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Wang Y, Fang Z, Fu Q, Yao D, Jin X. Association between non-alcoholic fatty liver disease and arterial stiffness measured by brachial-ankle pulse wave velocity: a cross-sectional population study. PeerJ 2025; 13:e19405. [PMID: 40406231 PMCID: PMC12097236 DOI: 10.7717/peerj.19405] [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: 07/19/2024] [Accepted: 04/10/2025] [Indexed: 05/26/2025] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is strongly linked with metabolic syndrome and atherosclerotic cardiovascular diseases (ASCVDs). This study aimed to assess the feasibility of using brachial-ankle pulse wave velocity (baPWV), a non-invasive technique, to monitor atherosclerosis (AS) in NAFLD patients and to evaluate the AS risk in various sub-populations of NAFLD patients. Materials and methods A cross-sectional study was conducted with 4,844 participants, enrolled from January 1, 2019, to December 31, 2021, at the Physical Examination Center of Zhongnan Hospital of Wuhan University. Participants were aged 18 to 88 years. According to the main points of the ultrasonic diagnosis of NAFLD, the ultrasonic image report was made for the subjects. AS is defined as baPWV ≥ 1,400 cm/s. We used multiple logistic regression analysis to explore the relationship between NAFLD and AS, and multiple linear regression analysis to explore the correlation between NAFLD and baPWV by modeling. Subgroup analysis was performed based on age and gender to adjust for confounding bias and complete sensitivity analysis. Results The prevalence of NAFLD was 38.3% in all participants, with 45.4% in men and 25.1% in women. Among the overall NAFLD population and male NAFLD patients, baPWV exceeded the diagnostic threshold for AS (1,419.70 ± 205.51, 1,429.71 ± 196.13) starting from the 45-55 age group. Through the analysis of the age-baPWV scatter plots and fitted lines, along with sensitivity analysis, it is recommended that male patients should start monitoring at 46 years old for AS using baPWV, while female patients should begin at 51 years old. NAFLD was associated with increased odds of AS (OR: 1.206, 95% CI [1.021-1.423], P = 0.027) after adjusting for confounders. NAFLD was independently positively correlated with baPWV (Model 2: β = 0.086, ΔR 2 = 0.006, P < 0.001; Model 3: β = 0.05, P < 0.001). This positive correlation was also observed in both males and females (male: Model 2: β = 0.081, ΔR 2 = 0.005, P < 0.001; Model 3: β = 0.052, P = 0.001; female: Model 2: β = 0.088, ΔR 2 = 0.006, P < 0.001; Model 3: β = 0.042, P = 0.02). Conclusion NAFLD demonstrated an independent association with AS assessed via baPWV, an accessible non-invasive tool for early AS evaluation. Regular baPWV monitoring is recommended for NAFLD patients > 45 years, with males and females initiating surveillance at 46 and 51 years, respectively. Study limitations, including potential biases in NAFLD diagnosis, gender distribution imbalances, and confounding variable interdependencies, necessitate further stratified population analyses.
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Affiliation(s)
- Yujie Wang
- The Emergency Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhicheng Fang
- Emergency Department, Taihe Hospital of Hubei University of Medicine, Shiyan, Hubei, China
| | - Qiuyue Fu
- The Emergency Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Dongai Yao
- Physical Examination Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xiaoqing Jin
- The Emergency Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
- Physical Examination Center, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, China
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Toffoli B, Comar C, Grillo A, Barbato V, Vincis E, Baldi V, Berti S, Volpato T, Zorat F, Crocè SL, Emmi G, Fabris B, Puato M, Bernardi S. PNPLA3 Polymorphism Is Inversely Correlated with Aortic Stiffness in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease Without Fibrosis. Int J Mol Sci 2025; 26:3256. [PMID: 40244110 PMCID: PMC11989603 DOI: 10.3390/ijms26073256] [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: 01/16/2025] [Revised: 03/25/2025] [Accepted: 03/29/2025] [Indexed: 04/18/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) corresponds to the condition of increased hepatic fat levels, which is the leading cause of hepatic failure and carcinoma. It is also an independent risk factor for cardiovascular disease (CVD) and mortality. MASLD can be due to obesity with insulin resistance and/or genetic predisposition, i.e., polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3) gene. PNPLA3 polymorphism has been associated with increased hepatic fat levels, fibrosis, cirrhosis, and hepatocellular carcinoma, while its association with CVD remains to be fully understood. The aim of the current study was to examine whether the vascular phenotype of patients with MASLD differed between carriers and noncarriers of the PNPLA3 polymorphism. Adult patients with MASLD underwent clinical assessment, PNPLA3 genotyping, arterial tonometry for aortic stiffness measurement, and ultrasound examination of carotid arteries. In total, 117 patients with MASLD and no fibrosis (median hepatic stiffness was 4.71 kPa) were recruited. Carriers of the PNPLA3 polymorphism were younger and exhibited higher levels of ALT and APRI, as compared to wild-type subjects. On the other hand, carriers of the PNPLA3 polymorphism had not only a better metabolic profile (i.e., lower glucose and glycated hemoglobin) but also lower blood pressure, carotid intima-media thickness (IMT), and cardiovascular risk. In addition, PNPLA3 polymorphism was negatively correlated with aortic stiffness, which is a marker of arteriolosclerosis and vascular ageing. Our data are consistent with previous observations that in case of genetically-driven MASLD, there is an inverse association with common predictors of CVD. Our data support the view that the main contributors to CVD risk in patients with MASLD remain conventional cardiometabolic risk factors (i.e., age, glucose) that are more likely to be found in metabolic syndrome-related MASLD rather than genetically-driven MASLD, at least in the first stages of the disease.
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Affiliation(s)
- Barbara Toffoli
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
| | - Consuelo Comar
- UCO Medicina Clinica ASUGI, Cattinara Teaching Hospital, Strada di Fiume, 34100 Trieste, Italy; (C.C.); (F.Z.)
| | - Andrea Grillo
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
- UCO Medicina Clinica ASUGI, Cattinara Teaching Hospital, Strada di Fiume, 34100 Trieste, Italy; (C.C.); (F.Z.)
| | - Vincenzo Barbato
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
| | - Emanuele Vincis
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
| | - Veronica Baldi
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
| | - Silvia Berti
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
| | - Teresa Volpato
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
| | - Francesca Zorat
- UCO Medicina Clinica ASUGI, Cattinara Teaching Hospital, Strada di Fiume, 34100 Trieste, Italy; (C.C.); (F.Z.)
| | - Saveria Lory Crocè
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
- Centro Clinico Studi Fegato ASUGI, Maggiore Teaching Hospital, Piazza dell’Ospitale, 34100 Trieste, Italy
| | - Giacomo Emmi
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
- UCO Medicina Clinica ASUGI, Cattinara Teaching Hospital, Strada di Fiume, 34100 Trieste, Italy; (C.C.); (F.Z.)
| | - Bruno Fabris
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
| | - Massimo Puato
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
- SSD Angiologia ASUGI, Cattinara Teaching Hospital, Strada di Fiume, 34100 Trieste, Italy
| | - Stella Bernardi
- Department of Medical Surgical and Health Sciences, University of Trieste, Cattinara Teaching Hospital Strada di Fiume, 34100 Trieste, Italy; (A.G.); (V.B.); (E.V.); (V.B.); (S.B.); (S.L.C.); (G.E.); (B.F.); (M.P.); (S.B.)
