Non-cirrhotic Non-alcoholic Fatty Liver Disease Research Articles

Portal Hypertension in NASH: Is It Different from Other Aetiologies?

In non-alcoholic fatty liver disease (NAFLD), an increased portal pressure is observed before signs of cirrhosis or even inflammation or fibrosis are histologically present. This review describes the differences between the mechanisms of cirrhotic portal hypertension (PHT) and PHT in non-cirrhotic NAFLD. The increased portal pressure in NAFLD is primarily a result of an increased intrahepatic vascular resistance. Vasodilation is decreased by endothelial dysfunction and the sensitivity to vasoconstrictors is increased. Furthermore, the activation of hepatic stellate cells and the presence of microvascular thrombosis could also be involved in the pathogenesis of PHT in NAFLD. Although the increased portal pressure in early NAFLD is not considered clinically significant PHT, it might play a role in the pathophysiology of NAFLD. Due to the increased intrahepatic vascular resistance, the hepatic blood flow is impaired and hence the oxygen delivery is decreased, potentially triggering transition to steatohepatitis. The underlying mechanisms of these alterations therefore represent promising targets for pharmacological treatment.

Predictors of advanced fibrosis in non-cirrhotic non-alcoholic fatty liver disease in Germany.

Advanced fibrosis has been established as the most important predictor of overall mortality in patients with non-alcoholic fatty liver disease (NAFLD). In contrast to cirrhosis, advanced, non-cirrhotic NAFLD is difficult to identify and data from Germany are lacking. To identify clinical factors associated with advanced, non-cirrhotic fibrosis. Patients were recruited in the prospectively enrolling European NAFLD Registry. Clinical characteristics and the performance of non-invasive surrogate scores compared with vibration-controlled transient elastography are reported. Two hundred and sixty-one patients with non-cirrhotic NAFLD on liver biopsy (mean age 51years, equal sex distribution) were included. The prevalence of stage 3 fibrosis on liver biopsy was 15.7%. These patients were significantly older (57 vs 50years, P<0.01), had a higher body mass index (32.3 vs 30.5, P<0.05), and more frequent arterial hypertension (78% vs 50%, P=0.001) and type 2 diabetes (61% vs 24.1%, P<0.001). On multivariate logistic regression, diabetes (OR=4.68, 95% CI 2.17-10.10) and hypertension (OR=2.91, 95% CI 1.12-7.18) were independent predictors of advanced fibrosis. Comedication included metformin in 50% and insulin in 33% of patients with diabetes. Despite the presence of cardiovascular risk factors, the use of statins was low. Liver stiffness measurement identified advanced fibrosis with an AUROC of 0.81 (95% CI 0.72-0.91). The performance of NAFLD fibrosis score, Fibrosis-4, and AST to platelet ratio index were lower with AUCs of 0.74, 0.71, and 0.67, respectively. The prevalence of metabolic comorbidities in a German population with non-cirrhotic biopsy-proven NAFLD is high. While the examined scores exhibit an acceptable specificity, liver stiffness measurement appeared to be superior to blood-based non-invasive surrogate scores in ruling out advanced fibrosis.

Non-alcoholic fatty liver disease-associated hepatocellular carcinoma: effect of hepatic steatosis on major hepatocellular carcinoma features at MRI.

