Hepatocellular Carcinoma In Non-alcoholic Steatohepatitis Research Articles

Artificial intelligence/neural network system that accurately diagnoses hepatocellular carcinoma in nonalcoholic steatohepatitis.

The aim of this study was to develop a novel noninvasive test using an artificial intelligence/neural network system (called HCC-Scope) to diagnose early-stage hepatocellular carcinoma (HCC) on the background of nonalcoholic steatohepatitis (NASH). In total, 175 patients with histologically proven nonalcoholic fatty liver disease and 55 patients with NASH-HCC were enrolled for training and validation studies. Of the 55 patients with NASH-HCC, 27 (49.1%) had very early-stage HCC, and six (10.9%) had early-stage HCC based on the Barcelona Clinic Liver Cancer staging system. Diagnosis with HCC-Scope was performed based on 12 items: age, sex, height, weight, AST level, ALT level, gamma-glutamyl transferase level, cholesterol level, triglyceride level, platelet count, diabetes status, and IgM-free apoptosis inhibitor of macrophage level. The FMVWG2U47 hardware (Fujitsu Co. Ltd, Tokyo, Japan) and the originally developed software were used. HCC-Scope had sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 100% for the differential diagnosis between non-HCC and HCC in a training study with gray zone analysis. It was also excellent in the validation study (95.0% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV with gray zone analysis and 95.2% sensitivity, 100% specificity, 100% PPV, and 97.1% NPV without gray zone analysis). HCC-Scope had a significantly higher sensitivity (85.3%) and specificity (85.1%) than alpha-fetoprotein (AFP) level, AFP-L3 level, des-gamma-carboxy prothrombin (DCP) level, and the gender-age-AFP-L3-AFP-DCP (GALAD) score. HCC-Scope can accurately differentially diagnose between non-HCC NASH and NASH-HCC, including very early-stage NASH-HCC.

Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.

Gut microbiota contribution to hepatocellular carcinoma manifestation in non-alcoholic steatohepatitis.

Recently, the gut microbiota has been recognized as an obvious active player in addition to liver steatosis/steatohepatitis in the pathophysiological mechanisms of the development of hepatocellular carcinoma (HCC), even in the absence of cirrhosis. Evidence from clinical and experimental studies shows the association of specific changes in the gut microbiome and the direct contribution to maintaining liver inflammation and/or cancerogenesis in nonalcoholic fatty liver disease-induced HCC. The composition of the gut microbiota differs significantly in obese and lean individuals, especially in the abundance of pro-inflammatory lipopolysaccharide-producing phyla, and, after establishing steatohepatitis, it undergoes minor changes during the progression of the disease toward advanced fibrosis. Experimental studies proved that the microbiota of obese subjects can induce steatohepatitis in normally fed mice. On the contrary, the transplantation of healthy microbiota to obese mice relieves steatosis. However, further studies are needed to confirm these findings and the mechanisms involved. In this review, we have evaluated well-documented clinical and experimental research on the role of the gut microbiota in the manifestation and promotion of HCC in nonalcoholic steatohepatitis (NASH). Furthermore, a literature review of microbiota alterations and consequences of dysbiosis for the promotion of NASH-induced HCC was performed, and the advantages and limitations of the microbiota as an early marker of the diagnosis of HCC were discussed.

Reduced Rates of Post-Transplant Recurrent Hepatocellular Carcinoma in Non-Alcoholic Steatohepatitis: A Propensity Score Matched Analysis.

Non-alcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) has become the second leading cause of HCC-related liver transplantation in the United States. This study investigated post-transplant recurrence and survival for patients transplanted for NASH-related HCC compared to non-NASH HCC etiologies. Retrospective review of the United Network for Organ Sharing (UNOS) Organ Procurement and Transplantation Network (OPTN) database identified 7,461 patients with HCC-1,405 with underlying NASH and 6,086 with non-NASH underlying diseases. After propensity score matching (PSM) to account for patient- and tumor-related confounders 1,175 remained in each group. Primary outcomes assessed were recurrence rate and recurrence-free survival. Recurrent malignancy at 5 years post-transplant was lower in NASH compared to non-NASH patients (5.80 vs. 9.41%, p = 0.01). Recurrence-free survival, however, was similar at 5years between groups. Patients with NASH-related HCC were less likely to have post-transplant recurrence than their non-NASH counterparts, although recurrence-free survival was similar at 5years.

