Nutrition and the Liver

Introduction

The components of nutrition include food intake, digestion, absorption, assimilation, and maintenance of different nutrients. Even though the liver is involved in each of these processes, the focus of this review will be to discuss the consequences of liver disease on nutritional status. The term most frequently applied to nutritional defects is malnutrition but the term is necessarily ambiguous because it does not specify the defects that occur and was believed to include protein loss and disordered energy metabolism. Clinically, malnutrition has been used to refer to the phenotype of skeletal muscle and fat loss. Recently there have been attempts to define specific components of malnutrition as sarcopenia or loss of skeletal muscle mass, disordered energy metabolism, and micronutrient deficiencies. The major component of malnutrition is, however, sarcopenia or loss of skeletal muscle mass. Even though the term sarcopenia has been used to refer primarily to aging-related muscle loss, sarcopenia of specific diseases (cirrhosis, heart failure, renal failure) is now accepted to refer to skeletal muscle loss in chronic diseases. Therefore the emphasis in this chapter will be on sarcopenia, with limited discussion of energy metabolism and micronutrient deficiencies, and the interested reader is referred to reviews on these topics. Recent advances in measurement of muscle mass, understanding the mechanistic basis for sarcopenia in cirrhosis, and novel targeted therapeutic options are expected to improve outcomes of cirrhotic patients. Few studies have systematically evaluated the impact of nutritional supplementation on outcomes in cirrhosis. The ESPEN guidelines for nutritional management of cirrhosis were published nearly a decade ago and need to be updated on the basis of the current understanding of the diagnosis and pathogenesis of malnutrition, specifically, sarcopenia in liver disease. More recently, guidelines on dietary management of hepatic encephalopathy were published by a working group in Europe that provide the rationale for therapeutic approaches on the basis of past clinical studies.

What Is Sarcopenia in Cirrhosis?

Malnutrition is known to be a nearly universal complication in cirrhosis, but the lack of a precise and a uniform definition has contributed to the difficulty in comparing the data from different investigators. Measures of muscle area quantified by anthropometry or other techniques and muscle strength determined by grip strength have been used most frequently. A few investigators have used measures of immune function and serum levels of nutrients, including albumin, which is truly a hepatocyte synthetic function. Most authors, however, use some measure of skeletal muscle loss as the major component of malnutrition. We defined malnutrition in cirrhosis to be composed of sarcopenia (from sarcos , meaning flesh , and penia , meaning deficiency ) and altered energy metabolism. The term sarcopenia translates to muscle loss, and a qualifying term needs to be added to specify the underlying cause of muscle loss. We and others have used the term sarcopenia to refer to muscle loss in liver, heart, and lung diseases with the appropriate qualifier to identify the underlying disease. A number of other consequences of muscle loss and consequent metabolic perturbations include impaired contractile strength and its effects on functional capacity. Deconditioning and frailty have been used to refer to consequences of muscle loss and are due to the reduction in muscle loss and contractile function. However, the term sarcopenia should be used to refer to the loss of skeletal muscle mass. The components of skeletal muscle loss included lower myofiber size and a switch in fiber type from a glycolytic, fast twitch, Type II fiber to an aerobic, oxidative, slow twitch Type I fiber. Cachexia has been suggested but has generally been used to refer to the phenotype of muscle and fat loss that is seen in terminal stages of wasting disorders that are rarely seen in patients with cirrhosis in the current era.

The other component of malnutrition is energy hypermetabolism with a reduction in fat mass, and a switch in substrate utilization to a predominantly fatty acid oxidative state. Unlike the clear clinical recognition of sarcopenia, energy dysfunction requires specific evaluations, and the increasing prevalence of cirrhosis due to nonalcoholic fatty liver disease is not necessarily accompanied by fat loss. There is increasing recognition that patients with nonalcoholic fatty liver disease have sarcopenic obesity, a combination of muscle loss with relatively preserved fat mass.

The term malnutrition is also used to refer to vitamin D, zinc, and other micronutrient deficiencies. However, for most clinicians the term malnutrition refers to the clinical syndrome of skeletal muscle loss or sarcopenia that has been consistently shown to adversely affect clinical outcomes. In liver disease, portal hypertension contributes to malabsorption of dietary components and hepatocellular dysfunction results in impaired albumin synthesis and perturbation in amino acid metabolism. For specificity, it is best to use the precise terms that are being defined instead of including them as components of the term malnutrition . The term malnutrition in cirrhosis is being gradually but consistently being replaced by terms referring to the specific clinical symptom/finding.

How Is Sarcopenia Diagnosed in Cirrhosis?

The most common symptoms reported by cirrhotic patients with malnutrition are loss of muscle mass, weakness, and/or whole body weight loss. These are relatively imprecise and clinical measures, and in the past anthropometric measures were used, including skin fold thickness and arm and thigh circumference, which also suffer from a number of limitations. These were then replaced by a number of techniques to quantify body composition that separated fat mass from lean or fat free mass, of which approximately 40% was composed of skeletal muscle mass ( Table 55-1 ). However, given the assumptions to translate lean body mass to skeletal muscle mass and the contribution of fluid accumulation in cirrhosis to the measurement of nonfat mass, there is nearly universal interest in the use of imaging methods, including computed tomography, magnetic resonance imaging, and potentially ultrasonography, to directly quantify muscle and fat area. These methods, especially computed tomography scans, are being used by most centers in association with one of the image analysis programs to estimate whole body muscle and fat mass with a relatively high degree of accuracy. Specific cutoff limits were proposed but did not take into considerate the physiologic differences between the sexes and the effect of age on normal muscle mass. Recently, age- and sex-based normal cutoff values to define sarcopenia normalized for height have been published.

