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Background While non-alcoholic fatty liver disease (NAFLD) has been well characterised in patients with diabetes mellitus (DM), less is known about NAFLD in non-DM patients. We investigated the clinical characteristics of NAFLD patients with and without DM and accuracy of the NAFLD fibrosis score (NFS) in these two NAFLD groups. Methods Clinical, biochemical and histological variables were evaluated in this prospective cross-sectional study of 503 patients with biopsy proven NAFLD. Comparisons between patients with and without DM were analysed. NFS was correlated with liver histology to assess its robustness in patients with and without DM. Results There were 503 biopsy proven NAFLD patients with 48% of the cohort being diabetic. Relative to patients without DM, patients with DM were older (52 vs. 46 years, p, Highlights • Patients with diabetes have more severe NAFLD based on histology. • Severe NAFLD can occur in a considerable proportion of non-diabetic NAFLD patients. • The NAFLD fibrosis score may be less accurate in non-diabetics.

Pediatric non-alcoholic fatty liver disease (NAFLD) may present with a distinct histopathological pattern characterized by the presence of predominant portal-based injury and portal inflammation (PI). We aimed at developing a new grading score for pediatric NAFLD to be used in clinical trials that takes into account the presence of PI and the weight of histological features.Our training set consisted of 203 children with biopsy-proven NAFLD. The diagnosis of non-alcoholic steatohepatitis (NASH) was based on Brunt's criteria. Histological features were scored: steatosis (0-3), lobular inflammation (0-3), ballooning (0-2), and PI (0-2). Logistic regression analysis was performed to apply weight to each feature. The new score was called the Pediatric NAFLD Histological Score or PNHS. The validation set consisted of 100 children with NAFLD.The mean age of the initial cohort was 12.4 ± 3.4 years and significant fibrosis (fibrosis stage ≥ 2) was present in 26 patients (12.8%). NASH was diagnosed in 135 patients with a mean NAS of 4.5 ± 1.4. The mean PNHS in the NASH group was 89 ± 20.5 compared to 21.9 ± 24.5 in the "not NASH" group, p0.001. PNHS correlated with the presence of NASH according to the pathologist's diagnosis, better than the NAFLD activity score (NAS), p=0.011. The area under the ROC curve (AUC) for the diagnosis of NASH was 0.96 for PNHS. Similar findings were observed in the validation set with an AUC of 0.94.PNHS may be used for histological grading of pediatric NAFLD with excellent correlation with the presence of NASH.

Glypican-3 (GPC3) is an oncofetal protein that has been demonstrated to be a useful diagnostic immunomarker for hepatocellular carcinoma and hepatoblastoma. Its expression in mesenchymal tumors of the liver, particularly undifferentiated embryonal sarcoma (UES) and mesenchymal hamartoma (MH), has not been investigated. In this study, a total of 24 UESs and 18 MHs were immunohistochemically stained for GPC3 expression. The results showed cytoplasmic staining for GPC3 in 14 (58%) UESs, of which 6 exhibited diffuse immunoreactivity and the remaining 8 showed focal positivity. The patients with GPC3-positive UES tended to be younger (mean 18 years; median 11 years) than those with GPC3-negative tumors (mean 39.4 years; median 27 years), although the difference did not reach statistical significance (P = .06). Eight MHs also exhibited GPC3 immunoreactivity (44%; 4 diffuse and 4 focal). Positive staining in all 8 cases was primarily seen in entrapped nonlesional hepatocytes with a canalicular and cytoplasmic staining pattern. In only 4 cases (22%) was GPC3 immunoreactivity also observed in the mesenchymal component. The patients with positive staining also tended to be younger (mean 2.6 years; median 1.1 years) compared with those with negative staining (mean 16.3 years; median 4.5 years), but the difference was not statistically significant (P = .15). Our data demonstrate that GPC3 is expressed in a subset of UES and MH of the liver. Caution should thus be exercised when evaluating a GPC3-expressing hepatic neoplasm, particularly on a needle biopsy when the differential diagnosis includes poorly differentiated hepatocellular carcinoma or hepatoblastoma.

