Evaluation of Five Screening Tools in Detecting Physical Frailty in Cirrhosis and Their Prognostic Role.

Background: Physical frailty (PF) is a syndrome of decreased physical function and reserves, preventing patients from coping with stressful events. PF screening tools in patients with liver cirrhosis (LC) can help evaluate the risk of complications and death. The aim of this study was to assess the performance of five screening tools in detecting PF and their ability to predict 18-month mortality in LC. Methods: The Short Physical Performance Battery (SPPB), Fried frailty phenotype (FFP), Clinical Frailty Scale (CFS) and 6-Minute Walk Test (6MWT) were compared with the Liver Frailty Index (LFI) as the method of reference. Patients with an LFI ≥ 4.5, SPPB ≤ 8, FFP ≥ 3, CFS ≥ 6 points, and those walking <250 m, were considered frail. Results: A total of 109 consecutive patients with stable LC were included [63.3% male, median age 62 years, (IQR 52-70), MELD 9 (7-14.5), 46.8% with decompensated LC (DC)]. PF was present in 23.9%, 27.5%, 41.3%, 13.8%, and 28.4% as assessed by the LFI, SPPB, FFP, CFS, and 6MWT, respectively. Cohen's kappa measurement of agreement of four of the tools with LFI was 0.568, 0.334, 0.439, and 0.502, respectively (p < 0.001 for each). Kaplan-Meier survival curves at 18 months showed higher mortality in frail patients compared to non-frail patients by any method (log rank p < 0.05). In the multivariate models, PF defined by any method emerged as an independent prognostic factor of 18-month mortality after adjustment for age, gender, and MELD-score. Conclusions: Patients characterized as frail by five screening tools were not identical. However, PF defined by either method was proven to be an independent poor prognostic factor for long-term mortality after adjustment for covariates.

Evaluation of parameters influencing the quality of colon preparation with a split-dose regimen of sulfate salts.

Background: Bowel cleansing is an important factor for the quality of colonoscopy. We aimed to evaluate the efficacy of split-dose oral sulfate salts on bowel preparation and to determine parameters influencing the quality of bowel cleaning. Method: Consecutive adults who completed their preparation for colonoscopy with a regimen of sulfate salts were enrolled. Results: Of the 446 patients, 11 were excluded from the analysis. Among the 435 patients, 257 (59.1%) were female, mean age was 62.0±11.6 years and median body mass index (BMI) 26.1 kg/m2 (interquartile range [IQR] 23.8-29.4). Indications for colonoscopy were screening 155 (35.6%), surveillance 102 (23.5%), or other 178 (40.9%). The median time between the end of second dose of the preparation regimen and colonoscopy initiation was 5:15 h (IQR 4:30-6:00, min: 2:20, max: 12:20). Minor adverse events were reported in 62 (14.3%) patients. BBPS=9 was observed in 279 (64.14%) patients. Segmental BBPS=3 was achieved in 387 (88.97%), 346 (79.54%) and 289 (66.44%) patients (P<0.001) in the descending, transverse and ascending colon, respectively. Multivariate analysis revealed that BMI (odds ratio [OR] 1.05, 95% confidence interval [CI] 1-1.1) and time between the end of the second laxative dose and colonoscopy initiation (OR 1.25, 95%CI 1.08-1.45) were associated with poorer bowel preparation. Conclusions: A split dose of oral sulfate salts is an efficacious and well tolerated regimen. Obesity and a longer time interval between the end of the second dose and colonoscopy initiation negatively influence bowel cleanliness.

Serial rotational thromboelastometry measurements show worsening hypocoagulability in acute-on-chronic liver failure and are associated with the severity of liver disease.

