A Multicenter Pilot Randomized Clinical Trial of a Home-Based Exercise Program for Patients With Cirrhosis: The Strength Training Intervention (STRIVE).

INTRODUCTION: We developed the strength training intervention (STRIVE), a home-based exercise program targeting physical function in patients with cirrhosis. In this pilot study, we aimed to evaluate the safety and efficacy of STRIVE. METHODS: Eligible were adult patients with cirrhosis at 3 sites. Patients were randomized 2:1-12 weeks of STRIVE, a 30-minute strength training video plus a health coach or standard of care (SOC). Physical function and quality of life were assessed using the Liver Frailty Index (LFI) and Chronic Liver Disease Questionnaire (CLDQ), respectively. RESULTS: Fifty-eight and 25 were randomized to STRIVE and SOC arms, respectively: 43% women, median age was 61 years, MELDNa, Model for End-Stage Liver Disease Sodium was 14, and 54% were Child-Pugh B/C. Baseline characteristics were similar in the STRIVE vs SOC arms except for rates of hepatic encephalopathy (19 vs 36%). LFI @ 12 weeks was available in 43 STRIVE and 20 SOC participants. After 12 weeks, the median LFI improved from 3.8 to 3.6 (ΔLFI -0.1) in the STRIVE arm and 3.7 to 3.6 (ΔLFI -0.1) in the SOC arm (P = 0.65 for ΔLFI difference). CLDQ scores improved from 4.6 to 5.2 in STRIVE participants (ΔCLDQ 0.38) and did not change in SOC participants (4.2-4.2; ΔCLDQ -0.03) (P = 0.09 for ΔCLDQ difference). One patient died (SOC arm) of bleeding. Only 14% of STRIVE participants adhered to the strength training video for 10-12 weeks. No adverse events were reported by STRIVE participants. DISCUSSION: STRIVE, a home-based structured exercise program for patients with cirrhosis, was safely administered at 3 sites, but adherence was low. Although all participants showed minimal improvement in the LFI, STRIVE was associated with a substantial improvement in quality of life.

Resistance training combined with blood flow restriction in cirrhosis: study protocol for a randomized controlled trial.

BACKGROUND: Patients affected by hepatic cirrhosis show reductions in muscle mass and function, with poor quality of life and functional performance. As such, resistance training with blood flow restriction (BFR-RT) could be a useful therapeutic tool for health promotion. Thus, we aim to verify the effects of this intervention on muscle strength, muscle mass, fiber Pennation angle, fascicle length, functional performance, quality of life, and fall risk scores in this population. METHODS: Thirty participants will be randomly distributed between 1) BFR-RT and 2) control (CTRL). Assessments will occur at three time points: before the training intervention (0 W), after 12 weeks (12 W), and at follow-up (24 W). The following variables will be assessed: Child-Pugh classification; MELD score; SF-36 questionnaire; fatigue severity index; 6-min walk test; timed-up and go; 30-s sitting and rising test; dietary record; one-repetition maximum (1-RM) strength test (knee extension exercise); and vastus lateralis' cross-sectional area, Pennation angle, and fascicle length. The BFR-RT group will undergo 12 weeks of knee extension exercise (1 × 30 repetitions and 3 × 15 repetitions at 20% 1-RM and 50% of total blood flow occlusion pressure), with two sessions per week. Data normality will be assessed using the Shapiro-Wilk test. In case of normal distribution, a one-way repeated measures analysis of variance will be implemented to test for differences in baseline values. A mixed model then will be applied for each dependent variable. In case of non-normal data distribution, a Kruskal-Wallis test will be implemented to test for differences in baseline values. Next, the Friedman test will be used to analyze repeated measures. Within- and between-group effect sizes will be calculated using Cohen's d for each outcome. Finally, the minimal clinically important difference will be analyzed with distribution-based methods. DISCUSSION: To our knowledge, this will be the first trial to investigate BFR-RT in patients with cirrhosis and evaluate the effects on neuromuscular parameters, functional performance, disease severity, and quality of life outcomes. TRIAL REGISTRATION: Brazilian Clinical Trials Registry (ReBec): RBR-395mfw. Registered on 25 August 2018.

Cardiovascular Acute Effects of Traditional vs. Paired Set Resistance Training in Patients With Liver Cirrhosis.

