Effectiveness of exercise in hepatic fat mobilization in nonalcoholic fatty liver disease: Systematic review

AIM: To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease(NAFLD) patients.METHODS: Ovid-Medline, Pub Med, EMBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged ≥ 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: "NASH", "NAFLD", "nonalcoholic steatohepatitis", "non-alcoholic fatty liver disease", "fat", "steatosis", "diet", "exercise", "MR spectroscopy" and "liver biopsy". NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy(H-MRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. RESULTS: Eight studies met selection criteria(6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-MRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared thetwo interventions. The beneficial effects of exercise on intrahepatic triglyceride(IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid contents.CONCLUSION: Prescribed exercise in subjects with NAFLD reduces IHTG independent of dietary intervention. Diet and exercise was more effective than exercise alone in reducing IHTG.

Importance of fatigue and its measurement in chronic liver disease

The mechanisms of fatigue in the group of people with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are protean. The liver is central in the pathogenesis of fatigue because it uniquely regulates much of the storage, release and production of substrate for energy generation. It is exquisitely sensitive to the feedback controlling the uptake and release of these energy generation substrates. Metabolic contributors to fatigue, beginning with the uptake of substrate from the gut, the passage through the portal system to hepatic storage and release of energy to target organs (muscle and brain) are central to understanding fatigue in patients with chronic liver disease. Inflammation either causing or resulting from chronic liver disease contributes to fatigue, although inflammation has not been demonstrated to be causal. It is this unique combination of factors, the nexus of metabolic abnormality and the inflammatory burden of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis that creates pathways to different types of fatigue. Many use the terms central and peripheral fatigue. Central fatigue is characterized by a lack of self-motivation and can manifest both in physical and mental activities. Peripheral fatigue is classically manifested by neuromuscular dysfunction and muscle weakness. Therefore, the distinction is often seen as a difference between intention (central fatigue) versus ability (peripheral fatigue). New approaches to measuring fatigue include the use of objective measures as well as patient reported outcomes. These measures have improved the precision with which we are able to describe fatigue. The measures of fatigue severity and its impact on usual daily routines in this population have also been improved, and they are more generally accepted as reliable and sensitive. Several approaches to evaluating fatigue and developing endpoints for treatment have relied of biosignatures associated with fatigue. These have been used singly or in combination and include: physical performance measures, cognitive performance measures, mood/behavioral measures, brain imaging and serological measures. Treatment with non-pharmacological agents have been shown to be effective in symptom reduction, whereas pharmacological agents have not been shown effective.

Advances in cirrhosis: Optimizing the management of hepatic encephalopathy

Hepatic encephalopathy(HE) is a major complication of cirrhosis resulting in significant socioeconomic burden, morbidity, and mortality. HE can be further subdivided into covert HE(CHE) and overt HE(OHE). CHE is a subclinical, less severe manifestation of HE and requires psychometric testing for diagnosis. Due to the time consuming screening process and lack of standardized diagnostic criteria, CHE is frequently underdiagnosed despite its recognized role as a precursor to OHE. Screening for CHE with the availability of the Stroop test has provided a pragmatic method to promptly diagnose CHE. Management of acute OHE involves institution of lactulose, the preferred first-line therapy. In addition, prompt recognition and treatment of precipitating factors is critical as it may result in complete resolution of acute episodes of OHE. Treatment goals include improvement of daily functioning, evaluation for liver transplantation, and prevention of OHE recurrence. For secondary prophylaxis, intolerance to indefinite lactulose therapy may lead to non-adherence and has been identified as a precipitating factor for recurrent OHE. Rifaximin is an effective add-on therapy to lactulose for treatment and prevention of recurrent OHE. Recent studies have demonstrated comparable efficacy of probiotic therapy to lactulose use in both primary prophylaxis and secondary prophylaxis.

Treatment strategies for chronic hepatitis C prior to andfollowing liver transplantation

Hepatitis C virus(HCV)-related liver disease is the leading indication for liver transplantation(LT) worldwide. However, HCV is an independent predictor of lower survival following LT, and recurrence of HCV postLT is virtually universal. The historic standard of care during the interferon era of HCV therapy was expectant management-initiation of antiviral therapy in the setting of documented disease progression following LT. With the advent of new direct acting antiviral(DAA) therapies for HCV, the paradigm of expectant treatment for recurrent HCV infection post-LT is shifting. The safety, tolerability, and efficacy of DAAs, even among the sickest patients with advanced liver disease, enables treatment of HCV in the pre-transplant setting among LT waitlist registrants. Finally, emerging data are supportive of preemptive therapy with DAAs in liver transplant recipients as the preferred approach. Expectant management of HCV following LT can rarely be justified in the modern era of HCV therapy.

Management of nonalcoholic fatty liver disease in the Middle East

The prevalence of nonalcoholic fatty liver disease(NAFLD)in the Middle East is increasing in parallel to an increase in the prevalence of associated risk factors such as obesity,metabolic syndrome,and type 2 diabetes mellitus.About 20%to 30%of the patients progress to develop nonalcoholic steatohepatitis(NASH),a histological subtype of NAFLD,with features of hepatocyte injury such as hepatocyte ballooning.NASH can progress to fibrosis,cirrhosis,and even hepatocellular carcinoma.NAFLD thus causes a substantial burden on healthcare systems and it is imperative that appropriate strategies are discussed at a regional level to facilitate effective management tailored to the needs of the region.To fulfil this unmet need,expert gastroenterologists,hepatologists,and endocrinologists from the region came together in three advisory board meetings that were conducted in Saudi Arabia,United Arab Emirates,and Kuwait,to discuss current local challenges in NAFLD screening and diagnosis,and the different available management options.The experts discussed the disease burden of NAFLD/NASH in the Middle East;screening,diagnosis,and referral patterns in NAFLD;and available treatment options for NAFLD and NASH.This paper summarizes the discussions and opinion of the expert panel on the management of NAFLD/NASH and also presents an extensive literature review on the topic.

