Binu John

Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: A randomized clinical trial

Recurrent hepatic encephalopathy (HE) is a leading cause of readmission despite standard of care (SOC) associated with microbial dysbiosis. Fecal microbiota transplantation (FMT) may improve dysbiosis; however, it has not been studied in HE. We aimed to define whether FMT using a rationally derived stool donor is safe in recurrent HE compared to SOC alone. An open‐label, randomized clinical trial with a 5‐month follow‐up in outpatient men with cirrhosis with recurrent HE on SOC was conducted with 1:1 randomization. FMT‐randomized patients received 5 days of broad‐spectrum antibiotic pretreatment, then a single FMT enema from the same donor with the optimal microbiota deficient in HE. Follow‐up occurred on days 5, 6, 12, 35, and 150 postrandomization. The primary outcome was safety of FMT compared to SOC using FMT‐related serious adverse events (SAEs). Secondary outcomes were adverse events, cognition, microbiota, and metabolomic changes. Participants in both arms were similar on all baseline criteria and were followed until study end. FMT with antibiotic pretreatment was well tolerated. Eight (80%) SOC participants had a total of 11 SAEs compared to 2 (20%) FMT participants with SAEs (both FMT unrelated; P = 0.02). Five SOC and no FMT participants developed further HE (P = 0.03). Cognition improved in the FMT, but not the SOC, group. Model for End‐Stage Liver Disease (MELD) score transiently worsened postantibiotics, but reverted to baseline post‐FMT. Postantibiotics, beneficial taxa, and microbial diversity reduction occurred with Proteobacteria expansion. However, FMT increased diversity and beneficial taxa. SOC microbiota and MELD score remained similar throughout. Conclusion: FMT from a rationally selected donor reduced hospitalizations, improved cognition, and dysbiosis in cirrhosis with recurrent HE. (Hepatology 2017;66:1727–1738)

Diagnosis of Minimal Hepatic Encephalopathy Using Stroop EncephalApp: A Multicenter US-Based, Norm-Based Study.

Objectives:Diagnosing minimal hepatic encephalopathy (MHE) is challenging, and point-of-care tests are needed. Stroop EncephalApp has been validated for MHE diagnosis in single-center studies. The objective of the study was to validate EncephalApp for MHE diagnosis in a multicenter study.Methods:Outpatient cirrhotics (with/without prior overt hepatic encephalopathy (OHE)) and controls from three sites (Virginia (VA), Ohio (OH), and Arkansas (AR)) underwent EncephalApp and two gold standards, psychometric hepatic encephalopathy score (PHES) and inhibitory control test (ICT). Age-/gender-/education-adjusted values for EncephalApp based on direct norms, and based on ICT and PHES, were defined. Patients were followed, and EncephalApp cutoff points were used to determine OHE prediction. These cutoff points were then used in a separate VA-based validation cohort.Results:A total of 437 cirrhotics (230 VA, 107 OH, 100 AR, 36% OHE, model for end-stage liver disease (MELD) score 11) and 308 controls (103 VA, 100 OH, 105 AR) were included. Using adjusted variables, MHE was present using EncephalApp based on norms in 51%, EncephalApp based on PHES in 37% (sensitivity 80%), and EncephalApp based on ICT in 54% of patients (sensitivity 70%). There was modest/good agreement between sites on EncephalApp MHE diagnosis using the three methods. OHE developed in 13% of patients, which was predicted by EncephalApp independent of the MELD score. In the validation cohort of 121 VA cirrhotics, EncephalApp directly and based on gold standards remained consistent for MHE diagnosis with >70% sensitivity.Conclusions:In this multicenter study, EncephalApp, using adjusted population norms or in the context of existing gold standard tests, had good sensitivity for MHE diagnosis and predictive capability for OHE development.

Sofosbuvir and simeprevir without ribavirin effectively treat hepatitis C virus genotype 1 infection after liver transplantation in a two-center experience.