The extrinsic death receptor-mediated pathway of apoptosis is involved in nonalcoholic steatohepatitis (NASH) development. Our aims were to create and validate a noninvasive prediction model for NASH diagnosis based on specific circulating markers of apoptosis.Our initial cohort consisted of 95 consecutive patients undergoing a liver biopsy for clinically suspected NASH. Blood was obtained from each patient at the time of liver biopsy. Plasma caspase 3 generated cytokeratin-18 fragments (CK-18), soluble Fas (sFas), and soluble Fas ligand (sFasL) were measured. Histology was assessed by an experienced hepatopathologist. The validation cohort consisted of 82 consecutive patients that underwent liver biopsy at the time of bariatric surgery.Patients with NASH had significantly higher levels of CK-18 and sFas than patients in the "not NASH" group [median (25th, 75th percentile): 508 (280, 846) U/L versus 176 (131, 224) U/L (p0.001), and 11.8 (7.8, 12.5) ng/ml versus 5.9 (4.8, 8.3) ng/ml (p0.001), respectively]. A significant positive correlation was revealed between the apoptosis markers and liver histopathology independent of other metabolic factors. A prediction model was generated including CK-18 fragments and sFas levels that showed an AUC of 0.93 and 0.79 in the initial and validation cohorts, respectively. A cutoff value using this model predicted NASH with a sensitivity and specificity of 88% and 89%, respectively.Quantification of circulating levels of two apoptotic markers accurately predicts the presence of NASH, supporting the potential usefulness of these markers in clinical practice for noninvasive diagnosis of NASH.

Little is known regarding the natural history of autoimmune hepatitis in children. The aims of this longitudinal cohort study were to determine the long-term prognosis of children with autoimmune hepatitis and to determine the effect of cirrhosis at presentation on survival.Thirty-three children with autoimmune hepatitis who were seen at our institution over a 25-year period were studied retrospectively.The median age of diagnosis was 12.9 years (2.7-18.1) with a female predominance of 3:1. Liver biopsies showed cirrhosis in 18 (55%) patients at time of diagnosis. Patients with cirrhosis at baseline had a similar 10-year survival 85% (70-100%) to those without cirrhosis 75% (49-100%) (p=0.97). The overall survival was significantly lower than the expected in the age- and gender-matched U.S. population (log-rank test; p0.001). In Cox regression models, weight loss (p=0.037), baseline elevated bilirubin (p=0.028), prolonged International Normalized Ratio (INR) (p=0.013), and positive LKM-1 antibodies (p=0.007) were associated with shorter survival.AIH in children is associated with a significant shorter survival rate than the expected in the general population. Cirrhosis on initial liver biopsy does not seem to impact long-term survival in children with AIH.

The metabolic syndrome (MS) is a unique condition in which the underlying mechanism is related to insulin resistance. In hepatitis C virus (HCV) patients, insulin resistance has been linked to treatment failure. The aim of this study was to estimate the prevalence of MS in HCV patients undergoing antiviral therapy and to assess its predictive value in treatment outcome.All HCV treatment-naive patients who met the inclusion/exclusion criteria were studied (n = 228). MS was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria. A logistic regression analysis was performed to study multivariable associations. The final model contained sex, ethnicity, body mass index, viral load, genotype, steatosis, fibrosis stage, and MS.MS was present in 59 of 228 (26%) patients. Genotype 1 (P = .002) and presence of steatosis (P.001) were found to be associated significantly with MS. Overall, sustained virologic response (SVR) was achieved in 108 of 228 (47%) patients. Male sex, non-Caucasian ethnicity, higher body mass index, high viral load, genotype 1, higher fibrosis stage, and MS were associated significantly with a lack of SVR. After adjusting for confounding variables, MS remained independently associated with a lack of SVR (P.01). Specifically, subjects with MS were 3.8 (95% confidence interval, 1.4-10.5) times more likely to fail treatment than those without MS.MS is seen frequently in patients with chronic HCV and is associated independently to lack of SVR. These findings support the concept that an aggressive intervention approach comprising lifestyle modification alone or in combination with drug treatment of the MS components may play an important role in improving antiviral responses in these patients.

