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Siriwong N, Sriphoosanaphan S, Decharatanachart P, Yongpisarn T, Kerr SJ, Treeprasertsuk S, Tiyarattanachai T, Apiparakoon T, Hagström H, Akbari C, Ekstedt M, Yip TCF, Wong GLH, Ito T, Ishigami M, Toyoda H, Peleg N, Shlomai A, Seko Y, Sumida Y, Kawanaka M, Hino K, Chaiteerakij R. Role of noninvasive tests on the prediction of hepatocellular carcinoma in nonalcoholic fatty liver disease patients without cirrhosis: a systematic review and meta-analysis of aggregate and individual patient data. Eur J Gastroenterol Hepatol 2025; 37:358-369. [PMID: 39919008 DOI: 10.1097/meg.0000000000002912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/09/2025]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) has been identified as an emerging risk factor for hepatocellular carcinoma (HCC). Identifying non-cirrhotic NAFLD patients at risk for HCC is crucial. We aimed to investigate the utility of noninvasive tests (NITs) as predictors for HCC and to determine optimal and cost-effective NIT cutoffs for HCC surveillance in non-cirrhotic NAFLD patients. METHODS Medline, EMBASE, and Scopus databases were searched for studies evaluating the relationship between NITs and HCC in this population. Random-effects models were used to estimate hazard ratios or risk ratios and 95% confidence interval (95% CI). Cutoffs of NITs for identifying high-risk patients for HCC were determined. RESULTS This systematic review comprised 20 studies. A meta-analysis of 379 194 patients was conducted using six studies with individual patient data and five studies with aggregate data. Among NITs studied, fibrosis-4 index (FIB-4), aspartate aminotransferase to platelet ratio index (APRI), and NAFLD fibrosis score (NFS) were significantly associated with HCC, with pooled risk ratio (95% CI) of 9.21 (5.79-14.64), pooled hazard ratio of 12.53 (6.57-23.90), and 13.32 (6.48-27.37), respectively. FIB-4, APRI, and NFS of more than 2.06, 0.65, and 0.51 resulted in the highest area under the receiver operating characteristics of 0.83, 0.80, and 0.85, respectively. Surveillance in patients with FIB-4 ≥ 5.91 and NFS ≥ 2.85 would be cost-effective with an annual HCC incidence of ≥15 per 1000 patient-years. CONCLUSION FIB-4, APRI, and NFS are associated with HCC development in non-cirrhotic NAFLD patients. Different NIT cutoffs may be used to enroll high-risk NAFLD patients for HCC surveillance, according to resource availability in different settings.
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Affiliation(s)
- Nanicha Siriwong
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Supachaya Sriphoosanaphan
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | | | - Tanat Yongpisarn
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Stephen J Kerr
- Biostatistics Excellence Centre, Faculty of Medicine, Chulalongkorn University
| | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Thodsawit Tiyarattanachai
- Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Terapap Apiparakoon
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm
| | | | - Mattias Ekstedt
- Division of Diagnostics and Specialist Medicine, Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Terry Cheuk-Fung Yip
- Department of Medicine and Therapeutics
- Medical Data Analytics Centre
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Grace Lai-Hung Wong
- Department of Medicine and Therapeutics
- Medical Data Analytics Centre
- State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Takanori Ito
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya
| | - Masatoshi Ishigami
- Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Noam Peleg
- Department of Gastroenterology and Hepatology, Rabin Medical Center, Beilinson Hospital, Petach-Tikva
| | - Amir Shlomai
- Department of Medicine D, Beilinson Hospital, Rabin Medical Center and the Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto
| | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Nagakute, Aichi
| | - Miwa Kawanaka
- Department of General Internal Medicine, Kawasaki Medical Center, Kawasaki Medical School, Okayama
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Japan
| | - Roongruedee Chaiteerakij
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University, and King Chulalongkorn Memorial Hospital, Thai Red Cross Society
- Center of Excellence for Innovation and Endoscopy in Gastrointestinal Oncology, Division of Gastroenterology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
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Stasi C, Brillanti S. Liver Stiffness Values to Predict Occurrence and Recurrence of Hepatocellular Carcinoma. Life (Basel) 2024; 14:342. [PMID: 38541667 PMCID: PMC10971191 DOI: 10.3390/life14030342] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2024] [Revised: 03/01/2024] [Accepted: 03/05/2024] [Indexed: 05/17/2025] Open
Abstract
Globally, liver cancer is the third most frequent etiology of cancer death, with the rates of occurrence of both new cases and mortality estimated to increase. Given the availability of multiple treatments, interdisciplinary management of the patient is crucial. Moreover, the diagnostic assessment of patients with severe liver fibrosis is essential for the staging of HCC and liver cirrhosis and early diagnosis of HCC. In this context, non-invasive evaluation plays a critical role in identifying prognostic factors of clinical application for the surveillance of the occurrence or recurrence of HCC. The new frontiers of transient elastography have become a useful tool to assess the risk of HCC occurrence and recurrence. There has been a major increase in studies investigating the cutoff liver stiffness value that best predicts the need for monitoring for the onset of HCC. Therefore, this review discusses the new advances that have occurred in the last four years on HCC, highlighting the new frontiers of non-invasive evaluation of HCC subjects, with particular attention regarding the clinical application of liver stiffness assessment for de novo HCC and predicting recurrence in patients with chronic HCV achieving sustained virological response after treatment with direct antiviral agents.