- SS Endocrinologia ASUGI, Cattinara Teaching Hospital, Strada di Fiume, 34100 Trieste, Italy
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Ikezaki H, Nakashima R, Matsumoto Y, Ohta A, Yamasaki S, Hiramine S, Takayama K, Ogawa E, Murata M, Furusyo N, Hayashi J, Shimono N, Schaefer EJ. Impact of NAFLD-related SNPs on the carotid atherosclerosis development; a five-year prospective observational study. ATHEROSCLEROSIS PLUS 2025; 59:10-17. [PMID: 39802653 PMCID: PMC11719292 DOI: 10.1016/j.athplu.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 11/10/2024] [Accepted: 12/04/2024] [Indexed: 01/16/2025]
Abstract
Background and aims The prevalence of metabolic dysfunction associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD), has become a significant public health concern with an increased atherosclerotic cardiovascular disease risk. This study investigates the impact of NAFLD-related single nucleotide polymorphisms (SNPs) on carotid atherosclerosis development in a Japanese population without diabetes, dyslipidemia, and hypertension. Methods The prospective observational study, part of the Kyushu and Okinawa Population Study (KOPS), included 945 participants (median age 55 [47, 63]) without carotid atherosclerosis, increased alcohol intake, diabetes, dyslipidemia, hypertension, or chronic hepatitis at baseline. NAFLD-related SNPs (GCKR, NCAN, and PNPLA3) were genotyped, and carotid intima-media thickness (cIMT) was measured using ultrasonography. Univariate and multivariate regression analyses were performed to assess the association of NAFLD-related SNPs on newly developed carotid atherosclerosis over five years. Results After five years, 125 (13.2 %) participants developed carotid atherosclerosis. The NCAN (rs2228603) T allele was associated with a lower incidence rate of carotid atherosclerosis (4.7 % in NCAN CT/TT genotype vs. 13.9 % in CC genotype; p = 0.04), and NCAN T allele carriers exhibited a favorable lipid profile. These associations were not altered by either recruiting area or obese. The GCKR T allele and PNPLA3 C allele were associated with low carotid atherosclerosis development rates but were not significant. Conclusions Our results suggested that some NAFLD-related SNPs may influence atherosclerosis through lipid metabolism among Japanese individuals without metabolic syndrome.
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Affiliation(s)
- Hiroaki Ikezaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
- Department of General Internal Medicine, Haradoi Hospital, 6-40-8 Aoba, Higashi-ku, Fukuoka, 8138588, Japan
- Cardiovascular Nutrition Laboratory, Human Nutrition Research Center on Aging at Tufts University, and Tufts University School of Medicine, Boston, MA, 711 Washington Street, 02111, USA
| | - Ryoko Nakashima
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Yuji Matsumoto
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Azusa Ohta
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Sho Yamasaki
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Satoshi Hiramine
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Koji Takayama
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Masayuki Murata
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Jun Hayashi
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
- Department of General Internal Medicine, Haradoi Hospital, 6-40-8 Aoba, Higashi-ku, Fukuoka, 8138588, Japan
| | - Nobuyuki Shimono
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka, 3-1-1 Maidashi, Higashi-ku, 8128582, Japan
| | - Ernst J. Schaefer
- Cardiovascular Nutrition Laboratory, Human Nutrition Research Center on Aging at Tufts University, and Tufts University School of Medicine, Boston, MA, 711 Washington Street, 02111, USA
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Petta S, Armandi A, Bugianesi E. Impact of PNPLA3 I148M on Clinical Outcomes in Patients With MASLD. Liver Int 2025; 45:e16133. [PMID: 39412170 PMCID: PMC11815615 DOI: 10.1111/liv.16133] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2024] [Revised: 09/23/2024] [Accepted: 10/02/2024] [Indexed: 01/03/2025]
Abstract
BACKGROUND AND AIMS Metabolic dysfunction-associated steatotic liver disease (MASLD) is a heterogenous clinical and histopathological entity, where multiple metabolic co-factors are intertwined with high interindividual variability. The impact and severity of each factor (including obesity and type 2 diabetes) define a systemic dysmetabolism that can lead to either advanced liver disease and its complication (including hepatocellular carcinoma and clinical events related to portal hypertension) or extrahepatic events: incident cardiovascular disease, chronic kidney disease and extrahepatic cancers. The balance between environmental factors and genetic susceptibility has unique implications in MASLD: the intermittent injury of metabolic co-factors, their fluctuation over time and their specific management, are counterbalanced by the presence of gene variants that can significantly impact the disease at multiple levels. The I148M variant in the PNPLA3 gene is the most investigated genetic susceptibility that induces a more severe steatohepatitis, enhanced fibrogenesis and can shape the incidence of long-term clinical events regardless of, or worsened by, other metabolic risk factors. METHODS AND RESULTS In this review, we will summarise the updated evidence on the natural history of MASLD accounting for classical metabolic risk factors, the role of PNPLA3 in clinical sub-phenotyping (e.g., 'lean MASLD'), impact on disease severity and fibrosis progression, as well as its role for prognostication, alone or in combination with non-invasive tools into polygenic risk scores.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia, Di.Bi.M.I.SUniversity of PalermoPalermoItaly
| | - Angelo Armandi
- Division of Gastroenterology and Hepatology, Department of Medical SciencesUniversity of TurinTurinItaly
| | - Elisabetta Bugianesi
- Division of Gastroenterology and Hepatology, Department of Medical SciencesUniversity of TurinTurinItaly
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Tulone A, Pennisi G, Ciccioli C, Infantino G, La Mantia C, Cannella R, Mercurio F, Petta S. Are we ready for genetic testing in metabolic dysfunction-associated steatotic liver disease? United European Gastroenterol J 2024; 12:638-648. [PMID: 38659291 PMCID: PMC11176907 DOI: 10.1002/ueg2.12556] [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: 11/03/2023] [Accepted: 01/18/2024] [Indexed: 04/26/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), with its steadily increasing prevalence, represents now a major problem in public health. A proper referral could benefit from tools allowing more precise risk stratification. To this end, in recent decades, several genetic variants that may help predict and refine the risk of development and progression of MASLD have been investigated. In this review, we aim to discuss the role genetics in MASLD plays in everyday clinical practice. We performed a comprehensive literature search of PubMed for relevant publications. Available evidence highlights the emergence of genetic-based noninvasive algorithms for diagnosing fatty liver, metabolic dysfunction-associated steatohepatitis, fibrosis progression and occurrence of liver-related outcomes including hepatocellular carcinoma. Nevertheless, their accuracy is not optimal and application in everyday clinical practice remains challenging. Furthermore, susceptible genetic markers have recently become subjects of great scientific interest as therapeutic targets in precision medicine. In conclusion, decisional algorithms based on genetic testing in MASLD to facilitate the clinician decisions on management and treatment are under growing investigation and could benefit from artificial intelligence methodology.
