Non-alcoholic Fatty Liver Disease Cirrhosis Research Articles

Liver Plaques: Portal Vein Deposition of Oxidized Low-density Lipoprotein in Non-alcoholic Fatty Liver Disease

ObjectivesThe interaction of accumulated oxidized low-density lipoprotein (oxLDL), a key pathogenic determinant of vascular atherosclerosis, with the hepatic microenvironment in non-alcoholic fatty liver disease (NAFLD) is unknown.MethodsWe aim to demonstrate the role of hepatic oxLDL deposition in the pathogenesis of NAFLD by immuno-fluoro-histo-chemistry. Cross-sectional human liver specimens of different stages of NAFLD (normal, fatty liver, hepatitis, and cirrhosis) were stained with antibodies against oxLDL, apolipoprotein B 100 (Apo-B 100), α smooth muscle actin (a marker of activated stellate cells), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD68 (a marker of Kupffer cell), and interleukin-1β (IL-1β) and compared in serial sections. OxLDL is confirmed by co-localized staining with Apo-B 100 and free cholesterol, which was stained with filipin.ResultsCompared to normal liver, oxLDL is deposited through the portal vein (rather than hepatic artery) in the early stage of NAFLD, forming plaques associated with Kupffer cell-related inflammation (marked by inducible expression of CD68, IL-1β and LOX-1) in the progressing stage. Further oxLDL accumulation extending to the hepatic sinusoid is closely associated with activated stellate cells in the cirrhosis stage.ConclusionsOxLDL-enriched portal plagues are closely associated with active inflammation and periportal fibrosis in the progression of NAFLD. Hepatic oxLDL deposition is of great significance in the pathogenesis of NAFLD and could be a potential useful clinical biomarker for the progression of NAFLD. ObjectivesThe interaction of accumulated oxidized low-density lipoprotein (oxLDL), a key pathogenic determinant of vascular atherosclerosis, with the hepatic microenvironment in non-alcoholic fatty liver disease (NAFLD) is unknown. The interaction of accumulated oxidized low-density lipoprotein (oxLDL), a key pathogenic determinant of vascular atherosclerosis, with the hepatic microenvironment in non-alcoholic fatty liver disease (NAFLD) is unknown. MethodsWe aim to demonstrate the role of hepatic oxLDL deposition in the pathogenesis of NAFLD by immuno-fluoro-histo-chemistry. Cross-sectional human liver specimens of different stages of NAFLD (normal, fatty liver, hepatitis, and cirrhosis) were stained with antibodies against oxLDL, apolipoprotein B 100 (Apo-B 100), α smooth muscle actin (a marker of activated stellate cells), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD68 (a marker of Kupffer cell), and interleukin-1β (IL-1β) and compared in serial sections. OxLDL is confirmed by co-localized staining with Apo-B 100 and free cholesterol, which was stained with filipin. We aim to demonstrate the role of hepatic oxLDL deposition in the pathogenesis of NAFLD by immuno-fluoro-histo-chemistry. Cross-sectional human liver specimens of different stages of NAFLD (normal, fatty liver, hepatitis, and cirrhosis) were stained with antibodies against oxLDL, apolipoprotein B 100 (Apo-B 100), α smooth muscle actin (a marker of activated stellate cells), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), CD68 (a marker of Kupffer cell), and interleukin-1β (IL-1β) and compared in serial sections. OxLDL is confirmed by co-localized staining with Apo-B 100 and free cholesterol, which was stained with filipin. ResultsCompared to normal liver, oxLDL is deposited through the portal vein (rather than hepatic artery) in the early stage of NAFLD, forming plaques associated with Kupffer cell-related inflammation (marked by inducible expression of CD68, IL-1β and LOX-1) in the progressing stage. Further oxLDL accumulation extending to the hepatic sinusoid is closely associated with activated stellate cells in the cirrhosis stage. Compared to normal liver, oxLDL is deposited through the portal vein (rather than hepatic artery) in the early stage of NAFLD, forming plaques associated with Kupffer cell-related inflammation (marked by inducible expression of CD68, IL-1β and LOX-1) in the progressing stage. Further oxLDL accumulation extending to the hepatic sinusoid is closely associated with activated stellate cells in the cirrhosis stage. ConclusionsOxLDL-enriched portal plagues are closely associated with active inflammation and periportal fibrosis in the progression of NAFLD. Hepatic oxLDL deposition is of great significance in the pathogenesis of NAFLD and could be a potential useful clinical biomarker for the progression of NAFLD. OxLDL-enriched portal plagues are closely associated with active inflammation and periportal fibrosis in the progression of NAFLD. Hepatic oxLDL deposition is of great significance in the pathogenesis of NAFLD and could be a potential useful clinical biomarker for the progression of NAFLD.

Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?

Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are associated with obesity, insulin resistance, metabolic syndrome, cardiovascular disease, cirrhosis, and liver tumors. On these grounds, we have hypothesized that NAFLD and PCOS occur more frequently than expected by chance alone. We have tested this hypothesis by reviewing the clinical and biological evidence that supports a significant association between NAFLD and PCOS. PubMed was extensively searched for articles published through March 2015 using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "PCOS." Several cross-sectional and case-control studies have consistently demonstrated that the prevalence of NAFLD is remarkably increased in young women with PCOS, independent of overweight/obesity and other coexisting metabolic syndrome features, and that these women are more likely to have the more severe forms of NAFLD (non-alcoholic steatohepatitis, advanced fibrosis, and cirrhosis). Accumulating evidence suggests that NAFLD, especially its necro-inflammatory form, may exacerbate hepatic and systemic insulin resistance and releases multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that may play important roles in the pathophysiology of PCOS. These findings call for more active and systematic search for NAFLD among women with PCOS. Conversely, gastroenterologists/hepatologists need to be aware of the presence of PCOS among female patients with NAFLD and compatible clinical features. Finally, all these patients should undergo regular follow-up not only for liver-related complications but also for cardio-metabolic diseases.

High-throughput sequencing reveals altered expression of hepatic microRNAs in nonalcoholic fatty liver disease–related fibrosis

Recent evidence suggests that microRNAs (miRNAs), small, noncoding RNA molecules that regulate gene expression, may play a role in the regulation of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). To identify miRNAs that mediate NAFLD-related fibrosis, we used high-throughput sequencing to assess miRNAs obtained from liver biopsies of 15 individuals without NAFLD fibrosis (F0) and 15 individuals with severe NAFLD fibrosis or cirrhosis (F3-F4), matched for age, sex, body mass index, type 2 diabetes status, hemoglobin A1c, and use of diabetes medications. We used DESeq2 and Kruskal-Wallis test to identify miRNAs that were differentially expressed between NAFLD patients with or without fibrosis, adjusting for multiple testing using Bonferroni correction. We identified a total of 75 miRNAs showing statistically significant evidence (adjusted P value <0.05) for differential expression between the 2 groups, including 30 upregulated and 45 downregulated miRNAs. Quantitative reverse-transcription polymerase chain reaction analysis of selected miRNAs identified by sequencing validated 9 of 11 of the top differentially expressed miRNAs. We performed functional enrichment analysis of dysregulated miRNAs and identified several potential gene targets related to NAFLD-related fibrosis including hepatic fibrosis, hepatic stellate cell activation, transforming growth factor beta signaling, and apoptosis signaling. We identified forkhead box O3 and F-box WD repeat domain containing 7, E3 ubiquitin protein ligase (FBXW7) as potential targets of miR-182, and found that levels of forkhead box O3, but not FBXW7, were significantly decreased in fibrotic samples. These findings support a role for hepatic miRNAs in the pathogenesis of NAFLD-related fibrosis and yield possible new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.

Epidemiology, disease burden and outcomes of cirrhosis in a large secondary care hospital in South Auckland, New Zealand.

Liver cirrhosis is an important cause of morbidity and mortality; however, little is known about its impact in New Zealand. We aim to determine the disease burden, epidemiology and outcomes of cirrhotic patients. This is a retrospective study of cirrhosis patients under secondary public hospital care in a geographically defined region, between the years 2000 and 2011. Cirrhosis complications and mortality was recorded. Poisson log-linear regression analysis was performed for incidence rate ratio (IRR) and Cox regression analysis was used to analyse time-related events. Seven hundred and forty-six cirrhotic patients were analysed; most were European/Other (39.9%), Pacific islanders (21.6%), Southeast Asian/Chinese (17.8%) and Maori (12.3%). 68.4% were male. The common primary aetiologies for cirrhosis were chronic hepatitis B (CHB) cirrhosis (37.3%), alcoholic liver disease (ALD) cirrhosis (24.1%), chronic hepatitis C (CHC) cirrhosis (22.3%) and non-alcoholic fatty liver disease (NAFLD) cirrhosis (16.4%). The hepatocellular carcinoma (HCC) mortality rates were highest in NAFLD and CHB cirrhosis groups (3.0 and 3.1 per 100 patient-year respectively), compared with ALD and CHC groups (2.2 and 1.4 per 100 patient-year, all P < 0.05 respectively). Patients with ALD and NAFLD cirrhosis had the highest all-cause and non-HCC mortality rate compared with viral hepatitis cirrhosis groups. The IRR for HCC incidence, liver-related mortality and HCC mortality were 1.087, 1.098 and 1.114, respectively (all P < 0.001), suggesting increasing incidence and disease burden over the study period. The number of cirrhotic patients in secondary care is increasing steadily. Cirrhosis complications and mortality rates are also rising, particularly the incidence and mortality of HCC.