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Affiliation(s)
- Cristina Stasi
- Department of Medical, Surgical and Neuroscience Sciences, University of Siena, 53100 Siena, Italy;
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3
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Demir M, Bornstein SR, Mantzoros CS, Perakakis N. Liver fat as risk factor of hepatic and cardiometabolic diseases. Obes Rev 2023; 24:e13612. [PMID: 37553237 DOI: 10.1111/obr.13612] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 06/26/2023] [Accepted: 07/10/2023] [Indexed: 08/10/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disorder characterized by excessive accumulation of fat in the liver that can progress to liver inflammation (non-alcoholic steatohepatitis [NASH]), liver fibrosis, and cirrhosis. Although most efforts for drug development are focusing on the treatment of the latest stages of NAFLD, where significant fibrosis and NASH are present, findings from studies suggest that the amount of liver fat may be an important independent risk factor and/or predictor of development and progression of NAFLD and metabolic diseases. In this review, we first describe the current tools available for quantification of liver fat in humans and then present the clinical and pathophysiological evidence that link liver fat with NAFLD progression as well as with cardiometabolic diseases. Finally, we discuss current pharmacological and non-pharmacological approaches to reduce liver fat and present open questions that have to be addressed in future studies.
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Affiliation(s)
- Münevver Demir
- Department of Hepatology and Gastroenterology, Campus Virchow Clinic and Campus Charité Mitte, Charité University Medicine, Berlin, Germany
| | - Stefan R Bornstein
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Diabetes and Nutritional Sciences, King's College London, London, UK
| | - Christos S Mantzoros
- Division of Endocrinology, Boston VA Healthcare System and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, 02215, USA
| | - Nikolaos Perakakis
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Paul Langerhans Institute Dresden (PLID), Helmholtz Center Munich, University Hospital and Faculty of Medicine, TU Dresden, Dresden, Germany
- German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany
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4
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Taru MG, Lupsor-Platon M. Exploring Opportunities to Enhance the Screening and Surveillance of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease (NAFLD) through Risk Stratification Algorithms Incorporating Ultrasound Elastography. Cancers (Basel) 2023; 15:4097. [PMID: 37627125 PMCID: PMC10452922 DOI: 10.3390/cancers15164097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), with its progressive form, non-alcoholic steatohepatitis (NASH), has emerged as a significant public health concern, affecting over 30% of the global population. Hepatocellular carcinoma (HCC), a complication associated with both cirrhotic and non-cirrhotic NAFLD, has shown a significant increase in incidence. A substantial proportion of NAFLD-related HCC occurs in non-cirrhotic livers, highlighting the need for improved risk stratification and surveillance strategies. This comprehensive review explores the potential role of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD and highlights the importance of effective screening tools for early, cost-effective detection and improved management of NAFLD-related HCC. The integration of non-invasive tools and algorithms into risk stratification strategies could have the capacity to enhance NAFLD-related HCC screening and surveillance effectiveness. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential perspectives that could enable readers to improve the personalized assessment of NAFLD-related HCC risk through a more methodical screening approach.
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Affiliation(s)
- Madalina-Gabriela Taru
- Hepatology Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania;
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Monica Lupsor-Platon
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Medical Imaging Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania
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5
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Zeng KY, Bao WYG, Wang YH, Liao M, Yang J, Huang JY, Lu Q. Non-invasive evaluation of liver steatosis with imaging modalities: New techniques and applications. World J Gastroenterol 2023; 29:2534-2550. [PMID: 37213404 PMCID: PMC10198053 DOI: 10.3748/wjg.v29.i17.2534] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/26/2023] [Accepted: 04/11/2023] [Indexed: 05/23/2023] Open
Abstract
In the world, nonalcoholic fatty liver disease (NAFLD) accounts for majority of diffuse hepatic diseases. Notably, substantial liver fat accumulation can trigger and accelerate hepatic fibrosis, thus contributing to disease progression. Moreover, the presence of NAFLD not only puts adverse influences for liver but is also associated with an increased risk of type 2 diabetes and cardiovascular diseases. Therefore, early detection and quantified measurement of hepatic fat content are of great importance. Liver biopsy is currently the most accurate method for the evaluation of hepatic steatosis. However, liver biopsy has several limitations, namely, its invasiveness, sampling error, high cost and moderate intraobserver and interobserver reproducibility. Recently, various quantitative imaging techniques have been developed for the diagnosis and quantified measurement of hepatic fat content, including ultrasound- or magnetic resonance-based methods. These quantitative imaging techniques can provide objective continuous metrics associated with liver fat content and be recorded for comparison when patients receive check-ups to evaluate changes in liver fat content, which is useful for longitudinal follow-up. In this review, we introduce several imaging techniques and describe their diagnostic performance for the diagnosis and quantified measurement of hepatic fat content.
