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1
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Pugliese N, Alfarone L, Arcari I, Giugliano S, Parigi TL, Rescigno M, Lleo A, Aghemo A. Clinical features and management issues of NAFLD-related HCC: what we know so far. Expert Rev Gastroenterol Hepatol 2023; 17:31-43. [PMID: 36576057 DOI: 10.1080/17474124.2023.2162503] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) is replacing viral hepatitis as the leading cause of chronic liver disease and hepatocellular carcinoma (HCC) in many Western countries. NAFLD-associated HCC usually affects older patients with multiple comorbidities, frequently develops in the absence of cirrhosis, and is often diagnosed later with worse chance of survival. The worse prognosis is also due to limited surveillance strategies and a lower efficacy of standard treatments. AREAS COVERED We evaluate the available literature to understand the current surveillance strategies and treatment limitations in the workup of NAFLD-associated HCC, focusing on the differences with HCC associated with other liver diseases. EXPERT OPINION In this review we discuss epidemiology and risk factors for HCC in NAFLD patients and address key HCC surveillance and management issues. Although most data are still preliminary, the detection of non-cirrhotic NAFLD patients at increased risk for HCC and the potential adoption of novel screening tools could lead to accurate and suitable HCC surveillance and management strategies for NAFLD patients.
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Affiliation(s)
- Nicola Pugliese
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Ludovico Alfarone
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Ivan Arcari
- Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Silvia Giugliano
- Laboratory of Mucosal Immunology and Microbiota, IRCCS Humanitas Research Hospital - IRCCS, via Manzoni 56, 20089 Rozzano, Italy
| | | | - Maria Rescigno
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Laboratory of Mucosal Immunology and Microbiota, IRCCS Humanitas Research Hospital - IRCCS, via Manzoni 56, 20089 Rozzano, Italy
| | - Ana Lleo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
| | - Alessio Aghemo
- Division of Internal Medicine and Hepatology, Department of Gastroenterology, IRCCS Humanitas Research Hospital, Milan, Italy.,Department of Biomedical Sciences, Humanitas University, Milan, Italy
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2
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Li Y, Wang X, Zhang J, Zhang S, Jiao J. Applications of artificial intelligence (AI) in researches on non-alcoholic fatty liver disease(NAFLD) : A systematic review. Rev Endocr Metab Disord 2022; 23:387-400. [PMID: 34396467 DOI: 10.1007/s11154-021-09681-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/07/2021] [Indexed: 10/20/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is one of the most important causes of chronic liver disease in the world, it has been found that cardiovascular and renal risks and diseases are also highly prevalent in adults with NAFLD. Diagnosis and treatment of NAFLD face many challenges, although the medical science has been very developed. Efficiency, accuracy and individualization are the main goals to be solved. Evaluation of the severity of NAFLD involves a variety of clinical parameters, how to optimize non-invasive evaluation methods is a necessary issue that needs to be discussed in this field. Artificial intelligence (AI) has become increasingly widespread in healthcare applications, and it has been also brought many new insights into better analyzing chronic liver disease, including NAFLD. This paper reviewed AI related researches in NAFLD field published recently, summarized diagnostic models based on electronic health record and lab test, ultrasound and radio imaging, and liver histopathological data, described the application of therapeutic models in personalized lifestyle guidance and the development of drugs for NAFLD. In addition, we also analyzed present AI models in distinguishing healthy VS NAFLD/NASH, and fibrosis VS non-fibrosis in the evaluation of NAFLD progression. We hope to provide alternative directions for the future research.
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Affiliation(s)
- Yifang Li
- Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Xuetao Wang
- Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Jun Zhang
- Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Shanshan Zhang
- Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China
| | - Jian Jiao
- Department of Gastroenterolgy & Hepatology, China-Japan Union Hospital, Jilin University, Changchun, 130033, China.
