Advances in omics-based biomarker discovery for biliary tract malignancy Diagnosis:A narrative review.

Biliary tract neoplasms, which originate from the intrahepatic or extrahepatic biliary epithelium, are relatively rare but diagnostically challenging types of tumours, and their morbidity and mortality have increased in recent years. Due to ineffective early diagnostic methods, once detected, patients are in an advanced stage with a poor prognosis and few treatment options. With the development of omics technologies, the associations between microorganisms, bile acid and salts, noncoding RNAs and biliary tract malignancies have been gradually revealed, providing new methods for the discovery of diagnostic biomarkers. Here, we review the research advances in microbiomics, transcriptomics, metabolomics, and proteomics in the discovery of diagnostic biomarkers for biliary tract malignancies.

The endoscopic ultrasound probe findings in prediction of esophageal variceal recurrence after endoscopic variceal eradication therapies in cirrhotic patients: a cohort prospective study.

BACKGROUND: The recurrence of esophageal varices remains high in patients with hepatic portal hypertension after the endoscopic esophageal variceal eradication therapies, including endoscopic variceal band ligation (EVL), injection sclerotherapy (EIS) or EVL plus EIS. The aim of this study was to evaluate the endoscopic ultrasound probe examinations (EUP) findings in the prediction of recurrence following esophageal variceal eradication in a prospective cohort. METHODS: A total of 206 cirrhotic portal hypertension patients with esophageal variceal eradication, who underwent endoscopic variceal therapy (EVL or EIS or EVL plus EIS) were initially enrolled. All patients were scheduled for a follow-up every 6 months for up to 3 years. EUP was performed to evaluate peri-esophageal collateral veins (peri-ECVs), perforating veins (PFV) and para-esophageal collateral veins (para-ECVs). In addition, computed tomography (CT) were conducted to detect portal vein diameter, portal vein embolus, and major portosystemic collateral shunts. The relationship between esophageal variceal recurrence and EUP findings were analyzed. RESULTS: We found that as high as 93.5% of patients developed esophageal variceal recurrence in the 3-year follow-up. The time of esophageal variceal recurrence after variceal eradication was 13.4 months (13.4 ± 9.2 months). Furthermore, the median time of recurrence in patients who were undertaken EVL,EIS and EVL plus EIS was 10, 13 and 12 months, respectively. We identified that the risk factors, including EVL (OR 0.23, 95% CI 0.08-0.71, p < 0.01), Child-Pugh score (OR 3.32,95% CI 1.31-35.35, p < 0.05), large peri-ECVs (OR 4.56, 95% CI 2.17-9.58, p < 0.0001), and existence of PFV (OR 2.14, 95% CI 1.44-3.16, p < 0.001), were significantly associated with the recurrence of esophageal varices. The peri-ECVs and PFV showed better ability to predict esophageal variceal recurrence. When cut-off value of peri-ECVs diameter was 3.5 mm, the specificity of prediction 1-year variceal recurrence was 86% and the sensitivity was 45%. CONCLUSIONS: The EUP appears to be very effective, convenient and economical examinations to predict esophageal varices recurrence after variceal eradication by endoscopic therapies. The high Child-pugh score, large peri-ECVs, and PFV are independent risk factors related to esophageal varices recurrence.

Measurement of serum procalcitonin levels for the early diagnosis of spontaneous bacterial peritonitis in patients with decompensated liver cirrhosis.

