Endpoints in NASH Clinical Trials: Are We Blind in One Eye?

This narrative review aims to illustrate the notion that nonalcoholic steatohepatitis (NASH), recently renamed metabolic dysfunction-associated steatohepatitis (MASH), is a systemic metabolic disorder featuring both adverse hepatic and extrahepatic outcomes. In recent years, several NASH trials have failed to identify effective pharmacological treatments and, therefore, lifestyle changes are the cornerstone of therapy for NASH. with this context, we analyze the epidemiological burden of NASH and the possible pathogenetic factors involved. These include genetic factors, insulin resistance, lipotoxicity, immuno-thrombosis, oxidative stress, reprogramming of hepatic metabolism, and hypoxia, all of which eventually culminate in low-grade chronic inflammation and increased risk of fibrosis progression. The possible explanations underlying the failure of NASH trials are also accurately examined. We conclude that the high heterogeneity of NASH, resulting from variable genetic backgrounds, exposure, and responses to different metabolic stresses, susceptibility to hepatocyte lipotoxicity, and differences in repair-response, calls for personalized medicine approaches involving research on noninvasive biomarkers. Future NASH trials should aim at achieving a complete assessment of systemic determinants, modifiers, and correlates of NASH, thus adopting a more holistic and unbiased approach, notably including cardiovascular-kidney-metabolic outcomes, without restricting therapeutic perspectives to histological surrogates of liver-related outcomes alone.

Liver Fibrosis Biomarkers Accurately Exclude Advanced Fibrosis and Are Associated with Higher Cardiovascular Risk Scores in Patients with NAFLD or Viral Chronic Liver Disease.

Liver fibrosis predicts liver-related and cardiovascular outcomes in chronic liver disease patients. We compared the diagnostic performance of various liver fibrosis biomarkers for identifying histological significant/advanced fibrosis. Additionally, the correlations of such liver fibrosis biomarkers with cardiovascular risk (CVR) scores were evaluated. 173 patients with viral hepatitis (157 HCV and 16 HBV) and 107 with a non-alcoholic fatty liver disease (NAFLD) were consecutively enrolled. Various liver fibrosis biomarkers: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (ARR), AST to Platelet Ratio Index (APRI), Fibrosis-4 (FiB-4), Forns index, NAFLD fibrosis score (NFS), BARD (body mass index (BMI), AAR, Diabetes) score, and Hepamet fibrosis score (HFS), were used to identify significant/advanced fibrosis. CVR was assessed by using the SCORE, the Progetto CUORE, or the Framingham risk scoring systems. Liver fibrosis biomarkers performed better in predicting advanced rather than significant liver fibrosis in all patients, regardless of chronic liver disease aetiology. Forns index and HFS performed best in predicting advanced fibrosis in patients with viral chronic liver disease and NAFLD. Lower cut-offs of these liver fibrosis biomarkers had high negative predictive values for advanced fibrosis overall, as well as in patients with NAFLD or viral chronic liver disease. FIB-4, Forns index, NFS, and HFS were positively correlated with SCORE and Framingham risk scores. In conclusion, liver fibrosis biomarkers accurately exclude advanced fibrosis and positively correlate with CVR scores in patients with chronic liver disease.

Semi-Quantitative Ultrasonographic Evaluation of NAFLD.

Nonalcoholic fatty liver disease (NAFLD) embraces histopathological entities ranging from the relatively benign simple steatosis to the progressive form nonalcoholic steatohepatitis (NASH), which is associated with fibrosis and an increased risk of progression to cirrhosis and hepatocellular carcinoma. NAFLD is the most common liver disease and is associated with extrahepatic comorbidities including a major cardiovascular disease burden. The non-invasive diagnosis of NAFLD and the identification of subjects at risk of progressive liver disease and cardio-metabolic complications are key in implementing personalized treatment schedules and follow-up strategies. In this review, we highlight the potential role of ultrasound semiquantitative scores for detecting and assessing steatosis severity, progression of NAFLD, and cardio-metabolic risk. Ultrasonographic scores of fatty liver severity act as sensors of cardio-metabolic health and may assist in selecting patients to submit to second-line non-invasive imaging techniques and/or liver biopsy.