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3
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Long-term surgical outcomes of Non alcoholic fatty liver disease associated hepatocellular carcinoma. Surg Oncol 2022; 41:101730. [DOI: 10.1016/j.suronc.2022.101730] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 02/04/2022] [Accepted: 02/22/2022] [Indexed: 11/24/2022]
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Chrysavgis L, Giannakodimos I, Diamantopoulou P, Cholongitas E. Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link. World J Gastroenterol 2022; 28:310-331. [PMID: 35110952 PMCID: PMC8771615 DOI: 10.3748/wjg.v28.i3.310] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/19/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common liver disorder worldwide mainly attributed to the epidemic spread of obesity and type 2 diabetes mellitus. Although it is considered a benign disease, NAFLD can progress to non-alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). Most data regarding the epidemiology of NAFLD-related HCC are derived from cohort and population studies and show that its incidence is increasing as well as it is likely to emerge as the leading indication for liver transplantation, especially in the Western World. Although cirrhosis constitutes the main risk factor for HCC development, in patients with NAFLD, HCC can arise in the absence of cirrhosis, indicating specific carcinogenic molecular pathways. Since NAFLD as an underlying liver disease for HCC is often underdiagnosed due to lack of sufficient surveillance in this population, NAFLD-HCC patients are at advanced HCC stage at the time of diagnosis making the management of those patients clinically challenging and affecting their prognostic outcomes. In this current review, we summarize the latest literature on the epidemiology, other than liver cirrhosis-pathogenesis, risk factors and prognosis of NAFLD-HCC patients. Finally, we emphasize the prevention of the development of NAFLD-associated HCC and we provide some insight into the open questions and issues regarding the appropriate surveillance policies for those patients.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Experimental Physiology, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Ilias Giannakodimos
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagiota Diamantopoulou
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
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5
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Bissoondial TL, Pellicano AJ, Goldberg ID, Narayan P. Identification of disease-associated microRNA in a diet-induced model of nonalcoholic steatohepatitis. Mol Omics 2021; 17:911-916. [PMID: 34757352 DOI: 10.1039/d1mo00274k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Emerging evidence suggests that microRNA dysregulation plays an important role in nonalcoholic steatohepatitis. Using a model of diet-induced liver disease that progresses to fibrosis and hepatocellular carcinoma, we identify a set of 22 microRNA with robust correlation with liver enzyme levels and liver collagen content. These disease-asssociated miRs play pivotal roles in steatosis, extracellular matrix deposition and liver cancer, and may form the basis for identification of therapeutic strategies against this form of liver disease.
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Affiliation(s)
| | | | | | - Prakash Narayan
- Department of Preclinical Research, Angion Biomedica Corp., USA.
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6
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Zhang Y, Gao J, Bao Y, Liu Y, Tong Y, Jin S, Zhao Q. Diagnostic accuracy and prognostic significance of osteopontin in liver cirrhosis and hepatocellular carcinoma: a Meta-analysis. Biomarkers 2021; 27:13-21. [PMID: 34787036 DOI: 10.1080/1354750x.2021.2008009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVE At present, there is no definite suggestion about effective tumour biomarkers for the diagnostic accuracy and prognostic significance of hepatocellular carcinoma (HCC) and liver cirrhosis (LC). The aim of our research was to determine the value of the tumour biomarker osteopontin (OPN), which is encoded by the Spp1 gene, in the diagnosis, prognosis and development of HCC and LC through meta-analysis. METHODS A systematic literature search was performed in the PubMed, Embase, Cochrane Library and China National Knowledge Infrastructure electronic databases up to March 2021. Studies evaluating the diagnostic and/or prognostic value of OPN in HCC and/or LC were included. RESULTS From the systematic search, 35 studies including 9150 participants were eligible, 25 of which provided data on the diagnostic value of OPN overexpression, while 15 studies provided data on the prognostic value. OPN had high diagnostic accuracy in both HCC and LC patients compared with healthy controls, and the diagnostic efficiency was increased by the biomarker combination OPN + AFP. CONCLUSIONS OPN may be adopted as a promising predictive tumour biomarker for the diagnosis and prognosis of HCC and LC and may be a potential therapeutic target.
