Talwalkar, Jayant A.

Previously regarded as an obscure disorder, nonalcoholic steatohepatitis (NASH) has recently emerged as an important chronic liver disease. NASH is within a spectrum of disorders characterized by excessive accumulation of fat in the liver, including simple hepatic steatosis (fatty liver), inflammation and necrosis (steatohepatitis), and fibrosis. Collectively, the disorders are called nonalcoholic fatty liver disease (NAFLD). Estimates of the prevalence of these individual conditions are suspect because liver biopsy is required for definitive diagnosis and is not generally performed. Although these conditions have traditionally been thought of as diseases of obese women, and are frequently associated with diabetes mellitus and hypertriglyceridemia, they have also been identified in lean men. Insulin resistance appears to be a common factor. These conditions are difficult to distinguish from each other clinically, and no biochemical or radiological test reliably establishes the diagnosis. A ratio of serum aspartate to alanine aminotransferase levels of less than one can distinguish NAFLD from alcoholic liver disease, but this is a nonspecific finding. Fatty infiltration imparts a diffuse echogenicity to the liver at ultrasonography, but this test cannot easily distinguish fat from fibrous tissue or identify cases of NASH. Only histological examination can establish the diagnosis of NASH, grade its severity, determine the prognosis and guide treatment.

Introduction Significant impairments in health-related quality of life (HRQL) in patients with non-alcoholic fatty liver disease have been previously described. The disease-specific HRQL among patients with non-alcoholic steatohepatitis (NASH), however, remains unknown. Aim To determine the degree of construct validity of the Chronic Liver Disease Questionnaire (CLDQ) in adults with NASH. Methods Participants referred for the evaluation of histology-proven NASH at Mayo Clinic, Rochester, between 1996 and 2000, were evaluated. HRQL assessment by the Short-Form 36 (SF-36) Health Survey and CLD) was performed. The primary outcome was to determine the level of correlation between overall and subscale scores for the CLDQ and SF-36 instruments. Results Among 79 participants (70%) with NASH completing both questionnaires (mean age, 51.2 years with 64% female gender), excellent reliability was noted for the CLDQ instrument. Significant reductions in all SF-36 domains (p<0.05 for all) including PCS and MCS scores (p<0.02 for both) among participants with NASH compared with normative data from an age-matched and sex-matched US general population sample was observed. Highly significant correlations were observed between overall CLDQ score with SF-36 PCS (r=0.82, p<0.0001) and SF-36 MCS (r=0.67, p<0.0001) scores. Similar degrees of correlation were observed between relevant subscales of the CLDQ and SF-36 as well. Discussion The CLDQ has excellent reliability and validity of construct for HRQL assessment in adults with NASH when compared with the SF-36. Future investigations among participants with NASH require assessing the responsiveness of the CLDQ to medical therapies and disease progression.

Background: Gastrointestinal tract cancers account for a significant proportion of the national cancer burden. Aim: We sought to explore patient- and hospital-level determinants of palliative care utilization among patients hospitalized with metastatic gastrointestinal tract cancers using a national database. Methods: An analysis of the 2012 National Inpatient Sample was performed. International Classification of Diseases, Ninth Revision codes were used to identify hospital discharges associated with metastatic digestive tract cancers and patient/hospital covariates for inclusion in a logistic regression model. Total charges and length of stay were analyzed in a linear regression model. Results: Compared to males, females were more likely to receive inpatient palliative care (adjusted odds ratio [OR] 1.12, P = .002). No difference was seen between white and Asian patients (adjusted OR 1.2, P = .11) or Native Americans patients (adjusted OR 1.4, P = .22). However, relative to white patients, African Americans (adjusted OR 1.13, P = .02) and Hispanics (adjusted OR 1.25, P = .001) had significantly higher odds of inpatient palliative care. Medicare patients were least likely to receive palliative care compared to those with Medicaid or commercial payers. Length of stay during these hospitalizations was longer in African Americans ( P = .0001), Asians ( P = .0001), and Native Americans ( P = .03) compared to white patients. No difference was seen when total charges were compared between white and African American patients ( P = .08). Conversely, total charges were higher in Hispanics ( P = .005) and Asians ( P = .001) relative to white patients. Conclusion: Gender and racial differences exist in utilization of inpatient palliative care among patients hospitalized with metastatic gastrointestinal tract cancers.

Summary Drug-induced liver injury (DILI) is often caused by innate and adaptive host immune responses. Characterization of inflammatory infiltrates in the liver may improve understanding of the underlying pathogenesis of DILI. This study aimed to enumerate and characterize leucocytes infiltrating liver tissue from subjects with acute DILI (n = 32) versus non-DILI causes of acute liver injury (n = 25). Immunostains for CD11b/CD4 (Kupffer and T helper cells), CD3/CD20 (T and B cells) and CD8/CD56 [T cytotoxic and natural killer (NK) cells] were evaluated in biopsies from subjects with acute DILI, either immunoallergic (IAD) or autoimmune (AID) and idiopathic autoimmune (AIH) and viral hepatitis (VH) and correlated with clinical and pathological features. All biopsies showed numerous CD8+ T cells and macrophages. DILI cases had significantly fewer B lymphocytes than AIH and VH and significantly fewer NK cells than VH. Prominent plasma cells were unusual in IAD (three of 10 cases), but were associated strongly with AIH (eight of nine) and also observed in most with AID (six of nine). They were also found in five of 10 cases with VH. Liver biopsies from subjects with DILI were characterized by low counts of mature B cells and NK cells in portal triads in contrast to VH. NK cells were found only in cases of VH, whereas AIH and VH both showed higher counts of B cells than DILI. Plasma cells were associated most strongly with AIH and less so with AID, but were uncommon in IAD.