The interferon‐free antiviral regimen, sofosbuvir (SOF) and simeprevir (SIM) without ribavirin has been reported to achieve high sustained virologic response (SVR) rates with few adverse effects when treating patients with hepatitis C genotype 1 (HCV GT1) infection. However, there is scarcity of safety and efficacy data in this regimen after liver transplantation (LT).

Liver transplant modulates gut microbial dysbiosis and cognitive function in cirrhosis

Liver transplantation (LT) improves daily function and cognition in patients with cirrhosis, but a subset of patients can remain impaired. Unfavorable microbiota or dysbiosis is observed in patients with cirrhosis, but the effect of LT on microbial composition, especially with poor post‐LT cognition, is unclear. The aims were to determine the effect of LT on gut microbiota and to determine whether gut microbiota are associated with cognitive dysfunction after LT. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Cognition (Psychometric Hepatic Encephalopathy score [PHES]), health‐related quality of life (HRQOL), and stool microbiota (multitagged sequencing for diversity and taxa) tests were performed at both visits. Persistent cognitive impairment was defined as a stable/worsening PHES. Both pre‐/post‐LT data were compared with age‐matched healthy controls. We enrolled 45 patients (56 ± 7 years, Model for End‐Stage Liver Disease score 26 ± 8). They received LT 6 ± 3 months after enrollment and were re‐evaluated 7 ± 2 months after LT with a stable course. A significantly improved HRQOL, PHES, with increase in microbial diversity, increase in autochthonous, and decrease in potentially pathogenic taxa were seen after LT compared with baseline. However, there was continued dysbiosis and HRQOL/cognitive impairment after LT compared with controls in 29% who did not improve PHES after LT. In these, Proteobacteria relative abundance was significantly higher and Firmicutes were lower after LT, whereas the reverse occurred in the group that improved. Delta PHES was negatively correlated with delta Proteobacteria and positively with delta Firmicutes. In conclusion, LT improves gut microbiota diversity and dysbiosis compared with pre‐LT baseline but residual dysbiosis remains compared with controls. There is cognitive and HRQOL enhancement in general after LT, but a higher Proteobacteria relative abundance change is associated with posttransplant cognitive impairment. Liver Transplantation 23 907–914 2017 AASLD.

Capnographic Monitoring in Routine EGD and Colonoscopy With Moderate Sedation: A Prospective, Randomized, Controlled Trial

Objectives:Regulatory changes requiring the use of capnographic monitoring for endoscopic procedures using moderate sedation have placed financial challenges on ambulatory and hospital endoscopy centers across the United States due to the increased cost of training endoscopy personnel and purchasing both capnography-monitoring devices and specialized sampling ports. To date, there has been no published data supporting the use of capnographic monitoring in adult patients undergoing routine endoscopic procedures with moderate sedation. The aim of this randomized, parallel group assignment trial was to determine whether intervention based on capnographic monitoring improves detection of hypoxemia in patients undergoing routine esophagogastroduodenoscopy (EGD) or colonoscopy with moderate sedation.Methods:Healthy patients (ASA Physical Classification (ASAPS) I and II)) scheduled for routine outpatient EGD or colonoscopy under moderate sedation utilizing opioid and benzodiazepine combinations were randomly assigned to a blinded capnography alarm or open capnography alarm group. In both study arms, standard cardiopulmonary monitoring devices were utilized with additional capnographic monitoring. The primary end point was the incidence of hypoxemia defined as a fall in oxygen saturation (SaO2) to <90% for ≥10 s. Secondary outcomes included severe hypoxemia, apnea, disordered respirations, hypotension, bradycardia, and early procedure termination for any cause.Results:A total of 452 patients were randomized; 218 in the EGD and 234 in the colonoscopy groups; 75 subjects in the EGD group (35.9%) and 114 patients (49.4%) in the colonoscopy group were male, and average body mass index was 27.9 and 29.1 (kg/m2), respectively. The blinded and open alarm groups in each study arm were similar in regards to use of opioids and/or benzodiazepines and ASAPS classification. There was no significant difference in rates of hypoxemia between the blinded and open capnography arms for EGD (54.1% vs. 49.5; P=0.5) or colonoscopy (53.8 vs. 52.1%; P=0.79).Conclusions:Capnographic monitoring in routine EGD or colonoscopy for ASAPS I and II patients does not reduce the incidence of hypoxemia (ClinicalTrials.gov number, NCT01994785).