Syndromic and sporadic fundic gland polyps are morphologically indistinguishable but may arise via different pathogenetic mechanisms involving mutations of the adenomatous polyposis coli (APC) and its downstream target beta-catenin genes. Although a higher frequency of dysplasia has been reported in syndromic forms, the risk of developing invasive carcinoma is exceedingly low. The current study was designed to investigate whether syndromic and sporadic fundic gland polyps differ in protein expression of a number of genes that are thought to be important in the control of neoplastic transformation. A total of 262 fundic gland polyps, including 155 syndromic polyps obtained from 35 patients with familial adenomatous polyposis or Gardner's syndrome and 107 sporadic polyps randomly selected from 45 patients with gastroesophageal reflux disease or Barrett's esophagus, were included in this study. Immunohistochemical evaluation showed that loss of immunoreactivity to the antibody against the carboxyl terminus of the APC protein, presumably resulting from APC gene mutations, was more frequent in syndromic than in sporadic cases (40% versus 6.7%, P

Backgrounds/aims De-novo autoimmune hepatitis (AIH) after liver transplantation (LT) is rising. Yet there is scarcity of data on the characteristics and the long-term outcomes of this condition. The aim of this study is to investigate the clinical characteristics and long-term outcomes of patients with de novo AIH following LT.Methods Using transplant liver biopsy database, we identified all patients with de-novo AIH following LT at our institution between 2008 and 2013. Patients with hepatitis C virus infection were excluded. The diagnosis of de-novo AIH was made according to the classical and simplified criteria defined by the International Autoimmune Hepatitis Group. Clinical information was gathered from electronic medical records. H&E stained sections and histochemical stains from the liver biopsies revealed findings compatible with AIH. Results A total of nineteen patients with de-novo AIH were identified (58% female, median age of 46 years), with mean international autoimmune hepatitis score of 12.1. Underlying liver disease were primary sclerosing cholangitis (n=4), primary biliary cirrhosis (n=3), biliary atresia (n=3), drug induced liver failure (n=2), alcoholic hepatitis (n=2) and others (n=5). The interval period from the LT to diagnosis of de-novo AIH was 19.6 months (1.6-197.8), during which 11 (58%) patients developed at least one episode of acute cellular rejection prior to the diagnosis of de-novo AIH. All patients were successfully treated with corticosteroids and incremental dose in immunosuppression. All showed complete biochemical response to treatment but 9 (47.4%) patients relapsed upon tapering down corticosteroids. Patients were followed over 6.7 year (1.5-17) years post-LT. Eight (42%) patients progressed to cirrhosis of whom 3 (15%) patients expired and 2 (10%) required second LT due to complications of end stage liver disease. Conclusion The present study shows the long term clinical outcomes of the patients with de-novo AIH post-LT. Although most patients exhibit a good initial response to medical therapy, de-novo AIH post-LT is likely to recur and progress to liver cirrhosis. Therefore, we should consider denovo AIH in patients who show abnormal liver tests or graft dysfunction after LT.

Aim In this study we aimed to estimate the frequency of post-liver transplant development of de novo HLA donor specific antibodies (dDSA) and to compare the incidence of histological findings commonly evaluated and C4d immunoreactivity in transplant liver biopsies with and without dDSA. Methods We retrospectively investigated liver allograft recipients transplanted at our institute between 2008-2012. HLA antibody testing was performed using Luminex single antigen beads. Separate liver core tissue biopsies were processed for C4d immunofluorescent staining. The incidence of C4d immunoreactivity, acute cellular rejection (ACR), recurrent chronic HCV hepatitis (Chr Hep) and central fibrosis (Cent Fib) were recorded for each biopsy for these cases. T & B cell flow crossmatch and pre-transplant DSA (pDSA) results were also compared between the 2 groups. Findings from multiple biopsies and DSA results from multiple post-transplant time points from the same patient were considered cumulatively. Results 35 liver transplant recipients had stored pre and post-transplant serum samples available for HLA antibody testing. Five patients developed dDSA (14%). The distribution of histological findings, C4d immunoreactivity, positive T & /or B cell flow crossmacth and pDSA in patients with (n=5) and without (n=30) dDSA is shown in the following:[ Table 1 ] Conclusions With limited number of study subjects, possible selection bias and the retrospective nature of the study, our results suggest that development of dDSA post-liver transplant is not uncommon. However, there is no evidence of increased incidence of ACR, Chr Hep, Cent Fib, or C4d immunoreactivity in patients who developed dDSA.

