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Sowton AP, Holzner LMW, Krause FN, Baxter R, Mocciaro G, Krzyzanska DK, Minnion M, O'Brien KA, Harrop MC, Darwin PM, Thackray BD, Vacca M, Feelisch M, Griffin JL, Murray AJ. Chronic inorganic nitrate supplementation does not improve metabolic health and worsens disease progression in mice with diet-induced obesity. Am J Physiol Endocrinol Metab 2025; 328:E69-E91. [PMID: 39653040 DOI: 10.1152/ajpendo.00256.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 10/16/2024] [Accepted: 11/07/2024] [Indexed: 01/11/2025]
Abstract
Inorganic nitrate (NO3-) has been proposed to be of therapeutic use as a dietary supplement in obesity and related conditions including the metabolic syndrome (MetS), type II diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Administration of NO3- to endothelial nitric oxide synthase-deficient mice reversed aspects of MetS; however, the impact of NO3- supplementation in diet-induced obesity is not well understood. Here we investigated the whole body metabolic phenotype and cardiac and hepatic metabolism in mice fed a high-fat, high-sucrose (HFHS) diet for up to 12 mo of age, supplemented with 1 mM NaNO3 (or NaCl) in their drinking water. HFHS feeding was associated with a progressive obesogenic and diabetogenic phenotype, which was not ameliorated by NO3-. Furthermore, HFHS-fed mice supplemented with NO3- showed elevated levels of cardiac fibrosis and accelerated progression of MASLD including development of hepatocellular carcinoma in comparison with NaCl-supplemented mice. NO3- did not enhance mitochondrial β-oxidation capacity in any tissue assayed and did not suppress hepatic lipid accumulation, suggesting it does not prevent lipotoxicity. We conclude that NO3- is ineffective in preventing the metabolic consequences of an obesogenic diet and may instead be detrimental to metabolic health against the background of HFHS feeding. This is the first report of an unfavorable effect of long-term nitrate supplementation in the context of the metabolic challenges of overfeeding, warranting urgent further investigation into the mechanism of this interaction.NEW & NOTEWORTHY Inorganic nitrate has been suggested to be of therapeutic benefit in obesity-related conditions, as it increases nitric oxide bioavailability, enhances mitochondrial β-oxidation, and reverses metabolic syndrome in eNOS-/- mice. However, we here show that over 12 months nitrate was ineffective in preventing metabolic consequences in high fat, high sucrose-fed mice and worsened aspects of metabolic health, impairing cholesterol handling, increasing cardiac fibrosis, and exacerbating steatotic liver disease progression, with acceleration to hepatocellular carcinoma.
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Affiliation(s)
- Alice P Sowton
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Lorenz M W Holzner
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Fynn N Krause
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
| | - Ruby Baxter
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Gabriele Mocciaro
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
| | - Dominika K Krzyzanska
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Magdalena Minnion
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Katie A O'Brien
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Matthew C Harrop
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Paula M Darwin
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Benjamin D Thackray
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
| | - Michele Vacca
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
- Wellcome Trust-MRC Institute of Metabolic Science Metabolic Research Laboratories, Addenbrooke's Hospital, Cambridge, United Kingdom
| | - Martin Feelisch
- Clinical & Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, United Kingdom
| | - Julian L Griffin
- Department of Biochemistry and Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
- The Rowett Institute, University of Aberdeen, Aberdeen, United Kingdom
| | - Andrew J Murray
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, United Kingdom
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Anastasaki M, Papadakis S, Gergianaki IN, Papastamatiou L, Aligizakis E, Grillaki N, Boutzoukaki E, Sivaropoulos N, Anastasiou F, Mendive J, de Juan-Asenjo C, Hernández-Ibáñez R, Martínez-Escudé A, Garcia-Retortillo M, Koek G, Heyens L, Muris J, Lionis CD. Development and pilot evaluation of an evidence-based algorithm for MASLD (formerly NAFLD) management in primary care in Europe. Front Med (Lausanne) 2024; 11:1383112. [PMID: 39640981 PMCID: PMC11617198 DOI: 10.3389/fmed.2024.1383112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD, formerly NAFLD), emerges as major cause of morbidity and mortality globally, with chronic patients facing increased risk. Guidelines on MASLD management in primary care (PC) are limited. This study aimed to develop and evaluate a clinical care pathway for use in PC to improve MASLD screening and management, including early detection, communication and treatment, in three European countries (Greece, Spain, the Netherlands). Methods An international multidisciplinary panel of experts oversaw pathway development, which was designed as a two-step algorithm with defined and sequenced tasks. To evaluate algorithm implementation, a controlled pilot study was conducted. Patients at risk of MASLD were assigned to general practitioners (GPs) trained in algorithm implementation (active group) or usual care (control group) and followed for 4-8 weeks. Primary outcomes were the number of patients screened for MASLD, managed in PC and referred to specialists. Results In this algorithm, patients with metabolic or liver dysfunction, confirmed MASLD or cardiovascular disease are screened with FIB-4 and classified as having risk of low-level (FIB-4 < 1.3), intermediate-level (1.3 ≤ FIB-4 < 2.67) or high-level MASLD (FIB-4 ≥ 2.67). The algorithm provides evidence-based tools to support GPs manage patients with risk of low-level MASLD in PC, coordinate linkage of patients with risk of high-level MASLD to specialists and refer patients with risk of intermediate-level MASLD for elastography (low-risk if <7.9 kPa or intermediate/high-risk if ≥7.9 kPa). During pilot evaluation, N = 37 participants were recruited in Spain (54.1% women, median age: 63 years). Significantly higher rates of patients in the active group (n = 17) than the control group (n = 20) were screened with FIB-4 (94.1% vs. 5.5%, p = 0.004). Patients in the active group received significantly more frequently a PC intervention for weight loss (70.6% vs. 10.0%, p < 0.001), alcohol regulation (52.9% vs. 0%, p < 0.001) and smoking cessation (29.4% vs. 0%, p = 0.005). In Greece no algorithm implementation was observed in either the active or control group, while the evaluation was not conducted in the Netherlands for logistic reasons. Conclusion This study provides evidence on the development and implementation of a new PC algorithm for MASLD screening and management. Variations among participating settings in algorithm implementation are indicative of context-specific particularities. Further research is necessary for integrating such pathways in tailored interventions to tackle this emerging public health issue.
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Affiliation(s)
- Marilena Anastasaki
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Sophia Papadakis
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | - Irini N. Gergianaki
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Greece
| | | | | | | | | | | | - Foteini Anastasiou
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Greece
- European Society for Primary Care Gastroenterology, Stockholm, Sweden
| | - Juan Mendive
- European Society for Primary Care Gastroenterology, Stockholm, Sweden
- La Mina Primary Health Care Centre—IDIAP Jordi Gol, Barcelona, Spain
| | | | - Rosario Hernández-Ibáñez
- La Marina Health Centre, Barcelona, Spain
- MASLD Working Group, Catalan Society of Family Medicine (CAMFiC), Barcelona, Spain
| | - Alba Martínez-Escudé
- MASLD Working Group, Catalan Society of Family Medicine (CAMFiC), Barcelona, Spain
- La LLagosta Primary Health Care Centre, La Llagosta, Barcelona, Spain
| | | | - Ger Koek
- Department of Gastroenterology and Hepatology, Maastricht University Medical Center, Maastricht, Netherlands
| | - Leen Heyens
- Faculty of Health and Life Sciences, Hasselt University, Diepenbeek, Belgium
- School of Nutrition and Translational Research in Metabolism, NUTRIM, Maastricht University, Maastricht, Netherlands
- Department of Endocrinology, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Jean Muris
- European Society for Primary Care Gastroenterology, Stockholm, Sweden
- Department of Family Medicine, CAPHRI Research Institute, Maastricht University, Maastricht, Netherlands
| | - Christos D. Lionis
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Greece
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Jung YH, Lee YJ, Dao T, Jung KH, Yu J, Oh AR, Jeong Y, Gi H, Kim YU, Ryu D, Carrer M, Pajvani UB, Lee SB, Hong SS, Kim K. KCTD17-mediated Ras stabilization promotes hepatocellular carcinoma progression. Clin Mol Hepatol 2024; 30:895-913. [PMID: 39098817 PMCID: PMC11540369 DOI: 10.3350/cmh.2024.0364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/31/2024] [Accepted: 08/01/2024] [Indexed: 08/06/2024] Open
Abstract
BACKGROUND/AIMS Potassium channel tetramerization domain containing 17 (KCTD17) protein, an adaptor for the cullin3 (Cul3) ubiquitin ligase complex, has been implicated in various human diseases; however, its role in hepatocellular carcinoma (HCC) remains elusive. Here, we aimed to elucidate the clinical features of KCTD17, and investigate the mechanisms by which KCTD17 affects HCC progression. METHODS We analyzed transcriptomic data from patients with HCC. Hepatocyte-specific KCTD17 deficient mice were treated with diethylnitrosamine (DEN) to assess its effect on HCC progression. Additionally, we tested KCTD17-directed antisense oligonucleotides for their therapeutic potential in vivo. RESULTS Our investigation revealed the upregulation of KCTD17 expression in both tumors from patients with HCC and mouse models of HCC, in comparison to non-tumor controls. We identified the leucine zipper-like transcriptional regulator 1 (Lztr1) protein, a previously identified Ras destabilizer, as a substrate for KCTD17-Cul3 complex. KCTD17-mediated Lztr1 degradation led to Ras stabilization, resulting in increased proliferation, migration, and wound healing in liver cancer cells. Hepatocyte-specific KCTD17 deficient mice or liver cancer xenograft models were less susceptible to carcinogenesis or tumor growth. Similarly, treatment with KCTD17-directed antisense oligonucleotides (ASO) in a mouse model of HCC markedly lowered tumor volume as well as Ras protein levels, compared to those in control ASO-treated mice. CONCLUSION KCTD17 induces the stabilization of Ras and downstream signaling pathways and HCC progression and may represent a novel therapeutic target for HCC.
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Affiliation(s)
- Young Hoon Jung
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Yun Ji Lee
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Tam Dao
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | - Kyung Hee Jung
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Junjie Yu
- Department of Medicine, Columbia University, New York, NY, USA
- Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, China
| | - Ah-Reum Oh
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Yelin Jeong
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - HyunJoon Gi
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Young Un Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - Dongryeol Ryu
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea
| | | | | | - Sang Bae Lee
- Division of Life Sciences, Jeonbuk National University, Jeonju, Korea
| | - Soon-Sun Hong
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
| | - KyeongJin Kim
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon, Korea
- Program in Biomedical Science & Engineering, College of Medicine, Inha University, Incheon, Korea
- Research Center for Controlling Intercellular Communication (RCIC), College of Medicine, Inha University, Incheon, Korea
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Brunson C, Struycken L, Schaub D, Ref J, Goldberg D, Hannallah J, Woodhead G, Young S. Comparative outcomes of trans-arterial radioembolization in patients with non-alcoholic steatohepatitis/non-alcoholic fatty liver disease-induced HCC: a retrospective analysis. Abdom Radiol (NY) 2024; 49:2714-2725. [PMID: 38709344 PMCID: PMC11300538 DOI: 10.1007/s00261-024-04295-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 05/07/2024]
Abstract
PURPOSE Tumorigenesis in NAFLD/NASH-induced HCC is unique and may affect the effectiveness of trans-arterial radioembolization in this population. The purpose of this study was to retrospectively compare the effectiveness of trans-arterial radioembolization for the treatment of hepatocellular carcinoma (HCC) between patients with non-alcoholic steatohepatitis (NASH)/non-alcoholic fatty liver disease (NAFLD) and non-NASH/NAFLD liver disease. MATERIALS AND METHODS Consecutive patients with HCC who underwent TARE at a single academic institution were retrospectively reviewed. Outcome measures including overall survival (OS), local progression-free survival (PFS), and hepatic PFS as assessed by modified response evaluation criteria in solid tumors (mRECIST) were recorded. Kaplan-Meier and Cox proportional hazard models were utilized to compare progression-free survival and overall survival. RESULTS 138 separate HCCs in patients treated with TARE between July 2013 and July 2022 were retrospectively identified. Etiologies of HCC included NASH/NAFLD (30/122, 22%), HCV (52/122, 43%), alcoholic liver disease (25/122, 21%), and combined ALD/HCV (14/122, 11%). NASH/NAFLD patients demonstrated a significantly higher incidence of type 2 diabetes mellitus (p < 0.0001). There was no significant difference in overall survival (p = 0.928), local progression-free survival (p = 0.339), or hepatic progression-free survival between the cohorts (p = 0.946) by log-rank analysis. When NASH/NAFLD patients were compared to all combined non-NASH/NAFLD patients, there was no significant difference in OS (HR 1.1, 95% C.I. 0.32-3.79, p = 0.886), local PFS (HR 1.2, 95% C.I. 0.58-2.44, p = 0.639), or hepatic PFS (HR 1.3, 95% C.I. 0.52-3.16, p = 0.595) by log-rank analysis. CONCLUSION TARE appears to be an equally effective treatment for NASH/NAFLD-induced HCC when compared to other causes of HCC. Further studies in a larger cohort with additional subgroup analyses are warranted.