Imaging features of hepatocellular carcinoma in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis: a systematic review and meta-analysis.

To investigate the imaging features of hepatocellular carcinoma (HCC) in patients with non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) through a systematic review and meta-analysis. MEDLINE, EMBASE, and the Cochrane Library database were searched for studies providing data on imaging features of HCC in NAFLD and NASH between January 1, 2011 and July 19, 2021. Random effects models were used to calculate the pooled percentages of the three major features of arterial-phase hyperenhancement (APHE), washout, and enhancing capsule. Sensitivity analysis and subgroup analysis were performed according to underlying liver disease (NASH vs. NAFLD) and imaging modality (CT vs. MRI). Five studies (170 patients with 193 HCCs) were included in the analysis. The pooled percentages of APHE, washout, and enhancing capsule were 94.0% (95% confidence interval [CI] 89.1-96.7%), 72.7% (95% CI 63.3-80.4%), and 57.5% (95% CI 45.1-69.1%), respectively. The percentages of these three major features did not significantly differ between NAFLD and NASH (p ≥ 0.21). MRI showed similar pooled percentages of APHE (94.3% vs. 93.4%, p = 0.82) and washout (70.4% vs. 77.2%, p = 0.38) to CT, but a higher pooled percentage of enhancing capsule (67.1% vs. 44.7%, p = 0.02). HCC in patients with NAFLD and NASH had a similar frequency of APHE to HCC with other etiology. However, it showed a relatively low frequency of washout and enhancing capsule.

LI-RADS v2018 major criteria: Do hepatocellular carcinomas in non-alcoholic steatohepatitis differ from those in virus-induced chronic liver disease on MRI?

PurposeLI-RADS v2018 diagnostic system is used to diagnose hepatocellular carcinoma (HCC) in at risk patients. However, its applicability to HCC in non-alcoholic steatohepatitis (NASH) has not been specifically studied. The purpose of this study was to assess the applicability of LI-RADS v2018 diagnostic system for HCC in patients with NASH. Materials and methodsThe MRI examinations of 41 patients with HCC and NASH (NASH group) were reviewed and compared to those obtained in 41 patients with HCC and virus-induced chronic liver disease (Virus group). MRI examinations of the two groups were compared for imaging presentation, LI-RADS major criteria and LI-RADS categorization. Qualitative variables were compared using Fisher exact test and quantitative variables using Mann-Whitney U test Interreader agreement was assessed using kappa statistic. ResultsNo significant differences in qualitative and quantitative variables were observed between the two groups. Most common findings in the two groups were hyperenhancement during the arterial phase and visibility on T2-weighted images (93 % vs. 98 %, P = 0.616 and 85 % vs. 88 %, P = 1.000 for NASH group and Virus group, respectively). No differences in prevalence between the two groups were found for any major LI-RADS v2018 criterion. Interreader agreement for LI-RADS categorization was strong for the NASH group (kappa = 0.802) and moderate for the virus group (kappa = 0.720). No differences were found between the two groups for LI-RADS categories (P = 0.303). ConclusionsThe LI-RADS v2018 diagnostic algorithm can be applied in patients with NASH.

Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC.