Background: Viscoelastic tests are used to better understand the complex picture of hemostasis in cirrhosis. Limited data exist regarding the clinical relevance of rotational thromboelastometry (ROTEM) in acute-on-chronic liver failure (ACLF) or acute decompensation (AD). We examined the pattern and role of sequential observations of 9 ROTEM components in both ACLF and AD groups. Method: ROTEM measurements were compared within and between groups at 3 time points: on admission (T1), at 24 h (T2) and 48 h post-admission (T3). Results: Forty-two consecutive patients (22 ACLF, 20 AD) were included. ROTEM determinants exhibited significant hypocoagulable deterioration in ACLF but not in AD over the 3 time points in clot formation time (CFT)EXTEM (P=0.01), maximum clot firmnessEXTEM (P=0.014), CFTINTEM (P<0.001), and alphaINTEM (P=0.028). The sum of hypocoagulable determinants increased from T1 to T3 in ACLF (P=0.029), but remained stable in AD. Five ROTEM variables showed significant differences towards hypocoagulability in ACLF compared to AD at T3. A "hypocoagulable" profile was associated with more severe liver disease (P<0.001 for model for end-stage liver disease [MELD] or Child-Pugh scores) and higher 30- and 90-day mortality (log-rank P=0.001 and P=0.013, respectively) but no more bleeding episodes or transfusions. Two ROTEM variables displayed strong correlations with MELD at T1 and 7 at T3 (|r coefficient|>0.5). Conclusions: ROTEM measurements indicated worsening hypocoagulability shortly post-admission compared to baseline in ACLF, but remained stable in AD. The hypocoagulable derangement was mostly correlated with the severity of liver disease and higher short-term mortality, but not more bleeding episodes.

A combination of clot formation abnormalities in thromboelastometry has a high prognostic value in patients with acute-on-chronic liver failure.

BACKGROUND: Global coagulation tests offer a better tool to assess procoagulant and anticoagulant pathways, fibrinolysis and clot firmness and evaluate more accurately coagulation defects compared to conventional coagulation tests. Their prognostic role in acute-on-chronic liver disease (ACLF) or acute decompensation (AD) has not been well established. AIMS: To assess the properties and prognostic value of the coagulation profile measured by rotational thromboelastometry (ROTEM) in ACLF and AD. METHODS: 84 consecutive patients (35 ACLF and 49 AD) were prospectively studied. Twenty healthy persons matched for age and gender were used as controls. 'Hypocoagulable' or 'hypercoagulable' profiles on admission were assessed based on nine ROTEM parameters and mortality was recorded at 30 and 90 days. RESULTS: Individual ROTEM parameters denoted significantly more hypocoagulability in patients compared to controls. 'Hypocoagulable' profile (defined as a composite of 4 or more ROTEM parameters outside the range) was associated with more severe liver disease assessed either as MELD or Child-Pugh scores ( P  < 0.001 for both) and higher 30-day mortality (Log-rank P  = 0.012). 'Hypocoagulable' profile (HR 3.160, 95% CI 1.003-9.957, P  = 0.049) and ACLF status (HR 23.786, 95% CI 3.115-181.614, P  = 0.002) were independent predictors of 30-day mortality, in multivariate model. A higher early mortality rate was shown in ACLF patients with 'hypocoagulable' phenotype compared to those without (Log-rank P  = 0.017). 'Hypocoagulable' profile was not associated with mortality in AD. CONCLUSION: 'Hypocoagulable' profile was associated with more advanced liver disease and higher short-term mortality in patients with ACLF.

Mechanisms of sarcopenia in liver cirrhosis and the role of myokines.

