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Background and Aims: The relationship between primary biliary cholangitis (PBC) and metabolic dysfunction-associated steatotic liver disease, and its impact on treatment response and prognosis, remains underexplored., Methods: Patient cohort from two centres comprising long-term follow-up data. All patients had histologically confirmed PBC. Biopsies were classified according to Non-Alcoholic Steatohepatitis Clinical Research Network. Diagnosis of metabolic dysfunction-associated steatotic liver disease was established when steatosis exceeded 5%, along with at least one metabolic risk factor. Patients with specific aetiologies of steatosis, other liver diseases, incomplete results and inadequate treatment with ursodeoxycholic acid were excluded. Data from patients initiating second-line treatment were censored. Treatment response was assessed using the Toronto, Paris II and AST-to-platelet at 12-month criteria. The UK PBC and Globe scores, and liver events were utilized as outcome measures., Results: The study included 129 patients, 36 showing histologically confirmed overlap between PBC and steatosis. Patients with overlap showed worse prognosis according to Paris II (61.1% vs. 33.3%, p = 0.004), Toronto (52.5% vs. 24.7%, p = 0.002), AST-to-platelet 12-month >0.54 (36.1% vs. 17.2%, p = 0.021), Globe >0.30 (49.2% vs. 29.2%, p = 0.033) and UK PBC at 5, 10 and 15 years (p ≤ 0.001). Liver-related mortality and liver transplant were more prevalent in the overlap group (p = 0.001). In the multivariate analysis, steatosis, dyslipidaemia and advanced fibrosis were independently associated to worse outcomes., Conclusions: Our findings suggest that metabolic dysfunction-associated steatotic liver disease worsens the prognosis of PBC., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related cirrhosis has been increasing these last decades. There are no data regarding the prevalence of MASLD-related cirrhosis in intensive care unit (ICU)., Methods: Prospective single-centre study in a cohort of patients hospitalized in the ICU of Hepatology La Pitié-Salpêtrière Hospital between January 2019 and September 2021. We analysed three groups of patients: MASLD-cirrhosis (alcohol ≤210 g for men and 140 g weekly for women), ALD (alcohol-related liver disease, alcohol>140 g weekly for women or >210 g for men)-cirrhosis alone and MetALD (metabolic and alcohol-related liver disease)-cirrhosis. Endpoints were 1-year transplant-free survival (TFS), further acute decompensation (AD) and re-admission., Results: A total of 410 patients were hospitalized, and 315 analysed: 39 in MASLD, 160 in ALD and 116 in MetALD groups. The global prevalence was 10% for MASLD, 41% ALD and 29.7% for MetALD. Patients in the MASLD group were significantly older (65 vs. 57 and 59 years, p < 0.001), and had lower Child-Pugh (8 vs. 11 vs. 10, p < 0.001) and MELD score (17 vs. 22 vs. 21, p < 0.001). The 1-year TFS was not different between groups (53% vs. 54% vs. 54%, p = 0.96). Cardiovascular mortality was <5% in all groups. The 1-year probability of developing hepatic encephalopathy was significantly higher in the MASLD group (73% vs. 27% and 21%, p < 0.001). There was no difference regarding the development of other complications between groups., Conclusion: MASLD or MetALD was responsible for 1/3 of the causes of cirrhosis in the ICU. MASLD-related cirrhosis is as severe as ALD-related cirrhosis. Liver transplantation should be rapidly discussed., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: A multi-society consensus group proposed a new nomenclature for steatotic liver disease (SLD) including metabolic-dysfunction associated steatotic liver disease (MASLD), MASLD and increased alcohol intake (MetALD) and alcohol-associated liver disease (ALD). However, the risk of liver-related events, major adverse cardiovascular events (MACE) and all-cause mortality among various sub-groups is unknown., Aims: To evaluate the risk of liver-related events, MACE and death among patients with SLD., Methods: We conducted a nationwide, population-based study and enrolled 761,400 patients diagnosed with MASLD, MetALD or ALD. The primary endpoint was the occurrence of liver-related events, MACE and death in patients with MASLD, MetALD and ALD., Results: The cumulative incidence of liver-related events and death were highest in ALD, followed by MetALD and MASLD (p < 0.001 for both liver-related events and death), while the incidence of MACE was highest in MASLD, followed by MetALD and ALD (p < 0.001). Using MASLD as the reference and adjusting for age, sex, smoking, diabetes mellitus, dyslipidaemia and hypertension, the adjusted hazard ratios (95% confidence intervals) for liver-related events, MACE and death in MetALD were 1.42 (1.1-1.8), 0.68 (0.63-0.73) and 1.13 (0.98-1.3), respectively. In ALD, they were 3.42 (2.6-4.6), 0.58 (0.49-0.67) and 1.60 (1.3-2.0), respectively, for liver-related events, MACE and death., Conclusions: The new consensus nomenclature can be used to stratify the risk of complications and prognosis. The nomenclature is beneficial for risk stratification and identifying new mechanisms for disease-specific therapeutic implications., (© 2024 John Wiley & Sons Ltd.)

Background: Recently, a panel of multi-society experts proposed steatotic liver disease (SLD) as an alternative terminology for metabolic dysfunction-associated fatty liver disease (MAFLD) or nonalcoholic fatty liver disease (NAFLD)., Aims: We compared the impact of SLD, subtype of SLD, MAFLD and NAFLD on all-cause and cause-specific mortality., Methods: A total of 7811 individuals in the third National Health and Nutrition Examination Survey and linked mortality through 2019 were analysed. SLD was defined based on ultrasonographic hepatic steatosis. SLD, subtype of SLD and MAFLD were defined using the proposed definitions. The Cox proportional hazard model assessed all-cause/cause-specific mortality., Results: During a median follow-up of 27.1 years, individuals with SLD and MAFLD experienced approximately 13%-23% higher risk of all-cause mortality (hazard ratio [HR]: 1.15, 95% confidence interval [CI]: 1.02-1.29 for SLD; HR: 1.23, 95% CI: 1.09-1.38 for MAFLD; HR: 1.13, 95% CI: 1.01-1.27 for metabolic dysfunction-associated steatotic liver disease [MASLD]). Individuals with MetALD demonstrated a higher risk of all-cause (HR: 1.68, 95% CI: 1.10-2.57) and cancer-related mortality (HR: 2.40, 95% CI: 1.23-4.66). MASLD with advanced fibrosis had an increased risk of all-cause mortality compared to MASLD without advanced fibrosis., Conclusions: SLD, especially MASLD and MetALD, is associated with increased all-cause mortality among adults in the US. Given this significant association between SLD or subtype of SLD (MASLD and MetALD) and all-cause mortality, adopting the proposed SLD criteria may help identify a sub-group of individuals with SLD who are at an increased risk for all-cause mortality., (© 2024 John Wiley & Sons Ltd.)

