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Skovgaard ET, de Zawadzki A, Kimer N, Busk TM, Karsdal M, Leeming DJ, Møller S. The heterogeneity of cirrhosis - systemically assessed endotypes described by fibrosis, apoptosis, and immunoregulatory-related biomarkers. Dig Liver Dis 2025:S1590-8658(25)00313-5. [PMID: 40254493 DOI: 10.1016/j.dld.2025.03.033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2025] [Revised: 03/31/2025] [Accepted: 03/31/2025] [Indexed: 04/22/2025]
Abstract
BACKGROUND Given the heterogeneity of advanced chronic liver disease, assessing disease activity-related biomarkers could aid in classifying cirrhosis endotypes for better patient monitoring and treatment selection. AIM To investigate cirrhosis endotypes described by disease activity biomarkers related to fibrogenesis, immune cell activity, apoptosis, and systemic inflammation. METHODS The study included plasma EDTA samples from 106 participants with mild, moderate, and severe liver cirrhosis undergoing hepatic venous pressure gradient (HVPG) measurements and 39 healthy control participants. The biomarkers nordicPROC3™ (fibrogenesis), GDF-15, CK18 M30 (apoptosis), CRP (systemic inflammation), nordicCPa9-HNE™ (neutrophil activity), and nordicVICM™ (macrophage activity) were measured. RESULTS PROC3, GDF-15, CK18 M30, and CRP increased with cirrhosis severity (p < 0.05-p < 0.0001) and the degree of portal hypertension (p < 0.05-p < 0.01). CPa9-HNE decreased from mild to moderate and mild to severe cirrhosis (p < 0.01-0.0001) and correlated with HVPG (r=-0.53, p < 0.0001). VICM decreased from mild to severe cirrhosis (p < 0.01). A heatmap clustered analysis revealed four potential cirrhosis endotypes, reflecting underlying biological processes. CONCLUSION Assessing markers related to active fibrogenesis, apoptosis, immune cell activity, and systemic inflammation revealed distinct molecular patterns among patients with cirrhosis. These findings suggest the presence of potential disease endotypes that could inform future strategies for patient monitoring, treatment selection, and prognostic assessment in cirrhosis management.
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Affiliation(s)
- Emilie Toft Skovgaard
- Nordic Bioscience A/S, Herlev Hovedgade 205-207, Herlev, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark.
| | | | - Nina Kimer
- Gastro Unit, Medical Division, University Hospital Hvidovre, Denmark
| | - Troels Malte Busk
- Department of Gastroenterology and Hepatology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
| | - Morten Karsdal
- Nordic Bioscience A/S, Herlev Hovedgade 205-207, Herlev, Denmark
| | | | - Søren Møller
- Department of Clinical Physiology, Hvidovre Hospital and Faculty of Health Sciences, University of Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark
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Ma X, Li B, Liu Y, Guo X. An inverted U-shaped association between high-sensitivity C-reactive protein and the albumin ratio and hepatic steatosis and liver fibrosis: a population-based study. Front Nutr 2025; 12:1534200. [PMID: 40303878 PMCID: PMC12037389 DOI: 10.3389/fnut.2025.1534200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2024] [Accepted: 03/24/2025] [Indexed: 05/02/2025] Open
Abstract
Background The high-sensitivity C-reactive protein to albumin (CAR) ratio is a comprehensive measure of inflammation in vivo. Hepatic steatosis and fibrosis are significantly correlated with inflammation. The present study aimed to explore the possible associations between CAR and hepatic steatosis and fibrosis in the American population. Methods The study population involved the National Health and Nutrition Examination Survey (NHANES) participants from 2017 to 2020. The natural logarithm of CAR, calculated as Ln(CAR) with base "e," was used for further analyses. The relationships between Ln(CAR) and the controlled attenuation parameter (CAP) and between Ln(CAR) and liver stiffness measurement (LSM) were investigated through multivariate linear regression analysis. Interaction and subgroup analysis identified factors affecting these variables. Nonlinear relationships were elucidated by smoothing curves and threshold effect analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the CAR for non-alcoholic fatty liver disease (NAFLD). The results were adjusted for U.S. population estimates. Results The study included a total of 7,404 individuals. Ln(CAR) was positively correlated with CAP in the fully adjusted model, with an effect value of β = 1.827 (95% CI, 0.611, 3.042). A more pronounced positive association was observed among participants with a BMI ≥ 25 kg/m2 in the subgroup analysis. An inverted U-shaped association was shown between Ln(CAR) and CAP through smooth curve fitting and a two-segment linear regression model, with an inflection point of (-9.594). ROC curve analysis showed that CAR had a moderate predictive value for NAFLD (AUC = 0.6895), with a sensitivity of 0.7276 and a specificity of 0.6092. No significant association was detected between Ln(CAR) and the LSM. Conclusion We demonstrate an inverted U-shaped relationship between Ln(CAR) and CAP risk within the U.S. demographic. Our results suggest that CAR may serve as a valuable diagnostic tool for NAFLD. Further prospective research is necessary to validate this conclusion.
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Affiliation(s)
| | | | | | - Xiaoyan Guo
- Department of Gastroenterology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China
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Wang H, Ye J, Chen Y, Sun Y, Gong X, Deng H, Dong Z, Xu L, Li X, Zhong B. High sensitivity C-reactive protein implicates heterogeneous metabolic phenotypes and severity in metabolic dysfunction associated-steatotic liver disease. BMC Gastroenterol 2025; 25:231. [PMID: 40200156 PMCID: PMC11980055 DOI: 10.1186/s12876-025-03778-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Accepted: 03/12/2025] [Indexed: 04/10/2025] Open
Abstract
BACKGROUND Whether include high-sensitivity C-reactive protein (Hs-CRP) in diagnostic flow remains debatable during the updated definition to metabolic dysfunction-associated steatotic liver disease (MASLD) despite systemic inflammation contributes to the disease development and progression. We aimed to identify values of hs-CRP compared to other inflammatory markers derived from routine blood tests in MASLD. MATERIALS AND METHODS This cross-sectional study included consecutive participants (ultrasound-diagnosed MASLD: 1,006, healthy controls: 582), and 175 patients received liver biopsy., with 733 and 310 patients underwent magnetic resonance imaging proton density fat fraction for liver fat content (LFC) quantification and two-dimensional shear-wave elastography liver stiffness measurements (LSM), respectively. RESULTS Multiple linear regression analysis revealed a significant positive association between hs-CRP and LFC among overweight/obesity group patients (β 0.19, P = 0.03), and LSM among lean/normal weight group (β 0.30, P < 0.001). For the metabolic dysfunction-associated steatohepatitis (MASH), the hs-CRP and the ratio of monocytes to high-density lipoprotein both performed well in the overweight/obesity group and type 2 diabetes group (Overweight/obesity group, hs-CPR AUC 0.65 and 0.74, P = 0.02), bu no valuable inflammatory indicators were observed in MASH and liver fibrosis. CONCLUSION Hs-CRP levels are associated with LFC in overweight/obese MASLD and liver stiffness in lean MASLD patients, yet the reported AUC values suggest weak predictive ability. TRIAL REGISTRATION The study protocol was registered at the Chinese Clinical Trial Registry, (ChiCTR-ChiCTR2000034197), approved by the First Affiliated Hospital of Sun Yat-sen University institutional with the regional medical ethics committees (Approval number: [2020] No. 187), and performed in accordance with the ethical standards of the 1964 Declaration of Helsinki. Written informed consent was obtained from all the patients.
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Affiliation(s)
- Hao Wang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Yuexiu District, No. 58 Zhongshan II Road, Guangzhou, 510080, China
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Junzhao Ye
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Yuexiu District, No. 58 Zhongshan II Road, Guangzhou, 510080, China
| | - Youpeng Chen
- Department of Infectious Diseases, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, 518107, China
| | - Yanhong Sun
- Department of Clinical Laboratory, The East Division of the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510080, China
| | - Xiaorong Gong
- Department of Gastroenterology, First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510000, Guangdong, China
| | - Hong Deng
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Zhiyong Dong
- The First Affiliated Hospital of Jinan University, Guangzhou, 510632, China
| | - Lishu Xu
- Department of Gastroenterology and Hepatology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, and Guangdong Provincial Geriatrics Institute, No. 106 Zhongshan II Road, Yuexiu District, Guangzhou, China
| | - Xin Li
- Department of Gastroenterology, The Tenth Affiliated of Southern Medical University (Dongguan People'S Hospital), Dongguan, 516000, Guangdong, China.
| | - Bihui Zhong
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Yuexiu District, No. 58 Zhongshan II Road, Guangzhou, 510080, China.
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Wu Y, Zheng G, Zhang F, Li W. Association of high-sensitivity C-reactive protein with hepatic fibrosis in patients with metabolic dysfunction-associated steatotic liver disease. Front Immunol 2025; 16:1544917. [PMID: 39995674 PMCID: PMC11847791 DOI: 10.3389/fimmu.2025.1544917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2024] [Accepted: 01/23/2025] [Indexed: 02/26/2025] Open
Abstract
Objective This study aimed to investigate the association between high-sensitivity C-reactive protein (hsCRP) levels and hepatic fibrosis in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and assess its predictive efficacy. Methods The study included 1,477 participants from the United States and 1,531 from China diagnosed with MASLD. Liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) were assessed by vibration-controlled transient elastography (VCTE) to evaluate the presence and degree of hepatic fibrosis and steatosis. The relationship between hsCRP levels and hepatic fibrosis in MASLD patients was examined using multivariable-adjusted and restricted cubic spline (RCS) models. Additionally, subgroup analyses were conducted to investigate the potential heterogeneity among different characteristic subgroups. Results The results demonstrated a significant correlation between elevated hsCRP levels and an increased risk of significant fibrosis, advanced fibrosis, and cirrhosis in the US cohort of MASLD patients (OR 2.22, 1.69, and 2.85, respectively; all P <0.05). The results of the Chinese cohort were consistent with those of the US cohort, and there was a significant and positive correlation between hsCRP levels and the risk of hepatic fibrosis in patients with MASLD (OR 2.53, 3.85, and 3.78, respectively, all P <0.001). The RCS analysis revealed a significant non-linear relationship between hsCRP levels and the degree of hepatic fibrosis, with disparate inflection point values observed across different cohorts (approximately 9 mg/L in the US cohort and 4 mg/L in the Chinese cohort). The impact of hsCRP levels on the risk of hepatic fibrosis varied across different subgroups with distinct characteristics. Conclusion The present study demonstrated a significant correlation between hsCRP levels and the degree of hepatic fibrosis in patients with MASLD, with notable dose-response relationships and subgroup differences.
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Affiliation(s)
- Yunfei Wu
- Department of Pathology, Changzhou Third People’s Hospital, Changzhou, China
- Changzhou Clinical College, Xuzhou Medical University, Changzhou, China
| | - Guojun Zheng
- Changzhou Clinical College, Xuzhou Medical University, Changzhou, China
- Clinical Laboratory, Changzhou Third People’s Hospital, Changzhou, China
| | - Fan Zhang
- Changzhou Clinical College, Xuzhou Medical University, Changzhou, China
- Department of Endocrinology, Changzhou Third People’s Hospital, Changzhou, China
- Department of Clinical Nutrition, Changzhou Third People’s Hospital, Changzhou, China
| | - Wenjian Li
- Changzhou Clinical College, Xuzhou Medical University, Changzhou, China
- Department of Urology, Changzhou Third People’s Hospital, Changzhou, China
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Jung H, Kyun ML, Kwon JI, Kim J, Kim JK, Park D, Lee YB, Moon KS. Amplified response of drug-induced liver fibrosis via immune cell co-culture in a 3D in vitro hepatic fibrosis model. Biomater Sci 2024. [PMID: 39483068 DOI: 10.1039/d4bm00874j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
Liver fibrosis, a critical consequence of chronic liver diseases, is characterized by excessive extracellular matrix (ECM) deposition driven by inflammation. This process involves complex interactions among hepatocytes, hepatic stellate cells (HSCs), and Kupffer cells, the liver's resident macrophages. Kupffer cells are essential in initiating fibrosis through the release of pro-inflammatory cytokines that activate HSCs. Although various in vitro liver fibrosis models have been developed, there is a lack of models that include the immune environment of the liver to clarify the influence of immune cells on the progression of liver fibrosis. We developed an in vitro liver fibrosis model by co-culturing hepatocytes (HepaRG), a hepatic stellate cell line (LX-2), and macrophages (differentiated THP-1). The effects of liver fibrosis inducers, transforming growth factor-beta1 (TGF-β1) and methotrexate (MTX), on the inflammatory response and stellate cell activation were evaluated in this triple co-culture model. A triple co-culture condition was developed as a 3D in vitro model using gelatin methacrylate (GelMA), offering a more biomimetic environment and achieving liver fibrosis via immune cell activation associated ECM deposition. In this study, the developed triple co-culture model has the potential to elucidate cell progression roles in liver fibrosis and can be applied in drug screening and toxicity assessments targeting liver fibrosis.
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Affiliation(s)
- Hyewon Jung
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
| | - Mi-Lang Kyun
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
| | - Ji-In Kwon
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Department of Food and Nutrition, University of Hannam, Daejeon, 34054, Republic of Korea
| | - Jeongha Kim
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Department of Food and Nutrition, University of Hannam, Daejeon, 34054, Republic of Korea
| | - Ju-Kang Kim
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
| | - Daeui Park
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
- Center for Biomimetic Research, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea
| | - Yu Bin Lee
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
| | - Kyoung-Sik Moon
- Center for Global Biopharmaceutical Research, Korea Institute of Toxicology, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea.