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Affiliation(s)
- Christopher Brunson
- University of California, 505 Parnassus Avenue, M-391, San Francisco, CA, 94143-0628, USA.
| | - Lucas Struycken
- Department of Medical Imaging, University of Arizona Health Sciences, Tucson, USA
| | - David Schaub
- University of Arizona Health Sciences, Tucson, USA
| | - Jacob Ref
- University of Arizona Health Sciences, Tucson, USA
| | - Daniel Goldberg
- Department of Medical Imaging, University of Arizona Health Sciences, Tucson, USA
| | - Jack Hannallah
- Department of Medical Imaging, University of Arizona Health Sciences, Tucson, USA
| | - Gregory Woodhead
- Department of Medical Imaging, University of Arizona Health Sciences, Tucson, USA
| | - Shamar Young
- Department of Medical Imaging, University of Arizona Health Sciences, Tucson, USA
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Ferenc K, Jarmakiewicz-Czaja S, Sokal-Dembowska A, Stasik K, Filip R. Common Denominator of MASLD and Some Non-Communicable Diseases. Curr Issues Mol Biol 2024; 46:6690-6709. [PMID: 39057041 PMCID: PMC11275402 DOI: 10.3390/cimb46070399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/25/2024] [Accepted: 06/27/2024] [Indexed: 07/28/2024] Open
Abstract
Currently, steatohepatitis has been designated as metabolic dysfunction-associated steatohepatitis (MASLD). MASLD risk factors mainly include metabolic disorders but can also include genetic, epigenetic, and environmental factors. Disease entities such as obesity, diabetes, cardiovascular disease, and MASLD share similar pathomechanisms and risk factors. Moreover, a bidirectional relationship is observed between the occurrence of certain chronic diseases and MASLD. These conditions represent a global public health problem that is responsible for poor quality of life and high mortality. It seems that paying holistic attention to these problems will not only help increase the chances of reducing the incidence of these diseases but also assist in the prevention, treatment, and support of patients.
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Affiliation(s)
- Katarzyna Ferenc
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland; (K.F.)
| | - Sara Jarmakiewicz-Czaja
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland; (S.J.-C.); (A.S.-D.)
| | - Aneta Sokal-Dembowska
- Institute of Health Sciences, Medical College of Rzeszow University, 35-959 Rzeszow, Poland; (S.J.-C.); (A.S.-D.)
| | - Katarzyna Stasik
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland; (K.F.)
- IBD Unit, Department of Gastroenterology, Clinical Hospital No. 2, 35-301 Rzeszow, Poland
| | - Rafał Filip
- Institute of Medicine, Medical College of Rzeszow University, 35-959 Rzeszow, Poland; (K.F.)
- IBD Unit, Department of Gastroenterology, Clinical Hospital No. 2, 35-301 Rzeszow, Poland
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Shi Y, Taherifard E, Saeed A, Saeed A. MASLD-Related HCC: A Comprehensive Review of the Trends, Pathophysiology, Tumor Microenvironment, Surveillance, and Treatment Options. Curr Issues Mol Biol 2024; 46:5965-5983. [PMID: 38921027 PMCID: PMC11202630 DOI: 10.3390/cimb46060356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2024] [Revised: 06/07/2024] [Accepted: 06/11/2024] [Indexed: 06/27/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a significant burden on global healthcare systems due to its considerable incidence and mortality rates. Recent trends indicate an increase in the worldwide incidence of metabolic dysfunction-associated steatotic liver disease (MASLD) and a shift in the etiology of HCC, with MASLD replacing the hepatitis B virus as the primary contributor to new cases of HCC. MASLD-related HCC exhibits distinct characteristics compared to viral HCC, including unique immune cell profiles resulting in an overall more immunosuppressive or exhausted tumor microenvironment. Furthermore, MASLD-related HCC is frequently identified in older age groups and among individuals with cardiometabolic comorbidities. Additionally, a greater percentage of MASLD-related HCC cases occur in noncirrhotic patients compared to those with viral etiologies, hindering early detection. However, the current clinical practice guidelines lack specific recommendations for the screening of HCC in MASLD patients. The evolving landscape of HCC management offers a spectrum of therapeutic options, ranging from surgical interventions and locoregional therapies to systemic treatments, for patients across various stages of the disease. Despite ongoing debates, the current evidence does not support differences in optimal treatment modalities based on etiology. In this study, we aimed to provide a comprehensive overview of the current literature on the trends, characteristics, clinical implications, and treatment modalities for MASLD-related HCC.
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Affiliation(s)
- Yuming Shi
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
| | - Erfan Taherifard
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
| | - Ali Saeed
- Department of Medicine, Ochsner Lafayette General Medical Center, Lafayette, LA 70503, USA;
| | - Anwaar Saeed
- Department of Medicine, Division of Hematology & Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA; (Y.S.); (E.T.)
- UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA
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Yamada A, Watanabe A, Nara A, Ishimaru N, Maeda K, Ido Y, Kotake K, Asano M, Shinohara Y, Yamamoto T. Longitudinal Analysis of Mitochondrial Function in a Choline-Deficient L-Amino Acid-Defined High-Fat Diet-Induced Metabolic Dysfunction-Associated Steatohepatitis Mouse Model. Int J Mol Sci 2024; 25:6193. [PMID: 38892381 PMCID: PMC11173319 DOI: 10.3390/ijms25116193] [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: 03/14/2024] [Revised: 05/21/2024] [Accepted: 06/01/2024] [Indexed: 06/21/2024] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is one of the most common chronic liver diseases worldwide. Some patients with MAFLD develop metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver fibrosis. However, the molecular mechanisms underlying this progression remain unknown, and no effective treatment for MASH has been developed so far. In this study, we performed a longitudinal detailed analysis of mitochondria in the livers of choline-deficient, methionine-defined, high-fat-diet (CDAHFD)-fed mice, which exhibited a MASH-like pathology. We found that FoF1-ATPase activity began to decrease in the mitochondria of CDAHFD-fed mice prior to alterations in the activity of mitochondrial respiratory chain complex, almost at the time of onset of liver fibrosis. In addition, the decrease in FoF1-ATPase activity coincided with the accelerated opening of the mitochondrial permeability transition pore (PTP), for which FoF1-ATPase might be a major component or regulator. As fibrosis progressed, mitochondrial permeability transition (PT) induced in CDAHFD-fed mice became less sensitive to cyclosporine A, a specific PT inhibitor. These results suggest that episodes of fibrosis might be related to the disruption of mitochondrial function via PTP opening, which is triggered by functional changes in FoF1-ATPase. These novel findings could help elucidate the pathogenesis of MASH and lead to the development of new therapeutic strategies.
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Affiliation(s)
- Akiko Yamada
- Department of Pathology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Akira Watanabe
- Institute for Genome Research, Tokushima University, Kuramoto, Tokushima 770-8503, Japan
- Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
| | - Atsushi Nara
- Institute for Genome Research, Tokushima University, Kuramoto, Tokushima 770-8503, Japan
- Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
| | - Naozumi Ishimaru
- Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549, Japan
| | - Kosuke Maeda
- Institute for Genome Research, Tokushima University, Kuramoto, Tokushima 770-8503, Japan
- Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
| | - Yusuke Ido
- Institute for Genome Research, Tokushima University, Kuramoto, Tokushima 770-8503, Japan
- Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
| | - Kazumasa Kotake
- Institute for Genome Research, Tokushima University, Kuramoto, Tokushima 770-8503, Japan
- Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
| | - Masatake Asano
- Department of Pathology, Nihon University School of Dentistry, Chiyoda-ku, Tokyo 101-8310, Japan
| | - Yasuo Shinohara
- Institute for Genome Research, Tokushima University, Kuramoto, Tokushima 770-8503, Japan
- Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
| | - Takenori Yamamoto
- Institute for Genome Research, Tokushima University, Kuramoto, Tokushima 770-8503, Japan
- Faculty of Pharmaceutical Sciences, Tokushima University, Shomachi, Tokushima 770-8505, Japan
- Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, Kawasaki-ku, Kanagawa 210-9501, Japan
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Vargas-Accarino E, Higuera M, Buti M, Mínguez B. Hepatitis-C-Related Hepatocellular Carcinoma, Still a Relevant Etiology beyond a Hepatitis C Infection Cure. Cancers (Basel) 2024; 16:1521. [PMID: 38672603 PMCID: PMC11048451 DOI: 10.3390/cancers16081521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/11/2024] [Accepted: 04/15/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND In the past decades, global changes, including hepatitis B vaccination, hepatitis B and C antiviral therapies, and the increasing prevalence of steatotic liver disease, have influenced the landscape of liver cancer etiologies. METHODS We performed a retrospective study focused on the etiological factors of de novo hepatocellular carcinoma (HCC) diagnoses in an academic center between 2019 and 2022. RESULTS Among 352 consecutive patients with HCC, alcohol-related liver disease was the predominant etiology (33.3%), followed by hepatitis C (HCV) infection (30.7%). Significant associations were found between HCC etiology and patient demographics, BCLC stage at diagnosis, and cirrhosis prevalence. CONCLUSIONS Whereas accessibility to antiviral therapy is granted, HCV infection remains as one of the main HCC etiologies. MASLD-related HCC, although growing globally, is not as relevant in our area. Strong public policies need to be implemented to prevent alcohol consumption, the main etiology of liver disease and liver cancer.
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Affiliation(s)
- Elena Vargas-Accarino
- Liver Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (B.M.)
| | - Mónica Higuera
- Liver Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (B.M.)
| | - María Buti
- Liver Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (B.M.)
- Department of Medicine, UAB Campus, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Liver Unit, Vall d’Hebron Hospital, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
| | - Beatriz Mínguez
- Liver Diseases Research Group, Vall d’Hebron Research Institute (VHIR), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; (E.V.-A.); (M.H.); (B.M.)
- Department of Medicine, UAB Campus, Universitat Autònoma de Barcelona (UAB), 08193 Cerdanyola del Vallès, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Liver Unit, Vall d’Hebron Hospital, Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain
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9
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Lekakis V, Papatheodoridis GV. Natural history of metabolic dysfunction-associated steatotic liver disease. Eur J Intern Med 2024; 122:3-10. [PMID: 37940495 DOI: 10.1016/j.ejim.2023.11.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/31/2023] [Accepted: 11/03/2023] [Indexed: 11/10/2023]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), which has been the term for non-alcoholic fatty liver disease (NAFLD) since June 2023, represents the most common liver disease worldwide and is a leading cause of liver-related morbidity and mortality. A thorough knowledge of the disease's natural history is required to promptly stratify patients' risks, since MASLD is a multifaceted disorder with a broad range of clinical phenotypes. The histological disease spectrum ranges from isolated hepatic steatosis, currently named as metabolic dysfunction-associated steatotic liver (MASL), to metabolic dysfunction-associated steatohepatitis (MASH) and eventually may accumulate hepatic fibrosis and develop cirrhosis and/or hepatocellular carcinoma (HCC). Several risk factors for fibrosis progression have been identified, while the disease's progression displays notable dynamism and bidirectionality. When compared to the general population, all MASLD histological stages are substantially related with greater overall mortality, and this association exhibits a disease severity-dependent pattern. Interestingly, the fibrosis stage is the most accurate predictor of mortality among MASLD patients. The mortality attributed to MASLD predominantly stems from issues linked with the liver and cardiovascular system, as well as HCC and extrahepatic cancers. In light of the disease natural course, it is crucial to prioritize the identification of at-risk patients for disease progression in order to effectively address and change modifiable risk factors, hence mitigating disease complications. Further investigation is required to define the phenotype of rapid progressors more precisely as well as to improve risk stratification for HCC in non-cirrhotic individuals.
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Affiliation(s)
- Vasileios Lekakis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", 17 Agiou Thoma Street, Athens 11527, Greece
| | - George V Papatheodoridis
- Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, General Hospital of Athens "Laiko", 17 Agiou Thoma Street, Athens 11527, Greece.
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10
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Rong S, Xia M, Vale G, Wang S, Kim CW, Li S, McDonald JG, Radhakrishnan A, Horton JD. DGAT2 inhibition blocks SREBP-1 cleavage and improves hepatic steatosis by increasing phosphatidylethanolamine in the ER. Cell Metab 2024; 36:617-629.e7. [PMID: 38340721 PMCID: PMC10939742 DOI: 10.1016/j.cmet.2024.01.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 11/28/2023] [Accepted: 01/18/2024] [Indexed: 02/12/2024]
Abstract
Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step of triglyceride (TG) synthesis. DGAT2 deletion in mice lowers liver TGs, and DGAT2 inhibitors are under investigation for the treatment of fatty liver disease. Here, we show that DGAT2 inhibition also suppressed SREBP-1 cleavage, reduced fatty acid synthesis, and lowered TG accumulation and secretion from liver. DGAT2 inhibition increased phosphatidylethanolamine (PE) levels in the endoplasmic reticulum (ER) and inhibited SREBP-1 cleavage, while DGAT2 overexpression lowered ER PE concentrations and increased SREBP-1 cleavage in vivo. ER enrichment with PE blocked SREBP-1 cleavage independent of Insigs, which are ER proteins that normally retain SREBPs in the ER. Thus, inhibition of DGAT2 shunted diacylglycerol into phospholipid synthesis, increasing the PE content of the ER, resulting in reduced SREBP-1 cleavage and less hepatic steatosis. This study reveals a new mechanism that regulates SREBP-1 activation and lipogenesis that is independent of sterols and SREBP-2 in liver.
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Affiliation(s)
- Shunxing Rong
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Mingfeng Xia
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Goncalo Vale
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Simeng Wang
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Chai-Wan Kim
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Shili Li
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Jeffrey G McDonald
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Arun Radhakrishnan
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA
| | - Jay D Horton
- Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
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11
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Lin X, Zhang J, Chu Y, Nie Q, Zhang J. Berberine prevents NAFLD and HCC by modulating metabolic disorders. Pharmacol Ther 2024; 254:108593. [PMID: 38301771 DOI: 10.1016/j.pharmthera.2024.108593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 02/03/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a global metabolic disease with high prevalence in both adults and children. Importantly, NAFLD is becoming the main cause of hepatocellular carcinoma (HCC). Berberine (BBR), a naturally occurring plant component, has been demonstrated to have advantageous effects on a number of metabolic pathways as well as the ability to kill liver tumor cells by causing cell death and other routes. This permits us to speculate and make assumptions about the value of BBR in the prevention and defense against NAFLD and HCC by a global modulation of metabolic disorders. Herein, we briefly describe the etiology of NAFLD and NAFLD-related HCC, with a particular emphasis on analyzing the potential mechanisms of BBR in the treatment of NAFLD from aspects including increasing insulin sensitivity, controlling the intestinal milieu, and controlling lipid metabolism. We also elucidate the mechanism of BBR in the treatment of HCC. More significantly, we provided a list of clinical studies for BBR in NAFLD. Taking into account our conclusions and perspectives, we can make further progress in the treatment of BBR in NAFLD and NAFLD-related HCC.
