Non-alcoholic Fatty Liver Disease Cirrhosis Research Articles

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis

ObjectiveHomozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants...

Differentially methylated loci in NAFLD cirrhosis are associated with key signaling pathways

Altered DNA methylation events contribute to the pathogenesis and progression of metabolic disorders, including nonalcoholic fatty liver disease (NAFLD). Investigations of global DNA methylation patterns in liver biopsies representing severe NAFLD fibrosis have been limited. We used the HumanMethylation 450K BeadChip to analyze genome-wide methylation in patients with biopsy-proven grade 3/4 NAFLD fibrosis/cirrhosis (N = 14) and age- and sex-matched controls with normal histology (N = 15). We identified 208 CpG islands (CGIs), including 99 hypomethylated and 109 hypermethylated CGIs, showing statistically significant evidence (adjusted P value < 0.05) for differential methylation between cirrhotic and normal samples. Comparison of β values for each CGI to the read count of its corresponding gene obtained from RNA-sequencing analysis revealed negative correlation (adjusted P value < 0.05) for 34 transcripts. These findings provide supporting evidence for a role for CpG methylation in the pathogenesis of NAFLD-related cirrhosis, including confirmation of previously reported differentially methylated CGIs, and contribute new insight into the molecular mechanisms underlying the initiation and progression of liver fibrosis and cirrhosis.

Nonalcoholic Fatty Liver Disease Cirrhosis: A Review of Its Epidemiology, Risk Factors, Clinical Presentation, Diagnosis, Management, and Prognosis.

Cirrhosis is the common end stage of a number of chronic liver conditions and a significant cause of morbidity and mortality. With the growing epidemic of obesity and metabolic syndrome, nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease worldwide and will become one of the leading causes of cirrhosis. Increased awareness and understanding of NAFLD cirrhosis are essential. To date, there has been no published systematic review on NAFLD cirrhosis. Thus, this article reviews recent studies on the epidemiology, risk factors, clinical presentation, diagnosis, management, and prognosis of NAFLD cirrhosis.

Non-invasive prediction of esophageal varices by stiffness and platelet in non-alcoholic fatty liver disease cirrhosis

Baveno VI and expanded Baveno VI criteria can avoid the need for esophagogastroduodenoscopy (EGD) to screen for varices needing treatment (VNT) in a substantial proportion of compensated patients with viral and/or alcoholic cirrhosis. This multicenter, cross-sectional study aims to validate these criteria in patients with compensated cirrhosis due to non-alcoholic fatty liver disease (NAFLD), accounting for possible differences in liver stiffness measurement (LSM) values between M and XL probes. We assessed 790 patients with NAFLD-related compensated cirrhosis who had EGD within six months of a reliable LSM, measured by FibroScan® using M and/or XL probe. Baveno VI and expanded Baveno VI criteria were tested. The main variable used to optimize criteria was the percentage of endoscopies spared, keeping the risk of missing large VNT below a 5% threshold. LSM was measured by both M and XL probes (training set) in 314 patients, while only M or XL probe (validation sets) were used to measure LSM in 338 and 138 patients, respectively. In the training set, use of Baveno VI and expanded Baveno VI criteria reduced the number of EGD by 33.3% and by 58%, with 0.9% and 3.8% of large esophageal varices missed, respectively. The best thresholds to rule-out VNT were identified as platelet count >110,000/mm3 and LSM <30 kPa for M probe, and platelet count >110,000/mm3 and LSM <25 kPa for XL probe (NAFLD cirrhosis criteria). Thus, usage of NAFLD cirrhosis criteria would have led to an absolute reduction in the number of EGD screened patients of 34.7% and 10.5% with respect to Baveno VI and expanded Baveno VI criteria, respectively. The new NAFLD cirrhosis criteria, established for the FibroScan probe, can reduce the use of EGD for screening of VNT in NAFLD cirrhosis by more than half, with a chance of missing VNT below 5%. In non-alcoholic fatty liver disease-related compensated cirrhosis, the expanded Baveno VI criteria work better than the Baveno VI criteria for ruling out the presence of varices needing treatment, sparing unnecessary and invasive screening procedures. New diagnostic criteria for this patient group, based on liver stiffness measurement and platelet count, and optimized for the specific FibroScan® probe used, work better than both Baveno VI and expanded Baveno VI criteria. The accuracy of all non-invasive scoring criteria was lower in non-obese patients.

Liver disease symptoms in non-alcoholic fatty liver disease and small intestinal bacterial overgrowth.