To evaluate the effect of hepatic steatosis on LI-RADS® major features at MRI in patients with non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC). HCC and liver parenchyma features at MRI from 48 consecutive patients with NAFLD and histology proven HCC (mean ± SD; 4.5 ± 3.4 cm) were independently reviewed by three radiologists. Inter-rater agreement was determined by prevalence/bias-adjusted kappa. Hepatic fat signal fraction (FS%) was independently calculated. HCC features were compared by FS% at MRI using logistic regression analysis and histologic steatosis grade using Cochran-Armitage test for trend, stratified by cirrhotic liver morphology or histologic fibrosis stage. Receiver operating characteristic curves were generated to determine the sensitivity and specificity for major HCC features by FS%. Major HCC features included arterial phase hyperenhancement (APHE) in 45 (93%), portal venous phase washout (PVWO) in 30 (63%), delayed phase washout (DPWO) in 38 (79%) and enhancing "capsule" in 34 (71%). Cirrhotic morphology was present in 22 (46%). Inter-rater agreement was 0.75 for APHE, 0.42-0.58 for PVWO, 0.58-0.71 for DPWO and 0.38-0.67 for enhancing "capsule". There was an 18%, 14% and 22% increase in the odds of absent PVWO, DPWO and capsule appearance for every 1% increase in hepatic FS% in patients with non-cirrhotic liver morphology (p = 0.011, 0.040 and 0.029, respectively). Hepatic FS% ≥ 14.8% had a sensitivity and specificity of 64 and 100% for absent PVWO and 71 and 90% for absent DPWO in patients with non-cirrhotic liver morphology. Absent washout and capsule appearance are associated with increasing hepatic steatosis in patients with non-cirrhotic, NAFLD-associated HCC. In patients with non-cirrhotic, non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC), absent HCC washout and capsule appearance are associated with increasing hepatic steatosis, thereby potentially impacting the noninvasive imaging diagnosis of HCC in these patients. Lack of washout or capsule appearance in steatotic livers at MRI may require alternative criteria for the diagnosis of HCC in patients with non-cirrhotic NAFLD.

Epidemiology of non-alcoholic fatty liver disease-related hepatocellular carcinoma and its implications.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and the second leading cause of cancer‐related mortality worldwide. Non‐alcoholic fatty liver disease (NAFLD) encompasses a spectrum of liver pathology that is characterized by the excessive accumulation of fat in the liver attributable to overnutrition and is strongly associated with the metabolic syndrome. Non‐alcoholic steatohepatitis is the more severe form of NAFLD that is defined histologically by the presence of lobular inflammation and hepatocyte ballooning. Non‐alcoholic steatohepatitis patients have a greater tendency to develop advanced liver fibrosis, cirrhosis, and HCC. This review focuses on the epidemiology of NAFLD‐related HCC and its implications. NAFLD has been estimated to contribute to 10–12% of HCC cases in Western populations and 1–6% of HCC cases in Asian populations. NAFLD‐related HCC is expected to increase in Asian populations, in line with the increased prevalence of NALFD similar to that of Western populations in recent years. The increasing burden of NAFLD‐related HCC over time has been demonstrated in studies from both Western and Asian populations. Certain factors such as ethnicity, obesity, and diabetes mellitus appear to have an incremental effect on the risk of developing HCC among NAFLD patients. The difficulty in identifying NAFLD patients with cirrhosis and the possibility of HCC developing in noncirrhotic NAFLD patients are challenges that need to be addressed. Further understanding of these gaps may contribute to better surveillance strategies for the early detection of HCC in NAFLD patients to reduce the mortality and improve the survival of these patients.

Steatohepatitic Variant of Hepatocellular Carcinoma: A Focused Review.

The incidence of hepatocellular carcinoma (HCC) has steadily increased over the past three decades and currently ranks as the fifth most common cancer worldwide. Likewise, non-alcoholic fatty liver disease (NAFLD), a known risk factor for the development of HCC, has emerged as the most common liver disease in Western countries. The underlying pathogenesis of NAFLD-related HCC remains unclear. The steatohepatitic variant of HCC (SH-HCC) typically presents in patients with metabolic risk factors and either cirrhotic or non-cirrhotic NAFLD and shares many of the histological features found in non-alcoholic steatohepatitis (NASH). Given their similar morphological features, distinguishing SH-HCC from background fatty liver can be a diagnostic challenge. Immunohistochemical studies to characterize and assist in the diagnosis are relatively limited. Whether the steatotic phenotype of SH-HCC results from the tumor’s adaptive response to an environment rich in fatty acids or from an independent pathogenic pathway remains to be seen. This review aims to summarize what is currently known regarding the pathogenesis and clinicopathological features of SH-HCC.

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.

Specificities of Human Hepatocellular Carcinoma Developed on Non-Alcoholic Fatty Liver Disease in Absence of Cirrhosis Revealed by Tissue Extracts ¹H-NMR Spectroscopy.