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Affiliation(s)
- Xinyue Lin
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Juanhong Zhang
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China; College of Life Science, Northwest Normal University, Lanzhou 730070, China
| | - Yajun Chu
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Qiuying Nie
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
| | - Junmin Zhang
- School of Pharmacy, State Key Laboratory of Applied Organic Chemistry, and College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China.
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12
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Phoolchund AGS, Khakoo SI. MASLD and the Development of HCC: Pathogenesis and Therapeutic Challenges. Cancers (Basel) 2024; 16:259. [PMID: 38254750 PMCID: PMC10814413 DOI: 10.3390/cancers16020259] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Revised: 12/29/2023] [Accepted: 01/02/2024] [Indexed: 01/24/2024] Open
Abstract
Metabolic-dysfunction-associated steatotic liver disease (MASLD, previously known as non-alcoholic fatty liver disease (NAFLD)) represents a rapidly increasing cause of chronic liver disease and hepatocellular carcinoma (HCC), mirroring increasing rates of obesity and metabolic syndrome in the Western world. MASLD-HCC can develop at an earlier stage of fibrosis compared to other causes of chronic liver disease, presenting challenges in how to risk-stratify patients to set up effective screening programmes. Therapeutic decision making for MASLD-HCC is also complicated by medical comorbidities and disease presentation at a later stage. The response to treatment, particularly immune checkpoint inhibitors, may vary by the aetiology of the disease, and, in the future, patient stratification will be key to optimizing the therapeutic pathways.
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Affiliation(s)
- Anju G. S. Phoolchund
- Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
| | - Salim I. Khakoo
- Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK
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13
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Choi HH, Kim S, Shum DJ, Huang CY, Shui A, Fox RK, Khalili M. Assessing Adherence to US LI-RADS Follow-up Recommendations in Vulnerable Patients Undergoing Hepatocellular Carcinoma Surveillance. Radiol Imaging Cancer 2024; 6:e230118. [PMID: 38214600 PMCID: PMC10825700 DOI: 10.1148/rycan.230118] [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: 07/18/2023] [Revised: 11/01/2023] [Accepted: 11/29/2023] [Indexed: 01/13/2024]
Abstract
Purpose To assess adherence to the US Liver Imaging Reporting and Data System (LI-RADS) recommendations for hepatocellular carcinoma (HCC) surveillance and associated patient-level factors in a vulnerable, diverse patient sample. Materials and Methods The radiology report database was queried retrospectively for patients who underwent US LI-RADS-based surveillance examinations at a single institution between June 1, 2020, and February 28, 2021. Initial US and follow-up liver imaging were included. Sociodemographic and clinical data were captured from electronic medical records. Adherence to radiologist recommendation was defined as imaging (US, CT, or MRI) follow-up in 5-7 months for US-1, imaging follow-up in 3-6 months for US-2, and CT or MRI follow-up in 2 months for US-3. Descriptive analysis and multivariable modeling that adjusted for age, sex, race, and time since COVID-19 pandemic onset were performed. Results Among 936 patients, the mean age was 59.1 years; 531 patients (56.7%) were male and 544 (58.1%) were Asian or Pacific Islander, 91 (9.7%) were Black, 129 (13.8%) were Hispanic, 147 (15.7%) were White, and 25 (2.7%) self-reported as other race. The overall adherence rate was 38.8% (95% CI: 35.7, 41.9). The most common liver disease etiology was hepatitis B (60.6% [657 of 936 patients]); 19.7% of patients (183 of 936) had current or past substance use disorder, and 44.8% (416 of 936) smoked. At adjusted multivariable analysis, older age (odds ratio [OR], 1.20; P = .02), male sex (OR, 1.62; P = .003), hepatology clinic attendance (OR, 3.81; P < .001), and recent prior US examination (OR, 2.44; P < .001) were associated with full adherence, while current smoking (OR, 0.39; P < .001) was negatively associated. Conclusion Adherence to HCC imaging surveillance was suboptimal, despite US LI-RADS implementation. Keywords: Liver, Ultrasound, Screening, Abdomen/GI, Cirrhosis, Metabolic Disorders, Socioeconomic Issues Supplemental material is available for this article. © RSNA, 2024.
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Affiliation(s)
- Hailey H. Choi
- From the Department of Radiology and Biomedical Imaging, University
of California San Francisco, Zuckerberg San Francisco General Hospital, 505
Parnassus Ave, Box 0628, Room 255, San Francisco, CA 94143 (H.H.C., D.J.S.); and
Department of Medicine, Division of General Internal Medicine (S.K., R.K.F.),
Department of Epidemiology and Biostatistics (C.Y.H., A.S.), and Department of
Medicine, Division of Gastroenterology and Hepatology (M.K.), University of
California San Francisco, San Francisco, Calif
| | - Stephanie Kim
- From the Department of Radiology and Biomedical Imaging, University
of California San Francisco, Zuckerberg San Francisco General Hospital, 505
Parnassus Ave, Box 0628, Room 255, San Francisco, CA 94143 (H.H.C., D.J.S.); and
Department of Medicine, Division of General Internal Medicine (S.K., R.K.F.),
Department of Epidemiology and Biostatistics (C.Y.H., A.S.), and Department of
Medicine, Division of Gastroenterology and Hepatology (M.K.), University of
California San Francisco, San Francisco, Calif
| | - Dorothy J. Shum
- From the Department of Radiology and Biomedical Imaging, University
of California San Francisco, Zuckerberg San Francisco General Hospital, 505
Parnassus Ave, Box 0628, Room 255, San Francisco, CA 94143 (H.H.C., D.J.S.); and
Department of Medicine, Division of General Internal Medicine (S.K., R.K.F.),
Department of Epidemiology and Biostatistics (C.Y.H., A.S.), and Department of
Medicine, Division of Gastroenterology and Hepatology (M.K.), University of
California San Francisco, San Francisco, Calif
| | - Chiung-Yu Huang
- From the Department of Radiology and Biomedical Imaging, University
of California San Francisco, Zuckerberg San Francisco General Hospital, 505
Parnassus Ave, Box 0628, Room 255, San Francisco, CA 94143 (H.H.C., D.J.S.); and
Department of Medicine, Division of General Internal Medicine (S.K., R.K.F.),
Department of Epidemiology and Biostatistics (C.Y.H., A.S.), and Department of
Medicine, Division of Gastroenterology and Hepatology (M.K.), University of
California San Francisco, San Francisco, Calif
| | - Amy Shui
- From the Department of Radiology and Biomedical Imaging, University
of California San Francisco, Zuckerberg San Francisco General Hospital, 505
Parnassus Ave, Box 0628, Room 255, San Francisco, CA 94143 (H.H.C., D.J.S.); and
Department of Medicine, Division of General Internal Medicine (S.K., R.K.F.),
Department of Epidemiology and Biostatistics (C.Y.H., A.S.), and Department of
Medicine, Division of Gastroenterology and Hepatology (M.K.), University of
California San Francisco, San Francisco, Calif
| | - Rena K. Fox
- From the Department of Radiology and Biomedical Imaging, University
of California San Francisco, Zuckerberg San Francisco General Hospital, 505
Parnassus Ave, Box 0628, Room 255, San Francisco, CA 94143 (H.H.C., D.J.S.); and
Department of Medicine, Division of General Internal Medicine (S.K., R.K.F.),
Department of Epidemiology and Biostatistics (C.Y.H., A.S.), and Department of
Medicine, Division of Gastroenterology and Hepatology (M.K.), University of
California San Francisco, San Francisco, Calif
| | - Mandana Khalili
- From the Department of Radiology and Biomedical Imaging, University
of California San Francisco, Zuckerberg San Francisco General Hospital, 505
Parnassus Ave, Box 0628, Room 255, San Francisco, CA 94143 (H.H.C., D.J.S.); and
Department of Medicine, Division of General Internal Medicine (S.K., R.K.F.),
Department of Epidemiology and Biostatistics (C.Y.H., A.S.), and Department of
Medicine, Division of Gastroenterology and Hepatology (M.K.), University of
California San Francisco, San Francisco, Calif
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14
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Imai K, Takai K, Unome S, Miwa T, Hanai T, Suetsugu A, Shimizu M. FIB‑4 index and NAFLD fibrosis score are useful indicators for screening high‑risk groups of non‑viral hepatocellular carcinoma. Mol Clin Oncol 2023; 19:80. [PMID: 37719044 PMCID: PMC10502796 DOI: 10.3892/mco.2023.2676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 08/09/2023] [Indexed: 09/19/2023] Open
Abstract
Non-viral hepatocellular carcinoma (HCC) tends to appear in non-cirrhotic livers, rendering it difficult to screen for a high-risk group. The present study aimed to identify the most suitable indicator for screening high-risk groups of non-viral HCC. A total of 190 patients with non-viral HCC, including 126 with non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), were enrolled in the present study. A total of two cut-off values, for low and high levels of fibrosis, were set for each of the indicators, including the Child-Pugh score (CPS; 6 and 7), platelet counts (15.8 and 10x104/µl), albumin-bilirubin (ALBI) score (-2.60 and -2.27), fibrosis 4 index (FIB-4 index; 1.30 and 2.67) and NAFLD fibrosis score (NFS; -1.455 and 0.675). The ratio of the number of patients who fell outside the cut-off value for all patients was defined as the overlooking rate. The overlooking rates of CPS, platelet counts, ALBI score, FIB-4 index and NFS for the low fibrosis cut-off value were 41.0, 48.9, 35.8, 4.2 and 5.8%, respectively. When performing analysis limited to the NAFLD cases, those of the FIB-4 index and NFS were 4.8 and 6.3%, respectively. Those for the high fibrosis cut-off value were 79.5, 73.2, 62.6, 30.0 and 37.4%, respectively. On the whole, the present study demonstrates that the cut-off values of ≥1.30 for the FIB-4 index or ≥-1.455 for the NFS may be used to screen high-risk groups of HCC among patients with non-viral hepatitis.
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Affiliation(s)
- Kenji Imai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Koji Takai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Shinji Unome
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Takao Miwa
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Tatsunori Hanai
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Atsushi Suetsugu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Masahito Shimizu
- Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
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15
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Taru MG, Lupsor-Platon M. Exploring Opportunities to Enhance the Screening and Surveillance of Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease (NAFLD) through Risk Stratification Algorithms Incorporating Ultrasound Elastography. Cancers (Basel) 2023; 15:4097. [PMID: 37627125 PMCID: PMC10452922 DOI: 10.3390/cancers15164097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/08/2023] [Accepted: 08/11/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), with its progressive form, non-alcoholic steatohepatitis (NASH), has emerged as a significant public health concern, affecting over 30% of the global population. Hepatocellular carcinoma (HCC), a complication associated with both cirrhotic and non-cirrhotic NAFLD, has shown a significant increase in incidence. A substantial proportion of NAFLD-related HCC occurs in non-cirrhotic livers, highlighting the need for improved risk stratification and surveillance strategies. This comprehensive review explores the potential role of liver ultrasound elastography as a risk assessment tool for HCC development in NAFLD and highlights the importance of effective screening tools for early, cost-effective detection and improved management of NAFLD-related HCC. The integration of non-invasive tools and algorithms into risk stratification strategies could have the capacity to enhance NAFLD-related HCC screening and surveillance effectiveness. Alongside exploring the potential advancement of non-invasive tools and algorithms for effectively stratifying HCC risk in NAFLD, we offer essential perspectives that could enable readers to improve the personalized assessment of NAFLD-related HCC risk through a more methodical screening approach.
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Affiliation(s)
- Madalina-Gabriela Taru
- Hepatology Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania;
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Monica Lupsor-Platon
- “Iuliu Hatieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
- Medical Imaging Department, Regional Institute of Gastroenterology and Hepatology “Octavian Fodor”, 400162 Cluj-Napoca, Romania
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16
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Polyzos SA, Chrysavgis L, Vachliotis ID, Chartampilas E, Cholongitas E. Nonalcoholic fatty liver disease and hepatocellular carcinoma:Insights in epidemiology, pathogenesis, imaging, prevention and therapy. Semin Cancer Biol 2023; 93:20-35. [PMID: 37149203 DOI: 10.1016/j.semcancer.2023.04.010] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/23/2023] [Accepted: 04/27/2023] [Indexed: 05/08/2023]
Abstract
Hepatocellular carcinoma (HCC) is estimated to be the third leading cause of cancer-related mortality and is characterized by low survival rates. Nonalcoholic fatty liver disease (NAFLD) is emerging as a leading cause of HCC, whose rates are increasing, owing to the increasing prevalence of NAFLD. The pathogenesis of NAFLD-associated HCC is multifactorial: insulin resistance, obesity, diabetes and the low-grade hepatic inflammation, which characterizes NAFLD, seem to play key roles in the development and progression of HCC. The diagnosis of NAFLD-associated HCC is based on imaging in the presence of liver cirrhosis, preferably computerized tomography or magnetic resonance imaging, but liver biopsy for histological confirmation is usually required in the absence of liver cirrhosis. Some preventive measures have been recommended for NAFLD-associated HCC, including weight loss, cessation of even moderate alcohol drinking and smoking, as well as the use of metformin, statins and aspirin. However, these preventive measures are mainly based on observational studies, thus they need validation in trials of different design before introducing in clinical practice. The treatment of NAFLD should be tailored on an individual basis and should be ideally determined by a multidisciplinary team. In the last two decades, new medications, including tyrosine kinase inhibitors and immune checkpoints inhibitors, have improved the survival of patients with advanced HCC, but trials specifically designed for patients with NAFLD-associated HCC are scarce. The aim of this review was to overview evidence on the epidemiology and pathophysiology of NAFLD-associated HCC, then to comment on imaging tools for its appropriate screening and diagnosis, and finally to critically summarize the currently available options for its prevention and treatment.
