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Importance: Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common chronic liver disease worldwide. It is important to develop noninvasive tests to assess the disease severity and prognosis., Objective: To study the prognostic implications of baseline levels and dynamic changes of the vibration-controlled transient elastography (VCTE)-based scores developed for the diagnosis of advanced fibrosis (Agile 3+) and cirrhosis (Agile 4) in patients with MASLD., Design, Setting, and Participants: This cohort study included data from a natural history cohort of patients with MASLD who underwent VCTE examination at 16 tertiary referral centers in the US, Europe, and Asia from February 2004 to January 2023, of which the data were collected prospectively at 14 centers. Eligible patients were adults aged at least 18 years with hepatic steatosis diagnosed by histologic methods (steatosis in ≥5% of hepatocytes) or imaging studies (ultrasonography, computed tomography or magnetic resonance imaging, or controlled attenuation parameter ≥248 dB/m by VCTE)., Main Outcomes and Measures: The primary outcome was liver-related events (LREs), defined as hepatocellular carcinoma or hepatic decompensation (ascites, variceal hemorrhage, hepatic encephalopathy, or hepatorenal syndrome), liver transplant, and liver-related deaths. The Agile scores were compared with histologic and 8 other noninvasive tests., Results: A total of 16 603 patients underwent VCTE examination at baseline (mean [SD] age, 52.5 [13.7] years; 9600 [57.8%] were male). At a median follow-up of 51.7 (IQR, 25.2-85.2) months, 316 patients (1.9%) developed LREs. Both Agile 3+ and Agile 4 scores classified fewer patients between the low and high cutoffs than most fibrosis scores and achieved the highest discriminatory power in predicting LREs (integrated area under the time-dependent receiver-operating characteristic curve, 0.89). A total of 10 920 patients (65.8%) had repeated VCTE examination at a median interval of 15 (IQR, 11.3-27.7) months and were included in the serial analysis. A total of 81.9% of patients (7208 of 8810) had stable Agile 3+ scores and 92.6% of patients (8163 of 8810) had stable Agile 4 scores (same risk categories at both assessments). The incidence of LREs was 0.6 per 1000 person-years in patients with persistently low Agile 3+ scores and 30.1 per 1000 person-years in patients with persistently high Agile 3+ scores. In patients with high Agile 3+ score at baseline, a decrease in the score by more than 20% was associated with substantial reduction in the risk of LREs. A similar trend was observed for the Agile 4 score, although it missed more LREs in the low-risk group., Conclusions and Relevance: Findings of this study suggest that single or serial Agile scores are highly accurate in predicting LREs in patients with MASLD, making them suitable alternatives to liver biopsy in routine clinical practice and in phase 2b and 3 clinical trials for steatohepatitis.

