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Chen R, Petrazzini BO, Duffy Á, Rocheleau G, Jordan D, Bansal M, Do R. Trans-ancestral rare variant association study with machine learning-based phenotyping for metabolic dysfunction-associated steatotic liver disease. Genome Biol 2025; 26:50. [PMID: 40065360 PMCID: PMC11892324 DOI: 10.1186/s13059-025-03518-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 02/26/2025] [Indexed: 03/14/2025] Open
Abstract
BACKGROUND Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case-control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power. RESULTS The trans-ancestral meta-analysis with PDFF and MASLD case-control status identifies two single variants and two gene-level associations in APOB, CDH5, MYCBP2, and XAB2. Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis (APOB, G6PC1, PPARG), 4 were previously associated with MASLD (APOB, APOC3, INSR, PPARG), and 23 had supporting clinical, experimental, and/or genetic evidence. CONCLUSIONS Our results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks.
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Affiliation(s)
- Robert Chen
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ben Omega Petrazzini
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Genomic Data Analytics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Áine Duffy
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Genomic Data Analytics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ghislain Rocheleau
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Genomic Data Analytics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Daniel Jordan
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Center for Genomic Data Analytics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Meena Bansal
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ron Do
- The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Center for Genomic Data Analytics, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Geng W, Liao W, Cao X, Yang Y. Therapeutic Targets and Approaches to Manage Inflammation of NAFLD. Biomedicines 2025; 13:393. [PMID: 40002806 PMCID: PMC11853636 DOI: 10.3390/biomedicines13020393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2024] [Revised: 01/18/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its advanced form, non-alcoholic steatohepatitis (NASH), are the leading causes of chronic liver disease globally. They are driven by complex mechanisms where inflammation plays a pivotal role in disease progression. Current therapies, including lifestyle changes and pharmacological agents, are limited in efficacy, particularly in addressing the advanced stages of the disease. Emerging approaches targeting inflammation, metabolic dysfunction, and fibrosis offer promising new directions, though challenges such as treatment complexity and heterogeneity persist. This review concludes the main therapeutic targets and approaches to manage inflammation currently and emphasizes the critical need for future drug development and combination therapy for NAFLD/NASH management.
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Affiliation(s)
- Wanying Geng
- 4+4 Medical Doctor Program, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China;
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Wanying Liao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Xinyuan Cao
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
| | - Yingyun Yang
- Department of Gastroenterology, Department of Internal Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100730, China; (W.L.); (X.C.)
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Jiménez-Luévano MÁ, Jiménez-Partida AE, Sierra-Díaz E, Orozco-Alonso E, Villaseñor-García M, Bravo-Hernández A, Gutiérrez-Ortíz JA, Bravo-Cuellar A, Hernández-Flores G. Prolonged use of pentoxifylline increases the life expectancy of patients with compensated cirrhosis: A 20‑year retrospective study. Biomed Rep 2024; 21:173. [PMID: 39355527 PMCID: PMC11443491 DOI: 10.3892/br.2024.1861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 07/29/2024] [Indexed: 10/03/2024] Open
Abstract
Liver cirrhosis is a pathology of varied etiology with a high prevalence and mortality, resulting in >1 million mortalities per year. Patients with liver cirrhosis typically have a survival time of 12 years following diagnosis. The treatment for this disease is directed at the complications of cirrhosis; however, to the best of our knowledge, the long-term management of patients with cirrhosis has been scarcely studied. Pentoxifylline (PTX) is a non-selective phosphodiesterase inhibitor with rheological activity and antioxidant, anti-inflammatory and antifibrotic properties. PTX has been used in the treatment of peripheral arterial disease, inflammatory liver diseases and hepatocellular carcinoma with encouraging results. The aim of the present study was to evaluate the effect of PTX use on the survival of patients with compensated cirrhosis. For this purpose, a cross-sectional study was performed at the Gastroenterology and Hepatitis C Department of Dr. Valentín Gómez Farias Hospital (Institute for Security and Social Services for State Workers, Zapopan, Mexico) from June, 1996 to December, 2019. The follow-up time for these patients was 22.6 years (up to the end of the study period). In the present study, 326 patient files were analyzed and 118 patients with the disease were identified, 81 of whom (68.64%) died within 12 years after diagnosis. Of the included patients, 26 received PTX combined with PEG IFN-α-2a plus ribavirin, and 11 received PTX plus propranolol, with a median treatment duration of 20.6±0.8 years. Furthermore, 16 patients (43%) did not develop co-morbidities within this time, and the transition to decompensated cirrhosis was 16.6 years, with a survival time of 20 years. Therefore, the results of the present study suggest that PTX may improve the long-term survival of patients with compensated cirrhosis, rendering PTX a candidate for repurposing in the treatment of hepatic cirrhosis.
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Affiliation(s)
- Miguel Ángel Jiménez-Luévano
- Gastroenterology Service, Institute for Security and Social Services for State Workers, Valentín Gómez Farías General Hospital, Zapopan, Jalisco 45100, Mexico
| | - Ana Emilia Jiménez-Partida
- Gastroenterology Service, Institute for Security and Social Services for State Workers, Valentín Gómez Farías General Hospital, Zapopan, Jalisco 45100, Mexico
| | - Erick Sierra-Díaz
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Eduardo Orozco-Alonso
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
| | - Martha Villaseñor-García
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
- University Center of Exact Sciences and Engineering, University of Guadalajara, Guadalajara, Jalisco 44840, Mexico
| | - Alejandro Bravo-Hernández
- Internal Medicine Service, Antonio González Guevara Civil Hospital, Tepic, Nayarit 63000, Mexico
- Program in Internal Medicine, The Autonomous University of Nayarit, Tepic, Nayarit 63000, Mexico
| | - Jesús Alejandro Gutiérrez-Ortíz
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
- Doctoral Program in Biomedical Science Orientation Immunology, University Center for Health Science, University of Guadalajara, Guadalajara, Jalisco 44340, Mexico
| | - Alejandro Bravo-Cuellar
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
- Department of Health Sciences, Los Altos University Center, University of Guadalajara, Tepatitlán de Morelos, Jalisco 47620, Mexico
| | - Georgina Hernández-Flores
- Division of Immunology, Western Biomedical Research Center, Mexican Social Security Institute, Guadalajara, Jalisco 44340, Mexico
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Vachliotis ID, Polyzos SA. The Role of Tumor Necrosis Factor-Alpha in the Pathogenesis and Treatment of Nonalcoholic Fatty Liver Disease. Curr Obes Rep 2023; 12:191-206. [PMID: 37407724 PMCID: PMC10482776 DOI: 10.1007/s13679-023-00519-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/20/2023] [Indexed: 07/07/2023]
Abstract
PURPOSE OF REVIEW To summarize experimental and clinical evidence on the association between tumor necrosis factor-α (TNF-α) and nonalcoholic fatty liver disease (NAFLD) and discuss potential treatment considerations. RECENT FINDINGS Experimental evidence suggests that TNF-α is a cytokine with a critical role in the pathogenesis of NAFLD. Although, the production of TNF-α may be an early event during the course of nonalcoholic fatty liver (NAFL), TNF-α may play a more substantial role in the pathogenesis of nonalcoholic steatohepatitis (NASH) and NAFLD-associated fibrosis. Moreover, TNF-α may potentiate hepatic insulin resistance, thus interconnecting inflammatory with metabolic signals and possibly contributing to the development of NAFLD-related comorbidities, including cardiovascular disease, hepatocellular carcinoma, and extra-hepatic malignancies. In clinical terms, TNF-α is probably associated with the severity of NAFLD; circulating TNF-α gradually increases from controls to patients with NAFL, and then, to patients with NASH. Given this potential association, various therapeutic interventions (obeticholic acid, peroxisome proliferator-activated receptors, sodium-glucose co-transporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, probiotics, synbiotics, rifaximin, vitamin E, pentoxifylline, ursodeoxycholic acid, fibroblast growth factor-21, n-3 polyunsaturated fatty acids, statins, angiotensin receptor blockers) have been evaluated for their effect on TNF-α and NAFLD. Interestingly, anti-TNF biologics have shown favorable metabolic and hepatic effects, which may open a possible therapeutic window for the management of advanced NAFLD. The potential key pathogenic role of TNF-α in NAFLD warrants further investigation and may have important diagnostic and therapeutic implications.
