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Tavaglione F, Pennisi G, Pelusi S. PNPLA3 I148M and Hepatocellular Carcinoma. Liver Int 2025; 45:e70051. [PMID: 40029157 DOI: 10.1111/liv.70051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 02/20/2025] [Accepted: 02/21/2025] [Indexed: 03/05/2025]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. With the widespread implementation of HBV vaccination and the availability of highly effective antiviral therapies, the incidence of metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC has proportionally increased. Notably, up to 20%-30% of MASLD-related HCC cases develop in the absence of overt cirrhosis. Several genetic variants, primarily in genes related to lipid metabolism, play a key role in HCC development in individuals with MASLD and alcohol-related liver disease. Among these, the rs738409 C>G polymorphism (I148M) in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene is the strongest genetic factor predisposing to the entire spectrum of MASLD conditions, including cirrhosis and HCC. Importantly, combining PNPLA3 I148M with multiple genetic variants robustly associated with progressive liver disease (i.e., polygenic risk scores) improves risk stratification and prediction of HCC in at-risk individuals compared to the single variant alone. In this review, we will discuss the latest evidence on the epidemiology of HCC and the contribution of PNPLA3 and PNPLA3-based polygenic risk scores to the development of HCC in at-risk individuals.
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Affiliation(s)
- Federica Tavaglione
- Division of Gastroenterology and Hepatology, MASLD Research Center, University of California at San Diego, La Jolla, California, USA
| | - Grazia Pennisi
- Section of Gastroenterology and Hepatology, Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo, Palermo, Italy
| | - Serena Pelusi
- Transfusion Medicine Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
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Chen VL, Vespasiani‐Gentilucci U. Integrating PNPLA3 into clinical risk prediction. Liver Int 2025; 45:e16103. [PMID: 39282715 PMCID: PMC11815612 DOI: 10.1111/liv.16103] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/02/2024] [Accepted: 09/04/2024] [Indexed: 02/05/2025]
Abstract
The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Umberto Vespasiani‐Gentilucci
- Research Unit of HepatologyUniversità Campus Bio‐Medico di RomeRomeItaly
- Hepatology and Clinical Medicine UnitFondazione Policlinico Universitario Campus‐Biomedico di RomaRomeItaly
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Chen VL, Brady GF. Recent advances in MASLD genetics: Insights into disease mechanisms and the next frontiers in clinical application. Hepatol Commun 2025; 9:e0618. [PMID: 39774697 PMCID: PMC11717516 DOI: 10.1097/hc9.0000000000000618] [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: 11/05/2024] [Accepted: 11/14/2024] [Indexed: 01/11/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in the world and a growing cause of liver-related morbidity and mortality. Yet, at the same time, our understanding of the pathophysiology and genetic underpinnings of this increasingly common yet heterogeneous disease has increased dramatically over the last 2 decades, with the potential to lead to meaningful clinical interventions for patients. We have now seen the first pharmacologic therapy approved for the treatment of MASLD, and multiple other potential treatments are currently under investigation-including gene-targeted RNA therapies that directly extend from advances in MASLD genetics. Here we review recent advances in MASLD genetics, some of the key pathophysiologic insights that human genetics has provided, and the ways in which human genetics may inform our clinical practice in the field of MASLD in the near future.
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Llamoza-Torres CJ, Fuentes-Pardo M, Ramos-Molina B. Metabolic dysfunction-associated steatotic liver disease: a key factor in hepatocellular carcinoma therapy response. METABOLISM AND TARGET ORGAN DAMAGE 2024; 4. [DOI: 10.20517/mtod.2024.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The conceptual evolution of non-alcoholic fatty liver disease (NAFLD) to what, since 2023, is called metabolic dysfunction-associated steatotic liver disease (MASLD) not only represents a change in the classification and definition of the disease but also reflects a broader understanding of this heterogeneous condition, which still with many aspects to refine. Although the definition of NAFLD can be interchanged to a high percentage with the new MASLD concept in different aspects, MASLD has been proposed as a relevant factor that influences the response to new immunotherapeutic treatments in the management of MASLD-related hepatocellular carcinoma (HCC), compared to HCC of other etiologies. This indicates that the etiology of HCC plays a relevant role in the prognosis, highlighting the urgency of evaluating treatment regimens for this subgroup of patients in upcoming clinical trials. A better understanding of the pathophysiology of MASLD generates strategies that not only aid in its management but also provide strategies to directly intervene in the carcinogenesis of HCC.
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Chen VL, Oliveri A, Raut C, Chen Y, Cushing-Damm KC, Speliotes EK. TM6SF2 -rs58542926 Genotype Has Opposing Effects on Incidence of Hepatic and Cardiac Events in a Community Cohort. Am J Gastroenterol 2024:00000434-990000000-01418. [PMID: 39471479 PMCID: PMC12041304 DOI: 10.14309/ajg.0000000000003169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 10/15/2024] [Indexed: 11/01/2024]
Abstract
INTRODUCTION TM6SF2 -rs58542926-T is associated with increased cirrhosis and modestly decreased coronary artery disease prevalence. However, relative effects of TM6SF2 genotype on major adverse cardiovascular events (MACE) vs liver-related events (LRE) are not known. METHODS We used the UK Biobank, a prospective cohort with genetic and inpatient diagnosis data. The primary predictor was TM6SF2 -rs58542926 genotype, and the primary outcomes were MACE and LRE. Effects were reported as subhazard ratios (sHRs) and 10-year cumulative incidence by Fine-Gray competing risk analyses. RESULTS More than 430,000 individuals met inclusion criteria. TM6SF2 -rs58542926-TT genotype (vs CC) was associated with higher incidence of LRE (adjusted sHR 3.16, 95% confidence interval 1.86-5.37) and lower incidence of MACE (adjusted sHR for TT vs CC genotype 0.76, 95% confidence interval 0.63-0.91). In individuals with fibrosis-4 (FIB4) < 1.3, 1.3-2.67, and > 2.67, 10-year LRE incidence in TM6SF2 -rs58542926-TT vs CC individuals was 0.08% vs 0.06% ( P > 0.05), 0.81% vs 0.20% ( P < 0.0001), and 10.5% vs 3.4% ( P = 0.00094), respectively. The corresponding values for MACE were 3.8% vs 5.1% ( P = 0.032), 6.4% vs 8.2% ( P = 0.040), and 17.1% vs 12.4% ( P > 0.05). The absolute decrease in MACE with rs58542926-TT (vs CC) genotype exceeded the absolute increase in LRE in all groups but FIB4 > 2.67. Associations of TM6SF2 genotype with LRE/MACE were significant in men but not women. TM6SF2 -rs58542926-T allele was also associated with increased hepatic steatosis and corrected T1 time by magnetic resonance imaging, with greater effect sizes in men than women. DISCUSSION TM6SF2 genotype has opposite effects on LRE vs MACE incidence, and absolute effects on MACE were greater except in those with highest FIB4 scores. Effects were strongest in men. These findings clarify implications of TM6SF2 genotype based on personalized clinical risk.
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Affiliation(s)
- Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Antonino Oliveri
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Chinmay Raut
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Yanhua Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Kelly C Cushing-Damm
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Elizabeth K Speliotes
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
- Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, Michigan, USA
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Sun B, Ding X, Tan J, Zhang J, Chu X, Zhang S, Liu S, Zhao Z, Xuan S, Xin Y, Zhuang L. TM6SF2 E167K variant decreases PNPLA3-mediated PUFA transfer to promote hepatic steatosis and injury in MASLD. Clin Mol Hepatol 2024; 30:863-882. [PMID: 39054606 PMCID: PMC11540376 DOI: 10.3350/cmh.2024.0268] [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: 04/16/2024] [Revised: 07/05/2024] [Accepted: 07/26/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUNDS/AIMS Transmembrane 6 superfamily member 2 (TM6SF2) E167K variant is closely associated with the occurrence and development of metabolic dysfunction-associated steatotic liver disease (MASLD). However, the role and mechanism of TM6SF2 E167K variant during MASLD progression are not yet fully understood. METHODS The Tm6sf2167K knock-in (KI) mice were subjected to high-fat diet (HFD). Hepatic lipid levels of Tm6sf2167K KI mice were detected by lipidomics analysis. Thin-layer chromatography (TLC) was used to measure the newly synthesized triglyceride (TG) and phosphatidylcholine (PC). RESULTS The TM6SF2 E167K variant significantly aggravated hepatic steatosis and injury in HFD-induced mice. Decreased polyunsaturated PC level and increased polyunsaturated TG level were found in liver tissue of HFD-induced Tm6sf2167K KI mice. Mechanistic studies demonstrated that the TM6SF2 E167K variant increased the interaction between TM6SF2 and PNPLA3, and impaired PNPLA3-mediated transfer of polyunsaturated fatty acids (PUFAs) from TG to PC. The TM6SF2 E167K variant increased the level of fatty acid-induced malondialdehyde and reactive oxygen species, and decreased fatty acid-downregulated cell membrane fluidity. Additionally, the TM6SF2 E167K variant decreased the level of hepatic PC containing C18:3, and dietary supplementation of PC containing C18:3 significantly attenuated the TM6SF2 E167K-induced hepatic steatosis and injury in HFD-fed mice. CONCLUSION The TM6SF2 E167K variant could promote its interaction with PNPLA3 and inhibit PNPLA3-mediated transfer of PUFAs from TG to PC, resulting in the hepatic steatosis and injury during MASLD progression. PC containing C18:3 could act as a potential therapeutic supplement for MASLD patients carrying the TM6SF2 E167K variant.
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Affiliation(s)
- Baokai Sun
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Xiaoqian Ding
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Jie Tan
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Jie Zhang
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Xueru Chu
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Shuimi Zhang
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Shousheng Liu
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Zhenzhen Zhao
- Clinical Research Center, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Shiying Xuan
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Yongning Xin
- Department of Infectious Diseases, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
| | - Likun Zhuang
- Central Laboratories, Qingdao Municipal Hospital, Qingdao University, Qingdao, China
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Pileckaite E, Vilkeviciute A, Kriauciuniene L, Liutkevicius V, Liutkeviciene R. Investigating the Link between STAT4 Genetic Variants, STAT4 Protein Concentrations, and Laryngeal Squamous Cell Carcinoma: A Comprehensive Analysis of Clinical Manifestations. Int J Mol Sci 2024; 25:10180. [PMID: 39337665 PMCID: PMC11432593 DOI: 10.3390/ijms251810180] [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: 08/09/2024] [Revised: 09/18/2024] [Accepted: 09/20/2024] [Indexed: 09/30/2024] Open
Abstract
According to recent research, inflammatory STAT4 and its protein impact may be important factors in developing cancerous diseases. Still unanalyzed is this effect in patients with laryngeal squamous cell carcinoma (LSCC). In the present study, we evaluated four single nucleotide variants (SNVs) of STAT4 (rs10181656, rs7574865, rs7601754, and rs10168266) and STAT4 serum levels to determine their link between LSCC development and its clinical manifestations. A total of 632 men (324 LSCC patients and 338 healthy individuals) were involved in this study. The genotyping was carried out using real-time PCR. Additionally, we measured 80 study subjects' (40 LSCC patients and 40 control subjects) STAT4 protein concentrations using an enzyme-linked immunosorbent assay (ELISA). In our study, the T allele of STAT4 rs7574865 significantly increases the likelihood of LSCC occurrence by 1.4-fold. Additionally, this SNV is associated with higher odds of early-stage disease, T1 size LSCC development, absence of metastasis to neck lymph nodes, and well-differentiated carcinoma. The G allele of rs10181656 is significantly associated with various clinical characteristics of LSCC, increasing the odds of early- and advanced-stage disease by 2.8-fold and 1.9-fold, respectively. Additionally, this allele is linked to an increased likelihood of developing tumors of different sizes and non-metastasized LSCC, as well as poorly differentiated carcinoma, highlighting its potential impact on the development and features of LSCC. Conclusion: The analysis of the STAT4 rs7574865 SNV revealed that the G allele is linked to a more favorable prognosis in LSCC. Additionally, it is hypothesized that the G allele of rs10181656 may be associated with the occurrence of LSCC but may not serve as a sensitive prognostic biomarker for distinguishing between disease stages, cell differentiation, or tumor size.
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Affiliation(s)
- Enrika Pileckaite
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.P.); (L.K.); (R.L.)
| | - Alvita Vilkeviciute
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.P.); (L.K.); (R.L.)
| | - Loresa Kriauciuniene
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.P.); (L.K.); (R.L.)
| | - Vykintas Liutkevicius
- Department of Otorhinolaryngology, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania;
| | - Rasa Liutkeviciene
- Neuroscience Institute, Lithuanian University of Health Sciences, LT-44307 Kaunas, Lithuania; (E.P.); (L.K.); (R.L.)
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Habib S. Team players in the pathogenesis of metabolic dysfunctions-associated steatotic liver disease: The basis of development of pharmacotherapy. World J Gastrointest Pathophysiol 2024; 15:93606. [PMID: 39220834 PMCID: PMC11362842 DOI: 10.4291/wjgp.v15.i4.93606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Revised: 05/14/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
Nutrient metabolism is regulated by several factors. Social determinants of health with or without genetics are the primary regulator of metabolism, and an unhealthy lifestyle affects all modulators and mediators, leading to the adaptation and finally to the exhaustion of cellular functions. Hepatic steatosis is defined by presence of fat in more than 5% of hepatocytes. In hepatocytes, fat is stored as triglycerides in lipid droplet. Hepatic steatosis results from a combination of multiple intracellular processes. In a healthy individual nutrient metabolism is regulated at several steps. It ranges from the selection of nutrients in a grocery store to the last step of consumption of ATP as an energy or as a building block of a cell as structural component. Several hormones, peptides, and genes have been described that participate in nutrient metabolism. Several enzymes participate in each nutrient metabolism as described above from ingestion to generation of ATP. As of now several publications have revealed very intricate regulation of nutrient metabolism, where most of the regulatory factors are tied to each other bidirectionally, making it difficult to comprehend chronological sequence of events. Insulin hormone is the primary regulator of all nutrients' metabolism both in prandial and fasting states. Insulin exerts its effects directly and indirectly on enzymes involved in the three main cellular function processes; metabolic, inflammation and repair, and cell growth and regeneration. Final regulators that control the enzymatic functions through stimulation or suppression of a cell are nuclear receptors in especially farnesoid X receptor and peroxisome proliferator-activated receptor/RXR ligands, adiponectin, leptin, and adiponutrin. Insulin hormone has direct effect on these final modulators. Whereas blood glucose level, serum lipids, incretin hormones, bile acids in conjunction with microbiota are intermediary modulators which are controlled by lifestyle. The purpose of this review is to overview the key players in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) that help us understand the disease natural course, risk stratification, role of lifestyle and pharmacotherapy in each individual patient with MASLD to achieve personalized care and target the practice of precision medicine. PubMed and Google Scholar databases were used to identify publication related to metabolism of carbohydrate and fat in states of health and disease states; MASLD, cardiovascular disease and cancer. More than 1000 publications including original research and review papers were reviewed.
