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Objective The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD. Design The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) 10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069). Conclusions Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds. Lay summary NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD. ©

Background: Non-alcoholic fatty liver disease (NAFLD) is the most frequent chronic liver disease in Western countries, and in particular in obese patients the prevalence is higher than in general population. It has a large clinical spectrum, ranging from simple steatosis to steatohepatitis (NASH) and cirrhosis. Aim of the study: To evaluate in obese patients who underwent bariatric surgery in the last 3 years: 1) the histological prevalence and severity of liver steatosis (LS) and fibrosis; 2) the reliability of ultrasound (US) in diagnosing steatosis. Patients and methods: We reviewed preoperative liver US and intraoperative liver biopsy results in 57 bariatric surgery patients (age 42 ± 12.0 years, Body Mass Index (BMI) 43.5 ± 7.1), along with their clinical characteristics. Steatosis was diagnosed when more than 5 % of liver parenchyma was involved, the NAFLD activity score (NAS) and grade of fibrosis were determined according to Clinical Research Network system for scoring activity and fibrosis in non-alcoholic fatty liver disease (NASH CRN). US was performed after a 12-hour fast. US diagnosis of LS was evaluated with bright liver echopattern. Results: The prevalence of liver steatosis was 81 % (CI 95 %: 71-90), in patients with LS, the NAS Score was: 0-2 (not NASH) in 11 patients (24%; 13-37); 3-4 (borderline) in 20 patients (43 %; 30-58); ≥ 5 (NASH) in 15 patients, (33 %; CI 95 %: 21-46). Fibrosis was present in 40 patients (87 %; CI 95 %:75-95), bridging fibrosis (F= 3) in 3 patients, cirrhosis in 1 patients. The Sensitivity of US in steatosis diagnosis was 93% (CI 95 %:81-98), Specificity 42% (CI 95 %:9-75), Positive Predictive Value 89.3% (CI 95 %:83-93), Negative Predictive Value 50 % (CI 95 %:13-72), Accuracy 84.9% (CI 95 %:72- 93). Conclusions: In obese patients the prevalence of steatosis was higher than in the general population (82%), NASH and borderline-NASH were present in 24 and 43%, respectively. Finally, severe fibrosis or cirrhosis was present in 3 and 1 patient, respectively (in total 10 %); this low prevalence may be due to the young age of patients, confirming that earlier therapy could be associated with less irreversible liver damage. The US in diagnosing liver steatosis showed a good sensitivity, but insufficient specificity, confirming that in severe obesity the US reliability is low.

FIBROSIS DIAGNOSTIC SCORES VALIDATION IN OBESE PATIENTS WITH NON-ALCOHOLIC LIVER DISEASE

Background: Blood tests of liver injury are less well validated in non-alcoholic fatty liver disease (NAFLD) than in patients with chronic viral hepatitis. Aims: To improve the validation of three blood tests used in NAFLD patients, FibroTest for fibrosis staging, SteatoTest for steatosis grading and ActiTest for inflammation activity grading. Methods: We pre-included new NAFLD patients with biopsy and blood tests from a single-centre cohort (FibroFrance) and from the multicentre FLIP consortium. Contemporaneous biopsies were blindly assessed using the new steatosis, activity and fibrosis (SAF) score, which provides a reliable and reproducible diagnosis and grading/staging of the three elementary features of NAFLD (steatosis, inflammatory activity) and fibrosis with reduced interobserver variability. We used nonbinary-ROC (NonBinAUROC) as the main endpoint to prevent spectrum effect and multiple testing. Results: A total of 600 patients with reliable tests and biopsies were included. The mean NonBinAUROCs (95% CI) of tests were all significant (P < 0.0001): 0.878 (0.864–0.892) for FibroTest and fibrosis stages, 0.846 (0.830–0.862) for ActiTest and activity grades, and 0.822 (0.804–0.840) for SteatoTest and steatosis grades. FibroTest had a higher NonBinAUROC than BARD (0.836; 0.820–0.852; P = 0.0001), FIB4 (0.845; 0.829–0.861; P = 0.007) but not significantly different than the NAFLD score (0.866; 0.850–0.882; P = 0.26). FibroTest had a significant difference in median values between adjacent stage F2 and stage F1 contrarily to BARD, FIB4 and NAFLD scores (Bonferroni test P < 0.05). Conclusions: In patients with NAFLD, SteatoTest, ActiTest and FibroTest are non-invasive tests that offer an alternative to biopsy, and they correlate with the simple grading/staging of the SAF scoring system across the three elementary features of NAFLD: steatosis, inflammatory activity and fibrosis. © 2016 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd