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Affiliation(s)
- Ilias D. Vachliotis
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- Second Department of Internal Medicine, 424 General Military Hospital, Thessaloniki, Greece
| | - Stergios A. Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
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Basha A, May SC, Anderson RM, Samala N, Mirmira RG. Non-Alcoholic Fatty Liver Disease: Translating Disease Mechanisms into Therapeutics Using Animal Models. Int J Mol Sci 2023; 24:9996. [PMID: 37373143 PMCID: PMC10298283 DOI: 10.3390/ijms24129996] [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: 05/17/2023] [Revised: 06/06/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a range of pathologies arising from fat accumulation in the liver in the absence of excess alcohol use or other causes of liver disease. Its complications include cirrhosis and liver failure, hepatocellular carcinoma, and eventual death. NAFLD is the most common cause of liver disease globally and is estimated to affect nearly one-third of individuals in the United States. Despite knowledge that the incidence and prevalence of NAFLD are increasing, the pathophysiology of the disease and its progression to cirrhosis remain insufficiently understood. The molecular pathogenesis of NAFLD involves insulin resistance, inflammation, oxidative stress, and endoplasmic reticulum stress. Better insight into these molecular pathways would allow for therapies that target specific stages of NAFLD. Preclinical animal models have aided in defining these mechanisms and have served as platforms for screening and testing of potential therapeutic approaches. In this review, we will discuss the cellular and molecular mechanisms thought to contribute to NAFLD, with a focus on the role of animal models in elucidating these mechanisms and in developing therapies.
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Affiliation(s)
- Amina Basha
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Sarah C. May
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Ryan M. Anderson
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
| | - Niharika Samala
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Raghavendra G. Mirmira
- Kovler Diabetes Center, Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Department of Medicine, The University of Chicago, Chicago, IL 60637, USA
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Cernea S, Onișor D. Screening and interventions to prevent nonalcoholic fatty liver disease/nonalcoholic steatohepatitis-associated hepatocellular carcinoma. World J Gastroenterol 2023; 29:286-309. [PMID: 36687124 PMCID: PMC9846941 DOI: 10.3748/wjg.v29.i2.286] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/06/2022] [Accepted: 12/21/2022] [Indexed: 01/06/2023] Open
Abstract
Liver cancer is the sixth most commonly diagnosed cancer worldwide, with hepatocellular carcinoma (HCC) comprising most cases. Besides hepatitis B and C viral infections, heavy alcohol use, and nonalcoholic steatohepatitis (NASH)-associated advanced fibrosis/cirrhosis, several other risk factors for HCC have been identified (i.e. old age, obesity, insulin resistance, type 2 diabetes). These might in fact partially explain the occurrence of HCC in non-cirrhotic patients without viral infection. HCC surveillance through effective screening programs is still an unmet need for many nonalcoholic fatty liver disease (NAFLD) patients, and identification of pre-cirrhotic individuals who progress to HCC represents a substantial challenge in clinical practice at the moment. Patients with NASH-cirrhosis should undergo systematic HCC surveillance, while this might be considered in patients with advanced fibrosis based on individual risk assessment. In this context, interventions that potentially prevent NAFLD/ NASH-associated HCC are needed. This paper provided an overview of evidence related to lifestyle changes (i.e. weight loss, physical exercise, adherence to healthy dietary patterns, intake of certain dietary components, etc.) and pharmacological interventions that might play a protective role by targeting the underlying causative factors and pathogenetic mechanisms. However, well-designed prospective studies specifically dedicated to NAFLD/NASH patients are still needed to clarify the relationship with HCC risk.
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Affiliation(s)
- Simona Cernea
- Department M3/Internal Medicine I, George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureș, Târgu Mureş 540139, Romania
- Diabetes, Nutrition and Metabolic Diseases Outpatient Unit, Emergency County Clinical Hospital, Târgu Mureş 540136, Romania
| | - Danusia Onișor
- Department ME2/Internal Medicine VII, George Emil Palade University of Medicine, Pharmacy, Science, and Technology of Târgu Mureş, Târgu Mureş 540139, Romania
- Gastroenterology Department, Mureș County Clinical Hospital, Târgu Mureș 540072, Romania
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Moosaie F, Rabizadeh S, Fallahzadeh A, Sheikhy A, Meysamie A, Dehghani Firouzabadi F, Nakhjavani M, Esteghamati A. Effects of Pentoxifylline on Serum Markers of Diabetic Nephropathy in Type 2 Diabetes. Diabetes Ther 2022; 13:1023-1036. [PMID: 35380410 PMCID: PMC9076784 DOI: 10.1007/s13300-022-01250-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 03/08/2022] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE To investigate the effects of pentoxifylline (PTX) in combination with losartan compared to the high dose of losartan alone on serum markers of diabetic nephropathy such as HSP70, copeptin, CRP, and TNFα in patients with type 2 diabetes and nephropathy. METHODS A single-center, randomized, double-blind, open-label clinical trial was conducted. Sixty-two patients were eligible and allocated to "PTX + losartan" and "high-dose losartan" arms of the trial using software for random number generation. The first arm received 400 mg PTX two times a day (BD) plus 50 mg losartan daily, while the second arm received 50 mg losartan two times a day (BD) for 12 weeks. Comparison of the biomarkers' levels before and after treatment was done using paired sample t test variance. ANCOVA was applied to evaluate the comparative efficacy of the two interventions. The effect size was calculated and reported for each biomarker. RESULTS Urine albumin excretion (UAE), hs-CRP, and HbA1c significantly decreased in both trial arms compared to the baseline measures. Copeptin and TNFα showed significant differences (after vs before) only in the losartan group (p = 0.017 and p = 0.043, respectively). The losartan arm was more successful in reducing TNFα, copeptin, HSP70, systolic blood pressure (SBP), and diastolic blood pressure (DBP) values (p = 0.045, effect size = 7.3%; p = 0.018, effect size 10.1%; p = 0.046, effect size 4.7%, p = 0.001, effect size 23%; p = 0.012, effect size 10.2%, respectively) and the PTX arm was associated with a superior reduction of UAE and hs-CRP levels (p = 0.018, effect size 9.1%; p = 0.028, effect size 9.2%, respectively). CONCLUSION Add-on PTX to losartan may have more effective anti-inflammatory and anti-albuminuric roles and therefore may be more applicable in the management of diabetic nephropathy compared with high-dose losartan alone. TRAIL REGISTRATION Trial number IRCT 20121104011356N10.
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Affiliation(s)
- Fatemeh Moosaie
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Soghra Rabizadeh
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Aida Fallahzadeh
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Ali Sheikhy
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Alipasha Meysamie
- Department of Community Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Dehghani Firouzabadi
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Manouchehr Nakhjavani
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran
| | - Alireza Esteghamati
- Endocrinology and Metabolism Research Center (EMRC), Vali-Asr Hospital, School of Medicine, Tehran University of Medical Sciences, P.O. Box 13145-784, Tehran, Iran.
