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Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Pathophysiology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 46888

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Special Issue Editors

Dr. Luca Miele

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Guest Editor

Division of Internal Medicine, Policlinico Universitario Agostino Gemelli, 00168 Rome, Italy
Interests: intestinal permeability in liver diseases

Prof. Helen L. Reeves

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Guest Editor

Northern Institute for Cancer Research Paul O'Gorman BuildingMedical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK
Interests: metabolic liver disease; liver cancer; HCC; genetic; biomarkers

Special Issue Information

Dear Colleagues,

Hepatocellular carcinoma (HCC) is becoming one of the most common cancers in world and is a leading cause of cancer-related deaths. In parallel with an epidemic spread of obesity and diabetes worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) has risen rapidly and is now a frequent cause of chronic liver disease and HCC (NAFLD-related HCC), even in the absence of frank cirrhosis. Despite this very real increase, subjects with non-cirrhotic NAFLD represent about 20%–25% of the general population, with the annual incidence of HCC in this at-risk population being very small. The risk is much lower than the cost-effective threshold level required to support active HCC surveillance in subjects with non-cirrhotic HCC. We are beginning to understand more about the biology and pathophysiology of NAFLD, and the contribution of multiple coexisting hits (metabolic, lipoperoxidation, genetic and epigenetic, dysbiosis, microbiota) to the “fertile-soil” which can promote liver carcinogenesis. Currently, despite ongoing studies (including omics, genetic, serum, microbiota markers), there are no clinically useful biomarkers that can effectively identify the subjects at the greatest risk of developing NAFLD-HCC, nor those that aid in treatment stratification.

Within this Special Issue, we aim to bring together contributions that will direct future research strategies, aiding the collaborative research required for the future development of clinically relevant guidelines. Topics covered will include (a) epidemiology, (b) environmental and individual risk factors, (c) genetic and molecular mechanisms, (d) diagnostic techniques (imaging and other omics biomarkers), (e) treatments (interventional radiology, surgery, transplantation, innovative drugs and immunotherapy), (f) prevention and surveillance policies, and (g) personalized and multidisciplinary team approaches.

Prof. Luca Miele
Prof. Helen L. Reeves
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

NAFLD (nonalcoholic fatty liver disease)
NASH (nonalcoholic steatohepatitis)
HCC (hepatocellular carcinoma)
Liver cancer
Biomarkers
Therapy
Microbiota
Diabetes
Obesity
Immunotherapy
Liver transplant
Hepatobiliary surgery

Published Papers (11 papers)

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Research

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16 pages, 4929 KiB

Open AccessArticle

A Comparative Study of Serum Angiogenic Biomarkers in Cirrhosis and Hepatocellular Carcinoma

by Krizia Pocino, Cecilia Napodano, Mariapaola Marino, Riccardo Di Santo, Luca Miele, Nicoletta De Matthaeis, Francesca Gulli, Raffaele Saporito, Gian Ludovico Rapaccini, Gabriele Ciasca and Umberto Basile

Cancers 2022, 14(1), 11; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010011 - 21 Dec 2021