As mentioned earlier, contractile dysfunction has been used in the past to define malnutrition. Grip strength has been used as an objective measure but other methods, including the 6-minute walk test, have recently been used to define functional impairment. Nutrient deficiencies, protein loss, and abnormal energy metabolism contribute to contractile dysfunction, but the term sarcopenia in cirrhosis should be used for the loss of muscle mass, and defects in muscle function should be referred to as such.

Clinical Significance of Sarcopenia in Cirrhosis

Malnutrition has been reported in 40% to 90% of cirrhotic patients depending on the diagnostic criteria used, the severity and cause of liver disease, and potentially the effect of activity, nutrient intake, and complications of cirrhosis. The prevalence of sarcopenia with specific cutoff values for muscle loss ranges from 40% to 70%. Other parameters, including grip strength, immune function, and serum albumin levels, have been used with variable prevalence. Sarcopenia is accompanied by lower survival, lower quality of life, increased risk of complications of cirrhosis, poor peritransplant outcomes, and higher mortality after liver transplant. Extensive literature on cirrhotic patients with muscle mass quantified initially anthropometric measures, and more recently direct measurement by image analysis has provided compelling evidence that sarcopenia results in higher mortality. The cause of death directly attributable to sarcopenia has not been carefully evaluated, but sepsis occurs more frequently in sarcopenic patients. The reason for greater severity and prevalence of infection in sarcopenic patients is not known but may be related to the impairment of immune function due to defective amino acid metabolism and protein turnover. Other reasons for greater infection in sarcopenic patients may be due to decreased mobility but this has not been evaluated. Elegant studies have shown that malnutrition, mainly muscle loss, is associated with increased risk of encephalopathy in cirrhosis. This may be because the skeletal muscle is a metabolic partner of the liver in ammonia disposal in individuals with liver disease. Portal hypertension and ascites have also been reported to be more frequent in sarcopenic cirrhotic patients. Lower muscle mass, decreased contractile function, and increased hospitalization in these patients contribute to lower quality of life.

Liver transplant is an integral part of the management strategy for cirrhotic patients. Sarcopenic patients are recognized to have poor outcomes, including higher graft rejection and increased mortality, compared with nonsarcopenic patients. Given that most cirrhotic patients do not receive a transplant, and even those who are listed for liver transplant have to wait for 6 months or longer with continued loss of muscle mass, there is an urgent need to prevent and treat sarcopenia in cirrhosis. Unlike other complications of cirrhosis that reverse after liver transplant, most studies published to date report that sarcopenia does not reverse or worsens in most patients after transplant. Furthermore, posttransplant mortality was higher in patients with ongoing muscle loss compared with patients who showed an increase in muscle mass after transplant.

Even though there are no established treatments to reverse sarcopenia, there are consistent data showing that following a transjugular portosystemic stent placement, lean body mass increases and sarcopenia is reversed. Furthermore, in that study, reversal of sarcopenia improved survival, reiterating the high clinical significance of sarcopenia and the large unmet need for therapies to prevent and treat this major complication of cirrhosis and liver disease. Skeletal muscle atrophy can develop fairly quickly but recovery is much slower, so evaluation of beneficial effects of interventions is time-consuming and therapeutic studies are very limited. Translation of data from studies to reverse sarcopenia of aging may be difficult because the underlying pathogenic mechanisms and therefore responses to interventions are likely to be different in patients with cirrhosis.

Contributors to Sarcopenia in Cirrhosis

A number of factors contribute to the nutritional consequences of cirrhosis ( Table 55-2 ). The cause and duration of cirrhosis, the severity of liver disease, and other complications of cirrhosis, including portal hypertension, ascites, hepatocellular carcinoma, and encephalopathy, contribute to the malnutrition and sarcopenia in cirrhosis. Alcoholic and cholestatic cirrhosis have been consistently reported to have the most severe muscle loss because of the direct effects of alcohol and bile salts, respectively, on the skeletal muscle. Nonalcoholic fatty liver disease is a state of sarcopenic obesity, and the adiposity may mask the underlying muscle loss. Portal hypertension affects almost the entire gastrointestinal tract with decreased motility, altered absorption, and protein-losing enteropathy, all of which contribute to sarcopenia and nutrient deficiencies. Alcohol and its metabolites directly cause disturbed gut absorption and mucosal integrity, both of which result in nutrient deficiencies. Cholestatic disorders aggravate fat-soluble vitamin deficiencies, including vitamin D deficiency. Ascites results in early satiety and decreased food intake. Recurrent sepsis causes a catabolic state with progressive muscle loss. Encephalopathy results in lower food intake because of the impaired mental state. Despite nearly universal recognition that protein intake need not be restricted in patients with cirrhosis, patients are often given a low-protein diet that aggravates sarcopenia. Additionally, patients with minimal encephalopathy may not take adequate and regular meals. Hospitalization of patients is another cause of worsening sarcopenia and nutrient deficiencies. Finally, cirrhotic patients with hepatocellular carcinoma have more severe nutrient deficiencies and sarcopenia than those without.