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Affiliation(s)
- Shahid Habib
- Department of Hepatology, Liver Institute PLLC, Tucson, AZ 85712, United States
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Morrill KE, Wightman P, Cruz A, Batai K, Block GD, Hsu CH, Garcia DO. Disparities in hepatocellular carcinoma incidence among Hispanic and non-Hispanic adults in Arizona: Trends between 2009-2017. Ann Epidemiol 2024; 96:48-52. [PMID: 38880361 PMCID: PMC11283343 DOI: 10.1016/j.annepidem.2024.05.012] [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: 08/28/2023] [Revised: 05/30/2024] [Accepted: 05/30/2024] [Indexed: 06/18/2024]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a highly lethal cancer with few treatment options available to patients. Most HCC cases in Arizona, a state with a high proportion of Hispanic adults, have not been included in recent reports of HCC incidence. This study describes trends in HCC incidence and stage at diagnosis among Arizona residents between 2009-2017 and reports on racial and ethnic disparities for these outcomes. METHODS The Arizona Cancer Registry was used to identify Arizonans aged 19 or older diagnosed with liver cell carcinoma diagnosed between 2009-2017. A total of 5043 cases were examined. Adjusted annual and 3-year HCC incidence rates (per 100,000) were examined for non-Hispanic White (NHW) and Hispanic adults. RESULTS The total age-adjusted HCC incidence rate increased significantly between 2009-2012 and then declined significantly between 2012-2017. Across nearly all years, age-adjusted HCC incidence in Hispanic adults was twice that of NHW adults. Hispanic adults were more likely to be diagnosed at a later stage across all time periods. The disparity in 3-year age-adjusted HCC incidence rate between NHW and Hispanic adults decreased between 2009-2017. CONCLUSION Whe total age-adjusted HCC incidence rate increased significantly between 2009-2012 and then declined significantly between 2012-2017. Across nearly all years, age-adjusted HCC incidence in Hispanic adults was twice that of NHW adults. Hispanic adults were more likely to be diagnosed at a later stage across all time periods. The disparity in 3-year age-adjusted HCC incidence rate between NHW and Hispanic adults decreased between 2009-2017.
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Affiliation(s)
- Kristin E Morrill
- Community & Systems Health Science Division, College of Nursing, University of Arizona, Tucson, AZ 85721, USA.
| | - Patrick Wightman
- Center for Population Health Sciences, University of Arizona, Tucson, AZ, USA.
| | - Alejandro Cruz
- Department of Surgery, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
| | - Ken Batai
- Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
| | - Geoffrey D Block
- Thomas Boyer Liver Institute and Department of Medicine, College of Medicine, University of Arizona, Tucson, AZ 85724, USA.
| | - Chiu-Hsieh Hsu
- Epidemiology and Biostatistics Department, Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA.
| | - David O Garcia
- Health Promotion Sciences Department, Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, AZ 85724, USA.
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Yuan H, Liu Z, Chen M, Xu Q, Jiang Y, Zhang T, Suo C, Chen X. Protein truncating variants in mitochondrial-related nuclear genes and the risk of chronic liver disease. BMC Med 2024; 22:239. [PMID: 38862964 PMCID: PMC11167739 DOI: 10.1186/s12916-024-03466-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2024] [Accepted: 06/05/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Mitochondrial (MT) dysfunction is a hallmark of liver diseases. However, the effects of functional variants such as protein truncating variants (PTVs) in MT-related genes on the risk of liver diseases have not been extensively explored. METHODS We extracted 60,928 PTVs across 2466 MT-related nucleus genes using whole-exome sequencing data obtained from 442,603 participants in the UK Biobank. We examined their associations with liver dysfunction that represented by the liver-related biomarkers and the risks of chronic liver diseases and liver-related mortality. RESULTS 96.10% of the total participants carried at least one PTV. We identified 866 PTVs that were positively associated with liver dysfunction at the threshold of P value < 8.21e - 07. The coding genes of these PTVs were mainly enriched in pathways related to lipid, fatty acid, amino acid, and carbohydrate metabolisms. The 866 PTVs were presented in 1.07% (4721) of participants. Compared with participants who did not carry any of the PTVs, the carriers had a 5.33-fold (95% CI 4.15-6.85), 2.82-fold (1.69-4.72), and 4.41-fold (3.04-6.41) increased risk for fibrosis and cirrhosis of liver, liver cancer, and liver disease-related mortality, respectively. These adverse effects were consistent across subgroups based on age, sex, body mass index, smoking status, and presence of hypertension, diabetes, dyslipidemia, and metabolic syndrome. CONCLUSIONS Our findings revealed a significant impact of PTVs in MT-related genes on liver disease risk, highlighting the importance of these variants in identifying populations at risk of liver diseases and facilitating early clinical interventions.
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Affiliation(s)
- Huangbo Yuan
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and School of Life Sciences, Fudan University, No. 2005 Songhu Road, Shanghai, 200438, China
| | - Zhenqiu Liu
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and School of Life Sciences, Fudan University, No. 2005 Songhu Road, Shanghai, 200438, China
| | - Mingyang Chen
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and School of Life Sciences, Fudan University, No. 2005 Songhu Road, Shanghai, 200438, China
| | - Qiaoyi Xu
- Department of Epidemiology, School of Public Health, Fudan University, No. 130 Dongan Road, Shanghai, 200032, China
| | - Yanfeng Jiang
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and School of Life Sciences, Fudan University, No. 2005 Songhu Road, Shanghai, 200438, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Tiejun Zhang
- Department of Epidemiology, School of Public Health, Fudan University, No. 130 Dongan Road, Shanghai, 200032, China
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China
| | - Chen Suo
- Department of Epidemiology, School of Public Health, Fudan University, No. 130 Dongan Road, Shanghai, 200032, China.
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China.
| | - Xingdong Chen
- State Key Laboratory of Genetic Engineering, Human Phenome Institute, Zhangjiang Fudan International Innovation Center, and School of Life Sciences, Fudan University, No. 2005 Songhu Road, Shanghai, 200438, China.
- Fudan University Taizhou Institute of Health Sciences, Taizhou, China.
- National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.
- Yiwu Research Institute of Fudan University, Yiwu, China.
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Caon E, Martins M, Hodgetts H, Blanken L, Vilia MG, Levi A, Thanapirom K, Al-Akkad W, Abu-Hanna J, Baselli G, Hall AR, Luong TV, Taanman JW, Vacca M, Valenti L, Romeo S, Mazza G, Pinzani M, Rombouts K. Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models. J Hepatol 2024; 80:941-956. [PMID: 38365182 DOI: 10.1016/j.jhep.2024.01.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/24/2024] [Accepted: 01/27/2024] [Indexed: 02/18/2024]
Abstract
BACKGROUND & AIMS The PNPLA3 rs738409 C>G (encoding for I148M) variant is a risk locus for the fibrogenic progression of chronic liver diseases, a process driven by hepatic stellate cells (HSCs). We investigated how the PNPLA3 I148M variant affects HSC biology using transcriptomic data and validated findings in 3D-culture models. METHODS RNA sequencing was performed on 2D-cultured primary human HSCs and liver biopsies of individuals with obesity, genotyped for the PNPLA3 I148M variant. Data were validated in wild-type (WT) or PNPLA3 I148M variant-carrying HSCs cultured on 3D extracellular matrix (ECM) scaffolds from human healthy and cirrhotic livers, with/without TGFB1 or cytosporone B (Csn-B) treatment. RESULTS Transcriptomic analyses of liver biopsies and HSCs highlighted shared PNPLA3 I148M-driven dysregulated pathways related to mitochondrial function, antioxidant response, ECM remodelling and TGFB1 signalling. Analogous pathways were dysregulated in WT/PNPLA3-I148M HSCs cultured in 3D liver scaffolds. Mitochondrial dysfunction in PNPLA3-I148M cells was linked to respiratory chain complex IV insufficiency. Antioxidant capacity was lower in PNPLA3-I148M HSCs, while reactive oxygen species secretion was increased in PNPLA3-I148M HSCs and higher in bioengineered cirrhotic vs. healthy scaffolds. TGFB1 signalling followed the same trend. In PNPLA3-I148M cells, expression and activation of the endogenous TGFB1 inhibitor NR4A1 were decreased: treatment with the Csn-B agonist increased total NR4A1 in HSCs cultured in healthy but not in cirrhotic 3D scaffolds. NR4A1 regulation by TGFB1/Csn-B was linked to Akt signalling in PNPLA3-WT HSCs and to Erk signalling in PNPLA3-I148M HSCs. CONCLUSION HSCs carrying the PNPLA3 I148M variant have impaired mitochondrial function, antioxidant responses, and increased TGFB1 signalling, which dampens antifibrotic NR4A1 activity. These features are exacerbated by cirrhotic ECM, highlighting the dual impact of the PNPLA3 I148M variant and the fibrotic microenvironment in progressive chronic liver diseases. IMPACT AND IMPLICATIONS Hepatic stellate cells (HSCs) play a key role in the fibrogenic process associated with chronic liver disease. The PNPLA3 genetic mutation has been linked with increased risk of fibrogenesis, but its role in HSCs requires further investigation. Here, by using comparative transcriptomics and a novel 3D in vitro model, we demonstrate the impact of the PNPLA3 genetic mutation on primary human HSCs' behaviour, and we show that it affects the cell's mitochondrial function and antioxidant response, as well as the antifibrotic gene NR4A1. Our publicly available transcriptomic data, 3D platform and our findings on NR4A1 could facilitate the discovery of targets to develop more effective treatments for chronic liver diseases.
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Affiliation(s)
- Elisabetta Caon
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Maria Martins
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Harry Hodgetts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Lieke Blanken
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Maria Giovanna Vilia
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Ana Levi
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Kessarin Thanapirom
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Walid Al-Akkad
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Jeries Abu-Hanna
- Research Department of Surgical Biotechnology, Division of Surgery and Interventional Science, University College London, London, UK
| | - Guido Baselli
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Andrew R Hall
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK; Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Tu Vinh Luong
- Sheila Sherlock Liver Centre, Royal Free London NHS Foundation Trust, London, UK; Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Jan-Willem Taanman
- Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London UK
| | - Michele Vacca
- Laboratory of Hepatic Metabolism and NAFLD, Roger Williams Institute of Hepatology, London, UK; Clinica Medica "Frugoni", Interdisciplinary Department of Medicine, University of Bari "Aldo Moro", Bari, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Precision Medicine, Biological Resource Center, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden
| | - Giuseppe Mazza
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Massimo Pinzani
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK
| | - Krista Rombouts
- Regenerative Medicine and Fibrosis Group, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London, UK.
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12
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Panduro A, Roman S, Mariscal-Martinez IM, Jose-Abrego A, Gonzalez-Aldaco K, Ojeda-Granados C, Ramos-Lopez O, Torres-Reyes LA. Personalized medicine and nutrition in hepatology for preventing chronic liver disease in Mexico. Front Nutr 2024; 11:1379364. [PMID: 38784134 PMCID: PMC11113077 DOI: 10.3389/fnut.2024.1379364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 04/01/2024] [Indexed: 05/25/2024] Open
Abstract
Chronic liver disease is a global health issue. Patients with chronic liver disease require a fresh approach that focuses on the genetic and environmental factors that contribute to disease initiation and progression. Emerging knowledge in the fields of Genomic Medicine and Genomic Nutrition demonstrates differences between countries in terms of genetics and lifestyle risk factors such as diet, physical activity, and mental health in chronic liver disease, which serves as the foundation for the implementation of Personalized Medicine and Nutrition (PerMed-Nut) strategies. Most of the world's populations have descended from various ethnic groupings. Mexico's population has a tripartite ancestral background, consisting of Amerindian, European, and African lineages, which is common across Latin America's regional countries. The purpose of this review is to discuss the genetic and environmental components that could be incorporated into a PerMed-Nut model for metabolic-associated liver disease, viral hepatitis B and C, and hepatocellular carcinoma in Mexico. Additionally, the implementation of the PerMed-Nut approach will require updated medicine and nutrition education curricula. Training and equipping future health professionals and researchers with new clinical and investigative abilities focused on preventing liver illnesses in the field of genomic hepatology globally is a vision that clinicians and nutritionists should be concerned about.
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Affiliation(s)
- Arturo Panduro
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Sonia Roman
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Irene M. Mariscal-Martinez
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Alexis Jose-Abrego
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Karina Gonzalez-Aldaco
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
| | - Claudia Ojeda-Granados
- Department of Medical and Surgical Sciences and Advanced Technologies “GF Ingrassia”, University of Catania, Catania, Italy
| | - Omar Ramos-Lopez
- Medicine and Psychology School, Autonomous University of Baja California, Tijuana, Baja California, Mexico
| | - Luis A. Torres-Reyes
- Department of Genomic Medicine in Hepatology, Civil Hospital of Guadalajara, Fray Antonio Alcalde, Health Sciences Center, University of Guadalajara, Guadalajara, Jalisco, Mexico
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13
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Yang W, Ebrahimi F, Romeo S, Holmer M, Vessby J, Ekstedt M, Ludvigsson JF, Shang Y, Hagström H. Risk of major adverse liver outcomes among first-degree relatives of individuals with MASLD. Liver Int 2024; 44:1253-1264. [PMID: 38385564 DOI: 10.1111/liv.15874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 02/23/2024]
Abstract
BACKGROUND & AIMS Previous studies have suggested an increased risk of major adverse liver outcomes (MALO) in relatives of patients with metabolic dysfunction-associated steatotic liver disease (MASLD). However, granular and longitudinal evidence is lacking on the future risk of MALO among family members of individuals with MASLD. METHODS We identified 3526 first-degree relatives (FDRs) and 11 079 general population comparators to 1328 patients with MASLD diagnosed between 1974 and 2021, with detailed clinical data, including liver histology in 71% of patients. MALO was defined through diagnostic coding for cirrhosis or its complications. Cox regression models were used to estimate adjusted hazard ratios (aHRs) for MALO among FDRs compared to general population comparators. Cumulative incidence accounting for competing risks was calculated. RESULTS During a median follow-up of 13.4 years, there were 65 (2%, 1.12/1000 person-years) and 225 (2%, 1.26/1000 person-years) MALO events in FDRs and general population comparators respectively. After adjusting for demographic factors and comorbidities, FDRs were at no increased risk of MALO (aHR = 0.99, 95% CI: 0.74-1.33). Increased relative rates of MALOs were, however, observed in some subgroups, including parents, although absolute risk estimates were low and comparable to the general population. CONCLUSIONS FDRs of patients with MASLD did not have a higher rate of incident MALO than the general population. Since the absolute risk of MALO in relatives of patients with MASLD was low, these results do not support systematic screening of MASLD-related fibrosis in relatives of patients with MASLD.