OBJECTIVES:The precipitous increase in nonalcoholic steatohepatitis (NASH) is accompanied by a dramatic increase in the incidence of NASH-related hepatocellular carcinoma (HCC). HCC in NASH has a higher propensity to arise without pre-existing cirrhosis compared with other chronic liver diseases.METHODS:To identify the potential links between liver and gut in NASH-related hepatocarcinogenesis, we compared the gut microbiota and mediators of bile acid (BA) signaling in the absence or presence of cirrhosis through the analysis of stool and serum samples from patients with NASH non-HCC and NASH-HCC and healthy volunteers.RESULTS:Serum levels of total and individual BA were higher in NASH compared with healthy controls. Furthermore, serum levels of the primary conjugated BAs glycine-conjugated cholic acid, taurine-conjugated cholic acid, glycine-conjugated chenodeoxycholic acid, and taurine-conjugated chenodeoxycholic acid were significantly increased in cirrhotic vs noncirrhotic patients, independent of the occurrence of HCC. By contrast, serum FGF19 levels were higher in patients with NASH-HCC and associated with tumor markers as well as an attenuation of BA synthesis. Specific alterations in the gut microbiome were found for several bacteria involved in the BA metabolism including Bacteroides and Lactobacilli. Specifically, the abundance of Lactobacilli was associated with progressive disease, serum BA levels, and liver injury in NASH and NASH-HCC.DISCUSSION:Here, we demonstrate a clear association of the altered gut microbiota and primary conjugated BA composition in cirrhotic and noncirrhotic patients with NASH-HCC. Microbiota-associated alterations in BA homeostasis and farnesoid X receptor signaling, via FGF19, might thus contribute to fibrogenesis, liver injury, and tumorigenesis in NASH-HCC.

Smad Phospho-Isoforms for Hepatocellular Carcinoma Risk Assessment in Patients with Nonalcoholic Steatohepatitis.

Nonalcoholic steatohepatitis (NASH)-related hepatocellular carcinoma (HCC) sometimes occurs in mildly fibrotic livers, while HCC incidence in NASH-related cirrhosis is lower than and less predictable than in hepatitis C virus (HCV)-related cirrhosis. Transforming growth factor (TGF)-β signaling in hepatocytic nuclei is implicated in fibrosis and carcinogenesis. TGF-βtype I receptor (TβRI) and c-Jun N-terminal kinase (JNK) differentially phosphorylate the mediator Smad3, resulting in 2 distinct phospho-isoforms: C-terminally phosphorylated Smad3 (pSmad3C) and linker-phosphorylated Smad3 (pSmad3L). In mature hepatocytes, oncogenic signaling via the JNK/pSmad3L pathway antagonizes signaling via the tumor-suppressive TβRI/pSmad3C pathway. We immunohistochemically examined domain-specific Smad3 phosphorylation in liver biopsy specimens from 30 NASH patients representing different fibrotic stages and 20 chronically infected hepatitis C patients as controls, correlating Smad3 phosphorylation with clinical course. HCC occurred during follow-up in 11 of 12 NASH patients with abundant pSmad3L and limited pSmad3C but in only 2 of 18 with limited pSmad3L. In contrast, HCC developed in 12 of 15 NASH patients with limited pSmad3C but only 1 of 15 with abundant pSmad3C. Two of fourteen NASH patients with mild fibrosis developed HCC, their hepatocytic nuclei showed abundant pSmad3L and limited pSmad3C. Five of sixteen patients with severe fibrosis did not develop HCC, their hepatocytic nuclei showed limited pSmad3L and abundant pSmad3C. Smad phospho-isoforms may represent important biomarkers predicting HCC in NASH and potential therapeutic targets for preventing NASH-related HCC.

1046 Quantifying Risk Factors and Comparing Clinical Parameters for Cirrhotic and Non-Cirrhotic Hepatocellular Carcinoma (HCC) in Non-Alcoholic Steatohepatitis (NASH)