It seems that there is a relationship between small intestinal bacterial overgrowth (SIBO) and non-alcoholic fatty liver disease (NAFLD). The main objective of this study was to evaluate the prevalence of SIBO among NAFLD patients. In this descriptive-analytical cross-sectional study, 98 eligible NAFLD patients were evaluated for SIBO using hydrogen breath test (HBT). They were divided into SIBO-positive and SIBO-negative groups. Demographic, clinical, and laboratory data were obtained. Based on the HBT, 38 patients (39%) had bacteria overgrowth. There were no significant differences between SIBO-positive and SIBO-negative regarding demographic data and BMI classification (P > 0.05). Biochemical variables, the results of abdominal ultrasound, and liver elastography did not show any significant difference between SIBO-positive and SIBO-negative patients (P > 0.05). Patients with SIBO were found to have higher rates of bloating, while abdominal pain was more prevalent in SIBO-negative patients (P < 0.001). SIBO is prevalent in NAFLD and associated with bloating in these patients. Further studies are necessary to elucidate if therapeutic manipulation of gut microbiota reduces the risk of NAFLD, fibrosis, and liver cirrhosis.

Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study

Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n= 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. During a mean follow-up time of 5.5 years (range, 2.7-8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%-99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%-89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%-29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%-60% vs 6%, 95% CI, 2%-13%) or hepatocellular carcinoma (17%; 95% CI, 8%-31% vs 2.3%, 95% CI, 1%-12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%-18%) than cirrhosis (2%; 95% CI, 0%-6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%-23%) than cirrhosis (6%; 95% CI, 2%-15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcoholconsumption was associated with these outcomes onlyin patients with cirrhosis. Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events.

Current Prevention and Treatment Options for NAFLD.

Non-alcoholic fatty liver disease (NAFLD) is now the most common chronic liver disease worldwide and the second leading indication for liver transplantation and the third leading cause of hepatocellular carcinoma (HCC) in the United States. This chapter focuses on the prevention and management of NAFLD. Healthy lifestyle is the cornerstone for the prevention and management of NAFLD and should be recommended to every patient at risk or having established NAFLD. Despite the high prevalence of NAFLD, it should be recognized that the majority of patients will not develop liver-related complications; cardiovascular disease remains the leading cause of death in NAFLD patients. Until further data are available, pharmacological treatment should be restricted to selected patients with confirmed non-alcoholic steatohepatitis. As some agents with primarily anti-fibrotic effect are currently being tested in NAFLD patients, significant fibrosis and cirrhosis may become additional indications for treatment in the future. Because of the surgical morbidity, currently bariatric surgery should only be performed in patients with morbid obesity, although the long-term impact of bariatric surgery on the histology of NAFLD is favorable.

Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma.

Non-alcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) incidence is increasing worldwide, paralleling the obesity epidemic. Although most cases are associated with cirrhosis, HCC can occur without cirrhosis in NAFLD. Diabetes and obesity are associated risk factors for HCC in patients. Given the sheer magnitude of the underlying risk factors (diabetes, obesity, non-cirrhotic NAFLD) screening for HCC in the non-cirrhotic population is not recommended. Optimal screening strategies in NAFLD cirrhosis are not completely elucidated with Ultrasound having significant limitations in detection of liver lesions in the presence of obesity and steatosis. Consequently NAFLD-HCC is more often diagnosed at a later stage with larger tumors and reduced opportunities for curative treatments as opposed to HCC in other causes of cirrhosis. When HCC is found at a curative stage treatments including liver transplantation, resection and loco-regional therapies are associated with good results similar to that seen in HCV-HCC. Future strategies under study include the use of chemopreventive and antioxidant agents to reduce development of cirrhosis and non-alcoholic steatohepatitis (NASH). Strategies to reverse NASH via weight loss, control of associated conditions like diabetes are key strategies in reducing the increasing incidence of NASH-HCC. Novel therapeutic agents for NASH are in trials and if successful in achieving reversal of NASH will be an important strategy in reducing NAFLD-HCC.

Risk factors for biopsy-proven advanced non-alcoholic fatty liver disease in the Veterans Health Administration.