Gastric Bypass Surgery Impacts Cardiac and Liver Outcomes With Better Survival in Patients With Non-Alcoholic Fatty Liver Disease

Introduction: Non-alcoholic fatty liver disease (NAFLD) is increasing due to current obesity epidemic. NAFLD patients are also at higher risk for cardiac events. Gastric bypass surgery (GBP) is increasingly utilized as a treatment for morbid obesity and is shown to improve liver fibrosis in NAFLD patients. The aim our study is to assess the impact of GBP on development of cirrhosis, occurrence of cardiac events, and overall survival among NAFLD patients. Methods: This is a single-center retrospective study on NAFLD patients (2007-2011) with diagnosis based on histology with changes of steatohepatitis or imaging with findings of steatosis, excluding other liver diseases. All patients had documented alcohol use of <10 g/d. Medical charts were reviewed for a) demographics, comorbidities, history of GBP, and b) follow-up from first clinic encounter for diagnosis of cirrhosis or of cardiac event (arrhythmia, congestive heart failure, angina, myocardial infarction, stroke, or peripheral arterial disease), transplantation, and survival. Results: Of 230 NAFLD patients, 29 with GBP differed from the remaining 201 for age (54±11 vs. 48±8 years, p=0.002), females (83% vs. 61%, p=0.024), and BMI (35±8 vs. 40±9 kg/m2, p=0.002). Compared to patients without GBP, those with GBP had fewer cardiac events (3.5% vs. 15%, p=0.090) and cirrhosis (24% vs. 57%, p=0.001). None of GBP patients needed liver transplantation (LT) compared to 20 (10%) patients without GBP who underwent LT, p=0.070. Overall survival tended to be better among GBP patients (96.5% vs. 90%, p=0.230) with significantly better LT-free survival (96.5% vs. 80%, p=0.035). Controlling for age, sex, cirrhosis, diabetes, BMI, use of beta blockers, and use of statins, the risk of cardiac events and the LT-free mortality were reduced with GPB, although not statistically significant due to small sample size: HR 0.29, 95% CI 0.04-2.34, p=0.25 and HR 0.58, 95% CI 0.05-4.56, p=0.52, respectively. LT-free mortality was 43-fold higher in presence of cirrhosis: 43 (5.3-353) and was reduced by 76% (0.24; 0.07-0.81) with use of statin and by 60% in females (0.4; 0.17-0.92). Conclusion: GBP improves the natural history of NAFLD with reduced risk of end organ damage, cardiac or liver-related complications, and mortality. Given the protective effect of statins on LT-free mortality, physicians may be encouraged to continue use of these drugs in NAFLD patients when indicated for treatment of dyslipidemia or cardiac disease. Further larger studies are suggested to examine the impact of GBP on hard end points, including LT-free mortality. Studies are urgently needed to identify patients at risk for cirrhosis in NAFLD, as a basis for using GBP as a potential personalized treatment option to improve their survival.

Hepatocellular Carcinoma Management in Nonalcoholic Fatty Liver Disease Patients

Background/Aims:Nonalcoholic fatty liver disease (NAFLD) has emerged as an important cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). The Barcelona Clinic Liver Cancer (BCLC) system is the preferred staging system to evaluate patients with HCC and links prognosis assessment with treatment recommendation. The aim of this retrospective study was to evaluate whether the BCLC staging system and its treatment algorithm are suitable for patients with HCC arising from NAFLD.Methods:Forty-two patients with HCC related to either to NAFLD or cryptogenic cirrhosis were retrieved retrospectively from 2 centers in Brazil. Patients were classified according to BCLC staging system. If the proposed HCC therapy could not be applied, the case was considered to represent deviations from the recommended BCLC guideline. Causes of treatment deviations were investigated.Results:There were 4 patients without evidence of cirrhosis according to liver biopsy and/or clinical evaluation. One (2%), 21 (50%), 10 (24%), 5 (12%), and 5 patients (12%) were classified initially to the very early (0), early (A), intermediate (B), advanced (C), and terminal (D) BCLC stages, respectively. Thirty-five patients (83%) were treated according to BCLC recommendations. There were 3 cases (of 5) of protocol deviation in BCLC C patients. The 1- and 2-year overall survival rates were 81% and 66%, respectively.Conclusions:The BCLC system is applied in most cases of NAFLD-related HCC cases. Deviation of BCLC is found more frequently in BCLC C stage patients.