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Affiliation(s)
- Wen Yang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Fahim Ebrahimi
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Gastroenterology and Hepatology, Clarunis University Center for Gastrointestinal and Liver Diseases, Basel, Switzerland
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Magnus Holmer
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
| | - Johan Vessby
- Department of Medical Sciences, Gastroenterology Research Group, Uppsala University, Uppsala, Sweden
| | - Mattias Ekstedt
- Department of Gastroenterology and Hepatology, Department of Health, Medicine, and Caring Sciences, Linköping University, Linköping, Sweden
| | - Jonas F Ludvigsson
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Pediatrics, Örebro University Hospital, Örebro, Sweden
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Ying Shang
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Hagström
- Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
- Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden
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14
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Fares S, Wehrle CJ, Hong H, Sun K, Jiao C, Zhang M, Gross A, Allkushi E, Uysal M, Kamath S, Ma WW, Modaresi Esfeh J, Linganna MW, Khalil M, Pita A, Kim J, Walsh RM, Miller C, Hashimoto K, Schlegel A, Kwon DCH, Aucejo F. Emerging and Clinically Accepted Biomarkers for Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1453. [PMID: 38672535 PMCID: PMC11047909 DOI: 10.3390/cancers16081453] [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: 02/21/2024] [Revised: 04/03/2024] [Accepted: 04/08/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death and the sixth most diagnosed malignancy worldwide. Serum alpha-fetoprotein (AFP) is the traditional, ubiquitous biomarker for HCC. However, there has been an increasing call for the use of multiple biomarkers to optimize care for these patients. AFP, AFP-L3, and prothrombin induced by vitamin K absence II (DCP) have described clinical utility for HCC, but unfortunately, they also have well established and significant limitations. Circulating tumor DNA (ctDNA), genomic glycosylation, and even totally non-invasive salivary metabolomics and/or micro-RNAS demonstrate great promise for early detection and long-term surveillance, but still require large-scale prospective validation to definitively validate their clinical validity. This review aims to provide an update on clinically available and emerging biomarkers for HCC, focusing on their respective clinical strengths and weaknesses.
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Affiliation(s)
- Sami Fares
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chase J. Wehrle
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Hanna Hong
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Keyue Sun
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Chunbao Jiao
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Mingyi Zhang
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Abby Gross
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Erlind Allkushi
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Melis Uysal
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Suneel Kamath
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Wen Wee Ma
- Department of Hematology and Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.K.); (W.W.M.)
| | - Jamak Modaresi Esfeh
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Maureen Whitsett Linganna
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (J.M.E.); (M.W.L.)
| | - Mazhar Khalil
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Alejandro Pita
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Jaekeun Kim
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - R. Matthew Walsh
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Charles Miller
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Koji Hashimoto
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Andrea Schlegel
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - David Choon Hyuck Kwon
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
| | - Federico Aucejo
- Department of Hepato-Pancreato-Biliary & Liver Transplant Surgery, Digestive Diseases and Surgery Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (S.F.); (H.H.); (K.S.); (C.J.); (M.Z.); (A.G.); (E.A.); (M.U.); (M.K.); (A.P.); (J.K.); (R.M.W.); (K.H.); (A.S.); (D.C.H.K.)
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15
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Leyh C, Coombes JD, Schmidt HH, Canbay A, Manka PP, Best J. MASLD-Related HCC-Update on Pathogenesis and Current Treatment Options. J Pers Med 2024; 14:370. [PMID: 38672997 PMCID: PMC11051566 DOI: 10.3390/jpm14040370] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 03/25/2024] [Accepted: 03/26/2024] [Indexed: 04/28/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is a common complication of chronic liver diseases and remains a relevant cause of cancer-related mortality worldwide. The global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) as a risk factor for hepatocarcinogenesis is on the rise. Early detection of HCC has been crucial in improving the survival outcomes of patients with metabolic dysfunction-associated steatohepatitis (MASH), even in the absence of cirrhosis. Understanding how hepatocarcinogenesis develops in MASH is increasingly becoming a current research focus. Additive risk factors such as type 2 diabetes mellitus (T2DM), genetic polymorphisms, and intestinal microbiota may have specific impacts. Pathophysiological and epidemiological associations between MASH and HCC will be discussed in this review. We will additionally review the available tumor therapies concerning their efficacy in MASH-associated HCC treatment.
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Affiliation(s)
- Catherine Leyh
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty of Heinrich Heine University Düsseldorf, 40225 Düsseldorf, Germany
| | - Jason D. Coombes
- Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA;
| | - Hartmut H. Schmidt
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
| | - Ali Canbay
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44801 Bochum, Germany
| | - Paul P. Manka
- Department of Internal Medicine, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, 44801 Bochum, Germany
| | - Jan Best
- Department of Gastroenterology, Hepatology and Transplant Medicine, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
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16
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Wang X, Zhang L, Dong B. Molecular mechanisms in MASLD/MASH-related HCC. Hepatology 2024:01515467-990000000-00739. [PMID: 38349726 PMCID: PMC11323288 DOI: 10.1097/hep.0000000000000786] [Citation(s) in RCA: 27] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 01/16/2024] [Indexed: 03/23/2024]
Abstract
Liver cancer is the third leading cause of cancer-related deaths and ranks as the sixth most prevalent cancer type globally. NAFLD or metabolic dysfunction-associated steatotic liver disease, and its more severe manifestation, NASH or metabolic dysfunction-associated steatohepatitis (MASH), pose a significant global health concern, affecting approximately 20%-25% of the population. The increased prevalence of metabolic dysfunction-associated steatotic liver disease and MASH is parallel to the increasing rates of obesity-associated metabolic diseases, including type 2 diabetes, insulin resistance, and fatty liver diseases. MASH can progress to MASH-related HCC (MASH-HCC) in about 2% of cases each year, influenced by various factors such as genetic mutations, carcinogen exposure, immune microenvironment, and microbiome. MASH-HCC exhibits distinct molecular and immune characteristics compared to other causes of HCC and affects both men and women equally. The management of early to intermediate-stage MASH-HCC typically involves surgery and locoregional therapies, while advanced HCC is treated with systemic therapies, including anti-angiogenic therapies and immune checkpoint inhibitors. In this comprehensive review, we consolidate previous research findings while also providing the most current insights into the intricate molecular processes underlying MASH-HCC development. We delve into MASH-HCC-associated genetic variations and somatic mutations, disease progression and research models, multiomics analysis, immunological and microenvironmental impacts, and discuss targeted/combined therapies to overcome immune evasion and the biomarkers to recognize treatment responders. By furthering our comprehension of the molecular mechanisms underlying MASH-HCC, our goal is to catalyze the advancement of more potent treatment strategies, ultimately leading to enhanced patient outcomes.
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Affiliation(s)
- Xiaobo Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Liang Zhang
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Bingning Dong
- Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
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17
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Miteva D, Peshevska-Sekulovska M, Snegarova V, Peruhova M, Vasilev GH, Vasilev GV, Sekulovski M, Lazova S, Gulinac M, Tomov L, Mihova A, Velikova T. Microbiome and Genetic Factors in the Pathogenesis of Liver Diseases. GASTROENTEROLOGY INSIGHTS 2023; 14:575-597. [DOI: 10.3390/gastroent14040041] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024] Open
Abstract
Our genetic background has not changed over the past century, but chronic diseases are on the rise globally. In addition to the genetic component, among the critical factors for many diseases are inhabitants of our intestines (gut microbiota) as a crucial environmental factor. Dysbiosis has been described in liver diseases with different etiologies like non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease (ALD), viral hepatitis, autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), cirrhosis, hepatocellular carcinoma (HCC). On the other hand, new technologies have increased our understanding of liver disease genetics and treatment options. Genome-wide association studies (GWAS) identify unknown genetic risk factors, positional cloning of unknown genes associated with different diseases, gene tests for single nucleotide variations (SNVs), and next-generation sequencing (NGS) of selected genes or the complete genome. NGS also allowed studying the microbiome and its role in various liver diseases has begun. These genes have proven their effect on microbiome composition in host genome–microbiome association studies. We focus on altering the intestinal microbiota, and supplementing some bacterial metabolites could be considered a potential therapeutic strategy. The literature data promote probiotics/synbiotics role in reducing proinflammatory cytokines such as TNF-α and the interleukins (IL-1, IL-6, IL-8), therefore improving transaminase levels, hepatic steatosis, and NAFLD activity score. However, even though microbial therapy appears to be risk-free, evaluating side effects related to probiotics or synbiotics is imperative. In addition, safety profiles for long-term usage should be researched. Thus, this review focuses on the human microbiome and liver diseases, recent GWASs on liver disease, the gut-liver axis, and the associations with the microbiome and microbiome during/after liver disease therapy.
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Affiliation(s)
- Dimitrina Miteva
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, 8 Dragan Tzankov Str., 1164 Sofia, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Monika Peshevska-Sekulovska
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Gastroenterology, University Hospital Lozenetz, Kozyak 1 Str., 1407 Sofia, Bulgaria
| | - Violeta Snegarova
- Clinic of Internal Diseases, Naval Hospital—Varna, Military Medical Academy, Medical Faculty, Medical University, Blvd. Hristo Smirnenski 3, 9000 Varna, Bulgaria
| | - Milena Peruhova
- Department of Gastroenterology, Heart and Brain Hospital, Zdrave 1 Str., 8000 Burgas, Bulgaria
| | - Georgi H. Vasilev
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Laboratory of Hematopathology and Immunology, National Specialized Hospital for Active Treatment of Hematological Diseases, “Plovdivsko Pole” Str. 6, 1756 Sofia, Bulgaria
| | - Georgi V. Vasilev
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Emergency Medicine and Clinic of Neurology, University Hospital “Sv. Georgi”, Blvd. Peshtersko Shose 66, 4000 Plovdiv, Bulgaria
| | - Metodija Sekulovski
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Anesthesiology and Intensive Care, University Hospital Lozenetz, 1 Kozyak Str., 1407 Sofia, Bulgaria
| | - Snezhina Lazova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Pediatric Department, University Hospital “N. I. Pirogov”, 21 “General Eduard I. Totleben” Blvd, 1606 Sofia, Bulgaria
- Department of Healthcare, Faculty of Public Health, “Prof. Tsekomir Vodenicharov, MD, DSc”, Medical University of Sofia, Bialo More 8 Str., 1527 Sofia, Bulgaria
| | - Milena Gulinac
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of General and Clinical Pathology, Medical University of Plovdiv, Bul. Vasil Aprilov 15A, 4000 Plovdiv, Bulgaria
| | - Latchezar Tomov
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
- Department of Informatics, New Bulgarian University, Montevideo 21 Str., 1618 Sofia, Bulgaria
| | - Antoaneta Mihova
- SMDL Ramus, Department of Immunology, Blvd. Kap. Spisarevski 26, 1527 Sofia, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str., 1407 Sofia, Bulgaria
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18
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Ayoub A, Anugwom CM, Prieto J, Balderramo D, Ferrer JD, Mattos AZ, Arrese M, Carrera E, Groothuismink ZMA, Oliveira J, Boonstra A, Debes JD. Assessment of STAT4 Variants and Risk of Hepatocellular Carcinoma in Latin Americans and Europeans. Cancers (Basel) 2023; 15:4530. [PMID: 37760499 PMCID: PMC10527221 DOI: 10.3390/cancers15184530] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/02/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The STAT4 rs7574865 genetic variant has been associated with an increased risk of developing HCC in Asian populations. However, this association has not been studied in Latin America and is poorly assessed in European populations. This case-control study investigated the association between STAT4 rs7574865 and HCC risk in these populations. We evaluated DNA samples from seven medical institutions across six Latin American countries and one Dutch institution in 1060 individuals (344 HCC and 716 controls). STAT4 rs7574865 SNP was genotyped using TaqMan-genotyping assay and analyzed using logistic regression. We found no significant association between the homozygous risk allele (G) of STAT4 and HCC development in either population, with odds ratios (OR) for GG versus TT of 0.85 (CI: 0.48-1.52, p = 0.58) and 0.81 (CI: 0.34-1.93, p = 0.67) for Latin Americans and Europeans respectively. No correlation was found between the risk allele and HCC based on underlying liver disease. However, we found that Latin Americans of European ancestry were more likely to carry the risk allele. Our results suggest that the STAT4 SNP rs7574865 does not influence the risk of developing HCC in Latin American or European populations, highlighting the importance of evaluating genetic risk factors in various ethnic groups and understanding the possible influence of ancestry on the genetic basis of disease.
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Affiliation(s)
- Alan Ayoub
- Faculty of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Chimaobi M. Anugwom
- Department of Medicine, Division of Gastroenterology, Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA;
- Health Partners Digestive Care, Saint Paul, MN 55130, USA
| | - Jhon Prieto
- Centro de Enfermedades Hepaticas y Digestives, Bogota 110121, Colombia;
| | - Domingo Balderramo
- Department of Gastroenterology, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba X5016, Argentina;
| | - Javier Diaz Ferrer
- Department of Gastroenterology, Universidad San Martin de Porres, Lima 15024, Peru;
| | - Angelo Z. Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil;
| | - Marco Arrese
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile;
| | - Enrique Carrera
- Department of Gastroenterology, Universidad San Francisco de Quito, Quito 170901, Ecuador;
| | - Zwier M. A. Groothuismink
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
| | - Jeffrey Oliveira
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
| | - Jose D. Debes
- Department of Medicine, Division of Gastroenterology, Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA;
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
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19
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Chen M, Zhong W, Xu W. Alcohol and the mechanisms of liver disease. J Gastroenterol Hepatol 2023; 38:1233-1240. [PMID: 37423758 DOI: 10.1111/jgh.16282] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/11/2023]
Abstract
Alcoholic liver disease (ALD), which is a leading cause of morbidity and mortality worldwide, covers a large spectrum of liver injuries ranging from simple steatosis to steatohepatitis, advanced fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of ALD includes genetic and epigenetic alterations, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation, metabolic reprogramming, immune damage, and dysbiosis of the gut microbiota. This review discusses the progress in the pathogenesis and molecular mechanism of ALD, which could provide evidence for further research on the potential therapeutic strategies targeting these pathways.
