Definite and indeterminate nonalcoholic steatohepatitis share similar clinical features and prognosis: A longitudinal study of 1893 biopsy-proven nonalcoholic fatty liver disease subjects.

BACKGROUND AND AIM: Histological score systems may not fully capture the essential nonalcoholic steatohepatitis (NASH) features, which is one of the leading causes of screening failure in clinical trials. We assessed the NASH distribution and its components across the fibrosis stages and their impact on the prognosis and their relationship with the concept of metabolic-associated fatty liver disease (MAFLD). METHODS: Spanish multicenter study including 1893 biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients from HEPAmet registry. NASH was diagnosed by NAS score ≥4 (including steatosis, ballooning and lobular inflammation) and fibrosis by Kleiner score. The presence of MAFLD was determined. Progression to cirrhosis, first episode of decompensated cirrhosis and death were collected during the follow-up (4.7 ± 3.8 years). RESULTS: Fibrosis was F0 34.3% (649/1893), F1 27% (511/1893), F2 16.5% (312/1893), F3 15% (284/1893) and F4 7.2% (137/1893). NASH diagnosis 51.9% (982/1893), and its individual components (severe steatosis, ballooning and lobular inflammation), increased from F0 (33.6%) to F2 (68.6%), and decreased significantly in F4 patients (51.8%) (P = .0001). More than 70% of non-NASH patients showed some inflammatory activity (ballooning or lobular inflammation), showing a similar MAFLD rate than NASH (96.2% [945/982] vs. 95.2% [535/562]) and significantly higher than nonalcoholic fatty liver (NAFL) subjects (89.1% [311/349]) (P < .0001). Progression to cirrhosis was similar between NASH (9.5% [51/539]) and indeterminate NASH (7.9% [25/316]), and higher than steatosis (5% [14/263]) (logRank 8.417; P = .015). Death and decompensated cirrhosis were similar between these. CONCLUSIONS: The prevalence of steatohepatitis decreased in advanced liver disease. However, most of these patients showed some inflammatory activity histologically and had metabolic disturbances. These findings should be considered in clinical trials whose main aim is to prevent cirrhosis progression and complications, liver transplant and death.

Significant fibrosis predicts new-onset diabetes mellitus and arterial hypertension in patients with NASH.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) could play a catalytic role in the development of metabolic comorbidities, although the magnitude of this effect in metabolically healthy patients with NAFLD remains unclear. We assessed the role of biopsy-proven NAFLD on the risk of developing type 2 diabetes mellitus (T2DM) and other metabolic comorbidities (arterial hypertension [AHT], and dyslipidemia) in metabolically healthy patients. METHODS: We included 178 metabolically healthy-defined by the absence of baseline T2DM, AHT, dyslipidemia-patients with biopsy-proven NAFLD from the HEPAmet Registry (N = 1,030). Hepamet fibrosis score (HFS), NAFLD fibrosis score, and Fibrosis-4 were calculated. Follow-up was computed from biopsy to the diagnosis of T2DM, AHT, or dyslipidemia. RESULTS: During a follow-up of 5.6 ± 4.4 years, T2DM occurred in 9% (16/178), AHT in 8.4% (15/178), low HDL in 9.6% (17/178), and hypertriglyceridemia in 23.6% (42/178) of patients. In multivariate analysis, significant fibrosis predicted T2DM and AHT. Independent variables related to T2DM appearance were significant fibrosis (HR 2.95; 95% CI 1.19-7.31; p = 0.019), glucose levels (p = 0.008), age (p = 0.007) and BMI (p = 0.039). AHT was independently linked to significant fibrosis (HR 2.39; 95% CI 1.14-5.10; p = 0.028), age (p = 0.0001), BMI (p = 0.006), glucose (p = 0.021) and platelets (p = 0.050). The annual incidence rate of T2DM was higher in patients with significant fibrosis (4.4 vs. 1.2 cases per 100 person-years), and increased in the presence of obesity, similar to AHT (4.6 vs. 1.1 cases per 100 person-years). HFS >0.12 predicted the risk of T2DM (25% [4/16] vs. HFS <0.12 4.5% [4/88]; logRank 6.658, p = 0.010). CONCLUSION: Metabolically healthy patients with NAFLD-related significant fibrosis were at greater risk of developing T2DM and AHT. HFS >0.12, but not NAFLD fibrosis score or Fibrosis-4, predicted the occurrence of T2DM. LAY SUMMARY: Patients with biopsy-proven non-alcoholic fatty liver disease and significant fibrosis were at risk of developing type 2 diabetes mellitus and arterial hypertension. The risk of metabolic outcomes in patients with significant fibrosis was increased in the presence of obesity. In addition to liver biopsy, patients at intermediate-to-high risk of significant fibrosis by Hepamet fibrosis score were at risk of type 2 diabetes mellitus.