Introduction Hepatocellular carcinoma (HCC) is an important but infrequent outcome in primary biliary cirrhosis (PBC). Improved risk evaluation is an important goal for stratified surveillance. Methods Risk-factor analysis of the ‘Global PBC Study Group’ comprising 15 centres across North America and Europe spanning >40-years follow-up was performed using Cox proportional hazards model, logistic regression and Kaplan-Meier estimates (SPSSv21). Results Of 3546 patients with PBC (med. follow-up 8.6 yrs; IQR 4.4–14.1), 131 developed HCC. Excluding those who developed HCC within 12 months of PBC diagnosis (n = 23), median time to HCC was 12.7 yrs (6.9–16.8) and subsequent survival 1.1 yrs. (0.2–2.7). At diagnosis, factors associated with HCC development were male gender (adj. HR: 4.4;1.4–12.2, p = 0.014) and thrombocytopenia (adj. HR: 4.5;1.4–14.8, p = 0.012). Use of ursodeoxycholic acid per-se was not associated with future risk of HCC, but stratification of risk by biochemical response at 12 months was effective by Rotterdam (adj. HR: 8.9;2.1–37.3, P = 0.003), Paris-I (adj. HR: 7.6;2.0–29.0, p = 0.003) or Toronto criteria (HR: 5.6;1.6–18.8, P = 0.006). Five (4.6 vs. 0.2%) and 10-year (13%vs.1.9%) HCC incidence was significantly increased for biochemical non-responders (p = 2.2 × 10 –9 ), and by multivariate analysis non-response remained the only significant risk factor. Conclusion Our uniquely powered cohort allows robust demonstration that 12-month biochemical non-response is associated with an increased risk of developing HCC in PBC. Routine surveillance in those achieving biochemical response is unlikely cost-effective. Disclosure of Interest None Declared.

AbstractBackground & AimsBecause of the lack of objective tests to diagnose drug‐induced liver injury (DILI), causality assessment is a matter of debate. Expert opinion is often used in research and industry, but its test–retest reliability is unknown. To determine the test–retest reliability of the expert opinion process used by the Drug‐Induced Liver Injury Network (DILIN).MethodsThree DILIN hepatologists adjudicate suspected hepatotoxicity cases to one of five categories representing levels of likelihood of DILI. Adjudication is based on retrospective assessment of gathered case data that include prospective follow‐up information. One hundred randomly selected DILIN cases were re‐assessed using the same processes for initial assessment but by three different reviewers in 92% of cases.ResultsThe median time between assessments was 938 days (range 140–2352). Thirty‐one cases involved >1 agent. Weighted kappa statistics for overall case and individual agent category agreement were 0.60 (95% CI: 0.50–0.71) and 0.60 (0.52–0.68) respectively. Overall case adjudications were within one category of each other 93% of the time, while 5% differed by two categories and 2% differed by three categories. Fourteen per cent crossed the 50% threshold of likelihood owing to competing diagnoses or atypical timing between drug exposure and injury.ConclusionsThe DILIN expert opinion causality assessment method has moderate interobserver reliability but very good agreement within one category. A small but important proportion of cases could not be reliably diagnosed as ≥50% likely to be DILI.

Primary sclerosing cholangitis (PSC) is an idiopathic, progressive, cholestatic liver disease with considerable morbidity and mortality and no established pharmacotherapy. In addition to the long-recognized association between PSC and inflammatory bowel disease, several lines of preclinical and clinical evidence implicate the microbiota in the etiopathogenesis of PSC. Here we provide a concise review of these data which, taken together, support further investigation of the role of the microbiota and antibiotics in PSC as potential avenues toward elucidating safe and effective pharmacotherapy for patients afflicted by this illness.

BACKGROUNDPatients diagnosed with primary sclerosing cholangitis (PSC) and dominant strictures often undergo endoscopic retrograde cholangiopancreatography with brush cytology to exclude or confirm the development of malignancy. Equivocal (atypical or suspicious) routine cytologic results may confound patient management decisions, especially in the absence of a mass on imaging. The objective of the current study was to identify independent predictors of malignancy in patients with PSC with an equivocal cytology diagnosis.METHODSPatients with PSC underwent brush cytology for routine cytology and fluorescence in situ hybridization (FISH) during endoscopy as per standard care. FISH slides were classified as polysomy if at least 5 cells displayed a gain of ≥ 2 probes. A retrospective search identified 102 patients without a mass lesion noted on initial imaging studies, an equivocal routine cytology, and ≥ 2 years of follow‐up.RESULTSOf 102 patients, 30 (29%) with an equivocal cytology result developed cancer within 2 years. Serum carbohydrate antigen 19‐9 (CA 19‐9) levels ≥ 129 U/mL (hazard ratio [HR] 3.19; P = .001) and polysomy (HR 8.70; P < .001) were each found to be predictive of cancer. Of 10 patients who had elevated CA 19‐9 levels and polysomy, all went on to develop cancer (9 within 2 years). Although only 10 patients were included in this subset, the combination of elevated CA 19‐9 and polysomy was found to be predictive of cancer (HR 10.92; P < .001).CONCLUSIONSPolysomy by FISH identified those patients most likely to have or develop malignancy in the challenging clinical scenario of PSC with no mass at baseline and equivocal cytology. The combination of an elevated serum CA 19‐9 level with polysomy is highly suspicious for the presence of malignancy. Cancer (Cancer Cytopathol) 2013;121:708–717. © 2013 American Cancer Society.