Background & Aims: The natural progression of hepatic decompensation in metabolic dysfunction-associated steatotic liver disease (MASLD) is not well-characterised. We aimed to describe it by conducting a retrospective analysis., Methods: This longitudinal, retrospective analysis of well-characterised MASLD cohorts followed for hepatic decompensation and death. The sequence of liver-related events was evaluated, and the median time between hepatic decompensation episodes and death versus. transplantation was measured., Results: Of the 2016 patients identified, 220 (11%) developed at least one episode of hepatic decompensation during a median follow-up of 3.2 years. Ascites was the most common first liver-related event [153 (69.5%)], followed by hepatic encephalopathy (HE) [55 (25%)] and variceal haemorrhage (VH) [30 (13.6%)]. Eighteen out of the 220 (8.1%) patients had more than one liver-related event as their first hepatic decompensation. Among the patients who had the first episode, 87 (39.5%) had a second episode [44 (50.5%) HE, 31 (35.6%) ascites, and 12 (13.7%) VH]. Eighteen out of 220 (8.1%) had a third episode [10 (55.5%) HE, 6 (33.3%) VH, and 2 (11.1%) ascites]. Seventy-three out of 220 (33.1%) died, and 31 (14%) received liver transplantation. The median time from the first episode to the second was 0.7 years and 1.3 years from the second episode to the third. The median survival time from the first episode to death or transplantation was 2.0 years., Conclusion: The most common first liver-related event in MASLD patients is ascites. The median survival from the first hepatic decompensation to either death or transplantation is 2 years., (© 2024 John Wiley & Sons Ltd.)

Background/aims: We examined the effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) initiation on long-term Adverse Liver Outcomes (ALO) in patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) cirrhosis and type 2 diabetes using real-world data from the MarketScan database., Methods: We conducted a retrospective cohort study of patients with MASLD cirrhosis and type 2 diabetes between 2012 and 2020. Cox proportional hazard models examine the association between GLP-1RAs initiation, modelled as time-dependent, and the risk of ALO, a composite endpoint defined by the first occurrence of hepatic decompensation(s), portal hypertension, hepatocellular carcinoma (HCC) or liver transplantation (LT). We used Overlap Propensity Score Weighting (OPSW) to account for confounding. The study included 459 GLP-1RAs and 4837 non-GLP-1RAs patients., Results: The non-GLP-1RAs patients presented with 1411 (29%) ALO over 7431.7 person years, while GLP-1RAs patients had 32 (7%) ALO over 586.6 person years - risk rate difference 13.5 (95% CI: 11.4-15.7) per 100 person-years. The OPSW-adjusted risk of ALO was reduced by 36% (hazard ratio [HR]: 0.64; 95% CI: 0.54-0.76) in patients with vs. without GLP-1RAs initiation. GLP-1RAs initiation was associated with significant reductions in the adjusted risk of hepatic decompensation (HR: 0.74; 95% CI: 0.61-0.88), portal hypertension (HR: 0.73; 95% CI: 0.60-0.88), HCC (HR: 0.37; 95% CI: 0.20-0.63) and LT (HR: 0.24; 95% CI: 0.12-0.43)., Conclusion: The use of GLP-1RAs was associated with significant risk reductions in long-term adverse liver outcomes, including hepatic decompensation, portal hypertension, HCC and LT, in MASLD cirrhosis patients with type 2 diabetes., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver condition recognised as an independent risk factor for cardiovascular disease (CVD). However, there is ongoing debate regarding the effective strategy for cardiovascular risk assessment in MASLD., Aim: To investigate the relationship between liver imaging, specifically focusing on the severity of steatosis and subclinical atherosclerosis., Methods: We conducted a thorough search across four databases, from 1950 to April 2023, to identify eligible studies employing imaging to explore the relationship between different degrees of steatosis and subclinical atherosclerosis among MASLD. Additionally, we conducted a quality assessment using the Newcastle Ottawa Scale, performed a meta-analysis employing the DerSimonian-Liard random-effects model, and conducted subgroup analyses for validation., Results: In total, 19 studies, encompassing 147,411 middle-aged individuals without previous CVD (74.94% male; mean age 45.53 years [SD 10.69]; mean BMI 24.3 kg/m 2 [SD 3.35]), were included. The pooled odds ratio for subclinical atherosclerosis was 1.27 (95% CI: 1.13-1.41, I 2  = 76.68%) in mild steatosis and significantly increased to 1.68 (95% CI: 1.41-2.00, I 2  = 89.02%) in moderate to severe steatosis. Sensitivity analysis, focusing on high-quality studies, consistently supported this finding and the results remained robust across subgroup analyses. Furthermore, meta-regression revealed that a higher mean AST and ALT, alongside a lower mean HDL, were significant moderators of this association., Conclusions: Even mild steatosis is associated with CVD risk, and steatosis severity further intensifies this association. These findings suggest that liver fat quantification enhances CVD risk stratification in patients with MASLD., (© 2024 John Wiley & Sons Ltd.)

Background: There are limited data regarding the longitudinal association between MEFIB-Index (MRE combined with FIB-4) versus MAST-Score (MRI-aspartate aminotransferase) and hepatic decompensation., Aim: To examine the longitudinal association between MEFIB-Index versus MAST-Score in predicting hepatic decompensation in patients with metabolic dysfunction-associated steatotic liver disease (MASLD)., Methods: This was a longitudinal, retrospective analysis of subjects from United States, Japan, and Turkey who underwent a baseline MRE and MRI-PDFF and were followed for hepatic decompensation. Cox-proportional hazard analyses were used to assess the association between MEFIB-Index versus MAST-Score with a composite primary outcome (hepatic decompensation) defined as ascites, hepatic encephalopathy, and varices needing treatment., Results: This meta-analysis of individual participants (IPDMA) included 454 patients (58% women) with a mean (±SD) age of 56.0 (±13.5) years. The MEFIB-Index (MRE ≥3.3 kPa + FIB 4 ≥1.6) and MAST-Score (>0.242) were positive for 34% and 9% of the sample, respectively. At baseline, 23 patients met criteria for hepatic decompensation. Among 297 patients with available longitudinal data with a median (IQR) of 4.2 (5.0) years of follow-up, 25 incident cases met criteria for hepatic decompensation. A positive MEFIB-Index [HR = 49.22 (95% CI: 6.23-388.64, p < 0.001)] and a positive MAST-Score [HR = 3.86 (95% CI: 1.46-10.17, p < 0.001)] were statistically significant predictors of the incident hepatic decompensation. MEFIB-Index (c-statistic: 0.89, standard error (SE) = 0.02) was statistically superior to the MAST-Score (c-statistic: 0.81, SE = 0.03) (p < 0.0001) in predicting hepatic decompensation., Conclusion: A combination of MRI-based biomarker and blood tests, MEFIB-Index and MAST-Score can predict the risk of hepatic decompensation in patients with MASLD., (© 2023 John Wiley & Sons Ltd.)