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Chan W, Tan S, Chan S, Lee Y, Tee H, Mahadeva S, Goh K, Ramli AS, Mustapha F, Kosai NR, Raja Ali RA. Malaysian Society of Gastroenterology and Hepatology consensus statement on metabolic dysfunction-associated fatty liver disease. J Gastroenterol Hepatol 2022; 37:795-811. [PMID: 35080048 PMCID: PMC9303255 DOI: 10.1111/jgh.15787] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/19/2021] [Accepted: 01/10/2022] [Indexed: 12/19/2022]
Abstract
The Malaysian Society of Gastroenterology and Hepatology saw the need for a consensus statement on metabolic dysfunction-associated fatty liver disease (MAFLD). The consensus panel consisted of experts in the field of gastroenterology/hepatology, endocrinology, bariatric surgery, family medicine, and public health. A modified Delphi process was used to prepare the consensus statements. The panel recognized the high and increasing prevalence of the disease and the consequent anticipated increase in liver-related complications and mortality. Cardiovascular disease is the leading cause of mortality in MAFLD patients; therefore, cardiovascular disease risk assessment and management is important. A simple and clear liver assessment and referral pathway was agreed upon, so that patients with more severe MAFLD can be linked to gastroenterology/hepatology care, while patients with less severe MAFLD can remain in primary care or endocrinology, where they are best managed. Lifestyle intervention is the cornerstone in the management of MAFLD. The panel provided a consensus on the use of statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, sodium-glucose cotransporter-2 inhibitor, glucagon-like peptide-1 agonist, pioglitazone, vitamin E, and metformin, as well as recommendations on bariatric surgery, screening for gastroesophageal varices and hepatocellular carcinoma, and liver transplantation in MAFLD patients. Increasing the awareness and knowledge of the various stakeholders on MAFLD and incorporating MAFLD into existing noncommunicable disease-related programs and activities are important steps to tackle the disease. These consensus statements will serve as a guide on MAFLD for clinicians and other stakeholders.
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Affiliation(s)
- Wah‐Kheong Chan
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Soek‐Siam Tan
- Department of HepatologySelayang HospitalBatu CavesSelangorMalaysia
| | | | - Yeong‐Yeh Lee
- School of Medical SciencesUniversiti Sains MalaysiaKota BharuKelantanMalaysia
| | - Hoi‐Poh Tee
- KPJ Pahang Specialist CentreKuantanPahangMalaysia
| | - Sanjiv Mahadeva
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Khean‐Lee Goh
- Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of MedicineUniversity of MalayaKuala LumpurMalaysia
| | - Anis Safura Ramli
- Department of Primary Care Medicine, Faculty of MedicineUniversiti Teknologi MARA, Selayang CampusBatu CavesSelangorMalaysia
- Institute of Pathology, Laboratory and Forensic Medicine, Centre of Excellence for Research on Atherosclerosis and CVD PreventionUniversiti Teknologi MARA, Sungai Buloh CampusSungai BulohSelangorMalaysia
| | - Feisul Mustapha
- Disease Control DivisionMinistry of Health, MalaysiaPutrajayaMalaysia
| | - Nik Ritza Kosai
- Upper Gastrointestinal, Metabolic and Bariatric Surgery Unit, Department of SurgeryUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
| | - Raja Affendi Raja Ali
- Gastroenterology Unit, Department of MedicineUniversiti Kebangsaan MalaysiaKuala LumpurMalaysia
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Lu S, Wang Y, Liu J. TNF-α signaling in non-alcoholic steatohepatitis and targeted therapies. J Genet Genomics 2021; 49:269-278. [PMID: 34757037 DOI: 10.1016/j.jgg.2021.09.009] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 09/07/2021] [Accepted: 09/29/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic steatohepatitis (NASH), an inflammatory subtype of nonalcoholic fatty liver disease (NAFLD), is featured by significantly elevated levels of various pro-inflammatory cytokines. Among numerous pro-inflammatory factors that contribute to NASH pathogenesis, the secreted protein, tumor necrosis factor-alpha (TNF-α) plays an essential role in multiple facets of NASH progression and is therefore considered as a potential therapeutic target. In this review, we will first systematically describe the preclinical studies on the biochemical function of TNF-α and its intracellular downstream signaling mechanisms through its receptors. Moreover, we extensively discuss its functions in regulating inflammation, cell death, and fibrosis of liver cells in the pathogenesis of NASH, and the molecular mechanism that TNF-α expression was regulated by NF-κB and other upstream master regulators during NASH progression. As TNF-α is one of the causal factors that remarkably contributes to NASH progression, combination of therapeutic modalities, including TNF-α-based therapies may lead to resolution of NASH via multiple pathways and thus generate clinical benefits. For translational studies, we summarize recent advances in strategies targeting TNF-α and its signaling pathway, which paves the way for potential therapeutic treatments for NASH in future.
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Affiliation(s)
- Sijia Lu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Yibing Wang
- School of Kinesiology, Shanghai University of Sports, Shanghai 200438, China.
| | - Junli Liu
- Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
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Changes in the transcriptional activity of the entero-insular axis genes in streptozotocin-induced diabetes and after the administration of TNF-α non-selective blockers. Endocr Regul 2021; 54:160-171. [PMID: 32857721 DOI: 10.2478/enr-2020-0019] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVE The aim of the present study was to investigate the transcriptional activity of the GLP-1R, DPP-4, SGLT-1, INSR, and IGF-1R genes in GALT cells of rats with streptozotocin-induced diabetes in both untreated and treated with pentoxifylline, as a non-specific blocker of TNF-α. METHODS The expression of GLP-1R, DPP-4, SGLT-1, INSR, and IGF-1R genes in GALT cells of rats was studied by real time quantitative polymerase chain reaction. RESULTS It was shown that the development of diabetes was accompanied by the decrease of GLP-1R and an increase of DPP-4 genes expression in rat ileum. The administration of pentoxifyl-line to diabetic animals led to an increase in the transcriptional activity of GLP-1R on the 4th week and decrease in transcriptional activity of DPP-4 on the 2nd and 4th weeks of the experiment. An increase in the normalized expression of SGLT-1 on the 4th week of the experimental diabetes was also noted, while the administration of pentoxifylline to diabetic animals did not lead to significant changes in this index. The transcriptional activity of the INSR and IGF-1R genes was reduced in diabetic rats and the administration of the non-specific TNF-α blocker - pentoxifylline led to a significant increase only for INSR gene in animals on the 4th week of the experimental diabetes. CONCLUSIONS The expression of incretins, glucose transporters, and pro-inflammatory cytokines (e.g. TNF-α) in immune cells may be used as markers of several autoimmune pathologies progression such as type 1 diabetes due to their effect on the balance of pro- and anti-inflammatory factors.
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Kedarisetty CK, Bhardwaj A, Kumar G, Rastogi A, Bihari C, Kumar M, Sarin SK. Efficacy of combining pentoxiphylline and vitamin E versus vitamin E alone in non-alcoholic steatohepatitis- A randomized pilot study. Indian J Gastroenterol 2021; 40:41-49. [PMID: 33772456 DOI: 10.1007/s12664-020-01131-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Accepted: 11/23/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIM Non-alcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease. Vitamin E (VE), an anti-oxidant, has shown improvement in NAFLD activity score (NAS) but not fibrosis. Pentoxiphylline (PTX), an anti-TNF-alpha agent, has been reported to reduce hepatic inflammation and fibrosis. We evaluated combination of these drugs in NASH patients. METHODS In a prospective study, consecutive histologically proven patients with NASH were randomized to receive either PTX, 400 mg thrice daily and VE 400 IU twice daily (group PTVE, n = 36) or VE alone (group VE, n = 33). Clinical, dietary and biochemical follow-up was done till 12 months. Primary end-point was change in alanine aminotransferase (ALT) levels. RESULTS: Both groups were comparable at baseline. On a strict diet and lifestyle modification regimen, both groups had similar reduction in body mass index and waist circumference. There was a similar reduction in ALT levels in the two groups. Metabolically, patients in PTVE group had greater reduction in fasting insulin levels and homeostatic model assessment of insulin resistance (HOMA-IR) than VE group (p = 0.05). Tumor necrosis factor alpha (TNFα) levels were also significantly lower in PTVE group from 6 months onwards. Twelve (10%) patients had repeat liver biopsy (7 in group PTVE, 5 in group VE) with no difference in reduction of NAS score (p = 0.45). However, there was a significant fibrosis regression in PTVE compared to VE group (p = 0.003). CONCLUSIONS These data show greater efficacy of a combination of PTX and VE in achieving fibrosis regression compared to VE alone with better metabolic homeostasis and amelioration of the pro-inflammatory status. TRIAL REGISTRATION Clinical Trials Registry no. NCT01384578.