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Affiliation(s)
- Mo Chen
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Wanglei Zhong
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Weiqi Xu
- Department of Hepatic Surgery, Shanghai Cancer Center, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
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20
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Sohal A, Chaudhry H, Kowdley KV. Genetic Markers Predisposing to Nonalcoholic Steatohepatitis. Clin Liver Dis 2023; 27:333-352. [PMID: 37024211 DOI: 10.1016/j.cld.2023.01.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
The growing prevalence of nonalcoholic fatty liver disease (NAFLD) has sparked interest in understanding genetics and epigenetics associated with the development and progression of the disease. A better understanding of the genetic factors related to progression will be beneficial in the risk stratification of patients. These genetic markers can also serve as potential therapeutic targets in the future. In this review, we focus on the genetic markers associated with the progression and severity of NAFLD.
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Affiliation(s)
- Aalam Sohal
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA
| | - Hunza Chaudhry
- Department of Internal Medicine, UCSF Fresno, 155 North Fresno Street, Fresno, CA 93722, USA
| | - Kris V Kowdley
- Liver Institute Northwest, 3216 Northeast 45th Place Suite 212, Seattle, WA 98105, USA; Elson S. Floyd College of Medicine, Washington State University, WA, USA.
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21
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Thrift AP, Kanwal F, Liu Y, Khaderi S, Singal AG, Marrero JA, Loo N, Asrani SK, Luster M, Al-Sarraj A, Ning J, Tsavachidis S, Gu X, Amos CI, El-Serag HB. Risk stratification for hepatocellular cancer among patients with cirrhosis using a hepatic fat polygenic risk score. PLoS One 2023; 18:e0282309. [PMID: 36854015 PMCID: PMC9974109 DOI: 10.1371/journal.pone.0282309] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/12/2023] [Indexed: 03/02/2023] Open
Abstract
BACKGROUND Polygenic risk scores (PRS) hold the promise to refine prognostication in hepatocellular cancer (HCC). The few available HCC PRS include germline risk variants identified among individuals of mostly European ancestry, but data are lacking on the transportability of these PRS in multiethnic U.S patients with cirrhosis from multiple etiologies. METHODS We used data from 1644 patients with cirrhosis enrolled in two prospective cohort studies in the U.S. Patients were followed until HCC diagnosis, death, liver transplantation, or last study visit through June 30, 2021. The high-risk variants in PNPLA3-MBOAT7-TM6SF2-GCKR were combined in a PRS and we evaluated its association with HCC. Discriminatory accuracy was assessed using the C-statistic. RESULTS During 4,759 person-years of follow-up, 93 patients developed HCC. Mean age was 59.8 years, 68.6% were male, 27.2% Hispanic, 25.1% non-Hispanic Black, 25.7% had NAFLD, 42.1% had heavy alcohol use, and 19.5% had active HCV. HCC risk increased by 134% per unit increase in PRS (HR = 2.30; 95% CI, 1.35-3.92). Compared to cirrhosis patients in the lowest tertile of the PRS, those in the highest tertile had 2-fold higher risk of HCC (HR = 2.05; 95% CI, 1.22-3.44). The PRS alone had modest discriminatory ability (C-statistic = 0.58; 95% CI, 0.52-0.63); however, adding PRS to a predictive model with traditional HCC risk factors had a C-statistic of 0.70 (95% CI, 0.64-0.76), increasing from 0.68 without the PRS (p = 0.0012). CONCLUSIONS Our findings suggest that PRS may enhance risk prediction for HCC in contemporary U.S. cirrhosis patients.
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Affiliation(s)
- Aaron P. Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Fasiha Kanwal
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, United States of America
| | - Yanhong Liu
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Saira Khaderi
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, United States of America
| | - Jorge A. Marrero
- Division of Digestive and Liver Diseases, Department of Medicine, UT Southwestern Medical Center, Dallas, Texas, United States of America
| | - Nicole Loo
- Texas Liver Institute, San Antonio, Texas, United States of America
| | - Sumeet K. Asrani
- Baylor University Medical Center, Dallas, Texas, United States of America
| | - Michelle Luster
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Abeer Al-Sarraj
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, United States of America
| | - Jing Ning
- Department of Biostatistics, UT MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Spiridon Tsavachidis
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Xiangjun Gu
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
| | - Christopher I. Amos
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, United States of America
| | - Hashem B. El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States of America
- Center for Innovations in Quality, Effectiveness and Safety (IQuESt), Michael E DeBakey Veterans Affairs Medical Center, Houston, TX, United States of America
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22
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Mohamed Fteah A, Abdel Rahim A, Ahmed AbdelHady A, Shawky H, A Elrefaiy M, Mamdouh Aly D. Association of PNPLA3 (rs738409) & TM6SF2 (rs58542926) and ATG16L1 (rs2241880) genetic variants with susceptibility to hepatocellular carcinoma in a group of Egyptian patients with HCV-induced liver cirrhosis. Tumour Virus Res 2023; 15:200256. [PMID: 36804832 PMCID: PMC9975679 DOI: 10.1016/j.tvr.2023.200256] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/16/2023] [Accepted: 02/10/2023] [Indexed: 02/17/2023] Open
Affiliation(s)
| | - Ali Abdel Rahim
- Hepato-gastroentrology Department - Theodor Bilharz Research Institute, Egypt
| | | | - Hanan Shawky
- Clinical Chemistry Department - Theodor Bilharz Research Institute, Egypt
| | - Mohamed A Elrefaiy
- Hepato-gastroentrology Department - Theodor Bilharz Research Institute, Egypt
| | - Doaa Mamdouh Aly
- Clinical Chemistry Department - Theodor Bilharz Research Institute, Egypt
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23
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Campani C, Zucman-Rossi J, Nault JC. Genetics of Hepatocellular Carcinoma: From Tumor to Circulating DNA. Cancers (Basel) 2023; 15:cancers15030817. [PMID: 36765775 PMCID: PMC9913369 DOI: 10.3390/cancers15030817] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary hepatic malignancies and is one of the major causes of cancer-related death. Over the last 15 years, the molecular landscape of HCC has been deciphered, with the identification of the main driver genes of liver carcinogenesis that belong to six major biological pathways, such as telomere maintenance, Wnt/b-catenin, P53/cell cycle regulation, oxidative stress, epigenetic modifiers, AKT/mTOR and MAP kinase. The combination of genetic and transcriptomic data composed various HCC subclasses strongly related to risk factors, pathological features and prognosis. However, translation into clinical practice is not achieved, mainly because the most frequently mutated genes are undruggable. Moreover, the results derived from the analysis of a single tissue sample may not adequately catch the intra- and intertumor heterogeneity. The analysis of circulating tumor DNA (ctDNA) is broadly developed in other types of cancer for early diagnosis, prognosis and monitoring under systemic treatment in order to identify primary and secondary mechanisms of resistance. The aim of this review is to describe recent data about the HCC molecular landscape and to discuss how ctDNA could be used in the future for HCC detection and management.
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Affiliation(s)
- Claudia Campani
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Internal Medicine and Hepatology Unit, Department of Experimental and Clinical Medicine, University of Firenze, 50134 Firenze, Italy
| | - Jessica Zucman-Rossi
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Hôpital Européen Georges Pompidou, APHP, 75015 Paris, France
| | - Jean-Charles Nault
- Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, Team «Functional Genomics of Solid Tumors», 75006 Paris, France
- Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, 75006 Paris, France
- Liver Unit, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, 93000 Bobigny, France
- Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, 93000 Bobigny, France
- Correspondence: ; Tel.: +33-6-1067-9461
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24
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Shah PA, Patil R, Harrison SA. NAFLD-related hepatocellular carcinoma: The growing challenge. Hepatology 2023; 77:323-338. [PMID: 35478412 PMCID: PMC9970023 DOI: 10.1002/hep.32542] [Citation(s) in RCA: 127] [Impact Index Per Article: 63.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is a common cause of cancer-related mortality and morbidity worldwide. With the obesity pandemic, NAFLD-related HCC is contributing to the burden of disease exponentially. Genetic predisposition and clinical risk factors for NAFLD-related HCC have been identified. Cirrhosis is a well-known and major risk factor for NAFLD-related HCC. However, the occurrence of NAFLD-related HCC in patients without cirrhosis is increasingly recognized and poses a significant challenge regarding cancer surveillance. It is of paramount importance to develop optimal risk stratification scores and models to identify subsets of the population at high risk so they can be enrolled in surveillance programs. In this review, we will discuss the risks and prediction models for NAFLD-related HCC.
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Affiliation(s)
- Pir Ahmad Shah
- Department of Internal Medicine, University of Texas Health Science Center, San Antonio, Texas, USA
| | - Rashmee Patil
- South Texas Research Institute, Edinburg, Texas, USA
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25
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Gutiérrez-Cuevas J, Lucano-Landeros S, López-Cifuentes D, Santos A, Armendariz-Borunda J. Epidemiologic, Genetic, Pathogenic, Metabolic, Epigenetic Aspects Involved in NASH-HCC: Current Therapeutic Strategies. Cancers (Basel) 2022; 15:23. [PMID: 36612019 PMCID: PMC9818030 DOI: 10.3390/cancers15010023] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/12/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and is the sixth most frequent cancer in the world, being the third cause of cancer-related deaths. Nonalcoholic steatohepatitis (NASH) is characterized by fatty infiltration, oxidative stress and necroinflammation of the liver, with or without fibrosis, which can progress to advanced liver fibrosis, cirrhosis and HCC. Obesity, metabolic syndrome, insulin resistance, and diabetes exacerbates the course of NASH, which elevate the risk of HCC. The growing prevalence of obesity are related with increasing incidence of NASH, which may play a growing role in HCC epidemiology worldwide. In addition, HCC initiation and progression is driven by reprogramming of metabolism, which indicates growing appreciation of metabolism in the pathogenesis of this disease. Although no specific preventive pharmacological treatments have recommended for NASH, dietary restriction and exercise are recommended. This review focuses on the molecular connections between HCC and NASH, including genetic and risk factors, highlighting the metabolic reprogramming and aberrant epigenetic alterations in the development of HCC in NASH. Current therapeutic aspects of NASH/HCC are also reviewed.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Silvia Lucano-Landeros
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Daniel López-Cifuentes
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Guadalajara 44340, Jalisco, Mexico
- Tecnologico de Monterrey, EMCS, Campus Guadalajara, Zapopan 45201, Jalisco, Mexico
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26
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Mo H, Wang X, Ji G, Liang X, Yang Y, Sun W, Jia X, Xu L, Qiao Y, Zhou H, Zhao W, Fu S, Zhang X. The effect of SNPs in lncRNA as ceRNA on the risk and prognosis of hepatocellular carcinoma. BMC Genomics 2022; 23:769. [DOI: 10.1186/s12864-022-09010-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 11/14/2022] [Indexed: 11/25/2022] Open
Abstract
Abstract
Background
Most susceptible loci of hepatocellular carcinoma (HCC) identified by genome-wide association studies (GWAS) are located in non-coding regions, and the mechanism of action remains unclear. The objective of this study was to explore the association of single nucleotide polymorphisms (SNPs) on long non-coding RNAs (lncRNAs) that affect competing endogenous RNAs (ceRNA) regulation mechanism with the risk and prognosis of HCC.
Methods
Based on a set of bioinformatics strategies, eight lncRNA genes that affect HCC through the mechanism of lncRNA-mediated ceRNA were systematically screened, and 15 SNPs that affect microRNA (miRNA) binding in these lncRNA genes were annotated. Genotyping was performed in 800 HCC cases and 801 healthy controls to examine associations of these SNPs with HCC in a northeastern Chinese Han population.
Results
The GG, GC and GG + GC genotypes of HOTAIR rs7958904 were associated with a 0.65, 0.59 and 0.63-fold decreased HCC risk, respectively. In addition, HCC patients with PVT1 rs3931282 AA + GA genotypes were less prone to develop late-stage cancers in a stratified analysis of clinical characteristics. When stratified by clinical biochemical indexes, rs1134492 and rs10589312 in PVT1 and rs84557 in EGFR-AS1 showed significant associations with aspartate aminotransferase (AST), alanine aminotransferase (ALT) or AST/ALT ratio in HCC patients. Furthermore, we constructed potential ceRNA regulatory axes that might be affected by five positive SNPs to explain the causes of these genetic associations.
Conclusions
HOTAIR rs7958904, PVT1 rs3931282, rs1134492 and rs10589312, and EGFR-AS1 rs84557 might be predictors for HCC risk or prognosis. Our results provide new insights into how SNPs on lncRNA-mediated ceRNAs confer interindividual differences to occurrence and progression of HCC.
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27
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Youssef SS, Youness RA, Abbas EAER, Osman NM, ELFiky A, El-Kassas M. miR-516a-3P, a potential circulating biomarker in hepatocellular carcinoma, correlated with rs738409 polymorphism in PNPLA3. Per Med 2022; 19:483-493. [PMID: 36239555 DOI: 10.2217/pme-2022-0005] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Accepted: 07/10/2022] [Indexed: 12/02/2022]
Abstract
Aim: The aim was to investigate the expression profile of miR-516a-3P and its correlation with the PNPLA3 rs738409 polymorphism in Egyptian hepatitis C virus (HCV) and hepatocellular carcinoma (HCC) patients. Materials & methods: miR-516a-3P was quantified and rs738409 was genotyped by quantitative reverse transcription PCR. Results: miR-516a-3P was significantly upregulated in HCC patients compared with HCV patients (p = 0.001). Receiver operating characteristic curve analysis confirmed that miR-516a-3P discriminates HCC from HCV (p = 0.001). A significant (p = 0.015) correlation between miR-516a-3p level and PNPLA3 rs738409 genotypes was recorded in HCV patients, yet it was not recorded in either healthy individuals or HCC patients. miR-516a-3p level was significantly (p = 0.001) higher in HCV patients carrying the rs738409 GG genotype than in those carrying the CC genotype. Conclusion: miR-516a-3P is a potential biomarker in HCC. PNPLA3 rs738409 GG carriers affect miR-516a-3P expression in HCV, and this may highlight a new mechanism in liver disease.