Extra-hepatic manifestations and complications of nonalcoholic fatty liver disease.

This review article aims to synthesize the evidence regarding nonalcoholic fatty liver disease (NAFLD) as a systemic disorder. We critically discuss the metabolic syndrome and its components; the cardiovascular and the endocrine system; chronic respiratory disorders; the musculoskeletal system; the skin; and extra-hepatic tumors. We conclude that, while some of these extra-hepatic conditions clearly predispose to the development of secondary forms of NAFLD (typically hypothyroidism-induced NAFLD), others result from pre-existent NAFLD (e.g., certain extra-hepatic tumors) and others (such as Type 2 Diabetes) have, with NAFLD, mutual and bidirectional associations. Analyzed data imply that NAFLD is not merely a hepatic disease. It is also and possibly more importantly, a systemic disorder requiring a special awareness, a multidisciplinary approach and a multidimensional vision.

A critical appraisal of the use of ultrasound in hepatic steatosis.

Introduction: Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). NAFLD carries an increased risk of cardio-metabolic and liver-related events accounting for a substantial economic burden. Given that the natural history of NAFLD is critically dependent on the stage of fibrosis, non-invasively identifying the subgroup of patients at a higher risk of progressive disease is key. Areas covered: This review highlights the recent developments in the use of ultrasound-based techniques in NAFLD and their performance in predicting metabolic derangements, cardiovascular risk, and progression of liver disease, notably including diagnosis of fibrosing NASH, identification, and treatment of HCC. Expert opinion: Our ability to identify NAFLD patients and to estimate steatofibrosis with various ultrasound-based techniques has undergone tremendous progress over the last few years. However, it is more difficult to capture the inflammatory component of NASH with such ultrasound-assisted techniques. Moreover, semi-quantitative, quantitative, elastographic, and contrast-enhanced ultrasound techniques are increasingly being appreciated and made available but not all such techniques will gain success in the clinical and research area. Therefore, further research will precisely define the role of the most innovative ultrasonographic techniques, while reducing costs and increasing feasibility.

Sex Differences in Nonalcoholic Fatty Liver Disease: State of the Art and Identification of Research Gaps.

Despite tremendous research advancements in nonalcoholic fatty liver disease (NAFLD), our understanding of sex differences in NAFLD remains insufficient. This review summarizes the current knowledge on sex differences in NAFLD, identifies gaps, and discusses important considerations for future research. The prevalence and severity of NAFLD are higher in men than in women during the reproductive age. However, after menopause, NAFLD occurs at a higher rate in women, suggesting that estrogen is protective. Sex differences also exist for the major risk factors of NAFLD. In general, animal models of NAFLD recapitulate the sex differences observed in patients, with more severe steatosis and steatohepatitis, more proinflammatory/profibrotic cytokines, and a higher incidence of hepatic tumors in male than female subjects. Based on computer modeling, female and male livers are metabolically distinct with unique regulators modulating sex-specific metabolic outcomes. Analysis of the literature reveals that most published clinical and epidemiological studies fail to examine sex differences appropriately. Considering the paucity of data on sex differences and the knowledge that regulators of pathways relevant to current therapeutic targets for NAFLD differ by sex, clinical trials should be designed to test drug efficacy and safety according to sex, age, reproductive stage (i.e., menopause), and synthetic hormone use. Conclusion: Sex differences do exist in the prevalence, risk factors, fibrosis, and clinical outcomes of NAFLD, suggesting that, while not yet incorporated, sex will probably be considered in future practice guidelines; adequate consideration of sex differences, sex hormones/menopausal status, age, and other reproductive information in clinical investigation and gene association studies of NAFLD are needed to fill current gaps and implement precision medicine for patients with NAFLD.

Pathogenesis of hypothyroidism-induced NAFLD: Evidence for a distinct disease entity?

Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD.

A round trip from nonalcoholic fatty liver disease to diabetes: molecular targets to the rescue?