Background & Aims: The MRI-AST (MAST) score accurately identifies patients with at-risk nonalcoholic steatohepatitis, defined as nonalcoholic steatohepatitis with nonalcoholic fatty liver disease activity score ≥4 and fibrosis stage ≥2 at highest risk for disease progression. It is important to determine the robustness of the MAST score in predicting major adverse liver outcomes (MALO), hepatocellular carcinoma (HCC), liver transplant, and death., Methods: This retrospective analysis included patients with nonalcoholic fatty liver disease from a tertiary care center who underwent magnetic resonance imaging proton density fat fraction, magnetic resonance elastography, and laboratory testing within 6 months from 2013 to 2022. Other causes of chronic liver disease were excluded. Hazard ratios between logit MAST and MALO (ascites, hepatic encephalopathy, or bleeding esophageal varices), liver transplant, HCC, or liver-related death were computed using a Cox proportional hazards regression model. We computed the hazard ratio of MALO or death associated with MAST scores 0.165-0.242 and 0.242-1.000, using MAST scores 0.000-0.165 as the reference group., Results: Among 346 total patients, average age was 58.8 years with 52.9% females and 34.4% with type 2 diabetes. Average alanine aminotransferase was 50.7 IU/L (24.3-60.0 IU/L), aspartate aminotransferase was 38.05 IU/L (22.00-41.00 IU/L), platelets were 242.9 × 10 9 /L (193.8-290.0 × 10 9 /L), proton density fat fraction was 12.90% (5.90%-18.22%), and liver stiffness on magnetic resonance elastography was 2.75 kPa (2.07-2.90 kPa). Median follow-up was 29.5 months. Fourteen had adverse outcomes, including 10 MALO, 1 HCC, 1 liver transplant, and 2 liver-related deaths. The Cox regression of MAST versus adverse event rate had a hazard ratio of 2.01 (95% confidence interval, 1.59-2.54; P < .0001) for each 1 logit unit increases in MAST. The corresponding Harrell concordance statistic (C statistic) was 0.919 (95% confidence interval, 0.865-0.953). The MAST score ranges of 0.165-0.242 and 0.242-1.0, respectively, had adverse event rate hazard ratio of 7.75 (1.40-42.9; P = .0189) and 22.11 (6.59-74.2; P < .0000) relative to MAST 0-0.165., Conclusions: The MAST score noninvasively identifies at-risk nonalcoholic steatohepatitis and accurately predicts MALO, HCC, liver transplant, and liver-related death., (Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease consists of a spectrum starting from nonalcoholic fatty liver disease that may progress to nonalcoholic steatohepatitis (NASH), which can lead to fibrosis, cirrhosis, hepatocellular carcinoma, or even liver failure. The prevalence of NASH has increased in parallel with the rising rate of obesity and type 2 diabetes. Given the high prevalence and deadly complications of NASH, there have been significant efforts to develop effective treatments. Phase 2A studies have assessed various mechanisms of action across the spectrum of the disease, while phase 3 studies have focused mainly on NASH and fibrosis stage 2 and higher, as these patients have a higher risk of disease morbidity and mortality. The primary efficacy endpoints also vary, by using noninvasive tests in early-phase trials while relying on liver histological endpoints in phase 3 studies as required by regulatory agencies. Despite initial disappointment due to the failure of several drugs, recent phase 2 and 3 studies have shown promising results, with the first Food and Drug Administration-approved drug for NASH expected to be approved in 2023. In this review, we discuss the various drugs under development for NASH, their mechanisms of action, and the results of their clinical trials. We also highlight the potential challenges in developing pharmacological therapies for NASH., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity worldwide. With the obesity pandemic, NAFLD-related HCC is contributing to the burden of disease exponentially. Genetic predisposition and clinical risk factors for NAFLD-related HCC have been identified. Cirrhosis is a well-known and major risk factor for NAFLD-related HCC. However, the occurrence of NAFLD-related HCC in patients without cirrhosis is increasingly recognized and poses a significant challenge regarding cancer surveillance. It is of paramount importance to develop optimal risk stratification scores and models to identify subsets of the population at high risk so they can be enrolled in surveillance programs. In this review, we will discuss the risks and prediction models for NAFLD-related HCC., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background & Aims: Current estimates of the population-based disease burden of liver failure or end-stage liver disease (ESLD) are lacking. We investigated recent trends in hospitalizations and in-hospital mortality among patients with ESLD in the United States (US)., Methods: A retrospective analysis was performed utilizing the National Inpatient Sample from 2005 to 2014. We defined ESLD as either decompensated cirrhosis or hepatocellular carcinoma (HCC), criteria obtained from the International Classification of Diseases, Ninth Revision. Nationwide rates of hospitalization and in-hospital mortality were analysed from 2005 to 2014., Results: Hospitalization rates for decompensated cirrhosis during this period increased from 105.3/100 000 persons to 159.9/100 000 persons. In terms of HCC, hospitalization rates increased from 13.6/100 000 to 22.1/100 000. In patients with non-alcoholic fatty liver disease (NAFLD)-related decompensated cirrhosis, the hospitalization rate increased from 13.4/100 000 to 32.1/100 000 with an annual incremental increase of 10.6%, a magnitude twofold higher than other aetiologies. The proportion of NAFLD among hospitalizations with ESLD steadily increased from 12.7% to 20.1% for decompensated cirrhosis while the proportion of chronic hepatitis C (HCV) and alcoholic liver disease (ALD) declined (from 29.3% to 27.6% for HCV; from 39.0% to 37.4% for ALD). Although the overall in-hospital mortality rates for ESLD declined during the study, mortality rates for NAFLD-related decompensated cirrhosis showed no significant change., Conclusions: Among aetiologies of chronic liver disease, NAFLD demonstrated the fastest growing rate of hospitalizations in non-HCC patients with ESLD in the US. Our study highlights the need for a focus on NAFLD-related hospitalizations and its impact on resource utilization., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

