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Jinato T, Anuntakarun S, Satthawiwat N, Chuaypen N, Tangkijvanich P. Distinct alterations of gut microbiota between viral- and non-viral-related hepatocellular carcinoma. Appl Microbiol Biotechnol 2024; 108:34. [PMID: 38183473 PMCID: PMC10771587 DOI: 10.1007/s00253-023-12845-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 11/06/2023] [Accepted: 11/16/2023] [Indexed: 01/08/2024]
Abstract
Altered gut microbiota has been connected to hepatocellular carcinoma (HCC) occurrence and advancement. This study was conducted to identify a gut microbiota signature in differentiating between viral-related HCC (Viral-HCC) and non-hepatitis B-, non-hepatitis C-related HCC (NBNC-HCC). Fecal specimens were obtained from 16 healthy controls, 33 patients with viral-HCC (17 and 16 cases with hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, respectively), and 18 patients with NBNC-HCC. Compositions of fecal microbiota were assessed by 16S rRNA sequencing. Bioinformatic analysis was performed by the DADA2 pipeline in the R program. Significantly different genera from the top 50 relative abundance were used to classify between subgroups of HCC by the Random Forest algorithm. Our data demonstrated that the HCC group had a significantly decreased alpha-diversity and changed microbial composition in comparison with healthy controls. Within the top 50 relative abundance, there were 11 genera including Faecalibacterium, Agathobacter, and Coprococcus that were significantly enhanced in Viral-HCC, while 5 genera such as Bacteroides, Streptococcus, Ruminococcus gnavus group, Parabacteroides, and Erysipelatoclostridium were enhanced in NBNC-HCC. Compared to Viral-HCC, the NBNC-HCC subgroup significantly reduced various short-chain fatty acid-producing bacteria, as well as declined fecal butyrate but elevated plasma surrogate markers of microbial translocation. Based on the machine learning algorithm, a high diagnostic accuracy to classify HCC subgroups was achieved with an area under the receiver-operating characteristic (ROC) curve (AUC) of 0.94. Collectively, these data revealed that gut dysbiosis was distinct according to etiological factors of HCC, which might play an essential role in hepatocarcinogenesis. These findings underscore the possible use of a gut microbiota signature for the diagnosis and therapeutic approaches regarding different subgroups of HCC. KEY POINTS: • Gut dysbiosis is connected to hepatocarcinogenesis and can be used as a novel biomarker. • Gut microbiota composition is significantly altered in different etiological factors of HCC. • Microbiota-based signature can accurately distinguish between Viral-HCC and NBNC-HCC.
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Affiliation(s)
- Thananya Jinato
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
- Doctor of Philosophy Program in Medical Sciences, Graduate Affairs, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Songtham Anuntakarun
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Nantawat Satthawiwat
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
| | - Pisit Tangkijvanich
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.
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Ismaiel A, Portincasa P, Dumitrascu DL. Natural History of Nonalcoholic Fatty Liver Disease. ESSENTIALS OF NON-ALCOHOLIC FATTY LIVER DISEASE 2023:19-43. [DOI: 10.1007/978-3-031-33548-8_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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3
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Jain A, Mazer B, Deng Y, Ciarleglio M, Jain D, Taddei T, Zhang X. Hepatocellular Carcinoma: Does the Background Liver With or Without Cirrhosis Matter? Am J Clin Pathol 2022; 157:305-313. [PMID: 34542582 DOI: 10.1093/ajcp/aqab125] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Accepted: 06/24/2021] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES The pathologic differences between hepatocellular carcinoma (HCC) arising in noncirrhotic and cirrhotic livers have not been well studied. METHODS We performed a retrospective analysis of 378 HCC cases (95 in noncirrhotic, 283 in cirrhotic livers) from pathology archives (2010-2017). RESULTS Patients without cirrhosis were more likely to have hepatitis B (13.68% vs 2.83%, P < .001) or no known liver disease (30.53% vs 4.24%, P < .001), while hepatitis C was more common in patients with cirrhosis (65.72% vs 30.53%, P < .001). HCCs in noncirrhotic livers were larger in size (P < .001); were more likely to have a macrotrabecular histologic pattern (13.68% vs 4.95%, P < .01); were more likely to have fibrolamellar (3.16% vs 0%, P = .02), macrotrabecular-massive (13.68% vs 6.01%, P = .03), and clear cell (16.84% vs 6.71%, P < .01) subtypes; have a higher histologic grade (P < .01); be anaplastic tumor cells (P < .001); have a higher rate of vascular invasion (P < .01); and have a higher tumor stage (P = .04). CONCLUSIONS The findings indicate that HCCs in noncirrhotic livers demonstrate a larger tumor size; have a more macrotrabecular histologic pattern; have fibrolamellar, macrotrabecular-massive, and clear cell subtypes; have a higher tumor grade and stage; have a higher rate of vascular invasion; and have more anaplastic tumor cells compared with cirrhotic livers. Further studies to explore different pathways that promote oncogenesis in noncirrhotic livers are needed to better understand the pathogenesis of HCC.
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Affiliation(s)
| | | | - Yanhong Deng
- Yale Center for Analytical Sciences, New Haven, CT, USA
| | | | | | - Tamar Taddei
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
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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: 41] [Impact Index Per Article: 13.7] [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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Trevisani F, Giannini EG. The ITA.LI.CA Consortium: How multicentre collaboration helped shape the management of patients with hepatocellular carcinoma on the basis of real-world evidence. Ann Hepatol 2022; 27 Suppl 1:100564. [PMID: 34688886 DOI: 10.1016/j.aohep.2021.100564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 02/04/2023]
Abstract
The growing diffusion of digitalisation and informatics has promoted the creation and analysis of large databases able to provide solid information. Analyses of "big data" generated by real-world practice are particularly useful for knowing incidence and mortality, disparities, temporal trends of diseases, identifying risk factors, predicting future scenarios, obtaining inputs for cost-effectiveness and treatment benefit modelling, designing new studies, and monitoring rare diseases. Although randomised controlled trials (RCTs) represent the gold-standard for generating evidence about new diagnostic, preventive or therapeutic procedures, their results should be integrated with real-world data to personalise patient management. Indeed, a substantial proportion of patients observed in field-practice have characteristics that prevent the access to RCTs or, when included, form sub-groups too small to provide robust post-hoc analyses. Furthermore, as RCTs are resource-consuming and designed to maximize the probability of success, they are generally performed in expert centres of high-income areas, excluding economically-deprived regions which could complementarily contribute to the medical progress as huge sources of real-world data. These considerations fuelled the creation in 1998 of the Italian Liver Cancer (ITA.LI.CA) consortium, with the aim to merge data of patients with hepatocellular carcinoma (HCC) managed in several centres. This cooperation permitted to analyse a multicentre, large cohort of HCC patients. Since then, the ITA.LI.CA group has progressively expanded to currently include 24 centres, and its database counts more than 9,000 patients. This article describes the history of the ITA.LI.CA consortium and presents its scientific production whose results greatly contributed to the incessant improvement of HCC management.
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Affiliation(s)
- Franco Trevisani
- Medical Semeiotics Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | - Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, University of Genoa, Genoa, Italy; IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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6
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Hester CA, Rich NE, Singal AG, Yopp AC. Comparative Analysis of Nonalcoholic Steatohepatitis- Versus Viral Hepatitis- and Alcohol-Related Liver Disease-Related Hepatocellular Carcinoma. J Natl Compr Canc Netw 2020; 17:322-329. [PMID: 30959469 DOI: 10.6004/jnccn.2018.7105] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 11/21/2018] [Indexed: 01/23/2023]
Abstract
BACKGROUND Despite an increasing burden of nonalcoholic steatohepatitis (NASH), limited data are available comparing outcomes of NASH-related hepatocellular carcinoma (HCC) versus other etiologies. METHODS Patient demographic and tumor characteristics were collected for 1,051 patients diagnosed with NASH-, alcohol-related liver disease (ALD)-, hepatitis C virus (HCV)-, and hepatitis B virus (HBV)-related HCC at 2 large health systems from January 2008 through December 2016. Patient demographics, clinical characteristics, and survival were compared. Risk-adjusted treatment receipt and overall survival (OS) were examined using multivariable analysis. RESULTS A total of 92 patients with NASH-related HCC were compared with 153 patients with ALD-, 719 with HCV-, and 87 with HBV-related HCC. Patients with NASH were older, more likely female, and more likely Hispanic white. Patients with NASH and HBV had more compensated liver disease than those with ALD or HCV, including significantly higher proportions having noncirrhotic HCC. Despite similar surveillance receipt and Barcelona Clinic Liver Cancer (BCLC) tumor stage at diagnosis, patients with NASH had higher rates of curative-intent therapy than those with other diseases. Unadjusted median OS was 16 months for NASH, 15 months for ALD, 14 months for HCV, and 8 months for HBV. In multivariable analysis, NASH was associated with worse OS compared with ALD (hazard ratio, 1.92; 95% CI, 1.3-2.5), but there was no difference between NASH- and HCV- or HBV-related HCC. CONCLUSIONS Patients with NASH-related HCC present with more preserved liver function, including a higher proportion having noncirrhotic HCC, than other diseases. Despite patients having similar tumor stage at diagnosis, NASH is independently associated with worse survival compared with ALD, but similar survival compared with HCV and HBV.