Evidence suggests a close relationship between nonalcoholic fatty liver disease (NAFLD) and type two diabetes (T2D). On the grounds of prevalence of disease, both conditions account for a significant financial cost for health care systems and individuals. Aim of this review article is to explore the epidemiological basis and the putative molecular mechanisms underlying the association of NAFLD with T2D. Epidemiological studies have shown that NAFLD is associated to the development of incident T2D and either reversal or improvement of NAFLD will result into decreased risk of developing incident T2D. On the other side of the coin data have shown that T2D will worsen the course of NAFLD doubling the risk of disease progression (i.e. evolution from simple steatosis to advanced fibrosis, cirrhosis, hepatocellular carcinoma, liver transplant and death). Conversely, NAFLD will contribute to metabolic decompensation of T2D. The pathogenesis of T2D in NAFLD patients may be mediated by several hepatokines impairing metabolic control. Among these, Fetuin-B, which causes glucose intolerance and is increased in patients with T2D and NAFLD with fibrosis is one of the most promising. T2D may affect the progression of NAFLD by acting at different levels of the pathogenic cascade involving gut microbiota and expanded, inflamed, dysfunctional adipose tissue. In conclusion, T2D and NAFLD are mutually, closely and bi-directionally associated. An improved understanding of molecular pathogenesis underlying this bi-directional association may allow us to be able to prevent the development of T2D by halting the progression of NAFLD.

Clinical relevance of liver histopathology and different histological classifications of NASH in adults.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) encompasses simple steatosis and steatohepatitis (NASH) with or without fibrosis/cirrhosis and hepatocellular carcinoma. NAFLD occurs epidemically in most areas of the world, contributes to cardiovascular events and liver-related mortality and therefore exacts a major economic toll. Areas covered: Here we summarize what clinicians should know about NAFLD histopathology in adults. We report on the individual histological features and scoring systems of NAFLD: the NAFLD activity score (NAS) introduced by the NASH-Clinical Research Network, the 'Fatty Liver Inhibition of Progression' algorithm and Steatosis, Activity, and Fibrosis (SAF) score. Pros and cons of histological classifications in NASH are discussed. Special emphasis is given to liver histopathology in some high-risk patient groups, such as those with severe obesity and type 2 diabetes. Moreover, we also examine the relationship between liver histopathology and clinical features, and the impact of liver histopathology on the long-term prognosis of NAFLD. Finally, we propose an integrated diagnostic approach which utilizes both non-invasive tools and liver biopsy in those individual patients with suspected NAFLD. Expert commentary: Based on expert opinions, we conclude with a research agenda on NAFLD which focuses on the most burning topics to be addressed over the next five years.

Ultrasonographic fatty liver indicator detects mild steatosis and correlates with metabolic/histological parameters in various liver diseases.

BACKGROUND AND AIMS: Fatty liver is a common feature of different types of liver diseases. The sensitivity and specificity of ultrasonography for diagnosing fatty liver are variable. A semi-quantitative ultrasound score, i.e., the ultrasonographic fatty liver indicator (US-FLI), is closely associated with metabolic/histological variables in patients with nonalcoholic fatty liver disease (NAFLD). The main aims of this study were to assess the diagnostic performance of US-FLI in detecting varying degrees of histological steatosis, and to examine the association of US-FLI with metabolic/histological parameters in 352 biopsied patients with various chronic liver diseases (173 with hepatitis C [HCV], 23 with hepatitis B [HBV], 123 with NAFLD and 33 with other etiologies). RESULTS: US-FLI accurately detected mild steatosis (minimum amount 10% on histology) with a cut-off value ≥2 (sensitivity 90.1%, specificity 90%), moderate steatosis (≥30%) with a cut-off value ≥3 (sensitivity 86.4%, specificity 92.5%) and severe steatosis (>66%) with a cut-off value ≥5 (sensitivity 88.5%, specificity 87%). US-FLI was correlated with steatosis percentage in each liver disease group as well as with lobular inflammation, ballooning, portal fibrosis, grading and staging in patients with NAFLD or HCV. US-FLI was also correlated with waist circumference, body mass index and insulin resistance both in the whole sample and in each liver disease group. CONCLUSIONS: US-FLI accurately identifies histological severity and is correlated with metabolic parameters in patients with various steatogenic liver diseases. US-FLI is an easy and versatile tool for the screening of steatosis and the metabolic health of these patients.

NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk.