Weight gain after orthotopic liver transplantation: is nonalcoholic fatty liver disease cirrhosis a risk factor for greater weight gain?

Posttransplant weight gain is common after orthotopic liver transplantation. We sought to determine the extent of weight gain at 5 years after transplantation in patients with nonalcoholic fatty liver disease (NAFLD) cirrhosis versus patients with other types of cirrhosis (non-NAFLD). We studied 126 liver transplants performed between 2005 and 2007 at Saint Luc Hospital, University of Montreal. Seventeen of the 126 patients (13.5%) had NAFLD cirrhosis. Ascites volume was difficult to assess, so we used the body mass index (BMI) at 3 months as the reference BMI. All patients gained weight after transplantation, but BMI increased significantly more and earlier among the NAFLD patients [4.8 versus 1.5 kg/m(2) at 1 year (P = 0.001), 5.0 versus 2.3 kg/m(2) at 2 years (P = 0.01), and 5.6 versus 2.6 kg/m(2) at 5 years (P = 0.009)] in comparison with non-NAFLD patients in unadjusted analyses. The greatest BMI increase over time was investigated with univariate and multivariate logistic regression analyses. The BMI increase was divided into tertiles for each period of time observed. The greatest BMI increase over time was defined as the top tertile of BMI increase. After adjustments for potential confounders (ie, total cholesterol, diabetes, and length of hospital stay), NAFLD was no longer associated with a risk of a greater BMI increase [odds ratio (OR) = 3.73 at 1 year (P = 0.11), OR = 2.15 at 2 years (P = 0.34), and OR = 2.87 at 5 years (P = 0.30)]. These findings suggest the need for multidisciplinary, early, and close weight monitoring for all patients. All patients could benefit from pretransplant counseling regarding weight gain and its consequences.

Clinical Predictors of Recurrent Non-Alcoholic Steatohepatitis Following Liver Transplantation for Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease (NAFLD) is expected to become the leading US indication for liver transplant (LT) in the near future. NAFLD after LT has been described in case series, heterogenous populations, and single center experiences. No study to date has described histologic recurrent non-alcoholic fatty liver disease (rNAFLD) and non-alcoholic steatohepatitis (rNASH) in LT patients undergoing annual per protocol liver biopsies. The aim of this study was to determine rNAFLD and rNASH rates and their predictive risk factors. Methods: Cohort study of deceased donor LT recipients at a single center from 4/2005-6/2012. Patients with a diagnosis of NAFLD and cryptogenic cirrhosis suspected to be NAFLD were included. Patients underwent per protocol annual liver biopsies up to 5 years from LT. Donor and recipient characteristics were explored as possible risk factors for rNAFLD and rNASH. rNASH was defined as the presence of NASH using the NASH-CRN Histologic Scoring System. General estimating equation with binomial distribution was used to analyze the repeated liver biopsies. Results: 76 patients with cirrhosis due to NAFLD underwent LT. 63 had ≥1 planned liver biopsy. 88.9% had documented NAFLD pre-LT. 11.1% were cryptogenic but clinical suspicion of NAFLD was documented. There were 173 annual protocol biopsies in this analysis: 105 biopsies from 42 patients showed rNAFLD, 17 biopsies from 11 patients showed rNASH. The cumulative rate of rNAFLD and rNASH was 66.6% and 17.5%, respectively. In multivariable analysis, risk factors for rNASH were donor BMI (p=0.0001), recipient pre-LT coronary artery disease (p=0.01), and number of years after LT (p<0.0001). Donor characteristics not predictive of rNASH include ischemic time and cause of death. Recipient characteristics not predictive of rNASH include gender, age, race, weight, BMI, immunosuppression, allograft rejection, diabetes, hepatocellular carcinoma, combined liver kidney transplant, hypertension, cholesterol, triglycerides, or HgbA1C%. Conclusion: Our study confirms high rates of rNAFLD and rNASH following LT and establishes possible risk factors for recurrence. This data supports the development of larger trials to better understand the impact of rNASH on long term LT outcomes and to explore treatments/interventions to prevent rNASH.

Simple scoring system for predicting cirrhosis in nonalcoholic fatty liver disease.