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Affiliation(s)
- Caitlin A Hester
- aDepartment of Surgery, Division of Surgical Oncology, Department of Medicine, and
| | - Nicole E Rich
- bDivision of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Amit G Singal
- bDivision of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Adam C Yopp
- aDepartment of Surgery, Division of Surgical Oncology, Department of Medicine, and
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Golabi P, Rhea L, Henry L, Younossi ZM. Hepatocellular carcinoma and non-alcoholic fatty liver disease. Hepatol Int 2019; 13:688-694. [PMID: 31701393 DOI: 10.1007/s12072-019-09995-8] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 10/10/2019] [Indexed: 12/19/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the most common liver disorder worldwide, affecting 25.2% of the general population. In fact, NAFLD is among the most common etiologies for hepatocellular carcinoma (HCC). The burden of NAFLD is primarily driven by the epidemic of obesity and type 2 diabetes which are expected to worsen throughout the world. In this context, the burden of NAFLD and associated HCC and cirrhosis are also expected to increase. Despite its growing disease burden, diagnostic tools and treatment modalities remain very limited. This conundrum of increasing prevalence and limited treatment options will be reflected as increasing number of NAFLD-related cirrhosis and HCC cases. This article reviews the most updated information about NAFLD-related HCC and provides some insight into strategies that must be considered to reduce its potential disease burden.
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Affiliation(s)
- Pegah Golabi
- Center For Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, USA
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Claude Moore Health Education and Research Building, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Logan Rhea
- Center For Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, USA
| | - Linda Henry
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Claude Moore Health Education and Research Building, 3300 Gallows Road, Falls Church, VA, 22042, USA
| | - Zobair M Younossi
- Center For Liver Disease, Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, USA.
- Betty and Guy Beatty Center for Integrated Research, Inova Health System, Claude Moore Health Education and Research Building, 3300 Gallows Road, Falls Church, VA, 22042, USA.
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8
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Francica G, Borzio M. Status of, and strategies for improving, adherence to HCC screening and surveillance. J Hepatocell Carcinoma 2019; 6:131-141. [PMID: 31440486 PMCID: PMC6664854 DOI: 10.2147/jhc.s159269] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 06/26/2019] [Indexed: 12/18/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents the second leading cause of cancer deaths worldwide and the main cause of death in patients with cirrhosis. Secondary prevention of HCC can be accomplished through the serial application of screening tests (ultrasound with or without alpha-fetoprotein) to detect the presence of subclinical lesions amenable to potentially curative treatment, such as surgery and ablation. The efficacy of HCC screening is accepted by hepatologists in terms of decline in cancer-specific mortality, but its translation into clinical practice is less than ideal. The effectiveness of HCC screening is hampered by several factors: failure to identify at-risk patients, failure to access care and failure to detect HCC. For each of these steps, possible improvements are discussed in order to face the changing etiology of cirrhosis and expand the screening of at-risk populations by including selected nonalcoholic fatty liver disease patients.
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Affiliation(s)
- Giampiero Francica
- Unità Operativa Ecografia ed Ecointerventistica, Pineta Grande Hospital, Castel Volturno, Italy
| | - Mauro Borzio
- Unità Operativa Complessa Gastroenterologia ed Endoscopia Digestiva, Azienda Socio Sanitaria Territoriale Melegnano e della Martesana, Milano, Italy
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Lonardo A, Ballestri S, Mantovani A, Nascimbeni F, Lugari S, Targher G. Pathogenesis of hypothyroidism-induced NAFLD: Evidence for a distinct disease entity? Dig Liver Dis 2019; 51:462-470. [PMID: 30733187 DOI: 10.1016/j.dld.2018.12.014] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Revised: 12/05/2018] [Accepted: 12/15/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), the most common liver disease worldwide, may be associated with primary hypothyroidism. However, the pathogenesis underlying such an association is complex and not completely understood. Here, we specifically discuss the pathogenic mechanisms potentially involved in hypothyroidism-induced NAFLD. To this end, we summarize the general pathophysiology of thyroid hormones (TH). Next, we analyze the published data from rodent studies by discussing whether hypothyroid rats may develop NAFLD via hyperphagia; whether mitochondria become energetically more efficient; what the overall energy balance is and if diversion of fatty substrates occurs; and the latest advancements in molecular pathogenesis brought about by metabolomics, cell imaging, lipophagy, autophagy and genetically engineered mouse models. Moreover, we discuss the data published regarding humans on the pathogenic role of TH, metabolic syndrome and other risk factors in hypothyroidism-related NAFLD as well as the putative mechanisms underlying the development of NAFLD-related hepatocellular carcinoma in hypothyroidism. In conclusion, although many research questions still remain unanswered, the pathophysiology of hypothyroidism-induced NAFLD makes this a potentially curable and distinct disease entity. However, further studies are needed to better elucidate the underlying mechanisms, and to ascertain whether treatment with either TH or thyromimetic agents improves NAFLD.
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Affiliation(s)
- Amedeo Lonardo
- Operating Unit Internal Medicine, Department of Medicine, Azienda Ospedaliero-Universitaria Modena, Italy.
| | - Stefano Ballestri
- Operating Unit Internal Medicine, Department of Medicine, Azienda USL Modena, Italy
| | - Alessandro Mantovani
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
| | - Fabio Nascimbeni
- Operating Unit Internal Medicine, Department of Medicine, Azienda Ospedaliero-Universitaria Modena, Italy
| | - Simonetta Lugari
- Post-graduate school of Internal Medicine, University of Modena and Reggio Emilia, Italy
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy
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Comparison of Hepatocellular Carcinoma in Patients with Cryptogenic Versus Hepatitis B Etiology: A Study of 1079 Cases Over 3 Decades. Dig Dis Sci 2019; 64:585-590. [PMID: 30327962 DOI: 10.1007/s10620-018-5331-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 10/09/2018] [Indexed: 01/11/2023]
Abstract
BACKGROUND Traditionally in Asia, hepatitis B (HBV) accounts for the majority of hepatocellular carcinoma (HCC), but increasingly, non-viral or nonalcoholic steatohepatitis (NASH) etiology may play a more prominent role with current socioeconomic changes. There remains a paucity in data comparing NASH-HCC to HBV-related HCC. In this study, we explored the differences in clinical characteristics between HBV- and cryptogenic-related HCC. METHODS Patients with HCC seen in the Department of Gastroenterology and Hepatology, Singapore General Hospital were enrolled in an ongoing database since 1980. Patients with HCC attributed to HBV or cryptogenic etiology were identified. Comparison of clinical characteristics was performed between the two groups. RESULTS There were 916 HBV-HCC patients and 163 cryptogenic HCC patients, accounting for 70.9% and 12.6% of the total HCC cases (1292 patients), respectively. Out of the total cohort enrolled from 1980 to 2005, the ratio of cryptogenic to HBV patients was 1:6.7, while from 2006 to the current year, the ratio of cryptogenic to HBV patients has increased significantly to 1:3.9. Relative to patients with HBV, cryptogenic HCC patients were older (67.6 vs. 59.4 years old; p < 0.001), had lower proportion of male patients (69.9% vs. 83.8%; p < 0.001), and had higher incidence of smoking (32.2% vs. 25.8%; p = 0.008). HBV group had higher alanine transaminase (60.9 ± 85.7 U/L vs. 48.0 ± 52.1 U/L; p = 0.003), hemoglobin (12.7 ± 2.28 g/dL vs. 12.0 ± 2.46 g/dL, p < 0.001), albumin (32.9 ± 6.8 g/L vs. 31.3 ± 7.7 g/L; p = 0.007), and prothrombin time (13.2 ± 2.95 s vs. 12.7 ± 2.01 s, p = 0.023), as compared to the cryptogenic group. Cryptogenic HCC patients presented more frequently with unifocal HCC (55.2% vs. 46.5%; p = 0.002). There was no difference in the proportions of patients receiving surgical resection in both groups (23.5% in HBV group vs. 17.9% in cryptogenic group; p = 0.202). Cox regression analysis revealed no survival difference between cryptogenic-related HCC and HBV-related HCC (p = 0.367). CONCLUSION Temporal trends suggest that HCC attributed to HBV is on the decline, while cryptogenic- or NASH-related HCC is an emerging clinical entity. A paradigm shift in approach to screening, surveillance, and management of HCC may be required in view of the changing landscape of HCC epidemiology into an increasing non-viral etiology.