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Affiliation(s)
- Ke-Yu Zeng
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wu-Yong-Ga Bao
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yun-Han Wang
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Min Liao
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jie Yang
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Jia-Yan Huang
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Qiang Lu
- Department of Medical Ultrasound, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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An Overview of Hepatocellular Carcinoma Surveillance Focusing on Non-Cirrhotic NAFLD Patients: A Challenge for Physicians. Biomedicines 2023; 11:biomedicines11020586. [PMID: 36831120 PMCID: PMC9953185 DOI: 10.3390/biomedicines11020586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/08/2023] [Accepted: 02/09/2023] [Indexed: 02/18/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease worldwide and it ranges from simple steatosis to hepatocellular carcinoma (HCC). HCC represents the first liver tumor and the third source of cancer death. In the next few years, the prevalence of NAFLD and consequently of HCC is estimated to increase, becoming a major public health problem. The NAFLD-HCC shows several differences compared to other causes of chronic liver disease (CLD), including the higher percentage of patients that develop HCC in the absence of liver cirrhosis. In HCC surveillance, the international guidelines suggest a six months abdominal ultrasound (US), with or without alpha-fetoprotein (AFP) evaluation, in patients with cirrhosis and in a subgroup of patients with chronic hepatitis B infection. However, this screening program reveals several limitations, especially in NAFLD patients. Thus, new biomarkers and scores have been proposed to overcome the limits of HCC surveillance. In this narrative review we aimed to explore the differences in the HCC features between NAFLD and non-NAFLD patients, and those between NAFLD-HCC developed in the cirrhotic and non-cirrhotic liver. Finally, we focused on the limits of tumor surveillance in NAFLD patients, and we explored the new biomarkers for the early diagnosis of HCC.
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7
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Cerrito L, Mignini I, Ainora ME, Mosoni C, Gasbarrini A, Zocco MA. Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease: The Prognostic Role of Liver Stiffness Measurement. Cancers (Basel) 2023; 15:637. [PMID: 36765595 PMCID: PMC9913338 DOI: 10.3390/cancers15030637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which is nowadays the most common etiology of chronic liver disease, is associated with an increased risk of hepatocellular carcinoma (HCC), with or without cirrhosis. Owing to the high prevalence of NAFLD worldwide, it becomes crucial to develop adequate strategies for surveillance of HCC and new prediction models aiming at stratifying NAFLD population for HCC risk. To this purpose, several noninvasive tests (NITs) have been proposed in the several last years, including clinical parameters, serum biomarkers, and imaging techniques. Most of these tools are focused on the assessment of liver fibrosis. Both ultrasound (US) elastography (especially transient elastography) and magnetic resonance (MR) elastography have been evaluated to estimate HCC risk in NAFLD patients. Recently, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include these techniques among the recommended NITs for the assessment of liver fibrosis. The aim of this review is to summarize the most recent data on the role of US and MR elastography in HCC risk stratification in patients with NAFLD.
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Affiliation(s)
| | | | | | | | | | - Maria Assunta Zocco
- CEMAD Digestive Disease Center, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
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Hari A. Ultrasound-Based Diagnostic Methods: Possible Use in Fatty Liver Disease Area. Diagnostics (Basel) 2022; 12:diagnostics12112822. [PMID: 36428882 PMCID: PMC9689357 DOI: 10.3390/diagnostics12112822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2022] [Revised: 11/11/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022] Open
Abstract
Liver steatosis is a chronic liver disease that is becoming one of the most important global health problems, due to its direct connection with metabolic syndrome, its significant impact on patients' socioeconomic status and frailty, and the occurrence of advanced chronic liver disease. In recent years, there has been rapid technological progress in the ultrasound-based diagnostics field that can help us to quantitatively assess liver steatosis, including continuous attenuation parameters in A and B ultrasound modes, backscatter coefficients (e.g., speed of sound) and ultrasound envelope statistic parametric imaging. The methods used in this field are widely available, have favorable time and financial profiles, and are well accepted by patients. Less is known about their reliability in defining the presence and degree of liver steatosis. Numerous study reports have shown the methods' favorable negative and positive predictive values in comparison with reference investigations (liver biopsy and MRI). Important research has also evaluated the role of these methods in diagnosing and monitoring non-alcoholic fatty liver disease (NAFLD). Since NAFLD is becoming the dominant global cause of liver cirrhosis, and due to the close but complex interplay of liver steatosis with the coexistence of liver fibrosis, knowledge regarding NAFLD's influence on the progression of liver fibrosis is of crucial importance. Study findings, therefore, indicate the possibility of using these same diagnostic methods to evaluate the impact of NAFLD on the patient's liver fibrosis progression risk, metabolic risk factors, cardiovascular complications, and the occurrence of hepatocellular carcinoma. The mentioned areas are particularly important in light of the fact that most of the known chronic liver disease etiologies are increasingly intertwined with the simultaneous presence of NAFLD.
