Treatment of Refractory Gastrointestinal Bleeding in Patients With Portal Hypertension: A Case Series and Treatment Algorithm.

In patients with portal hypertension, ectopic varices can develop at any site along the gastrointestinal tract outside the classically described gastroesophageal location. Like esophageal variceal hemorrhage, bleeding from ectopic varices can be life-threatening. Diagnosis and treatment of ectopic varices can be challenging; to date, no effective treatment algorithm has been described. A systematic teamwork approach to diagnosing and treatment of ectopic varices is required to successfully manage hemorrhage from ectopic varices.

All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.

BACKGROUND: Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. AIM: To assess efficacy of all-oral HCV therapy in advanced liver disease. METHODS: Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. RESULTS: Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. CONCLUSIONS: All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.

Association of in vitro fertilization with global and IGF2/H19 methylation variation in newborn twins.

In vitro fertilization (IVF) and its subset intracytoplasmic sperm injection (ICSI), are widely used medical treatments for conception. There has been controversy over whether IVF is associated with adverse short- and long-term health outcomes of offspring. As with other prenatal factors, epigenetic change is thought to be a molecular mediator of any in utero programming effects. Most studies focused on DNA methylation at gene-specific and genomic level, with only a few on associations between DNA methylation and IVF. Using buccal epithelium from 208 twin pairs from the Peri/Postnatal Epigenetic Twin Study (PETS), we investigated associations between IVF and DNA methylation on a global level, using the proxies of Alu and LINE-1 interspersed repeats in addition to two locus-specific regulatory regions within IGF2/H19, controlling for 13 potentially confounding factors. Using multiple correction testing, we found strong evidence that IVF-conceived twins have lower DNA methylation in Alu, and weak evidence of lower methylation in one of the two IGF2/H19 regulatory regions and LINE-1, compared with naturally conceived twins. Weak evidence of a relationship between ICSI and DNA methylation within IGF2/H19 regulatory region was found, suggesting that one or more of the processes associated with IVF/ICSI may contribute to these methylation differences. Lower within- and between-pair DNA methylation variation was also found in IVF-conceived twins for LINE-1, Alu and one IGF2/H19 regulatory region. Although larger sample sizes are needed, our results provide additional insight to the possible influence of IVF and ICSI on DNA methylation. To our knowledge, this is the largest study to date investigating the association of IVF and DNA methylation.

The Australia and New Zealand Fontan Registry: description and initial results from the first population-based Fontan registry.

BACKGROUND: The Fontan procedure is the final in a series of staged palliations for single-ventricle congenital heart disease, which encompasses rare and heterogeneous cardiac lesions. It represents an unusual and novel physiological state characterised by absence of a subpulmonary ventricle. AIMS: The population is growing steadily, prompting creation of this registry to study their epidemiology, demographic trends, treatment and outcomes. METHODS: This multicentre, binational, prospective and retrospective, web-based registry involving all congenital cardiac centres in the region has identified nearly all Fontan patients in Australia and New Zealand. Patients identified retrospectively were approached for recruitment. New recipients are automatically enrolled prospectively unless they choose to opt-out. Follow-up data are collected yearly. RESULTS: Baseline data were obtained in 1072 patients as at 1 January 2011. Ninety-nine patients died; 64 were lost to follow up. Forty-four per cent of patients lost were between 20 and 30 years of age. The size of the Fontan population is increasing steadily. Among 973 living patients, 541 (56%) gave consent for prospective collection of follow up. Between 1 January 2011 and 1 January 2013, an additional 47 subjects were enrolled prospectively. The current proportion of patients operated with hypoplastic left heart syndrome is currently 29% and is growing rapidly. CONCLUSION: The population surviving after the Fontan procedure has been growing in recent decades, especially since survival with hypoplastic left heart syndrome has improved. The Australia and New Zealand Fontan Registry provides population-based data, and only large databases like this will give opportunities for understanding the population and performing prospective trials.

Decreased cortical muscarinic M1 receptors in schizophrenia are associated with changes in gene promoter methylation, mRNA and gene targeting microRNA.