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Affiliation(s)
- Chandan Kumar Kedarisetty
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110 070, India.
- Departments of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai 600 116, India.
| | - Ankit Bhardwaj
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi 110 070, India
| | - Guresh Kumar
- Department of Clinical Research, Institute of Liver and Biliary Sciences, New Delhi 110 070, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi 110 070, India
| | - Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi 110 070, India
| | - Manoj Kumar
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110 070, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, 110 070, India.
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Ipsen DH, Skat-Rørdam J, Svenningsen M, Andersen M, Latta M, Buelund LE, Lintrup K, Skaarup R, Lykkesfeldt J, Tveden-Nyborg P. The effect of acetylsalicylic acid and pentoxifylline in guinea pigs with non-alcoholic steatohepatitis. Basic Clin Pharmacol Toxicol 2021; 128:583-593. [PMID: 33354924 DOI: 10.1111/bcpt.13549] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 11/29/2020] [Accepted: 12/19/2020] [Indexed: 12/14/2022]
Abstract
Therapeutic options are urgently needed for non-alcoholic fatty liver disease (NAFLD), but development is time-consuming and costly. In contrast, drug repurposing offers the advantages of re-applying compounds that are already approved, thereby reducing cost. Acetylsalicylic acid (ASA) and pentoxifylline (PTX) have shown promise for treatment of NAFLD, but have not yet been tested in combination. Guinea pigs were fed a high-fat diet for 16 weeks and then continued on the diet while being treated with ASA, PTX or ASA+PTX for 8 weeks. Chow-fed animals served as healthy controls. Guinea pigs were CT scanned before intervention start and at intervention end. Animals without steatosis (ie NAFLD) at week 16 were excluded from the data analysis. ASA and PTX alone or in combination did not improve hepatic steatosis, ballooning, inflammation or fibrosis nor did the treatments affect liver enzymes (aminotransferases and alkaline phosphatase) or circulating lipids. Liver triglyceride levels, relative liver weight and hepatic mRNA expression of monocyte chemoattractant protein 1, interleukin 8 and platelet-derived growth factor b were nominally decreased. Thus, in the current study, treatment with ASA and PTX alone or in combination for 8 weeks did not ameliorate NASH or hepatic fibrosis in guinea pigs.
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Affiliation(s)
- David Højland Ipsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Josephine Skat-Rørdam
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Marianne Svenningsen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Mia Andersen
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Markus Latta
- Liver Disease Research, Global Research, Novo Nordisk A/S, Måløv, Denmark
| | - Lene Elisabeth Buelund
- Section of Veterinary Imaging, Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Kristine Lintrup
- Section of Veterinary Imaging, Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - René Skaarup
- Section of Veterinary Imaging, Department of Veterinary Clinical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Pernille Tveden-Nyborg
- Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
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Kjær MB, George J, Kazankov K, Grønbæk H. Current perspectives on the pathophysiology of metabolic associated fatty liver disease: are macrophages a viable target for therapy? Expert Rev Gastroenterol Hepatol 2021; 15:51-64. [PMID: 32878486 DOI: 10.1080/17474124.2020.1817740] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Metabolic associated fatty liver disease (MAFLD) is a new nomenclature for fatty liver replacing nonalcoholic fatty liver disease (NAFLD). MAFLD has emerged as the leading cause of liver-related morbidity and mortality with increasing incidence due to its close association with the global epidemic of obesity and type 2 diabetes mellitus. Macrophages play a key role in MAFLD development and progression of steatohepatitis and fibrosis. Therefore, targeting macrophages may be a new therapeutic approach for MAFLD and MAFLD with steatohepatitis. AREAS COVERED We provide a comprehensive review of the significant role of macrophages in MAFLD. Further, we evaluate the current status of lifestyle interventions and pharmacological treatments with a focus on effects mediated through direct or indirect targeting of macrophages. EXPERT OPINION Targeting macrophages holds promise as a treatment option for the management of MAFLD and steatohepatitis. Improved stratification of patients according to MAFLD phenotype would contribute to more adequate design enhancing the yield of clinical trials ultimately leading to personalized medicine for patients with MAFLD. Furthermore, reflecting the multifactorial pathogenesis of MAFLD, combination therapies based on the various pathophysiological driver events including as pertinent to this review, macrophage recruitment, polarization and action, present an intriguing target for future investigation.
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Affiliation(s)
- Mikkel Breinholt Kjær
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Jacob George
- Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney , Sydney, Australia
| | - Konstantin Kazankov
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
| | - Henning Grønbæk
- Department of Hepatology and Gastroenterology, Aarhus University Hospital , Aarhus, Denmark
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Pentoxifylline with metformin treatment improves biochemical parameters in patients with nonalcoholic steatohepatitis. J Med Biochem 2019; 39:290-298. [PMID: 33269017 DOI: 10.2478/jomb-2019-0043] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 09/09/2019] [Indexed: 02/07/2023] Open
Abstract
Background The progression of the nonalcoholic fatty liver disease to nonalcoholic steatohepatitis (NASH) is multifactorial, and there is still a lack of approved medications for its treatment. The study aimed to evaluate the impact of combined treatment with Pentoxifylline and Metformin on biochemical parameters in patients with Nash. Setting: Outpatient hepatology clinic. Methods A prospective trial was conducted. The first cohort included patients with biopsy-proven Nash, while the second cohort consisted of patients with biopsy-confirmed NAFLD. Blood tests were checked at baseline and every three months. Pentoxifylline at a dosage of 400 mg t.i.d. and Metformin at the dosage of 500 mg t.i.d. were introduced for six months in Nash group. The impact of the treatment was assessed based on biochemical results after combined treatment with low-cost medications. Results All 33 Nash patients completed 24 weeks of treatment. We observed significant improvement (p<0.05) of median values after treatment for the following parameters: serum uric acid levels decreased by 51.0 mmol/L, calcium decreased for 0.27 mmoL/L, magnesium showed an increase of 0.11 mmoL/L. Insulin resistance improved as a reduction of HOMA - IR by 1.3 was detected. A significant decrease of median in liver enzymes, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyltransferase by 24.0 U/L, 9.1 U/L, 10.8 U/L respectively, was noted. Conclusions Pentoxifylline and Metformin may provide possible treatment option in Nash. Some new potential benefit of the therapy in improving liver function whilst decreasing cardiovascular risk was perceived.
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The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Nat Rev Gastroenterol Hepatol 2019; 16:145-159. [PMID: 30482910 DOI: 10.1038/s41575-018-0082-x] [Citation(s) in RCA: 632] [Impact Index Per Article: 105.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH.
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16
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Wahlang B, McClain C, Barve S, Gobejishvili L. Role of cAMP and phosphodiesterase signaling in liver health and disease. Cell Signal 2018; 49:105-115. [PMID: 29902522 PMCID: PMC6445381 DOI: 10.1016/j.cellsig.2018.06.005] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/08/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023]
Abstract
Liver disease is a significant health problem worldwide with mortality reaching around 2 million deaths a year. Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are the major causes of chronic liver disease. Pathologically, NAFLD and ALD share similar patterns of hepatic disorders ranging from simple steatosis to steatohepatitis, fibrosis and cirrhosis. It is becoming increasingly important to identify new pharmacological targets, given that there is no FDA-approved therapy yet for either NAFLD or ALD. Since the evolution of liver diseases is a multifactorial process, several mechanisms involving parenchymal and non-parenchymal hepatic cells contribute to the initiation and progression of liver pathologies. Moreover, certain protective molecular pathways become repressed during liver injury including signaling pathways such as the cyclic adenosine monophosphate (cAMP) pathway. cAMP, a key second messenger molecule, regulates various cellular functions including lipid metabolism, inflammation, cell differentiation and injury by affecting gene/protein expression and function. This review addresses the current understanding of the role of cAMP metabolism and consequent cAMP signaling pathway(s) in the context of liver health and disease. The cAMP pathway is extremely sophisticated and complex with specific cellular functions dictated by numerous factors such abundance, localization and degradation by phosphodiesterases (PDEs). Furthermore, because of the distinct yet divergent roles of both of its effector molecules, the cAMP pathway is extensively targeted in liver injury to modify its role from physiological to therapeutic, depending on the hepatic condition. This review also examines the behavior of the cAMP-dependent pathway in NAFLD, ALD and in other liver diseases and focuses on PDE inhibition as an excellent therapeutic target in these conditions.
