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.

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.

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.

Clinical presentation, diagnosis, and survival in cholangiocarcinoma: A prospective study.

BACKGROUND AND STUDY AIMS: The diagnosis of cholangiocarcinoma (CCA) is difficult. The present study aimed to assess the clinical features, diagnosis, and survival in CCA. PATIENTS AND METHODS: This is a prospective study on 46 patients with CCA who underwent endoscopic retrograde cholangiopancreatography (ERCP) or surgical resection and 20 controls with a clinical and ERCP suspicion for CCA in whom surgical biopsy and/or 4-year follow-up showed a benign biliary stricture. RESULTS: The median age at presentation was 71years (range 44-88). Thirty-four patients (73.9%) presented with painless jaundice. Median CA 19-9 value was 188IU/L (range 1-49,138), with a level of <100IU/L in 13 patients (28%). Total bilirubin was 11.9 (0.6-36.3)mg/dL. The tumour was intrahepatic in 3 (6.5%), hilar (Klatskin) in 25 (54.3%), and located in the lower third of the bile duct in 18 (39.1%) patients. The diagnosis was confirmed by positive cytology in 10 (21.7%), biopsy in 20 (43.5%), cholangioscopy in five (10.9%), and imaging and clinical grounds in 11 (23.9%) patients. Cytology was feasible in 36 patients; it was positive in 10 and "highly indicative" in two patients (33.3% sensitivity). Twenty-two patients (47.8%) were treated by surgical resection, and the rest were offered palliative biliary drainage. Mean estimated survival for the entire group of CCA patients was 21.5±3.3months. Survival was slightly longer in patients who underwent surgical resection than those who had palliative treatment; the estimated mean survival rates were 26.2±4.2 vs. 17.1±3.3months, respectively, but the difference was not statistically significant (p=0.115). CONCLUSION: The diagnosis of CCA is difficult and often delayed. The outcome is generally poor.

Soluble CD146, a novel endothelial marker, is related to the severity of liver disease.

OBJECTIVES: Angiogenesis and inflammation have been involved in the progression of fibrosis in patients with chronic liver disease (CLD). Soluble CD146 (sCD146), a biomarker that was recently characterized as a novel component of the endothelial junction is implicated in endothelial proliferation. Our study evaluates the performance of sCD146 in assessing liver fibrosis and cirrhosis, and determines if its levels are related to the severity of liver disease in patients with cirrhosis. MATERIAL AND METHODS: sCD146 levels were determined by a commercially available immunoenzymatic technique in 62 consecutive patients with cirrhosis, 43 patients with CLD and 27 healthy controls. RESULTS: Patients with cirrhosis compared to non-cirrhotics with CLD had a higher median sCD146 concentration (639 vs. 317 ng/ml). In receiver operating characteristic (ROC) curve analysis, the cut-off of 412 ng/ml showed a sensitivity of 78% and a specificity of 75% for diagnosis of cirrhosis, offering good diagnostic accuracy (area under the ROC curve [AUROC: 0.838]). Patients with compensated compared to those with decompensated cirrhosis had a lower median sCD146 concentration (399 vs. 848 ng/ml, respectively). A cut-off of 534 ng/ml offered a sensitivity of 83% and a specificity of 78% for differentiating compensated from decompensated cirrhosis (AUROC: 0.866). Furthermore, in cirrhotics, sCD146 correlated positively with AST, bilirubin levels and most importantly with international normalized ratio and model for end-stage liver disease (r = 0.648, p < 0.001 and r = 0.567, p < 0.001, respectively). CONCLUSION: sCD146 can be used as a surrogate, inexpensive biomarker for the diagnosis of cirrhosis. It is also well correlated with severity of liver disease in cirrhotic patients. Further studies are needed to define its role in clinical practice.

Presence of spur cells as a highly predictive factor of mortality in patients with cirrhosis.