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Affiliation(s)
- Samar Samir Youssef
- Microbial Biotechnology Department, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Rana Ahmed Youness
- School of Life & Medical Sciences, University of Hertfordshire Hosted by Global Academic Foundation, New Administrative Capital, Cairo, 11578, Egypt
- Pharmaceutical Biology Department, Faculty of Pharmacy & Biotechnology, German University in Cairo, Cairo, Egypt
| | - Eman Abd El-Razek Abbas
- Microbial Biotechnology Department, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Noha Mohamed Osman
- Cell Biology Department, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Asmaa ELFiky
- Environmental & Occupational Medicine Department, Environmental Research Division, National Research Centre, 33 El Buhouth St., Dokki, Cairo, 12622, Egypt
| | - Mohamed El-Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo, 11795, Egypt
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Youssef SS, Abbas EAER, Elfiky AM, Seif S, Nabeel MM, Shousha HI, Abdelaziz AO. The impact of polymorphism in PNPLA3 and TM6SF2 genes on the susceptibility and survival of hepatitis C-related hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2022; 12:56. [DOI: 10.1186/s43066-022-00212-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 08/28/2022] [Indexed: 12/02/2022] Open
Abstract
Abstract
Background
Genetic variants of Patatin-like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been reported with the development of hepatocellular carcinoma (HCC). This study aims to explore the role of The PNPLA3 rs738409 and TM6SF2 rs58542926 single-nucleotide polymorphisms (SNPs) on the incidence and survival of HCV-induced HCC in Egyptians.
Methods and results
This case-control study included (120) HCC and (144) hepatitis C virus (HCV) patients. Baseline clinical, laboratory, tumor characteristics data, HCC recurrence, and overall survival were collected. PNPLA3 rs738409 and TM6SF2 rs58542926 polymorphism were detected by TaqMan allelic discrimination assay. We found that HCC patients were significantly older with male predominance. A significant difference between the TT genotypes of TM6SF2 frequency was observed in HCC compared with HCV patients. Moreover, the T allele of TM6SF2 distributions revealed a significant contribution to the different stages of HCC (p=0.03). Both PNPLA3 rs738409 and TM6SF2 rs58542926 variants showed a significant relation with treatment response according to the modified RECIST criteria. Age and diabetes mellitus were the independent factors associated with the development of HCC by multivariate regression analysis.
Conclusions
TM6SF2 rs58542926 polymorphism, not PNPLA3 rs738409, could be implicated in the development of HCV-induced HCC and its progression.
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Tian Z, Xu C, Yang P, Lin Z, Wu W, Zhang W, Ding J, Ding R, Zhang X, Dou K. Molecular pathogenesis: Connections between viral hepatitis-induced and non-alcoholic steatohepatitis-induced hepatocellular carcinoma. Front Immunol 2022; 13:984728. [PMID: 36189208 PMCID: PMC9520190 DOI: 10.3389/fimmu.2022.984728] [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: 07/02/2022] [Accepted: 08/31/2022] [Indexed: 12/02/2022] Open
Abstract
Hepatocellular carcinoma(HCC) is the sixth most common cancer in the world and is usually caused by viral hepatitis (HBV and HCV), alcoholic, and non-alcoholic fatty liver disease(NAFLD). Viral hepatitis accounts for 80% of HCC cases worldwide. In addition, With the increasing incidence of metabolic diseases, NAFLD is now the most common liver disease and a major risk factor for HCC in most developed countries. This review mainly described the specificity and similarity between the pathogenesis of viral hepatitis(HBV and HCV)-induced HCC and NAFLD-induced HCC. In general, viral hepatitis promotes HCC development mainly through specific encoded viral proteins. HBV can also exert its tumor-promoting mechanism by integrating into the host chromosome, while HCV cannot. Viral hepatitis-related HCC and NASH-related HCC differ in terms of genetic factors, and epigenetic modifications (DNA methylation, histone modifications, and microRNA effects). In addition, both of them can lead to HCC progression through abnormal lipid metabolism, persistent inflammatory response, immune and intestinal microbiome dysregulation.
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Affiliation(s)
- Zelin Tian
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Chen Xu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Peijun Yang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Zhibin Lin
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenlong Wu
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Wenjie Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- Chinese Education Ministry’s Key Laboratory of Western Resources and Modern Biotechnology, Key Laboratory of Biotechnology Shaanxi Province, College of Life Sciences, Northwest University, Xi’an, China
| | - Jian Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Rui Ding
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
| | - Xuan Zhang
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Air Force Medical University, Xi’an, China
- *Correspondence: Xuan Zhang, ; Kefeng Dou,
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Baratta F, D'Erasmo L, Bini S, Pastori D, Angelico F, Del Ben M, Arca M, Di Costanzo A. Heterogeneity of non-alcoholic fatty liver disease (NAFLD): Implication for cardiovascular risk stratification. Atherosclerosis 2022; 357:51-59. [PMID: 36058083 DOI: 10.1016/j.atherosclerosis.2022.08.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/27/2022] [Accepted: 08/11/2022] [Indexed: 12/17/2022]
Abstract
NAFLD is currently considered the most common liver disease worldwide and mounting data support its strong link with atherosclerotic cardiovascular disease (ASCVD). This association is important as cardiovascular disease (CVD) is generally recognized as the leading cause of death in individuals with NAFLD. However, NAFLD represents a heterogeneous condition showing a wide spectrum of clinical and pathophysiological sub-phenotypes with different adverse outcomes ranging from ASCVD to liver damage progression. The contribution to NAFLD pathogenesis of different environmental, metabolic, and genetic factors underlies this heterogeneity. The more frequent phenotype of NAFLD patients is associated with metabolic dysfunctions such as obesity and insulin-resistant syndrome and this has been recently named as Metabolic Associated Fatty Liver disease (MAFLD). However, NAFLD is encountered also in subjects without insulin resistance and metabolic alterations and in whom genetic factors play a major role. It has been suggested that these individuals are at risk of liver disease progression but not of cardiovascular complications. Separating metabolic from genetic factors could be useful in disentangling the intricate relationship between NAFLD and atherosclerosis. In the present review, we aim to address the epidemic of NAFLD, its epidemiologically association with ASCVD complications and the overall mechanisms involved in the pathophysiology of atherosclerotic vascular damage in NAFLD patients. Finally, we will revise the potential role of genetics in identifying disease subtyping and predicting individualised CVD risk.
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Affiliation(s)
- Francesco Baratta
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161, Rome, Italy
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Simone Bini
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Daniele Pastori
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161, Rome, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00161, Rome, Italy
| | - Maria Del Ben
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161, Rome, Italy
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy.
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Sasaki-Tanaka R, Ray R, Moriyama M, Ray RB, Kanda T. Molecular Changes in Relation to Alcohol Consumption and Hepatocellular Carcinoma. Int J Mol Sci 2022; 23:ijms23179679. [PMID: 36077080 PMCID: PMC9456124 DOI: 10.3390/ijms23179679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Revised: 08/23/2022] [Accepted: 08/24/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol is the one of the major causes of liver diseases and promotes liver cirrhosis and hepatocellular carcinoma (HCC). In hepatocytes, alcohol is converted to acetaldehyde, which causes hepatic steatosis, cellular apoptosis, endoplasmic reticulum stress, peroxidation, production of cytokines and reduces immune surveillance. Endotoxin and lipopolysaccharide produced from intestinal bacteria also enhance the production of cytokines. The development of hepatic fibrosis and the occurrence of HCC are induced by these alcohol metabolites. Several host genetic factors have recently been identified in this process. Here, we reviewed the molecular mechanism associated with HCC in alcoholic liver disease.
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Affiliation(s)
- Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
| | - Ranjit Ray
- Departments of Internal Medicine, and Molecular Microbiology and Immunology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Mitsuhiko Moriyama
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
| | - Ratna B. Ray
- Department of Pathology, Saint Louis University, Saint Louis, MO 63104, USA
| | - Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan
- Correspondence: (R.S.-T.); (T.K.); Tel.: +81-3-3972-8111 (R.S.-T. & T.K.)
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Rauff B, Alzahrani B, Chudhary SA, Nasir B, Mahmood S, Bhinder MA, Faheem M, Amar A. PNPLA3 and TM6SF2 genetic variants and hepatic fibrosis and cirrhosis in Pakistani chronic hepatitis C patients: a genetic association study. BMC Gastroenterol 2022; 22:401. [PMID: 36028802 PMCID: PMC9414345 DOI: 10.1186/s12876-022-02469-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 08/02/2022] [Indexed: 01/10/2023] Open
Abstract
Background The present study investigates if common missense functional variants p.I148M and p.E167K in PNPLA3 and TM6SF2 genes, respectively, associate with development of hepatic fibrosis and cirrhosis in a geographically novel cohort of Pakistani chronic hepatitis C (CHC) patients.
Methods In total, 502 Pakistani CHC patients [242 males, median age 40 years, 220 with significant hepatic fibrosis, including 114 with cirrhosis] were genotyped for PNPLA3 and TM6SF2 variants using TaqMan genotyping assays. Associations between genotypes, biochemical and clinical parameters were evaluated. Results Genotypic distributions for PNPLA3 and TM6SF2 polymorphisms conformed to Hardy–Weinberg equilibrium and did not associate with fibrosis grades ≥ F2 or cirrhosis in any of the genetic models tested (all p = > 0.05). PNPLA3 and TM6SF2 variants did not modulate baseline characteristics and serum markers of liver injury in CHC patients. Similarly, increasing number of risk alleles of PNPLA3 and TM6SF2 polymorphisms had no trend effect on serum liver enzyme activities or proportion of CHC patients with significant or advanced fibrosis or cirrhosis (p = > 0.05). The same trend of no association with hepatic fibrosis or cirrhosis persisted in the multivariate logistic regression models adjusting for age, gender, body mass index and HCV viral load (p = > 0.05). Conclusions PNPLA3 and TM6SF2 variants do not appear to modulate development of hepatic fibrosis or cirrhosis in present CHC patients of Pakistani origin, and may be of more relevance in liver pathology involving abnormalities in hepatic fat accumulation. These results also reflect the divergent associations observed for different genetic modifiers of hepatic fibrosis and cirrhosis in distinct ethnicities.
Supplementary Information The online version contains supplementary material available at 10.1186/s12876-022-02469-6.
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Affiliation(s)
- Bisma Rauff
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Sydney, NSW, Australia.,Department of Biomedical Engineering, University of Engineering and Technology, Lahore, Narowal Campus, Narowal, Pakistan
| | - Badr Alzahrani
- Department of Clinical Laboratory Sciences, Jouf University, Sakaka, Kingdom of Saudi Arabia
| | - Shafiq A Chudhary
- Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan
| | - Bilal Nasir
- Department of Medicine, Lahore General Hospital, Lahore, Pakistan
| | - Saqib Mahmood
- Institute of Biomedical and Allied Health Sciences, University of Health Sciences, Lahore, Pakistan
| | - Munir Ahmad Bhinder
- Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan
| | - Muhammad Faheem
- Department of Biological Sciences, National University of Medical Sciences, Rawalpindi, Pakistan
| | - Ali Amar
- Department of Human Genetics and Molecular Biology, University of Health Sciences, Lahore, Pakistan.
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Patsenker E, Thangapandi VR, Knittelfelder O, Palladini A, Hefti M, Beil-Wagner J, Rogler G, Buch T, Shevchenko A, Hampe J, Stickel F. The Pnpla3 Variant I148M Reveals Protective Effects Towards Hepatocellular Carcinoma in Mice via Restoration of Omega-3 Polyunsaturated Fats. J Nutr Biochem 2022; 108:109081. [PMID: 35691594 DOI: 10.1016/j.jnutbio.2022.109081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 02/02/2022] [Accepted: 05/03/2022] [Indexed: 12/02/2022]
Abstract
Alcohol consumption and high caloric diet are leading causes of progressive fatty liver disease. Genetic variant rs738409 in patatin-like phospholipase domain-containing protein 3 (PNPLA3 rs738409 C>G) has been repeatedly described as one of the major risk loci for alcoholic liver cirrhosis (ALC) and hepatocellular carcinoma (HCC) in humans, however, the mechanism behind this association is incompletely understood. We generated mice carrying the rs738409 variant (PNPLA3 I148M) in order to detect genotype-phenotype relationships in mice upon chow and alcohol-high fat/high sugar diet (EtOH/WD). We could clearly demonstrate that the presence of rs738409 per se is sufficient to induce spontaneous development of steatosis after one year in mice on a chow diet, whereas in the setting of unhealthy diet feeding, PNPLA3 I148M did not affect hepatic inflammation or fibrosis, but induced a striking lipid remodelling, microvesicular steatosis and protected from HCC formation. Using shot gun lipidomics, we detected a striking restoration of reduced long chain-polyunsaturated fatty acids (LC-PUFA)-containing TGs, docosapentaenoic acid (C22:5 n3) and omega-3-derived eicosanoids (5-HEPE, 20-HEPE, 19,20-EDP, 21-HDHA) in PNPLA3 I148M mice upon EtOH/WD. At the molecular level, PNPLA3 I148M modulated enzymes for fatty acid and TG transport and metabolism. These findings suggest (dietary) lipids as an important and independent driver of hepatic tumorigenesis. Genetic variant in PNPLA3 exerted protective effects in mice, conflicting with findings in humans. Species-related differences in physiology and metabolism should be taken into account when modelling unhealthy human lifestyle, as genetic mouse models may not always allow for translation of insight gained in humans.