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Affiliation(s)
- Stergios A Polyzos
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
| | - Ilias D Vachliotis
- First Laboratory of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Evangelos Chartampilas
- Department of Radiology, University General Hospital of Thessaloniki AHEPA, Thessaloniki, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, General Hospital Laiko, Athens, Greece
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17
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Kotsari M, Dimopoulou V, Koskinas J, Armakolas A. Immune System and Hepatocellular Carcinoma (HCC): New Insights into HCC Progression. Int J Mol Sci 2023; 24:11471. [PMID: 37511228 PMCID: PMC10380581 DOI: 10.3390/ijms241411471] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 07/12/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
According to the WHO's recently released worldwide cancer data for 2020, liver cancer ranks sixth in morbidity and third in mortality among all malignancies. Hepatocellular carcinoma (HCC), the most common kind of liver cancer, accounts approximately for 80% of all primary liver malignancies and is one of the leading causes of death globally. The intractable tumor microenvironment plays an important role in the development and progression of HCC and is one of three major unresolved issues in clinical practice (cancer recurrence, fatal metastasis, and the refractory tumor microenvironment). Despite significant advances, improved molecular and cellular characterization of the tumor microenvironment is still required since it plays an important role in the genesis and progression of HCC. The purpose of this review is to present an overview of the HCC immune microenvironment, distinct cellular constituents, current therapies, and potential immunotherapy methods.
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Affiliation(s)
- Maria Kotsari
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Vassiliki Dimopoulou
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - John Koskinas
- B' Department of Medicine, Hippokration Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Athanasios Armakolas
- Physiology Laboratory, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece
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18
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Lin ZY, Zhang XP, Zhao GD, Li CG, Wang ZH, Liu R, Hu MG. Short-term outcomes of robotic versus open hepatectomy among overweight patients with hepatocellular carcinoma: a propensity score-matched study. BMC Surg 2023; 23:153. [PMID: 37286991 DOI: 10.1186/s12893-023-02058-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 05/26/2023] [Indexed: 06/09/2023] Open
Abstract
BACKGROUND Robotic hepatectomy (RH) has gradually been accepted as it has overcome some of the limitations of open hepatectomy (OH). This study was to compare short-term outcomes in RH and OH for overweight (preoperative body mass index ≥ 25 kg/m²) patients with hepatocellular carcinoma (HCC). METHODS Perioperative and postoperative data from these patients who underwent RH or OH between January 2010 and December 2020 were retrospectively analyzed. Propensity score matching (PSM) analysis was performed to determine the impact of RH versus OH on the prognosis of overweight HCC patients. RESULTS All 304 overweight HCC patients were included, 172 who were underwent RH, and 132 who were underwent OH. After the 1:1 PSM, there were 104 patients in both RH and OH groups. After PSM, the RH group of patients had a shorter operative time, less estimated blood loss (EBL), a longer total clamping time, a shorter postoperative length of stay (LOS), less chance of surgical site infection and less rates of blood transfusion (all P < 0.05) compared to the OH patients. The differences between operative time, EBL and LOS were more significant in obese patients. RH was found to be an independent protective factor of EBL ≥ 400ml relative to OH in overweight patients for the first time. CONCLUSIONS RH was safe and feasible in overweight HCC patients. Compared with OH, RH has advantages in terms of operative time, EBL, postoperative LOS, and surgical site infection. Carefully selected overweight patients should be considered for RH.
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Affiliation(s)
- Zhao-Yi Lin
- Medical School of Chinese PLA, Beijing, 100853, China
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Xiu-Ping Zhang
- Medical School of Chinese PLA, Beijing, 100853, China
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Guo-Dong Zhao
- Medical School of Chinese PLA, Beijing, 100853, China
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Cheng-Gang Li
- Medical School of Chinese PLA, Beijing, 100853, China
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Zhao-Hai Wang
- Medical School of Chinese PLA, Beijing, 100853, China
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China
| | - Rong Liu
- Medical School of Chinese PLA, Beijing, 100853, China.
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
| | - Ming-Gen Hu
- Medical School of Chinese PLA, Beijing, 100853, China.
- Faculty of Hepato-Pancreato-Biliary Surgery, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
- Department of Hepatobiliary, Pancreatic Surgical Oncology, The First Medical Center of Chinese PLA General Hospital, Beijing, 100853, China.
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19
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Beal EW, Owen M, McNamara M, McAlearney AS, Tsung A. Patient-, Provider-, and System-Level Barriers to Surveillance for Hepatocellular Carcinoma in High-Risk Patients in the USA: a Scoping Review. J Gastrointest Cancer 2023; 54:332-356. [PMID: 35879510 DOI: 10.1007/s12029-022-00851-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/17/2022] [Indexed: 12/12/2022]
Abstract
PURPOSE Hepatocellular carcinoma has a dismal prognosis, except in patients diagnosed early who are candidates for potentially curative therapies. Most HCC cases develop in patients with chronic liver disease. Therefore, expert society guidelines recommend surveillance every 6 months with ultrasound with or without serum alpha-fetoprotein for high-risk patients. However, fewer than 20% of patients in the USA undergo appropriate surveillance. METHODS A systematic scoping review was performed with the objective of identifying barriers to screening among high-risk patients in the USA including mapping key concepts in the relevant literature, identifying the main sources and types of evidence available, and identifying gaps in the literature. A total of 43 studies published from 2007 to 2021 were included. Data were extracted and a conceptual framework was created. RESULTS Assessment of quantitative studies revealed poor surveillance rates, often below 50%. Three categories of barriers to surveillance were identified: patient-level, provider-level, and system-level barriers. Prevalent patient-level barriers included financial constraints, lack of awareness of surveillance recommendations, and scheduling difficulties. Common provider-level barriers were lack of provider awareness of guidelines for surveillance, difficulty accessing specialty resources, and time constraints in the clinic. System-level barriers included fewer clinic visits and rural/safety-net settings. Proposed interventions include improved patient/provider education, patient navigators, increased community/academic collaboration, and EMR-based reminders. CONCLUSION Based on these findings, there is a crucial need to implement and evaluate proposed interventions to improve HCC surveillance.
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Affiliation(s)
- Eliza W Beal
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA.
- The Center for the Advancement of Team Science, Systems Thinking in Health Services and Implementation Science Research (CATALYST, The Ohio State University College of Medicine, AnalyticsColumbus, OH, 43210, USA.
| | - Mackenzie Owen
- The Ohio State University College of Medicine, Columbus, OH, 43210, USA
| | - Molly McNamara
- The Ohio State University College of Medicine, Columbus, OH, 43210, USA
| | - Ann Scheck McAlearney
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
- The Center for the Advancement of Team Science, Systems Thinking in Health Services and Implementation Science Research (CATALYST, The Ohio State University College of Medicine, AnalyticsColumbus, OH, 43210, USA
- The Department of Family and Community Medicine, The Ohio State University College of Medicine, Columbus, OH, 43210, USA
| | - Allan Tsung
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, 43210, USA
- The Center for the Advancement of Team Science, Systems Thinking in Health Services and Implementation Science Research (CATALYST, The Ohio State University College of Medicine, AnalyticsColumbus, OH, 43210, USA
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20
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Donne R, Lujambio A. The liver cancer immune microenvironment: Therapeutic implications for hepatocellular carcinoma. Hepatology 2023; 77:1773-1796. [PMID: 35989535 PMCID: PMC9941399 DOI: 10.1002/hep.32740] [Citation(s) in RCA: 257] [Impact Index Per Article: 128.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 07/26/2022] [Accepted: 08/18/2022] [Indexed: 12/19/2022]
Abstract
The liver is the sixth most common site of primary cancer in humans and the fourth leading cause of cancer-related death in the world. Hepatocellular carcinoma (HCC) accounts for 90% of liver cancers. HCC is a prevalent disease with a progression that is modulated by the immune system. Half of the patients with HCC receive systemic therapies, traditionally sorafenib or lenvatinib, as a first-line therapy. In the last few years, immune-checkpoint inhibitors (ICIs) have revolutionized cancer therapy and have gained an increased interest in the treatment of HCC. In 2020, the combination of atezolizumab (anti-programmed death-ligand 1) and bevacizumab (anti-vascular endothelial growth factor) improved overall survival over sorafenib, resulting in Food and Drug Administration (FDA) approval as a first-line treatment for patients with advanced HCC. Despite these major advances, a better molecular and cellular characterization of the tumor microenvironment is still needed because it has a crucial role in the development and progression of HCC. Inflamed (hot) and noninflamed (cold) HCC tumors and genomic signatures have been associated with response to ICIs. However, there are no additional biomarkers to guide clinical decision-making. Other immune-targeting strategies, such as adoptive T-cell transfer, vaccination, and virotherapy, are currently under development. This review provides an overview on the HCC immune microenvironment, different cellular players, current available immunotherapies, and potential immunotherapy modalities.
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Affiliation(s)
- Romain Donne
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
| | - Amaia Lujambio
- Department of Oncological Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai , Tisch Cancer Institute , New York , New York , USA
- Icahn School of Medicine at Mount Sinai , The Precision Immunology Institute , New York , New York , USA
- Graduate School of Biomedical Sciences , Icahn School of Medicine at Mount Sinai , New York , New York , USA
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21
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Bhatt A, Wu J. Immunotherapy for recurrent hepatocellular carcinoma. World J Gastroenterol 2023; 29:2261-2271. [PMID: 37124885 PMCID: PMC10134420 DOI: 10.3748/wjg.v29.i15.2261] [Citation(s) in RCA: 8] [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: 09/15/2022] [Revised: 01/25/2023] [Accepted: 03/14/2023] [Indexed: 04/14/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is presented frequently in late stages that are not amenable for curative treatment. Even for patients who can undergo resection for curative treatment of HCC, up to 50% recur. For patients who were not exposed to systemic therapy prior to recurrence, recurrence frequently cannot be subjected to curative therapy or local treatments. Such patients have several options of immunotherapy (IO). This includes programmed cell death protein 1 (PD-1) and cytotoxic T- lymphocyte associated protein 4 treatment, combination of PD-1 and vascular endothelial growth factor inhibitor or single agent PD-1 therapy when all other options are deemed inappropriate. There are also investigational therapies in this area that explore either PD-1 and tyrosine kinase inhibitors or a novel agent in addition to PD-1 with vascular endothelial growth factor inhibitors. This mini-review explored IO options for patients with recurrent HCC who were not exposed to systemic therapy at the initial diagnosis. We also discussed potential IO options for patients with recurrent HCC who were exposed to first-line therapy with curative intent at diagnosis.
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Affiliation(s)
- Ahan Bhatt
- Division of Hematology and Oncology, Perlmutter Cancer Center of NYU Langone Health, NYU School of Medicine, New York, NY 10016, United States
| | - Jennifer Wu
- Division of Hematology and Oncology, Perlmutter Cancer Center of NYU Langone Health, NYU School of Medicine, New York, NY 10016, United States
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22
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Song Y, Wang B, Wang W, Shi Q. Regulatory effect of orexin system on various diseases through mTOR signaling pathway. Trends Endocrinol Metab 2023; 34:292-302. [PMID: 36934048 DOI: 10.1016/j.tem.2023.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 02/19/2023] [Accepted: 02/21/2023] [Indexed: 03/18/2023]
Abstract
Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological processes through these two receptor pathways, such as feeding behavior, sleep/wake state, energy homeostasis, reward, and the coordination of emotion. Mammalian target of rapamycin (mTOR) can coordinate upstream signals with downstream effectors, thereby regulating fundamental cellular processes and also plays an essential role in the signaling network downstream of the orexin system. In turn, the orexin system can activate mTOR. Here, we review the association of the orexin system with the mTOR signaling pathway mainly by discussing that drugs in various diseases exert their effects on the orexin system, indirectly affecting the mTOR signaling pathway.
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Affiliation(s)
- Ying Song
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China.
| | - Beibei Wang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Wenjun Wang
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China
| | - Qiwen Shi
- Department of Pharmacology, Zhejiang University of Technology, Hangzhou, Zhejiang, China
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23
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van Son KC, Verschuren L, Hanemaaijer R, Reeves H, Takkenberg RB, Drenth JPH, Tushuizen ME, Holleboom AG. Non-Parenchymal Cells and the Extracellular Matrix in Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease. Cancers (Basel) 2023; 15:1308. [PMID: 36831649 PMCID: PMC9954729 DOI: 10.3390/cancers15041308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/06/2023] [Accepted: 02/16/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC) in the setting of non-alcoholic fatty liver disease (NAFLD)-related cirrhosis and even in the pre-cirrhotic state is increasing in incidence. NAFLD-related HCC has a poor clinical outcome as it is often advanced at diagnosis due to late diagnosis and systemic treatment response is poor due to reduced immune surveillance. Much of the focus of molecular research has been on the pathological changes in hepatocytes; however, immune cells, hepatic stellate cells, liver sinusoidal endothelial cells and the extracellular matrix may play important roles in the pathogenesis of NAFLD-related HCC as well. Here, we review the role of non-parenchymal cells in the liver in the pathogenesis of HCC in the context of NAFLD-NASH, with a particular focus on the innate and the adaptive immune system, fibrogenesis and angiogenesis. We review the key roles of macrophages, hepatic stellate cells (HSCs), T cells, natural killer (NK) cells, NKT cells and liver sinusoidal endothelial cells (LSECs) and the role of the extracellular matrix in hepatocarcinogenesis within the steatotic milieu.
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Affiliation(s)
- Koen C. van Son
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Lars Verschuren
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Roeland Hanemaaijer
- Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, 2333 BE Leiden, The Netherlands
| | - Helen Reeves
- Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne NE2 4HH, UK
| | - R. Bart Takkenberg
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
| | - Joost P. H. Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Maarten E. Tushuizen
- Department of Gastroenterology and Hepatology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
| | - Adriaan G. Holleboom
- Department of Vascular and Internal Medicine, Amsterdam University Medical Center, 1105 AZ Amsterdam, The Netherlands
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24
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Alba MM, Ebright B, Hua B, Slarve I, Zhou Y, Jia Y, Louie SG, Stiles BL. Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development. Front Physiol 2023; 14:1098467. [PMID: 36818443 PMCID: PMC9932286 DOI: 10.3389/fphys.2023.1098467] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
Liver cancer is a malignancy developed from underlying liver disease that encompasses liver injury and metabolic disorders. The progression from these underlying liver disease to cancer is accompanied by chronic inflammatory conditions in which liver macrophages play important roles in orchestrating the inflammatory response. During this process, bioactive lipids produced by hepatocytes and macrophages mediate the inflammatory responses by acting as pro-inflammatory factors, as well as, playing roles in the resolution of inflammation conditions. Here, we review the literature discussing the roles of bioactive lipids in acute and chronic hepatic inflammation and progression to cancer.