With recent improvements in the treatment of end-stage liver disease (ESLD), a better understanding of the burden of cirrhosis and hepatocellular carcinoma (HCC) is needed in the United States. A population-based study using the US Census and national mortality database was performed. We identified the age-standardized etiology-specific mortality rates for cirrhosis and HCC among US adults ages 20 years or older from 2007 to 2016. We determined temporal mortality rate patterns by joinpoint analysis with estimates of annual percentage change (APC). Age-standardized cirrhosis-related mortality rates increased from 19.77/100,000 persons in 2007 to 23.67 in 2016 with an annual increase of 2.3% (95% confidence interval [CI] 2.0-2.7). The APC in mortality rates for hepatitis C virus (HCV)-cirrhosis shifted from a 2.9% increase per year during 2007 to 2014 to a 6.5% decline per year during 2014 to 2016. Meanwhile, mortality for cirrhosis from alcoholic liver disease (ALD, APC 4.5%) and NAFLD (APC 15.4%) increased over the same period, whereas mortality for hepatitis B virus (HBV)-cirrhosis decreased with an average APC of -1.1%. HCC-related mortality increased from 3.48/100,000 persons in 2007 to 4.41 in 2016 at an annual rate of 2.0% (95% CI 1.3-2.6). Etiology-specific mortality rates of HCC were largely consistent with cirrhosis-related mortality. Minority populations had a higher burden of HCC-related mortality. Conclusion: Cirrhosis-related and HCC-related mortality rates increased between 2007 and 2016 in the United States. However, mortality rates in HCV-cirrhosis demonstrated a significant decline from 2014 to 2016, during the direct-acting antiviral era. Mortality rates for ALD/NAFLD-cirrhosis and HCC have continued to increase, whereas HBV-cirrhosis-related mortality declined during the 10-year period. Importantly, minorities had a disproportionately higher burden of ESLD-related mortality., (© 2018 by the American Association for the Study of Liver Diseases.)

Moderate alcohol consumption in patients with nonalcoholic fatty liver disease (NAFLD) is common, yet the effects on cardiovascular and liver health are unclear. Moderate alcohol use is associated with improved insulin sensitivity and decreased cardiovascular mortality in the general population, but whether similar benefits would be observed in persons with NAFLD remains largely unstudied. There is significant overlap in the pathogenesis of alcoholic liver disease (ALD) and NAFLD, although studies of ALD have focused on pathological alcohol intake and few mechanistic studies of moderate alcohol use in NAFLD exist. We undertook a critical review of the effect of moderate alcohol use on cardiovascular and liver disease in patients with NAFLD. A total of seven observational studies met the criteria for inclusion (one for cardiovascular endpoints and six for liver endpoints). Insufficient studies have assessed the association of moderate alcohol use with cardiovascular outcomes. There was a positive association between moderate alcohol use and decreased NASH and fibrosis; however, heavy episodic drinking may accelerate fibrosis progression and moderate alcohol use may increase the risk of hepatocellular carcinoma in patients with advanced fibrosis. Significant methodological limitations were present, including incomplete adjustment for confounding factors and failure to measure lifetime use or the pattern of alcohol intake. Thus, a strong recommendation of benefit of moderate alcohol use in NAFLD cannot be made. There remains a need for additional high-quality longitudinal studies that evaluate both cardiovascular and liver outcomes among NAFLD patients with moderate or lesser degrees of alcohol use. (Hepatology 2017;65:2090-2099)., (© 2017 by the American Association for the Study of Liver Diseases.)

