Indications and outcomes of transjugular intrahepatic portosystemic shunt insertion in two regional Australian hepatology centres.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is an important therapy for complications of portal hypertension but remains underutilised in regional settings. AIMS: The aim of this study is to explore the demographics, indications, outcomes and complications in patients undergoing TIPS in two regional hepatology centres. METHODS: Retrospective analysis was undertaken of all patients undergoing TIPS at two regional centres between January 2017 and March 2023. The primary outcome measures were efficacy and complications of TIPS. Patient demographics (such as age, baseline liver severity scores and aetiology of liver disease) and indications for TIPS are detailed. RESULTS: Forty-eight patients underwent TIPS. Median age was 56 years (interquartile range (IQR): 46-65). The most common indications for TIPS were refractory ascites (n = 17) and failure of secondary prophylaxis of variceal bleeding (n = 13). Cumulative survival at 3 months and 1 year was 93% and 77% respectively. There was no significant difference in outcomes based on TIPS indication. The median number of paracenteses in patients undergoing TIPS for refractory ascites 1 year pre- and post-TIPS were 10 (IQR: 4.5-16) and 2 (IQR: 0-4) respectively (P < 0.001). There were no procedure-related deaths. Inpatient management of liver disease complications had a mean cost of $32 874.67 (SEM: 7779) in 1 year pre-TIPS compared with $12 304.70 (SEM: 3531.1) in 1 year post-TIPS (P < 0.001). CONCLUSIONS: TIPS is a safe and effective treatment to reduce complications of portal hypertension and can be performed successfully in the regional setting.

The treatment of refractory ulcerative colitis.

Ulcerative proctitis is defined as a mucosal inflammation limited to the rectum. Ulcerative proctitis is responsible for distressing symptoms and alteration of patient quality of life. Effective treatment is important to prevent or delay proximal extension of the disease and to improve quality of life. Refractory ulcerative proctitis is defined as the failure of topical and oral 5-aminosalicylic acid and corticosteroids. Medical management of refractory ulcerative proctitis may be challenging as there is little evidence regarding drug efficacy in this clinical situation. Data are currently available for azathioprine, topical tacrolimus and anti-TNF monoclonal antibodies as rescue treatment for refractory ulcerative proctitis. Other biologics may be of benefit despite a lack of dedicated clinical trials. Ultimately, experimental therapies such as epidermal growth factor enemas, appendectomy or fecal transplantation may be tried before restorative proctocolectomy with J pouch anastomosis, which has demonstrated good results with regards to clinical remission and quality of life.

Oral vancomycin induces sustained deep remission in adult patients with ulcerative colitis and primary sclerosing cholangitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease of unknown etiology. The treatment of UC is challenging, especially when it is associated with primary sclerosing cholangitis (PSC), a chronic inflammatory disease of the bile ducts that affects around 5% of patients with UC, and leads to an increased risk of cholangiocarcinoma and colorectal cancer. Microbiota is considered to play an important role in the pathogenesis of UC, although the efficacy of antibiotics in this context is only limited and transient. Several studies have investigated the use of antibiotics for the treatment of PSC in adult and pediatric populations, with conflicting results. In this brief report, we describe the effect of oral vancomycin treatment in three patients with UC and PSC refractory to conventional and biologic therapies. All three patients achieved clinical remission and mucosal healing with vancomycin 500 mg twice a day administered orally. Maintenance treatment with oral vancomycin was well tolerated and led to sustained clinical and endoscopic remission in all three patients. Oral vancomycin also improved liver function tests in two patients who did not have pre-existing cirrhosis.

Diagnosis, Natural History and Treatment of Eosinophilic Enteritis: a Review.

