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Address for correspondence: Manuela Merli, Department of Clinical Medicine, Gastroenterology Unit, La Sapienza University of Rome, Italy. Tel.: +39 0649972002; fax: +39 0649972002.
Sarcopenia is an important burden in liver cirrhosis representing a negative prognostic factor for mortality. Moreover, sarcopenia is an independent predictor of complications in patients with liver cirrhosis, including Hepatic Encephalopathy (HE). An association between sarcopenia and HE in liver cirrhosis has been reported in recent studies, indeed both these complications often affect patients with advanced liver cirrhosis and may exert a synergic effect in deteriorating patients’ outcome. Episodes of HE occur more often in patients with muscle depletion. The rationale for these finding is based on the role played by muscle in ammonia detoxification due to the inability of urea synthesis in the cirrhotic liver. Consequently, muscle depletion may have relevant implications in favoring hyperammonemia and HE. At the same time hyperammonemia has been found to impair muscle protein synthesis through myostatin down-regulation. From this point of view, modulation of diet and amelioration of nutritional status and muscle mass can be considered a potential goal to prevent this vicious circle and improve the cognitive impairment in cirrhotic patients.
Alterations in nutritional status are a frequent complication associated with liver cirrhosis. The prevalence of malnutrition is related to the severity of liver disease and has been reported to be as high as 65–90% in advanced cirrhosis.
The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
A number of factors are involved in malnutrition in liver cirrhosis such as inadequate dietary intake, impaired nutrient absorption and alterations in substrate utilization due to liver disease.
European Working Group on sarcopenia in older people. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People.
The exact mechanisms causing sarcopenia in cirrhosis are still not completely clarified; one of the major reasons has been the difficulty in identifying the mediator(s) of the liver-muscle axis. Indeed, several potential mediators have been proposed including increased ammonia
The major limitations of these tools, despite their accuracy in identifying skeletal muscle mass, is due to their cost, radiation exposure and logistics.
Usually sarcopenia is CT assessed when a CT scan, performed by the patient for other reasons, is already available. Further limitations derive from non-homogeneous methods applied by different studies (either whole muscle area, or psoas area or psoas diameter have been utilized in different studies) which also provide the identification of uniform cut offs.
Fitness, Life Enhancement, and Exercise in Liver Transplantation Consortium. A multicenter study to define sarcopenia in patients with end-stage liver disease.
Other techniques, although less accurate, are also utilized for the assessment of sarcopenia in cirrhotic patients: anthropometry (Triceps-Skinfold-Thickness and Mid-Arm-Muscle-Circumference), non-invasive, rapid, easy to perform and cost-effective
Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry.
; dual-energy X-ray absorptiometry an easy, reproducible and accurate method to analyze body composition which also allows a regional body composition analysis to study fat mass and fat free mass of selected body sites.
Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry.
European Working Group on sarcopenia in older people. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People.
Fitness, Life Enhancement, and Exercise in Liver Transplantation Consortium. A multicenter study to define sarcopenia in patients with end-stage liver disease.
A number of cross sectional and longitudinal studies, using various methods to quantify muscle mass, have reported that median survival and probability of survival are lower in cirrhotic patients with sarcopenia than in those without sarcopenia.
For this reason, it has been suggested that sarcopenia may improve the prognostic value of the Model for End-stage Liver Disease (MELD) scoring system. However, data are still controversial and a recent study analysing 585 cirrhotic patients waiting for LT found that the MELD-Sarcopenia score
Bioelectrical impedance analysis and handgrip strength
To investigate the relationship between sarcopenia and MHE and to identify the predictors of MHE in cirrhotic patients.
The prevalence of MHE was higher in patients with sarcopenia than in those without sarcopenia (P = 0.01). In the multivariate analysis, sarcopenia (odds ratio = 3.31, 95% confidence interval = 1.19–9.42; P = 0.02) was found to be associated with MHE.
To investigate the relationship between sarcopenia and the incidence of HE in cirrhotic patients submitted to TIPS.
All the patients with HE after TIPS were sarcopenic and there was an increased occurrence of HE after TIPS in cirrhotic patients with sarcopenia (P < 0.0001).
Lower values of handgrip strength and adductor pollicis muscle thickness are associated with hepatic encephalopathy manifestations in cirrhotic patients.
54 cirrhotic outpatients with subclinical or clinical HE
Anthropometric measurements
To study the association between HE and measures related to muscle mass and strength.
Reductions of 1 mm of adductor pollicis muscle thickness and 1 kg in handgrip strength were associated with odds of 30.7% (P = 0.0177) and 12.2% (P = 0.023) of increasing HE grade, respectively.