Cited by 6 | Viewed by 2636

Abstract

Background: Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Its pathogenesis varies according to the underlying etiological factors, although in most cases it develops from liver cirrhosis. The disease progression is accompanied by pathological angiogenesis, which is a prerequisite that favors the development of HCC. Aims: This study aims at contributing to our understanding of the role of angiogenic factors in the progression of liver disease. For this purpose, we evaluate the clinical significance of serum angiogenic markers (VEGF, Ang-1, Ang-2, the angiopoietin receptor Tie1/2, HGF, and PECAM-1) first in cirrhotic and HCC patients separately, and then comparing cirrhotic patients with and without HCC. Materials and Methods: We enrolled 62 patients, out of whom 33 were diagnosed with HCC and 29 with liver cirrhosis without signs of neoplasia. Patients underwent venous blood sampling before and after receiving treatments for the diagnosed disease. Serum markers were evaluated using ELISA assays for Tie1 and the Bio-Plex Multiplex system for the remaining ones. Biomarker levels were investigated as a function of clinical scores for disease staging (MELD and Fibrosis Index, FI). Results: In cirrhotic patients, Ang-1 and Ang-2 correlate with MELD (ρ_Ang-1 = −0.73, p = 2E−5) and FI (ρ_Ang-1 = −0.52, p = 7E−3, ρ_Ang-2 = 0.53, p = 3E−3). A reduction of Ang-2 levels (p = 0.047) and of the Ang-2/Ang-1 ratio (p = 0.031) is observed in cirrhotic patients diagnosed with viral hepatitis after antiviral treatments. In HCC patients, Ang-1 negatively correlates with FI (ρ = −0.63, p = 1E−4), and PECAM-1 positively correlates with MELD (ρ = 0.44, p = 0.01). A significant Ang-1 reduction was observed in deceased patients during the study compared to ones who survived (p = 0.01). In HCC patients, VEGF levels were increased after tumor treatment (p = 0.037). Notably, HGF levels in cirrhotic patients with HCC are significantly raised (p = 0.017) compared to that in those without HCC. Conclusions: Our results suggest that serum angiogenic markers, with emphasis on Ang-1/2, can contribute to the development of quantitative tools for liver disease staging and therapy monitoring. The comparison between cirrhotic patients with and without HCC suggests that HGF levels are potentially useful for monitoring the insurgence of HCC after a cirrhosis diagnosis. High Ang-1 levels in HCC patients appear to have a protective role as well as prognostic significance. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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17 pages, 3562 KiB

Open AccessArticle

Phosphodiesterase 4D Depletion/Inhibition Exerts Anti-Oncogenic Properties in Hepatocellular Carcinoma

by Federica Ragusa, Nadia Panera, Silvia Cardarelli, Marco Scarsella, Marzia Bianchi, Stefano Biagioni, Mauro Giorgi, Anna Alisi and Mara Massimi

Cancers 2021, 13(9), 2182; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13092182 - 01 May 2021

Cited by 4 | Viewed by 2604

Abstract

Isoform D of type 4 phosphodiesterase (PDE4D) has recently been associated with several human cancer types with the exception of human hepatocellular carcinoma (HCC). Here we explored the role of PDE4D in HCC. We found that PDE4D gene/protein were over-expressed in different samples of human HCCs compared to normal livers. Accordingly, HCC cells showed higher PDE4D activity than non-tumorigenic cells, accompanied by over-expression of the PDE4D isoform. Silencing of PDE4D gene and pharmacological inhibition of protein activity by the specific inhibitor Gebr-7b reduced cell proliferation and increased apoptosis in HCC cells, with a decreased fraction of cells in S phase and a differential modulation of key regulators of cell cycle and apoptosis. PDE4D silencing/inhibition also affected the gene expression of several cancer-related genes, such as the pro-oncogenic insulin growth factor (IGF2), which is down-regulated. Finally, gene expression data, available in the CancerLivER data base, confirm that PDE4D over-expression in human HCCs correlated with an increased expression of IGF2, suggesting a new possible molecular network that requires further investigations. In conclusion, intracellular depletion/inhibition of PDE4D prevents the growth of HCC cells, displaying anti-oncogenic effects. PDE4D may thus represent a new biomarker for diagnosis and a potential adjuvant target for HCC therapy. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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21 pages, 2440 KiB

Open AccessArticle

The rs599839 A>G Variant Disentangles Cardiovascular Risk and Hepatocellular Carcinoma in NAFLD Patients

by Marica Meroni, Miriam Longo, Erika Paolini, Anna Alisi, Luca Miele, Emilia Rita De Caro, Giuseppina Pisano, Marco Maggioni, Giorgio Soardo, Luca Vittorio Valenti, Anna Ludovica Fracanzani and Paola Dongiovanni

Cancers 2021, 13(8), 1783; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13081783 - 08 Apr 2021