Development and Validation of Hepamet Fibrosis Scoring System-A Simple, Noninvasive Test to Identify Patients With Nonalcoholic Fatty Liver Disease With Advanced Fibrosis.

BACKGROUND & AIMS: Fibrosis affects prognoses for patients with nonalcoholic fatty liver disease (NAFLD). Several non-invasive scoring systems have aimed to identify patients at risk for advanced fibrosis, but inconclusive results and variations in features of patients (diabetes, obesity and older age) reduce their diagnostic accuracy. We sought to develop a scoring system based on serum markers to identify patients with NAFLD at risk for advanced fibrosis. METHODS: We collected data from 2452 patients with NAFLD at medical centers in Italy, France, Cuba, and China. We developed the Hepamet fibrosis scoring system using demographic, anthropometric, and laboratory test data, collected at time of liver biopsy, from a training cohort of patients from Spain (n = 768) and validated the system using patients from Cuba (n = 344), Italy (n = 288), France (n = 830), and China (n = 232). Hepamet fibrosis score (HFS) were compared with those of previously developed fibrosis scoring systems (the NAFLD fibrosis score [NFS] and FIB-4). The diagnostic accuracy of the Hepamet fibrosis scoring system was assessed based on area under the receiver operating characteristic (AUROC) curve, sensitivity, specificity, diagnostic odds ratio, and positive and negative predictive values and likelihood ratios. RESULTS: Variables used to determine HFS were patient sex, age, homeostatic model assessment score, presence of diabetes, levels of aspartate aminotransferase, and albumin, and platelet counts; these were independently associated with advanced fibrosis. HFS discriminated between patients with and without advanced fibrosis with an AUROC curve value of 0.85 whereas NFS or FIB-4 did so with AUROC values of 0.80 (P = .0001). In the validation set, cut-off HFS of 0.12 and 0.47 identified patients with and without advanced fibrosis with 97.2% specificity, 74% sensitivity, a 92% negative predictive value, a 76.3% positive predictive value, a 13.22 positive likelihood ratio, and a 0.31 negative likelihood ratio. HFS were not affected by patient age, body mass index, hypertransaminasemia, or diabetes. The Hepamet fibrosis scoring system had the greatest net benefit in identifying patients who should undergo liver biopsy analysis and led to significant improvements in reclassification, reducing the number of patients with undetermined results to 20% from 30% for the FIB-4 and NFS systems (P < .05). CONCLUSIONS: Using clinical and laboratory data from patients with NAFLD, we developed and validated the Hepamet fibrosis scoring system, which identified patients with advanced fibrosis with greater accuracy than the FIB-4 and NFS systems. the Hepamet system provides a greater net benefit for the decision-making process to identify patients who should undergo liver biopsy analysis.

Angiopoietin-Like Protein 8 Is a Novel Vitamin D Receptor Target Gene Involved in Nonalcoholic Fatty Liver Pathogenesis.