To investigate a simple noninvasive scoring system for predicting liver cirrhosis in nonalcoholic fatty liver disease (NAFLD) patients. A total of 1048 patients with liver-biopsy-confirmed NAFLD were enrolled from nine hepatology centers in Japan (stage 0, 216; stage 1, 334; stage 2, 270; stage 3, 190; stage 4, 38). The weight and height of the patients were measured using a calibrated scale after requesting the patients to remove their shoes and any heavy clothing. Venous blood samples were obtained in the morning after the patients had fasted overnight for 12 h. Laboratory evaluation was performed in all patients. Statistical analysis was conducted using SPSS version 12.0. Continuous variables were expressed as mean ± SD. The optimal cutoff value of platelet count, serum albumin, and aminotransferase/alanine aminotransferase ratio (AAR) was set at < 15.3 10(4)/μL, < 4.0 g/dL, and > 0.9, respectively, by the receiver operating characteristic curve. These three variables were combined in an unweighted sum (platelet count = 1 point, serum albumin = 1 point, AAR = 1 point) to form an easily calculated composite score for predicting cirrhosis in NAFLD patients, called the PLALA (platelet, albumin, AAR) score. The diagnosis of PLALA ≥ 2 had sufficient accuracy for detecting liver cirrhosis in NAFLD patients. The PLALA score may be an ideal scoring system for detecting cirrhosis in NAFLD patients with sufficient accuracy and simplicity to be considered for clinical use.

Hepatocarcinogenesis in non‐alcoholic fatty liver disease in Japan

In Japan, there has been a gradual increase in cases of non-viral chronic liver diseases, including non-alcoholic fatty liver disease (NAFLD), occurring with hepatocellular carcinoma (HCC). First, a national survey investigating the etiology of HCC in Japan was performed. Among HCCs based on non-viral disease, alcoholic liver disease with HCC accounted for 7.2% of all HCCs, followed by chronic liver disease of unknown etiology with HCC (5.1%) and NAFLD with HCC (2.0%). The clinical characteristics of these three HCC groups were clearly different. In our second analysis, the HCC development rates among liver cirrhosis with NAFLD, alcoholic cirrhosis, and cirrhosis with hepatitis C virus (HCV) were compared. HCC development rates were 11.3%/5 years in NAFLD cirrhosis, 30.5%/5 years in HCV cirrhosis, and 12.5%/5 years in alcoholic cirrhosis, suggesting that the hepatocarcinogenesis in NAFLD and alcoholic liver disease were similar but were lower than that in HCV. Using Cox hazards analysis, older age, higher serum γ-glutamyl transpeptidase level, and higher Child-Pugh score as risk factors of HCC were identified. Finally, clinical data of NAFLD-HCC with the data for HCC with HCV (HCV-HCC) were compared. The percentage of NAFLD-HCC patients with des-gamma-carboxy prothrombin-positive was higher than that with α-fetoprotein-positive. The 5-year survival and recurrence rates for NAFLD-HCC were almost similar to those for HCV-HCC. In Asian countries, the prevalence of NAFLD is increasing. Therefore, elucidating the pathogenesis and clinical features of HCC in patients with NAFLD is indeed an urgent problem.

Increased hepatic Chemerin and CMKLR1 gene expression in human nonalcoholic fatty liver disease

Objective: Inflammatory states of non-alcoholic fatty liver disease (NAFLD) are associated with obesity via adipocytokines. Circulating levels of the adipocytokine chemerin are in vivo associated with NAFLD and hepatic cirrhosis. However, hepatic gene transcription of chemerin and its receptor CMKLR1 are rarely studied, especially in human NAFLD.

Liver Stiffness Measurements in Patients with Different Stages of Nonalcoholic Fatty Liver Disease: Diagnostic Performance and Clinicopathological Correlation

The present study evaluated performance characteristics of liver stiffness measurement (LSM) by FibroScan in patients with different stages of nonalcoholic fatty liver disease (NAFLD). A total of 307 subjects (120 NAFLD, 85 NAFLD related cirrhosis, and 102 healthy controls) were studied. In NAFLD patients, LSM had significant correlation with fibrosis (r = 0.68, p < 0.001), and increased progressively with increasing fibrosis (p < 0.001). However, the difference between stage 1 and stage 2 fibrosis was not significant (p = 0.07). The LSM in NAFLD without fibrosis and healthy controls was similar (p = 0.37). The areas under receiver-operating characteristics (AUROC) curve of LSM for stages ≥1, ≥2, ≥3, and 4 were 0.82, 0.85, 0.94, and 0.96, respectively. The best LSM (kPa) cut-offs for fibrosis stages ≥1, ≥2, ≥3 and 4 were 6.1, 7.0, 9.0, and 11.8, respectively. The negative predictive value of LSM for excluding advanced fibrosis was 95%. For advanced fibrosis, the AUROC curve of LSM was 0.94, followed by FIB-4 (0.75), BARD score (0.68), NAFLD fibrosis score (0.66), and aspartate platelet ratio index (0.60). In multivariate analysis, LSM was the only independent predictor of advanced fibrosis (odds ratio 1.47). In patients with NAFLD cirrhosis, LSM correlated significantly with Child-Pugh score (r = 0.40, p < 0.001), serum bilirubin (r = 0.34, p = 0.02), and grades of esophageal varices (r = 0.23, p = 0.04). LSM is a useful tool for evaluation of patients with NAFLD, and is the best among other non-invasive predictors of liver fibrosis.