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Affiliation(s)
- Adele Tulone
- Sezione di GastroenterologiaPROMISEUniversity of PalermoPalermoItaly
| | - Grazia Pennisi
- Sezione di GastroenterologiaPROMISEUniversity of PalermoPalermoItaly
| | - Carlo Ciccioli
- Sezione di GastroenterologiaPROMISEUniversity of PalermoPalermoItaly
| | | | - Claudia La Mantia
- Sezione di GastroenterologiaPROMISEUniversity of PalermoPalermoItaly
| | - Roberto Cannella
- Dipartimento di Biomedicina, Neuroscienze e Diagnostica Avanzata (BIND)University of PalermoPalermoItaly
| | | | - Salvatore Petta
- Sezione di GastroenterologiaPROMISEUniversity of PalermoPalermoItaly
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Targher G, Byrne CD, Tilg H. MASLD: a systemic metabolic disorder with cardiovascular and malignant complications. Gut 2024; 73:691-702. [PMID: 38228377 DOI: 10.1136/gutjnl-2023-330595] [Citation(s) in RCA: 93] [Impact Index Per Article: 93.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 12/24/2023] [Indexed: 01/18/2024]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has rapidly become the most common chronic liver disease globally and is currently estimated to affect up to 38% of the global adult population. NAFLD is a multisystem disease where systemic insulin resistance and related metabolic dysfunction play a pathogenic role in the development of NAFLD and its most relevant liver-related morbidities (cirrhosis, liver failure and hepatocellular carcinoma) and extrahepatic complications, such as cardiovascular disease (CVD), type 2 diabetes mellitus, chronic kidney disease, and certain types of extrahepatic cancers. In 2023, three large multinational liver associations proposed that metabolic dysfunction-associated steatotic liver disease (MASLD) should replace the term NAFLD; the name chosen to replace non-alcoholic steatohepatitis was metabolic dysfunction-associated steatohepatitis (MASH). Emerging epidemiological evidence suggests an excellent concordance rate between NAFLD and MASLD definitions-that is, ~99% of individuals with NAFLD meet MASLD criteria. In this narrative review, we provide an overview of the literature on (a) the recent epidemiological data on MASLD and the risk of developing CVD and malignant complications, (b) the underlying mechanisms by which MASLD (and factors strongly linked with MASLD) may increase the risk of these extrahepatic complications and (c) the diagnosis and assessment of CVD risk and potential treatments to reduce CVD risk in people with MASLD or MASH.
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Affiliation(s)
- Giovanni Targher
- Metabolic Diseases Research Unit, IRCCS Sacro Cuore Don Calabria Hospital and Department of Medicine University of Verona, Negrar di Valpolicella (VR), Italy
| | | | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medizinische Universitat Innsbruck, Innsbruck, Austria
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Pourteymour S, Drevon CA, Dalen KT, Norheim FA. Mechanisms Behind NAFLD: a System Genetics Perspective. Curr Atheroscler Rep 2023; 25:869-878. [PMID: 37812367 DOI: 10.1007/s11883-023-01158-3] [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] [Accepted: 09/19/2023] [Indexed: 10/10/2023]
Abstract
PURPOSE OF REVIEW To summarize the key factors contributing to the onset and progress of nonalcoholic fatty liver disease (NAFLD) and put them in a system genetics context. We particularly focus on how genetic regulation of hepatic lipids contributes to NAFLD. RECENT FINDINGS NAFLD is characterized by excessive accumulation of fat in the liver. This can progress to steatohepatitis (inflammation and hepatocyte injury) and eventually, cirrhosis. The severity of NAFLD is determined by a combination of factors including obesity, insulin resistance, and lipotoxic lipids, along with genetic susceptibility. Numerous studies have been conducted on large human cohorts and mouse panels, to identify key determinants in the genome, transcriptome, proteome, lipidome, microbiome and different environmental conditions contributing to NAFLD. We review common factors contributing to NAFLD and put them in a systems genetics context. In particular, we describe how genetic regulation of liver lipids contributes to NAFLD. The combination of an unhealthy lifestyle and genetic predisposition increases the likelihood of accumulating lipotoxic specie lipids that may be one of the driving forces behind developing severe forms of NAFLD.
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Affiliation(s)
- Shirin Pourteymour
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway
| | - Christian A Drevon
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway
- Vitas Ltd. Oslo Science Park, Oslo, Norway
| | - Knut Tomas Dalen
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway
| | - Frode A Norheim
- Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Blindern, PO Box 1046, 0317, Oslo, Norway.
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Zhang D, Mi Z, Peng J, Yang T, Han Y, Zhai Y, Song C, Teng X, Sun W, Guo J, Bilonda KP. Nonalcoholic Fatty Liver Disease as an Emerging Risk Factor and Potential Intervention Target for Atherosclerotic Cardiovascular Diseases. J Cardiovasc Pharmacol 2023; 81:327-335. [PMID: 36917556 PMCID: PMC10155697 DOI: 10.1097/fjc.0000000000001418] [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: 11/20/2022] [Accepted: 02/23/2023] [Indexed: 03/16/2023]
Abstract
ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is an underappreciated independent risk factor for atherosclerotic cardiovascular diseases (ASCVDs). In recent years, the risk of ASCVD has increased along with the prevalence of NAFLD. ASCVD events are highly prevalent and are the main contributor to death in patients with NAFLD. The association between NAFLD and ASCVD has been validated in numerous observational, cohort, and genetic studies. Most of these studies agree that NAFLD significantly increases the risk of developing atherosclerosis and ASCVD. In addition, the underlying proatherosclerotic mechanisms of NAFLD have been gradually revealed; both disorders share several common pathophysiologic mechanisms including insulin resistance, whereas systemic inflammation and dyslipidemia driven by NAFLD directly promote atherosclerosis. Recently, NAFLD, as an emerging risk enhancer for ASCVD, has attracted attention as a potential treatment target for ASCVD. This brief review aims to illustrate the potential mechanistic insights, present recent clinically relevant investigations, and further explore the emerging therapies such as novel antidiabetic and lipid-lowering agents that could improve NAFLD and reduce ASCVD risk.
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Affiliation(s)
- Daqing Zhang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Zhen Mi
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Jiya Peng
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Tiangui Yang
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Yuze Han
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
- Department of Cardiology, Dalian Friendship Hospital, Dalian City, PR China; and
| | - Yujia Zhai
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Chenliang Song
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Xianzhuo Teng
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Wei Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
- Department of Cardiology, Dalian Third People's Hospital, Dalian City, PR China
| | - Jing Guo
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
| | - Kabeya Paulin Bilonda
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang City, PR China
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9
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Bello F, Bettiol A, Silvestri E, Mattioli I, Urban ML, Palermo A, Mazzetti M, Malandrino D, Calcaterra I, Vaglio A, Di Minno MND, Emmi G, Prisco D. Evidence of subclinical atherosclerosis in eosinophilic granulomatosis with polyangiitis. Rheumatology (Oxford) 2023; 62:835-840. [PMID: 35863050 DOI: 10.1093/rheumatology/keac427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2022] [Revised: 06/24/2022] [Accepted: 07/17/2022] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVES Patients affected by eosinophilic granulomatosis with polyangiitis (EGPA) display an increased risk of atherothrombotic events compared with the general population. An increased frequency of subclinical markers of atherosclerosis has been observed in other ANCA-associated vasculitis, but no specific study focused on EGPA. We therefore evaluated subclinical atherosclerosis in EGPA patients and in a control population. METHODS Forty EGPA patients and 80 controls matched by age, sex and traditional cardiovascular risk factors underwent sonographic assessment of common carotid artery (CCA) intima-media thickness (IMT). The presence of plaques of the CCA was also investigated. The correlation between CCA-IMT and clinical and laboratory features was also assessed. RESULTS Median CCA-IMT was significantly higher in EGPA patients compared with controls (P = 0.002). Also, the proportion of subjects with increased CCA-IMT and with presence of plaques was significantly higher among EGPA patients (P < 0.001 for both). Moreover, within the EGPA cohort, CCA-IMT tended to increase with disease duration (P = 0.034) and corticosteroid cumulative dose (P = 0.004). No significant associations were found between CCA-IMT, ANCA status, other clinical features and therapeutic regimens. Notably, the prevalence of traditional cardiovascular risk factors was comparable in patients with vs without an increased CCA-IMT. CONCLUSION Ultrasound markers of subclinical atherosclerosis are increased in EGPA patients as compared with controls, independently of traditional cardiovascular risk factors.