Nonalcoholic fatty liver disease (NAFLD) spans steatosis through nonalcoholic steatohepatis, cirrhosis, and hepatocellular carcinoma (HCC) associated with striking systemic features and excess cardiovascular and liver-related mortality. The pathogenesis of NAFLD is complex and multifactorial. Endocrine derangements are closely linked with dysmetabolic traits. For example, in animal and human studies, female sex is protected from dysmetabolism thanks to young individuals' ability to partition fatty acids towards ketone body production rather than very low density lipoprotein (VLDL)-triacylglycerol, and to sex-specific browning of white adipose tissue. Ovarian senescence facilitates both the development of massive hepatic steatosis and the fibrotic progression of liver disease in an experimental overfed zebrafish model. Consistently, estrogen deficiency, by potentiating hepatic inflammatory changes, hastens the progression of disease in a dietary model of nonalcoholic steatohepatitis (NASH) developing in ovariectomized mice fed a high-fat diet. In humans, NAFLD more often affects men; and premenopausal women are equally protected from developing NAFLD as they are from cardiovascular disease. It would be expected that early menarche, definitely associated with estrogen activation, would produce protection against the risk of NAFLD. Nevertheless, it has been suggested that early menarche may confer an increased risk of NAFLD in adulthood, excess adiposity being the primary culprit of this association. Fertile age may be associated with more severe hepatocyte injury and inflammation, but also with a decreased risk of liver fibrosis compared to men and postmenopausal status. Later in life, ovarian senescence is strongly associated with severe steatosis and fibrosing NASH, which may occur in postmenopausal women. Estrogen deficiency is deemed to be responsible for these findings via the development of postmenopausal metabolic syndrome. Estrogen supplementation may at least theoretically protect from NAFLD development and progression, as suggested by some studies exploring the effect of hormonal replacement therapy on postmenopausal women, but the variable impact of different sex hormones in NAFLD (i.e., the pro-inflammatory effect of progesterone) should be carefully considered.

Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis.

AIM: To characterize natural history of cryptogenic cirrhosis (CC) and compare its clinical features and outcomes to those of hepatitis C virus (HCV)-related cirrhosis. METHODS: A prospective cohort of 102 consecutive patients at their first diagnosis of CC were enrolled in this study. The clinical data and outcomes were compared to an age- and Child-Pugh class-matched cohort of 110 patients with HCV-related cirrhosis. Diagnosis of cirrhosis was based on compatible clinical and laboratory parameters, ultrasound/endoscopic parameters and, whenever possible, on histological grounds and transient elastography. All cases of cirrhosis without a definite etiology were enrolled in the CC group. The parameters assessed were: (1) severity of liver disease at the time of first diagnosis; (2) liver decompensation during follow-up; (3) hepatocellular carcinoma (HCC); (4) orthotopic liver transplantation; and (5) death. The independent associated factors were evaluated by multiple logistic regression analysis, and survival and its determinants by the Kaplan-Meier model, log-rank test and Cox regression. RESULTS: At the first observation, median age was 66 and 65 years and male gender was 36% and 58% for CC and HCV cirrhosis, respectively. CC showed Child-Pugh class A/B/C of 47%/31%/22%, respectively. Compared to HCV cirrhosis, CC exhibited a significantly higher prevalence of metabolic syndrome (12% vs 54%, respectively), overweight/obesity, high BMI, impaired glucose tolerance, high blood pressure, dyslipidemia, hyperuricemia, cardiovascular diseases, extrahepatic cancer, and gallstones. Over a median period of 42 mo of follow-up, liver decompensation, HCC development and death for CC and HCV-related cirrhosis were 60.8%, and 54.4%, 16.7% and 17.2%, 39.2% and 30%, respectively. The median survival was 60 mo for CC. Independent predictors of death were age and Child-Pugh class at diagnosis. CC showed an approximately twofold higher incidence of HCC in Child-Pugh class A. CONCLUSION: Undiagnosed nonalcoholic fatty liver disease has an etiologic role in CC that is associated with a poor prognosis, early HCC development, high risk of cardiovascular disease and extrahepatic cancer.

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection--Liver: The "Musketeer" in the Spotlight.

The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a "vicious circle", eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved.