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Affiliation(s)
- Andrej Hari
- Oddelek za Bolezni Prebavil, Splošna Bolnišnica Celje, Oblakova Cesta 3, 3000 Celje, Slovenia
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Miura K, Maeda H, Morimoto N, Watanabe S, Tsukui M, Takaoka Y, Nomoto H, Goka R, Kotani K, Yamamoto H. Utility of FibroScan-based scoring systems to narrow the risk group of nonalcoholic fatty liver disease with comorbidities. World J Gastrointest Pathophysiol 2022; 13:96-106. [PMID: 35720167 PMCID: PMC9157683 DOI: 10.4291/wjgp.v13.i3.96] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 03/21/2022] [Accepted: 05/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Vibration-controlled transient elastography (VCTE) is proposed as a second step of examination to assess liver fibrosis in patients with nonalcoholic fatty liver disease (NAFLD) after triaging by the fibrosis-4 (FIB-4) index. Recently, VCTE-based scoring systems, including FibroScan-AST (FAST), Agile 3+, and Agile 4, emerged to determine the status of NAFLD. However, the significance of these scoring systems remains unknown in narrowing the high-risk group of NAFLD patients with comorbidities, including hepatocellular carcinoma (HCC) and esophagogastric varices (EGV).
AIM To clarify the significance of VCTE-based scoring systems to narrow the high-risk group of NAFLD patients with comorbidities.
METHODS We performed a cross-sectional study to investigate the usefulness of VCTE-based scoring systems and other fibrosis markers to narrow the high-risk group of patients with NAFLD. FIB-4 index was used for the first triage. Risk groups of FAST, Agile 3+, and Agile 4 were stratified according to the published data. Among the 191 patients with NAFLD, there were 26 (14%) and 25 patients (13%) with HCC and EGV, respectively.
RESULTS When 1.3 was used as a cutoff value, the FIB-4 index narrowed the risk group to 120 patients, in which all patients with HCC and/or EGV were included. High risk group of Agile 3+ could subsequently narrow the risk group. The prevalence of HCC and EGV at this step were 33% (26/80) and 31% (25/80), respectively. In further narrowing of EGV, Agile 4 aggregated the patients with EGV into 43 patients, of whom 23 (53%) had EGV. FAST failed to narrow the risk group of patients with comorbidities. When 2.6 was used as a cutoff value of the FIB-4 index, three patients with HCC and two patients with EGV were missed at the first triage.
CONCLUSION Agile 3+ and Agile 4 are useful to narrow the NAFLD patient group, in which patients may have HCC and/or EGV.
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Affiliation(s)
- Kouichi Miura
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Hiroshi Maeda
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Naoki Morimoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Shunji Watanabe
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Mamiko Tsukui
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Yoshinari Takaoka
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Hiroaki Nomoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Rie Goka
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan
| | - Hironori Yamamoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke 329-0498, Tochigi, Japan
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Nakai M, Yamamoto Y, Baba M, Suda G, Kubo A, Tokuchi Y, Kitagataya T, Yamada R, Shigesawa T, Suzuki K, Nakamura A, Sho T, Morikawa K, Ogawa K, Furuya K, Sakamoto N. Prediction of hepatocellular carcinoma using age and liver stiffness on transient elastography after hepatitis C virus eradication. Sci Rep 2022; 12:1449. [PMID: 35087141 PMCID: PMC8795443 DOI: 10.1038/s41598-022-05492-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 01/12/2022] [Indexed: 12/27/2022] Open
Abstract
Liver stiffness measurement (LSM) is a useful tool for assessing advanced liver fibrosis, an important risk factor for hepatocellular carcinoma (HCC) following hepatitis C (HCV) eradication. This study aimed to clarify the non-invasive factors associated with HCC following sustained virological response (SVR) and to identify the low-risk group. 567 patients without history of HCC who achieved SVR at 24 weeks (SVR24) after IFN-free treatment were retrospectively analyzed. The cumulative incidence of HCC and the risk factors were examined using pre-treatment and SVR24 data. The median observation period was 50.2 months. Thirty cases of HCC were observed, and the 4-year cumulative incidence of HCC was 5.9%. In multivariate analysis, significant pre-treatment factors were age ≥ 71 years (hazard ratio [HR]: 3.402) and LSM ≥ 9.2 kPa (HR: 6.328); SVR24 factors were age ≥ 71 years (HR: 2.689) and LSM ≥ 8.4 kPa (HR: 6.642). In cases with age < 71 years and LSM < 8.4 kPa at the time of SVR24, the 4-year cumulative incidence of HCC was as low as 1.1%. Both pre-treatment LSM (≥ 9.2 kPa) and SVR24 LSM (≥ 8.4 kPa) and age (≥ 71 years) are useful in predicting the risk of HCC after SVR with IFN-free treatment. Identification of low-risk individuals may improve the efficiency of follow-up.
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Affiliation(s)
- Masato Nakai
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yoshiya Yamamoto
- Department of Gastroenterology, Hakodate Municipal Hospital, Hakodate, Hokkaido, Japan
| | - Masaru Baba
- Department of Gastroenterology, JCHO Hokkaido Hospital, Sapporo, Hokkaido, Japan
| | - Goki Suda
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Akinori Kubo
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Yoshimasa Tokuchi
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takashi Kitagataya
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Ren Yamada
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Taku Shigesawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kazuharu Suzuki
- Department of Gastroenterology, Hakodate Municipal Hospital, Hakodate, Hokkaido, Japan
| | - Akihisa Nakamura
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Takuya Sho
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Kenichi Morikawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Koji Ogawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan
| | - Ken Furuya
- Department of Gastroenterology, JCHO Hokkaido Hospital, Sapporo, Hokkaido, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, North 15, West 7, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan.