With its increasing incidence, nonalcoholic fatty liver disease (NAFLD) is of particular concern in the Veterans Health Administration (VHA). To evaluate risk factors for advanced fibrosis in biopsy-proven NAFLD in the VHA, to identify patients at risk for adverse outcomes. In randomly selected cases from VHA databases (2005-2015), we performed a retrospective case-control study in adults with biopsy-defined NAFLD or normal liver. Of 2091 patients reviewed, 399 met inclusion criteria. Normal controls (n=65) had normal liver function. The four NAFLD cohorts included: NAFL steatosis (n=76), nonalcoholic steatohepatitis (NASH) without fibrosis (n=68), NAFLD/NASH stage 1-3 fibrosis (n=82), and NAFLD/NASH cirrhosis (n=70). NAFLD with hepatocellular carcinoma (HCC) was separately identified (n=38). Most patients were older White men. NAFLD patients with any fibrosis were on average severely obese (BMI>35kg/m2 ). Diabetes (54.4%-79.6%) and hypertension (85.8%-100%) were more common in NAFLD with fibrosis or HCC. Across NAFLD, 12.3%-19.5% were enrolled in diet/exercise programs and 0%-2.6% had bariatric surgery. Hispanics exhibited higher rates of NASH (20.6%), while Blacks had low NAFLD rates (1.4%-11.8%), particularly NAFLD cirrhosis and HCC (1.4%-2.6%). Diabetes (OR 11.8, P<.001) and BMI (OR 1.4, P<.001) were the most significant predictors of advanced fibrosis. In the VHA, diabetes and severe obesity increased risk for advanced fibrosis in NAFLD. Of these patients, only a small proportion (~20%) had enrolled in diet/exercise programs or had bariatric surgery (~2%). These results suggest that providers should focus/tailor interventions to improve outcomes, particularly in those with diabetes and severe obesity.

Nonalcoholic fatty liver disease-related cirrhosis is commonly unrecognized and associated with hepatocellular carcinoma.

Determination of cirrhosis in nonalcoholic fatty liver disease (NAFLD) is important as it alters prognosis and management. We aimed to examine whether cirrhosis was diagnosed incidentally or intentionally in patients with NAFLD. We reviewed 100 patients with NAFLD cirrhosis to determine mode of cirrhosis diagnosis (incidental or by intent), severity of liver disease at diagnosis, diagnostician, and previous clinical imaging or laboratory evidence of unrecognized cirrhosis. The majority (66/100) of patients with NAFLD cirrhosis were diagnosed incidentally, with the majority of these (74%) diagnosed with NAFLD simultaneously. Those with incidental cirrhosis diagnoses had more deranged platelet and international normalized ratio levels (P < 0.05) and were more likely to have concomitant hepatocellular carcinoma (HCC) (12% versus 0%, P < 0.05). Incidental cirrhosis was diagnosed following imaging (32%) or liver tests (26%) performed for reasons unrelated to liver disease, following unexpected endoscopic finding of varices (21%) or an unexpected surgical finding (14%). Diagnoses by intent were predominantly made by gastroenterologists/hepatologists, whereas general practitioners, surgeons, and physicians tended to diagnose cirrhosis incidentally (P < 0.001). The majority of patients diagnosed incidentally (n = 48/66, 73%) had previous thrombocytopenia, splenomegaly, or high noninvasive fibrosis scores. Following diagnosis, patients diagnosed incidentally were less likely to undergo HCC screening. Conclusion: The majority of patients with NAFLD cirrhosis are diagnosed incidentally. These patients are more likely to have advanced liver disease and HCC. Increased awareness of screening for cirrhosis is needed in patients with NAFLD. (Hepatology Communications 2017;1:53–60)

Hepatology Clinical.

Hepatology Clinical.

Liver Transplantation for Nonalcoholic Fatty Liver Disease: Role of Bariatric Surgery for Comorbid Obesity

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent form of chronic liver disease throughout the world and is associated with substantial morbidity and mortality related to liver disease and the consequences of metabolic syndrome. NAFLD is projected to become the leading indication for liver transplantation in the United States in the near future, and presents unique challenges due to common comorbidities, particularly obesity. As obesity is often a barrier to transplant, distinctive decision-making and care is needed for this growing population. Bariatric surgery offers a promising option for liver transplant specialists to consider in obese patients with NAFLD cirrhosis. This research highlight reviews the rising burden of NAFLD, concerns regarding obesity and liver transplant, and the potential role of bariatric surgery in the liver transplantation paradigm.

Nonalcoholic Fatty Liver Disease: Key Considerations Before and After Liver Transplantation.

Nonalcoholic fatty liver disease (NAFLD) is the most common etiology of chronic liver disease in developed countries and is on trajectory to become the leading indication for liver transplantation in the USA and much of the world. Patients with NAFLD cirrhosis awaiting liver transplant face unique challenges and increased risk for waiting list stagnation and dropout due to burdensome comorbidities including obesity, diabetes, cardiovascular disease, and kidney disease. Thus far, patients transplanted for NAFLD cirrhosis have excellent mid- and long-term patient and graft survival, but concerns regarding short-term morbidity and mortality continue to exist. Post-liver transplantation, NAFLD occurs as both a recurrent and de novo manifestation, each with unique outcomes. NAFLD in the donor population is of concern given the growing demand for liver transplantation and mounting pressure to expand the donor pool. This review addresses key issues surrounding NAFLD as an indication for transplantation, including its increasing prevalence, unique patient demographics, outcomes related to liver transplantation, development of post-liver transplantation NAFLD, and NAFLD in the liver donor population. It also highlights exciting areas where further research is needed, such as the role of bariatric surgery and preconditioning of marginal donor grafts.

