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Friday, January 27, 2012

Muscle and Mortality in Cirrhosis


Uploaded by on Jan 19, 2012
Dr. Aldo J. Montano-Loza discusses his manuscript "Muscle Wasting Is Associated With Mortality in Patients With Cirrhosis" 


Muscle and Mortality in Cirrhosis

 
Clinical Gastroenterology and Hepatology
Volume 10, Issue 2 , Pages 100-102, February 2012

Virginia Commonwealth University, Hunter Holmes McGuire Department of Veterans Affairs Medical Center, Richmond, Virginia
published online 11 November 2011.

Skeletal muscle wasting, accompanied by weakness and poor functional capacity, is a frequent finding in advanced liver disease. Many factors contribute to cachexia in cirrhosis. Loss of appetite is common and might be related to metabolic and hormonal alterations, medications, hepatic encephalopathy, or inflammatory cytokines. Poor diet is frequent in cirrhotic patients with active alcoholism and substance abuse and might be aggravated by poverty, poor social support, and iatrogenic restrictions. Postprandial discomfort associated with tense ascites might limit oral intake. Impaired gut motility with small intestinal bacterial overgrowth might contribute to altered digestion and nutrient malabsorption. Cirrhosis is a hypermetabolic state, increasing demand for calories and protein. The cirrhotic liver has reduced gluconeogenic capacity, and relatively short periods of fasting in cirrhotic patients lead to muscle breakdown with mobilization of skeletal muscle amino acids (Figure 1).


The prognostic significance of cachexia in chronic liver disease has been recognized for at least half a century. Malnutrition was a component of the original Child–Turcotte prognostic classification of cirrhosis severity.1, 2 An anthropometric study by Alberino et al3 identified low muscle mass (defined by mid-arm muscle circumference) as an independent predictor of survival in hospitalized cirrhotic patients. Gunsar et al4 found that malnutrition as measured by a variety of parameters predicted survival independently of Model for End-Stage Liver Disease (MELD) score in cirrhotic patients awaiting liver transplantation. In Japan, a prognostic index incorporating nutritional indexes (CONUT) has been proposed to assign priority for organ allocation in liver transplantation.5 Malnutrition also increases mortality after surgery in cirrhotic patients6 and predicts length of intensive care unit and hospital stay after liver transplantation.7 Despite these consistent findings, the general incorporation of cachexia into cirrhosis prognostic models has been limited by lack of a reliable, objective, generally accepted method to quantify muscle wasting.

The term sarcopenia has been proposed to describe objectively a condition of progressive and generalized loss of skeletal muscle mass and strength.8 Sarcopenia is not synonymous with cachexia, reduced functional capacity, or malnutrition, although there is considerable overlap among these conditions.9 Much of the literature on sarcopenia has focused on age-related decline in muscle mass leading to progressive frailty in elderly populations. Clinical trials examining sarcopenia in elderly people have used a variety of different measures to estimate muscle mass, including anthropometrics, tests of strength and endurance, measures of body composition, and imaging. A particular difficulty is determining for each technique what constitutes the normal range, because muscle mass in health is influenced strongly by gender, race, body habitus, and other variables. Definitions and diagnostic criteria for sarcopenia remain in flux. A recent European Society for Clinical Nutrition and Metabolism consensus statement concluded that imaging with computed tomography (CT) and magnetic resonance imaging should be the gold standards for determining muscle mass in clinical trials, with abnormally low muscle mass being defined as 2 standard deviations below the mean reference values for young adults.8 To date there has been limited application of these principles to areas outside of geriatrics.

In this issue of Clinical Gastroenterology and Hepatology, Montano–Loza et al10 report on the use of a novel CT-based method to diagnose sarcopenia and assess its prognostic significance in 112 consecutive cirrhotic patients undergoing initial listing for liver transplantation. Their technique for quantifying sarcopenia used abdominal CT images, which were obtained routinely as part of the transplant pre-evaluation. An axial image, selected consistently at the level of the L3 vertebra, was analyzed, and the cross-sectional area of skeletal muscle on this section was determined by an automated computer algorithm based on tissue radiodensity. This measurement has been shown in previous studies11 to correlate with total body fat free mass, and norms for healthy men and women have been established. The authors found in this study that sarcopenia was present in 50% of cirrhotic men and 18% of cirrhotic women at time of listing for transplantation. Sarcopenia did not correlate with severity of liver dysfunction as measured by the MELD score. During follow-up, 46% of their patients died before transplantation. Sarcopenic patients, compared with those with normal muscle mass, had significantly poorer 6-month transplant-free survival (71% vs 90%, respectively; P < .005). The most common cause of death was liver failure (49%) or sepsis (25%). Sarcopenia was strongly associated with death from sepsis. In multivariable analysis, sarcopenia (as a dichotomous variable) and MELD were found to be independent predictors of pretransplant mortality.

Several notes of caution are in order. By the technique used here, normal values for women are substantially less than for men. Men with cirrhosis met the criteria for sarcopenia much more often than women. It is not clear whether these gender differences are associated with gender differences in prevalence of malnutrition and cachexia, or whether the technique is simply insensitive for detection of sarcopenia in women. Although the gender difference could confound the results, within the male subgroup sarcopenia also was associated with a higher mortality. Additional studies are needed to determine the ideal cutoff for sarcopenia as a determinant of functional impairment and survival in each gender. Racial and ethnic differences also need to be studied. In addition, the CT-based measure of sarcopenia needs to be correlated with other measures of nutritional and functional status to determine its ability to serve as an adequate surrogate marker. The effect of ascites and anasarca on the quantitative analysis of skeletal muscle area also needs to be examined systematically.
Despite these limitations, the findings of this study are intriguing because they suggest that information that is already routinely gathered in the course of evaluation of cirrhotic patients (abdominal CT axial images) can be used to objectively assess adequacy of muscle mass, and the finding of sarcopenia by this method might identify cirrhotic individuals who are at high risk of death from sepsis. Sarcopenia thus joins hyponatremia, uncontrolled ascites, hepatic encephalopathy, etiology of liver disease, and etiology of renal disease as supplemental factors that might add short-term prognostic information to the MELD model.12, 13, 14 With the small numbers of patients studied to date, additional studies are needed to validate the methodology. If sarcopenia measured in this way is confirmed to be an independent predictor of survival in cirrhosis, then a case could be made to include CT-based estimation of skeletal muscle mass as a factor in determining “sickest first” priority for organ allocation in patients awaiting liver transplantation. However, before such a change could be adopted, it would be important to determine to what extent sarcopenia adversely affects survival after liver transplantation. Englesbe et al15 measured psoas muscle mass by CT in patients undergoing liver transplantation and reported a strong association between sarcopenia and post-transplant mortality. Thus, rather than increasing transplant priority, sarcopenia could represent a relative contraindication to liver transplantation. Application of measures of sarcopenia to other areas of hepatology, such as estimation of surgical risk or assessing ability to tolerate antiviral or anticancer therapy, also needs to be explored. The most important use of this new technique might lie in serial measurement of muscle mass, both to predict decompensation in cirrhosis and to assess objectively the response to interventions such as appetite stimulants, nutritional supplements, or physical conditioning.
We owe a debt of gratitude to our colleagues in geriatrics for advancing the concept of sarcopenia. Montano–Losa and colleagues have provided us with a promising tool, along with tantalizing evidence of its potential usefulness in management of cirrhosis. Now it is up to the rest of us to confirm the general validity of the technique, define its limitations, and explore its applications. Whether it will ultimately find a permanent place in the diagnostic armamentarium remains to be seen.

References
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