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Affiliation(s)
- Mario M. Alba
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brandon Ebright
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Brittney Hua
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Ielyzaveta Slarve
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yiren Zhou
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Yunyi Jia
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Stan G. Louie
- Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
| | - Bangyan L. Stiles
- Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, Unites States
- Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, Unites States
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25
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Seif El Dahan K, Daher D, Singal AG. Hepatocellular carcinoma surveillance in patients with non-alcoholic fatty liver disease. Clin Mol Hepatol 2023; 29:S207-S219. [PMID: 36103899 PMCID: PMC10029960 DOI: 10.3350/cmh.2022.0247] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/01/2022] [Accepted: 09/05/2022] [Indexed: 11/05/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) may progress to cirrhotic or non-cirrhotic hepatocellular carcinoma (HCC), and is currently recognized as the fastest growing cause of HCC worldwide. Accordingly, professional society guidelines recommend HCC surveillance in patients with cirrhosis from any etiology, and some may consider it beneficial in subgroups with non-cirrhotic NAFLD at higher risk for HCC. Notably, patients with NAFLD-related HCC are more likely to have HCC diagnosed at more advanced stages and have poorer outcomes when compared to other etiologies, and suboptimal effectiveness of HCC surveillance programs is a major culprit. In this review, we summarize the current guidelines for HCC surveillance and discuss its benefits versus potential harms for NAFLD patients. We also address the unique challenges of HCC surveillance in NAFLD, including higher proportion of NAFLD-related HCC without cirrhosis, poor recognition of at-risk patients, lack of consensus regarding the value of surveillance in non-cirrhotic NAFLD, subpar effectiveness of surveillance tools related to NAFLD phenotype, and preponderant surveillance underuse among NAFLD patients. Finally, we examine the effectiveness of currently used surveillance tools (i.e., ultrasound and alpha fetoprotein) and outline future perspectives including emerging risk stratification tools, imaging surveillance strategies (e.g., abbreviated magnetic resonance imaging protocols), blood-based biomarkers (e.g., GALAD and circulating tumor DNA panels), and interventions to improve surveillance adherence.
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Affiliation(s)
- Karim Seif El Dahan
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Darine Daher
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
| | - Amit G. Singal
- Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA
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26
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Multifactorial Diseases of the Heart, Kidneys, Lungs, and Liver and Incident Cancer: Epidemiology and Shared Mechanisms. Cancers (Basel) 2023; 15:cancers15030729. [PMID: 36765688 PMCID: PMC9913123 DOI: 10.3390/cancers15030729] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/05/2023] [Accepted: 01/20/2023] [Indexed: 01/26/2023] Open
Abstract
Within the aging population, the frequency of cancer is increasing dramatically. In addition, multiple genetic and environmental factors lead to common multifactorial diseases, including cardiovascular disease, chronic kidney disease, chronic obstructive pulmonary disease, and metabolic-associated fatty liver disease. In recent years, there has been a growing awareness of the connection between cancer and multifactorial diseases, as well as how one can affect the other, resulting in a vicious cycle. Although the exact mechanistic explanations behind this remain to be fully explored, some progress has been made in uncovering the common pathologic mechanisms. In this review, we focus on the nature of the link between cancer and common multifactorial conditions, as well as specific shared mechanisms, some of which may represent either preventive or therapeutic targets. Rather than organ-specific interactions, we herein focus on the shared mechanisms among the multifactorial diseases, which may explain the increased cancer risk. More research on this subject will highlight the significance of developing new drugs that target multiple systems rather than just one disease.
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27
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Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease: The Prognostic Role of Liver Stiffness Measurement. Cancers (Basel) 2023; 15:cancers15030637. [PMID: 36765595 PMCID: PMC9913338 DOI: 10.3390/cancers15030637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/17/2023] [Accepted: 01/18/2023] [Indexed: 01/22/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), which is nowadays the most common etiology of chronic liver disease, is associated with an increased risk of hepatocellular carcinoma (HCC), with or without cirrhosis. Owing to the high prevalence of NAFLD worldwide, it becomes crucial to develop adequate strategies for surveillance of HCC and new prediction models aiming at stratifying NAFLD population for HCC risk. To this purpose, several noninvasive tests (NITs) have been proposed in the several last years, including clinical parameters, serum biomarkers, and imaging techniques. Most of these tools are focused on the assessment of liver fibrosis. Both ultrasound (US) elastography (especially transient elastography) and magnetic resonance (MR) elastography have been evaluated to estimate HCC risk in NAFLD patients. Recently, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) include these techniques among the recommended NITs for the assessment of liver fibrosis. The aim of this review is to summarize the most recent data on the role of US and MR elastography in HCC risk stratification in patients with NAFLD.
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28
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Vitale A, Svegliati-Baroni G, Ortolani A, Cucco M, Dalla Riva GV, Giannini EG, Piscaglia F, Rapaccini G, Di Marco M, Caturelli E, Zoli M, Sacco R, Cabibbo G, Marra F, Mega A, Morisco F, Gasbarrini A, Foschi FG, Missale G, Masotto A, Nardone G, Raimondo G, Azzaroli F, Vidili G, Oliveri F, Pelizzaro F, Ramirez Morales R, Cillo U, Trevisani F, Miele L, Marchesini G, Farinati F. Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database. Gut 2023; 72:141-152. [PMID: 34933916 DOI: 10.1136/gutjnl-2021-324915] [Citation(s) in RCA: 86] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 11/29/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort. METHODS We analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC. RESULTS MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002-2003, to 77.3% and 28.9% in 2018-2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006). CONCLUSIONS The prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.
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Affiliation(s)
- Alessandro Vitale
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy
| | - Gianluca Svegliati-Baroni
- Liver Disease and Transplant Unit, Polytechnic University of Marche, Ancona, Italy
- Obesity Center, Polytechnic University of Marche, Ancona, Italy
| | - Alessio Ortolani
- Department of Gastroenterology, Azienda Ospedaliera Marche Nord Pesaro, Pesaro, Italy
| | - Monica Cucco
- Liver Disease and Transplant Unit, Polytechnic University of Marche, Ancona, Italy
- Department of Gastroenterology, Polytechnic University of Marche, Ancona, Italy
| | - Giulio V Dalla Riva
- School of Mathematics and Statistics University of Canterbury, Statistics University of Canterbury, Canterbury, New Zealand
| | - Edoardo G Giannini
- Department of Internal Medicine, Gastroenterology Unit, University of Genova, IRCCS Policlinico San Martino, Genoa, Italy
| | - Fabio Piscaglia
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Gianludovico Rapaccini
- Gastroenterology Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | | | | | - Marco Zoli
- Department of Medical and Surgical Sciences, Internal Medicine-Zoli Unit, Alma Mater Studiorum - Università di Bologna, Padova, Italy
| | - Rodolfo Sacco
- Gastroenterology and Digestive Endoscopy Unit, Foggia University Hospital, Foggia, Puglia, Italy
| | - Giuseppe Cabibbo
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, Internal Medicine and Hepatology Unit, University of Florence, Florence, Italy
| | - Andrea Mega
- Gastroenterology Unit, Ospedale Generale Regionale di Bolzano, Bolzano, Italy
| | - Filomena Morisco
- Department of Clinical Medicine and Surgery, Gastroenterology Unit, University of Naples Federico II, Portici, Italy
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology, and Liver Unit, University Hospital Agostino Gemelli, Roma, Lazio, Italy
| | | | - Gabriele Missale
- Infectious Diseases and Hepatology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Emilia-Romagna, Italy
| | - Alberto Masotto
- Gastroenterology Unit, IRCCS Ospedale Sacro Cuore Don Calabria, Negrar, Veneto, Italy
| | - Gerardo Nardone
- Department of Clinical Medicine and Surgery, Hepato-Gastroenterology Unit, Federico II University Hospital, Napoli, Italy
| | - Giovanni Raimondo
- Clinical and Experimental Medicine, University Hospital of Messina, Messina, Italy
| | - Francesco Azzaroli
- Division of Gastroenterology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Gianpaolo Vidili
- Department of Clinical and Experimental Medicine, Universita degli Studi di Sassari, Sassari, Italy
| | - Filippo Oliveri
- Department of Clinical and Experimental Medicine, Hepatology and Liver Physiopathology Laboratory and Internal Medicine, University of Pisa, Pisa, Italy
| | - Filippo Pelizzaro
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy
| | - Rafael Ramirez Morales
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy
| | - Umberto Cillo
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy
| | - Franco Trevisani
- Division of Medical Semeiotics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Luca Miele
- Internal Medicine and Gastroenterology, Fondazione Policlinico Gemelli, Rome, Italy
- Internal Medicine, Universita Cattolica del Sacro Cuore, Roma, Italy
| | - Giulio Marchesini
- Department of Medical & Surgical Sciences, University of Bologna Hospital of Bologna Sant'Orsola-Malpighi Polyclinic, Bologna, Italy
| | - Fabio Farinati
- Department of Surgery, Oncology and Gastroenterology, University of Padua, Padova, Italy
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Lessons on Drug Development: A Literature Review of Challenges Faced in Nonalcoholic Fatty Liver Disease (NAFLD) Clinical Trials. Int J Mol Sci 2022; 24:ijms24010158. [PMID: 36613602 PMCID: PMC9820446 DOI: 10.3390/ijms24010158] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Revised: 11/24/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
NAFLD is the most common chronic liver disease worldwide, occurring in both obese and lean patients. It can lead to life-threatening liver diseases and nonhepatic complications, such as cirrhosis and cardiovascular diseases, that burden public health and the health care system. Current care is weight loss through diet and exercise, which is a challenging goal to achieve. However, there are no FDA-approved pharmacotherapies for NAFLD. This review thoroughly examines the clinical trial findings from 22 drugs (Phase 2 and above) and evaluates the future direction that trials should take for further drug development. These trialed drugs can broadly be categorized into five groups-hypoglycemic, lipid-lowering, bile-pathway, anti-inflammatory, and others, which include nutraceuticals. The multitude of challenges faced in these yet-to-be-approved NAFLD drug trials provided insight into a few areas of improvement worth considering. These include drug repurposing, combinations, noninvasive outcomes, standardization, adverse event alleviation, and the need for precision medicine with more extensive consideration of NAFLD heterogenicity in drug trials. Understandably, every evolution of the drug development landscape lies with its own set of challenges. However, this paper believes in the importance of always learning from lessons of the past, with each potential improvement pushing clinical trials an additional step forward toward discovering appropriate drugs for effective NAFLD management.
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Rusu I, Pirlog R, Chiroi P, Nutu A, Puia VR, Fetti AC, Rusu DR, Berindan-Neagoe I, Al Hajjar N. The Implications of Noncoding RNAs in the Evolution and Progression of Nonalcoholic Fatty Liver Disease (NAFLD)-Related HCC. Int J Mol Sci 2022; 23:12370. [PMID: 36293225 PMCID: PMC9603983 DOI: 10.3390/ijms232012370] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/12/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide. Meanwhile, liver cancer represents the sixth most common malignancy, with hepatocellular carcinoma (HCC) as the primary, most prevalent subtype. Due to the rising incidence of metabolic disorders, NAFLD has become one of the main contributing factors to HCC development. However, although NAFLD might account for about a fourth of HCC cases, there is currently a significant gap in HCC surveillance protocols regarding noncirrhotic NAFLD patients, so the majority of NAFLD-related HCC cases were diagnosed in late stages when survival chances are minimal. However, in the past decade, the focus in cancer genomics has shifted towards the noncoding part of the genome, especially on the microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), which have proved to be involved in the regulation of several malignant processes. This review aims to summarize the current knowledge regarding some of the main dysregulated, noncoding RNAs (ncRNAs) and their implications for NAFLD and HCC development. A central focus of the review is on miRNA and lncRNAs that can influence the progression of NAFLD towards HCC and how they can be used as potential screening tools and future therapeutic targets.
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Affiliation(s)
- Ioana Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
| | - Radu Pirlog
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Paul Chiroi
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Andreea Nutu
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Vlad Radu Puia
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Alin Cornel Fetti
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Daniel Radu Rusu
- Department of Pathology, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400337 Cluj-Napoca, Romania
| | - Nadim Al Hajjar
- 3rd Department of General Surgery, “Iuliu Hatieganu” University of Medicine and Pharmacy, 400186 Cluj-Napoca, Romania
- Department of Surgery, Regional Institute of Gastroenterology and Hepatology, 400162 Cluj-Napoca, Romania
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Cavalcante LN, Dezan MGF, Paz CLDSL, Lyra AC. RISK FACTORS FOR HEPATOCELLULAR CARCINOMA IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE. ARQUIVOS DE GASTROENTEROLOGIA 2022; 59:540-548. [PMID: 36515349 DOI: 10.1590/s0004-2803.202204000-93] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 08/29/2022] [Indexed: 11/16/2022]
Abstract
Non-alcoholic fatty liver disease is growing in worldwide prevalence and thus, is expected to have a higher number of NAFLD-related hepatocellular carcinoma (HCC) in the following years. This review describes the risk factors associated with HCC in NAFLD-patients. The presence of liver cirrhosis is the preponderant one. Male gender, PNPLA3 variants, diabetes, and obesity also appear to predispose to the development of HCC, even in non-cirrhotic subjects. Thus far, intensive lifestyle modifications, including glycemic control, and obesity treatment, are effective therapies for NAFLD/ non-alcoholic steatohepatitis and, therefore, probably, also for HCC. Some drugs that aimed at decreasing inflammatory activity and fibrosis, as well as obesity, were studied. Other data have suggested the possibility of HCC chemoprevention. So far, however, there is no definitive evidence for the routine utilization of these drugs. We hope, in the future, to be able to profile patients at higher risk of NAFLD-HCC and outline strategies for early diagnosis and prevention.
