6. Nutritional Therapy in the Management of Physical Frailty and Sarcopenia

Manuela Merli¹, Barbara Lattanzi¹, Daria D’Ambrosio¹, Nicoletta Fabrini¹ and Alice Liguori¹

(1)

Gastroenterology and Hepatology Unit, Department of Translation and Precision Medicine, Sapienza University of Rome, Rome, Italy

Manuela Merli

Email: Manuela.merli@uniroma1.it

Keywords

FrailtySarcopeniaNutritional therapyBranched-chain amino acidsLiver cirrhosis

Introduction

In patients with liver cirrhosis, progressive liver insufficiency is associated with multiple extra-hepatic alterations. Among these alterations, a gradual decline of muscle mass and function and the deterioration of physical performance are frequently recognized [1–3]. Sarcopenia and/or frailty are negative prognostic factors for morbidity and mortality in liver cirrhosis. For these reasons, the diagnosis, prevention, and treatment of these conditions are of great importance.

Despite the high prevalence and the clinical impact of sarcopenia and frailty in patients with liver disease, to date, these two entities are not included in the prognostic and severity scores of liver cirrhosis [4]. As a consequence, sarcopenia and frailty are not systematically investigated and may go even under-recognized in liver patients.

Being potentially reversible conditions [5–7], early identification of physical frailty and sarcopenia could help to plan early management of these conditions [8, 9]. However, there are few clinical studies specifically focused on the management of sarcopenia and physical frailty in patients with a diagnosis of liver cirrhosis.

What Can We Derive from the Results of Nutritional Intervention in Elderly Patients: Some Certainties

In elderly patients, the main therapeutic approaches that have been proposed to improve sarcopenia and frailty are adequate nutrition and cognitive and physical training [7, 10].

Some evidence suggests amelioration of frailty in older people with cognitive training and physical exercise [11–15]; other studies were mainly focused on nutritional interventions [16–21]. In a recent study conducted in 256 older adults, patients were randomized to five different 6-month interventions. These included nutritional supplementation (supplying 300 kcal in the form of carbohydrate, fat, protein, + vitamins), cognitive training, physical training, combination treatment, and usual care (controls). Results indicate that all the active treatments’ approaches were effective in reducing frailty vs controls. However, the best results were obtained in patients receiving the combination treatment [7].

Concerning the amelioration of sarcopenia, data are more encouraging, and specific nutritional interventions showed a significant amelioration in muscle mass and function in older adults, mainly when combined with physical exercise [5, 22]. In particular, a daily protein intake of 1.0 g/kg has been identified as the minimum amount required to maintain muscle mass in old age [22]. According to the available evidence, older people should, therefore, be encouraged to eat between 1.0 and 1.5 g/kg of proteins daily [23].

A large ongoing phase III, multi-center randomized controlled trial (“Sarcopenia and Physical Frailty in older people: multi-component Treatment strategies”(SPRINTT)) is testing long-term structured physical activity and nutritional counseling/dietary intervention to prevent mobility disability in community-dwelling older people with physical frailty and sarcopenia [24]. The results of this study will possibly increase our knowledge in this field in the near future.

Nutritional Intervention in the Management of Physical Frailty and Sarcopenia in Cirrhotic Patients: More Uncertainties

While in mixed patients’ populations, the benefits of nutritional therapy are evidenced by a reduction in mortality, infections, systemic inflammation, and hospital length of stay [5]; in cirrhotic patients, similar results have been limited by small cohort size and lack of randomized trials; therefore evidence-based efficacy of nutritional interventions is often lacking. The end points of these studies are frequently heterogeneous (muscle strength and/or muscle mass, mortality, complications of portal hypertension, etc.) which make the results difficult to analyze [25]. With regard to frailty, the Liver Frailty Index [15] has been only recently proposed and is not commonly utilized; consequently, studies evaluating the effect of nutritional supplementation on physical frailty in cirrhotic patients are still lacking. Nutritional treatment approaches in cirrhotic patients, have focused on different strategies: calories or protein supplementation, stimulation of protein synthesis, reinforcement to increase exercise and physical activity, and use of anabolic hormones and ammonia-lowering strategies. The use of anabolic hormones and the ammonia-lowering strategies will not be dealt with in this chapter.