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11
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Tamaki N, Ajmera V, Loomba R. Non-invasive methods for imaging hepatic steatosis and their clinical importance in NAFLD. Nat Rev Endocrinol 2022; 18:55-66. [PMID: 34815553 PMCID: PMC9012520 DOI: 10.1038/s41574-021-00584-0] [Citation(s) in RCA: 125] [Impact Index Per Article: 41.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/11/2021] [Indexed: 01/27/2023]
Abstract
Hepatic steatosis is a key histological feature of nonalcoholic fatty liver disease (NAFLD). The non-invasive quantification of liver fat is now possible due to advances in imaging modalities. Emerging data suggest that high levels of liver fat and its temporal change, as measured by quantitative non-invasive methods, might be associated with NAFLD progression. Ultrasound-based modalities have moderate diagnostic accuracy for liver fat content and are suitable for screening. However, of the non-invasive imaging modalities, MRI-derived proton density fat fraction (MRI-PDFF) has the highest diagnostic accuracy and is used for trial enrolment and to evaluate therapeutic effects in early-phase clinical trials in nonalcoholic steatohepatitis (NASH). In patients with NAFLD without advanced fibrosis, high levels of liver fat are associated with rapid disease progression. Furthermore, changes on MRI-PDFF (≥30% decline relative to baseline) are associated with NAFLD activity score improvement and fibrosis regression. However, an inverse association exists between liver fat and complications of cirrhosis. Liver fat decreases as liver fibrosis progresses towards cirrhosis, and the clinical importance of quantitative measurements of liver fat differs by NAFLD status. As such, patients with NAFLD should be stratified by fibrosis severity to investigate the utility of quantitative measurements of liver fat for assessing NAFLD progression and prognosis.
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Affiliation(s)
- Nobuharu Tamaki
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Veeral Ajmera
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, CA, USA.
- The Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.
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12
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Different Risk Factors for Early and Late Recurrence After Curative Resection of Hepatocellular Carcinoma. World J Surg 2021; 46:197-206. [PMID: 34533588 DOI: 10.1007/s00268-021-06308-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/28/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Factors of early and late recurrence after curative resection of hepatocellular carcinoma (HCC) may be different. The aim of this study was to identify clinical factors, including liver stiffness measurement (LSM), which are associated with HCC recurrence after curative resection. METHODS Patients who underwent preoperative LSM and primary curative resection for HCC between October 2015 and May 2018 were retrospectively reviewed, with 1 year as the cut-off between early and late recurrence. RESULTS Recurrence was observed in 42/149 (28.2%) patients over a median follow-up of 38.3 months (early recurrence: 10 [6.7%] patients; late recurrence: 32 [21.5%] patients). Multivariate analysis identified LSM (P = 0.026) and tumor size (P = 0.010) as the only factors that were significantly associated with recurrence-free survival. Compared with patients without recurrence, those with early recurrence had larger tumor size (P = 0.035) and those with late recurrence had higher LSM (P = 0.024). Receiver-operating characteristic analysis indicated that the optimal LSM cut-off value for predicting HCC recurrence was 7.4 kPa. CONCLUSION Tumor size was associated with early HCC recurrence after curative resection and LSM was associated with late recurrence. LSM cut-off of 7.4 kPa is recommended in predicting recurrence.
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13
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Oh JH, Lee HW, Sinn DH, Park JY, Kim BK, Kim SU, Kim DY, Ahn SH, Kang W, Gwak GY, Choi MS, Lee JH, Koh KC, Paik SW, Paik YH. Controlled attenuation parameter value and the risk of hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy. Hepatol Int 2021; 15:892-900. [PMID: 34260013 DOI: 10.1007/s12072-021-10205-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/30/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND Controlled attenuation parameter (CAP) can evaluate hepatic steatosis in patients with chronic hepatitis B (CHB). However, prognostic implications of CAP value remain unclear. We evaluated the association between CAP and the risk of hepatocellular carcinoma (HCC) in patients with CHB under antiviral therapy and maintained virologic response. METHODS A total of 1823 CHB patients who were taking nucleos(t)ide analogue and showing suppressed hepatitis B virus replication were analyzed. The primary outcome was incident HCC during follow-up. Patients were grouped into those with and without advanced chronic liver disease (ACLD) (liver stiffness measurement cutoff: 10 kPa), and those with and without hepatic steatosis (CAP cutoff: 222 dB/m). RESULTS During 6.4 years of follow-up, 127 patients (7.0%) newly developed HCC. Among patients with ACLD (n = 382), the cumulative HCC incidence rate was lower for those with CAP ≥ 222 (11.0% at 5 years) than those with CAP < 222 (24.0% at 5 years, p = 0.002), and was an independent factor associated with HCC. When CAP value was further stratified, the cumulative HCC incidence rate decreased in dose-dependent manner according to an increase in CAP value (24.0%, 13.9%, 12.8% and 6.0% at 5 years for those with CAP < 222, 222-246, 247-273 and ≥ 274, respectively). Among patients without ACLD (n = 1441), there was no significance difference in HCC risk according to CAP value (HCC incidence rate: 3.3% and 4.0% at 5 years for those with CAP < 222 and CAP ≥ 222, p = 0.20). CONCLUSIONS Among CHB patients under antiviral therapy showing suppressed HBV replication, low CAP value predicted higher risk for HCC among ACLD patients, indicating that CAP value has a prognostic implication in this population.