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Affiliation(s)
- Lourianne Nascimento Cavalcante
- Universidade Federal da Bahia, Salvador, BA, Brasil.,Hospital São Rafael, Serviço de Gastro-Hepatologia, Salvador, BA, Brasil
| | | | | | - André Castro Lyra
- Universidade Federal da Bahia, Salvador, BA, Brasil.,Hospital São Rafael, Serviço de Gastro-Hepatologia, Salvador, BA, Brasil
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Mahlapuu M, Caputo M, Xia Y, Cansby E. GCKIII kinases in lipotoxicity: Roles in NAFLD and beyond. Hepatol Commun 2022; 6:2613-2622. [PMID: 35641240 PMCID: PMC9512487 DOI: 10.1002/hep4.2013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/25/2022] [Accepted: 05/06/2022] [Indexed: 11/29/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is defined by excessive accumulation of lipid droplets within hepatocytes. The STE20-type kinases comprising the germinal center kinase III (GCKIII) subfamily - MST3, MST4, and STK25 - decorate intrahepatocellular lipid droplets and have recently emerged as critical regulators of the initiation and progression of NAFLD. While significant advancement has been made toward deciphering the role of GCKIII kinases in hepatic fat accumulation (i.e., steatosis) as well as the aggravation of NAFLD into its severe form nonalcoholic steatohepatitis (NASH), much remains to be resolved. This review provides a brief overview of the recent studies in patient cohorts, cultured human cells, and mouse models, which have characterized the function of MST3, MST4, and STK25 in the regulation of hepatic lipid accretion, meta-inflammation, and associated cell damage in the context of NAFLD/NASH. We also highlight the conflicting data and emphasize future research directions that are needed to advance our understanding of GCKIII kinases as potential targets in the therapy of NAFLD and its comorbidities. Conclusions: Several lines of evidence suggest that GCKIII proteins govern the susceptibility to hepatic lipotoxicity and that pharmacological inhibition of these kinases could mitigate NAFLD development and aggravation. Comprehensive characterization of the molecular mode-of-action of MST3, MST4, and STK25 in hepatocytes as well as extrahepatic tissues is important, especially in relation to their impact on carcinogenesis, to fully understand the efficacy as well as safety of GCKIII antagonism.
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Affiliation(s)
- Margit Mahlapuu
- Department of Chemistry and Molecular BiologyUniversity of Gothenburg and Sahlgrenska University HospitalGothenburgSweden
| | - Mara Caputo
- Department of Chemistry and Molecular BiologyUniversity of Gothenburg and Sahlgrenska University HospitalGothenburgSweden
| | - Ying Xia
- Department of Chemistry and Molecular BiologyUniversity of Gothenburg and Sahlgrenska University HospitalGothenburgSweden
| | - Emmelie Cansby
- Department of Chemistry and Molecular BiologyUniversity of Gothenburg and Sahlgrenska University HospitalGothenburgSweden
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El Ray A, Paradis V, Montasser A, Elghannam M, Shemis M, Nessim I, Abu-Taleb H, Asselah T, Mohamed A, Poté N, Akl M, Marcellin P. Usefulness of the SAF score to characterize NAFLD/NASH in non-cirrhotic HCV patients. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00209-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The SAF score (steatosis, activity, and fibrosis) has been developed for the assessment of the histological severity of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The aim of this study was to assess the usefulness of the SAF score in a homogenous cohort of Egyptian patients with chronic HCV infection (CHC) without any alcohol consumption and without cirrhosis. We performed a prospective cross-sectional study including 70 consecutive Egyptian patients with chronic HCV infection to assess the usefulness of the SAF score to characterize NAFLD/NASH in non-cirrhotic HCV patients. The inclusion criteria included positive serum anti-HCV IgG antibody and positive HCVRNA, absence of treatment, and absence of cirrhosis (fibrosis score < F4). Patients were divided into two groups: with metabolic syndrome (MS) and without metabolic syndrome (non-MS). All patients were exposed to thorough history taking, full clinical examination, and laboratory and ultrasound assessment. Histopathologic evaluation of the liver biopsy for the assessment of steatosis, activity, grade, and fibrosis stage was assessed by 2 pathologists with experience in liver diseases.
Results
We found that the degree of fibrosis increases with aging. Liver biopsies from CHC patients with metabolic syndrome (MS) exhibited a significantly higher stage of fibrosis than biopsies from those without MS; however, the grade of inflammation did not differ significantly between the two groups. No significant correlation was found between the SAF score and the body mass index (BMI) or serum HCV RNA. No significant relation between SAF score, fibrosis, and MS. No significant relation was found between the MS and the level of HCV viremia.
Conclusion
We concluded that steatosis was associated with the fibrosis stage, independently of MS. This suggests that in this population, steatosis might be more related to HCV infection than to NAFLD and that fibrosis progression might be related, at least in part, to the steatosis process, i.e., virus-associated fatty liver disease (VAFLD).
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Chen T, Zhang S, Zhou D, Lu P, Mo X, Tamrakar R, Yang X. Screening of co-pathogenic genes of non-alcoholic fatty liver disease and hepatocellular carcinoma. Front Oncol 2022; 12:911808. [PMID: 36033523 PMCID: PMC9410624 DOI: 10.3389/fonc.2022.911808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a risk factor for hepatocellular carcinoma (HCC). However, its carcinogenic mechanism is still unclear, looking for both diseases’ transcriptome levels, the same changes as we are looking for NAFLD may provide a potential mechanism of action of HCC. Thus, our study aimed to discover the coexisting pathogenic genes of NAFLD and HCC. Methods We performed a variance analysis with public data for both diseases. At the same time, weighted gene correlation network analysis (WGCNA) was used to find highly correlated gene modules in both diseases. The darkturquoise gene module was found to be highly correlated with both diseases. Based on the diagnosis related module genes and the differential genes of the two diseases, we constructed diagnostic and prognostic models by logistic regression, univariate Cox regression, and LASSO regression. Public datasets verified the results. Meanwhile, we built a competing endogenous RNA (ceRNA) network based on the model genes and explored the related pathways and immune correlation involved in the two diseases by using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and gene set enrichment analyses. Immunohistochemistry was used to verify the different expression of ABCC5 and TUBG1 among the normal liver, NAFLD, and HCC tissues. Sodium palmitate/sodium oleate was used to establish high-fat cell models, and Real Time Quantitative Polymerase Chain Reaction (RT-qPCR) was used to verify the messenger RNA (mRNA) expression of ABCC5 in lipidization cells. Results A total of 26 upregulated genes and 87 downregulated genes were found using limma package identification analysis. According to WGCNA, the darkturquoise gene module was highly correlated with the prognosis of both diseases. The coexisting genes acquired by the two groups were only three central genes, that is, ABCC5, DHODH and TUBG1. The results indicated that the diagnostic and prognostic models constructed by ABCC5 and TUBG1 genes had high accuracy in both diseases. The results of immunohistochemistry showed that ABCC5 and TUBG1 were significantly overexpressed in NAFLD and HCC tissues compared with normal liver tissues. The Oil Red O staining and triglyceride identified the successful construction of HepG2 and LO2 high-fat models using PA/OA. The results of RT-qPCR showed that the lipidization of LO2 and HepG2 increased the mRNA expression of ABCC5. Conclusions The gene model constructed by ABCC5 and TUBG1 has high sensibility and veracity in the diagnosis of NAFLD as well as the diagnosis and prognosis of HCC. ABCC5 and TUBG1 may play an important role in the development of NAFLD to HCC. In addition, lipidization could upregulate the mRNA expression of ABCC5 in HCC.
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Affiliation(s)
- Ting Chen
- Department of Endocrinology, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Siwen Zhang
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Guangxi Medical University, Nanning, China
- *Correspondence: Xi Yang, ; Siwen Zhang,
| | - Dongmei Zhou
- Department of Endocrinology, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Peipei Lu
- Department of Geriatric Endocrinology and Metabolism, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Xianglai Mo
- Department of Geriatric Endocrinology and Metabolism, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Rashi Tamrakar
- Department of Endocrinology, First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Xi Yang
- Department of Geriatric Endocrinology and Metabolism, First Affiliated Hospital, Guangxi Medical University, Nanning, China
- Guangxi Key Laboratory of Precision Medicine in Cardio-Cerebrovascular Diseases Control and Prevention, First Affiliated Hospital, Guangxi Medical University, Nanning, China
- Guangxi Clinical Research Center for Cardio-Cerebrovascular Diseases, Nanning, China
- *Correspondence: Xi Yang, ; Siwen Zhang,
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35
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Estimating global prevalence, incidence, and outcomes of non-alcoholic fatty liver disease from 2000 to 2021: systematic review and meta-analysis. Chin Med J (Engl) 2022; 135:1682-1691. [PMID: 36070463 PMCID: PMC9509027 DOI: 10.1097/cm9.0000000000002277] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND The increasing burden of non-alcoholic fatty liver disease (NAFLD) worldwide imposes an emerging public health issue. We perform the current study to estimate the global prevalence, incidence, disease progression, and clinical outcomes of NAFLD. METHODS A systematic search was conducted in Medline, Embase, Web of Science, Google Scholar, and Cochrane CENTRAL that screened articles in English language published from January 2000 to December 2021. NAFLD prevalence, incidence, rate of disease progression, and outcomes were calculated with the DerSimonian-Laird random effects model with arcsine transformation. RESULTS Our search identified 59,156 records, of which 578 studies fulfilled our inclusion criteria. The overall prevalence of NAFLD was 29.38% (95% confidence interval [CI] 28.09-30.69) regardless of the diagnostic techniques. Looking at the group in which the diagnosis was made by ultrasound exclusively, the pooled prevalence was 30.49% (95% CI 29.55-31.43). NAFLD has become more prevalent during the year 2011-2021 (31.63%, 95% CI 30.23-33.04) compared with year 2000-2010 (27.94%, 95% CI 26.23-29.69). The pooled estimation of non-alcoholic steatohepatitis prevalence was 8.26% (95% CI 1.13-21.01), 46.49% (95% CI 35.93-57.20), and 46.72% (95% CI 37.57-55.98) in general population, NAFLD patients, and severe/morbidly obese patients, respectively. Based on a total of 110,142 newly developed NAFLD patients, the pooled incident rate was estimated as 46.24 cases per 1000 person-years (95% CI 43.21-49.30). In patients with NAFLD, the incident rate of hepatocellular carcinoma was 1.46 (95% CI 0.90-2.03) cases per 1000 person-years. The overall pooled estimate of NAFLD related mortality was 23.91 (95% CI 13.55-37.18) death per 1000 person-years. CONCLUSIONS The prevalence of NAFLD is increasing globally. It is contributing to poor clinical outcomes including hepatocellular carcinoma and death. Rising awareness and urgent actions are warranted to control the NAFLD pandemic across the globe. REGISTRATION PROSPERO, No. CRD42020171104.
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Dufour JF, Anstee QM, Bugianesi E, Harrison S, Loomba R, Paradis V, Tilg H, Wong VWS, Zelber-Sagi S. Current therapies and new developments in NASH. Gut 2022; 71:gutjnl-2021-326874. [PMID: 35710299 PMCID: PMC9484366 DOI: 10.1136/gutjnl-2021-326874] [Citation(s) in RCA: 118] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 04/26/2022] [Indexed: 12/13/2022]
Abstract
Non-alcoholic steatohepatitis is becoming the most important aetiology for advanced liver disease. There has been important progress in the field in recent years and the complexity of the pathophysiology of NASH is better understood. Multiple non-invasive circulating and imaging biomarkers have been tested. The importance of lifestyle has been recognised and several drugs are being tested in clinical trials. This review addresses the challenges that healthcare professionals face in the management of NASH patients.
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Affiliation(s)
| | - Quentin M Anstee
- Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK
| | | | - Stephen Harrison
- Pinnacle clinical research, San Antonio, Texas, USA
- Visiting Professor of Hepatology, University of Oxford, Oxford, UK
| | - Rohit Loomba
- Division of Gastroenterology and Epidemiology, University of California at San Diego, La Jolla, California, USA
| | | | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Shira Zelber-Sagi
- School of Public Health, University of Haifa, Haifa, Israel
- Department of Gastroenterology, Tel-Aviv Medical Center, Tel-Aviv, Israel
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Ahmad MI, Khan MU, Kodali S, Shetty A, Bell SM, Victor D. Hepatocellular Carcinoma Due to Nonalcoholic Fatty Liver Disease: Current Concepts and Future Challenges. J Hepatocell Carcinoma 2022; 9:477-496. [PMID: 35673598 PMCID: PMC9167599 DOI: 10.2147/jhc.s344559] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/14/2022] [Indexed: 12/24/2022] Open
Abstract
Obesity has been labeled as the global pandemic of the 21st century, resulting from a sedentary lifestyle and caloric excess. Nonalcoholic fatty liver disease (NAFLD), characterized by excessive hepatic steatosis, is strongly associated with obesity and metabolic syndrome and is estimated to be present in one-quarter of the world population, making it the most common cause of the chronic liver disease (CLD). NAFLD spectrum varies from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The burden of NAFLD has been predicted to increase in the coming decades resulting in increased rates of decompensated cirrhosis, hepatocellular carcinoma (HCC), and liver-related deaths. In the current review, we describe the pathophysiology of NAFLD and NASH, risk factors associated with disease progression, related complications, and mortality. Later, we have discussed the changing epidemiology of HCC, with NAFLD emerging as the most common cause of CLD and HCC. We have also addressed the risk factors of HCC development in the NAFLD population (including demographic, metabolic, genetic, dietary, and lifestyle factors), presentation of NAFLD-associated HCC, its prognosis, and the issue of HCC development in non-cirrhotic NAFLD. Lastly, the problems related to HCC screening in the NAFLD population, the remaining challenges, and future directions, especially the need to identify the high-risk individuals, will be discussed. We will conclude the review by summarizing the clinical evidence for treating fibrosis and preventing HCC in those at risk with NAFLD-associated HCC.