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Affiliation(s)
- Eleonora Patsenker
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland.
| | - Veera Raghavan Thangapandi
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Oskar Knittelfelder
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Alessandra Palladini
- Paul Langerhans Institute Dresden of the Helmholtz Zentrum München at the University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; German Center for Diabetes Research, 85764 Neuherberg, Germany
| | - Michaela Hefti
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Jane Beil-Wagner
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
| | - Thorsten Buch
- Institute of Laboratory Animal Science, University of Zurich, 8952 Schlieren, Switzerland
| | - Andrej Shevchenko
- Max Plank Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany
| | - Jochen Hampe
- Department of Gastroenterology and Hepatology, Universitätsklinikum Dresden, 01304 Dresden, Germany; Center for Regenerative Therapies, TU Dresden, 01307 Dresden, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University of Zurich, 8091 Zurich, Switzerland
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Quintavalle C, Meyer‐Schaller N, Roessler S, Calabrese D, Marone R, Riedl T, Picco‐Rey S, Panagiotou OA, Uzun S, Piscuoglio S, Boldanova T, Bian CB, Semela D, Jochum W, Cathomas G, Mertz KD, Diebold J, Mazzucchelli L, Koelzer VH, Weber A, Decaens T, Terracciano LM, Heikenwalder M, Hoshida Y, Andersen JB, Thorgeirsson SS, Matter MS. miR-579-3p Controls Hepatocellular Carcinoma Formation by Regulating the Phosphoinositide 3-Kinase-Protein Kinase B Pathway in Chronically Inflamed Liver. Hepatol Commun 2022; 6:1467-1481. [PMID: 35132819 PMCID: PMC9134798 DOI: 10.1002/hep4.1894] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 12/06/2021] [Accepted: 12/16/2021] [Indexed: 12/02/2022] Open
Abstract
Chronic liver inflammation causes continuous liver damage with progressive liver fibrosis and cirrhosis, which may eventually lead to hepatocellular carcinoma (HCC). Whereas the 10-year incidence for HCC in patients with cirrhosis is approximately 20%, many of these patients remain tumor free for their entire lives. Clarifying the mechanisms that define the various outcomes of chronic liver inflammation is a key aspect in HCC research. In addition to a wide variety of contributing factors, microRNAs (miRNAs) have also been shown to be engaged in promoting liver cancer. Therefore, we wanted to characterize miRNAs that are involved in the development of HCC, and we designed a longitudinal study with formalin-fixed and paraffin-embedded liver biopsy samples from several pathology institutes from Switzerland. We examined the miRNA expression by nCounterNanostring technology in matched nontumoral liver tissue from patients developing HCC (n = 23) before and after HCC formation in the same patient. Patients with cirrhosis (n = 26) remaining tumor free within a similar time frame served as a control cohort. Comparison of the two cohorts revealed that liver tissue from patients developing HCC displayed a down-regulation of miR-579-3p as an early step in HCC development, which was further confirmed in a validation cohort. Correlation with messenger RNA expression profiles further revealed that miR-579-3p directly attenuated phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) expression and consequently protein kinase B (AKT) and phosphorylated AKT. In vitro experiments and the use of clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology confirmed that miR-579-3p controlled cell proliferation and cell migration of liver cancer cell lines. Conclusion: Liver tissues from patients developing HCC revealed changes in miRNA expression. miR-579-3p was identified as a novel tumor suppressor regulating phosphoinositide 3-kinase-AKT signaling at the early stages of HCC development.
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Affiliation(s)
- Cristina Quintavalle
- Institute of PathologyUniversity Hospital of BaselUniversity of BaselBaselSwitzerland
| | | | | | - Diego Calabrese
- Department of BiomedicineUniversity of BaselBaselSwitzerland
- Division of Hepatology and GastroenterologyUniversity Hospital of BaselBaselSwitzerland
| | - Romina Marone
- Department of BiomedicineUniversity Hospital of Basel, University of BaselBaselSwitzerland
| | - Tobias Riedl
- Division of Chronic Inflammation and CancerGerman Cancer Research CenterHeidelbergGermany
| | - Silvia Picco‐Rey
- Institute of PathologyUniversity Hospital of BaselUniversity of BaselBaselSwitzerland
| | - Orestis A. Panagiotou
- Department of Health Services, Policy and PracticeBrown University School of Public HealthProvidenceRIUSA
| | - Sarp Uzun
- Institute of PathologyUniversity Hospital of BaselUniversity of BaselBaselSwitzerland
| | - Salvatore Piscuoglio
- Institute of PathologyUniversity Hospital of BaselUniversity of BaselBaselSwitzerland
| | - Tuyana Boldanova
- Department of BiomedicineUniversity of BaselBaselSwitzerland
- Division of Hepatology and GastroenterologyUniversity Hospital of BaselBaselSwitzerland
| | - Chaoran B. Bian
- Department of Genetics and Genomic SciencesGraduate School of Biomedical SciencesIcahn School of Medicine at Mount SinaiNew YorkNYUSA
| | - David Semela
- Division of GastroenterologyKantonsspital St. GallenSt. GallenSwitzerland
| | - Wolfram Jochum
- Institute of PathologyKantonsspital St. GallenSt. GallenSwitzerland
| | - Gieri Cathomas
- Institute of PathologyKantonsspital BasellandLiestalSwitzerland
| | | | - Joachim Diebold
- Institute of PathologyLuzerner KantonsspitalLucerneSwitzerland
| | | | - Viktor H. Koelzer
- Department of Pathology and Molecular PathologyUniversity and University Hospital ZurichZurichSwitzerland
| | - Achim Weber
- Department of Pathology and Molecular PathologyUniversity and University Hospital ZurichZurichSwitzerland
| | - Thomas Decaens
- Institute for Advanced BiosciencesINSERM U1209/CNRS UMR 5309/Université Grenoble‐AlpesGrenobleFrance
- Université Grenoble AlpesGrenobleFrance
- Clinique Universitaire d'Hépato‐gastroentérologie, Pôle DigiduneCentre Hospitalier UniversitaireGrenobleFrance
| | - Luigi M. Terracciano
- Institute of PathologyUniversity Hospital of BaselUniversity of BaselBaselSwitzerland
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and CancerGerman Cancer Research CenterHeidelbergGermany
| | - Yujin Hoshida
- Liver Tumor ProgramSimmons Comprehensive Cancer CenterDivision of Digestive and Liver DiseasesUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Jesper B. Andersen
- Biotech Research and Innovation CenterDepartment of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Snorri S. Thorgeirsson
- Laboratory of Experimental CarcinogenesisCenter for Cancer ResearchNational Cancer Institute‐National Institutes of HealthBethesdaMDUSA
| | - Matthias S. Matter
- Institute of PathologyUniversity Hospital of BaselUniversity of BaselBaselSwitzerland
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Cisneros-Garza L, González-Huezo M, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño G, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez M, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva J, Gabutti-Thomas J, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández P, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz M, Ruíz-García E, Sánchez-Ávila J, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2022; 87:216-234. [DOI: 10.1016/j.rgmxen.2021.10.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 12/24/2022] Open
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36
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Cisneros-Garza LE, González-Huezo MS, Moctezuma-Velázquez C, Ladrón de Guevara-Cetina L, Vilatobá M, García-Juárez I, Alvarado-Reyes R, Álvarez-Treviño GA, Allende-Pérez S, Bornstein-Quevedo L, Calderillo-Ruiz G, Carrillo-Martínez MA, Castillo-Barradas M, Cerda-Reyes E, Félix-Leyva JA, Gabutti-Thomas JA, Guerrero-Ixtlahuac J, Higuera-de-la-Tijera F, Huitzil-Meléndez D, Kimura-Hayama E, López-Hernández PA, Malé-Velázquez R, Méndez-Sánchez N, Morales-Ruiz MA, Ruíz-García E, Sánchez-Ávila JF, Torrecillas-Torres L. The second Mexican consensus on hepatocellular carcinoma. Part I: Epidemiology and diagnosis. REVISTA DE GASTROENTEROLOGIA DE MEXICO (ENGLISH) 2022; 87:216-234. [PMID: 35431142 DOI: 10.1016/j.rgmx.2021.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/04/2021] [Accepted: 10/21/2021] [Indexed: 01/04/2025]
Abstract
Hepatocellular carcinoma (HCC) is more frequently manifesting as one of the main complications of cirrhosis of the liver, its principal risk factor. There have been modifications in its incidence over the past decade, related to an epidemiologic transition in the etiology of cirrhosis, with a decrease in the prevalence of hepatitis C and an increase in nonalcoholic fatty liver disease (NAFLD) as a cause, as well as the development of HCC in the non-cirrhotic liver due to NAFLD. Genetic markers associated with the disease have been identified, and surveillance and diagnosis have improved. Regarding treatment, surgical techniques, in both resection and transplantation, have advanced and radiologic techniques, at the curative stage of the disease, have enhanced survival in those patients. And finally, there have been radical changes in the systemic approach, with much more optimistic expectations, when compared with the options available a decade ago. Therefore, the Asociación Mexicana de Hepatología decided to carry out the Second Mexican Consensus on Hepatocellular Carcinoma, which is an updated review of the available national and international evidence on the epidemiology, risk factors, surveillance, diagnosis, and treatment of the disease, to offer the Mexican physician current information on the different topics regarding hepatocellular carcinoma. In this first part of the document, the topics related to epidemiology and diagnosis are presented.
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Affiliation(s)
- L E Cisneros-Garza
- Hospital Christus Muguerza Alta Especialidad, Monterrey, Nuevo León, Mexico
| | | | - C Moctezuma-Velázquez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - M Vilatobá
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | - I García-Juárez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - G A Álvarez-Treviño
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | | | - L Bornstein-Quevedo
- InmunoQ, Laboratorio de Patología, Inmunohistoquímica y Biología Molecular, Mexico City, Mexico
| | | | | | | | | | | | - J A Gabutti-Thomas
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | | | - D Huitzil-Meléndez
- Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
| | | | - P A López-Hernández
- Unidad de Medicina de Alta Especialidad 25 IMSS, Monterrey, Nuevo León, Mexico
| | - R Malé-Velázquez
- Instituto de Salud Digestiva y Hepática SA de CV, Guadalajara, Jalisco, Mexico
| | | | - M A Morales-Ruiz
- Centro Oncológico Estatal Issemym, Toluca, Estado de México, Mexico
| | - E Ruíz-García
- Instituto Nacional de Cancerología, Mexico City, Mexico
| | - J F Sánchez-Ávila
- Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, Monterrey, Nuevo León, Mexico
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Hsueh RC, Wu WJ, Lin CL, Liu CJ, Huang YW, Hu JT, Wu CF, Sung FY, Liu WJ, Yu MW. Impact of PNPLA3 p.I148M and Hepatic Steatosis on Long-Term Outcomes for Hepatocellular Carcinoma and HBsAg Seroclearance in Chronic Hepatitis B. J Hepatocell Carcinoma 2022; 9:301-313. [PMID: 35433529 PMCID: PMC9012500 DOI: 10.2147/jhc.s355540] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Accepted: 03/11/2022] [Indexed: 12/16/2022] Open
Abstract
Background Coexistence of hepatitis B and nonalcoholic fatty liver disease is common; however, little is known about the impact of hepatic steatosis and its major genetic determinants on the natural history of HBV infection. We aimed to study the effects of hepatic steatosis and PNPLA3 variant p.I148M on the risk of hepatocellular carcinoma (HCC) and the lifetime probability of HBsAg seroclearance, which is associated with functional remission and improved long-term outcome of HBV infection. Methods We conducted a cohort study of 2385 male, HBsAg-positive Taiwanese civil servants recruited in 1989–1992, and followed up until 2019. Cox regression with competing-risk models was used to estimate sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs). Results Of 2385 participants, 628 experienced HBsAg seroclearance and 217 developed HCC. Hepatic steatosis, excess body-mass index, and the PNPLA3-148M variant were significantly associated with higher HBsAg seroclearance rate. However, multivariate analyses accounting for HBsAg seroclearance and various HCC risk factors showed that, while steatosis was associated with decreased HCC risk (sHR [95% CI]: 0.49 [0.36–0.66]), carriage of the PNPLA3-148M variant allele (vs II homozygotes: 1.64 [1.20–2.25] for MI heterozygotes; 1.83 [1.20–2.78] for MM homozygotes) and obesity (1.51 [1.07–2.13]) were associated with increased risk. The inverse hepatic steatosis-HCC association persisted after additional adjustment for other viral factors or using different follow-up time cut-offs to account for reverse causality. Moreover, the PNPLA3 MM genotype was positively associated with elevations of ALT and AST and liver cirrhosis, while hepatic steatosis was positively associated with ALT but inversely associated with AST and liver cirrhosis. Conclusion Hepatic steatosis and PNPLA3-148M variant appeared to have distinct impacts on the development of HBV-related progressive liver disease and HCC. PNPLA3 p.I148M, but not a diagnosis of hepatic steatosis, can help to identify HBV carriers with high-risk fatty liver disease in the progression to HCC.
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Affiliation(s)
- Rei-Chi Hsueh
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Wan-Jung Wu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
| | - Chun-Jen Liu
- Division of Gastroenterology, Department of Internal Medicine, National Taiwan University Hospital and Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Yi-Wen Huang
- Clinical Research Center, Liver Center and Division of Gastroenterology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Jui-Ting Hu
- Liver Center, Cathay General Hospital Medical Center, School of Medicine, Fu-Jen Catholic University College of Medicine, Taipei, Taiwan
| | - Chih-Feng Wu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Feng-Yu Sung
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Wen-Jie Liu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
| | - Ming-Whei Yu
- Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
- Correspondence: Ming-Whei Yu, Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No. 17, Xuzhou Road Zhongzheng District, Taipei City, 10055, Taiwan, Email
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Luo F, Oldoni F, Das A. TM6SF2: A Novel Genetic Player in Nonalcoholic Fatty Liver and Cardiovascular Disease. Hepatol Commun 2022; 6:448-460. [PMID: 34532996 PMCID: PMC8870032 DOI: 10.1002/hep4.1822] [Citation(s) in RCA: 84] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 08/13/2021] [Accepted: 08/25/2021] [Indexed: 12/11/2022] Open
Abstract
Transmembrane 6 superfamily member 2 (TM6SF2) is located on chromosome 19 (19p12) and encodes for a protein of undetermined function. Genetic studies have reported the association between a nonsynonymous variant in TM6SF2 (E167K, rs58542926) with hepatic triglyceride content and its impact on the cardiovascular system. Clinical and epidemiological studies have confirmed the role of TM6SF2 in the development of nonalcoholic fatty liver disease (NAFLD). Recently, TM6SF2 was also shown to play an important role in promoting hepatic fibrosis and hepatocellular cancer in mouse models. This review aims to capture the physiological role of TM6SF2 in the regulation of lipid metabolism and its involvement in cardiometabolic diseases.
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Affiliation(s)
- Fei Luo
- Department of Cardiovascular MedicineThe Second Xiangya Hospital of Central South UniversityChangshaChina
- Department of Molecular GeneticsUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Federico Oldoni
- Department of Molecular GeneticsUniversity of Texas Southwestern Medical CenterDallasTXUSA
| | - Avash Das
- Department of Molecular GeneticsUniversity of Texas Southwestern Medical CenterDallasTXUSA
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Xue WY, Zhang L, Liu CM, Gao Y, Li SJ, Huai ZY, Dai J, Wang YY. Research progress on the relationship between TM6SF2 rs58542926 polymorphism and non-alcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2022; 16:97-107. [PMID: 35057689 DOI: 10.1080/17474124.2022.2032661] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION nonalcoholic fatty liver disease is a common liver disease with a global average prevalence of about 25%. In addition to the incidence of NAFLD being related to obesity, diabetes, hyperlipidemia, etc., genetic factors also have an important impact on the incidence of NAFLD. AREAS COVERED Current experimental results and clinical studies show that the transmembrane 6 superfamily member 2 (TM6SF2) gene plays an important role in the pathogenesis of NAFLD. The research on genetic polymorphism of TM6SF2 gene mainly focuses on rs58542926 locus (rs58542926 c.449 C > T, p. Glu167Lys, E167K). The Mutations of this site might increase the risk of NAFLD in carriers. EXPERT OPINION The mutation of this site causes the disorder of triglyceride metabolism in the liver, which leads to the deposition of a large amount of lipids in the liver, and further induces the incidence of NAFLD. With the study of the mechanism of TM6SF2 gene polymorphism in the pathogenesis of NAFLD, it is helpful to understand the molecular mechanism of the pathogenesis of NAFLD, which has a great value for the treatment of NAFLD.