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Giannini EG, Bodini G, Furnari M, Marabotto E. NASH-related and cryptogenic cirrhosis similarities extend beyond cirrhosis. J Hepatol 2018; 69:972-973. [PMID: 30227919 DOI: 10.1016/j.jhep.2018.05.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 05/03/2018] [Accepted: 05/06/2018] [Indexed: 01/19/2023]
Affiliation(s)
- Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, Unviersity of Genoa, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, Genoa, Italy.
| | - Giorgia Bodini
- Gastroenterology Unit, Department of Internal Medicine, Unviersity of Genoa, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, Genoa, Italy
| | - Manuele Furnari
- Gastroenterology Unit, Department of Internal Medicine, Unviersity of Genoa, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, Genoa, Italy
| | - Elisa Marabotto
- Gastroenterology Unit, Department of Internal Medicine, Unviersity of Genoa, Ospedale Policlinico San Martino-IRCCS per l'Oncologia, Genoa, Italy
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12
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Jun TW, Yeh ML, Yang JD, Chen VL, Nguyen P, Giama NH, Huang CF, Hsing AW, Dai CY, Huang JF, Chuang WL, Roberts LR, Yu ML, Nguyen MH. More advanced disease and worse survival in cryptogenic compared to viral hepatocellular carcinoma. Liver Int 2018; 38:895-902. [PMID: 29045023 DOI: 10.1111/liv.13613] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 10/10/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Although hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain major risk factors for hepatocellular carcinoma (HCC), non-viral causes of HCC, particularly non-alcoholic fatty liver disease (NAFLD), are becoming increasingly prevalent. The aim of this study was to compare the clinical characteristics and survival of cryptogenic and viral HCC. METHODS We conducted a retrospective cohort study involving 3878 consecutive HCC patients seen at two tertiary centres in the United States and one in Taiwan from 2004 to 2014. We compared the clinical characteristics, treatment and survival of patients by underlying aetiology: cryptogenic (n = 696), HBV (n = 1304) or HCV (n = 1878). RESULTS Cirrhosis was present in 66.8% of the cryptogenic HCC patients, compared with 74.7% of HBV-related HCC (HBV-HCC) (P = .001) and 85.9% of HCV-HCC (P < .001). Compared to viral HCC, cryptogenic HCC patients presented with larger tumours and at later stages of disease. Five-year overall survival was 16.3% among cryptogenic HCC patients compared with 31.9% among HBV-HCC patients and 27.7% among HCV-HCC patients (P < .001 for both by the log-rank test). HCC aetiology was not an independent predictor of survival, though ethnicity, cirrhosis status, meeting Milan criteria and treatment allocation were. CONCLUSIONS Compared with viral HCC patients, those with cryptogenic HCC had lower prevalence of cirrhosis, were diagnosed with larger tumours at more advanced stages of disease, and had poorer overall survival. Additional efforts are needed to identify patients at risk of cryptogenic HCC and to identify cryptogenic HCC at earlier stages of disease.
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Affiliation(s)
- Tomi W Jun
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ju Dong Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vincent L Chen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA.,Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA
| | - Pauline Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA
| | - Nasra H Giama
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Chung-Feng Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Ann W Hsing
- Stanford Prevention Research Center, Stanford Cancer Institute, Stanford, CA, USA
| | - Chia-Yen Dai
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Jee-Fu Huang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Wan-Long Chuang
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine and Hepatitis Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, USA
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Franke AJ, Iqbal A, Starr JS, Nair RM, George TJ. Management of Malignant Bowel Obstruction Associated With GI Cancers. J Oncol Pract 2018; 13:426-434. [PMID: 28697317 DOI: 10.1200/jop.2017.022210] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
For many patients with GI malignancies, the seeding of the abdominal cavity with tumor cells, called peritoneal carcinomatosis, is a common mode of metastases and disease progression. Prognosis for patients with this aspect of their disease remains poor, with high disease-related morbidity and complications. Uniform and proven practices that provide optimal palliative care and quality of life for these patients are needed. The objective of this review is to critically assess the current literature regarding palliative strategies in the management of peritoneal carcinomatosis and associated symptoms in patients with advanced GI cancers. Despite encouraging results in the select population where cytoreductive surgery and intraperitoneal chemotherapy are indicated, the majority of patients who develop peritoneal carcinomatosis in the setting of GI cancers have poor prognosis, with malignant bowel obstruction representing a common terminal phase of their disease process. For all patients with peritoneal carcinomatosis, aggressive symptom control and early multimodality palliative care as further outlined should be sought.
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Affiliation(s)
- Aaron J Franke
- University of Florida, Gainesville; and University of Florida Health Cancer Center at Orlando Health, Orlando, FL
| | - Atif Iqbal
- University of Florida, Gainesville; and University of Florida Health Cancer Center at Orlando Health, Orlando, FL
| | - Jason S Starr
- University of Florida, Gainesville; and University of Florida Health Cancer Center at Orlando Health, Orlando, FL
| | - Rajesh M Nair
- University of Florida, Gainesville; and University of Florida Health Cancer Center at Orlando Health, Orlando, FL
| | - Thomas J George
- University of Florida, Gainesville; and University of Florida Health Cancer Center at Orlando Health, Orlando, FL
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14
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease worldwide, and its clinical and economic burden will continue to grow with parallel increases in rates of obesity, diabetes, and the metabolic syndrome. Evolving understanding of the natural history of NAFLD suggests that these patients are at risk for disease progression to steatohepatitis, fibrosis, and cirrhosis. Recent studies also suggest that these patients are at elevated risk for cardiovascular-, malignancy-, and liver-related morbidity and mortality, although their risk for progression, decompensation, and hepatocellular carcinoma may be less than that of patients with alternative causes of chronic liver disease.
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Affiliation(s)
- Christina C Lindenmeyer
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Mail Code A30, Cleveland, OH 44195, USA
| | - Arthur J McCullough
- Department of Gastroenterology and Hepatology, Transplantation Center, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Mail Code A30, Cleveland, OH 44195, USA; Department of Pathobiology, Transplantation Center, Cleveland Clinic, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, 9500 Euclid Avenue, Mail Code A30, Cleveland, OH 44195, USA.
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15
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Said A, Ghufran A. Epidemic of non-alcoholic fatty liver disease and hepatocellular carcinoma. World J Clin Oncol 2017; 8:429-436. [PMID: 29291167 PMCID: PMC5740098 DOI: 10.5306/wjco.v8.i6.429] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2017] [Revised: 08/23/2017] [Accepted: 10/30/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) associated hepatocellular carcinoma (HCC) incidence is increasing worldwide, paralleling the obesity epidemic. Although most cases are associated with cirrhosis, HCC can occur without cirrhosis in NAFLD. Diabetes and obesity are associated risk factors for HCC in patients. Given the sheer magnitude of the underlying risk factors (diabetes, obesity, non-cirrhotic NAFLD) screening for HCC in the non-cirrhotic population is not recommended. Optimal screening strategies in NAFLD cirrhosis are not completely elucidated with Ultrasound having significant limitations in detection of liver lesions in the presence of obesity and steatosis. Consequently NAFLD-HCC is more often diagnosed at a later stage with larger tumors and reduced opportunities for curative treatments as opposed to HCC in other causes of cirrhosis. When HCC is found at a curative stage treatments including liver transplantation, resection and loco-regional therapies are associated with good results similar to that seen in HCV-HCC. Future strategies under study include the use of chemopreventive and antioxidant agents to reduce development of cirrhosis and non-alcoholic steatohepatitis (NASH). Strategies to reverse NASH via weight loss, control of associated conditions like diabetes are key strategies in reducing the increasing incidence of NASH-HCC. Novel therapeutic agents for NASH are in trials and if successful in achieving reversal of NASH will be an important strategy in reducing NAFLD-HCC.