BACKGROUND: It is difficult to diagnose spontaneous bacterial peritonitis (SBP) early in decompensated liver cirrhotic ascites patients (DCPs). The aim of the study was to measure serum procalcitonin (PCT) levels and peripheral blood leukocyte/platelet (WBC/PLT) ratios to obtain an early diagnostic indication of SBP in DCPs. METHODS: Our cohort of 129 patients included 112 DCPs (94 of whom had infections) and 17 cases with compensated cirrhosis as controls. Bacterial cultures, ascitic fluid (AF) leukocyte and peripheral WBC/PLT counts, and serum PCT measurements at admission were carried out prior to the use of antibiotics. Receiver operating characteristic (ROC) curves were generated to test the accuracies and cut-off values for different inflammatory markers. RESULTS: Among the 94 infected patients, 66 tested positive by bacterial culture, for which the positivity of blood, ascites and other secretions were 25.8%, 30.3% and 43.9%, respectively. Lung infection, SBP and unknown sites of infection accounted for 8.5%, 64.9% and 26.6% of the cases, respectively. Serum PCT levels (3.02 ± 3.30 ng/mL) in DCPs with infections were significantly higher than those in control patients (0.15 ± 0.08 ng/mL); p < 0.05. We used PCT ≥0.5 ng/mL as a cut-off value to diagnose infections, for which the sensitivity and specificity was 92.5% and 77.1%. The area under the curve (AUC) was 0.89 (95% confidence interval: 0.84-0.91). The sensitivity and specificity were 62.8% and 94.2% for the diagnosis of infections, and were 68.8% and 94.2% for the diagnosis of SBP in DCPs when PCT ≥2 ng/mL was used as a cut-off value. For the combined PCT and WBC/PLT measurements, the sensitivity was 76.8% and 83.6% for the diagnosis of infections or SBP in DCPs, respectively. CONCLUSION: Serum PCT levels alone or in combination with WBC/PLT measurements seem to provide a satisfactory early diagnostic biomarker in DCPs with infections, especially for patients with SBP.

Effects of Berberine on Diabetes and Cognitive Impairment in an Animal Model: The Mechanisms of Action.

Diabetes is a group of metabolic disorders with an increased risk of developing cognitive impairment and dementia. The hippocampus in the forebrain contains an abundance of insulin receptors related to cognitive function and plays an important role in the pathophysiology of neurodegenerative disorders. Berberine from traditional Chinese medicine has been used to treat diabetes and diabetic cognitive impairment, although its related mechanisms are largely unknown. In this study, a STZ diabetes rat model feeding with a high-fat diet was used to test the effects of berberine compared with metformin. Oral glucose tolerance and hyperinsulinemic-euglycemic clamp were used for glucose metabolism and insulin resistance. The Morris water maze was used to observe the compound effects on cognitive impairment. Serum and hippocampal [Formula: see text]-amyloid peptide (A[Formula: see text], Tau and phosphorylated Tau protein deposition in the hippocampi were measured. The TUNEL assay was used to detect the neuronal apoptosis, supported by histomorphological changes and transmissional electron microscopy (TEM) image. Our data showed that the diabetic rats had a significantly cognitive impairment. In addition to improving glucose metabolism and reducing insulin resistance, berberine significantly improved the cognitive function in the rat. Berberine also effectively decreased the expression of hippocampal tau protein, phosphorylated Tau, and increased insulin receptor antibodies. Moreover, berberine downregulated the abnormal phosphorylation of A[Formula: see text] and Tau protein and improved hippocampal insulin signaling. The TUNEL assay confirmed that berberine reduced hippocampal neuronal apoptosis supported by TEM. Thus, berberine significantly improved the cognitive function in diabetic rats by changing the peripheral and central insulin resistance. The reduction of neuronal injury, A[Formula: see text] deposition, abnormal phosphorylation of Tau protein, and neuronal apoptosis in the hippocampus were observed as the related mechanisms of action.

Rifaximin improves survival in cirrhotic patients with refractory ascites: A real-world study.

BACKGROUND: Rifaximin has been shown to reduce the incidence of hepatic encephalopathy and other complications in patients with cirrhosis. However, few studies have investigated the effect of rifaximin in cirrhotic patients with refractory ascites. AIM: To evaluate the effects of rifaximin in the treatment of refractory ascites and to preliminarily explore its possible mechanism. METHODS: A total of 75 cirrhotic patients with refractory ascites were enrolled in the study (50 in a rifaximin and 25 in a control group). Patients in the rifaximin group were divided into two subgroups according to the presence of spontaneous bacterial peritonitis and treatment with or without other antibiotics (19 patients treated with rifaximin and 31 patients treated with rifaximin plus intravenous antibiotics). All patients received conventional treatment for refractory ascites, while patients in the rifaximin group received oral rifaximin-α 200 mg four times daily for at least 2 wk. The ascites grade, fasting weight, liver and kidney function, and inflammatory factors in the plasma were evaluated before and after treatment. In addition, the gut microbiota was determined by metagenomics sequencing to analyse the changes in the characteristics of the gut microbiota before and after rifaximin treatment. The patients were followed for 6 mo. RESULTS: Compared with the control group, the fasting weight of patients significantly decreased and the ascites significantly subsided after treatment with rifaximin (P = 0.011 and 0.009, respectively). The 6-mo survival rate of patients in the rifaximin group was significantly higher than that in the control group (P = 0.048). The concentration of interferon-inducible protein 10 decreased significantly in the rifaximin group compared with that in the control group (P = 0.024). The abundance of Roseburia, Haemophilus, and Prevotella was significantly reduced after rifaximin treatment, while the abundance of Lachnospiraceae_noname, Subdoligranulum, and Dorea decreased and the abundance of Coprobacillus increased after treatment with rifaximin plus intravenous antibiotics. The gene expression of virulence factors was significantly reduced after treatment in both subgroups treated with rifaximin or rifaximin plus intravenous antibiotics. CONCLUSION: Rifaximin mitigates ascites and improves survival of cirrhotic patients with refractory ascites. A possible mechanism is that rifaximin regulates the structure and function of intestinal bacteria, thus improving the systemic inflammatory state.