There is a rising incidence of non-alcoholic fatty liver disease (NAFLD) as well as of the frequency of Hepato-Cellular Carcinoma (HCC) associated with NAFLD. To seek for putative metabolic pathways specific of the NAFLD etiology, we performed comparative metabolomics between HCC associated with NAFLD and HCC associated with cirrhosis. The study included 28 pairs of HCC tissue versus distant Non-Tumoral Tissue (NTT) collected from patients undergoing hepatectomy. HCC was associated with cirrhosis (n = 9), normal liver (n = 6) and NAFLD (n = 13). Metabolomics was performed using 1H-NMR Spectroscopy on tissue extracts and combined to multivariate statistical analysis. In HCC compared to NTT, statistical models showed high levels of lactate and phosphocholine, and low level of glucose. Shared and Unique Structures (SUS) plots were performed to remove the impact of underlying disease on the metabolic profile of HCC. HCC-cirrhosis was characterized by high levels of β-hydroxybutyrate, tyrosine, phenylalanine and histidine whereas HCC-NAFLD was characterized by high levels of glutamine/glutamate. In addition, the overexpression glutamine/glutamate on HCC-NAFLD was confirmed by both Glutamine Synthetase (GS) immuno-staining and NMR-spectroscopy glutamine quantification. This study provides evidence of metabolic specificities of HCC associated with non-cirrhotic NAFLD versus HCC associated with cirrhosis. These alterations could suggest activation of glutamine synthetase pathway in HCC-NAFLD and mitochondrial dysfunction in HCC-cirrhosis, that may be part of specific carcinogenic processes.

The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) may be a cause of hepatocellular carcinoma (HCC), but its high prevalence challenges current surveillance strategies. We aimed to evaluate HCC incidences in different risk stratifications for noncirrhotic NAFLD. Using Taiwan's National Health Insurance Research Database, we located 31,571 patients with NAFLD between the years 1998 and 2012. After excluding other causes of hepatitis, underlying cirrhosis or malignancy, 18,080 patients were recruited for final analysis. Cumulative incidences of HCC were analyzed after adjusting for competing mortality. With a median follow-up duration of 6.32 years in the study cohort, the 10-year cumulative incidence of HCC was 2.73% [95% confidence interval (CI): 1.69-3.76%]. Hepatoprotectant was used as a surrogate marker for elevated serum alanine transaminase (ALT). After adjusting for age, gender, hypertension, hypercholesterolemia, diabetes mellitus, gout, statin use, metformin use and aspirin use, elevated ALT was independently associated with an increased HCC risk [hazard ratio (HR) 6.80, 95% CI: 3.00-15.42; p < 0.001]. Multivariate stratified analysis verified this association in all subgroups (HR> 1.0). Moreover, increased age (HR 1.08 per year, 95% CI: 1.05-1.11) and statin use (HR 0.29, 95% CI: 0.12-0.68) were also identified as independent risk factors. The 10-year cumulative HCC incidence was highest in older (age >55 years) patients with ALT elevation (12.41%, 95% CI: 5.99-18.83%), but lowest in younger patients without ALT elevation (0.36%, 95% CI: 0-1.08%). The incidence of HCC was relatively low in patients with clinically noncirrhotic NAFLD, however, HCC risk was significantly increased in older patients experiencing an elevated serum ALT.

NAFLD-Related HCC: How Should the Shift in Epidemiology Change Our Prevention and Surveillance Strategies?

The purpose of this study is to review the recent literature on the epidemiology of NAFLD-related HCC and discuss published data on primary and secondary prevention of NAFLD-related HCC, including surveillance for HCC. Hepatocellular cancer (HCC) is the fastest rising cause of cancer-related deaths in the USA. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the USA, afflicting nearly one in three Americans and is increasingly linked to the development of HCC. NAFLD will likely become the major contributor to the burden of HCC in the USA. While cirrhosis remains the most important risk factor for HCC in NAFLD, mounting evidence indicates that NAFLD patients can rarely develop HCC in the absence of cirrhosis. While effective medical therapies for NAFLD exist, their role as chemopreventive agents against HCC is unclear. Major knowledge gaps remain in our understanding of the risk of HCC and the interplay between HCC-promoting factors in patients with NAFLD. Currently, efforts should focus on prompt diagnosis of NAFLD and cirrhosis with non-invasive methods, or liver biopsy as needed. This will identify the great majority of NAFLD patients at risk for HCC. Valid and reliable methods for identifying non-cirrhotic NAFLD patients at risk for HCC are lacking, so surveillance cannot be currently recommended in the absence of cirrhosis. Meanwhile, further studies are needed to determine the magnitude of risk and specific risk factors or biomarkers for HCC in patients with NAFLD with or without cirrhosis.