Cited by 20 | Viewed by 2790

Abstract

Background and Aims: Dyslipidemia and cardiovascular diseases (CVD) are comorbidities of nonalcoholic fatty liver disease (NAFLD), which ranges from steatosis to hepatocellular carcinoma (HCC). The rs599839 A>G variant, in the CELSR2-PSRC1-SORT1 gene cluster, has been associated CVD, but its impact on metabolic traits and on the severity liver damage in NAFLD has not been investigated yet. Methods: We evaluated the effect of the rs599839 variant in 1426 NAFLD patients (Overall cohort) of whom 131 had HCC (NAFLD-HCC), in 500,000 individuals from the UK Biobank Cohort (UKBBC), and in 366 HCC samples from The Cancer Genome Atlas (TCGA). Hepatic PSRC1, SORT1 and CELSR2 expressions were evaluated by RNAseq (n = 125). Results: The rs599839 variant was associated with reduced circulating LDL, carotid intima-media thickness, carotid plaques and hypertension (p < 0.05) in NAFLD patients and with protection against dyslipidemia in UKBBC. The minor G allele was associated with higher risk of HCC, independently of fibrosis severity (odds ratio (OR): 5.62; 95% c.i. 1.77–17.84, p = 0.003), poor prognosis and advanced tumor stage (p < 0.05) in the overall cohort. Hepatic PSRC1, SORT1 and CELSR2 expressions were increased in NAFLD patients carrying the rs599839 variant (p < 0.0001). SORT1 mRNA levels negatively correlated with circulating lipids and with those of genes involved in lipoprotein turnover (p < 0.0001). Conversely, PSRC1 expression was positively related to that of genes implicated in cell proliferation (p < 0.0001). In TCGA, PSRC1 over-expression promoted more aggressive HCC development (p < 0.05). Conclusions: In sum, the rs599839 A>G variant is associated with protection against dyslipidemia and CVD in NAFLD patients, but as one it might promote HCC development by modulating SORT1 and PSRC1 expressions which impact on lipid metabolism and cell proliferation, respectively. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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17 pages, 1018 KiB

Open AccessArticle

A PDCD1 Role in the Genetic Predisposition to NAFLD-HCC?

by Nardeen Eldafashi, Rebecca Darlay, Ruchi Shukla, Misti Vanette McCain, Robyn Watson, Yang Lin Liu, Nikki McStraw, Moustafa Fathy, Michael Atef Fawzy, Marco Y. W. Zaki, Ann K. Daly, João P. Maurício, Alastair D. Burt, Beate Haugk, Heather J. Cordell, Cristiana Bianco, Jean-François Dufour, Luca Valenti, Quentin M. Anstee and Helen L. Reeves

Cancers 2021, 13(6), 1412; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13061412 - 19 Mar 2021

Cited by 25 | Viewed by 3780

Abstract

Obesity and non-alcoholic fatty liver disease (NAFLD) are contributing to the global rise in deaths from hepatocellular carcinoma (HCC). The pathogenesis of NAFLD-HCC is not well understood. The severity of hepatic steatosis, steatohepatitis and fibrosis are key pathogenic mechanisms, but animal studies suggest altered immune responses are also involved. Genetic studies have so far highlighted a major role of gene variants promoting fat deposition in the liver (PNPLA3 rs738409; TM6SF2 rs58542926). Here, we have considered single-nucleotide polymorphisms (SNPs) in candidate immunoregulatory genes (MICA rs2596542; CD44 rs187115; PDCD1 rs7421861 and rs10204525), in 594 patients with NAFLD and 391 with NAFLD-HCC, from three European centres. Associations between age, body mass index, diabetes, cirrhosis and SNPs with HCC development were explored. PNPLA3 and TM6SF2 SNPs were associated with both progression to cirrhosis and NAFLD-HCC development, while PDCD1 SNPs were specifically associated with NAFLD-HCC risk, regardless of cirrhosis. PDCD1 rs7421861 was independently associated with NAFLD-HCC development, while PDCD1 rs10204525 acquired significance after adjusting for other risks, being most notable in the smaller numbers of women with NAFLD-HCC. The study highlights the potential impact of inter individual variation in immune tolerance induction in patients with NAFLD, both in the presence and absence of cirrhosis. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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26 pages, 8960 KiB