Hepatic vitamin D receptor (VDR) expression is increased in patients with nonalcoholic fatty liver (NAFL) and is required for liver steatosis in an NAFL mouse model. However, how hepatocyte VDR is involved in setting up steatosis remains unclear. The authors transduced human hepatocyte-derived cells with an adenoviral vector encoding human VDR and found that angiopoietin-like protein 8 (ANGPTL8) expression was increased upon VDR activation by vitamin D or lithocholic acid. The mRNA levels of hepatic VDR- and vitamin D-related genes [cytochrome P450 (CYP) 2R1, CYP27A1, and CYP3A4] were higher in NAFL patients compared with normal liver subjects. Noteworthy, hepatic ANGPTL8 mRNA and protein levels were elevated in NAFL patients, and its mRNA correlated with VDR mRNA and with the steatosis grade. Moreover, increases in serum conjugated bile acids, including the VDR agonist glycine-lithocholic acid, were observed in NAFL patients. Additionally, free fatty acids and insulin were able to up-regulate both VDR and ANGPTL8 mRNA in human hepatocytes, whereas ANGPTL8 gene knockdown attenuated free fatty acids-induced triglyceride accumulation in these cells. In conclusion, activated VDR up-regulates ANGPTL8 expression, contributing to triglyceride accumulation in human hepatocytes. Moreover, hepatic ANGPTL8 mRNA positively correlates with VDR mRNA content and the grade of steatosis in NAFL patients, suggesting that this novel pathway may play a key role in the pathogenesis of hepatosteatosis.

Consensus document. Management of non-alcoholic fatty liver disease (NAFLD). Clinical practice guideline. / Documento de consenso. Manejo de la enfermedad hepática grasa no alcohólica (EHGNA). Guía de práctica clínica.

Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville.

Corrigendum: Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients.

This corrects the article DOI: 10.1038/ajg.2016.439.

Fecal Gluten Peptides Reveal Limitations of Serological Tests and Food Questionnaires for Monitoring Gluten-Free Diet in Celiac Disease Patients.

OBJECTIVES: Treatment for celiac disease (CD) is a lifelong strict gluten-free diet (GFD). Patients should be followed-up with dietary interviews and serology as CD markers to ensure adherence to the diet. However, none of these methods offer an accurate measure of dietary compliance. Our aim was to evaluate the measurement of gluten immunogenic peptides (GIP) in stools as a marker of GFD adherence in CD patients and compare it with traditional methods of GFD monitoring. METHODS: We performed a prospective, nonrandomized, multicenter study including 188 CD patients on GFD and 84 healthy controls. Subjects were given a dietary questionnaire and fecal GIP quantified by enzyme-linked immunosorbent assay (ELISA). Serological anti-tissue transglutaminase (anti-tTG) IgA and anti-deamidated gliadin peptide (anti-DGP) IgA antibodies were measured simultaneously. RESULTS: Of the 188 celiac patients, 56 (29.8%) had detectable GIP levels in stools. There was significant association between age and GIP in stools that revealed increasing dietary transgressions with advancing age (39.2% in subjects ≥13 years old) and with gender in certain age groups (60% in men ≥13 years old). No association was found between fecal GIP and dietary questionnaire or anti-tTG antibodies. However, association was detected between GIP and anti-DGP antibodies, although 46 of the 53 GIP stool-positive patients were negative for anti-DGP. CONCLUSIONS: Detection of gluten peptides in stools reveals limitations of traditional methods for monitoring GFD in celiac patients. The GIP ELISA enables direct and quantitative assessment of gluten exposure early after ingestion and could aid in the diagnosis and clinical management of nonresponsive CD and refractory CD. Trial registration number NCT02711397.

Prevalence and risk factors for biopsy-proven non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in a prospective cohort of adult patients with gallstones.