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Affiliation(s)
- Federica Bello
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Alessandra Bettiol
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Elena Silvestri
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Irene Mattioli
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Maria Letizia Urban
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Adalgisa Palermo
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Matteo Mazzetti
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Danilo Malandrino
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Ilenia Calcaterra
- Department of Clinical Medicine and Surgery, Federico II University, Naples
| | - Augusto Vaglio
- Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Florence, Florence
| | | | - Giacomo Emmi
- Department of Experimental and Clinical Medicine, University of Florence, Florence
| | - Domenico Prisco
- Department of Experimental and Clinical Medicine, University of Florence, Florence
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10
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Pipitone RM, Ciccioli C, Infantino G, La Mantia C, Parisi S, Tulone A, Pennisi G, Grimaudo S, Petta S. MAFLD: a multisystem disease. Ther Adv Endocrinol Metab 2023; 14:20420188221145549. [PMID: 36726391 PMCID: PMC9885036 DOI: 10.1177/20420188221145549] [Citation(s) in RCA: 89] [Impact Index Per Article: 44.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/26/2022] [Indexed: 01/29/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), affecting about 25% of general population and more than 50% of dysmetabolic patients, is an emerging cause of chronic liver disease and its complications. Recently, an international consensus of experts proposed to rename this disease as 'Metabolic dysfunction-Associated Fatty Liver Disease' (MAFLD) to focus on the bidirectional interplay between fatty liver and metabolic alterations and to stress the need of assessing fatty liver independently from alcohol consumption and other coexisting causes of liver disease. The peculiarity of NAFLD/MAFLD lies in the presence of a higher risk of not only - as expected - liver-related events but also of extrahepatic events, mostly cardiovascular and cancers. Available evidence suggests that these associations are not only the expression of sharing the same risk factors but shed light about the ability of NAFLD/MAFLD and particularly of its progressive form - nonalcoholic/metabolic dysfunction-associated steatohepatitis - to act as an independent risk factor via promotion of atherogenic dyslipidemia and a proinflammatory, profibrogenic, and procoagulant systemic environment. The present review summarizes available epidemiological and clinical evidence supporting the concept of NAFLD/MAFLD as a multisystemic disease, and highlights potential explanatory mechanisms underlying the association between NAFLD/MAFLD and extrahepatic disorders.
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Affiliation(s)
- Rosaria Maria Pipitone
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Carlo Ciccioli
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Giuseppe Infantino
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Claudia La Mantia
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Stefanie Parisi
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Adele Tulone
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Grazia Pennisi
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
| | - Stefania Grimaudo
- Section of Gastroenterology and Hepatology,
PROMISE, University of Palermo, Palermo, Italy
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11
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Baratta F, D'Erasmo L, Bini S, Pastori D, Angelico F, Del Ben M, Arca M, Di Costanzo A. Heterogeneity of non-alcoholic fatty liver disease (NAFLD): Implication for cardiovascular risk stratification. Atherosclerosis 2022; 357:51-59. [PMID: 36058083 DOI: 10.1016/j.atherosclerosis.2022.08.011] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/27/2022] [Accepted: 08/11/2022] [Indexed: 12/17/2022]
Abstract
NAFLD is currently considered the most common liver disease worldwide and mounting data support its strong link with atherosclerotic cardiovascular disease (ASCVD). This association is important as cardiovascular disease (CVD) is generally recognized as the leading cause of death in individuals with NAFLD. However, NAFLD represents a heterogeneous condition showing a wide spectrum of clinical and pathophysiological sub-phenotypes with different adverse outcomes ranging from ASCVD to liver damage progression. The contribution to NAFLD pathogenesis of different environmental, metabolic, and genetic factors underlies this heterogeneity. The more frequent phenotype of NAFLD patients is associated with metabolic dysfunctions such as obesity and insulin-resistant syndrome and this has been recently named as Metabolic Associated Fatty Liver disease (MAFLD). However, NAFLD is encountered also in subjects without insulin resistance and metabolic alterations and in whom genetic factors play a major role. It has been suggested that these individuals are at risk of liver disease progression but not of cardiovascular complications. Separating metabolic from genetic factors could be useful in disentangling the intricate relationship between NAFLD and atherosclerosis. In the present review, we aim to address the epidemic of NAFLD, its epidemiologically association with ASCVD complications and the overall mechanisms involved in the pathophysiology of atherosclerotic vascular damage in NAFLD patients. Finally, we will revise the potential role of genetics in identifying disease subtyping and predicting individualised CVD risk.
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Affiliation(s)
- Francesco Baratta
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161, Rome, Italy
| | - Laura D'Erasmo
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Simone Bini
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Daniele Pastori
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161, Rome, Italy
| | - Francesco Angelico
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00161, Rome, Italy
| | - Maria Del Ben
- Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00161, Rome, Italy
| | - Marcello Arca
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy
| | - Alessia Di Costanzo
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00161, Rome, Italy.
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12
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Association of rs738409 Polymorphism in Adiponutrin Gene with Liver Steatosis and Atherosclerosis Risk Factors in Greek Children and Adolescents. Nutrients 2022; 14:nu14173452. [PMID: 36079710 PMCID: PMC9459993 DOI: 10.3390/nu14173452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 08/17/2022] [Accepted: 08/18/2022] [Indexed: 12/03/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) shares several risk factors with atherosclerosis, as it is associated with components of the metabolic syndrome. However, genetic variations have also been linked to the risk of NAFLD, such as adiponutrin/patatin-like phospholipase domain-containing the protein 3 (PNPLA3) rs738409 polymorphism. The aim of the study was to determine the associations of thePNPLA3 rs738409 polymorphism with NAFLD and atherosclerosis risk factors in children and adolescents from northern Greece. A total of 91 children/adolescents who followed a Mediterranean eating pattern with no particular restrictions were studied. They were divided into three subgroups, according to their body mass index (BMI) and the presence or absence of liver disease. Diagnosis of NAFLD was based on a liver ultrasound, while the distribution of the PNPLA3 rs738409 polymorphism was investigated in all the participants. From the components of metabolic syndrome, only BMI, waist circumference, blood pressure, and the homeostasis model of insulin resistance (HOMA-IR) differed significantly between groups. The rs738409 polymorphism was significantly associated with BMI and NAFLD, while lipid values had no significant association with either NAFLD or gene polymorphism. This study shows that in Greekchildren, there is a significant association between the rs738409polymorphism in the PNPLA3 gene and hepatic steatosis, regardless of bodyweight.
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13
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Zhao W, Mori H, Tomiga Y, Tanaka K, Perveen R, Mine K, Inadomi C, Yoshioka W, Kubotsu Y, Isoda H, Kuwashiro T, Oeda S, Akiyama T, Zhao Y, Ozaki I, Nagafuchi S, Kawaguchi A, Aishima S, Anzai K, Takahashi H. HSPA8 Single-Nucleotide Polymorphism Is Associated with Serum HSC70 Concentration and Carotid Artery Atherosclerosis in Nonalcoholic Fatty Liver Disease. Genes (Basel) 2022; 13:genes13071265. [PMID: 35886046 PMCID: PMC9323248 DOI: 10.3390/genes13071265] [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: 05/26/2022] [Revised: 07/01/2022] [Accepted: 07/14/2022] [Indexed: 11/29/2022] Open
Abstract
There is an association between nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, but the genetic risk of atherosclerosis in NAFLD remains unclear. Here, a single-nucleotide polymorphism (SNP) of the heat shock 70 kDa protein 8 (HSPA8) gene was analyzed in 123 NAFLD patients who had been diagnosed using a liver biopsy, and the NAFLD phenotype including the maximum intima–media thickness (Max-IMT) of the carotid artery was investigated. Patients with the minor allele (A/G or G/G) of rs2236659 showed a lower serum heat shock cognate 71 kDa protein concentration than those with the major A/A allele. Compared with the patients with the major allele, those with the minor allele showed a higher prevalence of hypertension and higher Max-IMT in men. No significant associations between the HSPA8 genotype and hepatic pathological findings were identified. In decision-tree analysis, age, sex, liver fibrosis, and HSPA8 genotype were individually associated with severe carotid artery atherosclerosis (Max-IMT ≥ 1.5 mm). Noncirrhotic men aged ≥ 65 years were most significantly affected by the minor allele of HSPA8. To predict the risk of atherosclerosis and cardiovascular disease, HSPA8 SNP genotyping might be useful, particularly for older male NAFLD patients.