Purpose: This study compared the acute effects of two different resistance training methods on heart rate variability, blood pressure, and rating of perceived exertion in patients with liver cirrhosis. Methods: Ten patients with Child-Pugh A (seven women and three men) participated in two experimental sessions, in random order: The traditional set condition consisted of three sets of six exercises performed in a sequential manner, while the paired set condition consisted of alternating sets between two exercises (three pairs of exercises). Ten repetitions were performed for each set with 70% of a 10 repetition maximum load and with 2 min rest between sets. Blood pressure and heart rate variability were assessed pre-workout and for 60 min post-workout. The rating of perceived exertion was assessed at the end of the third set for each exercise. Results: Significant alterations in heart rate variability were observed when considering the lowest value obtained during recovery, in which the SDNN was reduced in both the traditional set and paired set conditions, as well as the root mean square of standard deviation for the traditional set condition (p < .05). Additionally, for the paired set condition, there was a significant reduction in the HFnu band and a significant increase in the LFnu band (p < .05). Effect size showed reductions in diastolic and mean blood pressure until 30 min in a small magnitude for traditional sets. Conclusion: Similar cardiovascular responses were observed between methods eliciting normal physiological responses within safe limits for patients with liver cirrhosis.

An Outpatient Hospital-based Exercise Training Program for Patients With Cirrhotic Liver Disease Awaiting Transplantation: A Feasibility Trial.

BACKGROUND: Time spent on the waiting list before liver transplantation (LT) provides an opportunity to optimize recipient fitness through prehabilitation, potentially reducing the physiological impact of major surgery. We assessed the feasibility and effectiveness of a 6-week exercise program in patients with cirrhotic liver disease awaiting LT. METHODS: This single-center, prospective cohort, feasibility study, enrolled patients awaiting LT to a 6-week period of thrice weekly, supervised exercise on a static bike. Cardiopulmonary exercise testing (CPET) was used to objectively assess cardiopulmonary fitness at baseline and after 6 weeks of exercise. A follow-up CPET was performed at 12 weeks. CPET-derived measures were used to guide prescription of the training program. A nonrandomized control cohort of LT patients were selected to match the exercise group based on specific demographic data. Allocation to study arms was primarily based on the distance participants lived from the hospital where training occurred. Both groups received structured nutritional advice. RESULTS: The exercise program was feasible, with 9 of 16 (56%) patients completing the full program of 6 weeks. Peak oxygen consumption (VO2peak) in the exercise group rose from a mean (SD) of 16.2 (±3.4) mL/kg/min at baseline to 18.5 (±4.6) mL/kg/min at week 6 (P = 0.02). In the control group, VO2peak decreased from a mean (SD) of 19.0 (±6.1) mL/kg/min to 17.1 (±6.0) at week 6 (P = 0.03). CONCLUSIONS: We have demonstrated that it is feasible to engage patients awaiting LT in an intensive aerobic exercise program with a signal of improvement in fitness being detected.

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.

Changes in Muscle Strength and Six-Minute Walk Distance Before and After Living Donor Liver Transplantation.

BACKGROUND: Impaired exercise capacity and muscle weakness are important characteristics of liver transplantation recipients. Perioperative rehabilitation has been introduced to promote early mobilization of patients and to prevent postoperative pulmonary complications. However, it is unknown how physical status recovers during the hospital stay after a liver transplant. The purpose of this study was to evaluate the changes in clinical indicators that represent the functional exercise capacity and muscle strength before and after living donor liver transplantation (LDLT). METHODS: We retrospectively reviewed 21 consecutive patients who underwent LDLT with perioperative rehabilitation from April 2014 to December 2015. Twelve patients who were tested for 6-minute walk distance, hand-grip strength, and isometric knee extensor muscle strength before and 4 weeks after LDLT were enrolled. RESULTS: At the preoperative baseline, the 6-minute walk distance significantly correlated with the Model for End-stage Liver Disease score and pulmonary functions (vital capacity, forced vital capacity, and forced expiratory volume in 1 second of predictive values). Comparisons between the preoperative and postoperative values revealed significant decreases in weight, Barthel Index, hand-grip strength, and isometric knee extensor muscle strength. Changes in hand-grip strength and isometric knee extensor muscle strength after LDLT correlated with the preoperative Model for End-stage Liver Disease score. CONCLUSIONS: Physical functional status had not been fully recovered 4 weeks after LDLT. Further investigation regarding developing a strategy for prevention of muscle atrophy before LDLT and recovery of physical fitness after LDLT would be helpful.

