Overt hepatic encephalopathy: development of a novel clinician reported outcome tool and electronic caregiver diary.

Clinical management and clinical trials of patients with overt hepatic encephalopathy (OHE) are compromised by lack of standardized and reproducible tools for its clinical diagnosis or for caregiver (CG) identification of OHE manifestations which merit medical evaluation. Using an iterative Delphi method, Steering Committee and international hepatologist panel, the West Haven (WH) scale was modified to develop and operationalize a clinician tool for OHE identification and grading (HE Grading Instrument, HEGI™). Major diagnostic criteria included disorientation to time, place, and person, asterixis, lethargy, and coma. Minimum HEGI requirements for OHE diagnosis included: (1) disorientation, or (2) presence of both lethargy and asterixis, or (3) coma. Inter- and intra-rater HEGI reproducibility were 97 % and 98 %, respectively. When applied to a phase II clinical trial population of 178 patients with 388 OHE episodes, HEGI demonstrated excellent concordance with investigator judgement. Additionally, a multi-stage study was conducted to develop a daily CG e-diary, based on OHE manifestations recognizable by CG including speech difficulties, unusual behavior, forgetfulness, confusion, disorientation and level of consciousness. The e-diary was designed for use on smart phone, laptop or desktop, utilized branching logic and skip patterns, incorporated automatic daily completion reminders and real time alerts to clinical sites to facilitate daily standardized CG input and was found to be user friendly and understandable. The HEGI and e-diary, which were developed using methodology accepted by regulatory authorities, are designed to facilitate the design and interpretation of clinical trials for OHE and improve outcomes for OHE patients in clinical practice.

Prospective Multicenter Observational Study of Overt Hepatic Encephalopathy.

BACKGROUND: Overt hepatic encephalopathy (OHE) is a frequent complication of decompensated cirrhosis. AIMS: A multicenter prospective observational study was performed to assess the most commonly recorded presenting manifestations of OHE and its associated health-care burden. METHODS: Qualifying patients must have experienced ≥1 OHE episode within 30 days of enrollment (qualifying OHE) and were followed for recurrence (on-study OHE). RESULTS: Two hundred and sixty-five patients were enrolled at 30 sites and followed for up to 9 months (mean 72 days). Seventy-two patients experienced 122 on-study episodes; with 72, 23, and 13 having ≥1, ≥2, or ≥3 on-study episodes with median days to occurrence of the 1st, 2nd, and 3rd episode of 34, 19, and 11, respectively. The most frequently recorded OHE manifestations included confusion (78 %), change in mental status (57 %), disorientation (48 %), lethargy (46 %), and asterixis (45 %). West Haven grade was used inconsistently and recorded for only 28 % of episodes. Most qualifying and on-study episodes occurred on rifaximin (60 and 82 %, respectively) and were associated with hospitalization (68 and 85 %, respectively). Twenty-three patients experienced ≥2 on-study episodes within 2 months of enrollment on average (median 45 days) and accounted for 60 % of on-study episodes. CONCLUSIONS: In this prospective study, OHE's most commonly recorded presenting manifestations included confusion, altered mental status, disorientation, lethargy, and asterixis. As reflected by frequent recurrence and hospitalizations, OHE, particularly the approximately 10 % of "high-resource-utilizing" patients with frequent recurrence, continues to pose a major unmet medical need and health-care burden despite the use of rifaximin.

Elevated phenylacetic acid levels do not correlate with adverse events in patients with urea cycle disorders or hepatic encephalopathy and can be predicted based on the plasma PAA to PAGN ratio.

BACKGROUND: Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100). Both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥ 500 µg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels. METHODS: The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from: [1] healthy adults [2], UCD patients of ≥ 2 months of age, and [3] patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values. RESULTS: Only 0.2% (11) of 4683 samples exceeded 500 µg/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio>2.5 (both in µg/mL) in a random blood draw identified patients at risk for PAA levels>500 µg/ml. CONCLUSIONS: The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.

Interobserver agreement and accuracy among international experts with probe-based confocal laser endomicroscopy in predicting colorectal neoplasia.