BACKGROUND & AIMS: Relationship between gallstones and non-alcoholic fatty liver disease (NAFLD), and largely non-alcoholic steatohepatitis (NASH), is uncertain. AIM: To determine the prevalence, non-invasive fibrosis markers profile and risk factors for biopsy-proven NAFLD and NASH among patients with gallstones. METHODS: Anthropometric and laboratory evaluation, an abdominal ultrasound and a liver biopsy were performed to 215 consecutive patients with gallstones referred for cholecystectomy. RESULTS: Prevalence of NASH was 10.2% whereas that of simple steatosis (SS) was 41.4%. In the cohort of NAFLD patients, negative predictive values for advanced fibrosis of FIB-4 and NAFLD fibrosis score were 96 and 95% respectively. Gallstone patients with NASH had a higher mean homeostatic model assessment (HOMA) score than those with SS (P = 0.015). Noteworthy, NASH was 2.5-fold more frequent in patients with gallstones who had metabolic syndrome than in those who did not (P < 0.001). Fatty liver on ultrasound was observed in 90.9% of gallstone patients with NASH compared with 61.8% of those with SS (P = 0.044). Using multivariate logistic regression, increased HOMA score (OR, 3.47; 95% CI, 1.41-8.52; P = 0.007) and fatty liver on ultrasound (OR, 23.27; 95% CI, 4.15-130.55; P < 0.001) were the only factors independently associated with NASH. CONCLUSIONS: Prevalence of NASH among patients with gallstones is lower than estimated previously, but NASH is frequent particularly in those patients with concurrent metabolic syndrome. The combination of an increased HOMA score with fatty liver on ultrasound has a good accuracy for predicting NASH in patients with gallstones.

Increased soluble CD36 is linked to advanced steatosis in nonalcoholic fatty liver disease.

BACKGROUND: Soluble CD36 (sCD36) clusters with insulin resistance, but no evidence exists on its relationship with hepatic fat content. We determined sCD36 to assess its link to steatosis in nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) patients. MATERIALS AND METHODS: Two hundred and twenty-seven NAFLD, eighty-seven CHC, and eighty-five patients with histologically normal liver (NL) were studied. Steatosis was graded by Kleiner's histological scoring system. Serum sCD36 and hepatic CD36 expression was assessed by immunoassay and immunohistochemistry, respectively. RESULTS: In NAFLD, serum sCD36 levels were significantly higher in simple steatosis than in NL (361.4 ± 286.4 vs. 173.9 ± 137.4 pg/mL, respectively; P < 0.001), but not in steatohepatitis (229.6 ± 202.5 pg/mL; P = 0.153). In CHC, serum sCD36 levels were similar regardless of the absence (428.7 ± 260.3 pg/mL) or presence of steatosis (387.2 ± 283.6 pg/mL; P = 0.173). A progressive increase in serum sCD36 values was found in NAFLD depending on the histological grade of steatosis (P < 0.001), but not in CHC (P = 0.151). Serum sCD36 concentrations were independently associated with advanced steatosis in NAFLD when adjusted by demographic and anthropometric features [odds ratio (OR), 1.001; 95% confidence interval (CI), 1.000 to 1.002; P = 0.021] and by metabolic variables (OR, 1.002; 95% CI, 1.000 to 1.003; P = 0.001). Interestingly, a significant correlation was observed between hepatic CD36 and serum sCD36 (ρ = 0.499, P < 0.001). CONCLUSIONS: Increased serum sCD36 is an independent factor associated with advanced steatosis in NAFLD.

The biochemical pattern defines MASLD phenotypes linked to distinct histology and prognosis.