Hepatocellular carcinoma in patients with non-alcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the United States and represents an increasingly important etiology of hepatocellular carcinoma (HCC) with annual cumulative incidence rates ranging from 2% to 12% in cohorts of NAFLD cirrhosis. While the risk of progression of NAFLD to HCC remains higher among patients with fibrosis or cirrhosis, an increasing amount of literature describes NAFLD-HCC as a disease that can occur in the absence of cirrhosis. Efforts to characterize the pathogenesis of NAFLD-HCC have suggested mechanisms that strongly associate with states of hyperinsulinemia and chronic inflammation, cellular mechanisms including adaptive immune responses and hepatic progenitor cell populations, and genetic polymorphisms including mutations of PNPLA3. Current literature describes NAFLD-HCC mostly as a disease of late presentation with lower rates of receipt of curative therapy and worse prognosis. However, a growing body of evidence has reported comparable and potentially more favorable disease-free and overall survival rates among patients with NAFLD-HCC after receipt of curative treatment. This review summarizes current evidence of epidemiology, pathophysiology, disease presentation, demand and receipt of curative therapy, post-treatment outcomes, and overall survival of NAFLD-associated HCC.

Does Lysosomial Acid Lipase Reduction Play a Role in Adult Non-Alcoholic Fatty Liver Disease?

Lysosomal Acid Lipase (LAL) is a key enzyme involved in lipid metabolism, responsible for hydrolysing the cholesteryl esters and triglycerides. Wolman Disease represents the early onset phenotype of LAL deficiency rapidly leading to death. Cholesterol Ester Storage Disease is a late onset phenotype that occurs with fatty liver, elevated aminotransferase levels, hepatomegaly and dyslipidaemia, the latter characterized by elevated LDL-C and low HDL-C. The natural history and the clinical manifestations of the LAL deficiency in adults are not well defined, and the diagnosis is often incidental. LAL deficiency has been suggested as an under-recognized cause of dyslipidaemia and fatty liver. Therefore, LAL activity may be reduced also in non-obese patients presenting non-alcoholic fatty liver disease (NAFLD), unexplained persistently elevated liver transaminases or with elevation in LDL cholesterol. In these patients, it could be indicated to test LAL activity. So far, very few studies have been performed to assess LAL activity in representative samples of normal subjects or patients with NAFLD. Moreover, no large study has been carried out in adult subjects with NAFLD or cryptogenic cirrhosis.

A Review of Non-Alcoholic Fatty Liver Disease: From Obesity to Liver Transplant

Non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly common etiology of liver disease in the United States. As the prevalence of diabetes and obesity continues to increase, it will soon surpass hepatitis C as the most common etiology of end stage liver disease in the western world. NAFLD like many liver diseases can progress to cirrhosis, and patients often suffer morbidity secondary to the complications of portal hypertension. The exact percentage of hepatocellular carcinoma (HCC) that occurs in NAFLD patients is unknown, however, unlike many other liver diseases there is small potential for development of HCC independent of cirrhosis. Various conservative and pharmacologic therapies have been studied with varying degrees of efficacy including lifestyle modifications, bile acids, insulin sensitizers, vitamin E, and bariatric surgery. However, the only curative treatment for NAFLD cirrhosis is liver transplant. As the epidemic that is NAFLD continues to grow, more studies will need to be done to develop new therapies and curative treatments.

A Review of Non-Alcoholic Fatty Liver Disease: From Obesity to Liver Transplant

Non-alcoholic fatty liver disease (NAFLD) is becoming an increasingly common etiology of liver disease in the United States. As the prevalence of diabetes and obesity continues to increase, it will soon surpass hepatitis C as the most common etiology of end stage liver disease in the western world. NAFLD like many liver diseases can progress to cirrhosis, and patients often suffer morbidity secondary to the complications of portal hypertension. The exact percentage of hepatocellular carcinoma (HCC) that occurs in NAFLD patients is unknown, however, unlike many other liver diseases there is small potential for development of HCC independent of cirrhosis. Various conservative and pharmacologic therapies have been studied with varying degrees of efficacy including lifestyle modifications, bile acids, insulin sensitizers, vitamin E, and bariatric surgery. However, the only curative treatment for NAFLD cirrhosis is liver transplant. As the epidemic that is NAFLD continues to grow, more studies will need to be done to develop new therapies and curative treatments.

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.