Background: Population-based data are lacking regarding whether fatty liver is a risk factor for hepatocellular carcinoma (HCC) and mortality in patients with chronic viral hepatitis., Aim: To investigate the association of fatty liver with HCC incidence and mortality in patients with chronic viral hepatitis using a nationwide cohort METHODS: We included 57,385 patients with chronic hepatitis B (CHB) or chronic hepatitis C (CHC) who underwent health examinations. The patients were divided into three groups: no fatty liver, fatty liver index (FLI) <30, grade 1 (G1) fatty liver: 30≤ FLI <60, and grade 2 (G2) fatty liver: FLI >60., Results: During a median 8.4-year follow-up, we documented 3496 HCC cases and 4146 deaths. Compared to patients with no fatty liver (n = 35,018), the risk of HCC was significantly higher in patients with G1 fatty liver (n = 14,544) (adjusted hazard ratio [aHR] = 1.50, 95% confidence interval [CI] = 1.38-1.64) and G2 fatty liver (n = 7,823) (aHR = 1.88, 95% CI = 1.67-2.12). The risk of mortality was significantly higher in patients with G1 fatty liver (aHR = 1.53, 95% CI = 1.41-1.66) and G2 fatty liver (aHR = 2.16, 95% CI = 1.94-2.42) compared to patients with no fatty liver., Conclusions: Concurrent fatty liver was associated with a higher risk of HCC and mortality in patients with chronic viral hepatitis. Our results suggest the importance of management of fatty liver to reduce the risks of HCC and mortality in patients with chronic viral hepatitis., (© 2021 John Wiley & Sons Ltd.)

Background: The rs738409 C>G p.I148M variant in the patatin-like phospholipase domain containing 3 (PNPLA3)-gene promotes triglyceride accumulation in hepatocytes and hepatic stellate cell activation and has previously been linked to hepatic steatosis/liver fibrosis., Aim: To investigate its impact on hepatic decompensation and (liver-related) mortality in patients who had already developed portal hypertension. Moreover, we assessed its link with hepatic steatosis as evaluated by controlled attenuation parameter., Methods: We performed a retrospective analysis in prospectively characterised patients with viral hepatitis/fatty liver disease-induced portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) diagnosed at the Medical University of Vienna who underwent HVPG measurement (until 2013; n = 372; longitudinal study) or simultaneous HVPG and controlled attenuation parameter measurement (2014-2017; n = 153; cross-sectional study)., Results: While survival was similar between PNPLA3-C/C and -C/G patients, we observed substantially increased mortality in PNPLA3-G/G patients. PNPLA3-G/G had no impact on mortality in the subgroup of patients with viral hepatitis; however, we observed a strong independent association between PNPLA3-G/G and hepatic decompensation (adjusted subdistribution hazard ratio [aSHR]: 2.1, 95% confidence interval [95% CI]: 1.1-4; P = 0.024) as well as mortality (overall: aSHR: 2.2, 95% CI: 1.22-3.98; P = 0.009; liver-related: aSHR: 2.2, 95% CI: 1.08-4.46; P = 0.029) in patients with fatty liver disease. Interestingly, even in the subgroup of patients who had already progressed to clinically significant portal hypertension (HVPG ≥ 10 mm Hg), PNPLA3-G/G substantially increased mortality (aSHR: 2.33, 95% CI: 1.27-4.29; P = 0.006). PNPLA3-genotype had no influence on controlled attenuation parameter or the prevalence of values ≥248 dB/m., Conclusion: PNPLA3-G/G-genotype seems to double the risks of hepatic decompensation and (liver-related) mortality in patients with portal hypertension due to fatty liver disease. Further studies are warranted to investigate potential underlying pathophysiological mechanisms unrelated to hepatic steatosis., (© 2018 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Non-alcoholic fatty liver disease (NAFLD) is currently conceptualised as a clinical spectrum that results from a ‘multiple-hit’ process which begins with simple steatosis and subsequently renders the hepatocytes susceptible to a variety of insults. Ultimately, more serious liver injuries like non-alcoholic steatohepatitis (NASH) and cirrhosis may develop. Although the metabolic syndrome is considered the crucial player in the pathogenesis of NAFLD, recent studies have highlighted novel pathophysiological mechanisms in this clinical entity., Aim: To discuss the pathophysiology of NAFLD based on the hypothesis that simple steatosis and NASH are discrete entities rather than two points on a spectrum., Methods: A literature search was conducted in August 2012 on PubMed, Ovid Embase, Ovid Medline and Scopus using the following search terms: steatosis, non-alcoholic steatohepatitis, pathophysiology, fatty liver, natural history and genetics., Results: Simple steatosis and NASH appear as two distinct pathophysiological entities and progression from pure fatty liver to NASH appears to be so rare as to warrant publication. The possible pathogenetic pathways specifically related to NASH are highlighted., Conclusions: Although simple steatosis and non-alcoholic steatohepatitis are currently viewed as two histological subtypes of the unique spectrum of non-alcoholic fatty liver disease, the two conditions are likely distinct not only from a histological but also from a pathophysiological standpoint. Efforts to distinguish simple steatosis from non-alcoholic steatohepatitis using non-invasive modalities should be informed by the current pathophysiology of these two clinical entities.

Background: Low bone mineral density (BMD) has been reported in both paediatric and adult patients with non-alcoholic fatty liver disease (NAFLD). The mechanisms behind the reduced BMD in NAFLD are still not completely understood., Aim: To provide a critical overview of the pathophysiological pathways linking NAFLD, reduced BMD and osteoporosis, with a special focus on the alterations of soluble mediators which could link fat accumulation in the liver with bone health. The MEDLINE database was searched by a combination of keywords: non-alcoholic fatty liver disease OR hepatic steatosis OR metabolic syndrome OR insulin resistance AND bone mineral density OR osteoporosis OR bone AND biomarkers OR serum marker., Results: Several factors that may influence bone mineralisation and the increased risk of osteoporosis in NAFLD can be discussed. These include the release of cytokines from the inflamed liver which may influence the bone microenvironment, vitamin D deficiency, and limited physical activity. Circulating markers of bone metabolism, including osteopontin, osteoprotegerin, osteocalcin and fetuin-A, have been found to be altered in patients with NAFLD., Conclusion: A better understanding of the mechanisms that link bone metabolism and the liver may open a new frontier to fight two highly prevalent conditions like NAFLD and osteoporosis., (© 2012 Blackwell Publishing Ltd.)