BACKGROUND: MASLD can manifest as hepatocellular damage, which can result in mild elevation of aminotransferases. However, in some patients, MASLD presents with cholestatic pattern. OBJECTIVE: To assess the impact of the biochemical pattern on the natural course of MASLD, including liver damage in histology, the accuracy of non-invasive tests(NITs), and prognosis. METHODS: Multicenter study enrolling 2156 patients with biopsy-proven MASLD, who were classified based on their[ALT/ULN)]/[(ALP/ULN)] levels at the time of biopsy: (a) hepatocellular pattern(H), > 5; (b) mixed pattern(M),2-5; (c) cholestatic pattern(C), < 2. OUTCOMES: (a) histological evaluation of the single components of NAS, MASH, and fibrosis; (b) NITs and transient elastography assessing advanced fibrosis; (c) prognosis determined by the appearance of decompensated cirrhosis and death. RESULTS: Out of the 2156 patients, 22.9% exhibited the H-pattern, whilst 31.7% exhibited the C-pattern. Severe steatosis, ballooning, lobular inflammation, and MASH (56.4% H vs. 41.9% M vs. 31.9% C) were more common in H-pattern (p = 0.0001),whilst C-pattern was linked to cirrhosis (5.8% H vs. 5.6% M vs. 10.9% C; p = 0.0001). FIB-4(0.74(95% CI 0.69-0.79) vs. 0.83 (95% CI 0.80-0.85); p = 0.005) and Hepamet Fibrosis Score(0.77 (95% CI 0.69-0.85) vs. 0.84 (95% CI 0.80-0.87); p = 0.044)exhibited lower AUROCs in the H-pattern. The C-pattern[HR 2.37 (95% CI 1.12-5.02); p = 0.024], along with age, diabetes, and cirrhosis were independently associated with mortality. Most patients maintained their initial biochemical pattern during the second evaluation. CONCLUSIONS: The H-pattern exhibited greater necro-inflammation in the histology than the C-pattern, whereas the latter showed more cirrhosis. The accuracy of NITs in detecting fibrosis was decreased in H-pattern. The occurrence of decompensated events and mortality was predominant in C-pattern. Therefore, identifying MASLD phenotypes based on the biochemical presentation could be relevant for clinical practice.

Autophagy protects cells from HCV-induced defects in lipid metabolism.

BACKGROUND & AIMS: Autophagy is a lysosome-mediated catabolic process that mediates degradation and recycling of all major components of eukaryotic cells. Different stresses, including viral and bacterial infection, induce autophagy, which can promote cell survival by removing the stress inducer or by attenuating its dangerous effects. High levels of autophagy occur during infection of cells with hepatitis C virus (HCV), but the clinical relevance of this process is not clear. METHODS: Levels of autophagy were analyzed in liver biopsy samples from 22 patients with HCV infection using microtubule-associated protein-1 light chain 3 immunoblotting; associations with histological and metabolic parameters were evaluated by Pearson correlation analysis. We investigated the role of HCV-induced autophagy in lipid degradation in cells infected with the virus or replicons, and analyzed autophagosome contents by confocal microscopy and by measuring lipid levels after inhibition of autophagy by Beclin 1 knockdown or lysosome inhibitors. RESULTS: In liver biopsy samples from patients with HCV, there was an inverse correlation between microvesicular steatosis and level of autophagy (r = -0.617; P = .002). HCV selectively induced autophagy of lipids in virus-infected and replicon cells. In each system, autophagosomes frequently colocalized with lipid deposits, mainly formed by unesterified cholesterol. Inhibition of the autophagic process in these cells significantly increased the induction of cholesterol accumulation by HCV. CONCLUSIONS: Autophagy counteracts the alterations in lipid metabolism induced by HCV. Disruption of the autophagic process might contribute to development of steatosis in patients with HCV.

Prognostic value of hepatic venous pressure gradient in patients with compensated chronic hepatitis C-related cirrhosis.