Liver Cancer in a Patient with Non-cirrhotic Non-alcoholic Fatty Liver Disease

Liver Cancer in a Patient with Non-cirrhotic Non-alcoholic Fatty Liver Disease

Variables Associated With Inpatient and Outpatient Resource Utilization Among Medicare Beneficiaries With Nonalcoholic Fatty Liver Disease With or Without Cirrhosis.

Background:Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver disease worldwide with tremendous clinical burden. The economic burden of NAFLD is not well studied.Goal:To assess the economic burden of NAFLD.Study:Medicare beneficiaries (January 1, 2010 to December 31, 2010) with NAFLD diagnosis by International Classification of Diseases, Ninth Revision codes in the absence of other liver diseases were selected. Inpatient and outpatient resource utilization parameters were total charges and total provider payments. NAFLD patients with compensated cirrhosis (CC) were compared with decompensated cirrhosis (DC).Results:A total of 976 inpatients and 4742 outpatients with NAFLD were included—87% were white, 36% male, 30% had cardiovascular disease (CVD) or metabolic syndrome conditions, and 12% had cirrhosis. For inpatients, median total hospital charge was $36,289. NAFLD patients with cirrhosis had higher charges and payments than noncirrhotic NAFLD patients ($61,151 vs. $33,863 and $18,804 vs. $10,146, P<0.001). Compared with CC, NAFLD patients with DC had higher charges and payments (P<0.02). For outpatients, median total charge was $9,011. NAFLD patients with cirrhosis had higher charges and payments than noncirrhotic NAFLD patients ($12,049 vs. $8,830 and $2,586 vs. $1,734, P<0.001). Compared with CC, DC patients had higher total charges ($15,187 vs. $10,379, P=0.04). In multivariate analysis, variables associated with increased inpatient resource utilization were inpatient mortality, DC, and CVD; for outpatients, having CVD, obesity, and hypertension (all P<0.001).Conclusions:NAFLD is associated with significant economic burden to Medicare. Presence of cirrhosis and CVD are associated with increased resource utilization.

Preserved hemostatic status in patients with non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is associated with an increased risk of thrombosis. However, it remains unclear if hypercoagulability contributes to this risk. We, therefore, determined an in-depth hemostatic profile in a cohort of well-defined patients with NAFLD. We drew blood samples from 68 patients with biopsy-proven NAFLD (simple steatosis n=24, NASH n=22, and NASH cirrhosis n=22), 30 lean controls, 30 overweight controls (body mass index (BMI) >25kg/m2), and 15 patients with alcoholic (ASH) cirrhosis, and performed in-depth hemostatic profiling. Basal and agonist-induced platelet activation, plasma levels of markers of platelet activation, and plasma levels of the platelet adhesion regulators von Willebrand factor and ADAMTS13 were comparable between patients with non-cirrhotic NAFLD and controls. Agonist-induced platelet activation was decreased in patients with cirrhosis. Thrombomodulin-modified thrombin generation was comparable between all patients and controls, although patients with cirrhosis had a reduced anticoagulant response to thrombomodulin. Thromboelastography test results were comparable between controls and non-cirrhotic NAFLD patients, but revealed moderate hypocoagulability in cirrhosis. Plasma fibrinolytic potential was decreased in overweight controls and non-cirrhotic NAFLD, but accelerated fibrinolysis was observed in ASH cirrhosis. Clot permeability was decreased in overweight controls and patients with NAFLD. The overall hemostatic profile is comparable between patients with non-cirrhotic NAFLD and controls. Additionally, pro-thrombotic features (hypofibrinolysis and a pro-thrombotic structure of fibrin clot) in patients with NAFLD are likely driven by obesity. Our study suggests a limited role for hyperactive hemostasis in the increased thrombotic risk in NAFLD. The combined results of this study show that the overall hemostatic status is comparable between healthy individuals and patients with a fatty liver disease.