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Affiliation(s)
- Wan-Ying Xue
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Li Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Chuan-Miao Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yu Gao
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Shu-Jing Li
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Zi-You Huai
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Jing Dai
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
| | - Yuan-Yuan Wang
- School of Life Sciences, Bengbu Medical College, Bengbu, Anhui, China
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Common genetic variation in alcohol-related hepatocellular carcinoma: a case-control genome-wide association study. Lancet Oncol 2021; 23:161-171. [PMID: 34902334 DOI: 10.1016/s1470-2045(21)00603-3] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 10/03/2021] [Accepted: 10/15/2021] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatocellular carcinoma is a frequent consequence of alcohol-related liver disease, with variable incidence among heavy drinkers. We did a genome-wide association study (GWAS) to identify common genetic variants for alcohol-related hepatocellular carcinoma. METHODS We conducted a two-stage case-control GWAS in a discovery cohort of 2107 unrelated European patients with alcohol-related liver disease aged 20-92 years recruited between Oct 22, 1993, and March 12, 2017. Cases were patients with alcohol-related hepatocellular carcinoma diagnosed by imaging or histology. Controls were patients with alcohol-related liver disease without hepatocellular carcinoma. We used an additive logistic regression model adjusted for the first ten principal components to assess genetic variants associated with alcohol-related hepatocellular carcinoma. We did another analysis with adjustment for age, sex, and liver fibrosis. New candidate associations (p<1 × 10-6) and variants previously associated with alcohol-related hepatocellular carcinoma were evaluated in a validation cohort of 1933 patients with alcohol-related liver disease aged 29-92 years recruited between July 21, 1995, and May 2, 2019. We did a meta-analysis of the two case-control cohorts. FINDINGS The discovery cohort included 775 cases and 1332 controls. Of 7 962 325 variants assessed, we identified WNT3A-WNT9A (rs708113; p=1·11 × 10-8) and found support for previously reported regions associated with alcohol-related hepatocellular carcinoma risk at TM6SF2 (rs58542926; p=6·02 × 10-10), PNPLA3 (rs738409; p=9·29 × 10-7), and HSD17B13 (rs72613567; p=2·49 × 10-4). The validation cohort included 874 cases and 1059 controls and three variants were replicated: WNT3A-WNT9A (rs708113; p=1·17 × 10-3), TM6SF2 (rs58542926; p=4·06 × 10-5), and PNPLA3 (rs738409; p=1·17 × 10-4). All three variants reached GWAS significance in the meta-analysis: WNT3A-WNT9A (odds ratio 0·73, 95% CI 0·66-0·81; p=3·93 × 10-10), TM6SF2 (1·77, 1·52-2·07; p=3·84×10-13), PNPLA3 (1·34, 1·22-1·47; p=7·30 × 10-10). Adjustment for clinical covariates yielded similar results. We observed an additive effect of at-risk alleles on alcohol-related hepatocellular carcinoma. WNT3A-WNT9A rs708113 was not associated with liver fibrosis. INTERPRETATION WNT3A-WNT9A is a susceptibility locus for alcohol-related hepatocellular carcinoma, suggesting an early role of the Wnt-β-catenin pathway in alcohol-related hepatocellular carcinoma carcinogenesis. FUNDING Ligue Nationale contre le Cancer, Bpifrance, INSERM, AFEF, CARPEM, Labex OncoImmunology, and Agence Nationale de la Recherche.
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Wang Z, Budhu AS, Shen Y, Wong LL, Hernandez BY, Tiirikainen M, Ma X, Irwin ML, Lu L, Zhao H, Lim JK, Taddei T, Mishra L, Pawlish K, Stroup A, Brown R, Nguyen MH, Koshiol J, Hernandez MO, Forgues M, Yang H, Lee M, Huang Y, Iwasaki M, Goto A, Suzuki S, Matsuda K, Tanikawa C, Kamatani Y, Mann D, Guarnera M, Shetty K, Thomas CE, Yuan J, Khor CC, Koh W, Risch H, Wang XW, Yu H. Genetic susceptibility to hepatocellular carcinoma in chromosome 22q13.31, findings of a genome-wide association study. JGH Open 2021; 5:1363-1372. [PMID: 34950780 PMCID: PMC8674550 DOI: 10.1002/jgh3.12682] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 11/05/2021] [Accepted: 11/07/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIM Chronic hepatitis C virus (HCV) infection, long-term alcohol use, cigarette smoking, and obesity are the major risk factors for hepatocellular carcinoma (HCC) in the United States, but the disease risk varies substantially among individuals with these factors, suggesting host susceptibility to and gene-environment interactions in HCC. To address genetic susceptibility to HCC, we conducted a genome-wide association study (GWAS). METHODS Two case-control studies on HCC were conducted in the United States. DNA samples were genotyped using the Illumian microarray chip with over 710 000 single nucleotide polymorphisms (SNPs). We compared these SNPs between 705 HCC cases and 1455 population controls for their associations with HCC and verified our findings in additional studies. RESULTS In this GWAS, we found that two SNPs were associated with HCC at P < 5E-8 and six SNPs at P < 5E-6 after adjusting for age, sex, and the top three principal components (PCs). Five of the SNPs in chromosome 22q13.31, three in PNPLA3 (rs2281135, rs2896019, and rs4823173) and two in SAMM50 (rs3761472, rs3827385), were replicated in a small US case-control study and a cohort study in Singapore. The associations remained significant after adjusting for body mass index and HCV infection. Meta-analysis of multiple datasets indicated that these SNPs were significantly associated with HCC. CONCLUSIONS SNPs in PNPLA3 and SAMM50 are known risk loci for nonalcoholic fatty liver disease (NAFLD) and are suspected to be associated with HCC. Our GWAS demonstrated the associations of these SNPs with HCC in a US population. Biological mechanisms underlying the relationship remain to be elucidated.
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Affiliation(s)
- Zhanwei Wang
- University of Hawaii Cancer CenterHonoluluHawaiiUSA
| | - Anuradha S Budhu
- Laboratory of Human Carcinogenesis, Liver Cancer Program, Center for Cancer ResearchNational Cancer InstituteBethesdaMarylandUSA
| | - Yi Shen
- University of Hawaii Cancer CenterHonoluluHawaiiUSA
| | | | | | | | - Xiaomei Ma
- Yale School of Public HealthNew HavenConnecticutUSA
| | | | - Lingeng Lu
- Yale School of Public HealthNew HavenConnecticutUSA
| | - Hongyu Zhao
- Yale School of Public HealthNew HavenConnecticutUSA
| | | | | | - Lopa Mishra
- Center for Translational Medicine, Department of SurgeryThe George Washington UniversityWashingtonDistrict of ColumbiaUSA
| | - Karen Pawlish
- New Jersey State Cancer Registry, New Jersey Department of HealthTrentonNew JerseyUSA
| | - Antoinette Stroup
- Rutgers Cancer Institute, and Rutgers School of Public HealthNew BrunswickNew JerseyUSA
| | - Robert Brown
- Weill Cornell Medical College, and College of Physicians and Surgeons, Columbia UniversityNew YorkNew YorkUSA
| | - Mindie H Nguyen
- Division of Gastroenterology and HepatologyStanford University Medical CenterPalo AltoCaliforniaUSA
| | - Jill Koshiol
- Division of Cancer Epidemiology and GeneticsNational Cancer InstituteBethesdaMarylandUSA
| | - Maria O Hernandez
- Laboratory of Human CarcinogenesisCenter for Cancer Research, National Cancer InstituteBethesdaMarylandUSA
| | - Marshonna Forgues
- Laboratory of Human CarcinogenesisCenter for Cancer Research, National Cancer InstituteBethesdaMarylandUSA
| | - Hwai‐I Yang
- Genomics Research Center, Academia SinicaTaipeiTaiwan
- Institute of Clinical Medicine, National Yang Ming UniversityTaipeiTaiwan
| | - Mei‐Hsuan Lee
- Institute of Clinical Medicine, National Yang Ming UniversityTaipeiTaiwan
| | - Yu‐Han Huang
- Institute of Clinical Medicine, National Yang Ming UniversityTaipeiTaiwan
| | - Motoki Iwasaki
- Division of EpidemiologyCenter for Public Health Sciences, National Cancer CenterTokyoJapan
| | - Atsushi Goto
- Division of EpidemiologyCenter for Public Health Sciences, National Cancer CenterTokyoJapan
| | - Shiori Suzuki
- Division of EpidemiologyCenter for Public Health Sciences, National Cancer CenterTokyoJapan
| | - Koichi Matsuda
- Graduate School of Frontier Sciences, and Institute of Medical Science, University of TokyoTokyoJapan
| | - Chizu Tanikawa
- Graduate School of Frontier Sciences, and Institute of Medical Science, University of TokyoTokyoJapan
| | - Yoichiro Kamatani
- Graduate School of Frontier Sciences, and Institute of Medical Science, University of TokyoTokyoJapan
| | - Dean Mann
- Department of PathologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Maria Guarnera
- Department of PathologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Kirti Shetty
- Department of Gastroenterology and HepatologyUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Claire E Thomas
- Division of Cancer Control and Population SciencesUniversity of Pittsburgh Medical Center (UPMC) Hillman Cancer CenterPittsburghPennsylvaniaUSA
- Department of EpidemiologyGraduate School of Public Health, University of PittsburghPittsburghPennsylvaniaUSA
| | - Jian‐Min Yuan
- Division of Cancer Control and Population SciencesUniversity of Pittsburgh Medical Center (UPMC) Hillman Cancer CenterPittsburghPennsylvaniaUSA
- Department of EpidemiologyGraduate School of Public Health, University of PittsburghPittsburghPennsylvaniaUSA
| | - Chiea Chuen Khor
- Genome Institute of Singapore, Agency for Science, Technology and ResearchSingaporeSingapore
- Singapore Eye Research InstituteSingaporeSingapore
| | - Woon‐Puay Koh
- Health Systems and Services Research, Duke‐NUS Medical School SingaporeSingaporeSingapore
- Saw Swee Hock School of Public Health, National University of SingaporeSingaporeSingapore
| | - Harvey Risch
- Yale School of Public HealthNew HavenConnecticutUSA
| | - Xin Wei Wang
- Laboratory of Human Carcinogenesis, Liver Cancer Program, Center for Cancer ResearchNational Cancer InstituteBethesdaMarylandUSA
| | - Herbert Yu
- University of Hawaii Cancer CenterHonoluluHawaiiUSA
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Bainrauch A, Šisl D, Markotić A, Ostojić A, Gašparov S, Bralić Lang V, Kovačić N, Grčević D, Mrzljak A, Kelava T. NOTCH3 rs1043996 Polymorphism Is Associated with the Occurrence of Alcoholic Liver Cirrhosis Independently of PNPLA3 and TM6SF2 Polymorphisms. J Clin Med 2021; 10:4621. [PMID: 34640639 PMCID: PMC8509578 DOI: 10.3390/jcm10194621] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/22/2021] [Accepted: 10/05/2021] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver cirrhosis (ALC) is the most common indication for liver transplantation (LT) in Croatia and presents a risk factor for the development of hepatocellular carcinoma (HCC). However, genetic susceptibility has not yet been systematically studied. We aimed to investigate the contribution of the risk polymorphisms PNPLA3 rs738409, EGF rs4444903, TM6SF2 rs58542926, MTHFR rs1801133, previously identified in other populations and, additionally, the contribution of Notch-related polymorphisms (NOTCH1 rs3124591, NOTCH3 rs1043996 and rs1044116, NOTCH4 rs422951). The study included 401 patients. The ALC group consisted of 260 LT candidates, 128 of whom had histopathologically confirmed HCC, and 132 of whom were without HCC. The control group included 141 patients without liver disease. Genotyping was performed by PCR using Taqman assays. The patients' susceptibility to ALC was significantly associated with PNPLA3 rs738409, TM6SF2 rs58542926, and NOTCH3 rs1043996 polymorphisms. These polymorphisms remained significantly associated with ALC occurrence in a logistic regression model, even after additional model adjustment for sex and age. Cirrhotic patients with the PNPLA3 GG genotype demonstrated higher activity of ALT aminotransferases than patients with CC or CG genotypes. The susceptibility to the development of HCC in ALC was significantly associated with PNPLA3 rs738409 and EGF rs4444903 polymorphisms, and logistic regression confirmed these polymorphisms as independent predictors.
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Affiliation(s)
- Ana Bainrauch
- Department of Internal Medicine, Merkur University Hospital, 10000 Zagreb, Croatia;
| | - Dino Šisl
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb, 10000 Zagreb, Croatia; (D.Š.); (N.K.); (D.G.)
- Department of Physiology and Immunology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Antonio Markotić
- Department of Physiology, School of Medicine, University of Mostar, 88000 Mostar, Bosnia and Herzegovina;
- Center for Clinical Pharmacology, University Clinical Hospital Mostar, 88000 Mostar, Bosnia and Herzegovina
| | - Ana Ostojić
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, University of Zagreb, 10000 Zagreb, Croatia;
| | - Slavko Gašparov
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
- Department of Pathology and Cytology, Merkur University Hospital, 10000 Zagreb, Croatia
| | | | - Nataša Kovačić
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb, 10000 Zagreb, Croatia; (D.Š.); (N.K.); (D.G.)
- Department of Anatomy, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Danka Grčević
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb, 10000 Zagreb, Croatia; (D.Š.); (N.K.); (D.G.)
- Department of Physiology and Immunology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, University of Zagreb, 10000 Zagreb, Croatia;
- School of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Tomislav Kelava
- Laboratory for Molecular Immunology, Croatian Institute for Brain Research, University of Zagreb, 10000 Zagreb, Croatia; (D.Š.); (N.K.); (D.G.)