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Affiliation(s)
- Wenli Zhao
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
| | - Hitoe Mori
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Yuki Tomiga
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Kenichi Tanaka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Rasheda Perveen
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Keiichiro Mine
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Division of Mucosal Immunology, Research Center for Systems Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
| | - Chika Inadomi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Wataru Yoshioka
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Yoshihito Kubotsu
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Hiroshi Isoda
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
| | - Takuya Kuwashiro
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Satoshi Oeda
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
| | - Takumi Akiyama
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Ye Zhao
- Innovative Institute of Chinese Medicine and Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250014, China;
| | - Iwata Ozaki
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Health Administration Centre, Saga Medical School, Saga University, Saga 849-8501, Japan
| | - Seiho Nagafuchi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Atsushi Kawaguchi
- Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga 849-8501, Japan;
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga 849-8501, Japan;
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga 849-8501, Japan; (W.Z.); (H.M.); (Y.T.); (K.T.); (R.P.); (K.M.); (C.I.); (W.Y.); (Y.K.); (T.K.); (T.A.); (I.O.); (S.N.); (K.A.)
- Liver Center, Saga University Hospital Faculty of Medicine, Saga University, Saga 849-8501, Japan; (H.I.); (S.O.)
- Correspondence:
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14
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Jin Q, Yang RX, Fan JG. Does nonalcoholic fatty liver disease predispose patients to carotid arteriosclerosis and ischemic stroke? Clin Mol Hepatol 2022; 28:473-477. [PMID: 35730209 PMCID: PMC9293605 DOI: 10.3350/cmh.2022.0155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/18/2022] [Accepted: 06/20/2022] [Indexed: 11/09/2022] Open
Affiliation(s)
- Qian Jin
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rui-Xu Yang
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Gao Fan
- Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
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15
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Sonaglioni A, Cerini F, Nicolosi GL, Lombardo M, Rumi MG, Viganò M. Left ventricular strain predicts subclinical atherosclerosis in nonadvanced nonalcoholic fatty liver disease patients. Eur J Gastroenterol Hepatol 2022; 34:707-716. [PMID: 35412487 DOI: 10.1097/meg.0000000000002375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES The association between nonalcoholic fatty liver disease (NAFLD) and carotid atherosclerosis is still controversial. The present study was designed to assess the relationship between left ventricular systolic mechanics, noninvasively assessed by two-dimensional (2D) speckle-tracking echocardiography (STE) and common carotid artery (CCA) intima-media thickness (IMT), in patients with nonadvanced NAFLD. METHODS All consecutive NAFLD patients diagnosed with liver stiffness measurement (LSM) <12.5 kPa on transient elastography between September 2021 and December 2021 were prospectively enrolled. All participants underwent blood tests, transient elastography, 2D transthoracic echocardiography (TTE) implemented with 2D-STE analysis of left ventricular (LV) global longitudinal strain (GLS) and finally carotid ultrasonography. Main independent predictors of subclinical atherosclerosis, defined as CCA-IMT >0. 9 mm, were evaluated. RESULTS A total of 92 NAFLD patients (54.0 ± 11.1 years, 50% males) were prospectively analyzed. Mean LSM was 6.2 ± 2.4 kPa. FibroScan results revealed that 76.1% of patients had F0-F1, 5.4% F2 and 18.5% F3 liver fibrosis. Despite normal biventricular systolic function on 2D-TTE, LV-GLS was reduced (less negative than -20%) in 64.1% of patients. However, 62.0% of NAFLD patients were found with CCA-IMT >0. 9 mm. Age [odds ratio (OR),1.19; 95% confidence interval (CI), 1.05-1.36], hypertension (OR, 3.73; 95% CI, 1.53-9.11), LSM (OR, 4.83; 95% CI, 2.43-9.59), LV-GLS (OR, 0.49; 95% CI, 0.36-0.68) and statin therapy (OR, 0.10; 95% CI, 0.02-0.60) were independently associated with subclinical atherosclerosis. Age ≥51 years, LSM ≥5.5 kPa and LV-GLS less negative than -20% were the best cutoff values for predicting subclinical atherosclerosis. CONCLUSIONS Subclinical myocardial dysfunction and subclinical atherosclerosis are simultaneously present in patients with nonadvanced NAFLD.
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Affiliation(s)
| | - Federica Cerini
- Division of Hepatology, Ospedale San Giuseppe MultiMedica IRCCS, University of Milan, Milan
| | | | | | - Maria Grazia Rumi
- Division of Hepatology, Ospedale San Giuseppe MultiMedica IRCCS, University of Milan, Milan
| | - Mauro Viganò
- Division of Hepatology, Ospedale San Giuseppe MultiMedica IRCCS, University of Milan, Milan
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Abstract
PURPOSE OF REVIEW Nonalcoholic fatty liver disease (NAFLD) is a common comorbidity and has wide ranging extrahepatic manifestations, including through cardiometabolic pathways. As such, there is growing interest in the impact of NAFLD on cerebrovascular disease and brain health more broadly. In this review, we assess recent research into understanding the association between NAFLD and brain health while highlighting potential clinical implications. RECENT FINDINGS Mechanistically, NAFLD is characterized by both a proinflammatory and proatherogenic state, which results in vascular inflammation and neurodegeneration, potentially leading to clinical and subclinical cerebrovascular disease. Mounting epidemiological evidence suggests an association between NAFLD and an increased risk and severity of stroke, independent of other vascular risk factors. Studies also implicate NAFLD in subclinical cerebrovascular disease, such as carotid atherosclerosis and microvascular disease. In contrast, there does not appear to be an independent association between NAFLD and cognitive impairment. SUMMARY The current literature supports the formulation of NAFLD as a multisystem disease that may also have implications for cerebrovascular disease and brain health. Further prospective studies are needed to better assess a temporal relationship between the two diseases, confirm these early findings, and decipher mechanistic links.
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Affiliation(s)
- Sahil Khanna
- Division of Gastroenterology & Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine
| | - Neal S. Parikh
- Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute and Department of Neurology, Weill Cornell Medicine
| | - Lisa B. VanWagner
- Division of Gastroenterology & Hepatology, Department of Medicine, Northwestern University Feinberg School of Medicine
- Department of Preventive Medicine, Northwestern University Feinberg School of Medicine
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17
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Correlations between PNPLA3 Gene Polymorphisms and NAFLD in Type 2 Diabetic Patients. MEDICINA (KAUNAS, LITHUANIA) 2021; 57:medicina57111249. [PMID: 34833467 PMCID: PMC8620174 DOI: 10.3390/medicina57111249] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/03/2021] [Accepted: 11/12/2021] [Indexed: 12/20/2022]
Abstract
Background and Objectives: Non-alcoholic fatty liver disease is a worldwide significant public health problem, particularly in patients with type 2 diabetes mellitus. Identifying possible risk factors for the disease is mandatory for a better understandingand management of this condition. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been linked to the development and evolution of fatty liver but not to insulin resistance. The aim of this study isto evaluate the relationships between PNPLA3 and fatty liver, metabolic syndrome and subclinical atherosclerosis. Materials and Methods: The study group consisted of patients with type 2 diabetes mellitus without insulin treatment. The degree of liver fat loading was assessed by ultrasonography, and subclinical atherosclerosis was assessed using carotid intima-media thickness (CIMT). PNPLA3 rs738409 genotype determination was performed by high-resolution melting analysis that allowed three standard genotypes: CC, CG, and GG. Results: Among the 92 patients, more than 90% showed various degrees of hepatic steatosis, almost 62% presented values over the normal limit for the CIMT. The majority of the included subjects met the criteria for metabolic syndrome. Genotyping of PNPLA3 in 68 patients showed that the difference between subjects without steatosis and subjects with hepatic steatosis was due to the higher frequency of genotype GG. The CC genotype was the most common in the group we studied and was significantly more frequent in the group of subjects with severe steatosis; the GG genotype was significantly more frequent in subjects with moderate steatosis; the frequency of the CG genotype was not significantly different among the groups.When we divided the group of subjects into two groups: those with no or mild steatosis and those with moderate or severe steatosis it was shown that the frequency of the GG genotype was significantly higher in the group of subjects with moderate or severe steatosis. PNPLA3 genotypes were not associated with metabolic syndrome, subclinical atherosclerosis, or insulin resistance. Conclusions: Our results suggest that PNPLA3 does not independently influence cardiovascular risk in patients with type 2 diabetes mellitus. The hypothesis that PNPLA3 may have a cardioprotective effect requires future confirmation.