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Affiliation(s)
- Yingshi Zhang
- Department of Pharmacy, Northern Theater General Hospital, Shenyang, China.,Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Jiayue Gao
- National Center of Biomedical Analysis, Beijing, China
| | - Yu Bao
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Yang Liu
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Yimeng Tong
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Shuqing Jin
- Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Qingchun Zhao
- Department of Pharmacy, Northern Theater General Hospital, Shenyang, China.,Department of Clinical Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
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Hepatic mRNA Expression Levels of the Oncogenes Alpha-Fetoprotein and Osteopontin as Diagnostics for Liver Cancer in a Murine Model of Diet-Induced Non-Alcoholic Steatohepatitis. Processes (Basel) 2021. [DOI: 10.3390/pr9091516] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with an increased risk of hepatocellular carcinoma (HCC). Expression levels of hepatic oncogenes, alpha-fetoprotein (afp) and osteopontin (opn)/secreted phosphoprotein 1 (spp1), were investigated using a model of diet-induced NASH. Mice were randomized to a standard diet or a fast-food diet (FFD) for 17 months. Livers from the FFD cohort exhibited hallmark characteristics of NASH with liver fibrosis, with a subset of animals exhibiting HCC. Expression levels of hepatic afp and opn/spp1 were elevated ~2.5 and ~5-fold, respectively, in the FFD cohort. Hepatic opn/spp1 exhibited a direct (r = 0.65) and significant (p < 0.01) correlation with liver hydroxyproline content. Receiver operating characteristic (ROC) curve analysis for hepatic afp, as a diagnostic for HCC, returned an area under (AU) ROC 0.84, a sensitivity of 87.5%, a specificity of 77% and a threshold of >1.05-fold change in mRNA level. The use of hepatic opn/ssp1 as a diagnostic for HCC returned an AUROC 0.88, a sensitivity of 83.3%, a specificity of 86.7% and a threshold of >2.4-fold change in mRNA level. These data point to a transformation of NASH to an oncotype with hepatic oncogene levels as a diagnostic for NASH.
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Collagen Characterization in a Model of Nonalcoholic Steatohepatitis with Fibrosis; A Call for Development of Targeted Therapeutics. Molecules 2021; 26:molecules26113316. [PMID: 34205850 PMCID: PMC8198364 DOI: 10.3390/molecules26113316] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 05/20/2021] [Accepted: 05/27/2021] [Indexed: 02/06/2023] Open
Abstract
Left untreated, nonalcoholic fatty liver disease can progress to nonalcoholic steatohepatitis (NASH), fibrosis, and end-stage liver disease. To date, few if any therapies have proven effective against NASH with fibrosis. Quantification and qualification of hepatic scar might enable development of more effective targeted therapies. In a murine model of NASH induced by diet, we characterized fibrillar collagen deposition within the hepatic parenchyma. At harvest, livers from the modified diet cohort exhibited NASH with fibrosis. Transcriptomic analysis of hepatic tissue revealed increased col1a1, col1a2, and col3a1, each of which correlated directly with hepatic hydroxyproline content. Circular polarized microscopic analysis of Picrosirius red-stained liver sections revealed deposition of collagen type I within the parenchyma. Development of therapeutics designed to mitigate collagen type I accumulation might prove effective in NASH with fibrosis.