Clinical presentation and protocol for management of hepatic sarcoidosis

The liver is one of the most commonly involved extrapulmonary sites in sarcoidosis. Hepatic sarcoidosis has a broad range of presentations from scattered, asymptomatic noncaseating granulomas with normal liver enzymes, which are very common in patients with known pulmonary sarcoidosis, to portal hypertension and cirrhosis, which are relatively uncommon. Diagnosis is based on a combination of clinical, laboratory and histological manifestations. The authors’ protocol for management of patients with suspected sarcoidosis of the liver without focal lesions includes a transjugular liver biopsy with portal pressure measurements to confirm the diagnosis, rule out coexisting liver diseases and to identify select patients with fibrosis or portal hypertension for consideration of immunosuppression. Steroids and azathioprine are the preferred agents and methotrexate is not recommended.

Donor IFNL4 Genotype Is Associated with Early Post-Transplant Fibrosis in Recipients with Hepatitis C

Background and Aims Early post-transplant hepatic fibrosis is associated with poor outcomes and may be influenced by donor/recipient genetic factors. The rs368234815 IFNL4 polymorphism is related to the previously described IL28B polymorphism, which predicts etiology-independent hepatic fibrosis. The aim of this study was to identify the impact of donor and/or recipient IFNL4 genotype on early fibrosis among patients transplanted for hepatitis C (HCV). Methods Clinical data were collected for 302 consecutive patients transplanted for HCV. 116 patients who had available liver biopsies and donor/recipient DNA were included. 28% of these patients with stage 2 fibrosis or greater were compared to patients without significant post-transplant fibrosis with respect to clinical features as well as donor/recipient IFNL4 genotype. Results The IFNL4 TT/TT genotype was found in 26.0% of recipients and 38.6% of donors. Patients who developed early post-transplant fibrosis had a 3.45 adjusted odds of having donor IFNL4 TT/TT genotype (p = 0.012). Donor IFNL4 TT/TT genotype also predicted decreased overall survival compared to non-TT/TT genotypes (p = 0.016). Conclusions Donor IFNL4 TT/TT genotype, a favorable predictor of spontaneous HCV clearance pre-transplant, is associated with increased early post-transplant fibrosis and decreased survival.

Interleukin‐28B polymorphisms are associated with fibrosing cholestatic hepatitis in recurrent hepatitis C after liver transplantation