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Xiang H, Wu Z, Wang J, Wu T. Research progress, challenges and perspectives on PNPLA3 and its variants in Liver Diseases. J Cancer 2021; 12:5929-5937. [PMID: 34476007 PMCID: PMC8408107 DOI: 10.7150/jca.57951] [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: 01/07/2021] [Accepted: 07/26/2021] [Indexed: 12/02/2022] Open
Abstract
The human patatin-like phospholipase domain-containing 3 gene (PNPLA3) is highly expressed in liver and adipose tissue and encodes a transmembrane polypeptide chain containing 481 amino acids. The I148M variant of PNPLA3 is a single nucleotide polymorphism, which is related to a variety of liver and cardiovascular diseases and their complications (such as non-alcoholic fatty liver disease, liver fibrosis, coronary artery disease). This review mainly describes the pathophysiological effects of PNPLA3 and its variants, and their roles in the progression of liver disease and its complications.
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Affiliation(s)
- Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zecheng Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Liver fibrosis is associated with carotid atherosclerosis in patients with liver biopsy-proven nonalcoholic fatty liver disease. Sci Rep 2021; 11:15938. [PMID: 34354193 PMCID: PMC8342487 DOI: 10.1038/s41598-021-95581-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is related to subclinical atherosclerosis. However, whether the severity of the disease (or which histopathological component) is associated with subclinical atherosclerosis remains controversial. This study aimed to investigate the association between the histopathological severity of NAFLD and carotid intima-media thickness (CIMT) in Japanese patients with liver biopsy-proven NAFLD. Maximum-CIMT (max-CIMT) was measured as an index of carotid atherosclerosis in 195 biopsy-proven NAFLD patients. A significant association was observed between the severity of fibrosis (but not steatosis, inflammation, and ballooning) and max-CIMT. Older age, male gender, hypertension, and advanced fibrosis were independently linked to max-CIMT ≥ 1.2 mm. The prevalence of max-CIMT ≥ 1.2 mm was significantly higher in the advanced fibrosis group than in the non-advanced fibrosis group (75.4% versus 44.0%; p < 0.01). Non-invasive liver fibrosis markers and scoring systems, including fibrosis-4 index, NAFLD fibrosis score, hyaluronic acid, and Wisteria floribunda agglutinin positive Mac-2-binding protein, demonstrated that the diagnostic performance for max-CIMT ≥ 1.2 mm was similar to that of biopsy-based fibrosis staging. In conclusion, advanced fibrosis is significantly and independently associated with high-risk CIMT. Non-invasive fibrosis markers and scoring systems could help estimate the risk of atherosclerosis progression in patients with NAFLD.
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Iruzubieta P, Arias-Loste MT, Fortea JI, Cuadrado A, Rivas-Rivas C, Rodriguez-Duque JC, García-Ibarbia C, Hernández JL, Crespo J. National digestive disease specialists survey on cardiovascular risk management in non-alcoholic fatty liver disease in spanish hospitals. Liver Int 2021; 41:1243-1253. [PMID: 33527637 DOI: 10.1111/liv.14807] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Cardiovascular disease (CVD) is the main cause of mortality among non-alcoholic fatty liver disease (NAFLD) patients. The aim was to explore the level of knowledge and clinical management of cardiovascular risk (CVR) in NAFLD patients by Digestive Disease specialists. METHODS An anonymous web-based survey was designed with 44 close-ended questions, divided into five sections, that were based on current guidelines on CVD prevention. Between November 2019 and January 2020, Digestive Disease specialists from Spanish hospitals were invited to participate in this survey via email and Twitter. Student's t, chi-square and Fishers' exact tests, and logistic regression were used for data analysis. RESULTS 208 clinicians completed the survey. Most respondents (83.2%) believe that NAFLD is an independent risk factor for CVD, especially in the presence of NASH and fibrosis. Personal history of CVDs and cardiovascular risk-related comorbidities are collected by more than 75% of respondents. However, less than 17% perform an elementary physical examination to address the CVR, except weight which is evaluated by 69.8%. Over 54% of respondents do not perform or request any supplementary tests for CVR assessment, and only 10.2% use specific calculators. Furthermore, 54.3% spend less than 5 minutes giving lifestyle advice, and more than 52% do not start drug treatment after a recent diagnosis of any cardiovascular comorbidity. Only 25.6% have a multidisciplinary Unit for metabolic comorbidities in their hospitals, although 89% of the respondents would support the implementation of this Unit. CONCLUSIONS Cardiovascular risk management in daily clinical practice by Digestive Disease specialists in Spain remains suboptimal.
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Affiliation(s)
- Paula Iruzubieta
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain
| | - María Teresa Arias-Loste
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain
| | - José Ignacio Fortea
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain
| | - Antonio Cuadrado
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain
| | - Coral Rivas-Rivas
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain
| | - Juan Carlos Rodriguez-Duque
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain
| | - Carmen García-Ibarbia
- Lipid and Vascular Risk Unit, Department of Internal Medicine, Marqués de Valdecilla University Hospital, IDIVAL, University of Cantabria, Santander, Spain
| | - José Luis Hernández
- Lipid and Vascular Risk Unit, Department of Internal Medicine, Marqués de Valdecilla University Hospital, IDIVAL, University of Cantabria, Santander, Spain
| | - Javier Crespo
- Gastroenterology and Hepatology Department, Marqués de Valdecilla University Hospital. Clinical and Translational Digestive Research Group, IDIVAL, Santander, Spain
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Abstract
PURPOSE OF REVIEW Aging-related comorbidities, including liver disease, represent the main drivers of morbidity and mortality in people with HIV (PWH). Nonalcoholic fatty liver disease (NAFLD) seems a frequent comorbidity in aging PWH nowadays. NAFLD results from a fat deposition into the liver parenchyma that may evolve to nonalcoholic steatohepatitis (NASH), a state of hepatocellular inflammation and injury in response to the accumulated fat leading to liver fibrosis and cirrhosis. We here review the current status of knowledge regarding this emerging comorbidity in PWH. RECENT FINDINGS Recent studies suggest that PWH are at higher risk for both NASH and NASH-related liver fibrosis. Several hypothesized pathogenic mechanisms may account for this finding, including increased metabolic comorbidities, hepatotoxic effect of lifelong antiretroviral therapy, and chronic HIV infection. In clinical practice, non-invasive diagnostic tests, such as serum biomarkers and elastography, may help identify patients with NASH-related fibrosis, thus improving risk stratification, and enhancing clinical management decisions, including early initiation of interventions such as lifestyle changes and potential pharmacologic interventions. Clinicians should remain informed of the frequency, significance, and diagnostic and management approach to NASH in PWH.