Background: Metabolic factors have been associated with liver damage in patients with non-alcoholic fatty liver disease (NAFLD)., Aims: To test a new marker of adipose dysfunction, the visceral adiposity index (VAI), in NAFLD patients to assess whether or not it is associated with host factors, and to investigate a potential correlation with histological findings., Methods: One hundred and forty-two consecutive NAFLD patients were evaluated by liver biopsy, and clinical and metabolic measurements, including insulin resistance with the homeostasis model assessment (HOMA), and VAI by using waist circumference, body mass index, triglycerides and HDL. Serum levels of TNFα, IL-6, adiponectin and leptin were also assessed. All biopsies were scored for NAFLD activity score (NAS) and its components, and for staging (Kleiner)., Results: By multiple linear regression analysis, VAI was independently associated with higher HOMA (P = 0.04), and fibrosis (P = 0.04). In addition, an independent association was found between higher VAI and lower adiponectin levels (P = 0.002). Higher HOMA (OR 1.149, 95% CI 1.003-1.316, P = 0.04), higher VAI (OR 1.446, 95% CI 1.023-2.043, P = 0.03), lobular inflammation (OR 3.777, 95% CI 1.771-8.051, P = 0.001), and ballooning (OR 2.884, 95% CI 1.231-6.757, P = 0.01) were correlated with significant fibrosis (F2-F4) on multiple logistic regression analysis. In particular, the prevalence of significant fibrosis progressively increased from patients with a VAI ≤ 2.1 and HOMA ≤ 3.4 (26%) to those with a VAI > 2.1 and HOMA > 3.4 (83%)., Conclusions: In NAFLD patients, visceral adiposity index is an expression of both qualitative and quantitative adipose tissue dysfunction and, together with insulin resistance, is independently correlated with significant fibrosis., (© 2011 Blackwell Publishing Ltd.)

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. Liver disease can be a cause of low bone mineral density. Whether or not NAFLD influences bone health is not known., Aim: To evaluate bone mineral density in obese children with and without NAFLD., Methods: Thirty-eight children with biopsy-proven NAFLD were matched for age, gender, race, ethnicity, height and weight to children without evidence of liver disease from the National Health and Nutrition Examination Survey. Bone mineral density was measured by dual energy X-ray absorptiometry. Age and gender-specific bone mineral density Z-scores were calculated and compared between children with and without NAFLD. After controlling for age, gender, race, ethnicity and total per cent body fat, the relationship between bone mineral density and the severity of histology was analysed in children with NAFLD., Results: Obese children with NAFLD had significantly (P < 0.0001) lower bone mineral density Z-scores (-1.98) than obese children without NAFLD (0.48). Forty-five per cent of children with NAFLD had low-bone mineral density for age, compared to none of the children without NAFLD (P < 0.0001). Among those children with NAFLD, children with NASH had a significantly (P < 0.05) lower bone mineral density Z-score (-2.37) than children with NAFLD who did not have NASH (-1.58)., Conclusions: The NAFLD was associated with poor bone health in obese children. More severe disease was associated with lower bone mineralisation. Further studies are needed to evaluate the underlying mechanisms and consequences of poor bone mineralisation in children with NAFLD., (© 2011 Blackwell Publishing Ltd.)

Background: Thiazolidinediones (TZDs) have been used in the treatment of non-alcoholic steatohepatitis (NASH). However, the magnitude of treatment response associated with TZDs in improving liver histology in NASH has not been quantified systematically., Aim: To conduct a meta-analysis of randomised, placebo-controlled clinical trials (RPCTs) using pioglitazone and rosiglitazone in the treatment of NASH., Methods: Pubmed/MEDLINE and Cochrane Central Register of Controlled Trials 2010 were searched until September 2010 and four RPCTs were identified. Peto odds ratios (ORs) and their respective 95% confidence intervals (CIs) were used to assess the efficacy of TZDs in improving liver histological parameters., Results: Four good quality RPCTs derived from three continents were included. The meta-analysis showed that TZDs (n = 169) were significantly better than placebo (n = 165) in improving ballooning degeneration, lobular inflammation and steatosis with combined ORs of 2.11 (95% CI, 1.33-3.36), 2.58 (95% CI, 1.68-3.97) and 3.39 (95% CI, 2.19-5.25) respectively. The improvement in combined necroinflammation with TZD (n = 58) vs. placebo (n = 52) was also statistically significant (combined OR 6.52[95% CI, 3.03-14.06]), but improvement in fibrosis was not. When pioglitazone (n = 137) was analysed alone, the improvement in fibrosis with pioglitazone (n = 137) vs. placebo (n = 134) (combined OR 1.68 [95% CI, 1.02-2.77]) was statistically significant. The total body fat slightly decreased in the control, while it markedly and highly significantly increased with TZD treatment., Conclusions: Thiazolidinediones significantly improve ballooning degeneration, lobular inflammation, steatosis and combined necroinflammation in patients with NASH. Pioglitazone may improve fibrosis. Larger randomised, placebo-controlled clinical trials are needed to examine the efficacy of thiazolidinediones in improving NASH fibrosis., (© 2011 Blackwell Publishing Ltd.)

Background: Performance of non-invasive fibrosis biomarkers may be influenced by aetiology of chronic liver disease (CLD) and the stages of hepatic fibrosis, but large-scale studies are pending., Aim: To investigate the effect of aetiogy and stages of hepatic fibrosis on the performance of fibrosis biomarkers., Methods: A total of 2411 patients with compensated CLD (HCV=75.1%, HBV=10.5%, NASH=7.9%, HIV/HCV=6.5%) were consecutively enrolled in 9 centres. APRI, Forns'index, Lok index, AST-to-ALT ratio, Fib-4, platelets and Fibrotest-Fibrosure were tested against liver biopsy, considered the gold standard. The effect of the stages of hepatic fibrosis to diagnose significant fibrosis and cirrhosis (≥F2 and F4 respectively) was investigated through difference between advanced and non-advanced fibrosis stages (DANA). Performance was expressed as observed area under the ROC curve (ObAUROC) and AUROC adjusted for DANA (AdjAUROC)., Results: Performance of APRI and Fibrotest-Fibrosure was higher than other biomarkers. In all aetiologies, AdjAUROC was higher than ObAUROC. APRI showed its best performance in HCV monoinfected cases, with an AdjAUROC of 0.77 and 0.83 for ≥F2 and F4 respectively. In HBV and non-alcoholic steatohepatitis (NASH) patients, its performance was poor (AdjAUROC <0.70). Performance of Fibrotest-Fibrosure was good in all aetiologies for both ≥F2 and F4 (AdjAUROC >0.73), except for ≥F2 in NASH (AdjAUROC = 0.64). Performance of all biomarkers was reduced in HCV cases with normal ALT., Conclusions: Aetiology is a major factor influencing the performance of liver fibrosis biomarkers. Even after correction for DANA, APRI and Fibrotest-Fibrosure exhibit the best performance. However, liver biopsy is not replaceable, especially to diagnose ≥F2 and in HCV carriers with normal ALT., (© 2011 Blackwell Publishing Ltd.)