NAFLD-Associated Hepatocellular Carcinoma: a Threat to Patients with Metabolic Disorders

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its prevalence is increasing in relation to the epidemics of obesity and type 2 diabetes mellitus, via non-alcoholic fatty liver disease (NAFLD). Unhealthy lifestyles associated with metabolic disorders are per se risk conditions for NAFLD progression, and specific gene polymorphisms may also favor oncogenesis, particularly in the presence of advanced fibrosis or cryptogenic cirrhosis. However, NAFLD-associated HCC may also develop in non-cirrhotic NAFLD and is frequently diagnosed at a more advanced tumor stage, compared with virus/alcohol-related HCC. This highlights the need for screening programs and long-term surveillance for earlier HCC detection in patients with metabolic risk factors, a policy hindered by the large number of cases at risk, with costs unaffordable by National health systems. New screening tools and cost-utility studies are eagerly awaited to develop more appropriate programs for early detection and treatment of NAFLD-associated HCC.

The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies.

Hepatocellular Carcinoma in the Setting of Non-cirrhotic Nonalcoholic Fatty Liver Disease and the Metabolic Syndrome: US Experience.

Type 2 diabetes mellitus, obesity, and the metabolic syndrome (MS) have been growing in prevalence in the USA and are independent risk factors for the development of hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of the MS, with or without nonalcoholic steatohepatitis (NASH) can predispose to HCC in the absence of cirrhosis or advanced fibrosis. Nevertheless, the US literature investigating non-cirrhotic HCC in the setting of NAFLD/NASH and MS is lacking. To describe a retrospective case series of patients who developed HCC without cirrhosis in the setting of NAFLD/NASH or features of the MS. We identified NAFLD/NASH-associated HCC cases arising in the absence of cirrhosis between January 2010 and September 2012 from a tumor board database at Brooke Army Medical Center (BAMC). Of 44 cases of HCC reviewed, six cases of non-cirrhotic HCC associated with NAFLD/NASH and/or MS were identified. Only one patient underwent partial hepatectomy with curative intent. The other five might have been candidates for potential curative partial hepatectomy or liver transplantation had they been diagnosed earlier. Our case series highlights the development of NAFLD/NASH and MS-associated HCC in the absence of cirrhosis in the US population and raises the important question of HCC screening for this at-risk group.

Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.

Although hepatocellular carcinoma (HCC) primarily arises in the background of liver cirrhosis, the development of HCC in nonalcoholic fatty liver disease (NAFLD) without cirrhosis is increasingly recognized. The pathogenesis of NAFLD associated non-cirrhotic HCC is distinct from that of cirrhotic HCC because the metabolic syndrome (MS) along with obesity and insulin resistance (IR) underlie several unique mechanisms that promote tumorigenesis. IR associated with MS, NAFLD, and type 2 diabetes mellitus lead to the release of multiple pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, leptin and resistin, as well as decreased amounts of adiponectin. These processes favor the development of hepatic steatosis and inflammation within the liver, which precede HCC development. Nevertheless, further investigation is necessary to elucidate the determinants for development of HCC in patients with NAFLD in the absence of cirrhosis.