Validation of the chronic liver disease questionnaire in Serbian patients

AIM:To translate into Serbian and to investigate the validity of the cross-culturally adapted the chronic liver disease questionnaire(CLDQ).METHODS:The questionnaire was validated in 103 consecutive CLD patients treated between October 2009 and October 2010 at the Clinic for Gastroenterology,Clinical Centre of Serbia,Belgrade(Serbia).Exclusion criteria were:age < 18 years,psychiatric disorders,acute complications of CLD(acute liver failure,variceal bleeding,and spontaneous bacterial peritonitis),hepatic encephalopathy(grade > 2)and liver transplantation.Evaluation of the CLDQ was done based on the following parameters:(1)acceptance is shown by the proportion of missing items;(2)internal reliabilities were assessed for multiple item scales by using Cronbach alpha coefficient;and(3)in order to assess whether the allocation of items in the domain corresponds to their distribution in the original questionnaire(construction validity),an exploratory factor analysis was conducted.Discriminatory validity was determined by comparing the corresponding CLDQ score/sub-score in patients with different severity of the diseases.RESULTS:The Serbian version of CLDQ questionnaire completed 98% patients.Proportion of missing items was 0.06%.The total time needed to fill the questionnaire was ranged from 8 to 15 min.Assistance in completing the questionnaire required 4.8% patients,while 2.9% needed help in reading,and 1.9% involved writing assistance.The mean age of the selected patients was 53.8 ± 12.9 years and 54.4% were men.Average CLDQ score was 4.62 ± 1.11.Cronbach's alpha for the whole scale was 0.93.Reliability for all domains was above 0.70,except for the domain "Activity"(0.49).The exploratory factor analysis model revealed 6 factors with eigenvalue of greater than 1,explaining 69.7% of cumulative variance.The majority of the items(66%)in the Serbian version of the CLDQ presented the highest loading weight in the domain assigned by the CLDQ developers:"Fatigue"(5/5),"Emotional function"(6/8),"Worry"(5/5),"Abdominal symptoms"(0/3),"Activity"(0/3),"Systemic symptoms"(3/5).The scales "Fatigue" and "Worry" fully corresponded to the original.The factor analysis also revealed that the factors "Activity" and "Abdominal symptoms" could not be replicated,and two new domains "Sleep" and "Nutrition" were established.Analysis of the CLDQ score/sub-score distribution according to disease severity demonstrated that patients without cirrhosis had lower total CLDQ score(4.86 ± 1.05)than those with cirrhosis Child's C(4.31 ± 0.97).Statistically significant difference was detected for the domains "Abdominal symptoms" [F(3)= 5.818,P = 0.001] and "Fatigue" [F(3)= 3.39,P = 0.021].Post hoc analysis revealed that patients with liver cirrhosis Child's C had significantly lower sub-score "Abdominal symptoms" than patients without cirrhosis or liver cirrhosis Child's A or B.For domain "Fatigue",patients with cirrhosis Child's C had significantly lower score,than non-cirrhotic patients.CONCLUSION:The Serbian version of CLDQ is well accepted and represents a valid and reliable instrument in Serbian sample of CLD patients.

Interrelationship between physical activity and depression in nonalcoholic fatty liver disease

BACKGROUND Nonalcoholic fatty liver disease(NAFLD)is associated with a sedentary lifestyle and depressive symptoms.It is also well established that physical inactivity and depressive symptoms are related.However,an investigation of the interaction between all of these factors in NAFLD has not been previously conducted.AIM To investigate the interrelationship between physical inactivity and depressive symptoms in individuals with NAFLD.METHODS Data from the Rancho Bernardo Study of Healthy Aging were utilized.589 individuals were included in the analyses(43.1%male;95.8%non-Hispanic white;aged 60.0±7.0 years).NAFLD was defined by using the hepatic steatosis index,depression using the Beck Depression Inventory,and physical activity by selfreport of number of times per week of strenuous activity.Multivariable generalized linear regression models with Gamma distribution were performed to investigate the proposed relationship.RESULTS About 40%of the sample had evidence of NAFLD,9.3%had evidence of depression,and 29%were physically inactive.Individuals with NAFLD and depression were more likely to be physically inactive(60.7%)compared to individuals with neither NAFLD nor depression(22.9%),individuals with depression without NAFLD(37.0%),and individuals with NAFLD without depression(33.3%).After accounting for various comorbidities(i.e.,age,sex,diabetes,hypertension,obesity),individuals with NAFLD and higher levels of physical activity were at a decreased odds of having depressive symptoms[16.1%reduction(95%confidence interval:-25.6 to-5.4%),P=0.004],which was not observed in those without NAFLD.CONCLUSION Individuals with NAFLD have high levels of physical inactivity,particularly those with depressive symptoms.Because this group is at high risk for poor outcomes,practitioners should screen for the coexistence of depressive symptoms and NAFLD.This group should receive appropriate interventions aimed at increasing both participation and levels of intensity of physical activity.