Background: 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., Aim: To describe a retrospective case series of patients who developed HCC without cirrhosis in the setting of NAFLD/NASH or features of the MS., Methods: 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)., Results: 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., Conclusion: 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.

Management of hepatic malignancy is a challenging clinical problem involving several different medical and surgical disciplines. Because of the wide variety of potential therapies, treatment protocols for various malignancies continue to evolve. Consequently, development of appropriate therapeutic algorithms necessitates consideration of medical options, such as systemic chemotherapy; surgical options, such as resection or transplantation; and locoregional therapies, such as thermal ablation and transarterial embolization. The authors discuss treatment strategies for the 3 most common subtypes of hepatic malignancy treated with locoregional therapies: hepatocellular carcinoma, neuroendocrine metastases, and colorectal metastases. The ACR Appropriateness Criteria(®) are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment., (Copyright © 2012 American College of Radiology. Published by Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) is easily the most common cause of chronic liver disease in the United States (U.S.) as the hepatic manifestation of the metabolic syndrome. Although only 5 to 20% of patients with NAFLD are generally considered to meet criteria for nonalcoholic steatohepatitis (NASH), with its inherent risk for progression to cirrhosis, this still represents an alarmingly large number of individuals. The exponentially growing rates of hepatocellular carcinoma (HCC) in the U.S. may be partially attributable to increased numbers of NASH cirrhotics, although recent evidence has suggested that NAFLD may directly promote hepatic carcinogenesis independent of cirrhosis. This review focuses on HCC in noncirrhotic NASH with an emphasis on clinical presentation, pathogenesis, and implications for screening., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Hepatocellular carcinoma (HCC) is a common and deadly malignancy that is increasing in incidence in developed countries. The emergence of hepatitis C virus (HCV) accounts for about half of this increase in HCC, although the etiology of HCC in 15%-50% of new HCC cases remains unclear. The most common form of chronic liver disease in developed countries is nonalcoholic fatty liver disease (NAFLD), which encompasses a broad spectrum of histopathology. The prevalence of NAFLD, including the more aggressive nonalcoholic steatohepatitis (NASH), is increasing with the growing epidemics of diabetes and obesity. NASH can progress to cirrhosis and its related complications. Growing evidence suggests that NASH accounts for a large proportion of idiopathic or cryptogenic cirrhosis, which is associated with the typical risk factors for NASH. HCC is a rare, although important complication of NAFLD. Diabetes and obesity have been established as independent risk factors for the development of HCC. New evidence also suggests that hepatic iron deposition increases the risk of HCC in NASH-derived cirrhosis. Multiple case reports and case reviews of HCC in the setting of NASH support the associations of diabetes and obesity with the risk of HCC, as well as suggest age and advanced fibrosis as significant risks. Insulin resistance and its subsequent inflammatory cascade that is associated with the development of NASH appear to play a significant role in the carcinogenesis of HCC. The complications of NASH, including cirrhosis and HCC, are expected to increase with the growing epidemic of diabetes and obesity.