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Affiliation(s)
- Joo Hyun Oh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
- Department of Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, 280-1, Hangeulbiseok-ro, Nowon-gu, Seoul, 01830, Republic of Korea
| | - Hye Won Lee
- Department of Internal Medicine, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, 03722, Republic of Korea
| | - Dong Hyun Sinn
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea.
| | - Jun Yong Park
- Department of Internal Medicine, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
- Yonsei Liver Center, Severance Hospital, Seoul, 03722, Republic of Korea.
| | - Beom Kyung Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, 03722, Republic of Korea
| | - Seung Up Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, 03722, Republic of Korea
| | - Do Young Kim
- Department of Internal Medicine, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, 03722, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
- Yonsei Liver Center, Severance Hospital, Seoul, 03722, Republic of Korea
| | - Wonseok Kang
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Geum-Youn Gwak
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Moon Seok Choi
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Joon Hyeok Lee
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Kwang Cheol Koh
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Seung Woon Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
| | - Yong-Han Paik
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, 06351, Republic of Korea
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14
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Tamaki N, Kurosaki M, Yasui Y, Tsuchiya K, Izumi N. Attenuation coefficient (ATT) measurement for liver fat quantification in chronic liver disease. J Med Ultrason (2001) 2021; 48:481-487. [PMID: 34165645 DOI: 10.1007/s10396-021-01103-4] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Accepted: 05/17/2021] [Indexed: 10/21/2022]
Abstract
Liver fat is one of the main clinical features in chronic liver disease, and the number of fatty liver patients is increasing as the prevalence of obesity and metabolic syndrome increases globally. Noninvasive and quantitative assessment of liver fat content was made possible by recent technological advances. Attenuation coefficient (ATT) measurement is a noninvasive and quantitative liver fat measurement method used in clinical practice. The ATT value is significantly associated with histological steatosis grade. The diagnostic accuracy of ATT for histological steatosis grade is equivalent to controlled attenuation parameter (CAP), and ATT has a lower measurement failure rate than CAP because ATT can be measured on a B-mode image with the exact location of the region of interest. Furthermore, ATT measurement has high interobserver reproducibility. Since ATT measurement and other ultrasound-based modalities for liver fat quantification are easy to perform and inexpensive, these modalities are suitable for point-of-care and screening. Although emerging data suggest that quantitative liver fat content and its changes over time may be associated with disease progression in nonalcoholic fatty liver disease, the association between ATT and disease progression has not been evaluated yet. Therefore, further investigation and validation studies are necessary to strengthen the clinical significance of ATT measurement in chronic liver disease.
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Affiliation(s)
- Nobuharu Tamaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Masayuki Kurosaki
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Yutaka Yasui
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Kaoru Tsuchiya
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, 1-26-1 Kyonan-cho, Musashino-shi, Tokyo, 180-8610, Japan.
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15
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Dajti E, Alemanni LV, Marasco G, Montagnani M, Azzaroli F. Approaches to the Diagnosis of Portal Hypertension: Non-Invasive or Invasive Tests? Hepat Med 2021; 13:25-36. [PMID: 33776492 PMCID: PMC7987277 DOI: 10.2147/hmer.s278077] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 02/19/2021] [Indexed: 12/15/2022] Open
Abstract
Portal hypertension is the main driver of complications in patients with advanced chronic liver disease (ACLD) and is defined by values of hepatic venous pressure gradient measurement (HVPG) >5 mmHg. Values of HVPG ≥10 mmHg determine the presence of clinically significant portal hypertension (CSPH), the main predictor of the risk of variceal bleeding, hepatic decompensation, and mortality. However, its measurement is invasive and requires high expertise, so its routine use outside third level centers or clinical trials is limited. In the last decades, several non-invasive tests (NITs) have been developed and validated for the diagnosis of portal hypertension. Among these, liver (LSM) and spleen stiffness measurement (SSM) are the most promising tools available, as they have been proven accurate to predict CSPH, high-risk esophageal varices, decompensation, and mortality in patients with ACLD. In the last Baveno VI Consensus proceedings, LSM evaluation was recommended for the first time for diagnosis of CSPH (LSM >20-25 kPa) and the screening of patients with a low probability of having high-risk varices (LSM <20 kPa and platelet count >150.000/mm3). In this review, we aimed to summarize the growing evidence supporting the use of non-invasive tests for the evaluation of portal hypertension in patients with chronic liver disease.