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9
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Colli A, Nadarevic T, Miletic D, Giljaca V, Fraquelli M, Štimac D, Casazza G. Abdominal ultrasound and alpha-foetoprotein for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease. Cochrane Database Syst Rev 2021; 4:CD013346. [PMID: 33855699 PMCID: PMC8078581 DOI: 10.1002/14651858.cd013346.pub2] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) occurs mostly in people with chronic liver disease and ranks sixth in terms of global instances of cancer, and fourth in terms of cancer deaths for men. Despite that abdominal ultrasound (US) is used as an initial test to exclude the presence of focal liver lesions and serum alpha-foetoprotein (AFP) measurement may raise suspicion of HCC occurrence, further testing to confirm diagnosis as well as staging of HCC is required. Current guidelines recommend surveillance programme using US, with or without AFP, to detect HCC in high-risk populations despite the lack of clear benefits on overall survival. Assessing the diagnostic accuracy of US and AFP may clarify whether the absence of benefit in surveillance programmes could be related to under-diagnosis. Therefore, assessment of the accuracy of these two tests for diagnosing HCC in people with chronic liver disease, not included in surveillance programmes, is needed. OBJECTIVES Primary: the diagnostic accuracy of US and AFP, alone or in combination, for the diagnosis of HCC of any size and at any stage in adults with chronic liver disease, either in a surveillance programme or in a clinical setting. Secondary: to assess the diagnostic accuracy of abdominal US and AFP, alone or in combination, for the diagnosis of resectable HCC; to compare the diagnostic accuracy of the individual tests versus the combination of both tests; to investigate sources of heterogeneity in the results. SEARCH METHODS We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic-Test-Accuracy Studies Register, Cochrane Library, MEDLINE, Embase, LILACS, Science Citation Index Expanded, until 5 June 2020. We applied no language or document-type restrictions. SELECTION CRITERIA Studies assessing the diagnostic accuracy of US and AFP, independently or in combination, for the diagnosis of HCC in adults with chronic liver disease, with cross-sectional and case-control designs, using one of the acceptable reference standards, such as pathology of the explanted liver, histology of resected or biopsied focal liver lesion, or typical characteristics on computed tomography, or magnetic resonance imaging, all with a six-months follow-up. DATA COLLECTION AND ANALYSIS We independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest-plots, and tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses. MAIN RESULTS We included 373 studies. The index-test was AFP (326 studies, 144,570 participants); US (39 studies, 18,792 participants); and a combination of AFP and US (eight studies, 5454 participants). We judged at high-risk of bias all but one study. Most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time-interval between the index test and the reference standard was rarely defined. Most studies with AFP had a case-control design. We also had major concerns for the applicability due to the characteristics of the participants. As the primary studies with AFP used different cut-offs, we performed a meta-analysis using the hierarchical-summary-receiver-operating-characteristic model, then we carried out two meta-analyses including only studies reporting the most used cut-offs: around 20 ng/mL or 200 ng/mL. AFP cut-off 20 ng/mL: for HCC (147 studies) sensitivity 60% (95% CI 58% to 62%), specificity 84% (95% CI 82% to 86%); for resectable HCC (six studies) sensitivity 65% (95% CI 62% to 68%), specificity 80% (95% CI 59% to 91%). AFP cut-off 200 ng/mL: for HCC (56 studies) sensitivity 36% (95% CI 31% to 41%), specificity 99% (95% CI 98% to 99%); for resectable HCC (two studies) one with sensitivity 4% (95% CI 0% to 19%), specificity 100% (95% CI 96% to 100%), and one with sensitivity 8% (95% CI 3% to 18%), specificity 100% (95% CI 97% to 100%). US: for HCC (39 studies) sensitivity 72% (95% CI 63% to 79%), specificity 94% (95% CI 91% to 96%); for resectable HCC (seven studies) sensitivity 53% (95% CI 38% to 67%), specificity 96% (95% CI 94% to 97%). Combination of AFP (cut-off of 20 ng/mL) and US: for HCC (six studies) sensitivity 96% (95% CI 88% to 98%), specificity 85% (95% CI 73% to 93%); for resectable HCC (two studies) one with sensitivity 89% (95% CI 73% to 97%), specificity of 83% (95% CI 76% to 88%), and one with sensitivity 79% (95% CI 54% to 94%), specificity 87% (95% CI 79% to 94%). The observed heterogeneity in the results remains mostly unexplained, and only in part referable to different cut-offs or settings (surveillance programme compared to clinical series). The sensitivity analyses, excluding studies published as abstracts, or with case-control design, showed no variation in the results. We compared the accuracy obtained from studies with AFP (cut-off around 20 ng/mL) and US: a direct comparison in 11 studies (6674 participants) showed a higher sensitivity of US (81%, 95% CI 66% to 90%) versus AFP (64%, 95% CI 56% to 71%) with similar specificity: US 92% (95% CI 83% to 97%) versus AFP 89% (95% CI 79% to 94%). A direct comparison of six studies (5044 participants) showed a higher sensitivity (96%, 95% CI 88% to 98%) of the combination of AFP and US versus US (76%, 95% CI 56% to 89%) with similar specificity: AFP and US 85% (95% CI 73% to 92%) versus US 93% (95% CI 80% to 98%). AUTHORS' CONCLUSIONS In the clinical pathway for the diagnosis of HCC in adults, AFP and US, singularly or in combination, have the role of triage-tests. We found that using AFP, with 20 ng/mL as a cut-off, about 40% of HCC occurrences would be missed, and with US alone, more than a quarter. The combination of the two tests showed the highest sensitivity and less than 5% of HCC occurrences would be missed with about 15% of false-positive results. The uncertainty resulting from the poor study quality and the heterogeneity of included studies limit our ability to confidently draw conclusions based on our results.