PURPOSE OF REVIEW: To review recent findings regarding eosinophilic enteritis, including epidemiology, pathogenesis, natural history, and treatment. RECENT FINDINGS: A 2017 population-based study using a US healthcare system database identified 1820 patients with a diagnosis of eosinophilic enteritis among 35,826,830 individuals. The majority of patients with eosinophilic enteritis in this study were women (57.7%), Caucasian (77.5%), and adults (> 18 years of age) (83.5%). The overall prevalence of eosinophilic enteritis was estimated at 5.1/100,000 persons. Eosinophilic enteritis, also known as eosinophilic gastroenteritis, is a rare primary eosinophilic gastrointestinal disorder (EGID) of unknown etiology characterized by the presence of an intense eosinophilic infiltrate on histopathological examination of the intestinal mucosa. The etiology of eosinophilic enteritis remains unknown. However, there is evidence to support the role of allergens in the pathogenesis of this disorder, as children and adults with EGIDs often have positive skin testing to food allergens and a family history of allergic diseases. Recent studies unraveling the role of IgE-mediated but also delayed Th2-type responses have provided insight into the pathogenesis of this disease. Eosinophilic enteritis causes a wide array of gastrointestinal symptoms such as abdominal pain, diarrhea, nausea, vomiting, bloating, or ascites, and its diagnosis requires a high degree of clinical likelihood, given the nonspecific clinical presentation and physical examination findings. Oral corticosteroids are considered to be the mainstay of treatment and are generally used for a short period with good response rates. Antihistamine drugs and sodium cromoglycate have also been used to treat patients with eosinophilic enteritis. Preliminary studies have demonstrated the potential benefit of biological therapies targeting the eosinophilic pathway such as mepolizumab, an anti-IL5 antibody, or omalizumab, an anti-IgE monoclonal antibody. Eosinophilic enteritis is generally considered to be a benign disease without relapse, but up to 50% of patients may present a more complex natural history characterized by unpredictable relapses and a chronic course.

Stricturing Crohn's disease-like colitis in a patient treated with belatacept.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) modifying agents have been involved in the development of intestinal inflammation, especially therapeutic monoclonal antibodies directed against CTLA-4. Here we report the appearance of a severe stricturing Crohn's disease-like colitis in a patient with a kidney allograft who was treated with belatacept, a recombinant CTLA-4-Ig fusion protein.

The role of genetic factors in patients with hepatocellular carcinoma and iron overload - a prospective series of 234 patients.

BACKGROUND & AIMS: Iron overload (IO) in HFE-related hereditary haemochromatosis is associated with increased risk of liver cancer. This study aimed to investigate the role of other genes involved in hereditary IO among patients with hepatocellular carcinoma (HCC). METHODS: Patients with HCC diagnosed in our institution were included in this prospective study. Those with ferritin levels ≥300 µg/L (males) or ≥200 µg/L (females) and/or transferrin saturation ≥50% (males) or ≥45% (females) had liver iron concentration (LIC) evaluated by MRI. HFE C282Y and H63D mutations were screened. Genetic analyses of genes involved in hereditary IO (HFE, HJV/HFE2, HAMP, TFR2, SLC40A1, GNPAT) were performed in patients with increased LIC. RESULTS: A total of 234 patients were included; 215 (92%) had common acquired risk factors of HCC (mainly alcoholism or chronic viral hepatitis). 119 patients had abnormal iron parameters. Twelve (5.1%) were C282Y homozygotes, three were compound C282Y/H63D heterozygotes. LIC was measured by MRI in 100 patients. Thirteen patients with a LIC>70 µmol/g were enrolled in further genetic analyses: two unrelated patients bore the HAMP:c.-153C>T mutation at the heterozygous state, which is associated with increased risk of IO and severe haemochromatosis. Specific haplotypes of SLC40A1 were also studied. CONCLUSIONS: Additional genetic risk factors of IO were found in 18 patients (7.7%) among a large series of 234 HCC patients. Screening for IO and the associated at-risk genotypes in patients who have developed HCC, is useful for both determining etiologic diagnosis and enabling family screening and possibly primary prevention in relatives.

Endoscopic treatment of fistula after sleeve gastrectomy: results of a multicenter retrospective study.