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Affiliation(s)
- Elton Dajti
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Luigina Vanessa Alemanni
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Giovanni Marasco
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Marco Montagnani
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
| | - Francesco Azzaroli
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.,Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy
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16
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Eguchi Y, Wong G, Lee IH, Akhtar O, Lopes R, Sumida Y. Hepatocellular carcinoma and other complications of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Japan: A structured review of published works. Hepatol Res 2021; 51:19-30. [PMID: 33091191 DOI: 10.1111/hepr.13583] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 08/27/2020] [Accepted: 09/08/2020] [Indexed: 02/08/2023]
Abstract
AIMS Hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality in Japan. As the treatment of viral hepatitis improves, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are rapidly becoming leading causes of HCC in Japan. This structured review aims to characterize the morbidity and mortality of HCC and other malignant and non-malignant complications among Japanese NAFLD and NASH patients. METHODS An English and Japanese structured search of published works was undertaken in PubMed, Embase, and Ichushi Web databases, identifying 6553 studies, 34 of which met predefined inclusion criteria. RESULTS Hepatocellular carcinoma was the most common incident malignancy among NAFLD/NASH patients, with higher incidence in patients with advanced/severe fibrosis (F3/F4) of 10.5%-20.0%. Although NASH results in a lower HCC cumulative incidence than hepatitis C virus (HCV) (11.3% vs. 30.5%), they have similar impacts on health outcomes, including overall mortality. Among Japanese NASH patients, HCC was found to be the main driver of mortality (40.0% in 2.7 years in NASH-HCC). With longer follow-up, higher mortality rates are observed in F3/4 patients: 25.0% in NASH F3/F4 versus 0.0% in NASH F0/2 over 7.7 years. The NASH-HCC patients also have a higher post-operative mortality than HCV-HCC patients. Additionally, NAFLD/NASH patients had higher rates of cardiovascular disease than non-NAFLD/NASH controls, and slightly higher rates of gastric cancer than HCV patients. CONCLUSION Hepatocellular carcinoma is the most common malignancy and cause of death among NAFLD/NASH patients in Japan, with higher mortality observed among those with advanced disease and complications. Early identification and effective treatments are needed.
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Affiliation(s)
- Yuichiro Eguchi
- Liver Center, Saga University Hospital, Saga, Japan.,Department of Internal Medicine, Saga University, Japan
| | | | - I-Heng Lee
- Gilead Sciences Inc, Foster City, CA, USA
| | | | | | - Yoshio Sumida
- Division of Hepatology and Pancreatology, Department of Internal Medicine, Aichi Medical University, Japan
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17
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Watt GP, De La Cerda I, Pan J, Fallon MB, Beretta L, Loomba R, Lee M, McCormick JB, Fisher‐Hoch SP. Elevated Glycated Hemoglobin Is Associated With Liver Fibrosis, as Assessed by Elastography, in a Population-Based Study of Mexican Americans. Hepatol Commun 2020; 4:1793-1801. [PMID: 33305150 PMCID: PMC7706295 DOI: 10.1002/hep4.1603] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 07/18/2020] [Accepted: 07/31/2020] [Indexed: 12/13/2022] Open
Abstract
Diabetes is associated with liver disease and risk of hepatocellular carcinoma. In this study, we evaluated the association between liver fibrosis measured by transient elastography and four glucose metabolism measures in the Cameron County Hispanic Cohort, a population-based, randomly selected cohort of Mexican American Hispanics with high rates of diabetes and liver cancer. We measured liver fibrosis (a risk factor for hepatocellular carcinoma) in 774 well-characterized cohort participants using transient elastography. We evaluated the association of liver fibrosis with glycated hemoglobin (HbA1c), fasting blood glucose, insulin, and insulin resistance using multivariable linear regression models. In multivariable models, log-transformed HbA1c had the strongest association with liver fibrosis (β = 0.37, 95% confidence interval [CI] 0.04-0.69, P = 0.038), after controlling for waist circumference, aspartate aminotransferase, alanine aminotransferase, liver fat, and other known confounders. The association was statistically significant among women (β = 0.33, 95% CI 0.10-0.56, P = 0.009) and similar but nonsignificant among men (β = 0.41, 95% CI -0.17 to 0.98, P = 0.593). Waist circumference, platelet count, aspartate transaminase, and liver steatosis were each associated with liver stiffness. Conclusions: Elevated HbA1c is associated with liver fibrosis, a key risk factor for HCC, particularly among women. Our results indicate that Mexican Americans with uncontrolled HbA1c may benefit from routine screening by liver elastography to identify individuals at risk of liver disease progression.
