Reduced 3-year risk of hospital admission and mortality after 12-week resistance training of cirrhosis patients: A follow-up of a randomized clinical trial.

BACKGROUND AND AIM: Physical activity confers health benefits in many diseases but remains almost unstudied for cirrhosis. We investigated whether a period of resistance training affects the subsequent long-term risk of hospitalization or mortality among patients with cirrhosis. METHODS: The study includes 39 participants with cirrhosis Child-Pugh class A/B who participated in a prior clinical trial randomized to either resistance training three times per week for 12 weeks or a control group. We gathered data through medical records from trial entry and the following 3 years. The outcomes were time to first hospitalization and all-cause mortality. We used regression models to examine the associations between trial groups and outcomes, adjusting for Child-Pugh class, age, gender, and comorbidity. RESULTS: Nine patients who trained and 15 controls were hospitalized, resulting in a lower risk of first hospitalization in the training group (adjusted subdistribution hazard ratio of 0.40, 95% confidence interval [CI] [0.17, 0.92]; P = 0.03). One patient who trained and six controls died, resulting in a lower all-cause mortality in the training group (adjusted hazard ratio of 0.06, 95% CI [0.01, 0.66]; P = 0.02). CONCLUSION: Twelve weeks of resistance training was associated with a reduced risk of first hospitalization and mortality among patients with cirrhosis Child-Pugh class A/B 3 years after trial entry. The mechanisms of this effect are not identified, and larger studies are warranted.

Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats.

Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease.

Resistance Training Increases Muscle Strength and Muscle Size in Patients With Liver Cirrhosis.

BACKGROUND & AIMS: Cirrhosis is often complicated by reduced muscle mass and strength, which limits the ability to perform daily activities and affects quality of life. Resistance training can increase muscle strength and mass in elderly and chronically ill patients. We performed a randomized controlled trial to investigate whether resistance training increases muscle strength and size in patients with compensated cirrhosis. METHODS: We performed a prospective study of 39 patients with cirrhosis (Child-Pugh class A or B) seen at an outpatient clinic in Denmark from January 2015 through March 2017. Participants protein intake and activity levels were registered daily. Participants were randomly assigned (1:1) to a group that performed 36 1-hour sessions of physical exercise (supervised progressive resistance training for 1 hour, 3 times weekly for 12 weeks) or a control group (no change in daily activity level). Maximal muscle strength was measured as the peak torque in isokinetic knee extension and muscle size was measured as the cross-sectional area of the quadriceps muscle, assessed by magnetic resonance imaging of the thigh. RESULTS: The exercise group increased their muscle strength by 13% (from a mean 119 Nm to 134 Nm)-an 11 Nm greater gain in mean strength than that of the control group (P = .05). The exercise group increased their quadriceps cross-sectional area by 10% (from a mean 58.5 cm2 to 64.6 cm2)-a 4.4 cm2 greater gain than that of the control group (P < .01). The exercise group had significant increases in whole-body lean mass and body cell mass, and significant increases in 6-minute walking distance and the mental component summary of the short form-36 questionnaire. Adverse events were minor and equal between groups. CONCLUSIONS: In a randomized trial of patients with compensated cirrhosis, we found that 12 weeks of supervised progressive resistance training increased muscle strength and size and had beneficial effects on general performance measures, compared with patients who did not change their daily activity routine (control subjects). ClinicalTrials.gov no: NCT02343653.

Progressive resistance training prevents loss of muscle mass and strength in bile duct-ligated rats.

BACKGROUND: Loss of muscle mass and strength is common in cirrhosis and increases the risk of hyperammonaemia and hepatic encephalopathy. Resistance training optimizes muscle mass and strength in several chronic diseases. However, the beneficial effects of resistance training in cirrhosis remain to be investigated. Bile duct-ligated (BDL) rats develop chronic liver disease, hyperammonaemia, reduced muscle mass and strength. Our aim was to test the effects of resistance training on muscle mass, function and ammonia metabolism in BDL-rats. METHODS: A group of BDL-rats underwent a progressive resistance training programme and a group of non-exercise BDL-rats served as controls. Resistance training comprised of ladder climbing with a progressive increase in carrying weights attached to the tail. Training was performed 5 days a week during 4 weeks. Muscle strength and body composition were assessed using grip strength and EchoMRI. Weight and circumference of the gastrocnemius muscle (normalized to bodyweight), plasma ammonia and glutamine synthetase protein expression and activity were assessed. RESULTS: BDL + exercise rats had significantly larger gastrocnemius circumference compared to non-exercise BDL-rats: ratio 0.082 vs 0.075 (P < 0.05). Gastrocnemius muscle weight was higher in exercisers than controls: 0.006 vs 0.005 (P < 0.05). A tendency towards a lower plasma ammonia in the exercise group compared to controls was observed (P = 0.10). There were no differences in lean body mass, GS protein expression and activity between the groups. CONCLUSION: Resistance training in rats with chronic liver disease beneficially effects muscle mass and strength. The effects were followed by non-significant reduction in blood ammonia; however, a tendency was observed.