BACKGROUND AND STUDY AIMS: Fistula is the main complication of laparoscopic sleeve gastrectomy (LSG), for which healing is difficult to achieve. The aims of the study were to evaluate the efficacy of interventional endoscopy for post-LSG fistula treatment, to evaluate various endoscopic techniques used and identify their complications, and to identify predictive factors of healing following endoscopic treatment. PATIENTS AND METHODS: This retrospective multicenter study included patients with post-LSG fistula. Therapeutic procedures were evaluated, taking into account complications and healing times. Endoscopic procedures were considered to have promoted healing if no other surgical procedure was performed. Predictive factors of healing were identified by univariate and multivariate analysis. RESULTS: A total of 110 patients were included, of whom 6 (5.5 %) healed spontaneously, 81 (73.6 %) healed following endoscopic treatment, and 19 (17.3 %) healed following surgery. Healing rates following endoscopic treatment were 84.4 % in the first 6 months of treatment (65/77), 52.4 % for treatment lasting 6 - 12 months (11/21), and 41.7 % after 12 months of treatment (5/12). A drainage procedure (surgical, endoscopic, or percutaneous) was performed in 92 patients (83.6 %). A total of 177 esogastric stents were placed in 88 patients (80.0 %). Surgical debridement, clip placement, glue sealing, and plug placement were also performed. Multivariate analysis identified four predictive factors of healing following endoscopic treatment: interval < 21 days between fistula diagnosis and first endoscopy (P = 0.003), small fistula (P = 0.01), interval between LSG and fistula ≤ 3 days (P = 0.01), no history of gastric banding (P = 0.04). CONCLUSION: Endoscopic treatment facilitated healing of post-LSG fistula in 74 % of patients. Early endoscopic treatment increased the likelihood of success, and was most effective during the first 6 months of management. After this point, surgical treatment should be considered.

Human induced pluripotent stem cells in hepatology: beyond the proof of concept.

The discovery of the wide plasticity of most cell types means that it is now possible to produce virtually any cell type in vitro. This concept, developed because of the possibility of reprogramming somatic cells toward induced pluripotent stem cells, provides the opportunity to produce specialized cells that harbor multiple phenotypical traits, thus integrating genetic interindividual variability. The field of hepatology has exploited this concept, and hepatocyte-like cells can now be differentiated from induced pluripotent stem cells. This review discusses the choice of somatic cells to be reprogrammed by emergent new and nonintegrative strategies, as well as the application of differentiated human induced pluripotent stem cells in hepatology, including liver development, disease modeling, host-pathogen interactions, and drug metabolism and toxicity. The actual consensus is that hepatocyte-like cells generated in vitro present an immature phenotype. Currently, developed strategies used to resolve this problem, such as overexpression of transcription factors, mimicking liver neonatal and postnatal modifications, and re-creating the three-dimensional hepatocyte environment in vitro and in vivo, are also discussed.

Pegylated interferon-α2a and ribavirin versus pegylated interferon-α2b and ribavirin in chronic hepatitis C : a meta-analysis.