Background: Hyperuricemia has been associated with metabolic disorders. In this line recent studies observed an independent link between higher uric acid serum levels and clinical diagnosis of non-alcoholic fatty liver disease (NAFLD)., Aims: We aimed to assess the potential association between uric acid serum levels and histological liver damage in a homogeneous cohort of biopsy-proven NAFLD patients., Methods: Consecutive NAFLD patients (n = 166), assessed by liver biopsy (Kleiner score), anthropometric, biochemical and metabolic features, were included. Enzymatic colorimetric test was used for serum uric acid assays (Roche Diagnostics GmbH, Mannheim, Germany). Hyperuricemia was diagnosed when uric acid serum levels were > 7 mg/dL in men, and > 6 mg/dL in women., Results: Mean uric acid serum level was 5.75 mg/dL, and about 20% of patients had hyperuricemia, that was independently associated with younger age (OR 0.951, 95% CI 0.918-0.984, P = 0.004), lobular inflammation (OR 2.144, 95% CI 1.055-4.357, P = 0.03) and steatosis grade (OR 1.859, 95% CI 1.078-3.205, P = 0.02), by multivariate logistic regression analysis. Female gender (OR 2.656, 95% CI 1.190-5.928, P = 0.01), higher HOMA index (OR 1.219, 95% CI 1.043-1.426, P = 0.01), and hyperuricemia (OR 4.906, 95% CI 1.683-14.296, P = 0.004) were linked to NAFLD activity score (NAS) ≥ 5 by multiple logistic regression analysis. Conversely, higher HOMA index (OR 1.140, 95% CI 1.001-1.229, P = 0.04), and NAS (OR1.954, 95% CI 1.442-2.649, P < 0.001) were independently associated with significant fibrosis by logistic regression analysis., Conclusions: In NAFLD patients, hyperuricemia is independently associated with the severity of liver damage, representing, in this setting of patients, together with insulin resistance, a potential new therapeutic target in future intervention trials., (© 2011 Blackwell Publishing Ltd.)

Background: Polycystic ovary syndrome (PCOS) is a common disorder for women of child-bearing age and is associated with metabolic syndrome (MS)., Aim: To assess the literature for associations between polycystic ovary syndrome and non-alcoholic fatty liver disease (NAFLD)., Methods: We performed a systematic review using PubMed-search for peer-reviewed articles related to polycystic ovary syndrome and NAFLD. Articles were summarised and grouped according to different sections defining interactions of polycystic ovary syndrome with metabolic syndrome and non-alcoholic fatty liver disease as well as risk factors, pathogenic pathways and treatment options., Results: Obesity is a common factor involved in both polycystic ovary syndrome and non-alcoholic fatty liver disease. Obesity causes non-alcoholic fatty liver disease and aggravates hirsutism and menstrual disorders in polycystic ovary syndrome. Insulin resistance, a hallmark of metabolic syndrome is observed in 50-80% of women with polycystic ovary syndrome and patients with non-alcoholic fatty liver disease. Recent findings suggest that women with polycystic ovary syndrome may be at risk for developing non-alcoholic fatty liver disease and conversely, non-alcoholic fatty liver disease may be a risk for polycystic ovary syndrome. Based on the association of polycystic ovary syndrome and other metabolic abnormalities, such as insulin resistance, hyperandrogenism, obesity and non-alcoholic fatty liver disease, the candidate genes have been speculated for polycystic ovary syndrome. Closer scrutiny of these genes placed most of their proteins at the crossroads of three highly inter-related conditions: metabolic syndrome, obesity and non-alcoholic fatty liver disease. In most studies, the prevalence of both polycystic ovary syndrome and non-alcoholic fatty liver disease rises proportionally to the degree of insulin resistance and increases in the mass of adipose tissue., Conclusions: Non-alcoholic fatty liver disease is considered as the hepatic manifestation of metabolic syndrome. Similarly, it seems appropriate to consider polycystic ovary syndrome as the ovarian manifestation of metabolic syndrome. Both these conditions can co-exist and may respond to similar therapeutic strategies., (© 2011 Blackwell Publishing Ltd.)

Background: Non-alcoholic fatty liver disease generally has a benign course; however, patients with non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Currently, there is a lack of consensus about optimal NASH treatment., Aim: To assess the efficacy of insulin-sensitizing agents on histological and biochemical outcomes in randomized control trials of biopsy-proven NASH., Methods: Multiple online databases and conference abstracts were searched. Random effects meta-analyses were performed, with assessment for heterogeneity and publication bias., Results: Nine trials were included; five trials using thiazolidinediones (glitazones), three using metformin and one trial using both drugs. There was no publication bias. Compared with controls, glitazones resulted in improved steatosis (WMD = 0.57, 95% CI 0.36-0.77, P = <0.001), hepatocyte ballooning (WMD = 0.36, 95% CI 0.24-0.49, P < 0.001) and ALT (WMD = 16.4, 95% CI 7.7-25.0, P < 0.001), but not inflammation (P = 0.09) or fibrosis (P = 0.11). In patients without diabetes, glitazones significantly improved all histological and biochemical outcomes, most importantly including fibrosis (WMD = 0.29, 95% CI 0.078-0.51, P = 0.008). Metformin failed to improve any pooled outcome., Conclusions: Treatment of NASH with glitazones, but not metformin, demonstrates a significant histological and biochemical benefit, especially in patients without diabetes. Additional studies are needed to investigate long-term outcomes of glitazone therapy in patients without diabetes., (© 2010 Blackwell Publishing Ltd.)

Background: Patients with chronic liver disease and components of metabolic syndrome may be at higher risk for fibrosis., Aim: To assess the impact of clinicodemographic factors on hepatic fibrosis in CLD., Methods: Of 1028 chronic liver disease patients, 964 were included in the analysis. Extensive clinico-demographic and histological data were available. Significant baseline fibrosis (METAVIR stage > or =2) and fibrosis progression (increase of > or =1 stage in subsequent biopsy) were compared between groups using univariate and multivariate analyses., Results: Compared with HCV and HBV, NAFLD patients were more obese (higher BMI and waist circumference), diabetic, hypertensive and hyperlipidaemic. Significant fibrosis occurred in 55%, 43% and 20% of HCV, HBV and NAFLD, respectively. Factors independently associated with fibrosis in NAFLD included DM, elevated AST and ALT. For viral hepatitis, independent predictors of fibrosis were low platelet count (HBV and HCV), age (HBV) and elevated AST and ALT (HCV). A second biopsy was available for 96 patients with follow-up of about 4 years. Factors independently associated with progression of fibrosis were HCV infection, higher ALT and lower platelet count., Conclusions: Diabetes mellitus is an independent risk factor for fibrosis only in NAFLD. Elevated aminotransferases and/or low platelet counts are independently associated with significant baseline fibrosis or progression of fibrosis, in patients with chronic liver disease.