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Affiliation(s)
- Muhammad Imran Ahmad
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
| | - Muhammad Umair Khan
- Department of Gastroenterology and Hepatology, Hamad Medical Corporation, Doha, Qatar
- ECPE- Executive and Continuing Professional Education, Harvard T.H Chan School of Public Health, Boston, MA, 02115-5810, USA
| | - Sudha Kodali
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - Akshay Shetty
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - S Michelle Bell
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
| | - David Victor
- Lynda K and David M Underwood Center for Digestive Disorders, Division of Gastroenterology and Hepatology, Houston Methodist Hospital Houston, Houston, TX, USA
- Sherrie and Alan Conover Center for Liver Disease and Transplantation, Houston Methodist Hospital, Houston, TX, USA
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Ru L, Wang XM, Niu JQ. The miR-23-27-24 cluster: an emerging target in NAFLD pathogenesis. Acta Pharmacol Sin 2022; 43:1167-1179. [PMID: 34893685 PMCID: PMC9061717 DOI: 10.1038/s41401-021-00819-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 11/08/2021] [Indexed: 12/13/2022]
Abstract
The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing globally, being the most widespread form of chronic liver disease in the west. NAFLD includes a variety of disease states, the mildest being non-alcoholic fatty liver that gradually progresses to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma. Small non-coding single-stranded microRNAs (miRNAs) regulate gene expression at the miRNA or translational level. Numerous miRNAs have been shown to promote NAFLD pathogenesis and progression through increasing lipid accumulation, oxidative stress, mitochondrial damage, and inflammation. The miR-23-27-24 clusters, composed of miR-23a-27a-24-2 and miR-23b-27b-24-1, have been implicated in various biological processes as well as many diseases. Herein, we review the current knowledge on miR-27, miR-24, and miR-23 in NAFLD pathogenesis and discuss their potential significance in NAFLD diagnosis and therapy.
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Affiliation(s)
- Lin Ru
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China
| | - Xiao-mei Wang
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China ,grid.430605.40000 0004 1758 4110Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021 China
| | - Jun-qi Niu
- grid.430605.40000 0004 1758 4110Department of Hepatology, The First Hospital of Jilin University, Changchun, 130021 China ,grid.430605.40000 0004 1758 4110Key Laboratory of Zoonosis Research, Ministry of Education, The First Hospital of Jilin University, Changchun, 130021 China
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Ogresta D, Mrzljak A, Cigrovski Berkovic M, Bilic-Curcic I, Stojsavljevic-Shapeski S, Virovic-Jukic L. Coagulation and Endothelial Dysfunction Associated with NAFLD: Current Status and Therapeutic Implications. J Clin Transl Hepatol 2022; 10:339-355. [PMID: 35528987 PMCID: PMC9039716 DOI: 10.14218/jcth.2021.00268] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/24/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, type 2 diabetes mellitus and obesity. It is considered a multisystem disease and there is a strong association with cardiovascular disease and arterial hypertension, which interfere with changes in the coagulation system. Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage. Through a review of the literature, we consider and discuss possible disorders in the coagulation cascade and fibrinolysis, endothelial dysfunction and platelet abnormalities in patients with NAFLD.
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Affiliation(s)
- Doris Ogresta
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Maja Cigrovski Berkovic
- Department for Endocrinology, Diabetes and Pharmacology, University Hospital Dubrava, Zagreb, Croatia
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
| | - Ines Bilic-Curcic
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
- Department of Diabetes, Endocrinology and Metabolism Disorders, University Hospital Osijek, Osijek, Croatia
| | | | - Lucija Virovic-Jukic
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
- Correspondence to: Lucija Virović-Jukić, University of Zagreb School of Medicine, Department of Medicine; Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Vinogradska cesta 29, Zagreb 10000, Croatia. ORCID: https://orcid.org/0000-0002-6350-317X. Tel: +385-1-3787178, Fax: +385-1-3787448, E-mail:
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Chrysavgis L, Giannakodimos I, Diamantopoulou P, Cholongitas E. Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link. World J Gastroenterol 2022; 28:310-331. [PMID: 35110952 PMCID: PMC8771615 DOI: 10.3748/wjg.v28.i3.310] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/19/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has emerged as the most common liver disorder worldwide mainly attributed to the epidemic spread of obesity and type 2 diabetes mellitus. Although it is considered a benign disease, NAFLD can progress to non-alcoholic steatohepatitis, liver cirrhosis and hepatocellular carcinoma (HCC). Most data regarding the epidemiology of NAFLD-related HCC are derived from cohort and population studies and show that its incidence is increasing as well as it is likely to emerge as the leading indication for liver transplantation, especially in the Western World. Although cirrhosis constitutes the main risk factor for HCC development, in patients with NAFLD, HCC can arise in the absence of cirrhosis, indicating specific carcinogenic molecular pathways. Since NAFLD as an underlying liver disease for HCC is often underdiagnosed due to lack of sufficient surveillance in this population, NAFLD-HCC patients are at advanced HCC stage at the time of diagnosis making the management of those patients clinically challenging and affecting their prognostic outcomes. In this current review, we summarize the latest literature on the epidemiology, other than liver cirrhosis-pathogenesis, risk factors and prognosis of NAFLD-HCC patients. Finally, we emphasize the prevention of the development of NAFLD-associated HCC and we provide some insight into the open questions and issues regarding the appropriate surveillance policies for those patients.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Experimental Physiology, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Ilias Giannakodimos
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Panagiota Diamantopoulou
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
| | - Evangelos Cholongitas
- First Department of Internal Medicine, "Laiko" General Hospital of Athens, National and Kapodistrian University of Athens, Athens 11527, Greece
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Musunuri B, Shetty S, Bhat G, Udupa K, Pai A. Profile of patients with hepatocellular carcinoma: An experience from a tertiary care center in India. Indian J Gastroenterol 2022; 41:127-134. [PMID: 35226292 PMCID: PMC9108108 DOI: 10.1007/s12664-021-01209-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 06/07/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prevalence of hepatocellular carcinoma (HCC) is increasing worldwide and it is now the third most common cause of cancer-related death. HCC is becoming a major health burden with steadily increasing incidence globally. METHODS This is an observational study over a 3-year period in a tertiary care center in India. Three hundred and thirty-nine patients diagnosed to have HCC were included in this study. Patients' clinical, etiological, radiological and cytohistological data and therapy offered were recorded and analyzed. RESULTS Cirrhosis of the liver was seen in 73.2% of the patients. 16.8% of patients were asymptomatic at the time of presentation. Ascites (57.2%) and jaundice (22.4%) were the most common signs of hepatic decompensation. The most common etiology of HCC was cryptogenic/non-alcoholic fatty liver disease (NAFLD) in 51% of the patients, while hepatitis B and C were seen in 17.4% and 5.8% of the patients, respectively. Advanced and end-stage disease with Barcelona Clinic Liver Cancer (BCLC) stages C and D were seen in 62.4% of patients. 56.6% had Albumin-bilirubin (ALBI) score of 2, while 62.8% had Okuda stage II disease. High alpha-fetoprotein (AFP) levels (>400 ng/mL) were seen in 48.9% of patients. Macrovascular invasion and metastases were seen in 45.9% and 22.2% of the patients, respectively. 17.6% of patients had evidence of tumor thrombus. 14.5% of biopsy specimens showed associated steatosis/steatohepatitis along with confirmation of HCC. Only 26.6% of the cirrhotic HCC patients were diagnosed during surveillance. CONCLUSIONS HCC due to unknown cause/NAFLD appears to be overtaking hepatitis B as the commonest cause for HCC. Despite the advances in diagnostic methods and surveillance, most cases of HCC tend to be diagnosed at advanced stages.
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Affiliation(s)
- Balaji Musunuri
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576 104, India
| | - Shiran Shetty
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576 104, India
| | - Ganesh Bhat
- Department of Gastroenterology and Hepatology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576 104, India
| | - Karthik Udupa
- Department of Medical Oncology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576 104, India
| | - Ananth Pai
- Department of Medical Oncology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal 576 104, India
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Hymel E, Vlock E, Fisher KW, Farazi PA. Differential progression of unhealthy diet-induced hepatocellular carcinoma in obese and non-obese mice. PLoS One 2022; 17:e0272623. [PMID: 35994501 PMCID: PMC9394802 DOI: 10.1371/journal.pone.0272623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 07/22/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) ranks first among liver diseases in Western countries. NAFLD is typically associated with obesity and diabetes, however it also develops in lean individuals without metabolic syndrome. The prevalence of lean NAFLD is 7 percent in the U.S. and 25-30 percent in some Asian countries. NAFLD starts with excess liver fat accumulation (NAFL), progresses to nonalcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of lean NASH-HCC and how it differs from obese NASH-HCC is not well understood. METHODS In this work, we generated a mouse model of lean and obese NASH-HCC using a choline deficient/high trans-fat/fructose/cholesterol diet and a choline supplemented/high trans-fat/fructose/cholesterol diet, respectively, to compare progression to NASH-HCC in lean versus obese mice. Comparisons were made at the organismal, histological, and molecular level by investigating fatty acid metabolism in the plasma of these mice. RESULTS Obese mice showed more pronounced glucose intolerance and insulin resistance, higher levels of plasma cholesterol and triglycerides, and higher penetrance of NASH compared to lean mice. Despite the abnormal metabolic profile of obese mice, male obese and lean mice developed HCC with similar penetrance (53.3% and 53.8%, respectively), albeit lean mice showed faster tumor progression as evidenced by the larger tumor size and lower HCC-free survival. None of the female lean mice developed HCC, while 50% of female obese mice developed HCC. Both groups of mice showed a reduction in plasma polyunsaturated fatty acids (PUFAs), however, the levels were higher towards the endpoint in obese mice compared to lean mice. CONCLUSIONS Unhealthy diet composition appears to drive progression to NASH-HCC rather than the organismal effects of obesity. PUFA levels may increase due to systemic inflammation in obese mice and act as suppressors of tumor progression, thus delaying HCC progression in obese mice compared to lean mice. These models could be used to further dissect the molecular pathogenesis of lean and obese NASH-HCC and address the mechanisms whereby PUFAs may be implicated in hepatocarcinogenesis.
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Affiliation(s)
- Emma Hymel
- Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Elizabeth Vlock
- Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, Omaha, NE, United States of America
- Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, College of Education and Human Sciences, University of Nebraska Lincoln, Lincoln, NE, United States of America
| | - Kurt W. Fisher
- Department of Pathology and Microbiology, College of Medicine, University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Paraskevi A. Farazi
- Department of Epidemiology, College of Public Health, University of Nebraska Medical Center, Omaha, NE, United States of America
- Nebraska Center for the Prevention of Obesity Diseases through Dietary Molecules, College of Education and Human Sciences, University of Nebraska Lincoln, Lincoln, NE, United States of America
- * E-mail:
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Singal AG, Lok AS, Feng Z, Kanwal F, Parikh ND. Conceptual Model for the Hepatocellular Carcinoma Screening Continuum: Current Status and Research Agenda. Clin Gastroenterol Hepatol 2022; 20:9-18. [PMID: 32961340 PMCID: PMC8287785 DOI: 10.1016/j.cgh.2020.09.036] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 09/15/2020] [Accepted: 09/18/2020] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) continues to have a dismal prognosis, with 5-year survival below 20%. This poor prognosis can be in part attributed to failures along the cancer screening process continuum such as underuse of screening in at risk patients and appropriate treatments for patients with HCC. Better understanding these process failures, and how they compare to those seen in other cancer types, can help inform potential intervention targets and strategies to reduce HCC-related mortality. Herein, we outline a conceptual model with several discrete steps in the HCC screening process continuum including risk assessment, screening initiation, follow-up of screening results, diagnostic evaluation, and treatment evaluation. The conceptual model illustrates how each step in the screening process is prone to delays or failure, resulting in worse outcomes such as late stage diagnosis or poor survival, and how factors at the patient, provider, and health care system levels can contribute to these failures. We compare cancer screening processes for HCC with those employed in breast and colorectal cancer screening to identify opportunities for improvement. The Translational Liver Cancer consortium was recently established by the National Cancer Institute with the goal of improving early detection of HCC. Studies designed to address failures in the HCC screening process continuum will help accomplish this goal.
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Affiliation(s)
- Amit G Singal
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas.
| | - Anna S Lok
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| | - Ziding Feng
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Fasiha Kanwal
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
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Chen BR, Pan CQ. Non-invasive assessment of fibrosis and steatosis in pediatric non-alcoholic fatty liver disease. Clin Res Hepatol Gastroenterol 2022; 46:101755. [PMID: 34311134 DOI: 10.1016/j.clinre.2021.101755] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2020] [Revised: 06/19/2021] [Accepted: 06/21/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Non-Alcoholic Fatty Liver Disease (NAFLD) has become one of the most common causes of chronic liver disease in the pediatric population. Recent advances have been made in developing non-invasive measures for NAFLD assessment. This review presents an analysis of these latest developments and also proposes an algorithm for screening pediatric patients at risk for NAFLD. METHODS A systematic literature search on PUBMED and EMBASE was conducted. Guidelines for clinical care of pediatric NAFLD were also reviewed. RESULTS In imaging tests, transient elastography (TE) combined with controlled attenuation parameter (CAP) is a promising, relatively low-cost method offering an intermediate level of accuracy on accessing patient's fibrosis and steatosis in a singular package. Liver biopsy remains the gold standard for diagnosis and/or evaluation of NAFLD, but with our proposed algorithm on utilizing non-invasive testing, the number of liver biopsies required could decrease. The current evidence supports the implementation of TE and CAP in an evaluation algorithm for pediatric NAFLD. CONCLUSIONS Current data support the use of TE and CAP as a first-line tool in the diagnosis and evaluation of adolescent NAFLD, to better stratify high-risk patients and cut down on the number of liver biopsies needed.
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Affiliation(s)
- Bryan R Chen
- University of California, Los Angeles, Los Angeles, CA 90025 USA.
| | - Calvin Q Pan
- Center of Liver Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing 100015, China; Division of Gastroenterology and Hepatology, Department of Medicine, NYU Langone Health, New York University Grossman School of Medicine, New York, NY, USA.