- Human and Environmental Toxicology, University of Science and Technology, Daejeon, 34114, Republic of Korea.
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Maddineni G, Obulareddy SJ, Paladiya RD, Korsapati RR, Jain S, Jeanty H, Vikash F, Tummala NC, Shetty S, Ghazalgoo A, Mahapatro A, Polana V, Patel D. The role of gut microbiota augmentation in managing non-alcoholic fatty liver disease: an in-depth umbrella review of meta-analyses with grade assessment. Ann Med Surg (Lond) 2024; 86:4714-4731. [PMID: 39118769 PMCID: PMC11305784 DOI: 10.1097/ms9.0000000000002276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 06/03/2024] [Indexed: 08/10/2024] Open
Abstract
Background and aim Currently, there are no authorized medications specifically for non-alcoholic fatty liver disease (NAFLD) treatment. Studies indicate that changes in gut microbiota can disturb intestinal balance and impair the immune system and metabolism, thereby elevating the risk of developing and exacerbating NAFLD. Despite some debate, the potential benefits of microbial therapies in managing NAFLD have been shown. Methods A systematic search was undertaken to identify meta-analyses of randomized controlled trials that explored the effects of microbial therapy on the NAFLD population. The goal was to synthesize the existing evidence-based knowledge in this field. Results The results revealed that probiotics played a significant role in various aspects, including a reduction in liver stiffness (MD: -0.38, 95% CI: [-0.49, -0.26]), hepatic steatosis (OR: 4.87, 95% CI: [1.85, 12.79]), decrease in body mass index (MD: -1.46, 95% CI: [-2.43, -0.48]), diminished waist circumference (MD: -1.81, 95% CI: [-3.18, -0.43]), lowered alanine aminotransferase levels (MD: -13.40, 95% CI: [-17.02, -9.77]), decreased aspartate aminotransferase levels (MD: -13.54, 95% CI: [-17.85, -9.22]), lowered total cholesterol levels (MD: -15.38, 95% CI: [-26.49, -4.26]), decreased fasting plasma glucose levels (MD: -4.98, 95% CI: [-9.94, -0.01]), reduced fasting insulin (MD: -1.32, 95% CI: [-2.42, -0.21]), and a decline in homeostatic model assessment of insulin resistance (MD: -0.42, 95% CI: [-0.72, -0.11]) (P<0.05). Conclusion Overall, the results demonstrated that gut microbiota interventions could ameliorate a wide range of indicators including glycemic profile, dyslipidemia, anthropometric indices, and liver injury, allowing them to be considered a promising treatment strategy.
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Affiliation(s)
| | | | | | | | - Shika Jain
- MVJ Medical College and Research Hospital, Bengaluru, Karnataka, India
| | | | - Fnu Vikash
- Jacobi Medical Center, Albert Einstein College of Medicine, Bronx
| | - Nayanika C. Tummala
- Gitam Institute of Medical Sciences and Research, Visakhapatnam, Andhra Pradesh
| | | | - Arezoo Ghazalgoo
- Student Research Committee, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | | | | | - Dhruvan Patel
- Drexel University College of Medicine, Philadelphia, Pennsylvania, PA
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Wang JJ, Zheng Z, Zhang Y. Association of Hematological Biomarkers of Inflammation with 10-Year Major Adverse Cardiovascular Events and All-Cause Mortality in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: The ARIC Study. J Inflamm Res 2024; 17:4247-4256. [PMID: 38973998 PMCID: PMC11227334 DOI: 10.2147/jir.s466469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Accepted: 06/26/2024] [Indexed: 07/09/2024] Open
Abstract
Background Metabolic dysfunction-associated steatotic liver disease (MASLD) increases the risk of cardiovascular disease and existing evidence indicates that MASLD affects the cardiovascular system through systemic inflammation. Our aim was to assess the association of hematological biomarkers of inflammation with the 10-year risk of major adverse cardiovascular events (MACE) and all-cause mortality in MASLD patients. Methods A total of 1858 MASLD participants from the Atherosclerosis Risk in Communities cohort study at visit 2 (1990-1992) were included. A total of 1338 non-MASLD participants were also included in the comparison. At baseline, hematological biomarkers of inflammation such as leukocytes, neutrophils, lymphocytes, monocytes, and C-reactive protein (CRP) were measured. Participants were followed up for MACE and all-cause mortality for a period of 10 years. Multivariate adjusted Cox models were used to estimate hazard ratios (HR). Results The 10-year MACE was higher in MASLD participants than in non-MASLD participants (20.8% vs 9.3%). Monocytes (HR 1.114, [95% CI, 1.022-1.216] per 1-SD, P=0.015) and CRP (HR 1.109 [95% CI, 1.032-1.190] per 1-SD, P=0.005) were associated with an increased 10-year risk of MACE, independent of other cardiovascular risk factors. This association was specific to the MASLD population. None of these hematological biomarkers demonstrated a significant association with 10-year all-cause mortality. Conclusion Increased levels of monocytes and CRP were associated with an increased 10-year risk of MACE in the MASLD population. Hematological biomarkers of inflammation may help identify MASLD populations at higher risk for cardiovascular events.
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Affiliation(s)
- Jia-Jie Wang
- Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China
| | - Zhichao Zheng
- Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China
| | - Ying Zhang
- Department of Cardiology, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, People’s Republic of China
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Meyer M, Schwärzler J, Jukic A, Tilg H. Innate Immunity and MASLD. Biomolecules 2024; 14:476. [PMID: 38672492 PMCID: PMC11048298 DOI: 10.3390/biom14040476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications.
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Affiliation(s)
| | | | | | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University Innsbruck, 6020 Innsbruck, Austria; (M.M.); (A.J.)
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Koufakis T, Popovic DS, Papadopoulos C, Giouleme O, Doumas M. Effectively addressing cardiovascular risk in people with metabolic-dysfunction associated fatty liver disease: not yet ready for prime time! Expert Opin Pharmacother 2024; 25:123-126. [PMID: 38284365 DOI: 10.1080/14656566.2024.2312239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Accepted: 01/26/2024] [Indexed: 01/30/2024]
Affiliation(s)
- Theocharis Koufakis
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Djordje S Popovic
- Clinic for Endocrinology, Diabetes and Metabolic Disorders, Clinical Centre of Vojvodina, University of Novi Sad, Novi Sad, Serbia
- Medical Faculty, University of Novi Sad, Novi Sad, Serbia
| | - Christodoulos Papadopoulos
- Third Department of Cardiology, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Olga Giouleme
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Gastroenterology and Hepatology Division, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, Hippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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10
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Liu C, Sun X, Peng J, Yu H, Lu J, Feng Y. Association between dietary vitamin A intake from different sources and non-alcoholic fatty liver disease among adults. Sci Rep 2024; 14:1851. [PMID: 38253816 PMCID: PMC10803811 DOI: 10.1038/s41598-024-52077-5] [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: 09/01/2023] [Accepted: 01/12/2024] [Indexed: 01/24/2024] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become an urgent public health issue with high global prevalence, but data on NAFLD are inconsistent. The association of total dietary vitamin A intake with the NAFLD risk was not well documented in previous studies. To explore the relationship between dietary vitamin A intake from different sources and NAFLD risk among American adults. Data were collected from the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2014. Logistic regression and restricted cubic spline models were used to estimate the relationship between total dietary vitamin A intake and NAFLD risk. 6,613 adult participants were included. After adjusting potential confounders, the odds ratios (ORs) with 95% confidence intervals (CIs) of NAFLD for the highest quartile intake of total vitamin A, preformed vitamin A, provitamin A carotenoids were respectively 0.86 (0.69-1.06), 0.97 (0.74-1.28), and 0.78 (0.61-0.99), compared to the lowest quartile. Stratifying gender and age, provitamin A carotenoids intake was inversely associated with NAFLD risk in females and participants aged < 45 years. Dose-response analysis indicated a linear negative relationship between provitamin A carotenoids intake and NAFLD risk. Provitamin A carotenoids intake was inversely associated with NAFLD, especially in women and those aged < 45 years among adult American.
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Affiliation(s)
- Can Liu
- School of Public Health, Shanxi Medical University, Taiyuan, China
- School of Management, Shanxi Medical University, Taiyuan, China
| | - Xiaona Sun
- Department of Respiratory and Critical Care Medicine, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Jing Peng
- Department of Pediatrics, Qingdao Central Hospital, University of Health and Rehabilitation Sciences, Qingdao, China
| | - Haiqing Yu
- Shenzhen Maternity and Child Healthcare Hospital, Shenzhen, China
| | - Jiao Lu
- School of Public Policy and Administration, Xi'an Jiaotong University, Xi'an, China
| | - Yihui Feng
- School of Rehabilitation Science and Engineering, University of Health and Rehabilitation Sciences, Qingdao, China.
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11
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Harden JE, Tabacu L, Reynolds LJ. Physical activity intensity and markers of inflammation in those with non-alcoholic fatty liver disease. Diabetes Res Clin Pract 2024; 207:111047. [PMID: 38070545 DOI: 10.1016/j.diabres.2023.111047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/14/2023] [Accepted: 12/05/2023] [Indexed: 02/10/2024]
Abstract
AIMS To investigate associations between objectively measured light (LPA) and moderate-to-vigorous (MVPA) physical activity on plasma homocysteine and serum C-reactive protein (CRP) in individuals with Non-Alcoholic Fatty Liver Disease (NAFLD). METHODS This study was a secondary analysis using data from 2003 to 2006 National Health and Nutrition Examination Survey including a total of 983 individuals with NAFLD. Physical activity was assessed over 7 days with accelerometers. Participants were split into tertiles based on average daily minutes of LPA or MVPA and CRP and homocysteine were assessed across tertiles. RESULTS Adjusted plasma homocysteine and CRP were not different between groups regarding levels of LPA (Homocysteine: 1st tertile - 10.4 ± 0.7 µmol/L; 2nd tertile - 9.6 ± 0.4 µmol/L; 3rd tertile - 9.6 ± 0.4 µmol/L; p = 0.28; CRP: 1st tertile - 0.79 ± 0.12 mg/dL; 2nd tertile - 0.73 ± 0.09 mg/dL; 3rd tertile - 0.73 ± 0.09 mg/dL; p = 0.72). Adjusted CRP was significantly (p = 0.02) different across MVPA tertiles (1st: 0.87 ± 0.13 mg/dL; 2nd: 0.75 ± 0.10 mg/dL; 3rd:0.65 ± 0.09). CONCLUSIONS LPA does not appear to be effective at improving homocysteine or CRP levels in individuals with NAFLD. However, MVPA may be an effective therapy for decreasing CRP in NAFLD patients.
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Affiliation(s)
- Joel E Harden
- School of Exercise Science, Old Dominion University, Norfolk, VA, USA
| | - Lucia Tabacu
- Department of Mathematics and Statistics, Old Dominion University, Norfolk, VA, USA
| | - Leryn J Reynolds
- School of Exercise Science, Old Dominion University, Norfolk, VA, USA.
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12
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Lee TB, Kueh MTW, Jain V, Razavi AC, Alebna P, Chew NWS, Mehta A. Biomarkers of Hepatic Dysfunction and Cardiovascular Risk. Curr Cardiol Rep 2023; 25:1783-1795. [PMID: 37971635 PMCID: PMC10902719 DOI: 10.1007/s11886-023-01993-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/31/2023] [Indexed: 11/19/2023]
Abstract
PURPOSE OF REVIEW The objective of this manuscript is to examine the current literature on non-alcoholic fatty liver disease (NAFLD) biomarkers and their correlation with cardiovascular disease (CVD) outcomes and cardiovascular risk scores. RECENT FINDINGS There has been a growing appreciation for an independent link between NAFLD and CVD, culminating in a scientific statement by the American Heart Association in 2022. More recently, studies have begun to identify biomarkers of the three NAFLD phases as potent predictors of cardiovascular risk. Despite the body of evidence supporting a connection between hepatic biomarkers and CVD, more research is certainly needed, as some studies find no significant relationship. If this relationship continues to be robust and readily reproducible, NAFLD and its biomarkers may have an exciting role in the future of cardiovascular risk prediction, possibly as risk-enhancing factors or as components of novel cardiovascular risk prediction models.
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Affiliation(s)
- Terence B Lee
- VCU Health, Department of Internal Medicine, Richmond, VA, USA
| | - Martin T W Kueh
- UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland
- Royal College of Surgeons in Ireland & University College Dublin Malaysia Campus, George Town, Malaysia
| | - Vardhmaan Jain
- Emory Clinical Cardiovascular Research Institute, Atlanta, GA, USA
| | | | | | - Nicholas W S Chew
- Department of Cardiology, National University Heart Centre, National University Health System, Singapore, Singapore
| | - Anurag Mehta
- VCU Health Pauley Heart Center, Richmond, VA, USA.
- Preventive Cardiology, Internal Medicine, Virginia Commonwealth University School of Medicine, 1200 East Broad Street, PO Box 980036, Richmond, VA, 23298, USA.