Unexplained cholestasis in adults and adolescents: diagnostic benefit of genetic examination.

OBJECTIVES: A few adult and adolescent patients with even severe cholestatic liver disease remain unexplained after standard diagnostic work-up. We studied the value of genetic examination in such patients and developed a panel of eight genes with known cholestatic associations. MATERIALS AND METHODS: Thirty-three patients with unexplained cholestasis despite a thorough clinical work-up were examined for sequence variations in the coding regions of the ABCB4, ABCB11, ABCC2, ABCG5, ATP8B1, JAG1, NOTCH2, and UGT1A1 genes and the promoter region of UGT1A1 by massive parallel sequencing of DNA extracted from whole blood. Hepatologists and clinical geneticists evaluated the causal potential of genetic variants. RESULTS: In 9/33 patients (27%), we identified genetic variants as a certain causal factor and in further 9/33 (27%) variants as a possible contributing factor. In most cases, a detailed family history was necessary to establish the importance of genetic variants. Genetic causes were identified in 6/13 women (46%) with intrahepatic cholestasis during pregnancy and persisting abnormal biochemistry after delivery. CONCLUSIONS: Our study suggests that a small number of well-known genetic variants are involved in at least 27-54% of patients with unexplained cholestasis. An expanded panel will likely explain more cases. This motivates genetic testing of these patients. Genetic testing, however, cannot stand alone but should be combined with a clinical genetic work-up in collaboration between hepatologists and clinical geneticists.

Physical exercise for people with cirrhosis.

BACKGROUND: Loss of muscle mass and muscle weakness are common complications to cirrhosis and are associated with increased morbidity and mortality. Therefore, physical exercise may benefit people with cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of physical exercise versus sham exercise or no exercise for people with cirrhosis. SEARCH METHODS: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE Ovid, Embase Ovid, and three other databases, including manual searches through reference lists, abstracts, and presentations at conferences and meetings, Google Scholar, and online trial registers in February 2018. SELECTION CRITERIA: We included randomised clinical trials regardless of publication status or language. Inclusion criteria were cirrhosis irrespective of the aetiology or stage. Interventions were physical exercise compared with sham exercise or no intervention. DATA COLLECTION AND ANALYSIS: Three review authors independently extracted data. We undertook meta-analyses and presented results using risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, both with 95% confidence intervals (CI) and I2 values as markers of imprecision and heterogeneity. We assessed bias control using the Cochrane Hepato-Biliary Group domains and determined the credibility of the evidence using GRADE. MAIN RESULTS: We included six randomised clinical trials with 173 participants. All participants had Child-Pugh stage A or B cirrhosis. The intervention groups participated in eight to 14 weeks of physical exercise (aerobic: three trials; resistance: one trial; or aerobic plus resistance training: two trials). Control groups underwent sham exercise (supervised relaxation: one trial) or no intervention (five trials). None of the 89 participants allocated to exercise versus two of 84 participants in the control group died (RR 0.19, 95% CI 0.01 to 3.73; moderate-quality evidence). The cause of death was acute-on-chronic liver disease for both participants. Nine participants in the exercise group and 13 in the control group experienced serious adverse events (RR 0.61, 95% CI 0.19 to 1.94; low-quality evidence).Physical exercise showed no beneficial or detrimental effect on health-related quality of life assessed by the Chronic Liver Disease Questionnaire (MD 0.11, 95% CI -0.44 to 0.67; low-quality evidence). Likewise, physical exercise had no clear effect on physical fitness measured by peak exercise oxygen uptake (MD 0.3 mL/kg/minute, 95 % CI -2.74 to 3.35; low-quality evidence) and Six-Minute Walk Test (MD 56.06 min, 95% CI -9.14 to 121.26; very low-quality evidence). Physical exercise showed no clear effect on mid-thigh circumference (MD 1.76 cm, 95% CI -0.26 to 3.77; low-quality evidence), but showed an increase in mid-arm circumference (MD 2.61 cm, 95% CI 0.36 to 4.85; low-quality evidence). AUTHORS' CONCLUSIONS: We found no clear beneficial or harmful effect of physical exercise on mortality, morbidity, or health-related quality of life. Further evidence is needed to evaluate the beneficial and harmful effects of physical exercise on clinical outcomes.