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death in the United States. HCC is historically associated with cirrhosis from Hepatitis B virus, Hepatitis C virus (HCV), and alcohol abuse. Nonalcoholic fatty liver disease (NAFLD) is a key risk factor for the development of HCC. The prevalence of obesity and metabolic syndrome in the United States has likely contributed to the HCC epidemic. Epidemiological data reports that two-thirds of obese people have fatty liver ranging from steatosis to steatohepatitis, which in turn can progress to cirrhosis in 3-15% and eventually to HCC. The primary aim of our study is to ascertain the differences between cirrhotic and non-cirrhotic NASH-HCC patients based on demographics, risk factors, and laboratory abnormalities. Additionally, we wanted to quantify the risk factors that increase the likelihood of HCC in NASH patients. METHODS: We performed a retrospective analysis in the IBM Explorys database which has 63781930 unique patient data in the US. Data is reported as counts and percentages and an independent two sample t-test was used to compare epidemiological, clinical and laboratory features between cirrhotic and non-cirrhotic NASH-HCC. Odds ratios were calculated to determine the relationship between NASH-HCC sub-groups and risk factors and converted into Forest plots. RESULTS: There were 1120 cases of NASH-HCC of which 1040 were cirrhotic and 80 were non-cirrhotic. Patients with cirrhotic NASH-HCC were more likely to have type 2 diabetes mellitus, chronic kidney disease, coronary artery disease, and elevated alpha fetoprotein, direct bilirubin and INR compared to their non-cirrhotic counterpart. Patients with type 2 diabetes (OR 70, 95%CI 59.4-82.5) had the highest risk for HCC in cirrhotic NASH. Patients with elevated ferritin (OR 25, 95%CI 15.1-41.5) had the highest risk for HCC in non-cirrhotic NASH. CONCLUSION: Patients with type 2 diabetes are at the highest risk for HCC in NASH cirrhosis patients compared to other components of metabolic syndrome. Elevated ferritin levels conferred the highest risk for development of NASH-HCC in non-cirrhotic patients. OSA has been shown to promote HCC in early studies and our findings demonstrate similar but notable risk in both sub-groups. Identifying key differences in the epidemiology and disease traits of cirrhotic and non-cirrhotic NASH-HCC could be used to assist with the early identification of patients that are at risk for HCC

MRI presentation of hepatocellular carcinoma in non-alcoholic steatohepatitis (NASH)

PurposeTo describe the magnetic resonance imaging (MRI) features of hepatocellular carcinoma (HCC) in patients with non-alcoholic steatohepatitis (NASH). MethodsMRI examinations of 21 patients with HCC and NASH were analyzed by two observers. There were 18 men and 3 women with a mean age of 67.9 ± 10.2 (SD) years (range: 36–85 years). Images were qualitatively and quantitatively analyzed with respect to imaging presentation. ResultsHCC presented as a single tumor in 13/21 patients (62%), with a mean longest diameter of 26.9 ± 20.2 (SD) mm (range: 12–88 mm); 17/30 HCC (57%) had a largest diameter <20 mm. A signal drop between in- and out-of-phase T1-weighted MR images was observed in 16/30 HCC nodules (53%). All HCC nodules (30/30; 100%) showed hyperenhancement on arterial phase images and 12/30 HCC nodules (40%) did not show a wash-out on portal or delayed phase images. Encapsulation was observed in 18/30 HCC nodules (60%). MRI findings consistent with liver cirrhosis were present in 16/21 patients (76%). ConclusionsOur results show that 57% of HCC in NASH can present as a lesion smaller than 20 mm and 40% do not display wash-out. These results suggest that classical imaging criteria developed for noninvasive diagnosis of HCC should be applied with caution to HCC in patients with NASH.

A Tale of Two Complications of Obesity: NASH and Hepatocellular Carcinoma.

Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease in developed countries and its incidence is rapidly increasing. Cirrhosis, and the dreaded complication of hepatocellular carcinoma (HCC), are the major drivers of morbidity and mortality in NASH. Conventional understanding has been that chronic liver damage leads to a cycle of cell death, regeneration and fibrosis during which HCC precursor cells undergo malignant transformation and lead to cancer initiation. This is supported by epidemiologic data which shows that cirrhosis precedes HCC in more than 90% of patients with several forms of chronic liver disease like hepatitis C and alcohol cirrhosis. But the link between fibrosis and carcinogenesis seems less definitive in patients with NASH as a sizeable proportion of NASH patients with HCC do not have significant underlying fibrosis. Several case reports and case series have pointed out this phenomenon of HCC arising in non-cirrhotic NASH (1), and a recent meta-analysis of 19 studies has shown that the prevalence of HCC in non-cirrhotic NASH was up to 38.0% (2). The mechanisms that contribute to the development of HCC in obesity in the absence of NASH and/or overt fibrosis or cirrhosis have remained unexplored. A possible mechanism to explain the role of obesity in the pathogenesis of HCC independent of NASH, was recently reported in a paper in Cell (3) .