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Affiliation(s)
- Adriana Cervo
- Division of Infectious Diseases, Chronic Viral Illness Service, McGill University Health Centre, Montreal, Canada
- Department of Health Promotion Sciences and Mother and Child Care "Giuseppe D'Alessandro", University of Palermo, Palermo, Italy
| | - Mohamed Shengir
- Division of Experimental Medicine, McGill University, Montreal, Canada
| | - Keyur Patel
- Division of Gastroenterology, University Health Network Toronto, Toronto General Hospital, Toronto, Canada
| | - Giada Sebastiani
- Division of Gastroenterology and Hepatology, Chronic Viral Illness Service Royal Victoria Hospital, McGill University Health Centre, 1001 Blvd. Décarie, Montreal, QC H4A 3J1, Canada.
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Castaldo L, Laguzzi F, Strawbridge RJ, Baldassarre D, Veglia F, Vigo L, Tremoli E, de Faire U, Eriksson P, Smit AJ, Aubrecht J, Leander K, Pirro M, Giral P, Ritieni A, Di Minno G, Mälarstig A, Gigante B. Genetic Variants Associated with Non-Alcoholic Fatty Liver Disease Do Not Associate with Measures of Sub-Clinical Atherosclerosis: Results from the IMPROVE Study. Genes (Basel) 2020; 11:genes11111243. [PMID: 33105679 PMCID: PMC7690395 DOI: 10.3390/genes11111243] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 10/16/2020] [Accepted: 10/21/2020] [Indexed: 01/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis-related cardiovascular diseases (CVD) share common metabolic pathways. We explored the association between three NAFLD-associated single nucleotide polymorphisms (SNPs) rs738409, rs10401969, and rs1260326 with sub-clinical atherosclerosis estimated by the carotid intima-media thickness (c-IMT) and the inter-adventitia common carotid artery diameter (ICCAD) in patients free from clinically overt NAFLD and CVD. The study population is the IMPROVE, a multicenter European study (n = 3711). C-IMT measures and ICCAD were recorded using a standardized protocol. Linear regression with an additive genetic model was used to test for association of the three SNPs with c-IMT and ICCAD. In secondary analyses, the association of the three SNPs with c-IMT and ICCAD was tested after stratification by alanine aminotransferase levels (ALT). No associations were found between rs738409, rs1260326, rs10401969, and c-IMT or ICCAD. Rs738409-G and rs10401969-C were associated with ALT levels (p < 0.001). In patients with ALT levels above 28 U/L (highest quartile), we observed an association between rs10401969-C and c-IMT measures of c-IMTmax and c-IMTmean-max (p = 0.018 and 0.021, respectively). In conclusion, NAFLD-associated SNPs do not associate with sub-clinical atherosclerosis measures. However, our results suggest a possible mediating function of impaired liver function on atherosclerosis development.
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Affiliation(s)
- Luigi Castaldo
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy;
- Department of Pharmacy, University of Naples “Federico II”, 80138 Naples, Italy;
- Correspondence: ; Tel.: +39-081-678116
| | - Federica Laguzzi
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; (F.L.); (U.d.F.); (K.L.)
| | - Rona J. Strawbridge
- Mental Health and Wellbeing, Institute of Health and Wellbeing, University of Glasgow, Glasgow G12-8QQ, UK;
- Health Data Research University of Glasgow, College of Medicine, Veterinarian and Life Sciences, Glasgow G12-8RZ, UK
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
| | - Damiano Baldassarre
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
- Department of Medical Biotechnology and Translational Medicine, University of Milan, 20122 Milano MI, Italy
| | - Fabrizio Veglia
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
| | - Lorenzo Vigo
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
| | - Elena Tremoli
- Centro Cardiologico Monzino, Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Via Parea 4, 20138 Milan, Italy; (D.B.); (F.V.); (L.V.); (E.T.)
| | - Ulf de Faire
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; (F.L.); (U.d.F.); (K.L.)
| | - Per Eriksson
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
| | - Andries J. Smit
- Department of Medicine, Division of vascular medicine University Medical Center Groningen, 9713 GZ Groningen, The Netherlands;
| | - Jiri Aubrecht
- Takeda Pharmaceuticals International Co., Cambridge, 02139 MA, USA;
| | - Karin Leander
- Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; (F.L.); (U.d.F.); (K.L.)
| | - Matteo Pirro
- Unit of Internal Medicine, Department of Medicine, University of Perugia, 06123 Perugia PG, Italy;
| | - Philippe Giral
- Assistance Publique—Hopitaux de Paris; Service Endocrinologie-Metabolisme, Groupe Hôpitalier Pitie-Salpetriere, Unités de Prévention Cardiovasculaire, 75013 Paris, France;
| | - Alberto Ritieni
- Department of Pharmacy, University of Naples “Federico II”, 80138 Naples, Italy;
| | - Giovanni Di Minno
- Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80138 Naples, Italy;
| | - Anders Mälarstig
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
| | - Bruna Gigante
- Cardiovascular Medicine, Department of Medicine, Karolinska Institutet, Box 210, 171 77 Stockholm, Sweden; (P.E.); (A.M.); (B.G.)
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Chung GE, Shin E, Kwak MS, In Yang J, Lee JE, Choe EK, Yim JY. The association of genetic polymorphisms with nonalcoholic fatty liver disease in a longitudinal study. BMC Gastroenterol 2020; 20:344. [PMID: 33059586 PMCID: PMC7565807 DOI: 10.1186/s12876-020-01469-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 09/24/2020] [Indexed: 12/23/2022] Open
Abstract
Background Several genetic variants are known to be associated with nonalcoholic fatty liver disease (NAFLD). We aimed to evaluate the longitudinal associations between genetic variants and NAFLD. Methods We performed a genome-wide association study (GWAS) in Korean individuals who underwent repeated health check-ups. NAFLD was defined by ultrasonography and exclusion of secondary causes. Results The subjects had a median age of 50.0 years, and 54.8% were male. The median follow-up duration was 39 months. Among the 3905 subjects without NAFLD at baseline, 874 (22.4%) subjects developed NAFLD, and among the 1818 subjects with NAFLD at baseline, NAFLD regressed in 336 (18.5%) subjects during the follow-up period. After adjusting for age, sex and body mass index, no single-nucleotide polymorphism (SNP) passed Bonferroni correction for genome-wide significance in the development or regression of NAFLD. Among the SNPs that passed the genome-wide suggestiveness threshold (p = 1E-04) in the discovery set in the GWAS, only 1 SNP (rs4906353) showed an association with the development of NAFLD, with marginal significance in the validation set (p-value, discovery set = 9.68E-5 and validation set = 0.00531). Conclusions This exploratory study suggests that longitudinal changes in NAFLD are not associated with genetic variants in the Korean population. These findings provide new insight into genetic mechanisms in the pathogenesis of NAFLD.