The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans.

Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined.

The independent predictors of non-alcoholic steatohepatitis and its individual histological features.: Insulin resistance, serum uric acid, metabolic syndrome, alanine aminotransferase and serum total cholesterol are a clue to pathogenesis and candidate targets for treatment.

AIM: The diagnosis of non-alcoholic steatohepatitis (NASH) is based on the individual histological features: steatosis, lobular inflammation and ballooning. Non-alcoholic fatty liver disease (NAFLD) activity score (NAS ≥ 5) is used in clinical trials. Fibrosis dictates long-term NAFLD prognosis. Recently, more-than-mild portal inflammation has raised interest as a marker of NAFLD severity. We assessed the independent predictors of: (I) individual histological lesions of NASH; (II) diagnosis of NASH; (III) significant (stage ≥2) and advanced (stage ≥3) fibrosis; and (IV) more-than-mild portal inflammation. METHODS: Data from 118 consecutive biopsy-proven NAFLD patients observed at our institution were retrospectively analyzed. RESULTS: At stepwise multivariate logistic regression analyses, independent predictors were as follows. For the individual histological features of NASH: insulin resistance (IR), assessed with Homeostasis Model Assessment-IR (HOMA-IR), serum uric acid (SUA) and serum total cholesterol (TCH) for moderate-to-severe steatosis; waist circumference (waist), HOMA-IR and TCH for lobular inflammation; waist, HOMA-IR, metabolic syndrome (MS), serum alanine aminotransferase (ALT), SUA and TCH for ballooning. For NASH diagnosis: waist, HOMA-IR, MS, ALT, SUA and TCH (Brunt et al.'s classification); ALT, SUA and TCH for NAS ≥ 5. For significant and advanced fibrosis, respectively: waist, MS and ALT; age, platelets, HOMA-IR, diabetes and TCH. For more-than-mild portal inflammation: serum aspartate aminotransferase (AST), serum iron, NAS ≥ 5 and significant liver fibrosis. CONCLUSION: HOMA-IR, SUA, MS, ALT and TCH are independent predictors of NASH and its individual histological lesions, notably including fibrosis. Based on our findings, these factors should be considered major pathogenic drivers of NASH and, by inference, potential targets for treatment.

Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study.

OBJECTIVE: The biological heterogeneity of hepatocellular carcinoma (HCC) makes prognosis difficult. We translate the results of a genome-wide high-throughput analysis into a tool that accurately predicts at presentation tumour growth and survival of patients with HCC. DESIGN: Ultrasound surveillance identified HCC in 78 (training set) and 54 (validation set) consecutive patients with cirrhosis. Patients underwent two CT scans 6 weeks apart (no treatment in-between) to determine tumour volumes (V0 and V1) and calculate HCC doubling time. Baseline-paired HCC and surrounding tissue biopsies for microarray study (Agilent Whole Human Genome Oligo Microarrays) were also obtained. Predictors of survival were assessed by multivariate Cox model. RESULTS: Calculated tumour doubling times ranged from 30 to 621 days (mean, 107±91 days; median, 83 days) and were divided into quartiles: ≤53 days (n=19), 54-82 days (n=20), 83-110 days (n=20) and ≥111 days (n=19). Median survival according to doubling time was significantly lower for the first quartile versus the others (11 vs 41 months, 42, and 47 months, respectively) (p<0.0001). A five-gene transcriptomic hepatic signature including angiopoietin-2 (ANGPT2), delta-like ligand 4 (DLL4), neuropilin (NRP)/tolloid (TLL)-like 2 (NETO2), endothelial cell-specific molecule-1 (ESM1), and nuclear receptor subfamily 4, group A, member 1 (NR4A1) was found to accurately identify rapidly growing HCCs of the first quartile (ROC AUC: 0.961; 95% CI 0.919 to 1.000; p<0.0001) and to be an independent factor for mortality (HR: 3.987; 95% CI 1.941 to 8.193, p<0.0001). CONCLUSIONS: The hepatic five-gene signature was able to predict HCC growth in individual patient and the consequent risk of death. This implies a role of this molecular tool in the future therapeutic management of patients with HCC. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01657695.