INTRODUCTION: Results of trials and meta-analyses comparing pegylated interferon (PEG-IFN)-α2a and PEG-IFN-α2b for the treatment of chronic hepatitis C are conflicting. OBJECTIVE: Our objective was to determine which PEG-IFN (α2a or α2b), in association with ribavirin, is the most effective for the treatment of chronic hepatitis C by performing an updated meta-analysis. METHOD: MEDLINE (1950-2012) and EMBASE (1974-2012) databases, as well as the Cochrane Central Register of controlled trials and the Cochrane Database of Systematic Reviews, were searched. Reference lists of retrieved articles were scanned, and proceedings of major international conferences were manually searched for abstracts. Randomized clinical trials and non-randomized clinical studies comparing PEG-IFN-α2a with PEG-IFN-α2b in association with ribavirin in adult patients with chronic hepatitis C were included. Studies including HIV-positive patients or liver transplant recipients were excluded. The data extraction from each study was conducted independently by two authors, with disagreements resolved by consensus or by a third reviewer. The trial quality of randomized clinical trials was assessed by taking into account generation of allocation sequence, allocation concealment, efficacy of randomization, investigator blindness, description of withdrawals and dropouts and adherence to the intention-to-treat principle. Two meta-analyses were performed, the first including randomized clinical trials only, and the second including both randomized and non-randomized clinical studies. The primary outcome measure was frequency of sustained virological response (SVR). Heterogeneity and publication bias were systematically taken into account. RESULTS: This meta-analysis included 26 studies, 11 randomized and 15 non-randomized, with a total of 18,260 patients: 8,125 treated with PEG-IFN-α2a and 10,135 treated with PEG-IFN-α2b. In the meta-analysis that included randomized trials only, the SVR was significantly higher for patients treated with PEG-IFN-α2a than for those treated with PEG-IFN-α2b for genotypes 1 and 4 [odds ratio (OR) 1.45; 95 % CI 1.09-2.06; p = 0.013] and for all genotypes (OR 1.34; 95 % CI 1.05-1.72; p = 0.02). In the meta-analysis including both randomized and non-randomized studies, the SVR was significantly higher for PEG-IFN-α2a than for PEG-IFN-α2b for all genotypes (OR 1.24; 95 % CI 1.10-1.40; p < 0.001) and for genotypes 1 and 4 (OR 1.25; 95 % CI 1.14-1.36; p < 0.001); for genotypes 2 and 3, the SVR was greater for treatment with PEG-IFN-α2a than with PEG-IFN-α2b, with the difference tending towards significance (OR 1.15; 95 % CI 0.98-1.35; p = 0.08). A certain degree of heterogeneity was present amongst the various studies included in this meta-analysis. Publication bias was detected (particularly for analyses including only randomized controlled trials) and taken into account using appropriate statistical methods. CONCLUSION: Current evidence suggests that PEG-IFN-α2a and ribavirin is associated with a higher SVR than PEG-IFN-α2b and ribavirin in patients mono-infected with hepatitis C, particularly for genotypes 1 and 4.

Meta-analysis: beta-blockers versus banding ligation for primary prophylaxis of esophageal variceal bleeding.

AIM: To perform an updated meta-analysis comparing ß-blockers (BB) with endoscopic variceal banding ligation (EVBL) in the primary prophylaxis of esophageal variceal bleeding. MATERIAL AND METHODS: Randomized controlled trials were identified through electronic databases, article reference lists and conference proceedings. Analysis was performed using both fixed-effect and random-effect models. Heterogeneity and publication bias were systematically taken into account. Main outcomes were variceal bleeding rates and all-cause mortality, calculated overall and at 6, 12, 18 and 24 months. RESULTS: 19 randomized controlled trials were analyzed including a total of 1,483 patients. Overall bleeding rates were significantly lower for the EVBL group: odds ratio (OR) 2.06, 95% confidence interval (CI) [1.55-2.73], p < 0.0001, without evidence of publication bias. Bleeding rates were also significantly lower at 18 months (OR 2.20, 95% CI [1.04-4.60], P = 0.04), but publication bias was detected. When only high quality trials were taken into account, results for bleeding rates were no longer significant. No significant difference was found for either bleeding-related mortality or for all-cause mortality overall or at 6, 12, 18 or 24 months. BB were associated with more frequent severe adverse events (OR 2.61, 95% CI 1.60-4.40, P < 0.0001) whereas fatal adverse events were more frequent with EVBL (OR 0.14, 95% CI 0.02-0.99, P = 0.05). CONCLUSION: EVBL appears to be superior to BB in preventing the first variceal bleed, although this finding may be biased as it was not confirmed by high quality trials. No difference was found for mortality. Current evidence is insufficient to recommend EVBL over BB as first-line therapy.

Comparison of hepatic-like cell production from human embryonic stem cells and adult liver progenitor cells: CAR transduction activates a battery of detoxification genes.