Open AccessArticle

Exercise Attenuates the Transition from Fatty Liver to Steatohepatitis and Reduces Tumor Formation in Mice

by Maria Guarino, Pavitra Kumar, Andrea Felser, Luigi M. Terracciano, Sergi Guixé-Muntet, Bostjan Humar, Michelangelo Foti, Jean-Marc Nuoffer, Marie V. St-Pierre and Jean-François Dufour

Cancers 2020, 12(6), 1407; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061407 - 29 May 2020

Cited by 27 | Viewed by 5075

Abstract

Non-alcoholic fatty liver disease (NAFLD) leads to steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. For sedentary patients, lifestyle interventions combining exercise and dietary changes are a cornerstone of treatment. However, the benefit of exercise alone when dietary changes have failed is uncertain. We query whether exercise alone arrests the progression of NASH and tumorigenesis in a choline-deficient, high-fat diet (CD-HFD) murine model. Male C57Bl/6N mice received a control diet or CD-HFD for 12 weeks. CD-HFD mice were randomized further for 8 weeks of sedentariness (SED) or treadmill exercise (EXE). CD-HFD for 12 weeks produced NAFL. After 20 weeks, SED mice developed NASH and hepatic adenomas. Exercise attenuated the progression to NASH. EXE livers showed lower triglycerides and tumor necrosis factor-α expression, less fibrosis, less ballooning, and a lower NAFLD activity score than did SED livers. Plasma transaminases and triglycerides were lower. Exercise activated AMP-activated protein kinase (AMPK) with inhibition of mTORC1 and decreased S6 phosphorylation, reducing hepatocellular adenoma. Exercise activated autophagy with increased LC3-II/LC3-I and mitochondrial recruitment of phosphorylated PTEN-induced kinase. Therefore, exercise attenuates the transition from NAFL to NASH, improves biochemical and histological parameters of NAFLD, and impedes the progression of fibrosis and tumorigenesis associated with enhanced activation of AMPK signaling and favors liver autophagy. Our work supports the benefits of exercise independently of dietary changes. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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Review

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23 pages, 1041 KiB

Open AccessReview

Lifestyle and Hepatocellular Carcinoma What Is the Evidence and Prevention Recommendations

by Shira Zelber-Sagi, Mazen Noureddin and Oren Shibolet

Cancers 2022, 14(1), 103; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14010103 - 26 Dec 2021

Cited by 15 | Viewed by 3710

Abstract

The increasing burden of hepatocellular carcinoma (HCC) emphasizes the unmet need for primary prevention. Lifestyle measures appear to be important modifiable risk factors for HCC regardless of its etiology. Lifestyle patterns, as a whole and each component separately, are related to HCC risk. Dietary composition is important beyond obesity. Consumption of n-3 polyunsaturated fatty acids, as well as fish and poultry, are inversely associated with HCC, while red meat, saturated fat, and cholesterol are related to increased risk. Sugar consumption is associated with HCC risk, while fiber and vegetable intake is protective. Data from multiple studies clearly show a beneficial effect for physical activity in reducing the risk of HCC. However, the duration, mode and intensity of physical activity needed are yet to be determined. There is evidence that smoking can lead to liver fibrosis and liver cancer and has a synergistic effect with alcohol drinking. On the other hand, an excessive amount of alcohol by itself has been associated with increased risk of HCC directly (carcinogenic effect) or indirectly (liver fibrosis and cirrhosis progression. Large-scale intervention studies testing the effect of comprehensive lifestyle interventions on HCC prevention among diverse cohorts of liver disease patients are greatly warranted. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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20 pages, 772 KiB