Primary lymphoma of the spleen mimicking simple benign cysts: contrast-enhanced ultrasonography and other imaging findings.

We report on a case of incidentally detected primary splenic lymphoma mimicking simple benign cysts on abdominal ultrasonography. On contrast-enhanced ultrasonography (CEUS), the lesions showed isoenhancement in the arterial phase with progressive washout and marked hypoenhancement in the parenchymal phase. This pattern enabled us to suspect the malignant nature of the disease, thus preventing a dangerous misdiagnosis. Accordingly, further characterization with other imaging studies (computed tomography, magnetic resonance imaging, and positron emission tomography) was pursued based on CEUS and taking into account the patient's clinical picture and medical history. Collectively, imaging data led us to a diagnosis of suspected primary splenic malignancy, most probably lymphoma, which was histologically confirmed on the surgical specimen after splenectomy.

Sofosbuvir-based therapy cures hepatitis C virus infection after prior treatment failures in a patient with concurrent lymphoma.

We report on the first well-tolerated and successful use of sofosbuvir-based therapy in a patient in whom chronic infection with hepatitis C had preceded the development of B-cell non-Hodgkin's lymphoma. The patient had previously failed numerous attempts to clear the hepatitis C virus with traditional antiviral schedules. We demonstrate that sofosbuvir-based therapy resulted in cure of hepatitis C in a patient who had relapsed during combination therapy with an NS5A inhibitor, an NS3 protease inhibitor and ribavirin, as well as treatment failures to multiple courses of interferon-based therapy. This report also suggests that eradication of hepatitis C virus may result in the short-term prevention of B-cell non-Hodgkin's lymphoma relapse. The findings from our case require further validation in future cohorts of patients.

Role of ultrasound in the diagnosis and treatment of nonalcoholic fatty liver disease and its complications.

We review the role of liver ultrasonography (US) and related techniques as non-invasive tools in predicting metabolic derangements, liver histology, portal hypertension and cardiovascular risk as well as allowing early diagnosis and management of hepatocellular carcinoma in patients with nonalcoholic fatty liver disease. In this setting, US detects fatty changes as low as ≥20% and hepatic steatosis identified ultrasonographically, in its turn, closely mirrors coronary and carotid atherosclerosis burden. Semi-quantitative US indices (to exclude nonalcoholic steatohepatitis) and sonoelastography (to quantify fibrosis) help in predicting liver histology and selecting patients to submit to liver biopsy. Surveillance for hepatocellular carcinoma conducted through biannual US is mandatory and US has a role in guiding locoregional treatment and in evaluating the efficacy of treatment. High-intensity focused ultrasound can be delivered with precision resulting in coagulative necrosis of hepatocellular carcinoma without puncturing the liver. Costs and inconveniences have so far hampered its diffusion.

Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as an important cardiovascular risk (CVR) factor. This is a narrative clinical review aimed at answering how diagnosis and management of CVR should be conducted in the individual patient with NAFLD. To this end, the authors performed an extensive search of the existing literature on PubMed (1993-2014) using pertinent keywords. To date, CVR among patients with NAFLD might be assessed with the Framingham risk score equation or other risk calculators, to be adapted to the true CVR in the specific population being assessed; however, the use of these CVR calculators needs to be validated by future studies in larger cohorts of NAFLD patients of various ethnic backgrounds in order to substantiate their clinical relevance as a foundation for the primary prevention of cardiovascular diseases in this group of patients. Early and aggressive drug treatment of CVR should be started in NAFLD patients with a history of cardiovascular events, established diabetes or who are at high (calculated) CVR. Whether such an aggressive pharmacological approach is also justified in patients with NAFLD, who are at intermediate or low CVR, remains debatable. Currently, there are no clinical trials showing that the treatment of NAFLD per se (either associated or unassociated with traditional CVR factors) will result in decreased risk of cardiovascular events. Accordingly, drug treatment should be better individualized, aiming at correcting all the coexisting cardio-metabolic risk factors of the individual patient with NAFLD. To this end, an overview of the lifestyle interventions and the available drugs is offered, emphasis being conveyed to statins and metformin, which promise to cover worrying complications of NAFLD such as the risk of developing hepatocellular carcinoma.