Many studies have shown decreased cortical muscarinic M1 receptors (CHRM1) in schizophrenia (Sz), with one study showing Sz can be separated into two populations based on a marked loss of CHRM1 (-75%) in -25% of people (Def-Sz) with the disorder. To better understand the mechanism contributing to the loss of CHRM1 in Def-Sz, we measured specific markers of gene expression in the cortex of people with Sz as a whole, people differentiated into Def-Sz and people with Sz that do not have a deficit in cortical CHRM1 (Non-Def-Sz) and health controls. We now report that cortical CHRM1 gene promoter methylation and CHRM1 mRNA are decrease in Sz, Def-Sz and Non-Def-Sz but levels of the micro RNA (miR)-107, a CHRM1 targeting miR, are increased only in Def-Sz. We also report in vitro data strongly supporting the notion that miR-107 levels regulate CHRM1 expression. These data suggest there is a reversal of the expected inverse relationship between gene promoter methylation and CHRM1 mRNA in people with Sz and that a breakdown in gene promoter methylation control of CHRM1 expression is contributing to the global pathophysiology of the syndrome. In addition, our data argues that increased levels of at least one miR, miR-107, is contributing to the marked loss of cortical CHRM1 in Def-Sz and this may be a differentiating pathophysiology. These latter data continue to support the hypothesis that microRNAs (miRNA) have a role in the underlying neurobiology of Sz but argue they are differentially affected in subsets of people within that syndrome.

The role of choledochoscopy in the diagnosis and management of biliary tract diseases.

BACKGROUND: The diagnosis and management of biliary tract disorders in certain cases may be incomplete without direct visualization of the bile ducts. METHODS: We report our experience of 61 choledochoscopies (33 women, 27 men, mean age 44.6 years). Twenty patients had previously undergone orthotopic liver transplantation. All except two choledochoscopies were performed via the transpapillary route. Indications included suspected large bile duct stones in 18 patients, anastomotic strictures in 16, abnormal cholangiograms in 5, elevated liver function tests in 7, suspected cholangiocarcinoma in 4, occluded biliary metallic stent in 4, hemobilia in 4, primary sclerosing cholangitis in 2 and ischemic bile duct injury in 1 patient. RESULTS: Choledochoscopy confirmed the anticipated diagnosis in 36 of 61 (59%) patients. Importantly, it provided additional unsuspected diagnostic information in 18 of the 61 (29.5%) patients. In addition, for patients in whom standard cholangiography was deemed abnormal, choledochoscopy demonstrated normal results in 7 (11.4%) patients. Fifty-two choledochoscopies were performed with therapeutic intentions, and the procedure was helpful in providing targeted treatment in 27 (44.2%) patients. CONCLUSIONS: Choledochoscopy is a safe and useful endoscopic modality that can provide specific diagnoses and direct treatment in various biliary tract diseases. The additional information provided by choledochoscopy may change overall patient management and outcome.

Heterozygous alpha 1-antitrypsin phenotypes in patients with end stage liver disease.

OBJECTIVE: The objective of the study was to determine the prevalence and associations of abnormal alpha1-antitrypsin phenotypes in Caucasian adults with end stage liver disease with particular emphasis on heterozygous phenotypes and disease from hepatitis C virus. METHODS: All patients (788) with end stage liver disease considered for liver transplantation from July 1990 to June 1996 in a referral-based university hospital transplant center (University of Nebraska Medical Center, Omaha, NE) comprised the study population. Data for the study population was determined by retrospective review of the transplantation database at the transplant center. Hepatitis C virus infection was determined by a second generation ELISA method, and alpha1-antitrypsin phenotyping was performed on agarose gel with serum quantitation using a Behring Nephelometer. RESULTS: Among 683 Caucasian patients with severe liver disease, the prevalences of Pi ZZ, Pi MZ, and Pi MS were 0.4, 7.3, and 8.2%, respectively, compared with 0, 2.8, and 4.2% in the control population. The odds of having a heterozygous Z phenotype were significantly increased in Caucasian patients with hepatitis C virus (odds ratio (OR) = 4.3, 95% confidence interval (CI) = 2.1-9.0), alcoholic liver disease (OR = 5.0, 95% CI = 2.6-9.6), primary hepatic malignancy (OR = 7.4, 95% CI = 2.9-19.0), and cryptogenic cirrhosis (OR = 2.6, 95% CI = 1.1-6.3) compared with the control population. Caucasian patients with hepatitis C or B virus were 3.6 times more likely to have a heterozygous Z phenotype than a normal phenotype compared with patients with diseases of autoimmune etiology. CONCLUSION: This study provides evidence of an association of heterozygous Z alpha1-antitrypsin phenotype with end stage liver disease of several etiologies, not hepatitis C virus alone.

Gastric emptying and orocecal transit in portal hypertension and end-stage chronic liver disease.

Our aim was to evaluate gastric emptying and orocecal transit in patients with end-stage liver disease and portal hypertension undergoing evaluation for liver transplantation. Although gastric emptying half-times for both liquid and solid emptying were similar in patients with chronic liver disease and control subjects, orocecal transit, as measured by a scintigraphic technique, was significantly prolonged in the patients with liver disease (transit time, minutes, mean +/- SEM, patients versus controls: 127 +/- 10.5 versus 80 +/- 9.5, P < .003). Serum levels of progesterone and estradiol were similar in patients and controls. We conclude that small intestinal transit is delayed in patients with advanced liver disease and portal hypertension and may contribute to gastrointestinal symptoms and promote sepsis of enteric origin in this patient population.