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Ramezani M, Zobeiry M, Abdolahi S, Hatami B, Zali MR, Baghaei K. A crosstalk between epigenetic modulations and non-alcoholic fatty liver disease progression. Pathol Res Pract 2023; 251:154809. [PMID: 37797383 DOI: 10.1016/j.prp.2023.154809] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 09/08/2023] [Accepted: 09/08/2023] [Indexed: 10/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has recently emerged as a major public health concern worldwide due to its rapidly rising prevalence and its potential to progress into end-stage liver disease. While the precise pathophysiology underlying NAFLD remains incompletely understood, it is strongly associated with various environmental triggers and other metabolic disorders. Epigenetics examines changes in gene expression that are not caused by alterations in the DNA sequence itself. There is accumulating evidence that epigenetics plays a key role in linking environmental cues to the onset and progression of NAFLD. Our understanding of how epigenetic mechanisms contribute to NAFLD pathophysiology has expanded considerably in recent years as research on the epigenetics of NAFLD has developed. This review summarizes recent insights into major epigenetic processes that have been implicated in NAFLD pathogenesis including DNA methylation, histone acetylation, and microRNAs that have emerged as promising targets for further investigation. Elucidating epigenetic mechanisms in NAFLD may uncover novel diagnostic biomarkers and therapeutic targets for this disease. However, many questions have remained unanswered regarding how epigenetics promotes NAFLD onset and progression. Additional studies are needed to further characterize the epigenetic landscape of NAFLD and validate the potential of epigenetic markers as clinical tools. Nevertheless, an enhanced understanding of the epigenetic underpinnings of NAFLD promises to provide key insights into disease mechanisms and pave the way for novel prognostic and therapeutic approaches.
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Affiliation(s)
- Meysam Ramezani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Shahrokh Abdolahi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Behzad Hatami
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Gîlcă-Blanariu GE, Budur DS, Mitrică DE, Gologan E, Timofte O, Bălan GG, Olteanu VA, Ștefănescu G. Advances in Noninvasive Biomarkers for Nonalcoholic Fatty Liver Disease. Metabolites 2023; 13:1115. [PMID: 37999211 PMCID: PMC10672868 DOI: 10.3390/metabo13111115] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 10/15/2023] [Accepted: 10/24/2023] [Indexed: 11/25/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) currently represents one of the most common liver diseases worldwide. Early diagnosis and disease staging is crucial, since it is mainly asymptomatic, but can progress to nonalcoholic steatohepatitis (NASH) or cirrhosis or even lead to the development of hepatocellular carcinoma. Over time, efforts have been put into developing noninvasive diagnostic and staging methods in order to replace the use of a liver biopsy. The noninvasive methods used include imaging techniques that measure liver stiffness and biological markers, with a focus on serum biomarkers. Due to the impressive complexity of the NAFLD's pathophysiology, biomarkers are able to assay different processes involved, such as apoptosis, fibrogenesis, and inflammation, or even address the genetic background and "omics" technologies. This article reviews not only the currently validated noninvasive methods to investigate NAFLD but also the promising results regarding recently discovered biomarkers, including biomarker panels and the combination of the currently validated evaluation methods and serum markers.
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Affiliation(s)
- Georgiana-Emmanuela Gîlcă-Blanariu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Daniela Simona Budur
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Dana Elena Mitrică
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Elena Gologan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
| | - Oana Timofte
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gheorghe Gh Bălan
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Vasile Andrei Olteanu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
| | - Gabriela Ștefănescu
- Gastroenterology Department, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iași, Romania; (G.-E.G.-B.); (D.E.M.); (E.G.); (O.T.); (G.G.B.); (V.A.O.)
- Department of Gastroenterology, “Sf Spiridon” County Clinical Emergency Hospital, 100115 Iași, Romania
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Okekunle AP, Youn J, Song S, Chung GE, Yang SY, Kim YS, Lee JE. Predicted pro-inflammatory hs-CRP score and non-alcoholic fatty liver disease. Gastroenterol Rep (Oxf) 2023; 11:goad059. [PMID: 37842198 PMCID: PMC10568523 DOI: 10.1093/gastro/goad059] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 08/07/2023] [Accepted: 08/23/2023] [Indexed: 10/17/2023] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is a major contributor to liver diseases globally, yet there are limited studies investigating the impact of diet and lifestyle factors on its development. This study aimed to examine the association between the prevalence of NAFLD and predicted pro-inflammatory high-sensitivity C-reactive protein (hs-CRP) score. Methods We included 1,076 Korean adults who underwent a medical examination at the Seoul National University Hospital Gangnam Healthcare Center in Korea between May and December 2011 and updated in 2021. The predicted pro-inflammatory hs-CRP score was derived from pro-inflammatory demographic, lifestyle, dietary, and anthropometric factors, and NAFLD was diagnosed using liver ultrasound. Multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of NAFLD odds according to predicted pro-inflammatory hs-CRP score were estimated using logistic regression at a two-sided P < 0.05. Results Among the 1,076 participants, 320 had NAFLD. The multivariable-adjusted ORs and 95% CIs for NAFLD by tertiles of predicted pro-inflammatory hs-CRP score were 1.00, 3.30 (2.06, 5.30), 18.25 (10.47, 31.81; P < 0.0001) in men and women combined, 1.00, 1.77 (1.10, 2.84), and 3.26 (2.02, 5.28; P < 0.0001) among men only, and 1.00, 3.03 (1.39, 6.62), and 16.71 (7.05, 39.63; P < 0.0001) among women only. Conclusions Predicted pro-inflammatory hs-CRP score was associated with higher odds of NAFLD. Adopting dietary and lifestyle changes related to lower inflammation might be a valuable strategy for preventing NAFLD.
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Affiliation(s)
- Akinkunmi Paul Okekunle
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea
- Research Institute of Human Ecology, Seoul National University, Seoul, Korea
| | - Jiyoung Youn
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea
| | - Sihan Song
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea
| | - Goh Eun Chung
- Healthcare System Gangnam Center, Healthcare Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Sun Young Yang
- Healthcare System Gangnam Center, Healthcare Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Young Sun Kim
- Healthcare System Gangnam Center, Healthcare Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Jung Eun Lee
- Department of Food and Nutrition, College of Human Ecology, Seoul National University, Seoul, Korea
- Healthcare System Gangnam Center, Healthcare Research Institute, Seoul National University Hospital, Seoul, Korea
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Ding Z, Wei Y, Peng J, Wang S, Chen G, Sun J. The Potential Role of C-Reactive Protein in Metabolic-Dysfunction-Associated Fatty Liver Disease and Aging. Biomedicines 2023; 11:2711. [PMID: 37893085 PMCID: PMC10603830 DOI: 10.3390/biomedicines11102711] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Revised: 09/27/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), recently redefined as metabolic-dysfunction-associated fatty liver disease (MASLD), is liver-metabolism-associated steatohepatitis caused by nonalcoholic factors. NAFLD/MASLD is currently the most prevalent liver disease in the world, affecting one-fourth of the global population, and its prevalence increases with age. Current treatments are limited; one important reason hindering drug development is the insufficient understanding of the onset and pathogenesis of NAFLD/MASLD. C-reactive protein (CRP), a marker of inflammation, has been linked to NAFLD and aging in recent studies. As a conserved acute-phase protein, CRP is widely characterized for its host defense functions, but the link between CRP and NAFLD/MASLD remains unclear. Herein, we discuss the currently available evidence for the involvement of CRP in MASLD to identify areas where further research is needed. We hope this review can provide new insights into the development of aging-associated NAFLD biomarkers and suggest that modulation of CRP signaling is a potential therapeutic target.
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Affiliation(s)
- Zheng Ding
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100190, China
| | - Yuqiu Wei
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100190, China
| | - Jing Peng
- College of Biological Sciences, China Agricultural University, Beijing 100193, China
| | - Siyu Wang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100190, China
| | - Guixi Chen
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100190, China
| | - Jiazeng Sun
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100190, China
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17
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Mouliou DS. C-Reactive Protein: Pathophysiology, Diagnosis, False Test Results and a Novel Diagnostic Algorithm for Clinicians. Diseases 2023; 11:132. [PMID: 37873776 PMCID: PMC10594506 DOI: 10.3390/diseases11040132] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 09/15/2023] [Accepted: 09/19/2023] [Indexed: 10/25/2023] Open
Abstract
The current literature provides a body of evidence on C-Reactive Protein (CRP) and its potential role in inflammation. However, most pieces of evidence are sparse and controversial. This critical state-of-the-art monography provides all the crucial data on the potential biochemical properties of the protein, along with further evidence on its potential pathobiology, both for its pentameric and monomeric forms, including information for its ligands as well as the possible function of autoantibodies against the protein. Furthermore, the current evidence on its potential utility as a biomarker of various diseases is presented, of all cardiovascular, respiratory, hepatobiliary, gastrointestinal, pancreatic, renal, gynecological, andrological, dental, oral, otorhinolaryngological, ophthalmological, dermatological, musculoskeletal, neurological, mental, splenic, thyroid conditions, as well as infections, autoimmune-supposed conditions and neoplasms, including other possible factors that have been linked with elevated concentrations of that protein. Moreover, data on molecular diagnostics on CRP are discussed, and possible etiologies of false test results are highlighted. Additionally, this review evaluates all current pieces of evidence on CRP and systemic inflammation, and highlights future goals. Finally, a novel diagnostic algorithm to carefully assess the CRP level for a precise diagnosis of a medical condition is illustrated.
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Jamialahmadi T, Bo S, Abbasifard M, Sathyapalan T, Jangjoo A, Moallem SA, Almahmeed W, Ashari S, Johnston TP, Sahebkar A. Association of C-reactive protein with histological, elastographic, and sonographic indices of non-alcoholic fatty liver disease in individuals with severe obesity. JOURNAL OF HEALTH, POPULATION, AND NUTRITION 2023; 42:30. [PMID: 37029427 PMCID: PMC10080847 DOI: 10.1186/s41043-023-00372-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 03/31/2023] [Indexed: 04/09/2023]
Abstract
BACKGROUND Inflammation is critical in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). hs-CRP, an inflammatory marker, is considered one of the prognostic predictors of hepatic damage progression in NAFLD in some studies. METHODS We assessed the concordance of hs-CRP concentrations and liver steatosis, steatohepatitis, and fibrosis based on elastography, sonography and liver biopsy findings in patients with severe obesity undergoing bariatric surgery. RESULTS Among 90 patients, 56.7% showed steatohepatitis and 8.9% severe fibrosis. Hs-CRP were significantly associated with liver histology in an adjusted regression model (OR 1.155, 95% CI 1.029-1.297, p = 0.014; OR 1.155, 1.029-1.297, p = 0.014; OR 1.130, 1.017-1.257, p = 0.024 for steatosis, steatohepatitis, and fibrosis, respectively). The ROC curve, a cutoff of hs-CRP = 7 mg/L, showed a reasonable specificity (76%) for detecting biopsy-proven fibrosis and steatosis. CONCLUSION hs-CRP was associated with any degree of histologically diagnosed liver damage, and it had a reasonable specificity for predicting biopsy-proven steatosis and fibrosis in obese individuals. Further studies are needed to identify non-invasive biomarkers that could predict NALFD progression due to the relevant health risks linked to liver fibrosis.
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Affiliation(s)
- Tannaz Jamialahmadi
- Surgical Oncolgy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Simona Bo
- Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
| | - Mitra Abbasifard
- Immunology of Infectious Diseases Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Internal Medicine, Ali-Ibn Abi-Talib Hospital, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Thozhukat Sathyapalan
- Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull, UK
| | - Ali Jangjoo
- Surgical Oncolgy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Adel Moallem
- Department of Pharmacology and Toxicology, College of Pharmacy, Al-Zahraa University for Women, Karbala, Iraq
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Wael Almahmeed
- Heart and Vascular Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Sorour Ashari
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
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Valle-Martos R, Jiménez-Reina L, Cañete R, Martos R, Valle M, Cañete MD. Changes in liver enzymes are associated with changes in insulin resistance, inflammatory biomarkers and leptin in prepubertal children with obesity. Ital J Pediatr 2023; 49:29. [PMID: 36894963 PMCID: PMC9996910 DOI: 10.1186/s13052-023-01434-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 02/24/2023] [Indexed: 03/11/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease is associated with obesity. A subclinical inflammation state, endothelial dysfunction, and parameters related to metabolic syndrome (MetS), have been documented in children with obesity. We aimed to determine the changes that occur in liver enzymes levels in response to the standard treatment of childhood obesity, also assessing any associations with liver enzyme levels, leptin, and markers of insulin resistance (IR), inflammation, and parameters related to MetS in prepubertal children. METHODS We carried out a longitudinal study in prepubertal children (aged 6-9 years) of both sexes with obesity; a total of 63 participants were recruited. Liver enzymes, C-reactive protein (CRP), interleukin-6, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), soluble intercellular adhesion molecule-1 (sICAM-1), leptin, homeostasis model assessment for IR (HOMA-IR), and parameters related to MetS were measured. RESULTS After standard treatment for 9 months, children who lowered their standardised body mass index (SDS-BMI) had significantly lower systolic blood pressure (p = 0.0242), diastolic blood pressure (p = 0.0002), HOMA-IR (p = 0.0061), and levels of alanine aminotransferase (ALT) (p = 0.0048), CRP (p = 0.0001), sICAM-1 (p = 0.0460), and IL-6 (p = 0.0438). There was a significant association between the changes that occur with treatment, in the ALT levels, and changes in leptin (p = 0.0096), inflammation biomarkers [CRP (p = 0.0061), IL-6 (p = 0.0337), NLR (p = 0.0458), PLR (p = 0.0134)], and HOMA-IR (p = 0.0322). CONCLUSION Our results showed that a decrease in ALT levels after the standard treatment for 9 months was associated with favourable changes in IR markers (HOMA-IR) and inflammation (IL-6, CRP, NLR, and PLR).