BACKGROUND AND AIM: Hepatic venous pressure gradient (HVPG) is the main predictor of clinical decompensation in cirrhotic patients with compensated disease of any etiology without varices. However, the predictive factors of decompensation are not so well known in patients with hepatitis C-related compensated cirrhosis, in whom etiology-based therapy is difficult. The aim of this study was to identify predictors of decompensation in patients with compensated chronic hepatitis C (CHC)-related cirrhosis with and without esophageal varices (Baveno stages 1 and 2). METHODS: The study population was a cohort of 145 of such consecutive patients who received hepatic hemodynamic study. All patients were similarly followed every 6 months. Through multivariate Cox regression and bootstrap analyses, a prognostic index (PI) was developed and tested in an external cohort (n = 38). RESULTS: Forty-two patients (29%) suffered a first decompensation episode after a median follow-up of 27 months (2-110). Cox regression analysis identified HVPG (hazard ratio (HR) 1.11; 95% confidence interval (CI): 1.05-1.17) and albumin (HR 0.42; 95% CI: 0.22-0.82) as independent predictors of decompensation. Bootstrapping confirmed that HVPG (95% CI: 1.05-1.18) and albumin (95% CI: 0.12-0.74) were the most robust predictive variables. Using a cut-off level of 2.5, the PI [4 + (0.11 × HVPG - 0.8 × albumin)] was able to distinguish two populations of patients with very different risks of decompensation in both the exploratory and validation cohorts. A time-dependent ROC curve identified HVPG as the best predictive variable. CONCLUSION: HVPG and albumin are independent predictors of clinical decompensation in patients with compensated CHC-related cirrhosis irrespective of the existence of varices.

Serum level of soluble vascular cell adhesion molecule in patients with hepatocellular carcinoma and its association with severity of liver disease.

BACKGROUND: VCAM-1 (soluble vascular cell adhesion molecule-1) plays a role in liver angiogenesis. Hepatocellular carcinoma (HCC) has important angiogenic activity, so expression of VCAM-1 may be pathogenic. AIM: To assess the association between serum VCAM-1 (sVCAM-1) levels and features of tumour and liver disease in patients with and without HCC, and to study the influence of HCC treatment on sVCAM-1 levels. MATERIAL AND METHODS: Concentrations in peripheral (sVCAM-1-P) and hepatic (sVCAM-1-H) veins were analysed using ELISA in 134 consecutive patients with chronic liver disease between May 2004 and February 2006, who underwent a splanchnic haemodynamic study. Of these patients, 58 had HCC. RESULTS: sVCAM-1-P and sVCAM-1-H were well correlated in both groups. No association was found between sVCAM-1-H and tumour features. No differences were observed in sVCAM-1-H between HCC and non-HCC cirrhotic patients. There was a significant linear association between Child-Pugh stage and sVCAM-1-H in HCC-patients (Child-Pugh A [2,485 ± 1,294 ng/mL] vs. Child-Pugh B [3,408 ± 1,338 ng/mL] vs. Child-Pugh C [4,096 ± 862 ng/mL]; p = 0.007). Seven non-cirrhotic HCC patients had a significantly lower sVCAM-1-H than cirrhotic HCC patients. Treatment of HCC leads to an increase in sVCAM-1-H levels although this was not associated with the necrosis response to treatment. CONCLUSIONS: sVCAM-1 levels are more closely associated with the severity of underlying liver disease than with the presence of HCC. sVCAM-1 levels are not associated with tumour features or invasiveness; therefore, sVCAM-1 does not seem to play an important role in the angiogenic processes of HCC.

Predicting portal hypertension and variceal bleeding using non-invasive measurements of metabolic variables.

BACKGROUND & AIM: This study assessed the involvement of metabolic factors (anthropometric indices, insulin resistance (IR) and adipocytokines) in the prediction of portal hypertension, esophageal varices and risk of variceal bleeding in cirrhotic patients. MATERIAL AND METHODS: Two prospective and retrospective cohorts of cirrhotic patients were selected (n = 357). The first prospective cohort (n = 280) enrolled consecutively in three centers, underwent upper gastrointestinal endoscopy, seeking evidence of esophageal varices. Clinical, anthropometric, liver function tests, ultrasonographic, and metabolic features were recorded at the time of endoscopy, patients were followed-up every 6 months until death, liver transplantation or variceal bleeding. The second retrospective cohort (n = 48 patients) had measurements of the hepatic venous pressure gradient (HVPG). Statistical analyses of the data were with the SPSS package. RESULTS: The presence of esophageal varices was independently associated with lower platelet count, raised HOMA index and adiponectin levels. This relationship extended to subset analysis in patients with Child A cirrhosis. HOMA index and adiponectin levels significantly correlated with HVPG. Beside Child-Pugh class, variceal size and glucagonemia, HOMA index but not adiponectin and leptin plasma levels were associated with higher risk of variceal bleeding. CONCLUSION: In patients with cirrhosis, HOMA score correlates with HVPG and independently predict clinical outcomes. Three simple markers i.e. platelet count, IR assessed by HOMA-IR and adiponectin significantly predict the presence of esophageal varices in cirrhotic patients.