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Affiliation(s)
- Adnan Said
- Division of Gastroenterology and Hepatology, Department of Medicine, William S. Middleton VAMC, University of Wisconsin School of Medicine and Public Health, Madison, WI 53705, United States
| | - Aiman Ghufran
- Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI 53226, United States
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16
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Lonardo A, Nascimbeni F, Maurantonio M, Marrazzo A, Rinaldi L, Adinolfi LE. Nonalcoholic fatty liver disease: Evolving paradigms. World J Gastroenterol 2017; 23:6571-6592. [PMID: 29085206 PMCID: PMC5643282 DOI: 10.3748/wjg.v23.i36.6571] [Citation(s) in RCA: 132] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 08/21/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
In the last years new evidence has accumulated on nonalcoholic fatty liver disease (NAFLD) challenging the paradigms that had been holding the scene over the previous 30 years. NAFLD has such an epidemic prevalence as to make it impossible to screen general population looking for NAFLD cases. Conversely, focusing on those cohorts of individuals exposed to the highest risk of NAFLD could be a more rational approach. NAFLD, which can be diagnosed with either non-invasive strategies or through liver biopsy, is a pathogenically complex and clinically heterogeneous disease. The existence of metabolic as opposed to genetic-associated disease, notably including ”lean NAFLD” has recently been recognized. Moreover, NAFLD is a systemic condition, featuring metabolic, cardiovascular and (hepatic/extra-hepatic) cancer risk. Among the clinico-laboratory features of NAFLD we discuss hyperuricemia, insulin resistance, atherosclerosis, gallstones, psoriasis and selected endocrine derangements. NAFLD is a precursor of type 2 diabetes (T2D) and metabolic syndrome and progressive liver disease develops in T2D patients in whom the course of disease is worsened by NAFLD. Finally, lifestyle changes and drug treatment options to be implemented in the individual patient are also critically discussed. In conclusion, this review emphasizes the new concepts on clinical and pathogenic heterogeneity of NAFLD, a systemic disorder with a multifactorial pathogenesis and protean clinical manifestations. It is highly prevalent in certain cohorts of individuals who are thus potentially amenable to selective screening strategies, intensive follow-up schedules for early identification of liver-related and extrahepatic complications and in whom earlier and more aggressive treatment schedules should be carried out whenever possible.
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Affiliation(s)
- Amedeo Lonardo
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
| | - Fabio Nascimbeni
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
- University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Mauro Maurantonio
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
| | - Alessandra Marrazzo
- Azienda Ospedaliero-Universitaria di Modena, Ospedale Civile di Baggiovara, 41126 Modena, Italy
- University of Modena and Reggio Emilia, 41126 Modena, Italy
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
| | - Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania “Luigi Vanvitelli”, 80100 Naples, Italy
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17
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AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig Liver Dis 2017; 49:471-483. [PMID: 28215516 DOI: 10.1016/j.dld.2017.01.147] [Citation(s) in RCA: 225] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 01/08/2017] [Accepted: 01/10/2017] [Indexed: 02/07/2023]
Abstract
This review summarizes our current understanding of nonalcoholic fatty liver disease (NAFLD), a multi-factorial systemic disease resulting from a complex interaction between a specific genetic background and multiple environmental/metabolic "hits". The role of gut microbiota, lipotoxicity, inflammation and their molecular pathways is reviewed in-depth. We also discuss the epidemiology and natural history of NAFLD by pinpointing the remarkably high prevalence of NAFLD worldwide and its inherent systemic complications: hepatic (steatohepatitis, advanced fibrosis and cirrhosis), cardio-metabolic (cardiovascular disease, cardiomyopathy, arrhythmias and type 2 diabetes) and neoplastic (primary liver cancers and extra-hepatic cancers). Moreover, we critically report on the diagnostic role of non-invasive biomarkers, imaging techniques and liver biopsy, which remains the reference standard for diagnosing the disease, but cannot be proposed to all patients with suspected NAFLD. Finally, the management of NAFLD is also reviewed, by highlighting the lifestyle changes and the pharmacological options, with a focus on the innovative drugs. We conclude that the results of ongoing studies are eagerly expected to lead to introduce into the clinical arena new diagnostic and prognostic biomarkers, prevention and surveillance strategies as well as to new drugs for a tailored approach to the management of NAFLD in the individual patient.
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18
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Rinaldi L, Nascimbeni F, Giordano M, Masetti C, Guerrera B, Amelia A, Fascione MC, Ballestri S, Romagnoli D, Zampino R, Nevola R, Baldelli E, Iuliano N, Rosato V, Lonardo A, Adinolfi LE. Clinical features and natural history of cryptogenic cirrhosis compared to hepatitis C virus-related cirrhosis. World J Gastroenterol 2017; 23:1458-1468. [PMID: 28293093 PMCID: PMC5330831 DOI: 10.3748/wjg.v23.i8.1458] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Revised: 10/07/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To characterize natural history of cryptogenic cirrhosis (CC) and compare its clinical features and outcomes to those of hepatitis C virus (HCV)-related cirrhosis.
METHODS A prospective cohort of 102 consecutive patients at their first diagnosis of CC were enrolled in this study. The clinical data and outcomes were compared to an age- and Child-Pugh class-matched cohort of 110 patients with HCV-related cirrhosis. Diagnosis of cirrhosis was based on compatible clinical and laboratory parameters, ultrasound/endoscopic parameters and, whenever possible, on histological grounds and transient elastography. All cases of cirrhosis without a definite etiology were enrolled in the CC group. The parameters assessed were: (1) severity of liver disease at the time of first diagnosis; (2) liver decompensation during follow-up; (3) hepatocellular carcinoma (HCC); (4) orthotopic liver transplantation; and (5) death. The independent associated factors were evaluated by multiple logistic regression analysis, and survival and its determinants by the Kaplan-Meier model, log-rank test and Cox regression.
RESULTS At the first observation, median age was 66 and 65 years and male gender was 36% and 58% for CC and HCV cirrhosis, respectively. CC showed Child-Pugh class A/B/C of 47%/31%/22%, respectively. Compared to HCV cirrhosis, CC exhibited a significantly higher prevalence of metabolic syndrome (12% vs 54%, respectively), overweight/obesity, high BMI, impaired glucose tolerance, high blood pressure, dyslipidemia, hyperuricemia, cardiovascular diseases, extrahepatic cancer, and gallstones. Over a median period of 42 mo of follow-up, liver decompensation, HCC development and death for CC and HCV-related cirrhosis were 60.8%, and 54.4%, 16.7% and 17.2%, 39.2% and 30%, respectively. The median survival was 60 mo for CC. Independent predictors of death were age and Child-Pugh class at diagnosis. CC showed an approximately twofold higher incidence of HCC in Child-Pugh class A.
CONCLUSION Undiagnosed nonalcoholic fatty liver disease has an etiologic role in CC that is associated with a poor prognosis, early HCC development, high risk of cardiovascular disease and extrahepatic cancer.
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19
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Lonardo A, Ballestri S, Guaraldi G, Nascimbeni F, Romagnoli D, Zona S, Targher G. Fatty liver is associated with an increased risk of diabetes and cardiovascular disease - Evidence from three different disease models: NAFLD, HCV and HIV. World J Gastroenterol 2016; 22:9674-9693. [PMID: 27956792 PMCID: PMC5124973 DOI: 10.3748/wjg.v22.i44.9674] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2016] [Revised: 09/29/2016] [Accepted: 10/31/2016] [Indexed: 02/06/2023] Open
Abstract
Fatty liver, which frequently coexists with necro-inflammatory and fibrotic changes, may occur in the setting of nonalcoholic fatty liver disease (NAFLD) and chronic infections due to either hepatitis C virus (HCV) or human immunodeficiency virus (HIV). These three pathologic conditions are associated with an increased prevalence and incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). In this multidisciplinary clinical review, we aim to discuss the ever-expanding wealth of clinical and epidemiological evidence supporting a key role of fatty liver in the development of T2D and CVD in patients with NAFLD and in those with HCV or HIV infections. For each of these three common diseases, the epidemiological features, pathophysiologic mechanisms and clinical implications of the presence of fatty liver in predicting the risk of incident T2D and CVD are examined in depth. Collectively, the data discussed in this updated review, which follows an innovative comparative approach, further reinforce the conclusion that the presence of fatty/inflamed/fibrotic liver might be a shared important determinant for the development of T2D and CVD in patients with NAFLD, HCV or HIV. This review may also open new avenues in the clinical and research arenas and paves the way for the planning of future, well-designed prospective and intervention studies.