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Affiliation(s)
- Banrida Wahlang
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA
| | - Craig McClain
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA; Robley Rex Louisville VAMC, Louisville, KY, USA
| | - Shirish Barve
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA
| | - Leila Gobejishvili
- University of Louisville Alcohol Research Center, School of Medicine, University of Louisville, KY, USA; Department of Medicine, School of Medicine, University of Louisville, KY, USA; Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, KY, USA; Hepatobiology & Toxicology Center, School of Medicine, University of Louisville, KY, USA.
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Tratamiento actual de la enfermedad por hígado graso no alcohólico. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO 2018; 83:125-133. [DOI: 10.1016/j.rgmx.2017.10.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2017] [Revised: 09/23/2017] [Accepted: 10/05/2017] [Indexed: 12/13/2022]
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Moctezuma-Velázquez C. Current treatment for non-alcoholic fatty liver disease. REVISTA DE GASTROENTEROLOGÍA DE MÉXICO (ENGLISH EDITION) 2018. [DOI: 10.1016/j.rgmxen.2018.05.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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19
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Eshraghian A. Current and emerging pharmacological therapy for non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23:7495-7504. [PMID: 29204050 PMCID: PMC5698243 DOI: 10.3748/wjg.v23.i42.7495] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/14/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023] Open
Abstract
The main treatment of patients with non-alcoholic fatty liver disease (NAFLD) is life style modification including weight reduction and dietary regimen. Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis (NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients. Several medications, mainly targeting baseline mechanism of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as insulin sensitizing agent and vitamin E as an anti-oxidant have been recommended for treatment of NASH by international guidelines. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet. Several emerging medications are in development for treatment of NASH. Obeticholic acid, liraglutide, elafibranor, cenicriviroc and aramchol have been tested in clinical trials or are completing trials. Here in, current and upcoming medications with promising results in clinical trial for treatment of NAFLD were reviewed.
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Affiliation(s)
- Ahad Eshraghian
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 71937-11351, Iran
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20
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Singh S, Osna NA, Kharbanda KK. Treatment options for alcoholic and non-alcoholic fatty liver disease: A review. World J Gastroenterol 2017; 23:6549-6570. [PMID: 29085205 PMCID: PMC5643281 DOI: 10.3748/wjg.v23.i36.6549] [Citation(s) in RCA: 174] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2017] [Revised: 07/25/2017] [Accepted: 09/05/2017] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple steatosis to hepatitis to cirrhosis and hepatocellular carcinoma. Although most people with excessive alcohol or calorie intake display abnormal fat accumulation in the liver (simple steatosis), a small percentage develops progressive liver disease. Despite extensive research on understanding the pathophysiology of both these diseases there are still no targeted therapies available. The treatment for ALD remains as it was 50 years ago: abstinence, nutritional support and corticosteroids (or pentoxifylline as an alternative if steroids are contraindicated). As for NAFLD, the treatment modality is mainly directed toward weight loss and co-morbidity management. Therefore, new pathophysiology directed therapies are urgently needed. However, the involvement of several inter-related pathways in the pathogenesis of these diseases suggests that a single therapeutic agent is unlikely to be an effective treatment strategy. Hence, a combination therapy towards multiple targets would eventually be required. In this review, we delineate the treatment options in ALD and NAFLD, including various new targeted therapies that are currently under investigation. We hope that soon we will be having an effective multi-therapeutic regimen for each disease.
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Affiliation(s)
- Sukhpreet Singh
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105, United States
- Department of Internal Medicine, Nebraska Medical Center, Omaha, NE 68198, United States
- Department of Biochemistry and Molecular Biology, Nebraska Medical Center, Omaha, NE 68198, United States
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21
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Lisboa QC, Costa SMF, Couto CA. Current management of non-alcoholic fatty liver disease. Rev Assoc Med Bras (1992) 2017; 62:872-878. [PMID: 28001263 DOI: 10.1590/1806-9282.62.09.872] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 01/17/2016] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipid in patients who do not consume alcohol in amounts generally considered harmful to the liver. NAFLD is becoming a major liver disease in Eastern countries and it is related to insulin resistance and metabolic syndrome. Treatment has focused on improving insulin sensitivity, protecting the liver from oxidative stress, decreasing obesity and improving diabetes mellitus, dyslipidemia, hepatic inflammation and fibrosis. Lifestyle modification involving diet and enhanced physical activity associated with the treatment of underlying metabolic are the main stain in the current management of NAFLD. Insulin-sensitizing agents and antioxidants, especially thiazolidinediones and vitamin E, seem to be the most promising pharmacologic treatment for non-alcoholic steatohepatitis, but further long-term multicenter studies to assess safety are recommended.
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Affiliation(s)
- Quelson Coelho Lisboa
- MD, MSc in Sciences Applied to Adult Health with an emphasis on Gastroenterology, Instituto Alfa de Gastroenterologia, Hospital das Clínicas da Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Silvia Marinho Ferolla Costa
- Nutritionist, PhD in Sciences Applied to Adult Health, Instituto Alfa de Gastroenterologia, Hospital das Clínicas da UFMG, Belo Horizonte, MG, Brazil
| | - Cláudia Alves Couto
- MD, PhD in Gastroenterology. Associate Professor, Faculdade de Medicina da UFMG, Instituto Alfa de Gastroenterologia, Hospital das Clínicas da UFMG, Belo Horizonte, MG, Brazil
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Hansen HH, Feigh M, Veidal SS, Rigbolt KT, Vrang N, Fosgerau K. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today 2017; 22:1707-1718. [PMID: 28687459 DOI: 10.1016/j.drudis.2017.06.007] [Citation(s) in RCA: 164] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 06/06/2017] [Accepted: 06/27/2017] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the Western world. NAFLD is a complex spectrum of liver diseases ranging from benign hepatic steatosis to its more aggressive necroinflammatory manifestation, nonalcoholic steatohepatitis (NASH). NASH pathogenesis is multifactorial and risk factors are almost identical to those of the metabolic syndrome. This has prompted substantial efforts to identify novel drug therapies for correcting underlying metabolic deficits, and to prevent or alleviate hepatic fibrosis in NASH. Available mouse models of NASH address different aspects of the disease, have varying clinical translatability, and, therefore, also show different utility in drug discovery.
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Affiliation(s)
- Henrik H Hansen
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark.
| | - Michael Feigh
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
| | - Sanne S Veidal
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
| | | | - Niels Vrang
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
| | - Keld Fosgerau
- Gubra Aps, Hørsholm Kongevej 11b, Hørsholm DK-2970, Denmark
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Brea Á, Pintó X, Ascaso JF, Blasco M, Díaz Á, González-Santos P, Hernández-Mijares A, Mantilla T, Millán J, Pedro-Botet J. Enfermedad del hígado graso no alcohólico, asociación con la enfermedad cardiovascular y tratamiento (II). Tratamiento de la enfermedad del hígado graso no alcohólico. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2017; 29:185-200. [DOI: 10.1016/j.arteri.2016.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 06/28/2016] [Indexed: 12/12/2022]
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Wen WX, Lee SY, Siang R, Koh RY. Repurposing Pentoxifylline for the Treatment of Fibrosis: An Overview. Adv Ther 2017; 34:1245-1269. [PMID: 28484954 DOI: 10.1007/s12325-017-0547-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Indexed: 12/20/2022]
Abstract
Fibrosis is a potentially debilitating disease with high morbidity rates. It is estimated that half of all deaths that occur in the USA are attributed to fibrotic disorders. Fibrotic disorders are characterized primarily by disruption in the extracellular matrix deposition and breakdown equilibrium, leading to the accumulation of excessive amounts of extracellular matrix. Given the potentially high prevalence of fibrosis and the paucity of agents currently available for the treatment of this disease, there is an urgent need for the identification of drugs that can be utilized to treat the disease. Pentoxifylline is a methylxanthine derivative that is currently approved for the treatment of vascular diseases, in particular, claudication. Pentoxifylline has three main properties: improving the rheological properties of blood, anti-inflammatory, and antioxidative. Recently, the effectiveness of pentoxifylline in the treatment of fibrosis via attenuating and reversing fibrotic lesions has been demonstrated in several clinical trials and animal studies. As a result of the limited availability of antifibrotic agents in the long-term treatment of fibrosis that can attenuate and even reverse fibrotic lesions effectively, it would be of particular importance to consider the potential clinical utility of pentoxifylline in the treatment of fibrosis. Thus, this paper discusses the evolving roles of pentoxifylline in the treatment of different types of fibrosis.