Sarcopenia is a syndrome characterized by a decline in skeletal muscle quantity and/or quality, strength and performance, leading to unfortunate events, such as injurious falls or even death. It is not identical to frailty and malnutrition, even though there is a significant overlap among these syndromes. In patients with liver cirrhosis (LC), sarcopenia is classified as secondary and has been associated with increased morbidity and mortality during the pre- and post-transplantation period. It can be a result of malnutrition, hyperammonemia, low physical activity, endocrine abnormalities, accelerated starvation, metabolic disturbances, altered gut function leading to chronic inflammation, and alcohol abuse. Myokines are peptides mainly synthesized by contracting muscle and adipose tissue cells and may play a key role in the pathophysiology of sarcopenia. More than a hundred myokines have been recognized, but only a few have been investigated. They can be classified as negative regulators, such as myostatin, tumor growth factor-ß, activins, growth differentiation factor-11, and positive regulators of muscle growth including follistatin, bone morphogenic proteins, and irisin. So far, only myostatin, follistatin, irisin and decorin have been studied in LC-associated sarcopenia. In this review, we focused on the mechanisms of cirrhosis-related sarcopenia and the role of myokines that have already been studied in the literature, either as markers helping in the diagnostic evaluation of sarcopenia, or as prognostic factors of survival. Standard therapeutic options to prevent or treat sarcopenia in LC are also being reported, as well as the possible therapeutic implication of myokines.

The Presence of Myosteatosis Is Associated with Age, Severity of Liver Disease and Poor Outcome and May Represent a Prodromal Phase of Sarcopenia in Patients with Liver Cirrhosis.

BACKGROUND/AIMS: Myosteatosis implies impaired muscle quality. The aim of the study was to investigate the association of myosteatosis with other muscle abnormalities and its role in the prognosis of liver cirrhosis (LC). METHOD: Skeletal muscle index (SMI) and myosteatosis were measured by computed tomography. Myosteatosis was defined as muscle radiodensity and evaluated according to dry body mass index (BMI). Median values and interquartile range were used for continuous and count (percentage) for categorical variables. RESULTS: A total of 197 consecutive patients were included (age 61 (IQR 52-68); 67% male; MELD score 11 (interquartile range 7.5-16)). Myosteatosis was identified in 73.6% and sarcopenia in 44.6% of patients. Myosteatosis was positively associated with age (p = 0.024) and Child-Pugh (p = 0.017) and inversely associated with SMI (p = 0.026). Patients with myosteatosis exhibited lower 360-day survival (log-rank p = 0.001) compared to those without it. MELD (p < 0.001) and myosteatosis (p = 0.048) emerged as negative prognostic factors of survival in multivariate model. Individuals combining low muscle strength and impaired muscle quality and quantity displayed more advanced LC, impaired muscle performance, lower BMI (p < 0.001 each) and a three times higher mortality rate compared to those with low muscle quality alone. CONCLUSIONS: The presence of myosteatosis was associated with advanced age, low skeletal mass and more severe LC. Myosteatosis was associated with poor prognosis and may represent a prodromal phase of muscle degeneration before the development of sarcopenia.

Serum troponin is elevated in acute decompensation and acute-on-chronic liver failure and is associated with severity of liver disease and short-term mortality.

BACKGROUND: The role of high sensitive cardiac Troponin (hs-cTn) in patients with liver cirrhosis (LC) and liver-related acute events is not well established. AIM: To assess the prognostic performance of hs-cTn I in acute decompensation (AD) and acute-on-chronic liver failure (ACLF). METHODS: Two cohorts of consecutive patients, a derivation (retrospective) and a validation (prospective), were evaluated and 30-day-mortality was recorded. Hs-cTnI values were measured. Very low hs-cTnΙ (4 ng/L) was considered the cutoff-level. RESULTS: A total of 296 patients with LC [69.3% male, median age 57 (IQR 51-68) years, MELD score 19 (13-25), ACLF (29.4%), AD (48.3%), and without liver-related acute events (22.3%)] were included in the derivation cohort. The 66.2% of total patients had hs-cTnI ≥4 ng/L. Patients with hs-cTnI ≥4 ng/L were older and had more severe LC compared to those with <4ng/L. The multivariate analysis demonstrated that age (p < 0.001) and MELD (p = 0.001) were independent variables associated with elevated hs-cTnI after adjustment for age, sex and hepatic encephalopathy in total patients.When ACLF and AD were analyzed separately, the mortality was higher in patients with hs-cTnI ≥ 4 ng/L compared to lower values (log-rank p = 0.036 and p = 0.019, respectively). In multivariate analysis, MELD (p < 0.001) and hs-cTnI ≥4 ng/L (p = 0.032) were independent prognostic factors of mortality in ACLF/AD groups, after adjustment for age and sex. Similar results were obtained from the validation cohort (N = 148). CONCLUSIONS: hs-cTnI levels were higher in patients with severe liver disease. The low cutoff-point of 4 ng/L is accurate in ruling out non-survivors mainly in AD group.