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Yilma M, Saxena V, Mehta N. Models to Predict Development or Recurence of Hepatocellular Carcinoma (HCC) in Patients with Advanced Hepatic Fibrosis. Curr Gastroenterol Rep 2022; 24:1-9. [PMID: 35142988 PMCID: PMC8891098 DOI: 10.1007/s11894-022-00835-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
PURPOSE OF REVIEW Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death in the United States (U.S.).1 The purpose of this review is to highlight published models that predict development of HCC and estimate risk of HCC recurrence after treatments. RECENT FINDINGS There have been several models created for both de novo HCC and HCC recurrence, with the more recent models using a combination of age, sex, decompensation, and laboratory values (platelet count, albumin, bilirubin), and liver disease etiology to predict both 5 and 10-year HCC incidence. For chronic hepatitis C, sustained virologic response has been a useful component of understanding HCC risk reduction. BMI and diabetes have been utilized in non-alcoholic fatty liver disease (NAFLD) models to predict HCC risk. For HCC recurrence after treatment (for both surgical resection and liver transplant), tumor size and number, vascular invasion, alpha-fetoprotein (AFP) and neutrophil to lymphocyte ratio (NLR) are all components of HCC recurrence risk models. Although numerous HCC risk prediction models have been established over the last several years, challenges remain including how to best incorporate these models into clinical practice, improve surveillance for NAFLD-HCC development, and determine timing and duration of post-resection recurrence surveillance.
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Affiliation(s)
- Mignote Yilma
- Department of Surgery, University of California, San Francisco, CA, USA
| | - Varun Saxena
- Department of Gastroenterology and Transplant Hepatology, Kaiser Permanente South San Francisco, San Francisco, CA, USA
| | - Neil Mehta
- Division of Gastroenterology, University of California, San Francisco, CA, USA
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Grgurevic I, Bozin T, Mikus M, Kukla M, O’Beirne J. Hepatocellular Carcinoma in Non-Alcoholic Fatty Liver Disease: From Epidemiology to Diagnostic Approach. Cancers (Basel) 2021; 13:5844. [PMID: 34830997 PMCID: PMC8616369 DOI: 10.3390/cancers13225844] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/14/2021] [Accepted: 11/17/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming the leading cause of liver morbidity worldwide and, as such, represents the pathogenic background for the increasing incidence of hepatocellular carcinoma (HCC). The annual incidence of NAFLD-related HCC is expected to increase by 45-130% by 2030. Diabetes mellitus is the most important risk factor for HCC development in NAFLD, with the risk further increased when associated with other metabolic traits, such as obesity, arterial hypertension and dyslipidemia. The highest risk of HCC exists in patients with advanced fibrosis or cirrhosis, although 20-50% of HCC cases arise in NAFLD patients with an absence of cirrhosis. This calls for further investigation of the pathogenic mechanisms that are involved in hepatocarcinogenesis, including genetics, metabolomics, the influence of the gut microbiota and immunological responses. Early identification of patients with or at risk of NAFLD is of utmost importance to improve outcomes. As NAFLD is highly prevalent in the community, the identification of cases should rely upon simple demographic and clinical characteristics. Once identified, these patients should then be evaluated for the presence of advanced fibrosis or cirrhosis and subsequently enter HCC surveillance programs if appropriate. A significant problem is the early recognition of non-cirrhotic NAFLD patients who will develop HCC, where new biomarkers and scores are potential solutions to tackle this issue.
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Affiliation(s)
- Ivica Grgurevic
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10 000 Zagreb, Croatia;
- Faculty of Pharmacy and Biochemistry, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia
| | - Tonci Bozin
- Department of Gastroenterology, Hepatology and Clinical Nutrition, University Hospital Dubrava, 10 000 Zagreb, Croatia;
| | - Mislav Mikus
- Department of Obstetrics and Gynecology, University Hospital Centre Zagreb, 10 000 Zagreb, Croatia;
| | - Michal Kukla
- Department of Internal Medicine and Geriatrics, Faculty of Medicine, Jagiellonian University Medical College, 30688 Cracow, Poland;
| | - James O’Beirne
- Department of Hepatology, University of the Sunshine Coast, Sunshine Coast 4556, Australia;
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Sun EJ, Wankell M, Palamuthusingam P, McFarlane C, Hebbard L. Targeting the PI3K/Akt/mTOR Pathway in Hepatocellular Carcinoma. Biomedicines 2021; 9:biomedicines9111639. [PMID: 34829868 PMCID: PMC8615614 DOI: 10.3390/biomedicines9111639] [Citation(s) in RCA: 134] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/05/2021] [Accepted: 11/05/2021] [Indexed: 12/24/2022] Open
Abstract
Despite advances in the treatment of cancers through surgical procedures and new pharmaceuticals, the treatment of hepatocellular carcinoma (HCC) remains challenging as reflected by low survival rates. The PI3K/Akt/mTOR pathway is an important signaling mechanism that regulates the cell cycle, proliferation, apoptosis, and metabolism. Importantly, deregulation of the PI3K/Akt/mTOR pathway leading to activation is common in HCC and is hence the subject of intense investigation and the focus of current therapeutics. In this review article, we consider the role of this pathway in the pathogenesis of HCC, focusing on its downstream effectors such as glycogen synthase kinase-3 (GSK-3), cAMP-response element-binding protein (CREB), forkhead box O protein (FOXO), murine double minute 2 (MDM2), p53, and nuclear factor-κB (NF-κB), and the cellular processes of lipogenesis and autophagy. In addition, we provide an update on the current ongoing clinical development of agents targeting this pathway for HCC treatments.
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Affiliation(s)
- Eun Jin Sun
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
- College of Medicine and Dentistry, James Cook University, Townsville, QLD 4811, Australia
| | - Miriam Wankell
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
| | - Pranavan Palamuthusingam
- Institute of Surgery, The Townsville University Hospital, Townsville, QLD 4811, Australia;
- Mater Hospital, Townsville, QLD 4811, Australia
| | - Craig McFarlane
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
| | - Lionel Hebbard
- Centre for Molecular Therapeutics, Department of Molecular and Cell Biology, Australian Institute of Tropical Medicine and Health, College of Public Health, Medical and Veterinary Sciences, James Cook University, Townsville, QLD 4811, Australia; (E.J.S.); (M.W.); (C.M.)
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW 2145, Australia
- Correspondence:
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Kudo M. Changing the Treatment Paradigm for Hepatocellular Carcinoma Using Atezolizumab plus Bevacizumab Combination Therapy. Cancers (Basel) 2021; 13:5475. [PMID: 34771637 PMCID: PMC8582435 DOI: 10.3390/cancers13215475] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 12/12/2022] Open
Abstract
Atezolizumab plus bevacizumab combination therapy was approved worldwide for use in 2020. A 30% objective response rate with 8% complete response (CR) was achieved in a phase 3 IMbrave150 trial. Here, the change in the treatment strategy for hepatocellular carcinoma (HCC) using atezolizumab plus bevacizumab combination therapy is reviewed. The phase 3 IMbrave150 clinical trial was successful because of the direct antitumor effect of bevacizumab, which shifted the suppressive immune microenvironment to a responsive immune microenvironment, in addition to its synergistic effects when combined with atezolizumab. The analysis of CR cases was effective in patients with poor conditions, particularly tumor invasion in the main portal trunk (Vp4), making the combination therapy a breakthrough for HCC treatment. The response rate of the combination therapy was 44% against intermediate-stage HCC. Such a strong tumor-reduction effect paves the way for curative conversion (ABC conversion) therapy and, therefore, treatment strategies for intermediate-stage HCC may undergo a significant shift in the future. As these treatment strategies are effective in maintaining liver function, even in elderly patients, the transition frequency to second-line treatments could also be improved. These strategies may be effective against nonalcoholic steatohepatitis-related hepatocellular carcinoma and WNT/β-catenin mutations to a certain degree.
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka 589-8511, Japan
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Castellana M, Donghia R, Lampignano L, Castellana F, Zupo R, Sardone R, Pergola GD, Giannelli G. Prevalence of the Absence of Cirrhosis in Subjects with NAFLD-Associated Hepatocellular Carcinoma. J Clin Med 2021; 10:jcm10204638. [PMID: 34682759 PMCID: PMC8539355 DOI: 10.3390/jcm10204638] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 09/27/2021] [Accepted: 10/02/2021] [Indexed: 12/14/2022] Open
Abstract
Background. Hepatocellular carcinoma (HCC) is most commonly considered as a complication of cirrhosis. However, an increasing number of HCC in subjects with non-alcoholic fatty liver disease (NAFLD) without cirrhosis is being reported. We conducted a meta-analysis to assess the prevalence of the absence of cirrhosis in NAFLD-associated HCC. Methods. Four databases were searched until March 2021 (CRD42021242969). The original articles included were those reporting data on the presence or absence of cirrhosis among at least 50 subjects with NAFLD-associated HCC. The number of subjects with absent cirrhosis in each study was extracted. For statistical pooling of data, a random-effects model was used. Subgroup analyses according to the continent, target condition and reference standard for the diagnosis of cirrhosis were conducted. Results. Thirty studies were included, evaluating 13,371 subjects with NAFLD-associated HCC. The overall prevalence of cases without cirrhosis was 37% (95%CI 28 to 46). A higher prevalence was reported in Asia versus Europe, North America and South America (45, 36, 37 and 22%, respectively) as well as in studies adopting histology only as the reference standard for the diagnosis of cirrhosis versus histology and other modalities (e.g., radiology, endoscopy, biochemistry or overt clinical findings) (53 and 27%, respectively). No difference was found between studies including subjects with non-alcoholic steatohepatitis (NASH) only, versus NAFLD with or without NASH (p = 0.385). One in three subjects with NAFLD-associated HCC presented without cirrhosis. This should be reflected in future guidelines and surveillance programs adapted to allow for the early detection of these cancers too.
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Affiliation(s)
- Marco Castellana
- Unit of Research Methodology, Health Data Sciences and Technology, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (R.D.); (L.L.); (F.C.); (R.Z.); (R.S.); (G.D.P.)
- Correspondence: ; Tel.: +39-0804994111
| | - Rossella Donghia
- Unit of Research Methodology, Health Data Sciences and Technology, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (R.D.); (L.L.); (F.C.); (R.Z.); (R.S.); (G.D.P.)
| | - Luisa Lampignano
- Unit of Research Methodology, Health Data Sciences and Technology, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (R.D.); (L.L.); (F.C.); (R.Z.); (R.S.); (G.D.P.)
| | - Fabio Castellana
- Unit of Research Methodology, Health Data Sciences and Technology, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (R.D.); (L.L.); (F.C.); (R.Z.); (R.S.); (G.D.P.)
| | - Roberta Zupo
- Unit of Research Methodology, Health Data Sciences and Technology, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (R.D.); (L.L.); (F.C.); (R.Z.); (R.S.); (G.D.P.)
| | - Rodolfo Sardone
- Unit of Research Methodology, Health Data Sciences and Technology, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (R.D.); (L.L.); (F.C.); (R.Z.); (R.S.); (G.D.P.)
| | - Giovanni De Pergola
- Unit of Research Methodology, Health Data Sciences and Technology, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy; (R.D.); (L.L.); (F.C.); (R.Z.); (R.S.); (G.D.P.)
| | - Gianluigi Giannelli
- Scientific Direction, National Institute of Gastroenterology “Saverio de Bellis”, Research Hospital, Castellana Grotte, 70013 Bari, Italy;
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50
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Xia Y, Caputo M, Cansby E, Anand SK, Sütt S, Henricsson M, Porosk R, Marschall HU, Blüher M, Mahlapuu M. STE20-type kinase TAOK3 regulates hepatic lipid partitioning. Mol Metab 2021; 54:101353. [PMID: 34634521 PMCID: PMC8567304 DOI: 10.1016/j.molmet.2021.101353] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/01/2021] [Accepted: 10/05/2021] [Indexed: 12/12/2022] Open
Abstract
OBJECTIVE Nonalcoholic fatty liver disease (NAFLD), defined by excessive lipid storage in hepatocytes, has recently emerged as a leading global cause of chronic liver disease. The aim of this study was to examine the role of STE20-type protein kinase TAOK3, which has previously been shown to associate with hepatic lipid droplets, in the initiation and aggravation of human NAFLD. METHODS The correlation between TAOK3 mRNA expression and the severity of NAFLD was investigated in liver biopsies from 62 individuals. In immortalized human hepatocytes, intracellular fat deposition, lipid metabolism, and oxidative and endoplasmic reticulum stress were analyzed when TAOK3 was overexpressed or knocked down by small interfering RNA. Subcellular localization of TAOK3 was characterized in human and mouse hepatocytes by immunofluorescence microscopy. RESULTS We found that the TAOK3 transcript levels in human liver biopsies were positively correlated with the key lesions of NAFLD (i.e., hepatic steatosis, inflammation, and ballooning). Overexpression of TAOK3 in cultured human hepatocytes exacerbated lipid storage by inhibiting β-oxidation and triacylglycerol secretion while enhancing lipid synthesis. Conversely, silencing of TAOK3 attenuated lipid deposition in human hepatocytes by stimulating mitochondrial fatty acid oxidation and triacylglycerol efflux while suppressing lipogenesis. We also found aggravated or decreased oxidative/endoplasmic reticulum stress in human hepatocytes with increased or reduced TAOK3 levels, respectively. The subcellular localization of TAOK3 in human and mouse hepatocytes was confined to intracellular lipid droplets. CONCLUSIONS This study provides the first evidence that hepatic lipid droplet-coating kinase TAOK3 is a critical regulatory node controlling liver lipotoxicity and susceptibility to NAFLD.
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Affiliation(s)
- Ying Xia
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mara Caputo
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Emmelie Cansby
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Sumit Kumar Anand
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Silva Sütt
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Marcus Henricsson
- Biomarker Discovery and Development, Research and Early Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Rando Porosk
- Department of Biochemistry, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Institute of Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Matthias Blüher
- Department of Medicine, University of Leipzig, Leipzig, Germany
| | - Margit Mahlapuu
- Department of Chemistry and Molecular Biology, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
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