Background: Data on the quality of life (QOL) of children with non-alcoholic fatty liver disease (NAFLD) are needed to estimate the true burden of illness in children with NAFLD., Aim: To characterize QOL and symptoms of children with NAFLD and to compare QOL in children with NAFLD with that in a sample of healthy children., Methods: Quality of life and symptoms were assessed in children with biopsy-proven NAFLD enrolled in the NASH Clinical Research Network. PedsQL scores were compared with scores from healthy children. For children with NAFLD, between-group comparisons were made to test associations of demography, histological severity, symptoms and QOL., Results: A total of 239 children (mean age 12.6 years) were studied. Children with NAFLD had worse total (72.8 vs. 83.8, P < 0.01), physical (77.2 vs. 87.5, P < 0.01) and psychosocial health (70.4 vs. 81.9, P < 0.01) scores compared with healthy children. QOL scores did not significantly differ by histological severity of NAFLD. Fatigue, trouble sleeping and sadness accounted for almost half of the variance in QOL scores. Impaired QOL was present in 39% of children with NAFLD., Conclusions: Children with NAFLD have a decrement in QOL. Symptoms were a major determinant of this impairment. Interventions are needed to restore and optimize QOL in children with NAFLD.

Background: Both nonalcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC) are frequent causes of chronic liver disease. In recent years, there have been significant revelations as regards the relationship between NAFLD and CHC., Aim: To conduct a systematic, evidence-based review of the epidemiology, pathophysiology and potential treatments of coexistent NAFLD and CHC., Methods: The terms such as hepatitis C, fatty liver, NAFLD, nonalcoholic steatohepatitis and steatosis were searched on PubMed up to January 2008. References from selected articles and pertinent abstracts were also included., Results: Hepatic steatosis affects up to 80% of patients with CHC and is dependent on both viral and host factors. While insulin resistance (IR) is associated with hepatic steatosis and hepatitis C virus, genotype-specific pathogenic mechanisms have been identified and are currently the focus of intense investigation in the literature. Clinical implications of concurrent NAFLD, CHC and IR include increased disease progression, elevated risk of hepatocellular carcinoma, and decreased response to antiviral therapy., Conclusions: NAFLD and IR are common in patients with CHC virus infection. IR is a driving force in the development of hepatic steatosis. Because of the clinical implications of hepatic steatosis and IR in the setting of CHC, further studies evaluating treatments, which may increase response to antiviral therapy, are needed.

Background: Several adipocytokines have been implicated in the pathogenesis non-alcoholic fatty liver disease (NAFLD)., Aim: To assess adipocytokines in NAFLD patients and controls., Methods: A total of 95 patients (26 non-alcoholic steatohepatitis (NASH), 19 simple steatosis (SS), 38 obese controls and 12 non-obese controls) were included. Fasting serum insulin, glucose, visfatin, resistin, adiponectin, tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and IL-6 were determined. Univariate and multivariate analyses were used to compare groups and determine associations., Results: Serum TNF-alpha and IL-8 were higher in NAFLD patients when compared with both obese and non-obese controls. Analysis involving all patients revealed a significant correlation between serum TNF-alpha and IL-8 (P < 6.319e-08), and between IL-6 and IL-8 (P < 5.271e-15). Homeostatic model assessment scores negatively correlated with adiponectin in NAFLD (P < 0.0032). Serum visfatin was higher in all three obese groups than in non-obese controls (P < 0.02, P < 0.002 and P < 0.008). Visfatin in NASH patients was lower than SS and obese controls. Although TNF-alpha was associated with NAFLD (P < 0.02), it was interdependent on visfatin. In comparison to SS, four factors were independently associated with NASH: age, alanine aminotransferase, IL-8 and adiponectin (P < 0.05). Multivariate analysis indicated that TNF-alpha was the only independent predictor of fibrosis in NASH (P < 0.0004)., Conclusion: These findings support a complex interaction between adipocytokines and the pathogenesis of NAFLD.

Background: The prevalence of metabolic syndrome and its possible impact on the severity of liver histological lesions have not been studied prospectively in chronic liver diseases., Aim: To investigate the prevalence of metabolic syndrome in patients with chronic viral hepatitis or non-alcoholic steatohepatitis, and to determine its associations with histological severity., Methods: We prospectively included 317 patients (hepatitis B e antigen-negative chronic hepatitis B: 95, chronic hepatitis C: 176, non-alcoholic steatohepatitis: 46) with liver biopsy. Metabolic syndrome was defined using the Adult Treatment Panel III criteria. Histological lesions were evaluated according to Ishak's or Brunt's classification., Results: Metabolic syndrome was present in 10.4% of patients being significantly more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis (41.3% vs. 5.1%, P < 0.001). In chronic viral hepatitis, cirrhosis (stages 5-6) was independently associated with increasing age, higher aspartate aminotransferase and gamma-glutamyl-transpeptidase levels, severe necroinflammation and metabolic syndrome (P = 0.016). In non-alcoholic steatohepatitis, severe fibrosis (stages 3-4) was independently associated with severe necroinflammation and metabolic syndrome (P = 0.033). Presence of metabolic syndrome was not associated with presence or severity of steatosis both in chronic viral hepatitis and in non-alcoholic steatohepatitis., Conclusion: Metabolic syndrome is more prevalent in non-alcoholic steatohepatitis than in chronic viral hepatitis; it is associated independently with more severe fibrosis but not with the severity of steatosis, both in chronic viral hepatitis and in non-alcoholic steatohepatitis.