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Affiliation(s)
- Wei Xiong Wen
- International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
| | - Siang Yin Lee
- Colloids and Interface Science Centre, Centre of Excellence, RRIM Sungai Buloh Research Station, Malaysian Rubber Board, 47000, Sungai Buloh, Selangor, Malaysia
| | - Rafaella Siang
- International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia
- Acute Medicine, George Eliot Hospital NHS Trust, College St, Nuneaton, UK
| | - Rhun Yian Koh
- International Medical University, No. 126, Jalan Jalil Perkasa 19, Bukit Jalil, 57000, Kuala Lumpur, Malaysia.
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Baselga-Escudero L, Souza-Mello V, Pascual-Serrano A, Rachid T, Voci A, Demori I, Grasselli E. Beneficial effects of the Mediterranean spices and aromas on non-alcoholic fatty liver disease. Trends Food Sci Technol 2017. [DOI: 10.1016/j.tifs.2016.11.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut 2017; 66:180-190. [PMID: 27646933 DOI: 10.1136/gutjnl-2016-312431] [Citation(s) in RCA: 336] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/29/2016] [Accepted: 08/30/2016] [Indexed: 02/06/2023]
Abstract
Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.
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Affiliation(s)
- Yaron Rotman
- Liver and Energy Metabolism Unit, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland, USA
| | - Arun J Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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Rana H, Yadav SS, Reddy HD, Singhal S, Singh DK, Usman K. Comparative Effect of Insulin Sensitizers and Statin on Metabolic Profile and Ultrasonographical Score in Non Alcoholic Fatty Liver Disease. J Clin Diagn Res 2016; 10:OC19-23. [PMID: 27656480 DOI: 10.7860/jcdr/2016/19887.8336] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 04/27/2016] [Indexed: 01/22/2023]
Abstract
INTRODUCTION Non Alcoholic Fatty Liver Disease (NAFLD) is a metabolic disorder involving fat accumulation in the liver. The initial management for patients with NAFLD includes lifestyle modification and weight loss in overweight or obese patients. AIM The present study was conducted to compare the efficacy of insulin sensitizers and statin in the patients of NAFLD. MATERIALS AND METHODS The study included 98 patients diagnosed with NAFLD on USG (Ultrasonography) abdomen, divided into three Groups randomly and administered Metformin (Group I), Rosuvastatin (Group II) or Pioglitazone (Group III) along with dietary intervention and lifestyle modification. Their Body Mass Index (BMI), liver function tests, fasting lipid profile, USG scores for fatty liver were done and followed up at 4 weeks, 12 weeks and 24 week for change in above parameters. RESULTS Out of the three Groups, Group II showed a maximum improvements in usg scores for NAFLD (p<0.001) and fasting lipid profile. Group II also showed maximum derangement of liver enzymes at 24 weeks though none of the subjects had more than three times elevation of liver enzymes. CONCLUSION Rosuvastatin may be an effective therapy as add on treatment to dietary and lifestyle intervention in patients of NAFLD. As an add-on treatment Rosuvastatin was superior to Pioglitazone or Metformin and acute decompensation is unlikely with this drug. Metformin was not effective as add on therapy for NAFLD, rather rapid weight loss in short period of time resulted in worsening of hepatic steatosis.
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Affiliation(s)
- Himanshu Rana
- Junior Resident, Department of Medicine, King George's Medical University , Lucknow, Uttar Pradesh, India
| | - Suraj Singh Yadav
- Senior Resident, Department of Pharmacology, King George's Medical University , Lucknow, Uttar Pradesh, India
| | - Himanshu D Reddy
- Associate Professor, Department of Medicine, King George's Medical University , Lucknow, Uttar Pradesh, India
| | - Shubham Singhal
- Junior Resident, Department of Medicine, King George's Medical University , Lucknow, Uttar Pradesh, India
| | - Dinesh Kumar Singh
- Junior Resident, Department of Medicine, King George's Medical University , Lucknow, Uttar Pradesh, India
| | - Kauser Usman
- Professor, Department of Medicine, King George's Medical University , Lucknow, Uttar Pradesh, India
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Sawangjit R, Chongmelaxme B, Phisalprapa P, Saokaew S, Thakkinstian A, Kowdley KV, Chaiyakunapruk N. Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD): A PRISMA-compliant systematic review and network meta-analysis. Medicine (Baltimore) 2016; 95:e4529. [PMID: 27512874 PMCID: PMC4985329 DOI: 10.1097/md.0000000000004529] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased over the last decades. Despite existence of several interventions, there remains unclear which interventions work the best. METHODS A systematic review and network meta-analysis of randomized trials comparing efficacy of all treatment options in NAFLD were performed to determine comparative efficacy and safety of interventions in the management of NAFLD. Several electronic databases were searched up to Nov 15, 2015. Outcomes include liver histological outcomes (i.e., fibrosis), all-cause mortality, cirrhosis, and safety. A network meta-analysis was applied to estimate pooled risk ratios (RR). Quality of evidence was assessed using GRADE criteria. RESULTS A total of 44 studies (n = 3802) were eligible. When compared with placebo, obeticholic acid (OCA) was the only intervention that significantly improved fibrosis with RR (95% CI) of 1.91 (1.15, 3.16), while pentoxyfylline (PTX) demonstrated improved fibrosis without statistical significance with RR (95% CI) of 2.27 (0.81, 6.36). Only thiazolidinedione (TZD) and vitamin E use resulted in significant increase in resolution of NASH, while OCA, TZD, and vitamin E significantly improved other outcomes including NAS, steatosis, ballooning, and inflammation outcomes. Quality of evidence varied from very low (i.e., metformin, PTX on mean change of ballooning grade) to high (OCA, TZD, vitamin E on improving histological outcomes). Limitations of this study were lack of relevant long-term outcomes (e.g., cirrhosis, death, safety), possible small study effect, and few head-to-head studies. CONCLUSIONS Our study suggests potential efficacy of OCA, TZD, and vitamin E in improving histologic endpoints in NAFLD. These findings are however based on a small number of studies. Additional studies are awaited to strengthen this network meta-analysis.
