an interesting target. Even though it has been widely adopted, the model for end-stage liver disease (MELD) score has limitations inherent to the fact that only three objective variables are taken into account. In many aspects, the MELD score may be an oversimplification to assess the prognosis of cirrhosis, a condition which is highly heterogeneous. There is increasing evidence that the MELD score underestimates disease severity in a number of situations such as refractory ascites.9Durand F. Buyse S. Francoz C. Laouenan C. Bruno O. Belghiti J. et al.Prognostic value of muscle atrophy in cirrhosis using psoas muscle thickness on computed tomography.J Hepatol. 2014; 60: 1151-1157Abstract Full Text Full Text PDF PubMed Scopus (255) Google Scholar, 10Heuman D.M. Abou-Assi S.G. Habib A. Williams L.M. Stravitz R.T. Sanyal A.J. et al.Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.Hepatology. 2004; 40: 802-810Crossref PubMed Scopus (436) Google Scholar The superiority of the MELD-Na score over the MELD score in patients with refractory ascites has not been clearly demonstrated. Similarly, the MELD score disadvantages women who, due to a lower muscle mass compared to men, have lower serum creatinine for a similar glomerular filtration rate. Additional prognostic variables are needed to improve the MELD score in a substantial proportion of patients who are misclassified and to better take into account gender disparities. In recent years, a growing number of studies have shown that decreased muscle mass is associated with a worse outcome in patients with cirrhosis, independent of the MELD score. According to different populations with different endpoints, patients with cirrhosis and sarcopenia may be exposed to higher waiting list mortality, higher risk of post-transplant morbidity (sepsis in particular) and, in some series but not all, higher post-transplant mortality. Muscle mass has been estimated according to different methods, total muscle area on cross-sectional CT scan at the L3 level normalized for square height (cm2/m2) being the most widely used.11Montano-Loza A.J. Meza-Junco J. Prado C.M. Lieffers J.R. Baracos V.E. Bain V.G. et al.Muscle wasting is associated with mortality in patients with cirrhosis.Clin Gastroenterol Hepatol. 2012; 10 (173 e161): 166-173Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar, 12van Vugt J.L. Levolger S. de Bruin R.W. van Rosmalen J. Metselaar H.J. IJzermans J.N. Systematic review and meta-analysis of the impact of computed tomography-assessed skeletal muscle mass on outcome in patients awaiting or undergoing liver transplantation.Am J Transplant. 2016; 16: 2277-2292Crossref PubMed Scopus (214) Google Scholar However, it must be noted that the prognostic value of muscle mass has been evaluated in populations of patients where males were largely predominant, without distinction between gender apart from different cut-off values to define sarcopenia. In some series where males and females were analyzed separately, it appeared that sarcopenia was predictive of mortality in males, but not in females (Table 1).Table 1Studies exploring the impact of muscle mass and/or adipose tissue on outcomes in patients with cirrhosis where data concerning men and women are presented separately.AuthorYearPatientsEndpointVariableCut off values to predict the endpoint and p valuesMalesFemalesCut-offp valueCut-offp valueMontano-Loza AJ[11]Montano-Loza A.J. Meza-Junco J. Prado C.M. Lieffers J.R. Baracos V.E. Bain V.G. et al.Muscle wasting is associated with mortality in patients with cirrhosis.Clin Gastroenterol Hepatol. 2012; 10 (173 e161): 166-173Abstract Full Text Full Text PDF PubMed Scopus (562) Google Scholar2012112Mortality (including waiting list mortality)SMI<52.4 cm2/m2p = 0.009<38.5 cm2/m2n.s.DiMartini A[17]DiMartini A. Cruz Jr., R.J. Dew M.A. Myaskovsky L. Goodpaster B. Fox K. et al.Muscle mass predicts outcomes following liver transplantation.Liver Transpl. 2013; 19: 1172-1180Crossref PubMed Scopus (149) Google Scholar2013338Post-transplant outcomes*SMI<52.4 cm2/m2p <0.05<38.5 cm2/m2n.s.Montano-Loza AJ[18]Montano-Loza A.J. Severe muscle depletion predicts postoperative length of stay but is not associated with survival after liver transplantation.Liver Transpl. 2014; 20: 1424Crossref PubMed Scopus (35) Google Scholar2014248Post-transplant mortalitySMI≤53 cm2/m2n.s.≤41 cm2/m2n.s.Carey EJ[19]Carey E.J. Lai J.C. Wang C.W. Dasarathy S. Lobach I. Montano-Loza A.J. et al.A multicenter study to define sarcopenia in patients with end-stage liver disease.Liver Transpl. 2017; 23: 625-633Crossref PubMed Scopus (262) Google Scholar2017396Waiting list mortalitySMI≤50 cm2/m2p = 0.03≤39 cm2/m2p = 0.001Ebabi M[13]Ebadi M. Tandon P. Moctezuma-Velazquez C. Ghosh S. Baracos V.E. Mazurak V.C. et al.Low subcutaneous adiposity associates with higher mortality in female patients with cirrhosis.J Hepatol. 2018; 69: 608-616Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar201867Mortality (including waiting list mortality)SMI<50 cm2/m2p = 0.02<39 cm2/m2n.s.SATI–n.s.