The current standard of care (SoC) for chronic hepatitis C, i.e. the combination of a pegylated-interferon (PEG-IFN) with ribavirin (RBV), may activate underlying autoimmune conditions. Particularly, interferon (IFN) has been known to induce or exacerbate autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) in hepatitis C virus patients. We describe a severe, acute-onset antimitochondrial antibody (AMA)-M2 positive AIH appearing during the last weeks of SoC in a woman with chronic hepatitis C and no previous history of autoimmunity, and resolving on protracted steroids. In this context, the relevance of the characterization of the immunoglobulin isotype of portal plasma cells for a more appropriate diagnosis of autoimmune liver diseases can be emphasized.

Mycotic infection of the alimentary canal are rare and usually involve the upper digestive tract. Mycetes, especially of Candida family, are habitual saprophytes in the digestive tract of healthy individuals. Under certain conditions, fungal flora may overgrowth, resulting in lesions of the digestive mucosa, which, rarely, might evolve to local diffusion and/or systemic lympho-hematogenous spreading. In the stomach, sometimes, mycotic infections may appear like benign gastric ulcers. we described a case of woman, aged 64, affected by psoriasis, in chronic treatment with cyclosporine and type 2 diabetes mellitus, a well-known immunosoppressive condition, with endoscopic evidence of ulcerated vegetating gastric lesion, strongly suggestive for malignancy, due to Candida albicans infection, and completely healed after cyclosporine withdrawal and administration of oral antifungal drugs.

Background and aim: Steatosis and insulin resistance (IR) are the major disease modifying in patients with chronic hepatitis C (CHC). Only few studies evaluated these features in patients with chronic hepatitis B (CHB). We aimed to assess the prevalence and the characteristics of steatosis and IR in CHB patients, compared to CHC subjects, and to evaluate the potential association between these features and fibrosis severity. Material and methods: 170 consecutive patients with CHB (28 HBeAg positive, 128 HBeAg negative, and 14 HBeAg negative/anti-HDV positive), and 170 sex, age and BMI matched genotype 1 CHC patients were evaluated by liver biopsy and metabolic measurements, including IR, by the homeostasis model assessment (HOMA). Insulin resistance was defined if HOMA-IR>2.7. All biopsies were scored by one pathologist for staging and grading (Scheuer). Steatosis was considered significant if ≥10%. Results: The prevalence of significant steatosis was similar in both CHB and CHC patients (31% vs. 38%; p=0.14). IR rate was significantly higher in CHC than in CHB patients (42% vs. 26%; p=0.002). In CHB patients, at multivariate analysis, severe fibrosis (F3-F4) was independently associated with older age (OR 1.054,95%CI 1.007–1.103, p=0.02), low platelet levels (OR 0.984,95%CI 0.973–0.994, p=0.003), high GGT (OR 1.019,95%CI 1.001– 1.039, p=0.04), steatosis>10% (OR 3.601,95%CI 1.272–10.194, p=0.01), and moderate-severe necroinflammatory activity (OR 8.111,95%CI 1.884–34.925, p=0.005), regardless HBeAg status and HDV co-infection. Conclusions: CHB patients had high steatosis prevalence, similar to CHC controls, but lower IR rate. Steatosis, is independently associated with severe fibrosis in CHB patients.

BACKGROUND: The role of Barrett esophagus in carcinogenesis is widely accepted, but the significance of esophageal columnar mucosa without histological intestinal metaplasia, known as columnar-lined esophagus, is debated. MATERIAL/METHODS: We studied 128 patients free of Helicobacter pylori with reflux-related symptoms and columnar mucosa in the esophagus at endoscopy, 106 patients with Barrett esophagus (referred to as the Barrett group) and 22 patients without intestinal metaplasia (columnar group). Samples from 20 subjects free of H. pylori were used as controls. Immunostaining for keratin 7 (KRT7), keratin 20 (KRT20), caudal type homeobox 2 (CDX2), mucin 2, oligomeric mucus/gel-forming (MUC2), and tumor protein p53 (TP53) was assessed. RESULTS: Samples taken 1 cm above the gastroesophageal junction showed KRT7 staining in all cases in the Barrett and columnar groups and none in the control group. Immunostaining for TP53 was absent in the control group, and more frequent in the columnar group (7, 31.8%) compared with the Barrett group (14, 13.2%, P=0.033). In the columnar group, low grade dysplasia and TP53 expression was seen in 7 of 22 biopsy specimens (31.8%) at baseline and in 4 additional specimens after 2 years, for a total of 11 specimens (50.0%). CONCLUSIONS: The expression of KRT7 might help to explain the pathological, reflux-related nature of columnar-lined esophagus, as aberrant expression in a very early stage of the multistep Barrett esophagus progression. Expression of KRT7 may occur in basal glandular cells as a result of their multipotentiality and susceptibility to immunophenotype changes induced by reflux.