High mobility group box 1 release from cholangiocytes in patients with acute-on-chronic liver failure.

High mobility group box chromosomal protein 1 (HMGB1) is an important proinflammatory molecule in a number of inflammatory disorders, but little is known about its role in acute-on-chronic liver failure (ACLF). To elucidate the role of HMGB1 in ACLF, the expression of HMGB1 in liver specimens from patients with ACLF was investigated. Immunohistochemical staining was performed to confirm the expression and subcellular localization of HMGB1 in liver specimens obtained from 13 patients with ACLF caused by hepatitis B virus (HBV) infection, 20 patients with chronic viral hepatitis B and 20 healthy controls. In addition, TFK-1 cells (human cholangiocarcinoma cell line) were stimulated with lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-α. The extracellular level of HMGB1 in the culture medium was then determined by ELISA, and cell viability was also examined. In patients with ACLF caused by HBV infection, HMGB1 was found mainly in the cholangiocytes, and cytoplasmic translocation was observed in the cholangiocytes in the liver specimens. In the TFK-1 cell cultures, HMGB1 levels gradually increased from as early as 4 h after stimulation with LPS or TNF-α until the end of the stimulation. LPS and TNF-α actively induced the cytoplasmic translocation of the HMGB1 protein in TFK-1 cells. These data suggest that HMGB1 plays a critical role in the systemic inflammation associated with ACLF.

Clinical efficacy of tolvaptan for treatment of refractory ascites in liver cirrhosis patients.

AIM: To evaluate the efficacy and safety of tolvaptan to treat refractory ascites in decompensated liver cirrhosis patients with or without further complications, such as hepatorenal syndrome and/or hepatocellular carcinoma. METHODS: Thirty-nine patients (mean age 55 years, males: 32) with decompensated liver cirrhosis and refractory ascites were enrolled. All patients received a combination of tolvaptan (15 mg/d for 5-14 d) and diuretics (40-80 mg/d of furosemide and 80-160 mg/d of spironolactone). The etiology of cirrhosis included hepatitis B (69.2%), hepatitis C (7.7%) and alcohol-induced (23.1%). Changes in the urine excretion volume, abdominal circumference and edema were assessed. The serum sodium levels were also measured, and adverse events were recorded. A follow-up assessment was conducted 1 mo after treatment with tolvaptan. RESULTS: Tolvaptan increased the mean urine excretion volume (1969.2 ± 355.55 mL vs 3410.3 ± 974.1 mL, P < 0.001), and 89.7% of patients showed improvements in their ascites, 46.2% of whom showed significant improvements. The overall efficacy of tolvaptan in all patients was 89.7%; the efficacies in patients with hepatocellular carcinoma and hepatorenal syndrome were 84.2% and 77.8%, respectively. The incidence of hyponatremia was 53.8%. In patients with hyponatremia, the serum sodium levels increased after tolvaptan treatment (from 128.1 ± 4.22 mEq/L vs 133.1 ± 3.8 mEq/L, P < 0.001). Only mild drug-related adverse events, including thirst and dry mouth, were observed. CONCLUSION: Tolvaptan is a promising aquaretic for the treatment of refractory ascites in patients with decompensated liver cirrhosis.