The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

These recommendations are based on the following: (1) a formal review and analysis of the recently published world literature on the topic [Medline search up to June 2011]; (2) the American College of Physicians’ Manual for Assessing Health Practices and Designing Practice Guidelines; (3) guideline policies of the three societies approving this document; and (4) the experience of the authors and independent reviewers with regards to NAFLD. Intended for use by physicians and allied health professionals, these recommendations suggest preferred approaches to the diagnostic, therapeutic and preventive aspects of care. They are intended to be flexible and adjustable for individual patients. Specific recommendations are evidence-based wherever possible, and when such evidence is not available or inconsistent, recommendations are made based on the consensus opinion of the authors. To best characterize the evidence cited in support of the recommendations, the AASLD Practice Guidelines Committee has adopted the classification used by the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) workgroup with minor modifications (Table 1). The strength of recommendations in the GRADE system is classified as strong (1) or weak (2). The quality of evidence supporting strong or weak recommendations is designated by one of three levels: high (A), moderate (B) or low-quality (C). This is a practice guideline for clinicians rather than a review article and interested readers can refer to several comprehensive reviews published recently.

The Influence of Nonalcoholic Fatty Liver Disease and Its Associated Comorbidities on Liver Transplant Outcomes

To define the influence of nonalcoholic fatty liver disease (NAFLD) and its associated comorbidities on liver transplant outcomes. NAFLD cirrhosis is an increasing indication for transplant. The transplant outcomes of NAFLD patients with metabolic syndrome comorbidities remain unclear. We examined a single center, retrospective cohort between 2004 and 2007 to determine transplant mortality for NAFLD and non-NAFLD patients accounting for the possible independent effects of diabetes, hypertension, obesity, and hyperlipidemia. The primary outcomes were 30-day, 1-year, and 3-year all-cause mortality. Cox proportional hazard ratios were determined controlling for various recipient and donor covariates. In our study, of 118 liver transplants, 18% were performed for NAFLD cirrhosis. Adjusted hazard ratios for death for NAFLD compared with non-NAFLD patients at 30 days, 1 year, and 3 years were 8.96 (1.06, 75.8), 1.49 (0.38, 5.81), and 1.05 (0.29, 3.78), respectively. Compared with nondiabetic patients, diabetic patients had hazard ratios at 30 days, 1 year, and 3 years of 2.02 (0.31, 12.9), 2.82 (0.94, 8.47), 3.58 (1.32, 9.71), respectively. Obesity, hypertension, and hyperlipidemia did not have a significant impact on posttransplant mortality. We conclude that NAFLD increases 30-day transplant mortality whereas diabetes increases 3-year mortality. Future work should determine the strategies to decrease perioperative mortality among NAFLD patients and ways to improve long-term transplant survival among diabetics.

End-stage nonalcoholic fatty liver disease: evaluation of pathomorphologic features and relationship to cryptogenic cirrhosis from study of explant livers in a living donor liver transplant program

In a proportion of liver cirrhosis, the etiology continues to remain elusive. It is uncertain whether and to what extent cirrhosis evolving from nonalcoholic fatty liver disease contributes to this group of cryptogenic cirrhosis because the clinicopathologic features of nonalcoholic fatty liver disease cirrhosis are largely unknown. We explored these facets by examining the explant livers and clinical data in living donor liver transplant recipients. Among 103 adult liver transplant recipients with different types of chronic liver disease, 30 had a pre-liver transplant diagnosis of cryptogenic cirrhosis. A final categorization of the native liver disease was attempted in these cases on the basis of detail pathomorphological findings in adequately sampled explant liver correlated with careful review of pre-liver transplant clinical data. Of the 30 cryptogenic cirrhosis cases, 19 (63.3%) finally labeled as nonalcoholic fatty liver disease cirrhosis showed histologic features in several respects different from those reported for the early and established phases of nonalcoholic fatty liver disease. Steatosis was infrequent and focal or even absent, whereas variable grades of Mallory hyaline and inflammation were consistently present. Ductular proliferation and hydropic change of hepatocytes were also frequent. Only 9 (47%) of the 19 cases had nonalcoholic fatty liver disease associated risk factors like diabetes and obesity. It was concluded that appreciation of quantitative and qualitative differences in hepatic morphology between the cirrhotic and the early/established stage of nonalcoholic fatty liver disease will help in making a correct diagnosis of nonalcoholic fatty liver disease cirrhosis in the proper clinical setting. When appropriate criteria are used, nonalcoholic fatty liver disease appears to account for close to two thirds of cases currently labeled as cryptogenic cirrhosis.