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Affiliation(s)
- Agostino Colli
- Department of Transfusion Medicine and Haematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy
| | - Tin Nadarevic
- Department of Radiology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Damir Miletic
- Department of Radiology , Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Vanja Giljaca
- Department of Gastroenterology, Heart of England NHS Foundation Trust, Birmingham, UK
| | - Mirella Fraquelli
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca´ Granda - Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, Rijeka, Croatia
| | - Giovanni Casazza
- Dipartimento di Scienze Biomediche e Cliniche "L. Sacco", Università degli Studi di Milano, Milan, Italy
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Ramai D, Tai W, Rivera M, Facciorusso A, Tartaglia N, Pacilli M, Ambrosi A, Cotsoglou C, Sacco R. Natural Progression of Non-Alcoholic Steatohepatitis to Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9020184. [PMID: 33673113 PMCID: PMC7918599 DOI: 10.3390/biomedicines9020184] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 02/01/2021] [Accepted: 02/09/2021] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease (NAFLD). Its global incidence is increasing which makes NASH an epidemic and a public health threat. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma (HCC). The progression of NASH to HCC was initially defined according to a two-hit model which involved the development of steatosis, followed by lipid peroxidation and inflammation. However, current research defines a “multi-hit” or “multi-parallel hit” model which synthesizes several contributing pathways involved in progressive fibrosis and oncogenesis. This perspective considers the effects of cellular, genetic, immunologic, metabolic, and endocrine pathways leading up to HCC which underscores the complexity of this condition. This article will provide an updated review of the pathogenic mechanisms leading from NASH to HCC as well as an exploration of the role of biomarkers and screening.
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Affiliation(s)
- Daryl Ramai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Waqqas Tai
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Michelle Rivera
- Department of Internal Medicine, The Brooklyn Hospital Center, Brooklyn, NY 11201, USA; (D.R.); (W.T.); (M.R.)
| | - Antonio Facciorusso
- Section of Gastroenterology, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
| | - Nicola Tartaglia
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Mario Pacilli
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Antonio Ambrosi
- General Surgery Unit, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (N.T.); (M.P.); (A.A.)