In patients with liver cirrhosis, proinflammatory interleukins correlate with health-related quality of life irrespective of minimal hepatic encephalopathy.

BACKGROUND: Liver cirrhosis is associated with latent systemic inflammatory response syndrome as evidenced by elevated levels of proinflammatory cytokines. It has been proposed that inflammatory mediators play a role in the pathogenesis of minimal and overt hepatic encephalopathy (HE); hence, they may also have an effect on health-related quality of life (HRQL). The aim of this study was to investigate the relationship between serum levels of interleukin-1ß (IL-1ß), IL-6, and IL-18 and the occurrence of minimal HE and HRQL. METHODS: Forty-two consecutive patients with liver cirrhosis were prospectively enrolled to the study. Minimal HE was detected by the Psychometric Hepatic Encephalopathy Score (PHES) and critical flicker frequency. HRQL was assessed with Chronic Liver Disease Questionnaire and 36-Item Short Form Health Survey (SF-36) questionnaires. The interleukins studied were determined using colorimetric sandwich enzyme-linked immunosorbent assay. RESULTS: Serum levels of interleukins correlated with liver dysfunction, but did not discriminate patients with minimal HE from those with overt or absent HE. IL-1ß and IL-6 showed significant correlations with PHES, but showed no relationship with critical flicker frequency. Serum IL-6 and IL-18 correlated with both physical-related general health and mental component summary evaluated by the SF-36 questionnaire. CONCLUSION: This study shows that chronic inflammation plays a role in impaired HRQL in patients with cirrhosis irrespective of minimal HE.

The efficacy of nocturnal administration of branched-chain amino acid granules to improve quality of life in patients with cirrhosis.

BACKGROUND: Nocturnal administration of branched-chain amino acid (BCAA) granules improves serum albumin levels in patients with cirrhosis. However, it is unclear whether or not this administration method can improve the patients' quality of life (QOL). In this study, we aimed to investigate the efficacy of BCAA granules, given nocturnally, in improving QOL in these patients. METHODS: We performed a multicenter, randomized controlled trial examining the comparative effects of BCAA granules given orally for 3 months with daytime or nocturnal administration in patients with compensated cirrhosis. Health-related QOL was measured by a Japanese version of the questionnaire on subjective and objective symptoms, and the Short Form-8 (SF-8) questionnaire. RESULTS: Twenty-one patients received BCAA granules three times a day (one sachet after each meal: the daytime group), and 16 patients received the granules twice a day (one sachet after breakfast, and two sachets before bedtime: the nocturnal group). Baseline characteristics did not differ between the groups (whole cohort: Child-Pugh grade A/B, 21/16; mean age, 68.2 years). There was no significant difference in any of the subjects revealed by the questionnaire regarding subjective or objective symptoms, or by the SF-8 between the daytime group and the nocturnal group after 3 months of treatment. The daytime group showed a significant effect on general health, vitality, social functioning, mental health, and role emotional as revealed on the SF-8. Conversely, the nocturnal group exhibited a significant decrease in the occurrence of muscle cramps in the legs (P = 0.014) and significantly improved Fisher's ratio after 3 months (P = 0.04). CONCLUSIONS: Nocturnal administration of BCAA granules in patients with cirrhosis reduced the occurrence of muscle cramps in the leg but did not improve the patients' QOL.

Quality of life in cirrhosis.

Quality of life is a construct that reflects the positive and negative aspects of one's life, and is expanded upon by health-related quality of life (HRQL), which specifically address the impact of health on patients' well-being. Cirrhosis is the culmination of various pathways that leads into development of advanced hepatic fibrosis with its complications. This paper addresses the impact of cirrhosis on individuals HRQL. In addition, we will define what disease specific and general HRQL instruments aim to measure. We discuss the liver disease specific scales [Chronic Liver Disease Questionnaire (CLDQ), Liver Disease Quality of Life 1.0 (LDQOL)] and the most commonly used generic health profile [Short Form 36 Profile (SF-36)]. Furthermore, we examine recent literature which describes how to measure and what is known about quality of life of patients with cirrhosis. This information gives insight to health care providers concerning the impact of disease on patients if treatments are not only to improve health but also function and unexpected treatment outcomes.

[Chronic fatigue. IV--Assessment of a 40-year-old patient]. / Chronische Müdigkeit. IV-Abklärung eines 40-jährigen Exploranden.