<60 cm2/m2p <0.001SMI (cross-sectional surface area of muscles measured by CT scan at L3 level adjusted for height squared); *post-transplant outcomes include length of intensive care unit stay, total hospitalization in days and number of days on mechanical ventilation; SATI (cross-sectional area of subcutaneous adipose tissue at L3 level measured by CT scan and adjusted for height squared). SATI, subcutaneous adipose tissue index; SMI, skeletal muscle index. Open table in a new tab SMI (cross-sectional surface area of muscles measured by CT scan at L3 level adjusted for height squared); *post-transplant outcomes include length of intensive care unit stay, total hospitalization in days and number of days on mechanical ventilation; SATI (cross-sectional area of subcutaneous adipose tissue at L3 level measured by CT scan and adjusted for height squared). SATI, subcutaneous adipose tissue index; SMI, skeletal muscle index. In this issue of the Journal of Hepatology, Ebadi M and colleagues[13]Ebadi M. Tandon P. Moctezuma-Velazquez C. Ghosh S. Baracos V.E. Mazurak V.C. et al.Low subcutaneous adiposity associates with higher mortality in female patients with cirrhosis.J Hepatol. 2018; 69: 608-616Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar report data from 677 patients (67% males) with cirrhosis assessed for liver transplantation with measurements of muscle mass and adipose tissue at evaluation on CT scan. Using competing risk analysis, they confirmed that skeletal muscle index (SMI, cm2/m2) was predictive of mortality in males, independent of the MELD score. SMI was predictive of mortality in the subgroup of male patients with refractory ascites. However, SMI was not associated with mortality in female patients. By contrast, subcutaneous adipose tissue index (SATI, cm2/m2) was an independent predictor of mortality in female patients (including those with refractory ascites) but not in males. In female patients, a score combining MELD and SATI performed better than the MELD score alone to predict early (three-month) mortality. Finally, VAT had no prognostic value in males, nor females. This study nicely highlights that the reality behind malnutrition and sarcopenia in cirrhosis is more complex than expected. Reduced muscle mass should be definitely interpreted differently in male and female patients with cirrhosis. These results also illustrate the fact that changes in body composition in end-stage liver diseases are different in men and women as previously suggested.1Nutritional status in cirrhosis. Italian multicentre cooperative project on nutrition in liver cirrhosis.J Hepatol. 1994; 21: 317-325Abstract Full Text PDF PubMed Scopus (262) Google Scholar, 2Alberino F. Gatta A. Amodio P. Merkel C. Di Pascoli L. Boffo G. et al.Nutrition and survival in patients with liver cirrhosis.Nutrition. 2001; 17: 445-450Crossref PubMed Scopus (416) Google Scholar This study, however, has some limitations that hamper generalization. Indeed, mean MELD score was relatively low and it remains difficult to draw conclusions concerning the sickest patients. A substantial proportion of evaluated patients were not listed for transplantation (32%) which may represent a bias. Among those who were eventually listed, despite a low MELD score, waiting list mortality was higher than the average mortality rate reported in the US and European registries.14Agence de la Biomédecine. Available at: www.agence-biomedecine.fr. Accessed April 27 2018.Google Scholar, 15UNOS. Available at: www.unos.org. Accessed May 8 2018.Google Scholar Efforts have been made by several groups to identify single cut-off values that would universally define sarcopenia in patients with cirrhosis. This approach where sarcopenia is considered as "present" or "absent" may be too restrictive. Indeed, sarcopenia may rather represent a continuum and combining muscle mass as a continuous variable to other prognostic variables (those incorporated in the MELD score for instance) may provide more granular prognostic information. At least, sarcopenia should be interpreted according to a semi-quantitative scale with different levels corresponding to increasing severity, such as the t-score in the assessment of osteoporosis.[16]Cummings S.R. Bates D. Black D.M. Clinical use of bone densitometry: scientific review.JAMA. 2002; 288: 1889-1897Crossref PubMed Scopus (649) Google Scholar The issue of quantitative vs. qualitative measurement may also apply to adipose tissue in women. To what extent the addition of SMI and SATI to the MELD score in males and females, respectively, will improve prognostication in specific populations such as patients with refractory ascites should be further explored, taking into account gender differences. Practical implications on organ allocation and waiting list mortality, for instance, need further validation and/or statistical models based on large cohorts. Diabetes is associated with a worse prognosis in cirrhosis. Since subcutaneous fat is protective against insulin resistance, possible interactions between decreased subcutaneous fat and diabetes should also be explored in women. Overall, accumulation of VAT is one of the drivers of insulin resistance and NASH. However, this study by Ebadi M. and colleagues suggests that VAT has no effect on outcome in either men or women with advanced cirrhosis. This study also confirms that sarcopenia is not predictive of mortality in women. By contrast, SATI may be a new prognostic tool to better predict outcomes in female patients with cirrhosis. The authors received no financial support to produce this manuscript. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.09 MB) Help with pdf files Supplementary data