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Affiliation(s)
- Ratree Sawangjit
- Clinical Pharmacy Research Unit (CPRU), Department of Clinical Pharmacy, Faculty of Pharmacy, Mahasarakham University, Mahasarakham, Thailand
- School of Pharmacy, Monash University Malaysia, Selangor, Malaysia
| | - Bunchai Chongmelaxme
- Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok
| | - Pochamana Phisalprapa
- Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok
| | - Surasak Saokaew
- School of Pharmacy, Monash University Malaysia, Selangor, Malaysia
- Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok
- Center of Health Outcome Research and Therapeutic Safety, School of Pharmaceutical Sciences,University of Phayao, Phayao
| | - Ammarin Thakkinstian
- Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Kris V. Kowdley
- Liver Care Network and Organ Care Research, Swedish Medical Center, Seattle
| | - Nathorn Chaiyakunapruk
- School of Pharmacy, Monash University Malaysia, Selangor, Malaysia
- Center of Pharmaceutical Outcomes Research, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok
- School of Pharmacy, University of Wisconsin, Madison, WI
- School of Population Health, University of Queensland, Brisbane, QLD, Australia
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Katsiki N, Mikhailidis DP, Mantzoros CS. Non-alcoholic fatty liver disease and dyslipidemia: An update. Metabolism 2016; 65:1109-23. [PMID: 27237577 DOI: 10.1016/j.metabol.2016.05.003] [Citation(s) in RCA: 438] [Impact Index Per Article: 48.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Revised: 05/02/2016] [Accepted: 05/05/2016] [Indexed: 11/21/2022]
Abstract
Non-alcoholic fatty liver (NAFLD) is the most common liver disease worldwide, progressing from simple steatosis to necroinflammation and fibrosis (leading to non-alcoholic steatohepatitis, NASH), and in some cases to cirrhosis and hepatocellular carcinoma. Inflammation, oxidative stress and insulin resistance are involved in NAFLD development and progression. NAFLD has been associated with several cardiovascular (CV) risk factors including obesity, dyslipidemia, hyperglycemia, hypertension and smoking. NAFLD is also characterized by atherogenic dyslipidemia, postprandial lipemia and high-density lipoprotein (HDL) dysfunction. Most importantly, NAFLD patients have an increased risk for both liver and CV disease (CVD) morbidity and mortality. In this narrative review, the associations between NAFLD, dyslipidemia and vascular disease in NAFLD patients are discussed. NAFLD treatment is also reviewed with a focus on lipid-lowering drugs. Finally, future perspectives in terms of both NAFLD diagnostic biomarkers and therapeutic targets are considered.
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Affiliation(s)
- Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Dimitri P Mikhailidis
- Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital Campus, University College London Medical School, University College London (UCL), London, UK.
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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A Comprehensive Updated Review of Pharmaceutical and Nonpharmaceutical Treatment for NAFLD. Gastroenterol Res Pract 2016; 2016:7109270. [PMID: 27006654 PMCID: PMC4781972 DOI: 10.1155/2016/7109270] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Accepted: 01/27/2016] [Indexed: 02/08/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the western world with prevalence of 20–33%. NAFLD comprises a pathological spectrum. Nonalcoholic fatty liver (NAFL) is at one end and consists of simple hepatic steatosis. On the contrary, nonalcoholic steatohepatitis (NASH) consists of steatosis, inflammation, and ballooning degeneration and can progress to cirrhosis. Despite the rising incidence, definitive treatment for NAFLD, specifically NASH, has not yet been established. Lifestyle modification with dietary changes combined with regular aerobic exercise, along with multidisciplinary approach including cognitive behavior therapy, has been shown to be an effective therapeutic option, even without a significant weight loss. Pioglitazone and vitamin E have shown to be most effective in NASH patients. Surgery and weight loss medication are effective means of weight loss but can potentially worsen NASH related fibrosis. Other agents such as n-3 polyunsaturated fatty acids, probiotics, and pentoxifylline along with herbal agent such as milk thistle as well as daily intake of coffee have shown potential benefits, but further well organized studies are definitely warranted. This review focuses on the available evidence on pharmaceutical and nonpharmaceutical therapy in the treatment and the prevention of NAFLD, primarily NASH.
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Dajani A, AbuHammour A. Treatment of nonalcoholic fatty liver disease: Where do we stand? an overview. Saudi J Gastroenterol 2016; 22:91-105. [PMID: 26997214 PMCID: PMC4817303 DOI: 10.4103/1319-3767.178527] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, the prevalence of which had progressively increased over the past 10 years where other liver diseases remained at the same prevalence rates or are expected to decrease as in the case of hepatitis C virus (HCV). The treatment of NAFLD is of prime concern to health care professionals and patients due to the significant mortality and morbidity it implies; the problem is further escalated by the fact that standard of care medications targeting NAFLD remain experimental and without evidence base. Treatment nowadays is focused on lifestyle modification and managing the comorbid associated diseases, with a possible role for some hepatic protective agents. This review presents all the medications that had been proposed and used for the treatment of NAFLD with or without scientific rationale and includes agents for weight loss, insulin sensitizers, drugs that reduce blood lipids, glucagon-mimetics, drugs that may reduce fibrosis, angiotensin receptor blockers, and medicines believed to reduce endoplasmic reticular stress such as vitamin E, ursodeoxycholic acid, and S-adenosyl methionine. A quick review of the newer agents that proved to be promising such as obeticholic acid and GFT505 and the medicines that are still in the pipeline is also presented.
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Affiliation(s)
- Asad Dajani
- Department of Gastroenterology and Hepatology, Asad Dajani Specialized Center, Sharjah, UAE,Address for correspondence: Dr. Asad Dajani, Department of Gastroenterology and Hepatology, Asad Dajani Specialized Center, P.O. Box 6328, Sharjah, United Arab Emirates. E-mail:
| | - Adnan AbuHammour
- Department of Gastroenterology and Hepatology, Abuhammour Medical Center, Dubai, UAE
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Malhotra N, Beaton MD. Management of non-alcoholic fatty liver disease in 2015. World J Hepatol 2015; 7:2962-2967. [PMID: 26730275 PMCID: PMC4691699 DOI: 10.4254/wjh.v7.i30.2962] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Revised: 09/25/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
There is no single pharmacologic therapy that has been approved to treat nonalcoholic fatty liver disease in the general population. The backbone of therapy currently includes intensive lifestyle modification with established targets for diet and weight loss. The use of unsweetened, unfiltered coffee along with limiting high fructose corn syrup have emerged as beneficial dietary recommendations. The use of empiric oral hypoglycemic agents and vitamin E, however, has not been widely accepted. Developing bariatric surgical techniques are promising, but additional studies with long-term follow up are needed before it can be widely recommended. Finally, liver transplantation is an increasingly frequent consideration once complications of end-stage disease have developed. The future treatment of those with nonalcoholic fatty liver disease will likely involve a personalized approach. The importance of the gut microbiome in mediating hepatocyte inflammation and intestinal permeability is emerging and may offer avenues for novel treatment. The study of anti-fibrotic agents such as pentoxifylline and FXR agonists hold promise and new pathways, such as hepatocyte cannabinoid receptor antagonists are being studied. With the incidence of obesity and the metabolic syndrome increasing throughout the developed world, the future will continue to focus on finding novel agents and new applications of existing therapies to help prevent and to mediate the progression of nonalcoholic fatty liver disease.
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Marino L, Jornayvaz FR. Endocrine causes of nonalcoholic fatty liver disease. World J Gastroenterol 2015; 21:11053-76. [PMID: 26494962 PMCID: PMC4607905 DOI: 10.3748/wjg.v21.i39.11053] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Revised: 06/11/2015] [Accepted: 08/28/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. The prevalence of NAFLD is increasing, becoming a substantial public health burden. NAFLD includes a broad spectrum of disorders, from simple conditions such as steatosis to severe manifestations such as fibrosis and cirrhosis. The relationship of NAFLD with metabolic alterations such as type 2 diabetes is well described and related to insulin resistance, with NAFLD being recognized as the hepatic manifestation of metabolic syndrome. However, NAFLD may also coincide with endocrine diseases such as polycystic ovary syndrome, hypothyroidism, growth hormone deficiency or hypercortisolism. It is therefore essential to remember, when discovering altered liver enzymes or hepatic steatosis on radiological exams, that endocrine diseases can cause NAFLD. Indeed, the overall prognosis of NAFLD may be modified by treatment of the underlying endocrine pathology. In this review, we will discuss endocrine diseases that can cause NALFD. Underlying pathophysiological mechanisms will be presented and specific treatments will be reviewed.