HFA-PEFF score as an independent predictor of 2-year mortality in liver cirrhosis patients.

BACKGROUND AND AIMS: Cardiovascular complications of liver cirrhosis include high cardiac output heart failure with reduced afterload and diastolic dysfunction. Heart Failure Association Pre-test assessment, Echocardiography and natriuretic peptide, Functional testing, Final etiology (HFA-PEFF) (values 0-6) is a diagnostic tool for heart failure. It is a cluster of echocardiographic and biochemical parameters. The purpose of this prospective study was to assess if HFA-PEFF score is associated with the severity of liver disease and to determine its prognostic significance in patients with cirrhosis. METHODS: Patients with cirrhosis without an acute event were enrolled. A comprehensive echocardiography study was conducted, brain natriuretic peptide and N-terminal-pro-B-type Natriuretic Peptide levels were measured and HFA-PEFF score was calculated. All patients were prospectively followed up after enrollment. The study end-point was defined as the composite of all-cause death. RESULTS: Seventy-two consecutive patients [median age 59 years (inter-quartile range: 52-65), 72.2% males, Model for End-stage Liver Disease (MELD) 12.9 (8.5-16.3)] were included. The 52.8% had a high HFA-PEFF score (5 or 6) and the 47.2% intermediate/low score (0-4). HFA-PEFF score was correlated with MELD score (rho = 0.566, P < 0.001), but not with age, SBP and heart rate. The median follow-up was 24.2 (9.5-38.8) months. The 1- and 2-year cumulative mortality was higher in patients with high HFA-PEFF compared to those with intermediate/low (log-rank P < 0.001 for both). The predicted 2-year probability of survival in high vs intermediate/low HFA-PEFF was found to be a prognostic factor of death even when adjusted for age, gender and MELD score [hazard ratio = 3.539 (1.134-11.046), P = 0.029]. CONCLUSION: HFA-PEFF score is high among patients with liver cirrhosis, especially those with advanced liver disease. HFA-PEFF score is associated with survival even when adjusting for cirrhosis severity.

Bacterial DNA is a prognostic factor for mortality in patients who recover from spontaneous bacterial peritonitis.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is associated with a high mortality. The aim was to investigate whether bacterial deoxyribonucleic acid (bactDNA) could offer an accurate identification of pathogens and to explore its prognostic role during and early after an SBP episode. METHODS: Consecutive patients with SBP (SBP-group) and patients with decompensated cirrhosis without SBP/bacterascites (control-group) were enrolled. Standard culture methodology was used to isolate and identify pathogens from blood and ascitic fluid (AF). The SeptiFast test was used to identify bactDNA directly from AF. RESULTS: Fifty-five patients, median age 60 (interquartile range [IQR] 53-74), model-for-end-stage liver disease (MELD) score 18 (IQR 13-29), with SBP were prospectively included. AF cultures were positive in 52.7% (17.2% drug-resistant bacteria) and bactDNA in 29.1% (58.2% combined sensitivity). BactDNA results were 84.6% concordant with AF cultures. Three patients had positive bactDNA in the culture-negative SBP-group. BactDNA was negative in all 36 of the control group (100% specificity). In multivariate analysis for 7-day survival, factors adversely affecting outcome were MELD (P=0.049) and C-reactive protein (P=0.012). After patients who died during the first week post-admission were excluded, patients with positive bactDNA had a poor prognosis compared to those with a negative test (log-rank P=0.005). Variables independently associated with 30-day mortality were neutrophil-to-lymphocyte ratio (P=0.011) and positive bactDNA (P=0.020). CONCLUSIONS: No evidence was found for the usefulness of bactDNA to improve bacterial identification during an SBP episode. However, bactDNA was a predictor of 30-day mortality in the subset of patients who recovered from the infection episode.