In vitro production of human hepatocytes is of primary importance in basic research, pharmacotoxicology and biotherapy of liver diseases. We have developed a protocol of differentiation of human embryonic stem cells (ES) towards hepatocyte-like cells (ES-Hep). Using a set of human adult markers including CAAT/enhancer binding protein (C/EBPalpha), hepatocyte nuclear factor 4/7 ratio (HNF4alpha1/HNF4alpha7), cytochrome P450 7A1 (CYP7A1), CYP3A4 and constitutive androstane receptor (CAR), and fetal markers including alpha-fetoprotein, CYP3A7 and glutathione S-transferase P1, we analyzed the expression of a panel of 41 genes in ES-Hep comparatively with human adult primary hepatocytes, adult and fetal liver. The data revealed that after 21 days of differentiation, ES-Hep are representative of fetal hepatocytes at less than 20 weeks of gestation. The glucocorticoid receptor pathway was functional in ES-Hep. Extending protocols of differentiation to 4 weeks did not improve cell maturation. When compared with hepatocyte-like cells derived from adult liver non parenchymal epithelial (NPE) cells (NPE-Hep), ES-Hep expressed several adult and fetal liver makers at much greater levels (at least one order of magnitude), consistent with greater expression of liver-enriched transcription factors Forkhead box A2, C/EBPalpha, HNF4alpha and HNF6. It therefore seems that ES-Hep reach a better level of differentiation than NPE-Hep and that these cells use different lineage pathways towards the hepatic phenotype. Finally we showed that lentivirus-mediated expression of xenoreceptor CAR in ES-Hep induced the expression of several detoxification genes including CYP2B6, CYP2C9, CYP3A4, UDP-glycosyltransferase 1A1, solute carriers 21A6, as well as biotransformation of midazolam, a CYP3A4-specific substrate.

Hepatic encephalopathy: from pathophysiology to therapeutic management.

Hepatic encephalopathy is a complex and potentially reversible neuropsychiatric syndrome complicating acute or chronic liver disease. Clinical manifestations are multiple and varied, ranging from minimal neurological changes to coma. Ammonia is the main toxic substance involved in the pathogenesis of hepatic encephalopathy, although other mechanisms, such as modifications of the blood-brain barrier, disruptions in neurotransmission and abnormalities in GABAergic and benzodiazepine pathways may also play a role. The identification and treatment of precipitating factors is crucial in the management of patients with hepatic encephalopathy. Current treatments are based on reducing intestinal ammonia load by agents such as antibiotics or disaccharides, although their efficacy is yet to be clearly established.

Benefit of combination ß-blocker and endoscopic treatment to prevent variceal rebleeding: a meta-analysis.

AIM: To determine whether the association of ß-blockers with endoscopic treatment is superior to endoscopic treatment alone for the secondary prophylaxis of oesophageal variceal bleeding. METHODS: Randomised controlled trials comparing sclerotherapy (SCL) with SCL plus ß-blockers (BB) or banding ligation (BL) with BL plus BB were identified. Main outcomes were overall and 6, 12 and 24 mo rebleeding rates, as well as overall and 6, 12 and 24 mo mortality. Two statistical methods were used: Yusuf-Peto, and Der Simonian and Laird. Inter-trial heterogeneity was systematically taken into account. RESULTS: Seventeen randomised controlled trials were included, 14 with SCL and 3 with BL. Combination ß-blocker and endoscopic treatment significantly reduced rebleeding rates at 6, 12 and 24 mo and overall [odds ratio (OR): 2.20, 95% confidence interval (CI): 1.69-2.85, P < 0.0001] compared to endoscopic treatment alone. Mortality at 24 mo was significantly lower for the combined treatment group (OR: 1.83, 95% CI: 1.16-2.90, P = 0.009), as well as overall mortality (OR: 1.43, 95% CI: 1.03-1.98, P = 0.03). CONCLUSION: Combination therapy should thus be recommended as the first line treatment for secondary prophylaxis of oesophageal variceal bleeding.