Background: Non-alcoholic fatty liver disease is prevalent in affluent countries and is strongly associated with metabolic syndrome., Aim: To study the prevalence of undiagnosed diabetes and postchallenge hyperglycaemia in Chinese patients with non-alcoholic fatty liver disease., Methods: 73 consecutive patients with biopsy-proven non-alcoholic fatty liver disease and no history of diabetes underwent comprehensive metabolic screening. Diagnosis of diabetes and impaired glucose regulation was based on the 2006 American Diabetes Association criteria., Results: The prevalence of undiagnosed diabetes and impaired glucose tolerance in non-alcoholic fatty liver disease patients was 33% and 29%, respectively. Among patients with 2-h plasma glucose above 7.8 mm, 47% had normal fasting glucose (below 5.6 mm). Impaired glucose tolerance was more common in patients with non-alcoholic steatohepatitis than those with simple hepatic steatosis (P = 0.036), and 2-h plasma glucose correlated with fibrosis stage (Spearman coefficient: 0.25, P = 0.046). In a binary logistic regression analysis, high fasting glucose and low high-density lipoprotein cholesterol were independent factors associated with diabetes. Nevertheless, if oral glucose tolerance test was only performed in non-alcoholic fatty liver disease patients with impaired fasting glucose, 20.8% of diabetes cases would be missed., Conclusions: Isolated postchallenge hyperglycaemia is common among Chinese non-alcoholic fatty liver disease patients without history of diabetes. It is associated with histological severe disease, and cannot be accurately predicted by any fasting glucose cut-off.

Background: There is increasing evidence that hepatic steatosis contributes to the progression of liver fibrosis, whereas its impact on the efficacy of anti-viral treatment is still under investigation., Aim: To evaluate the effect of steatosis on the outcome of combined anti-viral treatment., Methods: We studied 102 consecutive naive patients with chronic hepatitis C receiving combined anti-viral therapy (peg-interferon alpha-2b and ribavirin)., Results: Fifty (49%) of 102 patients had evidence of hepatic steatosis (29 grade 1, 16 grade 2 and 5 grade 3). Sustained virological response was similar in patients with and without steatosis (58% vs. 56%); moreover, the grade of steatosis did not affect the rate of sustained virological response (grade 1: 58%, grade 2: 56% and grade 3: 60%). Patients with steatosis had significantly higher serum levels of aspartate transaminase, alanine transaminase and gamma-glutamyltransferase (P = 0.007, 0.004 and 0.03, respectively), higher histological activity (P = 0.03), more advanced stage of fibrosis (P = 0.0394) and more often hepatitis C virus genotype 3 (P = 0.04)., Conclusions: Our findings suggest that hepatic steatosis in chronic hepatitis C, irrespective of its grade, is not a negative prognostic factor of response to combined anti-viral therapy, even when the histological and biochemical profile of the disease is more aggressive.

Steatosis is a common feature of chronic hepatitis C, and may be caused directly by the virus, as in genotype 3 infection, or be associated with host metabolic factors. The interaction of hepatitis C virus core protein with the lipoprotein secretion pathways causes the characteristic alterations of lipid metabolism observed in hepatitis C virus-related steatosis. Several pathogenic mechanisms are likely involved into the pathogenesis of hepatitis C virus-related steatosis, including hyper-homocysteinaemia, hypoadiponectinaemia and insulin resistance. Steatosis is a major determinant of the liver damage progression in chronic hepatitis C (CHC), and negatively affects the response rate to the interferon (IFN)-based anti-viral treatment. Moreover, recent evidence suggests that steatosis may contribute to liver carcinogenesis. Chronic hepatitis C is a recognized risk factor for type 2 diabetes and it could be implicated into the pathogenesis of atherosclerosis. The role of hepatitis C virus (HCV)-related steatosis in these epidemiological associations remains to be determined.

Metabolic syndrome represents a common risk factor for premature cardiovascular disease and cancer whose core cluster includes diabetes, hypertension, dyslipidaemia and obesity. The liver is a target organ in metabolic syndrome patients in which it manifests itself with non-alcoholic fatty liver disease spanning steatosis through hepatocellular carcinoma via steatohepatitis and cirrhosis. Given that metabolic syndrome and non-alcoholic fatty liver disease affect the same insulin-resistant patients, not unexpectedly, there are amazing similarities between metabolic syndrome and non-alcoholic fatty liver disease in terms of prevalence, pathogenesis, clinical features and outcome. The available drug weaponry for metabolic syndrome includes aspirin, metformin, peroxisome proliferator-activated receptor agonists, statins, ACE (angiotensin I-converting enzyme) inhibitors and sartans, which are potentially or clinically useful also to the non-alcoholic fatty liver disease patient. Studies are needed to highlight the grey areas in this topic. Issues to be addressed include: diagnostic criteria for metabolic syndrome; nomenclature of non-alcoholic fatty liver disease; enlargement of the clinical spectrum and characterization of the prognosis of insulin resistance-related diseases; evaluation of the most specific clinical predictors of metabolic syndrome/non-alcoholic fatty liver disease and assessment of their variability over the time; characterization of the importance of new risk factors for metabolic syndrome with regard to the development and progression of non-alcoholic fatty liver disease.

The incidence of hepatocellular carcinoma is increasing, but the temporal changes of risk factors remain unclear. A significant proportion of hepatocellular carcinoma (7-30%) develops in cryptogenic cirrhosis, and may represent the most worrisome complication of non-alcoholic steatohepatitis. Non-alcoholic steatohepatitis is tightly related to insulin resistance and several features of the metabolic syndrome, i.e obesity, type 2 diabetes and dyslipidaemia. Nearly two-thirds of adults in the United States and an increasing percentage of the population worldwide are overweight or obese. Diabetes prevalence is increasing as well. The rising prevalence of risk factors associated with non-alcoholic steatohepatitis can partially account for the increasing incidence of cryptogenic cirrhosis and subsequent hepatocellular carcinoma. Moreover, recent evidence demonstrates that both obesity and diabetes are per se associated with an increased cancer risk. Large prospective studies show a significant association with obesity for several cancers, including cancers of the colon, female breast, endometrium, kidney, oesophagus and liver (hepatocellular carcinoma). Type 2 diabetes is also related with increased risks of colon, endometrial, kidney, pancreatic cancer and hepatocellular carcinoma. In western countries, the insulin resistance syndrome is emerging as a risk factor for a wide variety of cancers, including hepatocellular carcinoma.

The mechanisms responsible for the progression of nonalcoholic fatty liver disease (NAFLD) to more severe liver injury are still poorly understood. Data from animal models suggest that oxidative stress contributes to steatohepatitis and an increase of lipid peroxidation has been documented in human NAFLD. By measuring the titers of circulating antibodies against lipid peroxidation products as markers of oxidative stress we have observed that NAFLD patients have titers of these antibodies significantly higher than in controls. Moreover, the titers of lipid peroxidation-related antibodies are associated with a 3-fold increase in the risk of developing advanced fibrosis/cirrhosis. Although the mechanisms causing oxidative stress in NAFLD have not been elucidated, these results support the involvement of lipid peroxidation in the processes leading to liver fibrosis associated with NAFLD.