Myostatin in combination with creatine phosphokinase or albumin may differentiate patients with cirrhosis and sarcopenia.

In patients with liver cirrhosis (LC), sarcopenia is correlated with frequent complications and increased mortality. Myostatin, a myokine, is a potential biomarker of skeletal mass and/or sarcopenia. The aim of this study was to examine the association between myostatin and muscle mass and evaluate myostatin as a biomarker of sarcopenia in LC. Skeletal muscle index (SMI) and myosteatosis were evaluated by computed tomography scan. Muscle quantity and quality along with muscle strength and function were used to diagnose sarcopenia. Serum myostatin was measured by ELISA. One hundred and fifteen consecutive patients with LC [72.2% male, median age 59 yr (IQR 52-67), MELD 12 (8-16), 28.7% with compensated LC] were included. Low SMI was diagnosed in 49.6% and sarcopenia in 34.8% (21.7% severe). Myostatin levels were lower in low (P < 0.001) compared with patients with normal SMI and were strongly correlated with SMI in MELD score ≥ 15 (r = 0.571, P < 0.001). Myostatin was also lower in patients with sarcopenia compared with those without (P < 0.001) and even lower in severe sarcopenia (P < 0.001). In multivariate analysis, myostatin, age, and albumin remained significant predictors of low SMI after adjustment for sex, MELD, and creatine phosphokinase (CPK). Similarly, myostatin and age predicted sarcopenia after adjustment for sex, MELD, CPK, and albumin. The ratios log10myostatin-to-CPK or albumin-to-myostatin were found to have acceptable diagnostic accuracy in ruling out sarcopenia in total patients. However, the best diagnostic performance was shown in MELD ≥ 15 (AUROC 0.829 or 0.801, respectively). Myostatin is independently associated with both skeletal muscle mass and sarcopenia. Myostatin in combination with CPK or albumin are good surrogate markers in excluding sarcopenia.NEW & NOTEWORTHY Serum levels of myostatin were significantly lower in cirrhotic patients with impaired skeletal mass index (SMI) and sarcopenia than those without. Serum levels of myostatin have a positive correlation with SMI. Myostatin levels are independently associated with sarcopenia, diagnosed according to the latest criteria, in patients with cirrhosis. Myostatin in combination with creatine phosphokinase or albumin have good accuracy excluding sarcopenia in patients with cirrhosis.

New Approaches to the Treatment of Chronic Hepatitis B.

The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.

Human beta-defensin-1 is a highly predictive marker of mortality in patients with acute-on-chronic liver failure.

BACKGROUND & AIM: Human beta-defensin-1 (hBD-1) is a natural antimicrobial peptide expressed in the epithelia of multiple tissues including the digestive tract. In the current study, hBD-1 levels were determined in different subsets of patients with decompensated cirrhosis including acute-on-chronic liver failure (ACLF). In addition, the association with mortality of hBD-1, C-reactive protein (CRP) and procalcitonin (PCT) was assessed. METHODS: A total of 125 patients were divided into three groups: 39 with ACLF (derivation cohort), 46 with acute decompensation without ACLF (AD) and 40 with decompensated cirrhosis without an acute event (DC). The data from 24 different ACLF patients were used for validation and 15 healthy individuals as control group. RESULTS: Serum hBD-1, CRP and PCT levels were higher in ACLF compared to both AD and DC groups (P < 0.001). Healthy controls demonstrated similar hBD-1 and PCT values compared to DC group. In ROC curve, the performance of hBD-1 to predict 60-day mortality in ACLF group was similar in derivation and validation cohorts (c-statistic 0.834 and 0.879, respectively). CRP was a poor predictor of mortality. In ACLF group, patients with high hBD-1 (>36.625 ng/mL) had a poor prognosis at 60 days compared to those with lower values (log-rank P = 0.001). In Cox multivariate regression analysis, only hBD-1 (HR 1.020, 95%CI 1.006-1.035, P = 0.006) emerged as an independent predictor of death in ACLF group. In AD group, neither hBD-1 nor PCT or CRP variables were associated with mortality. CONCLUSIONS: High hBD-1 was detected at presentation in patients with ACLF who died during follow-up period. hBD-1 is an accurate predictor of short-term mortality in patients with ACLF.