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20
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Mercado‐Irizarry A, Torres EA. Cryptogenic cirrhosis: Current knowledge and future directions. Clin Liver Dis (Hoboken) 2016; 7:69-72. [PMID: 31041033 PMCID: PMC6490261 DOI: 10.1002/cld.539] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Revised: 01/11/2016] [Accepted: 01/24/2016] [Indexed: 02/04/2023] Open
Affiliation(s)
- Alex Mercado‐Irizarry
- University of Puerto Rico School of Medicine–Gastroenterology and Liver DiseasesSan JuanPR
| | - Esther A. Torres
- University of Puerto Rico School of Medicine–Gastroenterology and Liver DiseasesSan JuanPR
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21
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Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Targher G, Lonardo A. Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection--Liver: The "Musketeer" in the Spotlight. Int J Mol Sci 2016; 17:355. [PMID: 27005620 PMCID: PMC4813216 DOI: 10.3390/ijms17030355] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 02/29/2016] [Accepted: 03/02/2016] [Indexed: 02/07/2023] Open
Abstract
The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a "vicious circle", eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved.
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Affiliation(s)
- Stefano Ballestri
- Operating Unit Internal Medicine, Pavullo General Hospital, Azienda USL Modena, ViaSuore di San Giuseppe Benedetto Cottolengo, 5, Pavullo, 41026 Modena, Italy.
| | - Fabio Nascimbeni
- Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy.
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy.
| | - Dante Romagnoli
- Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy.
| | - Enrica Baldelli
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Via P. Giardini, 1355, 41126 Modena, Italy.
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Piazzale Stefani, 1, 37126 Verona, Italy.
| | - Amedeo Lonardo
- Outpatient Liver Clinic and Operating Unit Internal Medicine, NOCSAE, Azienda USL Modena, Via P. Giardini, 1355, 41126 Modena, Italy.
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22
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Ballestri S, Nascimbeni F, Romagnoli D, Baldelli E, Lonardo A. The Role of Nuclear Receptors in the Pathophysiology, Natural Course, and Drug Treatment of NAFLD in Humans. Adv Ther 2016; 33:291-319. [PMID: 26921205 DOI: 10.1007/s12325-016-0306-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) describes steatosis, nonalcoholic steatohepatitis with or without fibrosis, and hepatocellular carcinoma, namely the entire alcohol-like spectrum of liver disease though observed in the nonalcoholic, dysmetabolic, individual free of competing causes of liver disease. NAFLD, which is a major public health issue, exhibits intrahepatic triglyceride storage giving rise to lipotoxicity. Nuclear receptors (NRs) are transcriptional factors which, activated by ligands, are master regulators of metabolism and also have intricate connections with circadian control accounting for cyclical patterns in the metabolic fate of nutrients. Several transcription factors, such as peroxisome proliferator-activated receptors, liver X receptors, farnesoid X receptors, and their molecular cascades, finely regulate energetic fluxes and metabolic pathways. Dysregulation of such pathways is heavily implicated in those metabolic derangements characterizing insulin resistance and metabolic syndrome and in the histogenesis of progressive NAFLD forms. We review the role of selected NRs in NAFLD pathogenesis. Secondly, we analyze the role of NRs in the natural history of human NAFLD. Next, we discuss the results observed in humans following administration of drug agonists or antagonists of the NRs pathogenically involved in NAFLD. Finally, general principles of treatment and lines of research in human NAFLD are briefly examined.
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Affiliation(s)
| | - Fabio Nascimbeni
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
- University of Modena and Reggio Emilia, Modena, Italy
| | - Dante Romagnoli
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy
| | | | - Amedeo Lonardo
- NOCSAE, Outpatient Liver Clinic and Operating Unit Internal Medicine, Azienda USL Modena, Modena, Italy.
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23
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Margini C, Dufour JF. The story of HCC in NAFLD: from epidemiology, across pathogenesis, to prevention and treatment. Liver Int 2016; 36:317-24. [PMID: 26601627 DOI: 10.1111/liv.13031] [Citation(s) in RCA: 174] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 11/05/2015] [Indexed: 02/13/2023]
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. An increasing number of reports describe HCC in the setting of obesity and diabetes, two major risk factors for non-alcoholic fatty liver disease (NAFLD). The increasing incidence of these conditions and the emerging evidence of HCC in non-cirrhotic NAFLD prioritize a better understanding of NAFLD-related HCC epidemiology and pathogenesis in order to target screening policies and develop preventive-therapeutic strategies. In this review, we focus on the epidemiological impact of this condition, suggesting a possible link between HCC in cryptogenic cirrhosis and NAFLD. Furthermore, we analyse the suggested pathogenic mechanisms and the possible preventive-therapeutic strategies.
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Affiliation(s)
- Cristina Margini
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Jean F Dufour
- Hepatology, Department of Clinical Research, University of Bern, Bern, Switzerland.,University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
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24
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Semiannual Imaging Surveillance Is Associated with Better Survival in Patients with Non-B, Non-C Hepatocellular Carcinoma. Mediators Inflamm 2015; 2015:687484. [PMID: 26494948 PMCID: PMC4606410 DOI: 10.1155/2015/687484] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Accepted: 07/09/2015] [Indexed: 12/21/2022] Open
Abstract
Since it remains elusive whether and how the imaging surveillance affects the survival in patients with non-B, non-C hepatocellular carcinoma (NBNC-HCC), we conducted this retrospective study which investigated the association between the semiannual surveillance prior to HCC diagnosis and the survival in patients with the initial diagnosis of HCC induced by hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections (N = 141) and non-B, non-C etiology (N = 30). It was demonstrated that surveillance was less frequently performed in the NBNC-HCC patients compared to that in HCC patients with HBV and/or HCV infections (B/C-HCC patients), and the survival was unfavorable in NBNC-HCC patients. On the other hand, the survival of NBNC-HCC patients with semiannual surveillance was significantly favorable than those patients without semiannual surveillance, and the survival was similar between B/C-HCCs and NBNC-HCCs with semiannual surveillance. In conclusion, though NBNC-HCC patients compared to B/C-HCC patients had poorer prognosis overall, these NBNC-HCC patients with semiannual surveillance had a better survival almost equivalent to the survival of B/C-HCC patients with semiannual surveillance, demonstrating the clinical utility of the semiannual imaging surveillance program for NBNC-HCCs.
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25
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Takeishi K, Maeda T, Shirabe K, Tsujita E, Yamashita YI, Harimoto N, Itoh S, Ikegami T, Yoshizumi T, Maehara Y. Clinicopathologic Features and Outcomes of Non-B, Non-C Hepatocellular Carcinoma After Hepatectomy. Ann Surg Oncol 2015; 22 Suppl 3:S1116-24. [PMID: 26159442 DOI: 10.1245/s10434-015-4728-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Indexed: 01/14/2023]
Abstract
PURPOSE This retrospective study aimed to investigate the clinical characteristics and long-term outcomes after hepatectomy in patients with non-B, non-C (NBNC) hepatocellular carcinoma (HCC) who were negative for hepatitis B virus surface antigen and anti-hepatitis C virus antibody. METHODS We retrospectively reviewed 666 patients with HCC who underwent hepatectomy. The patients were divided into NBNC-HCC patients [n = 117 (17.6 %)] and hepatitis virus (HV)-HCC patients [n = 547 (82.4 %)]. We compared the clinicopathologic characteristics and long-term outcomes between the 2 groups. Two patients with incomplete virus-marker data were not analyzed. RESULTS NBNC-HCC patients had better liver function but more advanced and larger HCCs and a high incidence of intrahepatic metastasis compared to HV-HCC patients. Recurrence-free and overall survival were similar in both groups. Multivariate analysis showed that aspartate aminotransferase (AST) and α-fetoprotein were independently associated with disease-free and overall survival in NBNC-HCC patients after hepatectomy. High AST was significantly associated with tumor size and rate of capsule formation with cancer cell infiltration in NBNC-HCC patients, but not with other liver function tests, fibrosis, or necrosis of noncancerous lesions. CONCLUSIONS NBNC-HCC patients have better liver function than HV-HCC patients, despite having more advanced HCC at diagnosis. There were no differences in long-term outcomes after hepatectomy between NBNC-HCC and HV-HCC patients. Preoperative AST and α-fetoprotein were independently associated with the prognosis of NBNC-HCC after hepatectomy. Serum AST levels might be associated with tumor malignancy in NBNC-HCC patients.