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Affiliation(s)
- Gordon P. Watt
- Department of Epidemiology and BiostatisticsMemorial Sloan Kettering Cancer CenterNew YorkNYUSA
| | - Isela De La Cerda
- Division of EpidemiologyHuman Genetics and Environmental HealthUniversity of Texas Health Science Center at Houston School of Public Health. Brownsville campusBrownsvilleTXUSA
| | - Jen‐Jung Pan
- Division of Gastroenterology and HepatologyDepartment of MedicineThe University of Arizona College of Medicine—PhoenixPhoenixAZUSA
| | - Michael B. Fallon
- Department of MedicineThe University of Arizona College of Medicine—PhoenixPhoenixAZUSA
| | - Laura Beretta
- Department of Molecular and Cellular OncologyThe University of Texas MD Anderson Cancer CenterHoustonTXUSA
| | - Rohit Loomba
- NAFLD Research CenterDivision of GastroenterologyUniversity of California San Diego School of MedicineLa JollaCAUSA
| | - Miryoung Lee
- Division of EpidemiologyHuman Genetics and Environmental HealthUniversity of Texas Health Science Center at Houston School of Public Health. Brownsville campusBrownsvilleTXUSA
| | - Joseph B. McCormick
- Division of EpidemiologyHuman Genetics and Environmental HealthUniversity of Texas Health Science Center at Houston School of Public Health. Brownsville campusBrownsvilleTXUSA
| | - Susan P. Fisher‐Hoch
- Division of EpidemiologyHuman Genetics and Environmental HealthUniversity of Texas Health Science Center at Houston School of Public Health. Brownsville campusBrownsvilleTXUSA
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18
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Xing X, Wang Y, Zhang X, Gao X, Li M, Wu S, Zhao Y, Chen J, Gao D, Chen R, Ren Z, Zhang K, Cui J. Matrix stiffness-mediated effects on macrophages polarization and their LOXL2 expression. FEBS J 2020; 288:3465-3477. [PMID: 32964626 DOI: 10.1111/febs.15566] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 08/06/2020] [Accepted: 09/13/2020] [Indexed: 12/12/2022]
Abstract
Previously, we reported that the secreted lysyl oxidase like 2 (LOXL2) from hepatocellular carcinoma (HCC) cells under higher stiffness stimulation contributed to the formation of lung premetastatic niche. To further clarify whether matrix stiffness also alters LOXL2 expression in other cells within tumor microenvironment, we developed a gel-based culture system combined with a model of macrophage polarization to evaluate the effects of matrix stiffness on the polarization of M2 macrophages and their LOXL2 expression. THP-1 cells cultured on 6KPa, 10KPa, and 16KPa stiffness substrates were first incubated with 100nM phorbol 12-myristate 13-acetate (PMA) for 24 hours and subsequently treated with 20nM interleukin-4 (IL-4) and 20nM interleukin-13 (IL-13) for 48 hours. The polarization states of M2 macrophages under different stiffness stimulation were comparatively analyzed, and their LOXL2 expressions as well as the underlying molecular mechanism were further explored. Our results demonstrated that increased matrix stiffness remarkably strengthened M2 macrophage polarization and promoted their LOXL2 expression. Activation of integrin β5-FAK-MEK1/2-ERK1/2 pathway participated in matrix stiffness-mediated HIF-1α upregulation, and HIF-1α upregulation resulted in a significant improvement in LOXL2 expression. Additionally, M2 macrophage polarization state and LOXL2 expression in HCC tissues with COL1High /LOXHigh were consistent with the results in vitro, further confirming the regulation roles of matrix stiffness in macrophage polarization and LOXL2 expression. The findings about LOXL2 upregulation in the polarized macrophages under higher stiffness stimulation will be helpful to better understand the underlying mechanism of matrix stiffness-induced premetastatic niche formation in HCC.
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Affiliation(s)
- Xiaoxia Xing
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Yaohui Wang
- Department of Radiology, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Xi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Xiangyu Gao
- Department of Endocrinology, Huashan Hospital & Institute of Endocrinology and Diabetology, Fudan University, Shanghai, China
| | - Miao Li
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Sifan Wu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Yan Zhao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Jie Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Dongmei Gao
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Rongxin Chen
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Zhenggang Ren
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
| | - Kezhi Zhang
- Department of Hepatobiliary Surgery, Taizhou People's Hospital, Taizhou, China
| | - Jiefeng Cui
- Liver Cancer Institute, Zhongshan Hospital, Fudan University & Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, China
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19
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Marasco G, Colecchia A, Silva G, Rossini B, Eusebi LH, Ravaioli F, Dajti E, Alemanni LV, Colecchia L, Renzulli M, Golfieri R, Festi D. Non-invasive tests for the prediction of primary hepatocellular carcinoma. World J Gastroenterol 2020; 26:3326-3343. [PMID: 32655261 PMCID: PMC7327793 DOI: 10.3748/wjg.v26.i24.3326] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 04/08/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world and it is one of the main complications of cirrhosis and portal hypertension. Even in the presence of a well-established follow-up protocol for cirrhotic patients, to date poor data are available on predictive markers for primary HCC occurrence in the setting of compensated advanced chronic liver disease patients (cACLD). The gold standard method to evaluate the prognosis of patients with cACLD, beyond liver fibrosis assessed with histology, is the measurement of the hepatic venous pressure gradient (HVPG). An HVPG ≥10 mmHg has been related to an increased risk of HCC in cACLD patients. However, these methods are burdened by additional costs and risks for patients and are mostly available only in referral centers. In the last decade increasing research has focused on the evaluation of several, simple, non-invasive tests (NITs) as predictors of HCC development. We reviewed the currently available literature on biochemical and ultrasound-based scores developed for the non-invasive evaluation of liver fibrosis and portal hypertension in predicting primary HCC. We found that the most reliable methods to assess HCC risk were the liver stiffness measurement, the aspartate aminotransferase to platelet ratio index score and the fibrosis-4 index. Other promising NITs need further investigations and validation for different liver disease aetiologies.
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Affiliation(s)
- Giovanni Marasco
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Antonio Colecchia
- Unit of Gastroenterology, Borgo Trento University Hospital of Verona, Verona 37126, Italy
| | - Giovanni Silva
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Benedetta Rossini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Leonardo Henry Eusebi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Federico Ravaioli
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Elton Dajti
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Luigina Vanessa Alemanni
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Luigi Colecchia
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
| | - Matteo Renzulli
- Radiology Unit, Sant’Orsola Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Rita Golfieri
- Radiology Unit, Sant’Orsola Malpighi Hospital, University of Bologna, Bologna 40138, Italy
| | - Davide Festi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna 40138, Italy
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