Surveillance for Hepatocellular Carcinoma: Current Best Practice and Future Direction.

Hepatocellular cancer (HCC) is the fourth leading cause of cancer-related deaths worldwide and the fastest growing cause of cancer deaths in the United States. The overall prognosis of HCC remains dismal, except for the subset of patients who are diagnosed at early stage and receive potentially curative therapies, such as surgical resection and liver transplantation. Given this, expert society guidelines recommend HCC surveillance every 6 months in at-risk individuals. Despite these recommendations, the effectiveness of HCC surveillance remains a subject of debate. We discuss current best practices for HCC surveillance and the evidence that support these recommendations. We also describe several initiatives that are underway to improve HCC surveillance and outline areas that may serve as high-yield targets for future research. Overall, we believe these efforts will help the field move toward precision surveillance, where surveillance tests and intervals are tailored to individual HCC risk. Doing so can maximize surveillance benefits, minimize surveillance harms, and optimize overall value for all patients.

Recent Insight into the Role of Fibrosis in Nonalcoholic Steatohepatitis-Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most widespread tumors in the world and its prognosis is poor because of lack of effective treatments. Epidemiological studies show that non-alcoholic steatohepatitis (NASH) and advanced fibrosis represent a relevant risk factors to the HCC development. However little is known of pathophysiological mechanisms linking liver fibrogenesis to HCC in NASH. Recent advances in scientific research allowed to discover some mechanisms that may represent potential therapeutic targets. These include the integrin signaling, hepatic stellate cells (HSCs) activation, Hedgehog signaling and alteration of immune system. In the near future, knowledge of fibrosis-dependent carcinogenic mechanisms, will help optimize antifibrotic therapies as an approach to prevent and treat HCC in patients with NASH and advanced fibrosis.

Systematic review with meta-analysis: risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases.

Given the lack of long-term prospective studies, it is challenging for clinicians to make informed decisions about screening and treatment decisions regarding the risk of hepatocellular carcinoma (HCC) in patients with non-alcoholic steatohepatitis (NASH) who do not have cirrhosis. To characterise the pooled risk of HCC in the non-cirrhosis population. Published studies were identified through April 2016 in MEDLINE, Scopus, Science Citation Index, AMED and the Cochrane Library. Two independent reviewers screened citations and extracted data. Random effect odds ratios (OR) were calculated to obtain aggregate estimates of effect size between NASH and non-NASH groups. Between-study variability and heterogeneity were assessed. Nineteen studies with 168571 participants were included. Eighty-six per cent of included subjects had cirrhosis. The prevalence of HCC in non-cirrhotic NASH was 38.0%; among other aetiologies in non-cirrhotics, it was 14.2% (P<0.001). Non-cirrhotic NASH subjects were at greater odds of developing HCC than non-cirrhotic subjects of other aetiologies (OR 2.61, 95% CI 1.27-5.35, P=0.009). When examining all NASH subjects either with or without cirrhosis, those with NASH as the underlying liver disease did not have a significantly increased risk of HCC (OR 1.43, 95% CI 0.77-2.65, P=0.250). In non-cirrhotic subjects, those with NASH have a higher risk of HCC compared to other aetiologies of liver disease. Further study investigating the risk factors of HCC among non-cirrhotic NASH patients is needed.

Bile acid metabolism regulated by the gut microbiota promotes non-alcoholic steatohepatitis-associated hepatocellular carcinoma in mice.