Open AccessReview

Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach

by Ivica Grgurevic, Tonci Bozin, Mislav Mikus, Michal Kukla and James O’Beirne

Cancers 2021, 13(22), 5844; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225844 - 21 Nov 2021

Cited by 26 | Viewed by 3589

Abstract

Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of liver morbidity worldwide and, as such, represents the pathogenic background for the increasing incidence of hepatocellular carcinoma (HCC). The annual incidence of NAFLD-related HCC is expected to increase by 45–130% by 2030. Diabetes mellitus is the most important risk factor for HCC development in NAFLD, with the risk further increased when associated with other metabolic traits, such as obesity, arterial hypertension and dyslipidemia. The highest risk of HCC exists in patients with advanced fibrosis or cirrhosis, although 20–50% of HCC cases arise in NAFLD patients with an absence of cirrhosis. This calls for further investigation of the pathogenic mechanisms that are involved in hepatocarcinogenesis, including genetics, metabolomics, the influence of the gut microbiota and immunological responses. Early identification of patients with or at risk of NAFLD is of utmost importance to improve outcomes. As NAFLD is highly prevalent in the community, the identification of cases should rely upon simple demographic and clinical characteristics. Once identified, these patients should then be evaluated for the presence of advanced fibrosis or cirrhosis and subsequently enter HCC surveillance programs if appropriate. A significant problem is the early recognition of non-cirrhotic NAFLD patients who will develop HCC, where new biomarkers and scores are potential solutions to tackle this issue. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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23 pages, 1521 KiB

Open AccessReview

Performance of Ultrasound Techniques and the Potential of Artificial Intelligence in the Evaluation of Hepatocellular Carcinoma and Non-Alcoholic Fatty Liver Disease

by Monica Lupsor-Platon, Teodora Serban, Alexandra Iulia Silion, George Razvan Tirpe, Alexandru Tirpe and Mira Florea

Cancers 2021, 13(4), 790; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040790 - 14 Feb 2021

Cited by 17 | Viewed by 5487

Abstract

Global statistics show an increasing percentage of patients that develop non-alcoholic fatty liver disease (NAFLD) and NAFLD-related hepatocellular carcinoma (HCC), even in the absence of cirrhosis. In the present review, we analyzed the diagnostic performance of ultrasonography (US) in the non-invasive evaluation of NAFLD and NAFLD-related HCC, as well as possibilities of optimizing US diagnosis with the help of artificial intelligence (AI) assistance. To date, US is the first-line examination recommended in the screening of patients with clinical suspicion of NAFLD, as it is readily available and leads to a better disease-specific surveillance. However, the conventional US presents limitations that significantly hamper its applicability in quantifying NAFLD and accurately characterizing a given focal liver lesion (FLL). Ultrasound contrast agents (UCAs) are an essential add-on to the conventional B-mode US and to the Doppler US that further empower this method, allowing the evaluation of the enhancement properties and the vascular architecture of FLLs, in comparison to the background parenchyma. The current paper also explores the new universe of AI and the various implications of deep learning algorithms in the evaluation of NAFLD and NAFLD-related HCC through US methods, concluding that it could potentially be a game changer for patient care. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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26 pages, 1474 KiB

Open AccessReview

Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma

by Moritz Peiseler and Frank Tacke

Cancers 2021, 13(4), 730; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13040730 - 10 Feb 2021

Cited by 34 | Viewed by 5654

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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29 pages, 872 KiB

Open AccessReview

Hepatocellular Carcinoma and Non-Alcoholic Fatty Liver Disease: A Step Forward for Better Evaluation Using Ultrasound Elastography

by Monica Lupsor-Platon, Teodora Serban, Alexandra-Iulia Silion, Alexandru Tirpe and Mira Florea

Cancers 2020, 12(10), 2778; https://doi.org/10.3390/cancers12102778 - 28 Sep 2020