Calories and Protein Supplementation

A crucial aspect of nutritional management is to ensure that the patient’s rehabilitative diet contains the correct amount of each essential nutrient or macromolecule [26]. The approach of most nutritional intervention studies in liver cirrhosis is to supply at least 35 kcal/kg/d [26]. It is also recommended to shorten the duration of fasting periods during the day, and there is evidence that a late evening and an early morning snack containing proteins are likely to have the greatest benefit in preventing muscle loss in cirrhosis [27].

Since caloric and protein intakes are frequently decreased in patients with liver cirrhosis, regimens providing extra calories via high caloric oral nutritional supplements (ONS) feeding and/or enteral feeding have been proposed to increase the suboptimal oral intake. Results have, however, been controversial. Nutritional support with enteral nutrition in hospitalized malnourished cirrhotic patients [28] and perioperative nutrition in cirrhotic patients undergoing surgery for hepatocellular carcinoma were found to improve patients’ survival [29]. On the other hand, long-term nutritional supplementation before liver transplantation [30] and an immuno-nutrition supplement provided before and perioperatively to liver transplant patients [31] failed to obtain any significant improvement in survival and outcomes in treated patients vs controls, in randomized controlled trials. Therefore, despite promising results in some studies, systematic meta-analyses could not clearly demonstrate a significant benefit of nutritional therapy on survival [32–34]. Results have been conflicting also regarding the benefits of parenteral nutritional supplementation in patients with cirrhosis [35]. However, during prolonged periods of poor oral intake or fasting as in severe hepatic encephalopathy, gastrointestinal bleeding, and impaired gut motility or ileus, to provide nutritional support is considered to be beneficial by most authors [36].

An important strategy to approach malnutrition and sarcopenia in cirrhotic patients is protein supplementation. Adequate protein intake, to meet the increased protein requirements in patients with a diagnosis of liver cirrhosis with malnutrition, has been defined as 1.2–1.5 g/kg body weight daily by the EASL guidelines [26].

In the past, there has been controversy about whether protein intake could favor the development of hepatic encephalopathy (HE) in cirrhotic patients. Indeed, in the majority of patients suffering from HE, a transient protein restriction was recommended, in order to limit the synthesis of ammonia induced by protein deamination and impaired urea synthesis. Later on, a number of studies have shown that normal to high protein intake does not precipitate HE [37] and may even improve mental status [38, 39]. Furthermore, recovery from an acute episode of HE with standard pharmacologic treatment was found to be similar in patients with normal protein intake vs those following severe protein restriction [40]. At the same time, protein-restriction induced protein catabolism which is detrimental [40]. In cirrhotic patients hospitalized for HE, a hyper-caloric and hyper-proteic oral diet has been found to be beneficial [50], and protein refeeding is an important target for malnourished cirrhotic patients [41].

Branched-Chain Amino Acid (BCAA), Leucine, and HMB Supplementation

Hepatic damage causes an increase in aromatic amino acids (produced by decreased liver clearance) and a decrease in branched-chain amino acids (due to increased utilization as the energy source). BCAA supplementation is a strategy that has been initially utilized for the treatment of acute HE based on the false neurotransmitter hypothesis [42]. However, old studies supplementing BCAA in patients with HE did not investigate the effects of BCAA on nutritional status or muscle mass [43, 44]. Later on, long-term oral BCAA consumption was proposed to increase protein intake in those cirrhotic patients who are intolerant to normal dietary proteins [45]. Two randomized, double-blind, multicenter studies in advanced cirrhotic patients reported an improvement in muscle mass following a 12-month BCAA oral supplement [45, 46]. Further studies reported similar encouraging results, although important biases were present such as small cohorts of patients, lack of patients’ randomization, short-term observation time, and different kinds of nutritional supplements. Furthermore, BCAA are not freely available in many countries, and results are mainly reported where these supplements are most used [47–50] (Table 6.1).

Table 6.1

Effect of an adequate oral dietary intake with or without nutritional supplements enriched with BCAA on muscle mass or function in patients with liver cirrhosis (recent studies)

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