Gut microbiota plays a significant role in the development of hepatocellular carcinoma (HCC) in non-alcoholic steatohepatitis (NASH). However, understanding of the precise mechanism of this process remains incomplete. A new class steatohepatitis-inducing high-fat diet (HFD), namely STHD-01, can promote the development of HCC without the administration of chemical carcinogens. Using this diet, we comprehensively analyzed changes in the gut microbiota and its metabolic functions during the development of HCC in NASH. Mice fed the STHD-01 developed NASH within 9 weeks. NASH further progressed into HCC by 41 weeks. Treatment with antibiotics significantly attenuated liver pathology and suppressed tumor development, indicating the critical role of the gut microbiota in tumor development in this model. Accumulation of cholesterol and bile acids in the liver and feces increased after feeding the mice with STHD-01. Treatment with antibiotics did not reverse these phenotypes. In contrast, accumulation of secondary bile acids was dramatically reduced after the treatment with antibiotics, suggesting the critical role of the gut microbiota in the conversion of primary bile acids to secondary bile acids. Secondary bile acids such as deoxycholic acid activated the mTOR, pathway in hepatocytes. Activation of mTOR was observed in the liver of mice fed STHD-01, and the activation was reduced when mice were treated with antibiotics. Collectively, bile acid metabolism by the gut microbiota promotes HCC development in STHD-01-induced NASH.

Activation of apoptosis inhibitor of macrophage is a sensitive diagnostic marker for NASH-associated hepatocellular carcinoma.

A diagnostic marker is needed enabling early and specific diagnosis of hepatocellular carcinoma (HCC) associated with non-alcoholic steatohepatitis (NASH). Our recent findings have indicated that circulating apoptosis inhibitor of macrophage (AIM), which usually associates with IgM pentamer in the blood, is activated by its dissociation from IgM. We investigated the serum levels of IgM-free AIM for AIM activation and its possible relationship with development of HCC in NASH. Serum levels of IgM-associated and IgM-free AIM were evaluated in patients with non-alcoholic fatty liver, NASH, and NASH-HCC using enzyme-linked immunosorbent assays and immunoblots. Liver biopsy specimens were graded and staged using Brunt's classification. Forty-two patients with fatty liver, 141 with NASH, and 26 with NASH-HCC were evaluated. Patients with stage 4 or grade 3 NASH (with or without HCC) exhibited significantly higher levels of both IgM-free and total AIM than those with fatty liver, whereas the ratio of IgM-free-to-total AIM was equivalent in these groups. Among patients with the same fibrosis stage of NASH, those with HCC had significantly higher IgM-free but not total AIM levels, resulting in a proportional increase in the IgM-free/total AIM ratio. Analysis of the areas under the receiver operating characteristic curves indicated the high sensitivity of the IgM-free AIM for NASH-HCC. Our observations suggest the activation of AIM in blood in the presence of NASH-HCC, with a significant increase in IgM-free AIM levels. IgM-free AIM serum levels appear to be a sensitive diagnostic marker for NASH-HCC.

Hepatocellular Carcinoma in Nonalcoholic Steatohepatitis

AbstractNonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the United States. Approximately 10 to 20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis, which, in turn, can lead to hepatocellular carcinoma (HCC). However, evidence also supports that HCC can develop in patients with NASH who do not have cirrhosis or advanced fibrosis. Obesity, diabetes mellitus, hepatic iron deposition, and insulin resistance are potential risk factors for HCC in NASH. Mechanisms proposed include a role for tumor necrosis factor-α, interleukin-6, insulinlike growth factor, and nuclear factor κβ activation in progression of NASH to HCC. Polymorphisms in patatin-like phospholipase domain-containing 3 also support a genetic influence in NASH-related HCC. Surgical resection, liver directed therapy, and liver transplant remain the mainstay of therapy. Ultrasound has reduced sensitivity for surveillance of HCC in obese patients and alpha fetoprotein may have more value for HCC surveillance in the NASH patient as compared with the HCV patient. Although HCC can develop in noncirrhotic NASH, currently there are no guidelines to recommend surveillance in noncirrhotic NASH patients.