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Affiliation(s)
| | | | - Ramón Cañete
- Faculty of Medicine, University of Córdoba, IMIBIC, Córdoba, Spain
| | | | - Miguel Valle
- Valle de los Pedroches Hospital, IMIBIC, Córdoba, Spain.
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Kobayashi T, Iwaki M, Nogami A, Honda Y, Ogawa Y, Imajo K, Saito S, Nakajima A, Yoneda M. Involvement of Periodontal Disease in the Pathogenesis and Exacerbation of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis: A Review. Nutrients 2023; 15:1269. [PMID: 36904268 PMCID: PMC10004797 DOI: 10.3390/nu15051269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 02/23/2023] [Accepted: 02/28/2023] [Indexed: 03/08/2023] Open
Abstract
The increasing incidence of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), along with global lifestyle changes, requires further in-depth research to elucidate the mechanisms and develop new treatment strategies. In addition, the number of patients with periodontal disease has increased recently, suggesting that periodontal disease is sometimes associated with systemic conditions. In this review, we summarize recent studies linking periodontal disease and NAFLD, the concept of the mouth-gut-liver axis, oral and intestinal microbiota, and liver disease. We suggest new research directions toward a detailed mechanistic understanding and novel targets for treatment and prevention. Forty years have passed since the concepts of NAFLD and NASH were first proposed. however, no effective prevention or treatment has been established. We also found that the pathogenesis of NAFLD/NASH is not limited to liver-related diseases but has been reported to be associated with various systemic diseases and an increasing number of causes of death. In addition, changes in the intestinal microbiota have been shown to be a risk factor for periodontal diseases, such as atherosclerosis, diabetes, rheumatoid arthritis, nonalcoholic fatty liver disease, and obesity.
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Affiliation(s)
- Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan
| | - Yuji Ogawa
- National Hospital Organization Yokohama Medical Center, Gastroenterology Division, 3-60-2 Harajyuku, Yokohama 245-8575, Japan
| | - Kento Imajo
- Department of Gastroenterology, Shin-Yurigaoka General Hospital, 255 Tsuko, Furusawa, Kawasaki 215-0026, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa, Yokohama 236-0004, Japan
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Carretero-Gómez J, Carrasco-Sánchez FJ, Fernández-Rodríguez JM, Casado-Escribano P, Miramontes-González JP, Seguí-Ripoll JM, Ena J, Arévalo-Lorido JC. Effect of semaglutide on fatty liver disease biomarkers in patients with diabetes and obesity. Rev Clin Esp 2023; 223:134-143. [PMID: 36549643 DOI: 10.1016/j.rceng.2022.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Accepted: 11/17/2022] [Indexed: 12/23/2022]
Abstract
AIM This work aims to assess the effect of weekly subcutaneous semaglutide on biomarkers of metabolic-associated fatty liver disease (MAFLD), namely the hepatic steatosis index (HSI) and the fibrosis-4 (FIB-4) index, at 24 weeks in outpatients attended to in internal medicine departments. METHODS This study analyzed patients in an ongoing, multicenter, prospective, pre-post, uncontrolled cohort registry that enrolls unique, consecutive patients with type 2 diabetes treated with weekly subcutaneous semaglutide. Steatosis/fibrosis were determined by HSI (<30 ruled out, >36 steatosis) and FIB-4 (<1.3 ruled out, >2.67 fibrosis), respectively. RESULTS The sample included 213 patients (46.9% women) with a median age of 64 (19) years. The median baseline body mass index and weight were 36.1 (8.4) kg/m2 and 98 (26.9) kg, respectively. A total of 99.9% had HSI values indicating steatosis, with a mean HSI of 47.9 (8.2). Additionally, 10.8% had fibrosis (FIB-4 > 2.67) and 42.72% had values in intermediate ranges (FIB-4 1.3-2.67). At 24 weeks, there was a significant reduction in HSI (-2.36 (95%CI 1.83-2.9) p < 0.00001) and FIB-4 (-0.075 (95%CI 0.015-0.14) p < 0.016), mainly related to declines in body weight, triglyceride levels, insulin resistance (estimated by the triglyceride-glucose index), and liver enzymes. CONCLUSION These results show that weekly subcutaneous semaglutide had a beneficial effect on liver steatosis that went beyond glucose control. Its effects were mainly related to weight loss, a decline in biomarkers, and improvements in insulin sensitivity. For many patients, early detection is essential for improving MAFLD outcomes and may allow for selecting the most efficient treatment options.
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Affiliation(s)
| | | | | | | | - José Pablo Miramontes-González
- Servicio de Medicina Interna, Hospital Universitario Río Hortega, Valladolid, IBSAL - Instituto de Investigaciones Biomédicas de Salamanca, Salamanca, Spain
| | | | - Javier Ena
- Servicio de Medicina Interna, Hospital Universitario Marina Baixa Hospital, La Villajoyosa (Alicante), Spain
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22
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Setting up of a machine learning algorithm for the identification of severe liver fibrosis profile in the general US population cohort. Int J Med Inform 2023; 170:104932. [PMID: 36459836 DOI: 10.1016/j.ijmedinf.2022.104932] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 11/19/2022] [Accepted: 11/21/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND The progress of digital transformation in clinical practice opens the door to transforming the current clinical line for liver disease diagnosis from a late-stage diagnosis approach to an early-stage based one. Early diagnosis of liver fibrosis can prevent the progression of the disease and decrease liver-related morbidity and mortality. We developed here a machine learning (ML) algorithm containing standard parameters that can identify liver fibrosis in the general US population. MATERIALS AND METHODS Starting from a public database (National Health and Nutrition Examination Survey, NHANES), representative of the American population with 7265 eligible subjects (control population n = 6828, with Fibroscan values E < 9.7 KPa; target population n = 437 with Fibroscan values E ≥ 9.7 KPa), we set up an SVM algorithm able to discriminate for individuals with liver fibrosis among the general US population. The algorithm set up involved the removal of missing data and a sampling optimization step to managing the data imbalance (only ∼ 5 % of the dataset is the target population). RESULTS For the feature selection, we performed an unbiased analysis, starting from 33 clinical, anthropometric, and biochemical parameters regardless of their previous application as biomarkers of liver diseases. Through PCA analysis, we identified the 26 more significant features and then used them to set up a sampling method on an SVM algorithm. The best sampling technique to manage the data imbalance was found to be oversampling through the SMOTE-NC. For final model validation, we utilized a subset of 300 individuals (150 with liver fibrosis and 150 controls), subtracted from the main dataset prior to sampling. Performances were evaluated on multiple independent runs. CONCLUSIONS We provide proof of concept of an ML clinical decision support tool for liver fibrosis diagnosis in the general US population. Though the presented ML model represents at this stage only a prototype, in the future, it might be implemented and potentially applied to program broad screenings for liver fibrosis.
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23
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Carretero-Gómez J, Carrasco-Sánchez F, Fernández-Rodríguez J, Casado-Escribano P, Miramontes-González J, Seguí-Ripoll J, Ena J, Arévalo-Lorido J. Efecto de semaglutida sobre los biomarcadores de la enfermedad del hígado graso en pacientes con diabetes y obesidad. Rev Clin Esp 2023. [DOI: 10.1016/j.rce.2022.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/18/2023]
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Chu K, Cadar D, Iob E, Frank P. Excess body weight and specific types of depressive symptoms: Is there a mediating role of systemic low-grade inflammation? Brain Behav Immun 2023; 108:233-244. [PMID: 36462595 PMCID: PMC10567582 DOI: 10.1016/j.bbi.2022.11.016] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 11/25/2022] [Accepted: 11/26/2022] [Indexed: 12/02/2022] Open
Abstract
OBJECTIVES Obesity is associated with an increased risk of depression. Systemic low-grade inflammation, a plausible consequence of obesity, has also been linked to depression. However, the potential mediating effects of systemic low-grade inflammation on the association between excess body weight and specific symptom domains of depression remain uncertain. This study examined whether systemic low-grade inflammation mediated the associations of excess body weight (overweight and obesity) with subsequent overall, cognitive-affective, and somatic depressive symptoms. DESIGN This study used a prospective cohort design. METHODS The final analytical sample included 4,942 adults aged ≥50 years drawn from the English Longitudinal Study of Ageing (ELSA). Body mass index (BMI) and covariates were ascertained at baseline (wave 4, 2008/09). Continuous BMI scores were divided into four categories: 'normal weight' (18.5 ≤ BMI <25 kg/m2); 'overweight' (25 ≤ BMI <30 kg/m2); 'obesity' (BMI ≥30 kg/m2); in addition to 'excess body weight' ('overweight' and 'obesity' combined). Covariates included sociodemographic variables, behavioural factors, and chronic physical conditions. Serum concentrations of CRP were measured at wave 6 (2012/13). Depressive symptoms were assessed at baseline and ten years later (wave 9, 2018/19), using the 8-item Centre for Epidemiological Studies Depression (CES-D) Scale. Two symptom domains were constructed, distinguishing between cognitive-affective (depressed mood, loneliness, sadness, enjoyment in life, and happiness) and somatic (sleep problems, low energy levels, and fatigue) symptoms. Mediation analyses were performed to examine whether CRP statistically mediated the associations between BMI categories and depressive symptoms. RESULTS In multivariable-adjusted analyses, excess body weight was associated with elevated somatic (OR = 1.231, 95% CI: 1.029, 1.473), but not cognitive-affective or overall depressive symptoms at follow-up. Higher CRP was associated with elevated somatic (OR = 1.156, 95% CI: 1.061, 1.259), but not cognitive-affective or overall depressive symptoms. CRP acted as a partial mediator (14.92%) of the association between excess body weight and elevated somatic, but not cognitive-affective, or overall depressive symptoms. CONCLUSION Systemic low-grade inflammation may partially explain the association of excess body weight with somatic depressive symptoms, but not the associations with cognitive-affective or overall depressive symptoms.
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Affiliation(s)
- Keqin Chu
- Department of Behavioural Science and Health, University College London, London, UK.
| | - Dorina Cadar
- Department of Behavioural Science and Health, University College London, London, UK; Brighton and Sussex Medical School, Brighton, East Sussex, UK.
| | - Eleonora Iob
- Social, Genetic & Developmental Psychiatry (SGDP) Centre, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
| | - Philipp Frank
- Department of Behavioural Science and Health, University College London, London, UK.
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25
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Overview of Cellular and Soluble Mediators in Systemic Inflammation Associated with Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2023; 24:ijms24032313. [PMID: 36768637 PMCID: PMC9916753 DOI: 10.3390/ijms24032313] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 01/18/2023] [Accepted: 01/21/2023] [Indexed: 01/26/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently the most prevalent chronic liver disease in Western countries, affecting approximately 25% of the adult population. This condition encompasses a spectrum of liver diseases characterized by abnormal accumulation of fat in liver tissue (non-alcoholic fatty liver, NAFL) that can progress to non-alcoholic steatohepatitis (NASH), characterized by the presence of liver inflammation and damage. The latter form often coexists with liver fibrosis which, in turn, may progress to a state of cirrhosis and, potentially, hepatocarcinoma, both irreversible processes that often lead to the patient's death and/or the need for liver transplantation. Along with the high associated economic burden, the high mortality rate among NAFLD patients raises interest, not only in the search for novel therapeutic approaches, but also in early diagnosis and prevention to reduce the incidence of NAFLD-related complications. In this line, an exhaustive characterization of the immune status of patients with NAFLD is mandatory. Herein, we attempted to gather and compare the current and relevant scientific evidence on this matter, mainly on human reports. We addressed the current knowledge related to circulating cellular and soluble mediators, particularly platelets, different leukocyte subsets and relevant inflammatory soluble mediators.
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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Elsayed A, Ismaiel A, Procopio AC, Luzza F, Abenavoli L, Dumitrascu DL. Noninvasive biochemical markers and surrogate scores in evaluating nonalcoholic steatohepatitis. Minerva Med 2022; 113:864-874. [PMID: 35583419 DOI: 10.23736/s0026-4806.22.08185-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The histological features of nonalcoholic steatohepatitis (NASH) are the presence of hepatic steatosis with concomitant inflammation, ballooned hepatocytes, and potential fibrosis, which can lead to liver cirrhosis. To reduce the need for liver biopsy, that is still the gold standard for diagnosing NASH, various noninvasive biomarkers have been investigated. This narrative review summarizes the current knowledge about noninvasive diagnostic biomarkers and scores proposed for patients with NASH. A search was performed in the main medical literature databases. The following search terms were used: NASH, noninvasive biomarkers or NASH scores and panels. We focused only on studies assessing NASH diagnosis or predictive values for biomarkers, panels and scores. Data on their accuracy in predicting NASH were collected. Several panels such as NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4), and FibroMeter presented good predictive values of NASH, with novel proteomics panels such as the NAFLD Fibrosis Protein Panel (NFPP) using mainly the adisintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) that showed an advantage in predicting NASH compared to NFS and FIB-4. Another novel panel, Index of NASH (ION) performed better than cytokeratin 18 (CK-18) in excluding severe fibrosis, but the overall accuracy of ION and CK-18 was modest compared to NFS and FIB-4 as it did not provide any significant advantage. Noninvasive biomarkers are currently unable to replace liver biopsy and histological assessment. However, they may play a key and vital role in triaging patients for liver biopsy, lowering the related financial burden. Future studies are needed to verify the predictive values of the newly emerging tests and panels as well as to find more affordable and reliable noninvasive early diagnostic tools.