To investigate the effects of malnutrition and diabetes mellitus on HE in unselected patients with liver cirrhosis.
Patients with vs. without malnutrition had more frequently HE (46 vs. 27%; P = 0.031). Multivariate analysis showed that the time needed to perform number connection test was independently associated to age, the Child–Pugh score, diabetes and malnutrition (P < 0.05).
A reduction in Handgrip strength, utilized for the assessment of muscle function in 84 cirrhotic patients, was found to be an independent predictor of complications, including Hepatic Encephalopathy (HE).
Similarly, in a prospective study including 300 hospitalized cirrhotic patients, muscle depletion evaluated by anthropometry, and impaired muscle function assessed by handgrip strength, were both independently associated with clinically overt HE at admission, previous HE in the last 12 months, covert HE diagnosed by psychometric tests.
In a further study, including 128 unselected cirrhotic patients in whom the presence of HE was evaluated according to West-Haven criteria, cognitive alterations were more frequent in patients with malnutrition, and a multivariate analysis showed that the time needed to perform number connection test A was independently correlated to age, Child–Pugh class, malnutrition and diabetes.
However, in this study, malnutrition was not strictly based on the evaluation of muscle mass but also included BMI, weight loss in the last 6 months and triceps skinfold. At variance with this finding, other authors have reported that the prevalence of malnutrition (including muscle mass evaluated by Bioelectric Impedance Analysis) was not different between non-alcoholic cirrhotic patients with and without HE.
These controversial results could be due to difference in patients’ characteristics and lack of information that could better define the episode of HE such as timing, etiology and severity.
The relationship between sarcopenia and HE was also reported in a recent retrospective study including a cohort of 120 Japanese cirrhotic patients; the prevalence of Minimal Hepatic Encephalopathy (MHE) was found to be higher in patients with sarcopenia than in those without sarcopenia and sarcopenia was shown to be an independent predictor of MHE at multivariate analysis.
A further study showed that lower values of adductor pollicis muscle thickness and handgrip strength both correlated with the presence of HE in cirrhotic patient.
Lower values of handgrip strength and adductor pollicis muscle thickness are associated with hepatic encephalopathy manifestations in cirrhotic patients.
The presence of an interaction between muscle and cognitive alterations in cirrhotic patients is in agreement with the results of a recent study, in which muscle wasting in cirrhotic patients constitutes a strong and independent risk factor for the occurrence of HE after Transjugular Intrahepatic Portosystemic Shunt (TIPS) placement.
In this series, all patients with an episode of overt HE during the follow up after TIPS were sarcopenic before TIPS placement while the prevalence of sarcopenia in the patients without post TIPS HE was only 20%.
Ammonia Metabolism and Trafficking
The rationale for an association between muscle depletion and HE derives from the possible involvement of muscle tissue in ammonia metabolism and trafficking (Figure 1). Ammonia is a crucial metabolite in the pathogenesis of cognitive impairment in liver cirrhosis and its concentrations are increased in these patients because of the inability of the impaired liver in removing ammonia through urea synthesis.
In this scenario the muscle mass acquires importance because it contributes, through glutaminase, to remove ammonia by incorporating it into glutamine.
Although this metabolic pathway does not result in a definitive ammonia disposal, it has been proposed that muscle depletion may have relevant implications in favoring hyperammonemia.
Furthermore, the enhanced muscle protein catabolism, which contributes to muscle wasting, increases glutamine release from muscle. Glutamine is drained to the small intestine and kidney where it is converted to glutamic acid and ammonia, further contributing to increase the whole-body ammonia availability.
Moreover, studies investigating the molecular mechanism of sarcopenia in liver cirrhosis revealed that ammonia itself impairs muscle protein synthesis in part through the up-regulation of myostatin production.
Indeed, in cirrhosis, the skeletal muscle by removing large quantities of ammonia from the circulation, is exposed to high intramuscular concentration of this metabolite causing transcriptional up-regulation of myostatin in a p65 NF-κB-dependent manner.
Myostatin, a member of the TGFβ superfamily, is a powerful catabolic signal that inhibits protein synthesis and satellite cells proliferation and differentiation. Myostatin, binding to its muscle surface receptor, leads to activation of Smad2/3 promoting muscle proteolysis and wasting via activation of ubiquitin–proteasome system.
Moreover, the ammonia disposal in non-hepatic tissue results in loss of α-Ketoglutarate (αKG), an intermediate of Tricarboxylic Acid (TCA) cycle, leading to cataplerosis, which contributes to mitochondrial dysfunction.