Primary liver cancer is the fifth most common malignancy worldwide and the third leading cause of cancer mortality. Non-alcoholic fatty liver disease is the most common cause of chronic liver disease in the United States encompassing a spectrum of entities marked by hepatic steatosis in the absence of significant alcohol consumption. Although simple steatosis follows a generally benign course, the more aggressive form, non-alcoholic steatohepatitis, can progress to cirrhosis and result in complications including hepatocellular carcinoma. A significant number of cases of hepatocellular carcinoma remain cryptogenic without known underlying chronic liver disease. It is increasingly recognized that non-alcoholic steatohepatitis likely accounts for a substantial portion of cryptogenic hepatocellular carcinoma.

HH is a common inherited disorder of iron metabolism affecting about 1 out of 250 individuals of Northern European decent. Many of these patients do not have evident phenotypic expression and do not develop significant iron loading. Some patients, however, develop progressive iron overload and cirrhosis. These individuals are at risk of developing HCC. Cirrhotics with hemochromatosis should undergo regular screening for HCC. If HCC is identified early, treatment with either resection or liver transplantation is optimal. Palliative measures, including ablative therapy and chemoembolization, can be used. With increasing clinical recognition,hemochromatosis should be diagnosed earlier and progression to cirrhosis and HCC should be minimized.

Fatty liver disease represents a common clinical entity. It is classically divided into alcoholic fatty liver disease (AFLD) and nonalcoholic fatty liver disease (NAFLD). Whereas AFLD occurs in as many as 10 million Americans, NAFLD represents the most common chronic liver disease and is the most common cause of liver enzyme abnormalities in the United States. Both diseases encompass the clinical spectrum of steatosis, steatohepatitis, and cirrhosis. Although they are histologically indistinct, AFLD and NAFLD follow different clinical courses. This article compares the natural history of these diseases.

Complementary DNA encoding a facilitative glucose transporter was isolated from a human hepatoma cell line (HepG2) cDNA library and subcloned into a metal-inducible mammalian expression vector, pLEN (California Biotechnology) containing human metallothionein gene II promoter sequences. Chinese hamster ovary (CHO) cells transfected with this transporter expression vector, pLENGT, exhibited a 2-17-fold increase in immunoreactive HepG2-type glucose transporter protein, as measured by protein immunoblotting with antipeptide antibodies directed against the HepG2-type glucose transporter C-terminal domain. Expression of the human glucose transporter was verified by protein immunoblotting with a mouse polyclonal antiserum that recognizes the human but not the rodent HepG2-type transporter. 2-Deoxy-D-glucose uptake was increased 2-7-fold in transfected cell lines. Polyclonal antisera directed against purified red blood cell glucose transporter were raised in several rabbits. Antiserum from one rabbit, delta, was found to bind to the surface of intact red cells but not to inside-out red cell ghosts. Using this delta-antiserum in intact cell-binding assays, 1.6-9-fold increases in cell surface expression of the human glucose transporter were measured in CHO-K1 cell lines transfected with the transporter expression vector. Measurements of total cellular glucose transporter immunoreactive protein using anti-HepG2 transporter C-terminal peptide serum, cell surface glucose transporter protein using delta-antiserum and 2-deoxyglucose uptake revealed proportional relationships among these parameters in transfected cell lines expressing different levels of transporter protein. Insulin increased 2-deoxyglucose uptake 40% in control CHO-K1 cells and in CHO-K1 cells expressing modest levels of the human glucose transporter protein. However, stimulation of sugar-uptake by insulin was only 10% in cells overexpressing human glucose transporter protein 9-fold, and no effect of insulin on sugar uptake was detected in several cell lines expressing very high levels (12-17-fold over controls) of human HepG2 glucose transporter protein. No insulin stimulation of anti-cell surface glucose transporter antibody binding was detected in any control or transfected CHO-K1 cell lines. These data indicate that a glucose transporter protein that is insensitive to insulin in HepG2 cells is regulated by insulin when expressed at low but not at high levels in insulin-response CHO-K1 cells. Additionally, the results suggest that insulin does not increase 2-deoxyglucose uptake by increasing the number of cell surface HepG2-type glucose transporters in CHO-K1 fibroblasts.