Hepatic insulin resistance is associated with increased apoptosis and fibrogenesis in nonalcoholic steatohepatitis and chronic hepatitis C.

BACKGROUND & AIMS: We aimed to elucidate whether hepatic insulin resistance may contribute to hepatocyte apoptosis and fibrogenesis in nonalcoholic fatty liver disease (NAFLD) and in chronic hepatitis C virus (HCV) infection. METHODS: Twenty-seven nonalcoholic steatosis (NAST), 24 nonalcoholic steatohepatitis (NASH), 71 HCV, and 29 patients with histological normal liver (NL) were studied. Real-time PCR, the TUNEL assay, and Western blots were used to assess insulin-signaling molecules, hepatocyte apoptosis, antiapoptotic mediators, active caspase 3, and type I collagen in liver biopsies. HCV core-transfected human hepatocytes were used as an in vitro model. RESULTS: In NAFLD patients, hepatic levels of insulin receptor substrate (IRS) 1, IRS2 2, the p85α subunit of phosphatidylinositol 3-kinase (p85α), phosphorylated protein kinase B (pAkt), phosphorylated forkhead box-containing protein O subfamily-1 (FoxO), and phosphorylated 5' adenosine monophosphate-activated protein kinase (pAMPK) as well as the antiapoptotic mediators B-cell lymphoma 2 protein (Bcl-2) and myeloid cell leukemia protein-1 (Mcl-1) were significantly lower in NASH than in NAST and NL. Furthermore, hepatocyte apoptosis and increased active caspase 3 were only present in NASH. In HCV patients, hepatic insulin signaling was markedly impaired, regardless of viral genotype and the presence of steatosis paralleled with enhanced apoptosis. In cultured human hepatocytes, HCV core protein decreased pAkt and increased phosphorylation of c-Jun N-terminal kinase (JNK). This effect was more pronounced in lipid-loaded hepatocytes. CONCLUSIONS: Hepatic insulin signaling is impaired in NASH and HCV patients, and downregulation of insulin-sensitive targets is associated with increased apoptosis and fibrogenesis in both conditions. JNK might be a target for HCV-induced insulin resistance.

[Influence of treatment of hepatocellular carcinoma before liver transplantation on post transplant tumor recurrence and survival]. / Influencia del tratamiento del hepatocarcinoma antes del trasplante hepático en la recurrencia tumoral y supervivencia postrasplante.

OBJECTIVES: To evaluate the effectiveness of treatment of hepatocellular carcinoma (HCC) before liver transplantation (LT) and its influence on survival and tumor recurrence in patients transplanted for HCC. PATIENTS AND METHODS: We included 67 liver transplant patients with a preoperative diagnosis of HCC and pathological confirmation in the native liver between January 2000 and October 2007. Treatment before LT was performed in 46 (68.7%) patients [radiofrequency ablation in 18, transarterial chemoembolization in 31 and percutaneous ethanol injection in two]. RESULTS: The median time between inclusion on the waiting list and LT was 4 months and was similar in treated and untreated patients. The median time between pre-transplantation locoregional therapy and LT was less than 6 months in 65.2% of the patients. Treated patients had better liver function (Child A 52.2 vs 19%; Child B 39.1 vs 33.3%; Child C 8.7 vs. 47.6%; p=0.001) and a higher proportion of total tumor size > 3 cm (59.1% vs 30%; p=0.031). Total tumor necrosis was observed in 26.1% of the patients, with no differences according to treatment modality or tumor size. Tumor recurrence occurred in six patients (9%). The median time between LT and tumor recurrence was 26.5 months with a subsequent median survival of 6.6 months. Overall survival was 83.5%, 69.9% and 59.5%, and tumor recurrence-free survival was 83.5%, 68.3% and 58% at 1, 3 and 5 years, respectively. Previous HCC treatment showed no influence on survival or tumor recurrence. Likewise, the grade of tumor necrosis was unrelated to overall survival or the probability of recurrence. CONCLUSION: Treatment of HCC before LT in patients with a waiting list time of less than 6 months does not appear to influence survival or tumor recurrence.