Background: In patients with NASH, progression of liver fibrosis is the central determinant of poor liver related outcomes. Therefore, there is a critical need for treatment that improves or attenuates fibrosis in NASH. Recently, a RCT of pentoxifylline (PTX) in 55 patients with NASH showed greater decrease in fibrosis score among patients on PTX compared to placebo [Zein CO et al, Hepatology 2011]. In a smaller RCT of PTX in NASH hepatic expression of fibrosis genes was reduced by PTX [Van Wagner LB et al, Ann Hepatol 2011]. Liver biopsy is invasive, risky, and limited by discordance of fibrosis staging related to both sampling and inter-observer variability, thus accurate prediction of fibrosis using non-invasive markers is attractive. Thus far, studies of serum fibrosis markers in NASH have been few and limited to cross-sectional design. Aims: To compare levels of serum markers of fibrosis: TIMP-1, hyaluronic acid (HA) and amino-terminal propeptide of type 3 collagen (P3NP) in patients treated with PTX or placebo for one year. And, to correlate changes in these markers with the changes in fibrosis on liver biopsy before and after treatment. Methods: 80 patients treated with PTX (n=44) or placebo (n=36) who completed one year of therapy as part of two recently published RCTs were included. Biopsies of subjects in both trials were reviewed and scored by a single blinded pathologist. TIMP-1, HA, and P3NP were measured and a European Liver Fibrosis (ELF) panel score calculated using stored blood samples collected at entry and end of study. Changes from baseline were compared between treatment arms and correlated with histologic fibrosis stage. Results: After one year, patients treated with PTX had a greater decrease in all measured markers of fibrosis compared to those on placebo: TIMP-1 [mean change -14 (+/-41) vs +12.5 (+/-34), p=0.005]; HA [-15.7 (+/-50.7) vs +8.9 (+/-42.5), p=0.03]; P3NP [-1.3 (+/-2.3) vs +0.29 (+/-2), p=0.005]; and calculated ELF score [-0.18 (+/-0.4) vs +0.12 (+/-0.45), p=0.005]. In addition, subjects with improved or stable fibrosis on biopsy had significant decreases from baseline in levels of TIMP-1 (p=0.045), P3NP (p=0.033) and ELF calculation (p=0.041) compared to subjects with progression of fibrosis on histology. Conclusions: TIMP-1, HA, P3NP, and calculated ELF score decreased in patients with NASH treated with PTX compared to placebo. Furthermore, changes from baseline on TIMP-1, P3NP, and calculated ELF score correlated with non-progression or progression of fibrosis on follow up biopsy. These results not only further substantiate that PTX appears to have a favorable effect on fibrosis in patients with NASH, but also provide novel information on the performance of serum markers of fibrosis in relation to histological changes over time in the setting of a therapeutic intervention in NASH.