BACKGROUND AND STUDY AIMS: A recently developed probe-based, confocal laser endomicroscopy (pCLE) system provides images of surface colonic epithelium in vivo during any endoscopy. Our objective was to assess interobserver agreement, sensitivity, specificity, and overall accuracy in the diagnosis of neoplasia using pCLE. PATIENTS AND METHODS: 53 patients undergoing surveillance and screening colonoscopies were enrolled. A total of 75 lesions, were detected and all were inspected by pCLE prior to sampling or polypectomy. Intravenous fluorescein was used to optimize tissue contrast. Three pCLE users, blinded to histopathologic and endoscopic findings, reviewed the set of video sequences for crypt architecture, vessel architecture, and colorectal neoplasia diagnosis. Histopathologic diagnosis from the corresponding biopsies was the reference gold standard. RESULTS: Of the 75 colorectal lesions, 50 were neoplastic and 25 non-neoplastic. Interobserver agreement was moderate to good for the classification of neoplasia (kappa 0.55, 78 % pairwise agreement), and moderate for vessel architecture (kappa 0.41, 67 % pairwise agreement) and crypt architecture (kappa 0.49, 69 % pairwise agreement). In distinguishing between neoplastic and non-neoplastic lesions, sensitivity, specificity, and accuracy were 76 %, 72 % and 75 %, respectively. When videos of good or excellent quality only were considered, interobserver agreement for classification of neoplasia was higher (kappa 0.83, 92 % pairwise agreement), as were sensitivity (88 %), specificity (89 %), and accuracy (88 %). CONCLUSION: An international collaboration group had moderate to good interobserver agreement using a pCLE system to predict neoplasia, which is acceptable for this study.

Persistence of hepatitis C RNA in liver allografts is associated with histologic progression independent of serologic viral clearance.

Background. Hepatitis C virus (HCV) nondetectability in the liver may predict a sustained viral response (SVR) in patients with an end of treatment response. HCV RNA can be detected in liver tissue by in situ hybridization (ISH). Aim. To determine if HCV nondetectability in liver allografts by ISH can predict SVR in patients who cleared virus serologically on treatment. Methods. Twenty five patients with undetectable serum HCV on Interferon/Ribavirin therapy for HCV recurrence post liver transplant (LT) were studied. All had biopsies at 4 months post LT (baseline) and follow up with HCV ISH analysis performed. Results. 10 were ISH positive (group 1); 15 were ISH negative (group 2). Groups 1 and 2 had similar patient, donor, and viral characteristics at LT, as well as treatment duration at the time of the ISH assayed liver biopsy (13 +/- 16 versus 10 +/- 4 months P = .24). However, group 1 had longer total treatment duration (24 +/- 10 versus 14 +/- 5 months, P = .001). Eight (80%) group 1 and 9 (60%) group 2 patients achieved SVR. Mean grade and stage (modified Ishak score) were similar at 4 months, however, group 1 had higher grade (3 +/- 1.7 versus 1.6 +/- 1.3, P = .039) and stage (1.4 +/- 1.4 versus 0.5 +/- 0.6, P = .084) on the ISH assayed biopsy, after similar post LT intervals (23 +/- 10 versus 24 +/- 12 months, P = .91). Conclusion. Allograft HCV ISH nondetectability does not predict SVR in treatment responsive HCV recurrence, but is associated with less severe histologic disease.

Improving outcomes of liver retransplantation: an analysis of trends and the impact of Hepatitis C infection.

UNLABELLED: Retransplantation (RT) in Hepatitis C (HCV) patients remains controversial. AIMS: To study trends in RT and evaluate the impact of HCV status in the context of a comprehensive recipient and donor risk assessment. The UNOS database between 1994 and October 2005 was utilized to analyze 46 982 LT and RT. Graft and patient survival along with patient and donor characteristics were compared for 2283 RT performed in HCV and non-HCV patients during 1994-1997, 1998-2001 and 2002-October 2005. Overall HCV prevalence at RT increased from 36% in the initial period to 40.6% after 2002. In our study group, 1-year patient and graft survival post-RT improved over the same time intervals from 65.0% to 70.7% and 54.87% to 65.8%, respectively. HCV was only associated with decreased patient and graft survival with a retransplant (LT-RT) interval (RI) >90 days. Independent predictors of mortality for RT with RI >90 days were patient age, MELD score >25, RI <1 year, warm ischemia time > or =75 min and donor age > or =60 (significant for HCV patients only). Outcomes of RT are improving, but can be optimized by weighing recipient factors, anticipation of operative factors and donor selection.

Hyperplastic Polyposis following Treatment of Gastric Vascular Ectasia: A Case Report and Review of Clinical Correlates.

The etiology of gastric antral vascular ectasia (GAVE) and hyperplastic polyps (HP) is not fully understood, but there is no known overlap. We report a case of gastroduodenal HP arising in a patient treated for GAVE.