Background: Neurofibromas are sporadic or associated with type 1 neurofibromatosis (NF1), with a higher risk of malignant progression. Materials and Methods: We investigated CD10 immunoexpression in 39 peripheral nerve sheath lesions. They were 18 typical, solitary, sporadic neurofibromas (group A) and 21 cases (group B) consisting of 11 NF1-associated cases, 3 malignant peripheral sheath tumors (MPNST) and 8 atypical neurofibromas. Results: CD10 immunopositivity was absent or very weak and focal in group A. On the contrary, CD10 was strongly expressed in group B, including all the MPNST and their metastases, with 95% sensitivity and 72% specificity in distinguishing between the two groups. Conclusion: CD10 is useful in the assessment of peripheral sheath tumors and could give evidence that atypical myxoid and/or diffuse neurofibromas, sometimes histologically difficult to distinguish from low-grade MPNST, represent not only a histological but also an immunohistochemical continuum with MPNST

Biopsy is still the gold standard for the diagnosis of nonalcoholic steatohepatitis but the definition may vary among pathologists, a drawback especially in evaluation of biopsies for clinical trials. We previously developed a scoring system (steatosis, activity, fibrosis [SAF]) allowing the use of an algorithm (fatty liver inhibition of progression [FLIP]) for the classification of liver injury in morbid obesity. The aim of this study was to determine whether the use of the SAF score and FLIP algorithm can decrease interobserver variations among pathologists. In a first session, pathologists categorized 40 liver biopsies of patients with nonalcoholic fatty liver disease (NAFLD) according to their own experience. In a second reading session, each pathologist reclassified the same slides by using the FLIP algorithm and SAF score, blinded to their first evaluation. The experiment was repeated with two different groups of pathologists at varying levels of training in liver pathology. The percentage of biopsy interpretation concordant with reference evaluation increased from 77% to 97% in Group 1 and from 42% to 75% in Group 2 after the use of the SAF score and FLIP algorithm. The strength of concordance in classification increased in Group 1 from moderate (κ=0.54) to substantial (κ=0.66) and from fair (κ=0.35) to substantial (κ=0.61) in Group 2 with application of the algorithm. With regard to the SAF score, concordance was substantial in Group 1 for steatosis (κ=0.61), activity (κ=0.75), and almost perfect for fibrosis (κ=0.83 after pooling 1a, 1b, and 1c together into a single score F1). Similar trends were observed in Group 2 (κ=0.54 for S, κ=0.68 for A, and κ=0.72 for F). Conclusion: The FLIP algorithm based on the SAF score should decrease interobserver variations among pathologists and are likely to be implemented in pathology practice. (Hepatology 2014;60:565-575) © 2014 by the American Association for the Study of Liver Diseases.

Iron overload and hepatitis virus C infection cause liver fibrosis in thalassemics. In a monocentric retrospective analysis of liver disease in a cohort of 191 transfusion-dependent thalassemics, in 126 patients who had undergone liver biopsy (mean age 17.2 years; 58 hepatitis virus C-RNA positive and 68 hepatitis virus C-RNA negative) the liver iron concentration (median 2.4 mg/gr dry liver weight) was closely related to serum ferritin levels (R = 0.58; p

BACKGROUND: To date an accurate evaluation of predictive markers in breast cancer is mainly conducted at the primary site, although the main goal of the adjuvant therapy is the control of micrometastases. Adjuvant therapy drugs need a high proliferative cell rate to be effective. The proliferating activity can be evaluated by the Ki-67 marker and even by thymidylate synthase (TS), a cell cycle enzyme present in proliferating cells. In this study the TS levels in primary tumours were compared to those of their metastases. PATIENTS AND METHODS: The TS expression and Ki-67 were evaluated by means of immunohistochemistry in 80 primary breast tumours (PTs) and in their matched axillary metastatic lymph-nodes (ALNs). RESULTS: In 16% of patients, malignant cells of involved nodes showed a lower TS expression than the PTs. In the same group, we also found a lower number of Ki-67 immunoreactive cells in lymph node metastases when compared with primary tumours. CONCLUSION: The group of patients with lower TS and Ki-67 expression in lymph node metastatic cells may be less sensitive to 5-fluorouracil and high dose methotrexate requiring them to be treated with other drug combinations.