Hepatocellular carcinoma in non-alcoholic steatohepatitis: Current knowledge and implications for management.

With the prevalence of hepatitis C virus expected to decline, the proportion of hepatocellular carcinoma (HCC) related to non-alcoholic steatohepatitis (NASH) is anticipated to increase exponentially due to the growing epidemic of obesity and diabetes. The annual incidence rate of developing HCC in patients with NASH-related cirrhosis is not clearly understood with rates ranging from 2.6%-12.8%. While multiple new mechanisms have been implicated in the development of HCC in NASH; further prospective long-term studies are needed to validate these findings. Recent evidence has shown a significant proportion of patients with non-alcoholic fatty liver disease and NASH progress to HCC in the absence of cirrhosis. Liver resection and transplantation represent curative therapeutic options in select NASH-related HCC patients but have placed a significant burden to our healthcare resources and utilization. Currently NASH-related HCC is the fastest growing indication for liver transplant in HCC candidates. Increased efforts to implement effective screening and preventative strategies, particularly in non-cirrhotic NASH patients, are needed to reduce the future impact imposed by NASH-related HCC.

Hepatocellular Carcinoma Developed From Non-Cirrhotic Liver: A Case Report

Non-alcoholic steatohepatitis (NASH) is recognized as a crucial factor in the development of hepatocellular carcinoma (HCC) from non-viral cirrhosis. It is generally known that cirrhosis, fibrosis of the liver, works as a carcinogenic promoter, and it is uncommon for non-cirrhotic liver to develop into HCC. Here we report a case of HCC that developed from non-cirrhotic NASH. A 76-year-old male presented to our hospital with abdominal distention. His medical history included impaired glucose tolerance and hypertension. He denied any use of alcohol. Ultrasonography revealed a lobular mass in S5 of the liver with a marginal low echo that measured 50 × 40 mm. Contrast-enhanced computed tomography confirmed HCC. Laboratory analysis revealed normal hepatic and biliary enzymes, as well as normal levels of tumor markers, including alpha-fetoprotein and protein induced by vitamin K absence or antagonist-II. Virus markers were negative for HBs-Ag, HBV-DNA, HCV-Ab, and HCV-RNA. As a result, he was chosen as a candidate for surgical resection; subsegmental resection of S5 and S6 was performed. The resected specimens of the tumor revealed moderately differentiated HCC; rich macrovesicular lipid depositions were observed over the background liver, which was compatible with A2F1. Based on the histological findings, he was diagnosed with HCC developed from non-cirrhotic NASH. This case report is informative for clinicians by raising awareness of the potential risk of HCC in non-cirrhotic NASH. J Med Cases. 2016;7(11):508-511 doi: https://doi.org/10.14740/jmc2681w

Metformin prevents liver tumorigenesis induced by high-fat diet in C57Bl/6 mice

The prevalence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is increasing with the growing epidemics of obesity and diabetes. NAFLD encompasses a clinicopathologic spectrum of disease ranging from isolated hepatic steatosis to NASH, which is a more aggressive form of fatty liver disease, to cirrhosis and, finally, hepatocellular carcinoma (HCC). The exact mechanism behind the development of HCC in NASH remains unclear; however, it has been established that hepatic steatosis is the important risk factor in the development of HCC. Metformin has recently drawn attention because of its potential antitumor effect. Here, we investigated the effects of metformin on high-fat diet (HFD)-induced liver tumorigenesis, using a mouse model of NASH and liver tumor. Metformin prevented long-term HFD-induced liver tumorigenesis in C57Bl/6 mice. Of note, metformin failed to protect against liver tumorigenesis in mice that had already begun to develop NAFLD. Metformin improved short-term HFD-induced fat accumulation in the liver, associated with the suppression of adipose tissue inflammation. Collectively, these results suggest that metformin may prevent liver tumorigenesis via suppression of liver fat accumulation in the early stage, before the onset of NAFLD, which seems to be associated with a delay in the development of inflammation of the adipose tissue.