Cardiac dysfunction during liver transplantation: incidence and preoperative predictors.

BACKGROUND: The aim was to investigate the cardiac response during liver transplantation (LT) and analyze its relationship with clinical factors, echocardiographic, and hemodynamic findings. METHODS: All patients undergoing LT for cirrhosis from 1998 to 2004 were included. Clinical data, comprehensive echocardiography, hepatic, and right heart hemodynamic measurements were analyzed. During LT patients underwent continuous right-heart pressure monitorization. Measurements 10 min after reperfusion were compared with baseline values. Abnormal cardiac response was defined as a decrease in left ventricular stroke work index despite a rise in pulmonary wedge capillary pressure. Predictors of abnormal cardiac response were investigated using logistic regression. RESULTS: Data were available from 209 patients (mean age 52 (9) yrs; Child A 27; B 93; C 89) with a mean model for end-stage liver disease score 16.3 (4.7). Abnormal cardiac response was observed in 47 (22.5%) patients after reperfusion. Patients who developed this response had hyponatremia, lower central venous pressure, lower pulmonary artery pressure, and lower pulmonary wedged capillary pressure. Abnormal cardiac response was related to a longer postoperative intubation time. CONCLUSION: Abnormal cardiac response is observed during LT and may be a manifestation of occult cirrhotic cardiomyopathy. This finding is underestimated with usual diagnostic tools and could be related to indirect signs of circulatory dysfunction of advanced liver disease.

Serum levels of soluble vascular cell adhesion molecule are related to hyperdynamic circulation in patients with liver cirrhosis.

BACKGROUND: In patients with liver cirrhosis, serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1) have been associated with increasing fibrosis and are related to angiogenesis. AIM: To assess the possible correlation between sVCAM-1 and splanchnic and systemic haemodynamic and clinical staging of cirrhotic patients. METHODS: We assessed, using immunoassays, the serum levels of sVCAM-1, in the peripheral and hepatic vein, in all consecutive patients with liver cirrhosis, who underwent a haemodynamic study as part of its routine clinical work-up. RESULTS: We studied 86 patients [61 M/25 F; age 51.1 (8.3) years] with alcoholic (31) or viral (HBV:6, HCV:49) cirrhosis, 10 of them with hepatocellular carcinoma (Milan criteria). The mean follow-up was 391(187) days; 29 patients died or underwent transplantion during follow-up. A strong correlation in serum levels of sVCAM-1 was observed between the peripheral and the hepatic vein (r=0.8; P=0.0001). There was no correlation between levels of sVCAM-1 and hepatic venous pressure gradient. At univariate analysis, sVCAM-1 was inversely related with mean arterial pressure (r=-0.292; P=0.007), systemic vascular resistance (SVR) (r=-0.37; P=0.005) and serum sodium levels (r=-0.326; P=0.002). In multivariate linear regression only SVR remained as an independent variable associated to sVCAM-1. A correlation of sVCAM-1 with Child-Pugh scores, model for end-stage liver disease (MELD) and the clinical stage proposed in the Baveno IV consensus conference was also observed. Finally, patients who died or underwent transplantion during follow-up had significantly greater values of sVCAM-1 at baseline than those who did not [3505(1329) vs. 2488(1208) P=0.001]. CONCLUSION: This study supports a potential role of sVCAM-1 as a marker of hyperdynamic circulation, closely related to the different stage of liver cirrhosis.