Chronic hepatitis C virus (HCV) infection is a frequent cause of cirrhosis and hepatocellular carcinoma and has become the most common indication for orthotopic liver transplantation (OLT) in the Western world (1, 2). Recurrent HCV, following OLT, is a universal event with serious consequences including cirrhosis and liver failure (3). Approximately between 1% and 5% of OLT recipients with recurrent HCV develop fibrosing cholestatic hepatitis (FCH), a severe form of HCV recurrence following OLT associated with early graft failure and death (4). Genome-wide association studies have recently identified single-nucleotide polymorphisms or SNPs (rs12979860 and rs8099917) located near the interleukin-28B (IL-28B) gene that was associated with the response to hepatitis C treatment (5). A recent publication showed that recipient and donor liver IL28B genotype are strongly and independently associated with interferon-based treatment response in patients with recurrent HCV following OLT (6). Additionally, the unfavorable IL28B rs12979860 genotype was significantly predictive of fibrosis stage and more severe histological recurrence of HCV among OLT recipients with recurrent HCV (6). The aim of our study was to determine the impact of donor and recipient IL28B genotypes on the development of FCH among liver transplant recipients with recurrent HCV. Using the liver transplant database, we identified all adult patients who underwent OLT for chronic HCV infection at the Cleveland Clinic between 2005 and 2010. Patients who developed FCH in the setting of recurrent HCV following OLT were identified. The diagnosis of FCH was made by histological examination of the liver biopsies (4). A control group was identified by random selection among patients with recurrent HCV following OLT who did not develop FCH. The IL28B genotype tests were performed using stored genomic DNA extracted from whole blood samples of both the donor and the recipient at the time of the liver transplantation. Donor and recipient DNA was tested for the polymorphism rs12979860 and rs8099917. The possible genotypes were as follows: CC, CT, and TT for polymorphism (rs12979860); and GG, GT, and TT for polymorphism (rs8099917). Descriptive statistics were computed for all factors. A Kaplan–Meier plot was constructed and log-rank tests were used to compare the different genotype groups. A total of 260 patients underwent OLT for chronic HCV infection of whom eight patients developed FCH post-transplant (3.1%). The FCH and control groups were comparable with regard to recipient and donor age, gender, and race distribution. The median follow-up was 11 months post-OLT. All subjects underwent cadaveric liver transplant. The cold ischemia time was not different between the two study groups (p = 0.16). The predominant HCV genotype was genotype 1. Compared to non-FCH group, the peak post-OLT viral load was significantly higher in the FCH patients (5.0 ± 4.4 9 10 vs. 14.9 ± 10.6 9 10, p = 0.018). Tacrolimus was the main immunosuppressant agent used post-transplant, while corticosteroids were discontinued on day 21 after surgery. None of our study subjects experienced acute cellular rejection or infection with cytomegalovirus postOLT in the first year after transplant. The frequency of donor and recipient IL28B polymorphisms is summarized in Table 1. IL28B donor genotype was significantly associated with the risk of FCH in patients with recurrent HCV following OLT, with the favorable donor rs8099917 TT genotype being associated with a 9.6 (95% CI: 1.1, 83.2) times higher hazard of

Antibiotic‐Associated Disruption of Microbiota Composition and Function in Cirrhosis Is Restored by Fecal Transplant

Patients with cirrhosis are often exposed to antibiotics that can lead to resistance and fungal overgrowth. The role of fecal microbial transplant (FMT) in restoring gut microbial function is unclear in cirrhosis. In a Food and Drug Administration–monitored phase 1 clinical safety trial, patients with decompensated cirrhosis on standard therapies (lactulose and rifaximin) were randomized to standard‐of‐care (SOC, no antibiotics/FMT) or 5 days of broad‐spectrum antibiotics followed by FMT from a donor enriched in Lachnospiraceae and Ruminococcaceae. Microbial composition (diversity, family‐level relative abundances), function (fecal bile acid [BA] deconjugation, 7α‐dehydroxylation, short‐chain fatty acids [SCFAs]), and correlations between Lachnospiraceae, Ruminococcaceae, and clinical variables were analyzed at baseline, postantibiotics, and 15 days post‐FMT. FMT was well tolerated. Postantibiotics, there was a reduced microbial diversity and autochthonous taxa relative abundance. This was associated with an altered fecal SCFA and BA profile. Correlation linkage changes from beneficial at baseline to negative after antibiotics. All of these parameters became statistically similar post‐FMT to baseline levels. No changes were seen in the SOC group. Conclusion: In patients with advanced cirrhosis on lactulose and rifaximin, FMT restored antibiotic‐associated disruption in microbial diversity and function. (Hepatology 2018; 00:000‐000).

Editorial: Not All Nodules Are Created Equal: A Personalized Approach to Indeterminate (<2 cm) Nodules Identified on HCC Surveillance.

Indeterminate small (<2 cm) nodules are often discovered in cirrhotics who undergo contrast enhanced imaging for further characterization of lesions detected on ultrasound surveillance for hepatocellular carcinoma (HCC). These are either arterially enhancing (without venous washout or capsule) or are non-enhancing (with washout). Differentials include small HCCs (14–23%), atypical arterio-portal shunts, regenerative, and dysplastic nodules. A risk score that combines imaging features (arterial enhancement and nodule size) with clinical (age, prior h/o HCC) and laboratory features (albumin, AFP, hepatitis B ‘e’ antigen) appear to be superior to radiological features alone in the risk stratification of these nodules.