Serum adipokine profile in Indian men with nonalcoholic steatohepatitis: Serum adiponectin is paradoxically decreased in lean vs. obese patients

Background Asian Indians are known to be more insulin resistant for the same degree of weight gain. It is therefore likely that the adipokine profile in nonalcoholic fatty liver disease (NAFLD) in Asian Indian population could be different from the Western subjects. Aims To study the serum adiponectin, resistin, leptin and TNF-α profile in NAFLD and cryptogenic cirrhosis patients. Subjects and methods Body mass indices, insulin resistance and serum adipokine levels were studied in 56 patients; 10 with fatty liver, 30 with nonalcoholic steatohepatitis (NASH) and 16 with cryptogenic cirrhosis. Eighteen healthy controls were also included. Results Patients in general were obese compared to controls (mean BMI 26.9 ± 4.5 vs. 22.6 ± 2.5, respectively, p < 0.0001). In patients with NASH, adiponectin levels were lower than controls (5.4 ± 3 μg/ml vs.7.2 ± 2.9 μg/ml, p = 0.037). Insulin Resistance as assessed by homeostasis model assessment (HOMA) was higher in obese than lean, NAFLD patients (HOMA IR obese, median = 2.8, range = 0.8–16.3 and lean: median = 1.05, range = 0.51–2.75, p = 0.003). Lean NAFLD patients had adiponectin levels lower than obese patients (3 ± 1 μg/ml vs.6.7 ± 3.8 μg/ml respectively, p = 0.003). Serum resistin levels were higher in NAFLD patients (3.7 ± 3 ng/ml) than controls (2.1 ± 1.7 ng/ml, p = 0.007). This difference was significant even when cirrhotic patients were excluded (3.4 ± 2.7 ng/ml, p = 0.036). Serum leptin levels were raised in cryptogentic cirrhosis compared to NASH ( p = 0.03). All adipokines tested were raised in cirrhotic patients compared to NAFLD and controls. Conclusions A significant reduction in serum adiponectin and increase in serum resistin levels were observed in NAFLD patients, more so in lean than obese NAFLD. This paradoxical decrease of serum adiponectin as well as low frequency of insulin resistance in lean NAFLD suggests a possible different etiology for this subset of patients.

Hedgehog-Mediated Epithelial-to-Mesenchymal Transition and Fibrogenic Repair in Nonalcoholic Fatty Liver Disease

Repair responses define the ultimate outcomes of liver disease. This study evaluated the hypothesis that fibrogenic repair in nonalcoholic fatty liver disease (NAFLD) is mediated by Hedgehog (Hh) pathway activation and consequent induction of epithelial-to-mesenchymal transitions (EMT) in ductular-type progenitors. Immature ductular cells were exposed to Sonic hedgehog (Shh) in the presence or absence of the Hh inhibitor cyclopamine to determine whether Hh-pathway activation directly modulates EMT in liver progenitors. Potential biologic correlates of progenitor cell EMT were assessed using mice fed methionine-choline-deficient + ethionine (MCDE) diets with or without cyclopamine. The effects of increased Hh signaling on EMT and fibrogenic repair during diet-induced NAFLD were also compared in wild-type (WT) and Patched haplo-insufficient (Ptc(+/-)) mice. Finally, evidence of Hh-pathway activation and EMT was examined in liver sections from patients with NAFLD. In cultured progenitors, Shh repressed expression of epithelial genes and EMT inhibitors but induced genes that are expressed by myofibroblasts. Cyclopamine reversed these effects. In mouse NAFLD models, Hh-pathway activation, EMT, expansion of myofibroblastic populations, and liver fibrosis occurred. Cyclopamine inhibited Hh-pathway activation and induction of EMT. Ptc(+/-) mice, which have an overactive Hh pathway, exhibited sustained overinduction of Hh target genes and more EMT, myofibroblast accumulation, and fibrosis than WT mice. Numbers of Shh-producing cells and Hh-responsive ductular cells that expressed EMT markers increased in parallel with liver fibrosis in patients with NAFLD. Hh-mediated EMT in ductular cells contributes to the pathogenesis of cirrhosis in NAFLD.