Cited by 15 | Viewed by 4148

Abstract

The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) in the general population prompts for a quick response from physicians. As NAFLD can progress to liver fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC), new non-invasive, rapid, cost-effective diagnostic methods are needed. In this review, we explore the diagnostic performance of ultrasound elastography for non-invasive assessment of NAFLD and NAFLD-related HCC. Elastography provides a new dimension to the conventional ultrasound examination, by adding the liver stiffness quantification in the diagnostic algorithm. Whilst the most efficient elastographic techniques in staging liver fibrosis in NAFLD are vibration controlled transient elastography (VCTE) and 2D-Shear wave elastography (2D-SWE), VCTE presents the upside of assessing steatosis through the controlled attenuation parameter (CAP). Hereby, we have also critically reviewed the most important elastographic techniques for the quantitative characterization of focal liver lesions (FLLs), focusing on HCC: Point shear wave elastography (pSWE) and 2D-SWE. As our paper shows, elastography should not be considered as a substitute for FLL biopsy because of the stiffness values overlap. Furthermore, by using non-invasive, disease-specific surveillance tools, such as US elastography, a subset of the non-cirrhotic NAFLD patients at risk for developing HCC can be detected early, leading to a better outcome. A recent ultrasomics study exemplified the wide potential of 2D-SWE to differentiate benign FLLs from malignant ones, guiding the clinician towards the next steps of diagnosis and contributing to better long-term disease surveillance. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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24 pages, 811 KiB

Open AccessReview

Surveillance for Hepatocellular Carcinoma in Patients with Non-Alcoholic Fatty Liver Disease: Universal or Selective?

by Maria Corina Plaz Torres, Giorgia Bodini, Manuele Furnari, Elisa Marabotto, Patrizia Zentilin, Mario Strazzabosco and Edoardo G. Giannini

Cancers 2020, 12(6), 1422; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers12061422 - 31 May 2020

Cited by 38 | Viewed by 5436

Abstract

Hepatocellular carcinoma (HCC), the most frequent primary liver cancer, is the sixth most common cancer, the fourth leading cause of cancer-related deaths worldwide, and accounts globally for about 800,000 deaths/year. Early detection of HCC is of pivotal importance as it is associated with improved survival and the ability to apply curative treatments. Chronic liver diseases, and in particular cirrhosis, are the main risk factors for HCC, but the etiology of liver disease is rapidly changing due to improvements in the prevention and treatment of HBV (Hepatitis B virus) and HCV (Hepatitis C virus) infections and to the rising incidence of the metabolic syndrome, of which non-alcoholic fatty liver (NAFLD) is a manifestation. NAFLD is now a recognized and rapidly increasing cause of cirrhosis and HCC. Indeed, the most recent guidelines for NAFLD management recommend screening for HCC in patients with established cirrhosis. Screening in NAFLD patients without cirrhosis is not recommended; however, the prevalence of HCC in this group of NAFLD patients has been reported to be as high as 38%, a proportion significantly higher than the one observed in the general population and in non-cirrhotic subjects with other causes of liver disease. Unfortunately, solid data regarding the risk stratification of patients with non-cirrhotic NAFLD who might best benefit from HCC surveillance are scarce, and specific recommendations in this field are urgently needed due to the increasing NAFLD epidemic, at least in Western countries. To further complicate matters, liver ultrasonography, which represents the current standard for HCC surveillance, has a decreased diagnostic accuracy in patients with NAFLD, and therefore disease-specific surveillance tools will be required for the early identification of HCC in this population. In this review, we summarize the most recent evidence on the epidemiology and risk factors for HCC in patients with NAFLD, with and without cirrhosis, and the evidence supporting surveillance for early HCC detection in these patients, reviewing the potential limitations of currently recommended surveillance strategies, and assessing data on the accuracy of potential new screening tools. At this stage it is difficult to propose general recommendations, and best clinical judgement should be exercised, based on the profile of risk factors specific to each patient. Full article

(This article belongs to the Special Issue Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma)

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