As protein synthesis is a highly energy-requiring cellular process, mitochondrial dysfunction with low ATP content contributes to dysregulated proteostasis. In addition to mitochondrial dysfunction, because of cataplerosis of αKG, hyperammonemia also results in increase of reactive oxygen species leading to autophagy.
These pathways lead to imagine the existence of a vicious circle: on one side hyperammonemia is generated by sarcopenia due to the inability of the depleted muscle to metabolize ammonia, on the other hand, increased ammonia concentrations, through myostatin up-regulation, mitochondrial dysfunction and cellular stress response, induces further muscle wasting. From this viewpoint, an improvement in nutritional status and muscle mass can be considered a potential goal to ameliorate the cognitive function in cirrhotic patients and a modulation of diet may represent a promising option when seeking to prevent HE.
Restriction of protein intake has been abandoned as a therapy in patients with acute HE. Indeed, in a randomized controlled study, in addition to standard treatment of HE, a protein-restricted diet vs. a normal protein diet for 14 days was found to have no advantage in cognitive recovery. The protein restricted diet caused an increased protein catabolism which is detrimental for these patients.
In a more recent study, a high protein meal in decompensated cirrhotic patients did not precipitate HE, despite of the accumulation of some amino acids.
These results support the current nutritional guidelines that recommend a protein intake of 1.2–1.5 g/kg body weight/day for patients with cirrhosis and HE.
While a low protein diet does not seem to be beneficial in HE, selection of protein quality should be considered as an opportunity. In patients with recurrent HE it has been shown that vegetable proteins are better tolerated.
A higher intestinal clearance of nitrogen-waste products, a shortened transit time, a reduced colonic pH, a higher ornithine and arginine and a lower methionine and tryptophan content compared to animal proteins are among the proposed beneficial effects. Additional benefits of a vegetal-enriched diet may derive from the modulation of gut microbiota.
In decompensated cirrhosis alterations in gut microbiota are frequent, and modulation of gut microbiota may be effective for treating and preventing HE.
In a recent randomized controlled trial performed in India, six-month nutritional therapy (30–35 kcal/kg/day, 1.0–1.5 g vegetable protein/kg/day) was effective to ameliorate MHE score and was associated with an improvement in health-related quality of life. The authors suggest that multiple factors (improvement in liver functions, recovery of muscle mass, positive nitrogen metabolism, and modifications in gut flora) may have contributed to the improvement in MHE. Moreover, episodes of overt HE appeared to be lower in the group on nutritional therapy than in controls.
Nutritional supplements have been shown to improve cognitive status in cirrhotic patients. Oral supplementation with Branched Chain Amino Acids (BCAA) also has a role for its effect in reducing the risk of recurrence of HE. Indeed, a Cochrane database systematic review, examining clinical trials on BCAA supplement vs. standard therapy in cirrhotic patients with HE, reported that BCAA had a significant beneficial effect on HE either overt or minimal.
Theoretically even, physical exercise might improve cognitive status by its effect on sarcopenia but at present, no studies have explored this opportunity.
Conclusion
In conclusion, sarcopenia is an important burden in liver cirrhosis and evidences support that it is strictly correlated with cognitive impairment in cirrhotic patients. This gives a glimpse of the relationship between muscle and brain in liver cirrhosis which is mediated by metabolic changes in which the role of hyperammonemia is of great importance.
Few evidences showed beneficial effect of nutritional supplementation in cognitive impairment in cirrhotic patients but more extensive studies are still needed. Taking into account the improving knowledge about molecular mechanism of sarcopenia in liver cirrhosis, target therapies, through myostatin antagonists, direct mTORC1 activators, antioxidants, and mitochondrial protective agents, might have the potential to benefit the brain-muscle axis in liver cirrhosis.
Understanding the complexity of this correlation can lead to a better strategy of treatment of these two important complications of liver cirrhosis that negatively affect morbidity and mortality.
Conflicts of Interest
The authors have none to declare.
References
Amodio P.
Bemeur C.
Butterworth R.
et al.
The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus.
European Working Group on sarcopenia in older people. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People.
Fitness, Life Enhancement, and Exercise in Liver Transplantation Consortium. A multicenter study to define sarcopenia in patients with end-stage liver disease.
Sarcopenia in liver cirrhosis: the role of computed tomography scan for the assessment of muscle mass compared with dual-energy X-ray absorptiometry and anthropometry.
Lower values of handgrip strength and adductor pollicis muscle thickness are associated with hepatic encephalopathy manifestations in cirrhotic patients.
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