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Affiliation(s)
- Abdalla Elsayed
- Department of Internal Medicine, County Emergency Hospital Ilfov, Bucharest, Romania
| | - Abdulrahman Ismaiel
- Second Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania -
| | - Anna C Procopio
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Francesco Luzza
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Dan L Dumitrascu
- Second Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Shavakhi M, Nourigheimasi S, Dioso E, Goutnik M, Lucke-Wold B, Khanzadeh S, Heidari F. Prognostic Role of Neutrophil to Lymphocyte Ratio in Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Can J Gastroenterol Hepatol 2022; 2022:1554079. [PMID: 37601979 PMCID: PMC10432763 DOI: 10.1155/2022/1554079] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 08/19/2022] [Accepted: 08/29/2022] [Indexed: 08/22/2023] Open
Abstract
INTRODUCTION Nonalcoholic steatohepatitis (NASH) and liver fibrosis are the most common complications of nonalcoholic fatty liver disease (NAFLD). In this systematic review and meta-analysis, we aim to analyze the current literature to evaluate the association of neutrophil to lymphocyte ratio (NLR) with NASH and fibrosis in patients with NAFLD. METHODS PubMed, Web of Science, and Scopus were used to conduct a systematic search for relevant publications published before May 24, 2022. The Newcastle-Ottawa scale was used for quality assessment. RESULTS Thirteen studies were included in our study. The pooled results showed that NAFLD patients with significant NASH had elevated levels of NLR compared to those with nonsignificant or without NASH (SMD = 0.97, 95% CI = 0.59-1.39, p < 0.001). The pooled sensitivity and specificity of NLR were 78.16% (95% CI = 73.70%-82.04%), and 76.93% (95% CI = 70.22%-82.50%), respectively. In addition, NAFLD patients with significant liver fibrosis had elevated levels of NLR compared to those with nonsignificant or without fibrosis (SMD = 1.59, 95% CI = 0.76-2.43, p < 0.001). The pooled sensitivity and specificity of NLR were 82.62% (95% CI = 70.235%-90.55%) and 81.22% (95% CI = 75.62%-85.78%), respectively. CONCLUSION Our findings support NLR to be a promising biomarker that can be readily integrated into clinical settings to aid in the prediction and prevention of NASH and fibrosis among patients with NAFLD.
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Affiliation(s)
- Mitra Shavakhi
- Department of Pathology, School of Medicine, Isfahan University of Medical Sciences, Iran
| | | | - Emma Dioso
- Department of Neurosurgery, University of Utah, Salt Lake City, USA
| | - Michael Goutnik
- Department of Neurosurgery, University of Florida, Gainesville, USA
| | | | - Shokoufeh Khanzadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fariba Heidari
- Department of Community and Family Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Duan Y, Pan X, Luo J, Xiao X, Li J, Bestman PL, Luo M. Association of Inflammatory Cytokines With Non-Alcoholic Fatty Liver Disease. Front Immunol 2022; 13:880298. [PMID: 35603224 PMCID: PMC9122097 DOI: 10.3389/fimmu.2022.880298] [Citation(s) in RCA: 171] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Accepted: 04/11/2022] [Indexed: 01/30/2023] Open
Abstract
Background Inflammatory cytokines have been considered to be significant factors contributing to the development and progression of non-alcoholic fatty liver disease (NAFLD). However, the role of inflammatory cytokines in NAFLD remains inconclusive. Objective This study aimed to evaluate the association between inflammatory cytokines and NAFLD. Methods PubMed, Web of Science, the Cochrane Library, and EMBASE databases were searched until 31 December 2021 to identify eligible studies that reported the association of inflammatory cytokine with NAFLD and its subtypes. We pooled odds ratios (ORs) and hazard risk (HRs) with 95% confidence intervals (CIs) and conducted heterogeneity tests. Sensitivity analysis and analysis for publication bias were also carried out. Results The search in the databases identified 51 relevant studies that investigated the association between 19 different inflammatory cytokines and NAFLD based on 36,074 patients and 47,052 controls. The results of the meta-analysis showed significant associations for C-reactive protein (CRP), interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) with NAFLD (ORs of 1.41, 1.08, 1.50, 1.15 and 2.17, respectively). In contrast, we observed non-significant associations for interferon-γ (IFN-γ), insulin-like growth factor (IGF-II), interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-12 (IL-12), monocyte chemoattractant protein-1(MCP-1), and transforming growth factor-β (TGF-β) with NAFLD. Our results also showed that CRP, IL-1β, and TNF-α were significantly associated with non-alcoholic steatohepatitis (NASH) and hepatic fibrosis. Conclusions Our results indicated that increased CRP, IL‐1β, IL-6, TNF‐α, and ICAM-1 concentrations were significantly associated with increased risks of NAFLD. These inflammatory mediators may serve as biomarkers for NAFLD subjects and expect to provide new insights into the aetiology of NAFLD as well as early diagnosis and intervention.
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Affiliation(s)
- Yamei Duan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiongfeng Pan
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jiayou Luo
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Xiang Xiao
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Jingya Li
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Prince L. Bestman
- Department of Maternal and Child Health, Xiangya School of Public Health, Central South University, Changsha, China
| | - Miyang Luo
- Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China
- *Correspondence: Miyang Luo,
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Hepatic Steatosis Is Associated with High White Blood Cell and Platelet Counts. Biomedicines 2022; 10:biomedicines10040892. [PMID: 35453642 PMCID: PMC9025046 DOI: 10.3390/biomedicines10040892] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/11/2022] [Accepted: 04/12/2022] [Indexed: 12/12/2022] Open
Abstract
The incidence of hepatic steatosis is increasing globally, and it is important to identify those at risk to prevent comorbidities. Complete blood count is a simple, convenient, and inexpensive laboratory examination which can be used to obtain white blood cell (WBC) and platelet counts. The aims of this study were to investigate the relationships between WBC and platelet counts with hepatic steatosis, and whether WBC and platelet counts were associated with the severity of hepatic steatosis. We enrolled 1969 participants residing in southern Taiwan who took part in a health survey from June 2016 to September 2018 in this cross-sectional study. None of the participants were heavy alcohol users or had a history of hepatitis B or C. We collected laboratory data, and the severity of hepatic steatosis was determined by abdominal ultrasound. The overall prevalence rate of hepatic steatosis was 42.0%. There were significant trends of stepwise increases in WBC count (p < 0.001) corresponding to the severity of hepatic steatosis. After multivariable linear regression analysis, hepatic steatosis was significantly associated with high WBC count (coefficient β, 0.209; 95% confidence interval (CI), 0.055 to 0.364; p = 0.008) and high platelet count (coefficient β, 12.213; 95% CI, 6.092 to 18.334; p < 0.001); also, higher WBC counts corresponded with the severity of hepatic steatosis.
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The Association between Non-Alcoholic Fatty Liver Disease (NAFLD) and Advanced Fibrosis with Serological Vitamin B12 Markers: Results from the NHANES 1999-2004. Nutrients 2022; 14:nu14061224. [PMID: 35334881 PMCID: PMC8948655 DOI: 10.3390/nu14061224] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/08/2022] [Accepted: 03/09/2022] [Indexed: 01/31/2023] Open
Abstract
Background: There is evidence that vitamin B12 and associated metabolite levels are changed in non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH); however, their association has been in dispute. Methods: We included 8397 individuals without previous liver condition or excess alcohol intake from the National Health and Nutrition Examination Survey (NHANES) 1999–2004. NAFLD was diagnosed with Fatty Liver Index (FLI) ≥ 60 or USFLI ≥ 30, and participants with advanced fibrosis risks were identified with elevated non-alcoholic fatty liver disease fibrosis score (NFS), fibrosis 4 index (FIB-4), or aspartate aminotransferase (AST)/platelet ratio index (APRI). Step-wide logistic regression adjusting for confounders was used to detect the association between NAFLD or advanced fibrosis with serum vitamin B12, folate, red blood cell folate (RBC folate), homocysteine (HCY), and methylmalonic acid (MMA). Results: The weighted prevalence of NAFLD was 44.2%. Compared with non-NAFLD participants, patients with NAFLD showed significantly increased RBC folate level and RBC counts, decreased serum vitamin B12 and folate, and similar HCY and MMA levels. NAFLD with advanced fibrosis risk had higher MMA and HCY, reduced serum vitamin B12, and similar serum folate and RBC folate levels than NAFLD with low fibrosis risk. Only RBC folate was independently associated with an increased risk of NAFLD (OR (95% CI): 2.24 (1.58, 3.18)). In all participants, MMA (OR: 1.41 (1.10, 1.80)) and HCY (OR: 2.76 (1.49, 5.11)) were independently associated with increased risk for advanced fibrosis. In participants with NAFLD, this independent association still existed (OR: 1.39 (1.04, 1.85) for MMA and 1.95 (1.09, 3.46) for HCY). In all participants, the area under the receiver operating characteristic curve (ROC AUC) on fibrosis was 0.6829 (0.6828, 0.6831) for MMA and 0.7319 (0.7318, 0.7320) for HCY; in participants with NAFLD, the corresponding ROC AUC was 0.6819 (0.6817, 0.6821) for MMA and 0.6926 (0.6925, 0.6928) for HCY. Conclusion: Among vitamin B12-associated biomarkers, RBC folate was independently associated with elevated NAFLD risk, whereas MMA and HCY were associated with increased risk for advanced fibrosis in the total population and NAFLD participants. Our study highlighted the clinical diagnostic value of vitamin B12 metabolites and the possibility that vitamin B12 metabolism could be a therapeutic target for NASH. Further studies using recent perspective data with biopsy proven NASH could be conducted to validate our results.
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Xue J, Liang S, Ma J, Xiao Y. Effect of growth hormone therapy on liver enzyme and other cardiometabolic risk factors in boys with obesity and nonalcoholic fatty liver disease. BMC Endocr Disord 2022; 22:49. [PMID: 35216556 PMCID: PMC8881210 DOI: 10.1186/s12902-022-00967-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Accepted: 02/21/2022] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) has become the most common causes of liver disease in children and adolescents. Although several reports have confirmed the significant correlation between NAFLD and growth hormone (GH)-insulin-like growth factor 1(IGF-1) axis, no study further investigates whether or not recombinant human GH (rhGH) treatment can improve NAFLD in obese children. METHODS This study was a randomized, open-label study comprising 44 boys with obesity and NAFLD (11.76 ± 1.67 year) to evaluate the effects of 6 months of rhGH administration for boys with obesity and NAFLD. The subjects were randomized divided into treatment group (subjects with recombinant human GH (rhGH)) and control group for 6 months. RESULTS After 6 months, IGF-1 increased significantly during rhGH treatment, in comparison with the control group (582.45 ± 133.00 vs. 359.64 ± 129.00 ng/ml; p < 0.001). A significant reduction in serum alanine aminotransferase(ALT) (15.00 vs. 28.00 U/L; p = 0.001), aspartate aminotransferase(AST) (20.00 vs. 24.50U/L; p = 0.004), gamma glutamyl transferase(GGT) (14.50 vs. 28.50 U/L; p < 0.001) was observed in the GH-treated boys. In addition, the rhGH group showed a significant decrease in C reactive protein (CRP) (1.17 ± 0.76 vs. 2.26 ± 1.43 mg/L) and body mass index standard deviation scores (BMI SDS) (2.28 ± 0.80 vs. 2.71 ± 0.61) than the control group (p = 0.003, p = 0.049 respectively). GH treatment also reduced low density lipoprotein cholesterol (LDL-C) (2.19 ± 0.42 vs. 2.61 ± 0.66 mmol/L; p = 0.016) and increased high density lipoprotein cholesterol (HDL-C) (1.30 vs. 1.15 mmol/L; p = 0.005), and there were no changes in total cholesterol (TC), triglycerides (TG) and uric acid(UA) between the treatment group and the control group. CONCLUSION Our findings suggest that 6 months treatment with rhGH may be beneficial for liver enzyme and can improve obesity-related other cardiovascular and metabolic complications in boys with obesity and NAFLD.
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Affiliation(s)
- Jiang Xue
- Department of Pediatrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuang Liang
- Department of Pediatrics, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Jiahui Ma
- Department of Cardiology, Yankuang New Journey General Hospital, Zoucheng, China
| | - Yanfeng Xiao
- Department of Pediatrics, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
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Fairfield CJ, Drake TM, Pius R, Bretherick AD, Campbell A, Clark DW, Fallowfield JA, Hayward C, Henderson NC, Joshi PK, Mills NL, Porteous DJ, Ramachandran P, Semple RK, Shaw CA, Sudlow CL, Timmers PR, Wilson JF, Wigmore SJ, Harrison EM, Spiliopoulou A. Genome-Wide Association Study of NAFLD Using Electronic Health Records. Hepatol Commun 2022; 6:297-308. [PMID: 34535985 PMCID: PMC8793997 DOI: 10.1002/hep4.1805] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 07/04/2021] [Indexed: 12/20/2022] Open
Abstract
Genome-wide association studies (GWAS) have identified several risk loci for nonalcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for body mass index (BMI) and adjusting for alcohol intake. A total of 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components, and genotyping batch. We performed a GWAS meta-analysis using available summary association statistics. Six risk loci were identified (P < 5*10-8 ) (apolipoprotein E [APOE], patatin-like phospholipase domain containing 3 [PNPLA3, transmembrane 6 superfamily member 2 [TM6SF2], glucokinase regulator [GCKR], mitochondrial amidoxime reducing component 1 [MARC1], and tribbles pseudokinase 1 [TRIB1]). All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals), with others demonstrating consistent direction and magnitude of effect. All six loci were significant on meta-analysis. Rs429358 (P = 2.17*10-11 ) is a missense variant within the APOE gene determining ϵ4 versus ϵ2/ϵ3 alleles. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95% confidence interval 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusion: This GWAS replicates six known NAFLD-susceptibility loci and confirms that the ϵ4 allele of APOE is associated with protection against NAFLD. The results are consistent with published GWAS using histological and radiological measures of NAFLD, confirming that NAFLD identified through diagnostic codes from consensus guidelines is a valid alternative to more invasive and costly approaches.