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Affiliation(s)
- Kazuki Takeishi
- Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan. .,Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Takashi Maeda
- Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Ken Shirabe
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Eiji Tsujita
- Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan
| | - Yo-Ichi Yamashita
- Department of Surgery, Hiroshima Red Cross Hospital and Atomic Bomb Survivors Hospital, Hiroshima, Japan.,Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Norifumi Harimoto
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Shinji Itoh
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toru Ikegami
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Tomoharu Yoshizumi
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshihiko Maehara
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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26
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Mittal S, Sada YH, El-Serag HB, Kanwal F, Duan Z, Temple S, May SB, Kramer JR, Richardson PA, Davila JA. Temporal trends of nonalcoholic fatty liver disease-related hepatocellular carcinoma in the veteran affairs population. Clin Gastroenterol Hepatol 2015; 13:594-601.e1. [PMID: 25148760 PMCID: PMC4333060 DOI: 10.1016/j.cgh.2014.08.013] [Citation(s) in RCA: 188] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 08/07/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, no systemic studies from the United States have examined temporal trends, HCC surveillance practices, and outcomes of NAFLD-related HCC. METHODS We identified a national cohort of 1500 patients who developed HCC from 2005 through 2010 from Veterans Administration (VA) hospitals. We reviewed patients' full VA medical records; NAFLD was diagnosed based on histologic evidence for, or the presence of, the metabolic syndrome in the absence of hepatitis C virus (HCV) infection, hepatitis B, or alcoholic liver disease. We compared annual prevalence values for the main risk factors (NAFLD, alcohol abuse, and HCV), as well a HCC surveillance and outcomes, among HCC patients. RESULTS NAFLD was the underlying risk factor for HCC in 120 patients (8.0%); the annual proportion of NAFLD-related HCC remained relatively stable (7.5%-12.0%). In contrast, the proportion of HCC cases associated with HCV increased from 61.0% in 2005 (95% confidence interval, 53.1%-68.9%) to 74.9% in 2010 (95% confidence interval, 69.0%-80.7%). The proportion of HCC cases associated with only alcohol abuse decreased from 21.9% in 2005 to 15.7% in 2010, and the annual proportion of HCC cases associated with hepatitis B remained relatively stable (1.4%-3.5%). A significantly lower proportion of patients with NAFLD-related HCC had cirrhosis (58.3%) compared with patients with alcohol- or HCV-related HCC (72.4% and 85.6%, respectively; P < .05). A significantly higher percentage of patients with NAFLD-related HCC did not receive HCC surveillance in the 3 years before their HCC diagnosis, compared with patients with alcohol- or HCV-associated HCC. A lower proportion of patients with NAFLD-related HCC received HCC-specific treatment (61.5%) than patients with HCV-related HCC (77.5%; P < .01). However, the 1-year survival rate did not differ among patients with HCC related to different risk factors. CONCLUSIONS NAFLD is the third most common risk factor for HCC in the VA population. The proportion of NAFLD-related HCC was relatively stable from 2005 through 2010. Although patients with NAFLD-related HCC received less HCC surveillance and treatment, a similar proportion survive for 1 year, compared with patients with alcohol-related or HCV-related HCC.
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Affiliation(s)
- Sahil Mittal
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology, Houston, Texas; Baylor College of Medicine, Houston, Texas.
| | - Yvonne H. Sada
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas
| | - Hashem B. El-Serag
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas,Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Baylor College of Medicine, Houston, Texas
| | - Fasiha Kanwal
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas,Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas,Baylor College of Medicine, Houston, Texas
| | - Zhigang Duan
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas
| | - Sarah Temple
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas
| | - Sarah B. May
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas
| | - Jennifer R. Kramer
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas
| | - Peter A. Richardson
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas
| | - Jessica A. Davila
- Center of Innovation, Effectiveness and Quality, Sections of Health Services Research, Section of Gastroenterology and Hepatology at the Houston, Texas
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Bertolotti M, Lonardo A, Mussi C, Baldelli E, Pellegrini E, Ballestri S, Romagnoli D, Loria P. Nonalcoholic fatty liver disease and aging: Epidemiology to management. World J Gastroenterol 2014; 20:14185-14204. [PMID: 25339806 PMCID: PMC4202348 DOI: 10.3748/wjg.v20.i39.14185] [Citation(s) in RCA: 208] [Impact Index Per Article: 18.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 02/17/2014] [Accepted: 06/17/2014] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is common in the elderly, in whom it carries a more substantial burden of hepatic (nonalcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma) and extra-hepatic manifestations and complications (cardiovascular disease, extrahepatic neoplasms) than in younger age groups. Therefore, proper identification and management of this condition is a major task for clinical geriatricians and geriatric hepatologists. In this paper, the epidemiology and pathophysiology of this condition are reviewed, and a full discussion of the link between NAFLD and the aspects that are peculiar to elderly individuals is provided; these aspects include frailty, multimorbidity, polypharmacy and dementia. The proper treatment strategy will have to consider the peculiarities of geriatric patients, so a multidisciplinary approach is mandatory. Non-pharmacological treatment (diet and physical exercise) has to be tailored individually considering the physical limitations of most elderly people and the need for an adequate caloric supply. Similarly, the choice of drug treatment must carefully balance the benefits and risks in terms of adverse events and pharmacological interactions in the common context of both multiple health conditions and polypharmacy. In conclusion, further epidemiological and pathophysiological insight is warranted. More accurate understanding of the molecular mechanisms of geriatric NAFLD will help in identifying the most appropriate diagnostic and therapeutic approach for individual elderly patients.
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Giannini EG, Sammito G, Farinati F, Ciccarese F, Pecorelli A, Rapaccini GL, Di Marco M, Caturelli E, Zoli M, Borzio F, Cabibbo G, Felder M, Gasbarrini A, Sacco R, Foschi FG, Missale G, Morisco F, Svegliati Baroni G, Virdone R, Trevisani F. Determinants of alpha-fetoprotein levels in patients with hepatocellular carcinoma: implications for its clinical use. Cancer 2014; 120:2150-7. [PMID: 24723129 DOI: 10.1002/cncr.28706] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 02/02/2014] [Accepted: 03/07/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND α-Fetoprotein (AFP) is a biomarker commonly used in the management of patients with hepatocellular carcinoma (HCC), although the possible determinants of its serum levels in these patients have not been adequately explored. For this study, the authors evaluated the relevance of demographic, clinical, and oncologic factors to the presence of elevated AFP levels in large cohort of patients with HCC. METHODS In 4123 patients with HCC who were managed by the Italian Liver Cancer Group, AFP levels were assessed along with their association with demographic, biochemical, clinical, and oncologic characteristics. Patients were subdivided according to the presence of elevated AFP (ie, >10 ng/mL). RESULTS AFP levels were elevated in 62.4% of patients with HCC. Multivariate logistic regression analysis indicated that being a woman (odds ratio [OR], 1.497; 95% confidence interval [95%CI], 1.250-1.793; P < .0001), the presence of cirrhosis (OR, 1.538; 95% CI, 1.050-2.254; P = .027), liver disease with viral etiology (OR, 1.900; 95% CI, 1.589-2.272; P < .0001), an elevated alanine aminotransferase level (OR, 1.878; 95% CI, 1.602-2.202; P < .0001), a low albumin level (OR, 1.301; 95% CI, 1.110-1.525; P = .012), an HCC tumor size >2 cm (OR, 1.346; 95% CI, 1.135-2.596; P = .001), multinodular HCC (OR, 1.641; 95% CI, 1.403-1.920; P < .0001), and the presence of vascular invasion (OR, 1.774; 95% CI, 1.361-2.311; P < .0001) were associated independently with elevated levels of AFP. Both the median AFP level and the proportion of patients who had elevated levels increased with decreasing degrees of HCC differentiation (P < .0001). CONCLUSIONS Sex and features of chronic liver disease were identified as nontumor characteristics that influence serum AFP levels in patients with HCC. These findings should be taken into account as limitations in interpreting the oncologic meaning of this biomarker in clinical practice.