Background: In patients with NASH, progression of liver fibrosis is the central determinant of poor liver related outcomes. Therefore, there is a critical need for treatment that improves or attenuates fibrosis in NASH. Recently, a RCT of pentoxifylline (PTX) in 55 patients with NASH showed greater decrease in fibrosis score among patients on PTX compared to placebo [Zein CO et al, Hepatology 2011]. In a smaller RCT of PTX in NASH hepatic expression of fibrosis genes was reduced by PTX [Van Wagner LB et al, Ann Hepatol 2011]. Liver biopsy is invasive, risky, and limited by discordance of fibrosis staging related to both sampling and inter-observer variability, thus accurate prediction of fibrosis using non-invasive markers is attractive. Thus far, studies of serum fibrosis markers in NASH have been few and limited to cross-sectional design. Aims: To compare levels of serum markers of fibrosis: TIMP-1, hyaluronic acid (HA) and amino-terminal propeptide of type 3 collagen (P3NP) in patients treated with PTX or placebo for one year. And, to correlate changes in these markers with the changes in fibrosis on liver biopsy before and after treatment. Methods: 80 patients treated with PTX (n=44) or placebo (n=36) who completed one year of therapy as part of two recently published RCTs were included. Biopsies of subjects in both trials were reviewed and scored by a single blinded pathologist. TIMP-1, HA, and P3NP were measured and a European Liver Fibrosis (ELF) panel score calculated using stored blood samples collected at entry and end of study. Changes from baseline were compared between treatment arms and correlated with histologic fibrosis stage. Results: After one year, patients treated with PTX had a greater decrease in all measured markers of fibrosis compared to those on placebo: TIMP-1 [mean change -14 (+/-41) vs +12.5 (+/-34), p=0.005]; HA [-15.7 (+/-50.7) vs +8.9 (+/-42.5), p=0.03]; P3NP [-1.3 (+/-2.3) vs +0.29 (+/-2), p=0.005]; and calculated ELF score [-0.18 (+/-0.4) vs +0.12 (+/-0.45), p=0.005]. In addition, subjects with improved or stable fibrosis on biopsy had significant decreases from baseline in levels of TIMP-1 (p=0.045), P3NP (p=0.033) and ELF calculation (p=0.041) compared to subjects with progression of fibrosis on histology. Conclusions: TIMP-1, HA, P3NP, and calculated ELF score decreased in patients with NASH treated with PTX compared to placebo. Furthermore, changes from baseline on TIMP-1, P3NP, and calculated ELF score correlated with non-progression or progression of fibrosis on follow up biopsy. These results not only further substantiate that PTX appears to have a favorable effect on fibrosis in patients with NASH, but also provide novel information on the performance of serum markers of fibrosis in relation to histological changes over time in the setting of a therapeutic intervention in NASH.

Background & Aims Data vary on the progression of low-grade dysplasia (LGD) in patients with Barrett's esophagus (BE); in patients with LGD, we investigated the incidence of high-grade dysplasia (HGD) and esophageal adenocarcinoma (EAC) and compared progression in patients with different forms of LGD (prevalent vs incident and multifocal vs unifocal). We assessed the effects of consensus diagnosis of LGD on progression rates to HGD and EAC among expert pathologists. Methods In a multicenter outcomes project, 210 patients with BE and LGD (classified as incident, prevalent, or persistent) were included. Patients were followed up for an average of 6.2 years (959.6 patient-years). Persistent LGD was defined as detection of LGD on ≥2 consecutive occasions during the follow-up period and extent as either unifocal (LGD at one level of BE segment) or multifocal (>1 level). Histology specimens were reviewed by 2 blinded pathologists. Results Six patients developed EAC (incidence of 0.44%/year), and 21 developed HGD (incidence of 1.6%/year). The incidence of the combination of HGD and EAC was 1.83%/year. There were no associations between presence of prevalent, incident, or persistent LGD and the extent of LGD with progression rates. Based on consensus diagnosis of 88 reviewed specimens, there was no difference in the progression of LGD to either EAC (the incidence based on analyses by the local pathologist was 0.18%/year, the incidence when there was agreement between the local and one central pathologist was 0.21%/year, and the incidence when all 3 pathologists were in agreement was 0.39%/year) or combined HGD and EAC (0.94%/year, 0.87%/year, and 0.84%/year, respectively). Conclusions Overall, patients with BE and LGD have a low annual incidence of EAC, similar to nondysplastic BE. There are no risk factors for progression and there is significant interobserver variation in diagnosis, even among expert pathologists.