A forty year old patient was referred by the federal insurance for medical assessment. His presenting complaint was chronic fatigue. The patient had been an intravenous drug user for years and had been infected with hepatitis C. He was treated with interferon. The patient history showed that he also suffered from anaemia and depression. He participated in a methadone substitution program. Our diagnostic procedures showed that he also has Hashimoto's thyroiditis.

Enteral nutrition in severely malnourished and anorectic cirrhotic patients in clinical practice.

OBJECTIVES: To determine among severely malnourished cirrhotic patients remaining anorectic during hospital stay which patients may benefit from enteral nutrition in clinical practice. METHODS: A prospective study including malnourished cirrhotic patients fed by enteral nutrition because of inadequate dietary intake after one-month hospitalization was carried out in a department receiving patients from other hospitals. Patients who died during hospital stay (N=35, group I) were compared to surviving patients (N=28, group II). RESULTS: Nutritional status and spontaneous dietary intake on admission to our department were in the same range in the two groups, Pugh score was higher in group I (11.1 +/- 1.9 vs 9.1 +/- 2.0, P=0.0001). The delay between previous hospital admission and the outset of enteral nutrition was comparable in the two groups. Its duration and total dietary intake during enteral nutrition were higher in group II (respectively 42.2 +/- 30.9 vs 15.2 +/- 33.1 days, P=0.0016 and 41.1 +/- 13.0 vs 29.9 +/- 10.0 kcal/kg/d, P=0.0004). Prevalence of side effects was higher in group I (54.3 vs 17.9%, P=0.0031). Multivariate analysis showed that Pugh score and septic complications were negatively associated with survival (respectively P=0.0196 and P=0.0078) while duration of enteral nutrition was positively associated (P=0.0435). Eighty six per cent of patients receiving enteral nutrition with bilirubin levels above 74 micromol/L on admission to our department died during hospital stay. Mid-term effects of enteral nutrition in surviving patients were improvement in Pugh score (7.5 +/- 2.0 vs 9.1 +/- 2.0, P<0.0001) and increase in spontaneous caloric and protein intake (29.7 +/- 15.3 vs 18.1 +/- 10.1 kcal/kg/d, P=0.0150 and 1.0 +/- 0.5 vs 0.6 +/- 0.3 g/kg/d, P=0.0049). CONCLUSIONS: In severely malnourished cirrhotic patients remaining anorectic after one-month hospitalization, patients with bilirubin level below 74 micromol/L may benefit from six-week enteral nutrition with mid-term improvement in liver function and increase in spontaneous dietary intake.

Maintained cerebral and skeletal muscle oxygenation during maximal exercise in patients with liver cirrhosis.

BACKGROUND/AIMS: In cirrhotic patients, insufficient redistribution of blood from splanchnic organs to the central circulation could limit blood supply to skeletal muscles and the brain during exercise. METHODS: Eight cirrhotic patients performed incremental cycling to exhaustion (74 (49-123) W; median with range). RESULTS: Heart rate increased from 68 (62-88)beats/min at rest to 142 (116-163)beats/min, cardiac output from 5.1 (3.3-7.2) to 12.9 (8.5-15.9)l/min, and mean arterial pressure from 89 (75-104) to 115 (92-129)mmHg (P<0.05), while the indocyanine green elimination determined hepatosplanchnic blood flow declined from 0.97 (0.55-1.46) to 0.62 (0.36-1.06)l/min (P<0.05). As assessed by near-infrared spectrophotometry, cerebral oxygenation (NIRS) was 61% (48-85%) and increased to 72% (57-86%) during exercise (P<0.05). The NIRS determined oxygenation of the vastus lateralis muscle also increased: the concentrations of oxygenated haemoglobin by 5.9 (0.57-9.47)micromol/l, deoxygenated haemoglobin by 7.2 (1.8-12.0)micromol/l, and thus total haemoglobin by 12.1 (3.6-21.5)micromol/l (P<0.05). CONCLUSIONS: In patients with cirrhosis, exercise reduces hepatosplanchnic blood flow, while O(2) supply to muscle and brain appears to increase indicating that blood redistribution from splanchnic organs does not limit blood flow to working muscles and the brain.