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Affiliation(s)
- Edoardo G Giannini
- Gastroenterology Unit, Department of Internal Medicine, IRCCS-University Hospital San Martino-IST, University of Genoa, Genoa, Italy
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Giannini EG, Cucchetti A, Erroi V, Garuti F, Odaldi F, Trevisani F. Surveillance for early diagnosis of hepatocellular carcinoma: How best to do it? World J Gastroenterol 2013; 19:8808-8821. [PMID: 24379604 PMCID: PMC3870532 DOI: 10.3748/wjg.v19.i47.8808] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2013] [Revised: 10/31/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
Surveillance for hepatocellular carcinoma (HCC) is considered a standard of care for patients with chronic liver disease who are at risk of developing this malignancy. Several studies have shown that surveillance can improve the prognosis of patients diagnosed with HCC through an increased likelihood of application of curative or effective treatments. Repetition of liver ultrasonography (US) every 6 mo is the recommended surveillance program to detect early HCCs, and a positive US has to entrain a well-defined recall policy based on contrast-enhanced, dynamic radiological imaging or biopsy for the diagnosis of HCC. Although HCC fulfills the accepted criteria regarding cost-effective cancer screening and surveillance, the implementation of surveillance in clinical practice is defective and this has a negative impact on the cost-effectiveness of the procedure. Education of both physicians and patients is of paramount importance in order to improve the surveillance application and its benefits in patients at risk of HCC. The promotion of specific educational programs for practitioners, clinicians and patients is instrumental in order to expand the correct use of surveillance in clinical practice and eventually improve HCC prognosis.
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30
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Nishikawa H, Osaki Y. Non-B, non-C hepatocellular carcinoma (Review). Int J Oncol 2013; 43:1333-42. [PMID: 23969900 DOI: 10.3892/ijo.2013.2061] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 07/16/2013] [Indexed: 11/06/2022] Open
Abstract
Although most hepatocellular carcinoma (HCC) is related to viral infection, there is a substantial population of HCC patients (5-20%) who are negative for both markers of hepatitis B virus and hepatitis C virus infection [non-B, non-C (NBNC) hepatitis] in Japan and the incidence of NBNC-HCC has recently tended to increase. The most common cause of liver disease in developed countries is non‑alcoholic fatty liver disease (NAFLD), which includes non‑alcoholic steatohepatitis (NASH) and its related complications. Increased body mass index and diabetes mellitus are associated with developing NAFLD and NASH, which is a severe form of NAFLD. Furthermore, increasing clinical evidence supports the fact that NAFLD and NASH can progress to liver cirrhosis and even HCC. A detailed understanding of the epidemiology, etiology, molecular mechanism, clinical features and prognosis of NBNC-HCC could improve our screening and therapy of this disease. In this review, we primarily focus on clinical aspects of NBNC-HCC and refer to our current knowledge of this cancer.
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Affiliation(s)
- Hiroki Nishikawa
- Department of Gastroenterology and Hepatology, Osaka Red Cross Hospital, Tennoji-ku, Osaka 543-0027, Japan
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31
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Resection of nonalcoholic steatohepatitis-associated hepatocellular carcinoma: a Western experience. Int J Surg Oncol 2012; 2012:915128. [PMID: 22988496 PMCID: PMC3440935 DOI: 10.1155/2012/915128] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Accepted: 07/31/2012] [Indexed: 12/14/2022] Open
Abstract
Introduction. Hepatocellular carcinoma is now known to arise in association with nonalcoholic steatohepatitis. The aim of this study is to examine the clinicopathological features of this entity using liver resection cases at a large Western center. Methods. We retrospectively reviewed all cases of partial liver resection for hepatocellular carcinoma over a 10-year period. We included for the purpose of this study patients with histological evidence of nonalcoholic steatohepatitis and excluded patients with other chronic liver diseases such as viral hepatitis and alcoholic liver disease. Results. We identified 9 cases in which malignancy developed against a parenchymal background of histologically-active nonalcoholic steatohepatitis. The median age at diagnosis was 58 (52-82) years, and 8 of the patients were male. Median body mass index was 30.2 (22.7-39.4) kg/m(2). Hypertension was present in 77.8% of the patients and diabetes mellitus, obesity, and hyperlipidemia in 66.7%, respectively. The background liver parenchyma was noncirrhotic in 44% of the cases. Average tumor diameter was 7.0 ± 4.8 cm. Three-fourths of the patients developed recurrence within two years of resection, and 5-year survival was 44%. Conclusion. Hepatocellular carcinoma may arise in the context of nonalcoholic steatohepatitis, often before cirrhosis has developed. Locally advanced tumors are typical, and long-term failure rate following resection is high.
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Hashimoto E, Tokushige K. Hepatocellular carcinoma in non-alcoholic steatohepatitis: Growing evidence of an epidemic? Hepatol Res 2012; 42:1-14. [PMID: 21917086 DOI: 10.1111/j.1872-034x.2011.00872.x] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The incidence of hepatocellular carcinoma in non-viral-related chronic liver disease has gradually increased in Japan. Obesity and diabetes mellitus type 2 have been established as a significant risk factor for hepatocellular carcinoma (HCC) by epidemiologic observations and experimental studies. The risks of these factors for HCC are likely conferred by two factors: the increased risk for development of non-alcoholic steatohepatitis (NASH) and the carcinogenic potential of themselves. Hepatocellular carcinoma in NASH is difficult to evaluate because histological diagnosis is required for diagnosis of NASH, which can lead selection bias. Furthermore, end-stage NASH is in effect "burned-out" NASH, for which the diagnosis of NASH cannot be made any more. At all events, previous studies on the etiology of Japanese HCC showed that non-alcoholic fatty liver disease accounts for 1-5% of all HCC (male predominant, median age 72 years). They have high prevalences of obesity and/or diabetes mellitus type 2 and 10-75% of the HCC arose from non-cirrhotic livers. HCC in NASH may be of multicentric origin, similar to HCC based on viral hepatitis. Regular screening for HCC is extremely important especially in cirrhotic NASH patients and recurrence should be warned. In western and Asian countries, the prevalence of non-alcoholic fatty liver disease in the general population is increasing dramatically. Therefore, there is an urgent need to elucidate pathogenesis and clinical features of HCC in NASH. In this review we summarize current concepts for HCC in NASH.
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Affiliation(s)
- Etsuko Hashimoto
- Department of Internal Medicine and Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
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Czaja AJ. Cryptogenic chronic hepatitis and its changing guise in adults. Dig Dis Sci 2011; 56:3421-38. [PMID: 21647651 DOI: 10.1007/s10620-011-1769-9] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Accepted: 05/20/2011] [Indexed: 12/11/2022]
Abstract
Cryptogenic chronic hepatitis is a disease that is unexplained by conventional clinical, laboratory and histological findings, and it can progress to cirrhosis, develop hepatocellular carcinoma, and require liver transplantation. The goals of this review are to describe the changing phenotype of cryptogenic chronic hepatitis in adults, develop a diagnostic algorithm appropriate to current practice, and suggest treatment options. The frequency of cryptogenic hepatitis is estimated at 5.4%. Cryptogenic cirrhosis is diagnosed in 5-30% of patients with cirrhosis, and it is present in 3-14% of adults awaiting liver transplantation. Nonalcoholic fatty liver disease has been implicated in 21-63% of patients, and autoimmune hepatitis is a likely diagnosis in 10-54% of individuals. Viral infections, hereditary liver diseases, celiac disease, and unsuspected alcohol or drug-induced liver injury are recognized infrequently in the current cryptogenic population. Manifestations of the metabolic syndrome heighten the suspicion of nonalcoholic fatty liver disease, and the absence of hepatic steatosis does not discount this possibility. The diagnostic scoring system of the International Autoimmune Hepatitis Group can support the diagnosis of autoimmune hepatitis in some patients. Certain genetic mutations may have disease-specificity, and they suggest that some patients may have an independent and uncharacterized disease. Corticosteroid therapy is effective in patients with autoimmune features, and life-style changes and specific therapies for manifestations of the metabolic syndrome are appropriate for all obese patients. The 1- and 5-year survivals after liver transplantation have ranged from 72-85% to 58-73%, respectively.