Response to intraluminal gas in irritable bowel syndrome. Motility versus perception.

Our aim was to evaluate the response to intraluminal gas in irritable bowel syndrome and to determine whether this response was consequent upon disordered motility or altered perception. We evaluated 10 patients who satisfied the clinical criteria for the diagnosis of irritable bowel syndrome and 10 healthy controls. An eight-lumen perfused catheter assembly was positioned to monitor motor activity in the duodenum and proximal jejunum; a separate side port in the distal duodenum permitted gas infusion. Subjects recorded symptoms of abdominal pain, bloating, and nausea throughout the study, using a visual analog scale. Following an overnight fast and a 60-min basal recording period in the fasted state, subjects ate a standard meal; 60 min later, "sham" gas was administered for 20 min, followed by the actual infusion of nitrogen gas at 40 ml/min. Subjects were randomized to receive atropine (7 micrograms/kg) or placebo intravenously during the period of actual gas infusion. Patients with irritable bowel syndrome described more pain (score, mean +/- SE, control versus irritable bowel: 0.22 +/- 0.16 vs 1.65 +/- 0.5, P < 0.01) and nausea (0.25 +/- 0.21 vs 1.45 +/- 0.64, P < 0.04) during sham gas; motility indices were similar in both groups. During active gas, irritable bowel syndrome patients reported more pain (0.40 +/- 0.39 vs 2.94 +/- 1.16, P < 0.03); motility indices at all sites were similar in both groups. Symptom severity in irritable bowel syndrome subjects randomized to receive atropine was similar to control subjects during active gas infusion; motility indices were similar.(ABSTRACT TRUNCATED AT 250 WORDS)

The nature of complications following liver biopsy in transplant patients with Roux-en-Y choledochojejunostomy.

Liver biopsy is an important diagnostic tool in the management of patients following orthotopic liver transplant. We evaluated complications following percutaneous liver biopsy in a group of liver transplant patients who had Roux-en-Y choledochojejunostomies fashioned as part of their biliary reconstruction during liver transplantation. Complications were divided into two major groups: septic complications (including fever, symptomatic bacteremia, cholangitis, infected hematoma and hypotension related to sepsis) and bleeding (defined as hypotension requiring volume expansion greater than 500 cm3 or blood transfusion, hemothorax, intrahepatic or peritoneal hemorrhage and hemobilia occurring within 1 wk of liver biopsy). One hundred ninety-two biopsies were performed in 46 patients with choledochojejunostomies, and 118 biopsies were carried out in an age- and sex-matched control group of patients with choledochocholedochostomy biliary anastomosis. There were no septic complications in the choledochojejunostomy patients and one (0.32%) septic complication in the choledochocholedochostomy patients (NS). Eight bleeding complications occurred (2.6%) in eight patients (8.3%). Five (2.6%) occurred in five (10.8%) of the choledochojejunostomy patients, vs. three (2.5%) in three (6.5%) choledochocholedochostomy patients (NS). None of the bleeding complications required surgical intervention or was fatal. We conclude that liver biopsy in posttransplant patients with Roux-en-Y choledochojejunostomies is a safe procedure and that the incidences of complications were similar in our two groups. The negligible incidence of septic complications in the choledochojejunostomy patients does not appear to warrant the administration of prophylactic antibiotics, as has been previously suggested.

Delayed gastric emptying of both the liquid and solid components of a meal in chronic liver disease.

OBJECTIVES: To evaluate gastric emptying in patients with chronic liver disease and portal hypertension. METHODS: We measured gastric emptying of both the liquid and solid components of a meal in 10 consecutive patients with chronic liver disease and portal hypertension, but free of ascites, and 14 age- and sex-matched healthy controls. In the patients with liver disease, relationships between emptying and liver function were examined. To measure gastric emptying, subjects consumed a test meal that consisted of scrambled eggs labeled with 99mTc-sulfur colloid and 4 oz of water labeled with 111In-diethylene triamine pentacetic acid (DTPA). RESULTS: Patients with liver disease and portal hypertension demonstrated delayed emptying of both the liquid (t1/2, min, mean +/- SE, patients vs. CONTROLS: 69.4 +/- 19.4 vs. 31.4 +/- 1.8, p < 0.01) and solid (post-lag phase solid emptying: 141 +/- 32.9 vs. 69.8 +/- 4.6, p < 0.006) components of the meal. We could not identify any correlation between gastric emptying and tests of liver function. CONCLUSIONS: Gastric emptying is delayed in patients with liver disease and portal hypertension; this abnormal gastric motor function may contribute to the pathophysiology of foregut complaints in this patient population.