The treatment of non-alcoholic fatty liver disease may be worthwhile to prevent progression to advanced liver failure, but no therapy is definitely evidence-based. Weight loss or lifestyle modifications remain the primary line of intervention, particularly in overweight or obese subjects. In adult non-alcoholic fatty liver disease, they are effective in the short-term, but require a multidisciplinary team approach that is rarely available in liver units. Insulin-sensitizing agents are probably the treatment of choice. They definitely reduce the insulin resistance that promotes steatosis. Several uncontrolled and controlled studies have documented an improvement in liver biochemistry and in histology, but the long-term results remain unsettled. This is an area where significant advances are expected in the next few years.

Hepatitis C and non-alcoholic fatty liver disease (NAFLD) are the two most common liver diseases in the Western hemisphere. It is therefore natural that these conditions often co-exist in the same individual. Hepatitis C, especially genotype 3, is often associated with hepatic steatosis. In subjects with genotype 3 infection, a sustained virologic response to treatment is associated with improvement in hepatic steatosis. The diagnosis of NAFLD in a subject with hepatitis C infection is based on the presence of hepatic steatosis. Most investigators require the presence of at least grade II steatosis to warrant a diagnosis of concomitant NAFLD because the significance of minimal steatosis is uncertain. The presence of steatohepatitis is surmised by the additional presence of Mallory bodies, cytologic ballooning and pericellular fibrosis. It is of paramount importance to exclude alcohol as a cause of these histologic findings in this population before a diagnosis of NAFLD is made. The presence of NAFLD in subjects with hepatitis C genotype 1 infection is most strongly associated with the presence of the metabolic syndrome and insulin resistance. The degree of hepatic steatosis correlates with the degree of hepatic fibrosis and the presence of concomitant steatosis is associated with more advanced fibrosis. The presence of cytologic ballooning confers an additional risk for increased fibrosis. Insulin resistance and hyperinsulinemia have been associated with increased collagen production by hepatic stellate cells. Subjects with hepatitis C and NAFLD are more likely to be virologic nonresponders following anti-HCV therapy. The value of treating insulin resistance and NAFLD prior to antiviral therapy remains to be experimentally verified.

Non-alcoholic steatohepatitis has been recognized as a significant cause of end-stage liver disease and hepatic decompensation. Despite the growing interest in this condition, the molecular mechanisms underlying the development of fibrosis in this setting are only partially understood. In this article, the cellular and molecular basis of fibrosis in chronic liver disease are briefly outlined. In addition, mechanisms specifically operating in the context of fatty liver and steatohepatitis are examined, including: insulin resistance, oxidative stress, and inflammation. Finally, recent developments indicating the possible contribution of cytokines derived from adipose tissue (adipokines) to liver fibrosis is discussed.

Non-alcoholic liver steatosis is associated with metabolic syndrome and type 2 diabetes. The prevalence of this condition in type 2 diabetes is estimated to be between 28 and 55%. Non-alcoholic liver steatosis is not a benign disease because of its potential progression to liver fibrosis, cirrhosis and cancer. The Verona diabetes study, a population-based observational study, on 7148 type 2 diabetic patients after 5 years of follow-up has reported an increased risk of death from gastrointestinal diseases, particularly from chronic liver cirrhosis. Moreover, in the same population after 10 years of follow-up a higher risk of mortality from liver cancer was observed and this risk increased significantly in obese patients (body mass index >30 kg/m2). Of note is that obese diabetic patients suffer an even higher prevalence of non-alcoholic liver steatosis. In conclusion, the Verona diabetes study showed an increased risk of mortality from liver cirrhosis and liver cancer in type 2 diabetic patients. Diverse pathophysiological mechanisms can be responsible, i.e. higher alcohol consumption, hepatitis and others but, considering the high prevalence of non-alcoholic liver steatosis in these patients, it is plausible to hypothesize that non-alcoholic liver steatosis may play a significant role in predisposing the liver of diabetics to chronic diseases.

Background: Whether liver steatosis affects sustained virological response in patients with chronic hepatitis C is still under discussion., Aim: To evaluate the impact of liver steatosis in patients treated (for chronic hepatitis C) with combination therapy., Methods: We evaluated 97 (male/female 82/15, mean age 41.1 years) consecutive naive patients treated with pegylated interferon alpha-2b plus ribavirin., Results: Prevalence and severity of liver steatosis were significantly associated with genotype 3a [grade 3-4 in 14 of 32 patients (44%) vs. 8 of 65 patients (12%) with other genotypes; P = 0.001], while steatosis grade 1 (<10% of hepatocytes affected) was more frequently associated with genotype 1a/1b [9/39 (23%) vs. 4/57 (7%); P = 0.02]. Overall, sustained virological response was 62.8%, and was statistically uninfluenced by the presence/absence of liver steatosis. On the contrary, the following variables were independently associated with sustained virological response at logistic regression analysis: genotype other than 1a/1b, positive association, (odds ratio 3.4, P < 0.04), and low-grade liver steatosis, negative association, (odds ratio 9.0, P = 0.009), whereas sustained virological response was unaffected by severe liver steatosis, which was mainly associated with genotypes 2 and 3 [steatosis grade 2, 18/29 (62%); grade 3, 10/12 (83%); grade 4, 7/10 (70%)]., Conclusions: Only low-grade liver steatosis negatively affects the outcome of combination therapy, with peginterferon alpha-2b plus ribavirin, while severe steatosis (which is virus-related in most cases) has no impact on virological response.

Background: Treatment options for non-alcoholic steatohepatitis (NASH) are limited. Weight loss remains the most recommended therapy. Orlistat is an effective adjunct to dietary weight loss therapy., Aim: To evaluate the efficacy of orlistat, given for 6 months to patients with obesity and biopsy confirmed NASH., Methods: Ten obese patients with biopsy proven NASH were enrolled. Orlistat was given with meals for 6 months. Body Mass Index (BMI), liver enzymes, haemoglobin A1c, fasting lipids and glucose were assessed at baseline and at completion of the study. Paired liver histology was obtained., Results: Six women and four men were enrolled. The mean weight loss was 22.7 lb and ranged from 0 to 24.3%. The following clinical values significantly improved: mean BMI: 43.4-39.8 (P = 0.007); mean haemoglobin A1c (%): 7.14-5.95 (P = 0.021); mean alanine aminotransferase (ALT) (U/L): 93 -54 (P = 0.009); and mean aspartate aminotransferase (AST) (U/L): 79-48 (P = 0.008). Steatosis improved in six patients, and fibrosis improved in three patients., Conclusions: Orlistat therapy and dietary counselling were associated with significant decreases in body weight, haemoglobin A1c, ALT and AST. A 10% or greater reduction in weight improved steatosis and fibrosis as well as haemoglobin A1c levels in the majority of patients treated for 6 months. Controlled trials of longer duration are warranted to assess for histopathologic improvement as well as cost-efficacy in comparison to diet and exercise alone.