Evaluation of noninvasive markers for the diagnosis of cystic fibrosis liver disease.

OBJECTIVES: In cystic fibrosis (CF), liver disease (LD) is the third leading cause of mortality. As liver biopsy was considered inconsistent in CFLD diagnosis, a combination of modalities were utilized in the conventional Debray criteria (DC). More recently, noninvasive liver fibrosis biomarkers were applied by Koh et al (New criteria-NC). In the current study, we aimed to evaluate noninvasive biomarkers for the CFLD diagnosis. METHODS: Longitudinal data were collected from a cohort of genetically confirmed CF patients. CFLD was diagnosed by both DC and NC. Apart from transient elastography (TE) > 6.8 kPa, biomarkers incorporated in the NC included AST/ALT-ratio (AAR) ≥ 1, FIB-4 index ≥3.25 and APRI >0.50. RESULTS: 62 patients with CF, [56.5% male, age at enrollment 25 (22-31) years], were prospectively followed-up for 33 (28-36) months. Sixteen (25.8%) and 27 (43.5%) patients met DC and NC, respectively. Twenty-four fulfilling NC had at least one positive biomarker (6 TE, 7 AAR, 6 both TE and AAR, 2 both APRI and AAR and 3 both APRI and TE). Thirteen (48.1%) had diffuse LD/cirrhosis by the NC and all had at least one additional parameter classifying them as CFLD. From the 14 (51.8%) with no-diffuse-LD, 64.3%, 14.3% and 21.4% had 2, 3 and 4 of the necessary modalities incorporated in NC, respectively, confirming their classification as CFLD. TE was 100% specific to rule in CFLD but had a moderate sensitivity. CONCLUSIONS: NC were able to identify 17.7% more CFLD patients compared to DC. The multiple biomarkers incorporated in NC may enhance the ability to detect CFLD.

Bacterial translocation markers in liver cirrhosis.

Bacterial translocation (BT) is an important mechanism in the development of infection in liver cirrhosis. The migration and colonization of bacteria and/or bacterial products from the bowel to mesenteric lymph nodes is a controlled process in healthy persons. Increased intestinal permeability, bacterial overgrowth and defect of gut-associated lymphatic tissue promote impaired BT in cirrhotics. We reviewed the reports on markers used for the evaluation of BT published between 1987 and 2016. We focused on the clinical consequences of BT in cirrhosis, as indicated by the values of the BT markers. Patients with cirrhosis are reported to have elevated levels of surrogate markers associated with BT compared with controls. The most widely used BT parameters are C-reactive protein, procalcitonin, bacterial DNA, endotoxin or lipopolysaccharide, lipopolysaccharide binding protein, calprotectin, and bactericidal/permeability increasing protein. High levels of these factors in serum and/or ascitic fluid in humans may be associated with advanced liver disease, hemodynamic instability, high levels of proinflammatory cytokines, susceptibility to the development of severe or recurrent infections, acute-on-chronic liver failure, hepatic encephalopathy, hepatorenal syndrome and poor prognosis during follow up. In conclusion, high levels of BT markers are associated with a high inflammatory response, increased complications of liver cirrhosis and occasionally high fatality rates.