| | - Christian Cotsoglou
- General Surgey Unit, Department of Surgery, ASST-Vimercate, 20871 Vimercate, Italy;
| | - Rodolfo Sacco
- Section of Gastroenterology, Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy;
- Correspondence:
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11
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Geh D, Manas DM, Reeves HL. Hepatocellular carcinoma in non-alcoholic fatty liver disease-a review of an emerging challenge facing clinicians. Hepatobiliary Surg Nutr 2021; 10:59-75. [PMID: 33575290 DOI: 10.21037/hbsn.2019.08.08] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Accepted: 08/21/2019] [Indexed: 12/14/2022]
Abstract
Importance Non-alcoholic fatty liver disease (NAFLD) is a rapidly growing cause of chronic liver disease and is becoming a leading cause of hepatocellular carcinoma (HCC) in many developed countries. This presents major challenges for the surveillance, diagnosis and treatment of HCC. Objective To discuss the clinical challenges faced by clinicians in managing the rising number of NAFLD-HCC cases. Evidence Review MEDLINE, PubMed and Embase databases were searched using the keywords; NAFLD, HCC, surveillance, hepatectomy, liver transplantation, percutaneous ablation, transarterial chemoembolization (TACE), selective internal radiotherapy treatment (SIRT) and sorafenib. Relevant clinical studies were included. Findings Current HCC surveillance programmes are inadequate because they only screen for HCC in patients with cirrhosis, whereas in NAFLD a significant proportion of HCC develops in the absence of cirrhosis. Consequently NAFLD patients often present with a more advanced stage of HCC, with a poorer prognosis. NAFLD-HCC patients also tend to be older and to have more co-morbidities compared to HCC of other etiologies. This limits the use of curative treatments such as liver resection and orthotopic liver transplantation (OLT). Evidence suggests that although NAFLD-HCC patients who undergo liver resection or OLT have worse perioperative and short-term outcomes, overall long-term survival is comparable to HCC of other etiologies. This highlights the importance of careful patient selection, pre-habilitation and perioperative planning for NAFLD-HCC patients being considered for surgical treatment. Careful consideration is also important for non-surgical treatments, although the evidence supporting treatment selection is frequently lacking, as these patients tend to be poorly represented in clinical trials. Locoregional therapies such as percutaneous ablation and TACE may be less well tolerated and less effective in NAFLD patients with obesity or diabetes. The tyrosine kinase inhibitor sorafenib may also be less effective. Conclusions and Relevance This review highlights how international guidelines, for which NAFLD traditionally has made up a small part of the evidence base, may not be appropriate for all NAFLD-HCC patients. Future guidelines need to reflect the changing landscape of HCC, by making specific recommendations for the management of NAFLD-HCC.
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Affiliation(s)
- Daniel Geh
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
| | - Derek M Manas
- Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Helen L Reeves
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.,Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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12
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Liver Biopsy Hydroxyproline Content Is a Diagnostic for Hepatocellular Carcinoma in Murine Models of Nonalcoholic Steatohepatitis. Diagnostics (Basel) 2020; 10:diagnostics10100784. [PMID: 33020436 PMCID: PMC7601536 DOI: 10.3390/diagnostics10100784] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 09/20/2020] [Accepted: 10/01/2020] [Indexed: 02/06/2023] Open
Abstract
There is increasing evidence that nonalcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC) in the absence of cirrhosis, a phenomenon termed noncirrhotic HCC. Early diagnosis of HCC is critical to a favorable prognosis. We tested the hypothesis that hydroxyproline content of liver biopsy samples is diagnostic for HCC in murine models of NASH induced by diet or by diet and chemicals. The training set comprised mice fed a standard diet or a fast-food diet with or without administration of thioacetamide. At harvest, livers from the modified diet cohort exhibited NASH with a subset of NASH livers exhibiting HCC. Hydroxyproline content was measured in liver biopsy samples with tissue in the NASH+HCC cohort sampled from the remote, nontumor parenchyma. Plotting the receiver operating characteristics (ROC) with hydroxyproline as the continuous variable against the absence or presence of HCC yielded an area under ROC of 0.87, a threshold of >0.18 μg hydroxyproline/mg liver and sensitivity of 91% with a specificity of 83.3%. The use of liver hydroxyproline content as a diagnostic for HCC in a test set comprising healthy, NASH and NASH+HCC livers proved 87% accurate.