BACKGROUND AND AIM: The presence of spur-cell anemia (SCA) is due to lipid disturbances of the erythrocyte membrane and may develop in patients with advanced liver cirrhosis. The accurate predicting value of SC for survival has not been clarified. The aim of this study was to evaluate SCA as a prognostic indicator in patients with cirrhosis. METHODS: We prospectively evaluated clinical, laboratory parameters, and survival in patients with cirrhosis, with or without SCA, during the period 2008-2011. Patients who had at admission renal failure, other causes of hemolytic anemia, hepatocellular carcinoma, sepsis, and/or active bleeding, were excluded. One hundred sixteen patients with cirrhosis were included. The presence of SCA (SC rate higher or equal to 5% [≥ 5%]) was diagnosed in 36 (31%) patients. RESULTS: Patients with SCA compared to those without had more advanced liver disease (higher Model for End-Stage Liver Disease [MELD], P < 0.001), higher total bilirubin (P < 0.001), and International Normalized Ratio (P < 0.001). Patients with SCA had worse survival (log rank P < 0.001). Survival of patients with SCA at the first, second, and third month of follow-up was 77%, 45%, and 33%, respectively. In multivariate Cox's regression analysis, the presence of SCA was an independent predictor of mortality (hazard ratio = 3.17 [95% CI 1.55-6.48]). CONCLUSIONS: The presence of spur-cell anemia is not uncommon in cirrhosis and seems to be strongly associated with mortality. SCA can be used in combination with MELD as an additional predictor of early mortality.

An extended fluorescence in situ hybridization approach for the cytogenetic study of cholangiocarcinoma on endoscopic retrograde cholangiopancreatography brushing cytology preparations.

The cytological diagnosis of cholangiocarcinoma has been significantly aided by applying a 4-probe fluorescence in situ hybridization system on endoscopic retrograde cholangiopancreatography brushing smears, aiming mainly at the detection of hyperdiploidy. However, this approach adds little to our understanding of the genetic background of the disease. With the prospect of obtaining additional data on chromosomal aberrations, we have extended the fluorescence in situ hybridization study, with the application of 4 independent 2-probe systems in 35 patients with documented cholangiocarcinoma. Fluorescence in situ hybridization assays were performed on endoscopic retrograde cholangiopancreatography brushing smears, with probes for the 7q31, 11q13 (CCND1), 17p53 (TP53), and 9p21 (INK4 locus) bands, together with the respective centromeric probe. Hyperdiploidy, involving at least 2 of the 4 chromosomes targeted, was found in 31 patients. 17p13 deletion was detected in 3, and 9p21 deletion, in 5 of the hyperdiploid cases, with the 2 aberrations concurrent in 1. CCND1 amplification was found in 1 case as the sole abnormality and in another together with hyperdiploidy, but in apparently unrelated clones. This work indicates that interphase fluorescence in situ hybridization is a practical and useful tool for the cytogenetic study of cholangiocarcinoma on endoscopic retrograde cholangiopancreatography brushing smears, which is often the only available tissue specimen of the tumor. Apart from hyperdiploidy, it provides additional data on the genetic profile of cholangiocarcinoma, especially regarding structural chromosomal aberrations and clonal diversity. This line of investigation may prove useful in the delineation of oncogenesis and the interpretation of the diverse clinical features of the disease.

Modern diagnostic approaches to cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma is a very aggressive tumor with poor survival. Therefore, early diagnosis and surgical resection are of paramount importance. Its diagnosis is difficult because access to the tumor is not easy. Biopsy is possible only for intrahepatic cholangiocarcinoma, which accounts for 10% of cases. Routine brush cytology from endoscopic retrograde cholangiopancreatography (ERCP) has a high specificity of 100% but unfortunately a low sensitivity of 30%. In this review we briefly describe new diagnostic techniques applicable to ERCP brush cytology specimens and targeting the genetic background of the disease, in particular fluorescence in situ hybridization (FISH) and digital image analysis (DIA). DATA SOURCES: The PubMed database up to 2011 was used for the retrieval of relevant articles. The search terms FISH, fluorescence in situ hybridization, DIA, digital image analysis and cholangiocarcinoma were used. Both original and review articles were used. RESULTS: FISH identifies cells with chromosomal abnormalities, mainly numerical aberrations, using a mixture of fluorescence-labeled probes. FISH offers a higher sensitivity than routine cytology, retaining a high level of specificity. The DIA criterion for malignancy is demonstration of aneuploidy. This technique increases the sensitivity to 40%, but the specificity remains low. Preliminary data from application to other tumors suggest that combination of FISH and DIA may be of further benefit. CONCLUSIONS: The new techniques offer a significantly enhanced diagnostic efficacy in the evaluation of ERCP brush specimens. Apart from contributing to a more timely diagnosis, their wider application to cholangiocarcinoma may also facilitate the genetic study of the disease and add to our understanding of oncogenesis at the molecular level, with the prospect of identifying targets for novel therapeutic interventions.