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Affiliation(s)
- Cameron J. Fairfield
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Thomas M. Drake
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Riinu Pius
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Andrew D. Bretherick
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Archie Campbell
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
- Centre for Genomic and Experimental MedicineInstitute of Genetics & Molecular MedicineUniversity of EdinburghEdinburghScotland
- Health Data Research UKUniversity of EdinburghEdinburghScotland
| | - David W. Clark
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Jonathan A. Fallowfield
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Caroline Hayward
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
| | - Neil C. Henderson
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Peter K. Joshi
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Nicholas L. Mills
- Centre for Cardiovascular ScienceQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - David J. Porteous
- Centre for Genomic and Experimental MedicineInstitute of Genetics & Molecular MedicineUniversity of EdinburghEdinburghScotland
| | - Prakash Ramachandran
- Centre for Inflammation ResearchQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Robert K. Semple
- Centre for Cardiovascular ScienceQueen’s Medical Research InstituteUniversity of EdinburghEdingburghScotland
| | - Catherine A. Shaw
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Cathie L.M. Sudlow
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
| | - Paul R.H.J. Timmers
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - James F. Wilson
- MRC Human Genetics UnitInstitute of Genetics and CancerUniversity of EdinburghEdinburghScotland
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
| | - Stephen J. Wigmore
- Department of Clinical SurgeryDivision of Health SciencesUniversity of EdinburghEdingburghScotland
| | - Ewen M. Harrison
- Centre for Medical InformaticsUsher InstituteUniversity of EdinburghEdinburghScotland
- Department of Clinical SurgeryDivision of Health SciencesUniversity of EdinburghEdingburghScotland
| | - Athina Spiliopoulou
- Centre for Global Health ResearchUsher InstituteUniversity of EdinburghEdingburghScotland
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Zhu C, Huang D, Ma H, Qian C, You H, Bu L, Qu S. High-Sensitive CRP Correlates With the Severity of Liver Steatosis and Fibrosis in Obese Patients With Metabolic Dysfunction Associated Fatty Liver Disease. Front Endocrinol (Lausanne) 2022; 13:848937. [PMID: 35620390 PMCID: PMC9128592 DOI: 10.3389/fendo.2022.848937] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Accepted: 03/24/2022] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Metabolic dysfunction associated fatty liver disease (MAFLD) is the most common hepatopathy worldwide due to the obesity epidemic and is associated with chronic low-grade inflammation. High-sensitive C-reactive protein (hsCRP) as an inflammatory marker has been used in diagnosing MAFLD. However, the association between hsCRP and the severity of liver steatosis and fibrosis among obese patients with MAFLD remains to be elucidated. OBJECTIVE To explore the correlation of hsCRP with the severity of liver steatosis and fibrosis among Chinese obese patients with MAFLD. METHODS A total of 393 obese patients with mean BMI 34.8 ± 6.6 kg/m2 were selected and categorized as MAFLD and non-MAFLD groups. Anthropometric data, biochemical indices, and hsCRP were measured. The severity of hepatic steatosis and fibrosis was assessed using FibroScan. Multivariate logistic regression analysis was performed to determine the relationship between hsCRP and the risk of MAFLD and its disease severity. RESULTS Patients with MAFLD showed significantly elevated hsCRP levels and were more likely to have severe steatosis and fibrosis compared to those without MAFLD. The proportions of MAFLD, severe steatosis, and severe fibrosis were significantly increased across the hsCRP quartiles (P-trend = 0.004, 0.021, and 0.006, respectively). After multivariable adjustments, the adjusted ORs (AORs) and 95%CI for MAFLD were 1.00 (reference), 1.298 (0.587-2.872), 2.407 (1.002-5.781), and 2.637(1.073-6.482) (Q1-Q4, P-trend = 0.014). Likewise, the AORs (95%CI) for severe steatosis and severe fibrosis were remarkably increased with the increment of serum hsCRP quartiles (P-trend < 0.001, P-trend = 0.021, respectively). CONCLUSIONS Elevated serum hsCRP levels were associated with increased risk of MAFLD among Chinese obese patients and correlated positively with the severity of liver steatosis and fibrosis, suggesting that hsCRP can be used as a potential biomarker to monitor and predict disease severity among Chinese obese population with MAFLD.
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Affiliation(s)
- Cuiling Zhu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, School of Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Dongdong Huang
- Department of Respiratory Medicine, School of Medicine, Shanghai Pulmonary Hospital of Tongji University, Shanghai, China
| | - Huihui Ma
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, School of Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Chunhua Qian
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, School of Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Hui You
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, School of Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Le Bu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, School of Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
- National Metabolic Management Center, School of Medicine, Shanghai Tenth People’s Hospital of Tongji University, Shanghai, China
- *Correspondence: Shen Qu,
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Vitamin C Deficiency May Delay Diet-Induced NASH Regression in the Guinea Pig. Antioxidants (Basel) 2021; 11:antiox11010069. [PMID: 35052573 PMCID: PMC8772888 DOI: 10.3390/antiox11010069] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 12/21/2021] [Accepted: 12/22/2021] [Indexed: 12/14/2022] Open
Abstract
Oxidative stress is directly linked to non-alcoholic fatty liver disease (NAFLD) and the progression to steaotohepatitis (NASH). Thus, a beneficial role of antioxidants in delaying disease progression and/or accelerating recovery may be expected, as corroborated by recommendations of, e.g., vitamin E supplementation to patients. This study investigated the effect of vitamin C deficiency—often resulting from poor diets low in fruits and vegetables and high in fat—combined with/without a change to a low fat diet on NAFLD/NASH phenotype and hepatic transcriptome in the guinea pig NASH model. Vitamin C deficiency per se did not accelerate disease induction. However, the results showed an effect of the diet change on the resolution of hepatic histopathological hallmarks (steatosis, inflammation, and ballooning) (p < 0.05 or less) and indicated a positive effect of a high vitamin C intake when combined with a low fat diet. Our data show that a diet change is important in NASH regression and suggest that a poor vitamin C status delays the reversion towards a healthy hepatic transcriptome and phenotype. In conclusion, the findings support a beneficial role of adequate vitamin C intake in the regression of NASH and may indicate that vitamin C supplementation in addition to lifestyle modifications could accelerate recovery in NASH patients with poor vitamin C status.
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The promising role of CCL2 as a noninvasive marker for nonalcoholic steatohepatitis diagnosis in Egyptian populations. Eur J Gastroenterol Hepatol 2021; 33:e954-e960. [PMID: 34907983 DOI: 10.1097/meg.0000000000002324] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common liver problem, including both nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). In this study, we investigated the role of CCL2 and IL6 as a noninvasive tool for the diagnosis of NASH in clinical practice and to establish criteria for discrimination NASH from NAFL in Egyptian populations with NAFLD. METHOD In addition to 30 healthy controls, serum samples from 66 NAFLD patients histologically diagnosed by biopsy (32 NAFL and 34 NASH) were analyzed for serum IL6, CCL2, liver biomarkers, complete blood count and lipid profile. Serum IL6 or CCL2 levels were tested for correlation with the NASH activity score (NAS score). RESULT Both IL6 and CCL2 were significantly upregulated in NASH patients compared with NAFL patients or control. Serum CCL2 was significantly correlated with the degree of hepatocytes ballooning (the diagnostic endpoint for NASH) without any significant correlation with steatosis or lobular inflammation. Serum IL6 was not correlated with the NAS score. The ROC curve analysis of CCL2 for NASH diagnosis revealed an area under curve (AUROC) of 0.959 at cutoff ≥227 pg/ml. While IL6 revealed an (AUROC) of 0.790. CONCLUSION Serum CCL2 but not IL6 is a promising noninvasive tool for NASH diagnosis and CCL2 can provide a reliable, validated scoring system to discriminate NAFL from NASH in the Egyptian population confirming the role of CCL2 in NASH pathogenesis. These findings will aid in the development of innovative NASH treatment strategies in Egypt and improve the quality of clinical care.
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Pettersson-Pablo P, Samyn D, Wasim J, Vink M. Reference interval for type III procollagen (PIIINP) using the Advia centaur PIIINP assay in adults and elderly. Scandinavian Journal of Clinical and Laboratory Investigation 2021; 81:649-652. [PMID: 34779323 DOI: 10.1080/00365513.2021.2001045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
OBJECTIVE The amino-terminal peptide of type III procollagen (PIIINP) is a byproduct of type III collagen synthesis that exhibits promise as a biomarker of fibrosis, specifically in monitoring hepatic fibrosis in methotrexate treated patients. The Advia Centaur® PIIINP assay is developed for track-based automated laboratory systems and is suitable for large volume analysis. Reference intervals in children and younger adults have been published previously. Here we measured PIIINP to determine reference ranges, specifically including elderly patients, for whom such are currently lacking. METHODS Samples were collected from subjects ranging from 20 to 98 years of age. Blood donors and clinical samples from primary care patients were used for reference interval calculation. Samples were analysed using the Advia Centaur® PIIINP assay. After exclusion of samples high in alanine transaminase (AST), aspartate transaminase (ALT), and C-reactive protein (CRP) 386 samples were used in the reference interval calculation. RESULTS AND CONCLUSION We determined the following reference interval for the Advia Centaur® PIIINP assay: the lower limit of the reference interval (2.5% percentile with 95% CI) was 4.42 (4.20-4.65) µg/L and the upper limit of the reference interval (97.5% percentile 95% CI) 16.0 (15.04-17.02) µg/L.No significant differences in mean PIIINP concentrations were found between men and women. While differing mean PIIINP concentrations were seen among subjects in different age groups, the differences were small and partitioning of reference range was determined not to be necessary.
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Affiliation(s)
- Paul Pettersson-Pablo
- Department of Laboratory Medicine, Clinical Chemistry, Örebro University Hospital, Örebro, Sweden.,School of Medicine, Faculty of Medicine, Örebro University, Örebro, Sweden
| | - Dieter Samyn
- Department of Laboratory Medicine, Clinical Chemistry, Örebro University Hospital, Örebro, Sweden.,School of Medicine, Faculty of Medicine, Örebro University, Örebro, Sweden
| | - Jamil Wasim
- Department of Dermatology, School of Medical Sciences, Örebro University Hospital, Örebro, Sweden.,Faculty of Medicine, Section of Medical Sciences, Örebro University, Örebro, Sweden
| | - Martin Vink
- Department of Laboratory Medicine, Clinical Chemistry, Örebro University Hospital, Örebro, Sweden.,School of Medicine, Faculty of Medicine, Örebro University, Örebro, Sweden
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Guzel FB, Ozturk I, Gisi K, Ispiroglu M, Akkus G, Erken E, Altunoren O, Gungor O. The relationship between hepatic fibrosis and arterial stiffness in hemodialysis patients. Semin Dial 2021; 35:222-227. [PMID: 34390271 DOI: 10.1111/sdi.13011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 07/16/2021] [Accepted: 07/19/2021] [Indexed: 12/01/2022]
Abstract
INTRODUCTION The main cause of death in hemodialysis patients is cardiovascular diseases. Increased arterial stiffness is a predictor of cardiovascular events for hemodialysis patients. Among the nondialysis patient population, arterial stiffness increases in those with hepatic fibrosis and nonalcoholic fatty liver disease. This study aims to examine the relationship between hepatic fibrosis and arterial stiffness in hemodialysis patients for the first time in the literature. MATERIAL AND METHOD The study includes chronic hemodialysis patients over 18 years of age who had been treated for hemodialysis for at least 6 months. Patients with chronic liver disease, chronic viral hepatitis (HBV and HCV), alcohol use, or liver disease accompanied by polycystic kidney disease and active infection were excluded. Hepatic fibrosis scores were measured using the FibroScan device. Single-cuff Mobil-o-Graph was used for measurement of arterial stiffness. RESULTS Fifty-nine patients were enrolled; 54.2% of the patients were male, and the mean age was 53.9 ± 12.9 years. Thirty-nine percent of the patients had diabetes. Average pulse wave velocity (PWV) value of the patients was 8.3 ± 1.6 m/s, and it had positive correlation with age, CAP score, fibrosis score, and body mass index and showed negative correlation to albumin. It was seen that the patients with a PWV value ≥ 10 m/s have significantly higher CAP score compared with the patients with a PWV < 10 m/s. When the factors predicting PWV were examined in the regression analysis, age and systolic blood pressure were found to be determinants. CONCLUSION Increased hepatic fibrosis in hemodialysis patients is associated with increased arterial stiffness, but this relationship is not independent.