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Liao K, Pellicano AJ, Jiang K, Prakash N, Li J, Bhutkar S, Hu Z, Ali Q, Goldberg ID, Narayan P. Glycerol-3-phosphate Acyltransferase1 Is a Model-Agnostic Node in Nonalcoholic Fatty Liver Disease: Implications for Drug Development and Precision Medicine. ACS OMEGA 2020; 5:18465-18471. [PMID: 32743224 PMCID: PMC7391940 DOI: 10.1021/acsomega.0c02350] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 07/03/2020] [Indexed: 05/04/2023]
Abstract
Left untreated nonalcoholic fatty liver disease (NAFLD) can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The observed failure of clinical trials in NASH may suggest that current model systems do not fully recapitulate human disease, and/or hallmark pathological features of NASH may not be driven by the same pathway in every animal model let alone in each patient. Identification of a model-agnostic disease-associated node can spur the development of effective drugs for the treatment of liver disease. Glycerol-3-phosphate acyltransferase1 (GPAT1) plays a pivotal role in lipid accumulation by shunting fats away from oxidation. In the present study, hepatic GPAT1 expression was evaluated in three etiologically different models of NAFLD. Compared to the sham cohort, hepatic GPAT1 mRNA levels were elevated by ∼5-fold in steatosis and NASH with fibrosis with immunofluorescent staining revealing increased GPAT1 in the fatty liver. A significant and direct correlation (r = 0.88) was observed between hepatic GPAT1 mRNA expression and severity of the liver disease. Picrosirius red staining revealed a logarithmic relation between hepatic GPAT1 mRNA expression and scar. These data suggest that hepatic GPAT1 is an early disease-associated model-agnostic node in NAFLD and form the basis for the development of a potentially successful therapeutic against NASH.
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Anstee QM, Reeves HL, Kotsiliti E, Govaere O, Heikenwalder M. From NASH to HCC: current concepts and future challenges. Nat Rev Gastroenterol Hepatol 2019; 16:411-428. [PMID: 31028350 DOI: 10.1038/s41575-019-0145-7] [Citation(s) in RCA: 919] [Impact Index Per Article: 153.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC.
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Affiliation(s)
- Quentin M Anstee
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK.
| | - Helen L Reeves
- The Liver Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
- Northern Institute for Cancer Research, Medical School, Newcastle upon Tyne, UK
- Hepatopancreatobiliary Multidisciplinary Team, Newcastle upon Tyne NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK
| | - Elena Kotsiliti
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Olivier Govaere
- Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
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Chavre BM, Jiang K, St Surin LG, Bissoondial T, Zhou P, Li J, Gadhiya SV, Goldberg ID, Narayan P. Remodeling of Intrahepatic Ducts in a Model of Caroli Syndrome: Is Scar Carcinoma a Consequence of Laplace's Law? Med Sci (Basel) 2019; 7:medsci7040055. [PMID: 30939854 PMCID: PMC6524066 DOI: 10.3390/medsci7040055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2018] [Revised: 03/25/2019] [Accepted: 03/27/2019] [Indexed: 12/28/2022] Open
Abstract
Caroli syndrome, characterized by saccular dilatation of intrahepatic ducts and congenital hepatic fibrosis, is without therapy in part due to its ultra-rare prevalence and the apparent lack of availability of a suitable experimental model. While the PCK rat has long been used as a model of fibropolycystic kidney disease, hepatobiliary biophysics in this animal model is incompletely characterized. Compared to age-matched, wild-type controls, the PCK rat demonstrated severe hepatomegaly and large saccular dilated intrahepatic ducts. Nevertheless, hepatic density was greater in the PCK rat, likely due to severe duct wall sclerosis accompanied by scarring across the hepatic parenchyma. Extracellular matrix accumulation appeared proportional to duct cross-sectional area and liver volume and appeared compensatory in nature. The PCK rat livers exhibited both cholangiocarcinoma and hepatocellular carcinoma coincident with areas of increased extracellular matrix deposition. Together, these data suggest that the PCK rat model mimics at least in part the spectrum of hepatobiliary pathology observed in Caroli syndrome and highlights the attendant risk associated with this disease.
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Affiliation(s)
- Bharvi M Chavre
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Kai Jiang
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Luce G St Surin
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Terrence Bissoondial
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Ping Zhou
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Jingsong Li
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Satishkumar V Gadhiya
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Itzhak D Goldberg
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
| | - Prakash Narayan
- Department of Preclinical Research, Angion Biomedica Corp., Uniondale, NY 11553, USA.
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