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Affiliation(s)
- Albert J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street S.W., Rochester, MN 55905, USA.
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Takuma Y, Nouso K. Nonalcoholic steatohepatitis-associated hepatocellular carcinoma: Our case series and literature review. World J Gastroenterol 2010; 16:1436-41. [PMID: 20333782 PMCID: PMC2846247 DOI: 10.3748/wjg.v16.i12.1436] [Citation(s) in RCA: 95] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Recently, nonalcoholic steatohepatitis (NASH) has been considered to be another cause of liver cirrhosis and hepatocellular carcinoma (HCC). The natural history and prognosis of NASH are controversial. Accordingly, we assessed the clinicopathological features of NASH-associated HCC in our experience and reviewed the literature of NASH-associated HCC. We experienced 11 patients with NASH-associated HCC (6 male, 5 female; mean age 73.8 ± 4.9 years) who received curative treatments. Most (91%) patients had been diagnosed with obesity, diabetes, hypertension, or dyslipidemia. Seven patients (64%) also had a non-cirrhotic liver. The recurrence-free survival rates at 1, 3 and 5 years were 72%, 60%, and 60%. We also summarized and reviewed 94 cases of NASH-associated HCC which were reported in the literature (64 male; mean age 66 years). The majority of patients (68%) were obese, 66% of patients had diabetes, and 24% had dyslipidemia. Furthermore, 26% of the HCCs arose from the non-cirrhotic liver. In conclusion, patients with non-cirrhotic NASH may be a high-risk group for HCC, and regular surveillance for HCC is necessary in non-cirrhotic NASH patients as well as cirrhotic patients.
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Marmur J, Bergquist A, Stål P. Liver transplantation of patients with cryptogenic cirrhosis: clinical characteristics and outcome. Scand J Gastroenterol 2010; 45:60-9. [PMID: 20030578 DOI: 10.3109/00365520903384742] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Non-alcoholic fatty liver disease (NAFLD), autoimmune hepatitis (AIH) and unapparent alcohol abuse may be underlying causes of cryptogenic cirrhosis, but the frequencies of these underlying factors differ between studies. Also, previous studies have shown various outcomes after orthotopic liver transplantation (OLT) for cryptogenic cirrhosis. The aims of this study were (1) to evaluate the presence of NAFLD in patients with cryptogenic cirrhosis evaluated for OLT and (2) to compare the severity of liver disease and patient survival in OLT candidates with cryptogenic cirrhosis and those with cirrhosis of another known origin. MATERIAL AND METHODS Four-hundred and seventy adult patients with end-stage liver cirrhosis evaluated for OLT between 1990 and 2004 were included, of whom 39 had cryptogenic cirrhosis. Clinical, histological and laboratory data that had been prospectively collected were re-evaluated. RESULTS Seventeen (44%) of the cryptogenic patients had NAFLD in a previous liver biopsy and/or clinical features of the metabolic syndrome. Two patients had occult alcohol over-consumption and one patient had burnt-out AIH. Cryptogenic patients had significantly higher frequencies of diabetes, ascites, and hyponatraemia and weight loss. Patient survival was similar between cryptogenic patients and cirrhotics with a known aetiology. CONCLUSIONS Re-evaluation of patient data discovered probable underlying aetiologies in 51% of patients with cryptogenic cirrhosis evaluated for OLT, of which NAFLD was the most common (44%). Although cryptogenic patients had a more advanced liver disease when evaluated for OLT, patient survival was similar. Recent weight loss was significantly more common in cryptogenic patients, possibly being a sign of liver decompensation and signalling a need for OLT evaluation.
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Affiliation(s)
- Joel Marmur
- Department of Gastroenterology and Hepatology, Karolinska Institutet, Ersta Hospital, Stockholm, Sweden.
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Abstract
Hepatitis C virus (HCV) causes significant morbidity and mortality worldwide with nearly 3% of the world population infected by this virus. Fortunately, this virus does not establish latency, and hence it may be possible to eradicate it. HCV is strongly associated with liver cirrhosis and hepatocellular carcinoma and is currently treated with pegylated interferon-alpha (peg-IFN-alpha) and ribavirin. Unfortunately, these limited treatment options often produce significant side effects, and currently, complete eradication of virus with combined drug modalities has not yet been achieved for the majority of chronically HCV-infected individuals. Restricted treatment options, lack of a universal cure for HCV and the link between chronic infection, liver cirrhosis and hepatocellular carcinoma necessitate design of novel drugs and treatment options. Understanding the relationship between the immune response, viral clearance and inhibition of viral replication with pharmacology-based design can ultimately allow for complete eradication of HCV. This review focuses upon significant novel preclinical and clinical specifically targeted antiviral therapy (STAT-C) drugs under development, highlights their mechanism of action, and discusses their impact on systemic viral loads and permanent clearance of infection.
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Affiliation(s)
- R F Schinazi
- Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Veterans Affairs Medical Center/Emory University School of Medicine, Atlanta, GA, USA.
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Liver disorders in the elderly. Best Pract Res Clin Gastroenterol 2009; 23:909-17. [PMID: 19942167 DOI: 10.1016/j.bpg.2009.10.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 09/24/2009] [Accepted: 10/01/2009] [Indexed: 02/07/2023]
Abstract
Although there are no specific age-related liver diseases, it is increasingly recognized that the percentage and the actual number of elderly will increase substantially over the next twenty years. Moreover, the developments of new emerging conditions (e.g. non-alcoholic steatohepatitis) and novel therapeutic approaches have provoked increasing enthusiasm among hepatologists. Some liver diseases are particularly frequent in the elderly, e.g. chronic hepatitis C and hepatocellular carcinoma. The clinical course and management of liver disease in the elderly may differ in several aspects from those of younger adults. The problem of whether to offer antiviral treatment to a wide range of patients with chronic hepatitis C has arisen over the last eight to ten years, since the reduction in the risk of hepatocellular carcinoma was analyzed. Selected patients aged 65 and older have a chance of treatment with pegylated interferon plus ribavirin, despite a higher likelihood of side effects. The diagnosis of autoimmune hepatitis should be suspected in a patient over 65 years of age in case of 'acute' presentation with 10-fold increase in transaminases, jaundice and hyper-gammaglobulinemia, to avoid any delay in starting immunosuppressive therapy. The age of an end stage liver disease will increase over the next years, thus we will expects an increasing number of decompensated liver disease and hepatocellular carcinomas.
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Lonardo A, Loria P. Article Commentary: Insulin Resistance, Type 2 Diabetes and Chronic Liver Disease. A Deadly Trio. CLINICAL MEDICINE. ENDOCRINOLOGY AND DIABETES 2009; 2:CMED.S3518. [DOI: 10.4137/cmed.s3518] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
In this commentary to the paper by Donadon V. et al (Clinical Medicine: Endocrinology and Diabetes. 2009;2:25–33.) the association and significance of insulin resistance with chronic liver disease are shortly reviewed and the molecular mechanisms underlying the diabetogenic and oncogenic potentials of advanced liver disease are summarized. Literature studies demonstrate that hepatocellular carcinoma (HCC) can be part of the natural history of NASH. HCCs in patients with features of metabolic syndrome as the only risk factor for liver disease have distinct morphological characteristics and mainly occur in the absence of significant fibrosis in the background liver. Moreover, data indicate that the presence of diabetes carries an approximately three to four-fold increased risk of HCC and such a risk is strongly increased by concurrent viral infections. Finally, the relationship between insulin resistance, steatosis and diabetes in NAFLD and HCV infection will be commented, along with the directions for future studies.
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Affiliation(s)
- Amedeo Lonardo
- University of Modena and Reggio Emilia Department of Internal Medicine, Endocrinology, Geriatrics Nuovo Ospedale Sant'Agostino Estense di Baggiovara, Baggiovara, Modena, Italy
| | - Paola Loria
- University of Modena and Reggio Emilia Department of Internal Medicine, Endocrinology, Geriatrics Nuovo Ospedale Sant'Agostino Estense di Baggiovara, Baggiovara, Modena, Italy
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