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Affiliation(s)
- Fatma Betul Guzel
- Internal Medicine Department, Kahramanmaraş Necip Fazil City Hospital, Kahramanmaraş, Turkey
| | - Ilyas Ozturk
- Faculty of Medicine, Nephrology Department, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey
| | - Kadir Gisi
- Faculty of Medicine, Gastroenterology Department, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey
| | - Murat Ispiroglu
- Faculty of Medicine, Gastroenterology Department, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey
| | - Gulsum Akkus
- Internal Medicine Department, Ankara Etimesgut Şehit Sait Ertürk State Hospital, Ankara, Turkey
| | - Ertugrul Erken
- Faculty of Medicine, Nephrology Department, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey
| | - Orcun Altunoren
- Faculty of Medicine, Nephrology Department, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey
| | - Ozkan Gungor
- Faculty of Medicine, Nephrology Department, Kahramanmaraş Sütçü İmam University, Kahramanmaraş, Turkey
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Johnson ND, Wu X, Still CD, Chu X, Petrick AT, Gerhard GS, Conneely KN, DiStefano JK. Differential DNA methylation and changing cell-type proportions as fibrotic stage progresses in NAFLD. Clin Epigenetics 2021; 13:152. [PMID: 34353365 PMCID: PMC8340447 DOI: 10.1186/s13148-021-01129-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/05/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is characterized by changes in cell composition that occur throughout disease pathogenesis, which includes the development of fibrosis in a subset of patients. DNA methylation (DNAm) is a plausible mechanism underlying these shifts, considering that DNAm profiles differ across tissues and cell types, and DNAm may play a role in cell-type differentiation. Previous work investigating the relationship between DNAm and fibrosis in NAFLD has been limited by sample size and the number of CpG sites interrogated. RESULTS Here, we performed an epigenome-wide analysis using Infinium MethylationEPIC array data from 325 individuals with NAFLD, including 119 with severe fibrosis and 206 with no histological evidence of fibrosis. After adjustment for latent confounders, we identified 7 CpG sites whose DNAm associated with fibrosis (p < 5.96 × 10-8). Analysis of RNA-seq data collected from a subset of individuals (N = 56) revealed that gene expression at 288 genes associated with DNAm at one or more of the 7 fibrosis-related CpGs. DNAm-based estimates of cell-type proportions showed that estimated proportions of natural killer cells increased, while epithelial cell proportions decreased with disease stage. Finally, we used an elastic net regression model to assess DNAm as a biomarker of fibrotic stage and found that our model predicted fibrosis with a sensitivity of 0.93 and provided information beyond a model based solely on cell-type proportions. CONCLUSION These findings are consistent with DNAm as a mechanism underpinning or marking fibrosis-related shifts in cell composition and demonstrate the potential of DNAm as a possible biomarker of NAFLD fibrosis.
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Affiliation(s)
- Nicholas D Johnson
- Department of Human Genetics, Emory University, Atlanta, GA, USA.,Population Biology, Ecology, and Evolution Program, Emory University, Atlanta, GA, USA
| | - Xiumei Wu
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, Phoenix, AZ, USA
| | | | - Xin Chu
- Geisinger Obesity Institute, Danville, PA, USA
| | | | - Glenn S Gerhard
- Lewis Katz School of Medicine, Temple University School of Medicine, Philadelphia, PA, USA
| | - Karen N Conneely
- Department of Human Genetics, Emory University, Atlanta, GA, USA.,Population Biology, Ecology, and Evolution Program, Emory University, Atlanta, GA, USA
| | - Johanna K DiStefano
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute, Phoenix, AZ, USA.
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Hong SH, Lee JS, Kim JA, Lee YB, Roh E, Hee Yu J, Kim NH, Yoo HJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi KM. Glycemic variability and the risk of nonalcoholic fatty liver disease : A nationwide population-based cohort study. Diabetes Res Clin Pract 2021; 177:108922. [PMID: 34146602 DOI: 10.1016/j.diabres.2021.108922] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 06/01/2021] [Accepted: 06/14/2021] [Indexed: 12/15/2022]
Abstract
AIM Although few recent studies have reported the association between the glycemic variability and the development of type 2 diabetes mellitus and cardiovascular disease in individuals without diabetes mellitus, the impact of the long-term variability in fasting plasma glucose (FPG) levels on the incident nonalcoholic fatty liver disease (NAFLD) has not been evaluated. METHODS The study included 57,636 Korean men and women without NAFLD and diabetes mellitus from the Korean National Health Insurance System cohort. FPG variability was calculated using the coefficient of variation (FPG-CV), standard deviation (FPG-SD), variability independent of the mean (FPG-VIM), and average successive variability (FPG-ASV). RESULTS The cumulative incidence of NAFLD demonstrated progressively increasing trends according to the higher quartiles of FPG variability in Kaplan-Meier curves. A multivariable Cox proportional hazard analysis revealed that the hazard ratio for incident NAFLD was 1.15 (95% confidence interval, 1.06-1.24) in the highest quartile of FPG-CV compared with the lowest quartile of FPG-CV after adjusting for various confounding factors, including mean FPG levels. When using FPG-SD, FPG-VIM, and FPG-ASV, the results were similar. The 10-unit increase in FPG variability was associated with a 14% increased risk of NAFLD in the fully adjusted model. Moreover, this effect remained consistent in the subgroup and sensitivity analyses. CONCLUSION Increased long-term FPG variability is associated with the development of NAFLD, independent of confounding risk variables including mean FPG levels.
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Affiliation(s)
- So-Hyeon Hong
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Ji Sung Lee
- Clinical Research Center, Asan Medical Center, College of Medicine, Seoul, Republic of Korea
| | - Jung A Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - You-Bin Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Sungkyunkwan University, Seoul, Republic of Korea
| | - Eun Roh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Ji Hee Yu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Nam Hoon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Hye Jin Yoo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Ji A Seo
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Sin Gon Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Sei Hyun Baik
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Republic of Korea.
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Parikh NS, Jesudian A, Kamel H, Hanley DF, Ziai WC, Murthy SB. Liver Fibrosis and Perihematomal Edema Growth in Primary Intracerebral Hemorrhage. Neurocrit Care 2021; 34:983-989. [PMID: 32808155 PMCID: PMC7887133 DOI: 10.1007/s12028-020-01081-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Accepted: 08/06/2020] [Indexed: 01/03/2023]
Abstract
BACKGROUND Liver disease is associated with altered serum osmolality, increased thrombin generation, and systemic inflammation, all of which may contribute to perihematomal edema (PHE) after intracerebral hemorrhage (ICH). We evaluated the association between a validated liver fibrosis index and PHE growth in a cohort of patients with primary ICH. METHODS We performed a retrospective cohort study using data from the Virtual International Stroke Trials Archive-ICH. We included adult patients with primary ICH presenting within 6 h of symptom onset. The exposure of interest was the Fibrosis-4 (FIB-4) score, a validated liver fibrosis index; this was modeled as a continuous variable. The primary outcome was absolute PHE growth over 96 h. Secondary outcomes were absolute admission and 96-h PHE volumes. We used multiple linear regression models adjusted for established determinants of PHE. In a secondary analysis, the FIB-4 score was modeled as a categorical variable to compare patients with versus without liver fibrosis. RESULTS Among 354 patients with ICH, 8% had evidence of liver fibrosis based on a validated cutoff. The FIB-4 score was not associated with PHE growth in unadjusted (β, 0.03; 95% CI, - 0.01 to 0.12) or adjusted models (β, 0.04; 95% CI, - 0.03 to 0.13). In a secondary analysis treating FIB-4 as a categorical variable, patients with liver fibrosis did not have greater PHE growth than those without liver fibrosis. FIB-4 score was also not associated with absolute admission or 96-h PHE volumes. CONCLUSIONS In a multicenter cohort of patients with primary intracerebral hemorrhage, a liver fibrosis score was not associated with PHE volume or growth.
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Affiliation(s)
- Neal S Parikh
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine/New York Presbyterian Hospital, 420 E 70th St, 4th Floor, New York, NY, 10021, USA.
| | - Arun Jesudian
- Division of Gastroenterology and Hepatology, Weill Cornell Medicine, New York, NY, USA
| | - Hooman Kamel
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine/New York Presbyterian Hospital, 420 E 70th St, 4th Floor, New York, NY, 10021, USA
| | - Daniel F Hanley
- Brain Injury Outcomes Division, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Wendy C Ziai
- Department of Neurology, Neurosurgery and Anesthesiology, Johns Hopkins University School of Medicine, Baltimore, USA
| | - Santosh B Murthy
- Clinical and Translational Neuroscience Unit, Department of Neurology, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine/New York Presbyterian Hospital, 420 E 70th St, 4th Floor, New York, NY, 10021, USA
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Jeon D, Son M, Shim J. Dynamics of Serum Retinol and Alpha-Tocopherol Levels According to Non-Alcoholic Fatty Liver Disease Status. Nutrients 2021; 13:1720. [PMID: 34069568 PMCID: PMC8161312 DOI: 10.3390/nu13051720] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 05/16/2021] [Accepted: 05/17/2021] [Indexed: 12/18/2022] Open
Abstract
The available data on the association between micronutrients in the blood and non-alcoholic fatty liver disease (NAFLD) are limited. To investigate the clinical implications of this relationship, we sought to identify the difference in the serum levels of vitamins A and E according to NAFLD status using data from the seventh Korea National Health and Nutrition Examination Survey. In this cross-sectional study of the Korean population, NAFLD and its severity were defined using prediction models. Differences in the prevalence and severity of NAFLD were analyzed according to serum retinol (vitamin A) and alpha (α)-tocopherol (vitamin E) levels. Serum levels of retinol and α-tocopherol were positively correlated with the prevalence of NAFLD. In most prediction models of the NAFLD subjects, serum retinol deficiency was significantly correlated with advanced fibrosis, while serum α-tocopherol levels did not differ between individuals with or without advanced fibrosis. Similar trends were also noted with cholesterol-adjusted levels of α-tocopherol. In summary, while circulating concentrations of retinol and α-tocopherol were positively associated with the presence of NAFLD, advanced liver fibrosis was only correlated with serum retinol levels. Our findings could provide insight into NAFLD patient care at a micronutrient level.
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Affiliation(s)
- Dongsub Jeon
- Liver Center, Asan Medical Center, Department of Gastroenterology, University of Ulsan College of Medicine, Seoul 05505, Korea;
| | - Minkook Son
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 61005, Korea;
| | - Juhyun Shim
- Liver Center, Asan Medical Center, Department of Gastroenterology, University of Ulsan College of Medicine, Seoul 05505, Korea;
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Banerjee A, Mukherjee S, Maji BK. Worldwide flavor enhancer monosodium glutamate combined with high lipid diet provokes metabolic alterations and systemic anomalies: An overview. Toxicol Rep 2021; 8:938-961. [PMID: 34026558 PMCID: PMC8120859 DOI: 10.1016/j.toxrep.2021.04.009] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 04/20/2021] [Accepted: 04/25/2021] [Indexed: 12/13/2022] Open
Abstract
Flavor enhancing high lipid diet acts as silent killer. Monosodium glutamate mixed with high lipid diet alters redox-status. Monosodium glutamate mixed with high lipid diet induces systemic anomalies. In this fast-food era, people depend on ready-made foods and engage in minimal physical activities that ultimately change their food habits. Majorities of such foods have harmful effects on human health due to higher percentages of saturated fatty acids, trans-fatty acids, and hydrogenated fats in the form of high lipid diet (HLD). Moreover, food manufacturers add monosodium glutamate (MSG) to enhance the taste and palatability of the HLD. Both MSG and HLD induce the generation of reactive oxygen species (ROS) and thereby alter the redox-homeostasis to cause systemic damage. However, MSG mixed HLD (MH) consumption leads to dyslipidemia, silently develops non-alcoholic fatty liver disease followed by metabolic alterations and systemic anomalies, even malignancies, via modulating different signaling pathways. This comprehensive review formulates health care strategies to create global awareness about the harmful impact of MH on the human body and recommends the daily consumption of more natural foods rich in antioxidants instead of toxic ingredients to counterbalance the MH-induced systemic anomalies.
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Jamialahmadi T, Nematy M, Bo S, Ponzo V, Jangjoo A, Goshayeshi L, Tasbandi A, Nikiforov NG, Sahebkar A. Associations between Pre-Bariatric High-Sensitivity C-Reactive Protein and Post-Surgery Outcomes. Diagnostics (Basel) 2021; 11:721. [PMID: 33919641 PMCID: PMC8073671 DOI: 10.3390/diagnostics11040721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 04/08/2021] [Accepted: 04/12/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Obesity is a chronic inflammatory condition associated with increased circulating levels of C-reactive protein (CRP). Bariatric surgery has been reported to be effective in improving both inflammatory and liver status. Our aims were to elucidate the relationships between pre-surgery high sensitivity-CRP (hs-CRP) values and post-surgery weight loss and liver steatosis and fibrosis in patients with severe obesity undergoing Roux-en-Y gastric bypass. METHODS We conducted an observational prospective study on 90 individuals with morbid obesity, who underwent gastric bypass. Anthropometric indices, laboratory assessment (lipid panel, glycemic status, liver enzymes, and hs-CRP), liver stiffness and steatosis were evaluated at baseline and 6-months after surgery. RESULTS There was a significant post-surgery reduction in all the anthropometric variables, with an average weight loss of 33.93 ± 11.79 kg; the mean percentage of total weight loss (TWL) was 27.96 ± 6.43%. Liver elasticity was significantly reduced (from 6.1 ± 1.25 to 5.42 ± 1.52 kPa; p = 0.002), as well as liver aminotransferases, nonalcoholic fatty liver disease fibrosis score (NFS) and the grade of steatosis. Serum hs-CRP levels significantly reduced (from 9.26 ± 8.45 to 3.29 ± 4.41 mg/L; p < 0.001). The correlations between hs-CRP levels and liver fibrosis (elastography), steatosis (ultrasonography), fibrosis-4 index, NFS, and surgery success rate were not significant. Regression analyses showed that serum hs-CRP levels were not predictive of liver status and success rate after surgery in both unadjusted and adjusted models. CONCLUSIONS In patients with morbid obesity, bariatric surgery caused a significant decrease in hs-CRP levels, liver stiffness and steatosis. Baseline hs-CRP values did not predict the weight-loss success rate and post-surgery liver status.