Health‐related quality of life in patients with non‐alcoholic fatty liver disease

The relative impact of non-alcoholic fatty liver disease (NAFLD) on health-related quality of life (HRQL) compared to other chronic liver diseases has not been fully explored. To compare the domain scores of the 29-item Chronic Liver Disease Questionnaire (CLDQ) for patients with NAFLD to those with chronic hepatitis B and chronic hepatitis C. A HRQL questionnaire, CLDQ, was routinely administered to patients attending a liver clinic. Additional clinical and laboratory data were obtained on patients with NAFLD, chronic hepatitis B, and chronic hepatitis C from our quality of life database. Scores for each of the six CLDQ domains were compared using one-way anova and multiple regression. Complete data were available for 237 patients. NAFLD patients scored lowest on multiple CLDQ domains. Based on the bivariate data, NAFLD patients have the poorest HRQL, followed by chronic hepatitis C and chronic hepatitis B patients. Multivariate analysis showed that some specific domain score correlations remained significant for NAFLD diagnosis, cirrhosis, gender, and body mass index. NAFLD patients had significantly lower quality of life scores compared with patients with hepatitis B or hepatitis C on multiple CLDQ domains, suggesting that HRQL was severely impaired in patients with NAFLD.

Familial Aggregation of Insulin Resistance in First-Degree Relatives of Patients With Nonalcoholic Fatty Liver Disease

An association between nonalcoholic fatty liver disease (NAFLD) and the insulin resistance (IR) syndrome exists. Familial clustering of IR may support a genetic predisposition to NAFLD or cryptogenic cirrhosis (CC). Patients with NAFLD (n = 20) and healthy controls (n = 20) matched for age, sex, and body mass index with at least 4 living relatives and 2 generations of lineage participated in a familial aggregation study. A medical history was obtained from each subject and confirmed with first-degree family members. NAFLD patients were more likely to have cirrhosis (odds ratio [OR] = 12.0), cardiac disease (OR, 3.0), hyperlipidemia (OR, 12.1), diabetes mellitus (DM) (OR, 9.1), renal stones (OR, 4.1), and arthritis (OR, 6.1). IR (P = .042) (the primary dependent variable) and DM (P = .013) were noted in their first-degree relatives. A trend for familial clustering of NAFLD or CC (P = .059) with a maternal linkage for disease expression also may exist. Cholelithiasis (P = .047), presumed NAFLD and/or CC (P = .049), and a trend toward IR (P = .07) were noted in the mothers, but not the fathers, of patients with NAFLD. An increased risk of DM (OR, 4.2; 95% confidence interval, 1.26-18.7; P = .013), IR (OR, 2.86; 95% confidence interval, 1.02-9.38; P = .042), and smoking (OR, 3.41; 95% confidence interval, 1.43-9.07; P = .003) was observed in first-degree relatives of NAFLD patients. No significant survival difference was observed between family cohorts. Familial clustering and a potential maternal linkage for IR support a genetic predisposition for NAFLD. Alternatively, the presence of suppressor genes modifying the expression of IR in paternal lineage warrants further investigation.

Advances in the understanding and treatment of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a well recognised form of chronic liver disease that has recently gained greater recognition. Originally described in the late 1950s, NAFLD is currently considered the leading cause of abnormal liver enzyme levels in the US, closely paralleling the increase in obesity and diabetes mellitus. NAFLD has a worldwide distribution, affecting both adults and children, and typically is seen in association with obesity, diabetes, hypertension and hypertriglyceridaemia. Most patients are asymptomatic and usually present with mild elevations in aminotransferases. The natural history of NAFLD is not clearly defined but progression to cirrhosis and end-stage liver disease is well recognised in some patients. The accumulation of hepatic steatosis is thought to occur initially, primarily through hepatic and peripheral insulin resistance, which leads to altered glucose and free fatty acid metabolism. The progression from simple fatty liver to more severe forms of NAFLD (nonalcoholic steatohepatitis and cirrhosis) is much less clear but evidence suggests that oxidative stress may preferentially enhance proinflammatory cytokines, which leads to cellular adaptations and dysfunction followed by development of inflammation, necrosis and fibrosis. Therapeutic modalities remain limited and are largely focused on correcting the underlying insulin resistance or reducing oxidative stress. However, at the present time, there are several limitations to the current potential therapies, mainly because of the lack of large-scale, prospective, randomised studies, as well as clearly defined histological endpoints. Ultimately, the future for potential therapeutic modalities to treat this disease are quite promising, but further research is needed to clearly demonstrate which therapy or therapies will be effective at eliminating fatty liver disease and its potential complications.