Role of Exercise in the Management of Hepatic Encephalopathy: Experience From Animal and Human Studies.

Sarcopenia and malnutrition are common features in patients with hepatic encephalopathy. Ammonia, a factor implicated in the pathophysiology of hepatic encephalopathy, may be cleared by the muscle via the enzyme glutamine synthetase when the liver function is impaired. Hence, optimizing muscle mass in patients suffering from hepatic encephalopathy is a potential strategy to decrease ammonia levels. Exercise could be an efficient therapeutic approach to optimize muscle mass and therefore potentially reduce the risk of hepatic encephalopathy in patients with chronic liver disease. This review reports the current evidence regarding exercise and hepatic encephalopathy from animal and human studies. After defining concepts such as frailty, sarcopenia, and malnutrition, the present knowledge regarding exercise as potential therapy in cirrhotic patients with or without hepatic encephalopathy is discussed. Recommendations and future aspects are also considered.

The role of Branched Chain Amino Acids in the treatment of hepatic Encephalopathy.

The relationship between intake of nutrients and Hepatic Encephalopathy (HE) dates back to the historical roots of experimental hepatology. Branched-Chain Amino Acids (BCAA; Isoleucine, leucine and valine) have attracted particular interest and in 1956 Müting described the amino acid pattern in patients with cirrhosis. The abnormal plasma pattern has been characterized by the ratio between BCAA and aromatic amino acids in plasma, the so called 'Fischer´s ratio'. This ratio has been associated with the grade of HE. Under normal conditions, ammonia detoxification predominantly takes place in the liver. When the liver fails, the homeostasis is altered and muscle tissue becomes the main alternative organ for at least temporary detoxification of ammonia. BCAA are believed to support this muscle ammonia detoxification and the ammonia lowering effect of BCAA has been intensely investigated. In this review the effect of BCAA on muscle ammonia metabolism and the protein sparing and anabolic effects of BCAA are discussed. A Cochrane metaanalysis showed that BCAA had beneficial effects on HE with a number needed to treat of 5 patients (RR 0.73, 95% CI 0.61 to 0.88). The combined evidence suggests that although the pathophysiology is poorly understood, there is evidence to support clinical benefits of BCAA. BCAAs enhance muscle mass and exert anabolic effects via stimulation of protein synthesis. The beneficial long-term effects of BCAA on HE could be related to these effects and not only related to Branched-Chain Amino Acid increased ammonia metabolism.

Development and predictive validity of the cirrhosis-associated ascites symptom scale: A cohort study of 103 patients.

AIM: To develop a scale of domains associated with the health-related quality-of-life (HRQOL) in patients with cirrhosis-related ascites. METHODS: We initially undertook literature searches and a qualitative study in order to design a cirrhosis-associated ascites symptom (CAS) scale describing symptoms with a potential detrimental impact on health related quality of life (HRQL) (the higher the score, the worse the symptoms). Discriminatory validity was assessed in a validation cohort including cirrhotic patients with (1) tense/severe; (2) moderate/mild; or (3) no ascites (controls). Patients also completed chronic liver disease questionnaire (CLDQ) and the EuroQoL 5-Dimensions 5-Level (EQ-5D-5L) questionnaire evaluating HRQL. The relation between scale scores was analysed using Spearman correlations. RESULTS: The final CAS scale included 14 items. The equivalent reliability was high (Chronbach's alpha 0.88). The validation cohort included 103 patients (72% men, mean age 62.4 years). The mean scores for each question in the CAS scale were higher for patients with severe/tense ascites than for mild/moderate ascites and controls. Compared with controls (mean = 9.9 points), the total CAS scale score was higher for severe/tense ascites (mean = 23.8 points) as well as moderate/mild ascites (mean = 18.6 points) (P < 0.001 both groups). We found a strong correlation between the total CAS and CLDQ score (rho = 0.82, P < 0.001) and a moderate correlation between the CAS and the EQ-5D-5L score (0.67, P < 0.001). CONCLUSION: The CAS is a valid tool, which reflects HRQOL in patients with ascites.

[Hepatocellular adenoma - new classification and recommendations]. / Leveradenomer ­ ny klassifikation og anbefalinger

Hepatocellular adenoma (HCA) is a rare benign hepatocellular tumour developed in an otherwise healthy liver. The two main complications are bleeding from the HCA or malignant transformation to hepatocellular carcinoma (HCC). Risk factors for HCC include gender (men), size (> 8 cm) and subtype. Based on new molecular genetic analyses this review describes a new classification of adenomas using both genotype and phenotype. We want to provide an update on adenomas and give updated recommendations for diagnosis and treatment.

Trefoil factors in inflammatory bowel disease.

Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn's disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.