- Department of Physiology and Immunology, School of Medicine, University of Zagreb, 10000 Zagreb, Croatia
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Meroni M, Longo M, Tria G, Dongiovanni P. Genetics Is of the Essence to Face NAFLD. Biomedicines 2021; 9:1359. [PMID: 34680476 PMCID: PMC8533437 DOI: 10.3390/biomedicines9101359] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 09/27/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the commonest cause of chronic liver disease worldwide. It is closely related to obesity, insulin resistance (IR) and dyslipidemia so much so it is considered the hepatic manifestation of the Metabolic Syndrome. The NAFLD spectrum extends from simple steatosis to nonalcoholic steatohepatitis (NASH), a clinical condition which may progress up to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). NAFLD is a complex disease whose pathogenesis is shaped by both environmental and genetic factors. In the last two decades, several heritable modifications in genes influencing hepatic lipid remodeling, and mitochondrial oxidative status have been emerged as predictors of progressive hepatic damage. Among them, the patatin-like phospholipase domain-containing 3 (PNPLA3) p.I148M, the Transmembrane 6 superfamily member 2 (TM6SF2) p.E167K and the rs641738 membrane bound-o-acyltransferase domain-containing 7 (MBOAT7) polymorphisms are considered the most robust modifiers of NAFLD. However, a forefront frontier in the study of NAFLD heritability is to postulate score-based strategy, building polygenic risk scores (PRS), which aggregate the most relevant genetic determinants of NAFLD and biochemical parameters, with the purpose to foresee patients with greater risk of severe NAFLD, guaranteeing the most highly predictive value, the best diagnostic accuracy and the more precise individualized therapy.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
- Department of Clinical Sciences and Community Health, Università Degli Studi di Milano, 20122 Milano, Italy
| | - Giada Tria
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Pad. Granelli, Via F Sforza 35, 20122 Milan, Italy; (M.M.); (M.L.); (G.T.)
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Newberry EP, Hall Z, Xie Y, Molitor EA, Bayguinov PO, Strout GW, Fitzpatrick JA, Brunt EM, Griffin JL, Davidson NO. Liver-Specific Deletion of Mouse Tm6sf2 Promotes Steatosis, Fibrosis, and Hepatocellular Cancer. Hepatology 2021; 74:1203-1219. [PMID: 33638902 PMCID: PMC8390580 DOI: 10.1002/hep.31771] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 12/17/2020] [Accepted: 01/13/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Human transmembrane 6 superfamily 2 (TM6SF2) variant rs58542926 is associated with NAFLD and HCC. However, conflicting reports in germline Tm6sf2 knockout mice suggest no change or decreased very low density lipoprotein (VLDL) secretion and either unchanged or increased hepatic steatosis, with no increased fibrosis. We generated liver-specific Tm6Sf2 knockout mice (Tm6 LKO) to study VLDL secretion and the impact on development and progression of NAFLD. APPROACH AND RESULTS Two independent lines of Tm6 LKO mice exhibited spontaneous hepatic steatosis. Targeted lipidomic analyses showed increased triglyceride species whose distribution and abundance phenocopied findings in mice with liver-specific deletion of microsomal triglyceride transfer protein. The VLDL triglyceride secretion was reduced with small, underlipidated particles and unchanged or increased apolipoprotein B. Liver-specific adeno-associated viral, serotype 8 (AAV8) rescue using either wild-type or mutant E167K-Tm6 reduced hepatic steatosis and improved VLDL secretion. The Tm6 LKO mice fed a high milk-fat diet for 3 weeks exhibited increased steatosis and fibrosis, and those phenotypes were further exacerbated when mice were fed fibrogenic, high fat/fructose diets for 20 weeks. In two models of HCC, either neonatal mice injected with streptozotocin (NASH/STAM) and high-fat fed or with diethylnitrosamine injection plus fibrogenic diet feeding, Tm6 LKO mice exhibited increased steatosis, greater tumor burden, and increased tumor area versus Tm6 flox controls. Additionally, diethylnitrosamine-injected and fibrogenic diet-fed Tm6 LKO mice administered wild-type Tm6 or E167K-mutant Tm6 AAV8 revealed significant tumor attenuation, with tumor burden inversely correlated with Tm6 protein levels. CONCLUSIONS Liver-specific Tm6sf2 deletion impairs VLDL secretion, promoting hepatic steatosis, fibrosis, and accelerated development of HCC, which was mitigated with AAV8- mediated rescue.
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Affiliation(s)
- Elizabeth P. Newberry
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Zoe Hall
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
- Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Yan Xie
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Elizabeth A. Molitor
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
| | - Peter O. Bayguinov
- Washington University Center for Cellular Imaging, Washington University in Saint Louis, St. Louis, MO 63130
| | - Gregory W. Strout
- Washington University Center for Cellular Imaging, Washington University in Saint Louis, St. Louis, MO 63130
| | - James A.J. Fitzpatrick
- Washington University Center for Cellular Imaging, Washington University in Saint Louis, St. Louis, MO 63130
- Departments of Cell Biology & Physiology and Neuroscience, Washington University School of Medicine, Louis, St. Louis, MO 63130
- Department of Biomedical Engineering, Washington University in Saint Louis, St. Louis, MO 63130
| | - Elizabeth M. Brunt
- Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
| | - Julian L. Griffin
- Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United Kingdom
- Biomolecular Medicine, Division of Systems Medicine, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
| | - Nicholas O. Davidson
- Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110
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Protopapas AA, Cholongitas E, Chrysavgis L, Tziomalos K. Alcohol consumption in patients with nonalcoholic fatty liver disease: yes, or no? Ann Gastroenterol 2021; 34:476-486. [PMID: 34276185 PMCID: PMC8276351 DOI: 10.20524/aog.2021.0641] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 03/03/2021] [Indexed: 02/06/2023] Open
Abstract
Excessive alcohol intake is an established risk factor for chronic liver disease. At the same time, moderate alcohol intake appears to reduce cardiovascular morbidity. Accordingly, recommendations for alcohol intake in patients with nonalcoholic fatty liver disease (NAFLD), who are at increased risk for liver-related and cardiovascular events, are a point of debate. Some studies have shown beneficial effects of alcohol on cardiovascular and overall mortality in this specific subset of patients. Nonetheless, even light alcohol intake appears to aggravate liver disease and increase the risk of hepatocellular cancer. Therefore, patients with nonalcoholic steatohepatitis or advanced fibrosis should be advised against consuming alcohol. On the other hand, only light alcohol consumption (<10 g/day) might be permitted in patients without significant hepatic fibrosis, provided that they are carefully followed-up. As the research field focusing on NAFLD keeps widening, more prospective studies regarding this specific subject are expected, and may provide a basis for less ambiguous recommendations.
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Affiliation(s)
- Adonis A. Protopapas
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki (Adonis A. Protopapas, Konstantinos Tziomalos)
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens (Evangelos Cholongitas, Lampros Chrysavgis), Greece
| | - Lampros Chrysavgis
- First Department of Internal Medicine, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens (Evangelos Cholongitas, Lampros Chrysavgis), Greece
| | - Konstantinos Tziomalos
- First Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki (Adonis A. Protopapas, Konstantinos Tziomalos)
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Diagnosis and management of secondary causes of steatohepatitis. J Hepatol 2021; 74:1455-1471. [PMID: 33577920 DOI: 10.1016/j.jhep.2021.01.045] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 01/09/2021] [Accepted: 01/25/2021] [Indexed: 02/06/2023]
Abstract
The term non-alcoholic fatty liver disease (NAFLD) was originally coined to describe hepatic fat deposition as part of the metabolic syndrome. However, a variety of rare hereditary liver and metabolic diseases, intestinal diseases, endocrine disorders and drugs may underlie, mimic, or aggravate NAFLD. In contrast to primary NAFLD, therapeutic interventions are available for many secondary causes of NAFLD. Accordingly, secondary causes of fatty liver disease should be considered during the diagnostic workup of patients with fatty liver disease, and treatment of the underlying disease should be started to halt disease progression. Common genetic variants in several genes involved in lipid handling and metabolism modulate the risk of progression from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma development in NAFLD, alcohol-related liver disease and viral hepatitis. Hence, we speculate that genotyping of common risk variants for liver disease progression may be equally useful to gauge the likelihood of developing advanced liver disease in patients with secondary fatty liver disease.
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Liu SY, Tsai IT, Hsu YC. Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives. Int J Mol Sci 2021; 22:5170. [PMID: 34068269 PMCID: PMC8153142 DOI: 10.3390/ijms22105170] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 05/07/2021] [Accepted: 05/12/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD.
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Affiliation(s)
- Szu-Yi Liu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
| | - I-Ting Tsai
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
| | - Yin-Chou Hsu
- Department of Emergency Medicine, E-Da Hospital, I-Shou University, Kaohsiung 82445, Taiwan; (S.-Y.L.); (I.-T.T.)
- School of Medicine for International Student, I-Shou University, Kaohsiung 82445, Taiwan
- School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung 82445, Taiwan
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Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021; 184:2537-2564. [PMID: 33989548 DOI: 10.1016/j.cell.2021.04.015] [Citation(s) in RCA: 1135] [Impact Index Per Article: 283.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 03/21/2021] [Accepted: 04/09/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide. Its more advanced subtype, nonalcoholic steatohepatitis (NASH), connotes progressive liver injury that can lead to cirrhosis and hepatocellular carcinoma. Here we provide an in-depth discussion of the underlying pathogenetic mechanisms that lead to progressive liver injury, including the metabolic origins of NAFLD, the effect of NAFLD on hepatic glucose and lipid metabolism, bile acid toxicity, macrophage dysfunction, and hepatic stellate cell activation, and consider the role of genetic, epigenetic, and environmental factors that promote fibrosis progression and risk of hepatocellular carcinoma in NASH.
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Affiliation(s)
- Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
| | - Scott L Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Gerald I Shulman
- Departments of Internal Medicine and Cellular & Molecular Physiology, Yale Diabetes Research Center, Yale School of Medicine, New Haven, CT 06520, USA.
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Oliveira AIN, Malta FM, Zitelli PMY, Salles APM, Gomes-Gouvea MS, Nastri ACS, Pinho JRR, Carrilho FJ, Oliveira CP, Mendes-Corrêa MC, Pessoa MG, Mazo DF. The role of PNPLA3 and TM6SF2 polymorphisms on liver fibrosis and metabolic abnormalities in Brazilian patients with chronic hepatitis C. BMC Gastroenterol 2021; 21:81. [PMID: 33622266 PMCID: PMC7901065 DOI: 10.1186/s12876-021-01654-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/07/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Despite the growing body of knowledge about TM6SF2 and PNPLA3 polymorphisms in non-alcoholic fatty liver disease, their influence in the spectrum of HCV liver disease is not yet fully defined. Besides that, admixed populations, such as Brazilians, were not included in most of the studies. METHODS This cross-sectional study enrolled 365 treatment-naïve patients with HCV and 134 healthy individuals. TM6SF2 (rs58542926 c.499C > T) and PNPLA3 (rs738409 c.444C > G) polymorphisms were evaluated regarding their association with clinical and laboratory data, histological liver steatosis and fibrosis, and with components of the metabolic syndrome. RESULTS In HCV subjects, the frequencies of TM6SF2 CC and CT + TT were 89% and 11%, while PNPLA3 frequencies of CC and CG + GG were 51.4% and 48.6%. In the univariate logistic regression analysis, the TM6SF2 CT + TT genotype in HCV was associated with significant liver fibrosis (p = 0.047; OR 1.953; 95% CI 1.009-3.788). In comparison to the CT + TT genotype, the TM6SF2 CC genotype in HCV was associated with older age (p = 0.002), higher frequency of arterial hypertension (p = 0.032), obesity (p = 0.030), metabolic syndrome (p = 0.014) and lower total cholesterol levels (p = 0.036). The PNPLA3 GG subjects had lower body mass index than CG/ CC individuals (p = 0.047). None of the polymorphisms, or their combinations, was independently associated with hepatic steatosis or fibrosis. On the other hand, older age, lower serum levels of total cholesterol, and higher serum levels of alanine aminotransferase and alkaline phosphatase were associated with liver fibrosis in the multivariate logistic regression analysis. CONCLUSION In this evaluation of an admixed HCV population, neither TM6SF2 nor PNPLA3 polymorphisms were independently associated with hepatic steatosis or fibrosis. Other factors seem more influential than these specific polymorphisms in isolation. More studies are warranted to clarify the role of the TM6SF2 and PNPLA3 polymorphisms in Brazilians with HCV.
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Affiliation(s)
- Arthur Ivan N Oliveira
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Fernanda M Malta
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Patricia Momoyo Y Zitelli
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Ana Paula M Salles
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Michele S Gomes-Gouvea
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Ana Catharina S Nastri
- Department of Infectious Diseases, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, São Paulo, 05403-900, Brazil
| | - Joao Renato R Pinho
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Flair J Carrilho
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Claudia P Oliveira
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Maria Cássia Mendes-Corrêa
- Department of Infectious Diseases, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, São Paulo, 05403-900, Brazil
| | - Mario G Pessoa
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil
| | - Daniel F Mazo
- Division of Clinical Gastroenterology and Hepatology, LIM07, Department of Gastroenterology, University of São Paulo School of Medicine (FMUSP), Av. Dr. Enéas de Carvalho Aguiar no 255, Instituto Central, # 9159, São Paulo, 05403-900, Brazil.
- Division of Gastroenterology (Gastrocentro), School of Medical Sciences, University of Campinas (UNICAMP), Rua Carlos Chagas no 420, Campinas, 13083-878, Brazil.
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Shi T, Kobara H, Oura K, Masaki T. Mechanisms Underlying Hepatocellular Carcinoma Progression in Patients with Type 2 Diabetes. J Hepatocell Carcinoma 2021; 8:45-55. [PMID: 33604315 PMCID: PMC7886236 DOI: 10.2147/jhc.s274933] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 01/25/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths from solid tumors worldwide. The incidence of type 2 diabetes mellitus (T2DM) has increased worldwide in conjunction with the expansion of the Western lifestyle. Furthermore, patients with T2DM have been documented to have an increased risk of HCC, as well as bile tract cancer. Growing evidence shows that T2DM is a strong additive metabolic risk factor for HCC, but how diabetes affects the incidence of HCC requires additional investigation. In this review, we discuss the underlying mechanisms of HCC in patients with T2DM. Topics covered include abnormal glucose and lipid metabolism, hyperinsulinemia, and insulin resistance; the effect of activated platelets; hub gene expression associated with HCC; inflammation and signaling pathways; miRNAs; altered gut microbiota and immunomodulation. The evidence suggests that reducing obesity, diabetes, and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis through efficient measures of prevention may lead to decreased rates of T2DM-related HCC.
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Affiliation(s)
- Tingting Shi
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Hideki Kobara
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Kyoko Oura
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
| | - Tsutomu Masaki
- Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Kida, Kagawa, 761-0793, Japan
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