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Strategies to prevent and reverse liver fibrosis in humans and laboratory animals. Arch Toxicol 2015; 89:1727-50. [PMID: 25963329 DOI: 10.1007/s00204-015-1525-6] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 04/28/2015] [Indexed: 02/07/2023]
Abstract
Liver fibrosis results from chronic damage to the liver in conjunction with various pathways and is mediated by a complex microenvironment. Based on clinical observations, it is now evident that fibrosis is a dynamic, bidirectional process with an inherent capacity for recovery and remodeling. The major mechanisms involved in liver fibrosis include the repetitive injury of hepatocytes, the activation of the inflammatory response after injury stimulation, and the activation and proliferation of hepatic stellate cells (HSCs), which represents the major extracellular matrix (ECM)-producing cells, stimulated by hepatocyte injury and inflammation. The microenvironment in the liver is synergistically regulated abnormal ECM deposition, scar formation, angiogenesis, and fibrogenesis. Moreover, recent studies have clarified novel mechanism in fibrosis such as epigenetic regulation of HSCs, the leptin and PPARγ pathways, the coagulation system, and even autophagy. Uncovering the mechanisms of liver fibrogenesis provides a basis to develop potential therapies to reverse and treat the fibrotic response, thereby improving the outcomes of patients with chronic liver disease. Although both scientific and clinical challenges remain, emerging studies attempt to reveal the ideal anti-fibrotic drug that could be easily delivered to the liver with high specificity and low toxicity. This review highlights the mechanisms, including novel pathways underlying fibrogenesis that may be translated into preventive and treatment strategies, reviews both current and novel agents that target specific pathways or multiple targets, and discusses novel drug delivery systems such as nanotechnology that can be applied in the treatment of liver fibrosis. In addition, we also discuss some current treatment strategies that are being applied in animal models and in clinical trials.
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A concise review of non-alcoholic fatty liver disease. Atherosclerosis 2015; 239:192-202. [PMID: 25617860 DOI: 10.1016/j.atherosclerosis.2015.01.001] [Citation(s) in RCA: 208] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Revised: 01/08/2015] [Accepted: 01/12/2015] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and the incidence of which is rising rapidly due to the increasing epidemic of obesity in both adults and children. The initial accumulation of fat followed by subsequent inflammation is central to the development of liver damage, and is critically influenced by host factors including age, gender, presence of diabetes, genetic polymorphisms and more recently by the gut microbiome. An increasing body of data suggest that NAFLD is also an independent risk factor of cardiovascular disease, which remains the commonest cause of mortality in such patients. This review focusses on the pathogenesis of NAFLD, and the evolution of new approaches to the management and treatment of NAFLD.
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Han SJ, Kim HJ, Kim DJ, Sheen SS, Chung CH, Ahn CW, Kim SH, Cho YW, Park SW, Kim SK, Kim CS, Kim KW, Lee KW. Effects of pentoxifylline on proteinuria and glucose control in patients with type 2 diabetes: a prospective randomized double-blind multicenter study. Diabetol Metab Syndr 2015; 7:64. [PMID: 26300986 PMCID: PMC4546105 DOI: 10.1186/s13098-015-0060-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 07/09/2015] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Pentoxifylline is a methylxanthine derivative with significant anti-inflammatory, anti-fibrotic, and anti-proliferative properties. Studies have shown that pentoxifylline may have renoprotective effects in patients with diabetic nephropathy. However, most of these studies were limited by small sample sizes. Therefore, we investigated whether pentoxifylline could reduce proteinuria in patients with diabetic nephropathy and residual proteinuria who received an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin II receptor blocker (ARB). We also studied the effects of pentoxifylline on glycemic control, insulin resistance, and inflammatory parameters. METHODS This was a prospective, randomized double-blind, placebo-controlled, multi-center study. A total of 174 patients with type 2 diabetes and albuminuria (>30 mg/g of creatinine) who were taking the recommended dosage of ACEI or ARB for > 6 months and receiving conventional therapy for diabetes were randomly assigned to receive pentoxifylline (1200 mg, daily; n = 87) or a placebo (n = 87) for 6 months. The endpoints were the effects of pentoxifylline on proteinuria, renal function, glucose control, and inflammatory parameters. RESULTS The percentage changes in proteinuria from baseline in the pentoxifylline and placebo groups were a decrease of 23 % and 4 %, respectively (p = 0.012). In addition, significant reductions in fasting plasma glucose, glycated hemoglobin, and insulin resistance according to the homeostasis model assessment were observed in the pentoxifylline group compared to those in the placebo group. However there was no significant difference in serum tumor necrosis factor (TNF)-α between the groups. CONCLUSIONS Pentoxifylline therapy reduced proteinuria and improved glucose control and insulin resistance without significant change of serum TNF-α in patients with type 2 diabetic nephropathy. Therefore, pentoxifylline is a potential therapeutic alternative for treating diabetes and diabetic nephropathy. TRIAL REGISTRATION NCT01382303.
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Affiliation(s)
- Seung Jin Han
- />Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon, 443-380 Korea
| | - Hae Jin Kim
- />Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon, 443-380 Korea
| | - Dae Jung Kim
- />Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon, 443-380 Korea
| | - Seung Soo Sheen
- />Section of Clinical Epidemiology and Biostatistics in Clinical Trial Center, Ajou University School of Medicine, Suwon, 443-380 Korea
| | - Choon Hee Chung
- />Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, 220-701 Korea
| | - Chul Woo Ahn
- />Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, 135-720 Korea
| | - Se Hwa Kim
- />Division of Endocrinology, Department of Internal Medicine, Catholic Kwandong University College of Medicine, Incheon, 404-834 Korea
| | - Yong-Wook Cho
- />Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, 463-712 Korea
| | - Seok Won Park
- />Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, 463-712 Korea
| | - Soo-Kyung Kim
- />Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam, 463-712 Korea
| | - Chul Sik Kim
- />Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, 431-796 Korea
| | - Kyung Wook Kim
- />Dongtan jeil Women’s Hospital, Hwaseong, 445-170 Korea
- />Severance Institute for Vascular and Metabolic Research, Yonesei University College of Medicine, Seoul, 120-752 Korea
| | - Kwan Woo Lee
- />Department of Endocrinology and Metabolism, Ajou University School of Medicine, 164, World Cup-ro, Yeongtong-gu, Suwon, 443-380 Korea
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Metwally AH. Pentoxifylline in the management of metabolic syndrome and chronic hepatitis C. Med Hypotheses 2014; 83:832-4. [PMID: 25468788 DOI: 10.1016/j.mehy.2014.10.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Revised: 10/09/2014] [Accepted: 10/23/2014] [Indexed: 11/29/2022]
Abstract
Metabolic syndrome (MS) and chronic hepatitis C (CHC) are prevalent diseases with many serious and fatal outcomes. Many of these outcomes are attributed to increased level of TNF-α which causes insulin resistance (IR), liver damage, increased incidence and mortality of hepatorenal syndrome (HRS), liver fibrosis and nonalcoholic steatohepatitis (NASH). So, an approach that depends on reducing the TNF-α levels is considered a reasonable method to help treat these conditions. Putting together the available data in the previous literature about pentoxifylline (PTX) would highly suggest that this drug is perfect for managing these conditions. Through its inhibitory effect on the production of TNF-α, it would improve the IR state and improve MS. It would also improve the liver condition in NASH which is associated with IR. And by its effect on enhancing the blood flow and decreasing its viscosity, it could also have a protective role against the cardiovascular incidents that develop with IR and MS. In CHC, it would decrease the IR that is associated with HCV infection and this would subsequently increase the response to the antiviral therapy and reduce the liver damage. It was also proven to decrease the incidence and mortality of HRS that develops in cirrhosis. PTX also has anti-fibrotic effects which can stop the liver fibrosis. The PTX effect should be evaluated experimentally and by clinical trials on patients as it can be a breakthrough in the management of MS and CHC. Such an affordable drug would remarkably decrease the expense of the management of these conditions, and would reduce the morbidity and mortality in those patients, which would indirectly increase the productivity in the societies that have a high prevalence of these diseases.
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Della Corte C, Liccardo D, Ferrari F, Alisi A, Nobili V. Current pharmacotherapy for treating pediatric nonalcoholic fatty liver disease. Expert Opin Pharmacother 2014; 15:2501-11. [DOI: 10.1517/14656566.2014.960389] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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