Avaliação do intervalo QT corrigido em diferentes estágios da cirrose hepática pós-viral / QT interval analysis in different stages of post viral liver cirrhosis

Fundamentos: Estudos prévios demosntram uma associação direta entre o prolongamentodo intervalo QT corrigido(QTc) e o estágio da cirrose hepática pós viral(CH). Estes dados sugerem que o QTc pode representar um marcador prognóstico de mortalidade e disfunçãoautonômica na cardiomiopatia cirrótica. Objetivo: Estabelecer possíveis correlações entre o prolongamento do QTc, o estágio da CH e os níveis séricos de bilirrubina em pacientes cirróticos sem evidências de comprometimento cardiovascular primário. Métodos: estudo prospectivo e randomizado de 35 pacientes com CH, estratificados em 3 grupos de acordo com a classificação de Child-Pugh. O eletrocardiograma de 12 derivações foi obtido na posição supina, contendo pelo menos 5 complexos QRS em cada derivação. Utilizou-se a fórmula d Bazett modificada para mensuração do QTc[QT+0,00175X(FC-60)]. Também foram realizadas dosagens séricas de bilirrubina e demais marcadores de gravdade da CH. Resultados: Todos os pacientes estavam em ritmo sinusal, com frequência cardíaca(FC) média de 65,8 bpm e QTc entre 353 ms e 508 ms(426,7 ms). O prolongamento do QTc na população amostral não se associou às diferenças encontradas em relação à FC, ao sexo, à cor, à idade ou ao tempo de diagnóstico da CH. Intervalos QT mais longos foram encontrados em pacientes Child C x Child B(469,6 ms x 418,9 ms) e Child C x Child A (469,6 ms x 408,7 ms; p igual 0,0001). O QTc também se correlacionou diretamente com os níveis séricos de bilirrubina total (r igual 0,35; p igual 0,03). Houve associação significativa(p igual 0,001) entre o número de pontos do escore Child Pugh e o QTc. Conclusão: A avaliação do intervalo QTc identificou uma associação direta entre seu prolongamento e o estágio da CH. Níveis elevados de bilirrubina estiveram associados a intervalos QTc mais longos no grupo de pacientes cirróticos estudados. Futuros estudos, incluindo outras variáveis associadas à disfunção autonômica, poderão auxiliar na caracterização do QTc como marcador de disfunção autonômica nos estágios mais avançados da CH que apresentem cardiomiopatia cirrótica

[Social-medical aspects of chronic liver diseases]. / Sozialmedizinische Aspekte chronischer Lebererkrankungen.

In our country liver diseases are frequent and have many different causes. They can often develop into cirrhosis of the liver with mortality beetween 13.5% and 24.5%. Hepatitis B and C-viral infections frequently play a significant role in the recognition of an occupational disease in the case of medical staff, with histological criteria of major importance in this respect. A consequence of cirrhosis of the liver may be the development of hepatoencephalopathia of varying degrees of severity. As it is then likely that a patient will no longer be able to drive motor vehicles, it is important that attending physicians inform their patients accordingly. Liver transplants are an acknowledged method of treatment in the therapy of advanced liver cirrhosis. Rehabilitation shortly after transplantation is highly important to help ensure a speedy return to work. Surprisingly, reintegration is more difficult in patients suffering from alcohol related liver disease than in those with non-alcohol-related liver disease.

[Health education for chronic liver and pancreatic diseases: Discussion groups "chronic liver disease" (CL), "chronic pancreatic disease" (CP)]. / Schulung bei Leber- und Pankreaserkrankungen: Gesprächsgruppe "Chronische Lebererkrankungen" (CL) /"Chronische Pankreaserkrankungen" (CP).

The article deals with our experience in the educational programs for patients with chronic liver diseases and chronic pancreatic diseases.The structure of our educational programs is modular, the main event is the discussion group "Chronic Liver Diseases" (CL) (2 meetings are headed by physicians, 1 by psychologists, duration in all 3,6 hours) respectively the discussion group "Chronic Pancreatic Diseases" (CP) (2 meetings headed by physicians, 1 by nutrition consultants, duration in all 2,6 hours). As needed, additional modules can be added, for example specific seminars in case of alcohol abuse or educational programs for diabetics. The average number of participants is between 7 - 15 persons in the discussion group CL, respectively 11 - 20 in the discussion group CP. An overhead projector is used to address the various topics, the patients are encouraged to actively participate in the discussion. The contents can be found in a structured curriculum and focus on anatomical basics, diagnostic and therapeutic aspects, physical fitness and performance in professional life.