Obesity, an independent risk factor for hepatocellular carcinoma (HCC) in NAFLD non-cirrhotic patients

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignancies with increasing incidence in developed countries. Epidemiological studies show that the cause of new discovered HCC cases remains unclear in 15%-50% of cases. Obesity and the subsequent/ underlying nonalcoholic fatty liver disease (NAFLD) can be responsible for most of these cases. The aim of our study was to estimate the risk of HCC in obese patients diagnosed with NAFLD, without clinical or imagistic features of liver cirrhosis, in order to see if HCC can develop in fatty liver in the absence of cirrhosis. Patients with regular/daily alcohol consumption or diagnosed with liver viral infections were excluded. We studied 214 obese patients with NAFLD over a period of 5 years. We evaluated all patients using abdominal ultrasound and serum alpha-fetoprotein every 6 month, in order to detect the HCC occurrence. Kaplan-Meier analysis estimated the cumulative incidence of HCC. Univariate and multivariate Cox regression analysis were used to assess associations between HCC and obesity. The median follow-up was 4.3 years. During the study period, 16 from 118 cirrhotic NFLAD patients (13.5%) and 12 from 96 non-cirrhotic NAFLD patients (12.5 %) developed HCC (p = 0.07, ns). The cumulative incidence of HCC was found to be 2.9% in obese patients with NAFLD-cirrhosis, compared with 2.2% in obese patients without cirrhosis (p = 0.09, ns). Multivariate regression analysis revealed that older age (p = 0.04) was independent variable associated with development of HCC in patients with/without NAFLDcirrhosis. Obesity seems to be an independent risk factor for HCC occurrence, regardless the presence of mild or advanced liver fibrosis in NAFLD patients.

PMO-141 Flagellin-induced IL-6 production is selectively impaired in patients with cirrhosis

IntroductionThe innate immune response is an important determinant of progression in chronic inflammatory liver diseases such as alcoholic (ALD) and non-alcoholic fatty liver disease (NAFLD). Sepsis is a frequent cause...

Hepatocellular carcinoma in non-alcoholic fatty liver disease: An emerging menace

Hepatocellular carcinoma (HCC) is a common cancer worldwide that primarily develops in cirrhosis resulting from chronic infection by hepatitis B virus and hepatitis C virus, alcoholic injury, and to a lesser extent from genetically determined disorders such as hemochromatosis. HCC has recently been linked to non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity and related metabolic disorders such as diabetes. This association is alarming due to the globally high prevalence of these conditions and may contribute to the rising incidence of HCC witnessed in many industrialized countries. There is also evidence that NAFLD acts synergistically with other risk factors of HCC such as chronic hepatitis C and alcoholic liver injury. Moreover, HCC may complicate non-cirrhotic NAFLD with mild or absent fibrosis, greatly expanding the population potentially at higher risk. Major systemic and liver-specific molecular mechanisms involved include insulin resistance and hyperinsulinemia, increased TNF signaling pathways, and alterations in cellular lipid metabolism. These provide new targets for prevention, early recognition, and effective treatment of HCC associated with NAFLD. Indeed, both metformin and PPAR gamma agonists have been associated with lower risk and improved prognosis of HCC. This review summarizes current evidence as it pertains to the epidemiology, pathogenesis, and prevention of NAFLD-associated HCC.

Altered clot kinetics in patients with non-alcoholic fatty liver disease

Background. Emerging evidence has linked the presence of non-alcoholic fatty liver disease (NAFLD) with an increased risk for cardiovascular events. We hypothesised that altered clot kinetics and platelet function may contribute to this increased risk. This study compared whole blood clotting kinetics in patients with 1) non-cirrhotic NAFLD (n = 28) and 2) healthy control subjects (n = 22).Methods. Clotting kinetics were assessed in whole blood using thromboelastography (TEG) and assessed for correlations with cardiovascular risk factors.Results. Clot kinetics in patients with NAFLD showed significantly stronger clot development (maximum amplitude (MA); 58.3 ± 6.3 mm vs. 52.0 ± 10.1 mm, p = 0.01) and reduced clot lysis in the presence of thrombin (35 ± 307 vs. 51 ± 267 clot lysis 30 minutes after MA, p = 0.03) compared to control subjects. Clot strength was independently positively associated with body mass index in NAFLD, but not in control subjects. There was a greater platelet contribution to clot strength in patients with NAFLD compared to controls despite similar platelet counts. There was no association between clot kinetics and features of the metabolic syndrome or presence of type 2 diabetes.Conclusion. Patients with NAFLD have disturbances in ex-vivo clot kinetics including increased clot strength and clots that are more resistant to thrombin-stimulated lysis.