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Affiliation(s)
- Tannaz Jamialahmadi
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| | - Mohsen Nematy
- Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| | - Simona Bo
- Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, 10126 Torino, Italy
| | - Valentina Ponzo
- Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, 10126 Torino, Italy
| | - Ali Jangjoo
- Surgical Oncology Research Center, Imam Reza Hospital, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| | - Ladan Goshayeshi
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
- Gastroenterology and Hepatology Research Center, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| | - Aida Tasbandi
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
| | - Nikita G. Nikiforov
- Laboratory of Cellular and Molecular Pathology of Cardiovascular System, Institute of Human Morphology, 3 Tsyurupa Street, 117418 Moscow, Russia
- Laboratory of Medical Genetics, Institute of Experimental Cardiology, National Medical Research Center of Cardiology, 121552 Moscow, Russia
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 91779-48564, Iran
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91779-48954, Iran
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad P.O. Box 91779-48564, Iran
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Ramadan MS, Russo V, Nigro G, Durante-Mangoni E, Zampino R. Interplay between Heart Disease and Metabolic Steatosis: A Contemporary Perspective. J Clin Med 2021; 10:1569. [PMID: 33917867 PMCID: PMC8068259 DOI: 10.3390/jcm10081569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 03/26/2021] [Accepted: 04/03/2021] [Indexed: 12/12/2022] Open
Abstract
The liver-heart axis is a growing field of interest owing to rising evidence of complex bidirectional interplay between the two organs. Recent data suggest non-alcoholic fatty liver disease (NAFLD) has a significant, independent association with a wide spectrum of structural and functional cardiac diseases, and seems to worsen cardiovascular disease (CVD) prognosis. Conversely, the effect of cardiac disease on NAFLD is not well studied and data are mostly limited to cardiogenic liver disease. We believe it is important to further investigate the heart-liver relationship because of the tremendous global health and economic burden the two diseases pose, and the impact of such investigations on clinical decision making and management guidelines for both diseases. In this review, we summarize the current knowledge on NAFLD diagnosis, its systemic manifestations, and associations with CVD. More specifically, we review the pathophysiological mechanisms that govern the interplay between NAFLD and CVD and evaluate the relationship between different CVD treatments and NAFLD progression.
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Affiliation(s)
- Mohammad Said Ramadan
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
| | - Vincenzo Russo
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Gerardo Nigro
- Department of Translational Medical Sciences, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy; (V.R.); (G.N.)
- Cardiology Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy
| | - Emanuele Durante-Mangoni
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy;
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
| | - Rosa Zampino
- Infectious and Transplant Medicine Unit, AORN Ospedali dei Colli-Monaldi Hospital, 80131 Naples, Italy;
- Department of Advanced Medical and Surgical Sciences, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
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Kuroda R, Nogawa K, Watanabe Y, Morimoto H, Sakata K, Suwazono Y. Association between High-Sensitive C-Reactive Protein and the Development of Liver Damage in Japanese Male Workers. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2021; 18:ijerph18062985. [PMID: 33799436 PMCID: PMC7998110 DOI: 10.3390/ijerph18062985] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND The aim of this study was to determine whether a causative relationship exists between the development of liver damage and increased high-sensitivity C-reactive protein (HsCRP) levels by long-term follow-up in Japanese workers. METHODS The target participants comprised 7830 male workers in a Japanese steel company. The prospective cohort study was performed over a 6-year period, and annual health screening information was analyzed by pooled logistic regression. The endpoint, regarded as the development of liver damage, was defined as aspartate aminotransferase (AST) ≥ 40 IU/L. RESULTS A significant relationship between the development of liver damage and increased HsCRP levels was observed after adjusting for confounding factors such as various physiological and blood chemistry parameters and lifestyle factors. The odds ratio of a 1.5-fold increase in HsCRP was 1.07 (95% confidence interval: 1.03-1.10, p < 0.001). CONCLUSIONS The results suggested that an increase of HsCRP is associated with the development of liver damage.
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Affiliation(s)
- Reiko Kuroda
- Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (R.K.); (K.N.); (Y.W.); (H.M.); (K.S.)
- Division for Environment, Health and Safety, The University of Tokyo, Tokyo 113-8654, Japan
| | - Kazuhiro Nogawa
- Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (R.K.); (K.N.); (Y.W.); (H.M.); (K.S.)
| | - Yuuka Watanabe
- Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (R.K.); (K.N.); (Y.W.); (H.M.); (K.S.)
| | - Hideki Morimoto
- Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (R.K.); (K.N.); (Y.W.); (H.M.); (K.S.)
| | - Kouichi Sakata
- Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (R.K.); (K.N.); (Y.W.); (H.M.); (K.S.)
| | - Yasushi Suwazono
- Department of Occupational and Environmental Medicine, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan; (R.K.); (K.N.); (Y.W.); (H.M.); (K.S.)
- Correspondence: ; Tel.: +81-43-226-2065
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Lambrecht J, Tacke F. Controversies and Opportunities in the Use of Inflammatory Markers for Diagnosis or Risk Prediction in Fatty Liver Disease. Front Immunol 2021; 11:634409. [PMID: 33633748 PMCID: PMC7900147 DOI: 10.3389/fimmu.2020.634409] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
In the Western society, non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat in the liver, represents the most common cause of chronic liver disease. If left untreated, approximately 15%-20% of patients with NAFLD will progress to non-alcoholic steatohepatitis (NASH), in which lobular inflammation, hepatocyte ballooning and fibrogenesis further contribute to a distorted liver architecture and function. NASH initiation has significant effects on liver-related mortality, as even the presence of early stage fibrosis increases the chances of adverse patient outcome. Therefore, adequate diagnostic tools for NASH are needed, to ensure that relevant therapeutic actions can be taken as soon as necessary. To date, the diagnostic gold standard remains the invasive liver biopsy, which is associated with several drawbacks such as high financial costs, procedural risks, and inter/intra-observer variability in histology analysis. As liver inflammation is a major hallmark of disease progression, inflammation-related circulating markers may represent an interesting source of non-invasive biomarkers for NAFLD/NASH. Examples for such markers include cytokines, chemokines or shed receptors from immune cells, circulating exosomes related to inflammation, and changing proportions of peripheral blood mononuclear cell (PBMC) subtypes. This review aims at documenting and critically discussing the utility of such novel inflammatory markers for NAFLD/NASH-diagnosis, patient stratification and risk prediction.
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Affiliation(s)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
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Valle-Martos R, Valle M, Martos R, Cañete R, Jiménez-Reina L, Cañete MD. Liver Enzymes Correlate With Metabolic Syndrome, Inflammation, and Endothelial Dysfunction in Prepubertal Children With Obesity. Front Pediatr 2021; 9:629346. [PMID: 33665176 PMCID: PMC7921725 DOI: 10.3389/fped.2021.629346] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 01/28/2021] [Indexed: 12/11/2022] Open
Abstract
Background: Metabolic syndrome (MetS) can start in children with obesity at very young ages. Non-alcoholic fatty liver disease (NAFLD) is considered to be the hepatic component of metabolic syndrome. If left untreated, the clinical course of NAFLD can be progressive and can become chronic if not detected at an early stage. Objective: We aimed to quantify the differences in liver enzymes between prepubertal children with obesity and children with normal weight to determine any associations between them and parameters related to MetS, adipokines, or markers of endothelial dysfunction and inflammation. Methods: This cross-sectional study included 54 prepuberal children with obesity (aged 6-9 years) and 54 children with normal weight, matched by age and sex. Liver enzymes, C-reactive protein (CRP), interleukin-6, soluble intercellular adhesion molecule-1 (sICAM-1), adipokines, and parameters related to metabolic syndrome (MetS) were all measured. Results: Alanine aminotransferase (ALT) levels, serum butyryl cholinesterase (BChE), leptin, CRP, sICAM-1, triglycerides, blood pressure, and homeostasis model assessment for insulin resistance were significantly higher in children with obesity, while Apolipoprotein A-1, HDL-cholesterol, and adiponectin were significantly lower. In the children with obesity group, ALT and BChE levels correlated with anthropometric measurements, insulin resistance, and lipid parameters, leptin, interleukin-6, CRP, and sICAM-1 while BChE levels negatively correlated with adiponectin. Conclusions: Compared to children with normal weight, prepubertal children with obesity had elevated values for liver enzymes, leptin, markers of insulin resistance, inflammation, and endothelial dysfunction, and variables associated with MetS. There was also a correlation between these disorders and liver enzyme levels.
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Affiliation(s)
- Rosario Valle-Martos
- Maimonides Biomedical Research Institute of Córdoba, University of Cordoba, Córdoba, Spain
| | - Miguel Valle
- Valle de los Pedroches Hospital, Maimonides Biomedical Research Institute of Córdoba, Córdoba, Spain
| | - Rosario Martos
- Health Center of Pozoblanco, Maimonides Biomedical Research Institute of Córdoba, Córdoba, Spain
| | - Ramón Cañete
- Faculty of Medicine, Maimonides Biomedical Research Institute of Córdoba, Biomedical Research Networking Center for Physiopathology of Obesity and Nutrition, University of Cordoba, Córdoba, Spain
| | - Luis Jiménez-Reina
- Faculty of Medicine, Maimonides Biomedical Research Institute of Córdoba, University of Cordoba, Córdoba, Spain
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The Role of Elastography in Non-Alcoholic Fatty Liver Disease. CURRENT HEALTH SCIENCES JOURNAL 2020; 46:255-269. [PMID: 33304627 PMCID: PMC7716767 DOI: 10.12865/chsj.46.03.07] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Accepted: 08/10/2020] [Indexed: 11/18/2022]
Abstract
The most common liver disease in developing countries is non-alcoholic fatty liver disease (NAFLD). This involves the abnormal accumulation of lipids in the liver, the pathogenesis of the disease being related to dyslipidemia, obesity, insulin resistance and type 2 diabetes. Most often, the diagnosis of NAFLD is incidental, when performing routine blood tests or when performing a transabdominal ultrasound. The NAFLD spectrum ranges from simple forms of hepatic steatosis to the most advanced form of the disease, steatohepatitis (NASH), which in evolution can cause inflammation, fibrosis, cirrhosis of the liver and even liver cancer. For the evaluation of the prognosis and the clinical evolution, the most important parameter to define is the degree of liver fibrosis. Currently, the gold standard remains the liver biopsy, the differentiation between NAFLD and NASH being made only on the basis of histological analysis. However, liver biopsy is an invasive procedure, with numerous risks such as bleeding, lesions of the other organs and complications related to anesthesia, which significantly reduces its widespread use. Moreover, the risk of a false negative result and the increased costs of the procedure further limits its use in current practice. For this reason, non-invasive methods of evaluating the degree of liver fibrosis have gained ground in recent years. Imaging techniques such as elastography have shown promising results in evaluating and staging NAFLD. The aim of this article is to review the current status of the non-invasive tests for the assessment of NAFLD with a focus on the ultrasound-based elastography techniques.
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ASC, IL-18 and Galectin-3 as Biomarkers of Non-Alcoholic Steatohepatitis: A Proof of Concept Study. Int J Mol Sci 2020; 21:ijms21228580. [PMID: 33203036 PMCID: PMC7698245 DOI: 10.3390/ijms21228580] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 11/11/2020] [Accepted: 11/12/2020] [Indexed: 12/14/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease that is growing in prevalence. Symptoms of NASH become apparent when the disease has progressed significantly. Thus, there is a need to identify biomarkers of NASH in order to detect the disease earlier and to monitor disease severity. The inflammasome has been shown to play a role in liver diseases. Here, we performed a proof of concept study of biomarker analyses (cut-off points, positive and negative predictive values, receiver operating characteristic (ROC) curves, and likelihood ratios) on the serum of patients with NASH and healthy controls on apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18, Galectin-3 (Gal-3), and C-reactive protein (CRP). ASC, IL-18, and Gal-3 were elevated in the serum of NASH patients when compared to controls. The area under the curve (AUC) for ASC was the highest (0.7317) with an accuracy of 68%, followed by IL-18 (0.7036) with an accuracy of 66% and Gal-3 (0.6891) with an accuracy of 61%. Moreover, we then fit a stepwise multivariate logistic regression model using ASC, IL-18, and Gal-3 to determine the probability of patients having a NASH diagnosis, which resulted in an AUC of 0.71 and an accuracy of 79%, indicating that combining these biomarkers increases their diagnostic potential for NASH. These results indicate that ASC, IL-18, and Gal-3 are reliable biomarkers of NASH and that combining these analytes increases the biomarker potential of these proteins.
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