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Affiliation(s)
- Goh Eun Chung
- Department of Internal Medicine, Gangnam Healthcare Center, Seoul National University Hospital, 39FL., Gangnam Finance center 737, Yeoksam-Dong, Gangnam-Gu, Seoul, 135-984, South Korea.
| | | | - Min-Sun Kwak
- Department of Internal Medicine, Gangnam Healthcare Center, Seoul National University Hospital, 39FL., Gangnam Finance center 737, Yeoksam-Dong, Gangnam-Gu, Seoul, 135-984, South Korea
| | - Jong In Yang
- Department of Internal Medicine, Gangnam Healthcare Center, Seoul National University Hospital, 39FL., Gangnam Finance center 737, Yeoksam-Dong, Gangnam-Gu, Seoul, 135-984, South Korea
| | | | - Eun Kyung Choe
- Healthcare Research Institute, Seoul National University Hospital, Healthcare System Gangnam Center, Seoul, South Korea
| | - Jeong Yoon Yim
- Department of Internal Medicine, Gangnam Healthcare Center, Seoul National University Hospital, 39FL., Gangnam Finance center 737, Yeoksam-Dong, Gangnam-Gu, Seoul, 135-984, South Korea
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24
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Parikh NS, Dueker N, Varela D, Del Brutto VJ, Rundek T, Wright CB, Sacco RL, Elkind MSV, Gutierrez J. Association between PNPLA3 rs738409 G variant and MRI cerebrovascular disease biomarkers. J Neurol Sci 2020; 416:116981. [PMID: 32592869 DOI: 10.1016/j.jns.2020.116981] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 05/28/2020] [Accepted: 06/05/2020] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Nonalcoholic fatty liver disease (NAFLD) has been associated with greater cerebral white matter hyperintensity (WMH) volume and microbleeds. The adiponutrin (PNPLA3) rs738409 G variant, a robust NAFLD susceptibility variant, has been variably associated with carotid atherosclerosis. We hypothesized that this variant is associated with WMH volume, microbleeds, covert brain infarction (CBI), and small perivascular spaces. METHODS We performed a cross-sectional analysis of the Northern Manhattan Study-MRI Substudy. The associations between the rs738409 G variant allele and outcomes were assessed using linear regression for WMH volume, logistic regression for microbleeds and CBI, and Poisson regression for small perivascular spaces. Models were adjusted for age, sex, principal components, diabetes, and body mass index. RESULTS We included 1063 Northern Manhattan Study participants who had brain MRI and genotype data available (mean age 70 ± 9 years, 61% women). The G allele frequency was 24%. The prevalence of any microbleeds and CBI were 8% and 18%, respectively. The median WMH volume and small perivascular space count score were 7.7 mL and 6, respectively. GG homozygosity, but not heterozygosity, was associated with WMH volume (β = 0.27; 95% CI, 0.03, 0.51) compared to non-carriers. Having at least one G allele was associated with the presence of microbleeds (Odds ratio, 1.78; 95% CI, 1.02, 3.12); the association was attenuated in other models. No associations were observed for CBI and small perivascular spaces. CONCLUSION The PNPLA3 rs738409 G allele was associated with greater WMH volume, and inconsistent associations with microbleeds were seen.
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Affiliation(s)
- Neal S Parikh
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA.
| | - Nicole Dueker
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA
| | - Dalila Varela
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Victor J Del Brutto
- Department of Neurology, Epidemiology and Public Health, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - Tatjana Rundek
- Department of Neurology, Epidemiology and Public Health, Miller School of Medicine, University of Miami, Miami, FL, USA; Evelyn F. McKnight Brain Institute, University of Miami, Miami, FL, USA
| | - Clinton B Wright
- National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA
| | - Ralph L Sacco
- John P. Hussman Institute for Human Genomics, University of Miami, Miami, FL, USA; Department of Neurology, Epidemiology and Public Health, Miller School of Medicine, University of Miami, Miami, FL, USA; Evelyn F. McKnight Brain Institute, University of Miami, Miami, FL, USA
| | - Mitchell S V Elkind
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA; Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Jose Gutierrez
- Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
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Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 73:948-963. [PMID: 30819364 DOI: 10.1016/j.jacc.2018.11.050] [Citation(s) in RCA: 282] [Impact Index Per Article: 56.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/14/2018] [Accepted: 11/26/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) and cardiovascular disease (CVD) are both manifestations of end-organ damage of the metabolic syndrome. Through multiple pathophysiological mechanisms, CVD and NAFLD are associated with each other. Systemic inflammation, endothelial dysfunction, hepatic insulin resistance, oxidative stress, and altered lipid metabolism are some of the mechanisms by which NAFLD increases the risk of CVD. Patients with NAFLD develop increased atherosclerosis, cardiomyopathy, and arrhythmia, which clinically result in cardiovascular morbidity and mortality. Defining the mechanisms linking these 2 diseases offers the opportunity to further develop targeted therapies. The aim of this comprehensive review is to examine the association between CVD and NAFLD and discuss the overlapping management approaches.
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Affiliation(s)
- Eric P Stahl
- Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Devinder S Dhindsa
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Suegene K Lee
- Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia
| | - Pratik B Sandesara
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
| | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Laurence S Sperling
- Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia.
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Chandrasekharan K, Alazawi W. Genetics of Non-Alcoholic Fatty Liver and Cardiovascular Disease: Implications for Therapy? Front Pharmacol 2020; 10:1413. [PMID: 31969816 PMCID: PMC6960381 DOI: 10.3389/fphar.2019.01413] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 11/07/2019] [Indexed: 12/16/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. The most common cause of mortality in NAFLD is cardiovascular disease (CVD), and a key of focus in drug development is to discover therapies that target both liver injury and CVD risk. NAFLD and CVD are complex disease spectra with complex heritability patterns. Nevertheless, genome wide association studies and meta-analyses of these have identified genetic loci that are associated with increased risk of relevant pathological features of disease or clinical endpoints. This review focuses on the genetic risk loci identified in the NAFLD spectrum and asks whether any of these are also risk factors for CVD. Surprisingly, given the shared co-morbidities and risk factors, little robust evidence exists that NAFLD and CVD share genetic risk. Despite this, therapeutic intervention that targets both liver disease and CVD remains an important clinical need and a major focus for pharmaceutical development.
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Affiliation(s)
- Karthik Chandrasekharan
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, United Kingdom
| | - William Alazawi
- Barts Liver Centre, Blizard Institute, Queen Mary University of London, London, United Kingdom
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Abstract
Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of the metabolic syndrome (MetS) and comprises one of the largest health threats of the twenty-first century. In this chapter, we review the current state of knowledge of NAFLD and underline the striking similarities with atherosclerosis. We first describe current epidemiological data showing the staggering increase of NAFLD numbers and its related clinical and economic costs. We then provide an overview of pathophysiological hepatic processes in NAFLD and highlight the systemic aspects of NAFLD that point toward metabolic crosstalk between organs as an important cause of metabolic disease. Finally, we end by highlighting the currently investigated therapeutic approaches for NAFLD, which also show strong similarities with a range of treatment options for atherosclerosis.
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Käräjämäki AJ, Hukkanen J, Kauma H, Kesäniemi YA, Ukkola O. Metabolic syndrome but not genetic polymorphisms known to induce NAFLD predicts increased total mortality in subjects with NAFLD (OPERA study). Scandinavian Journal of Clinical and Laboratory Investigation 2019; 80:106-113. [PMID: 31851849 DOI: 10.1080/00365513.2019.1700428] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Metabolic syndrome (MetS) and genetic polymorphisms PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 are known inductors of non-alcoholic fatty liver disease (NAFLD). However, knowledge about how these affect the mortality of subjects with NAFLD is scarce. Therefore, we investigated the impact of MetS, PNPLA3 rs738409, TM6SF2 rs58542926 and MBOAT7 rs641738 on overall and cardiovascular disease (CVD) specific mortality among subjects with or without NAFLD. NAFLD diagnosis was based on liver ultrasound at the baseline. After this and other comprehensive examinations, 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years. The mortality data was gathered from the National Death Registry. After multiple adjustments, the NAFLD individuals with MetS had increased risk of overall mortality as compared to the NAFLD subjects without MetS [2.054 (1.011-4.173, p = .046)]. However, PNPLA3 rs738409 [1.049 (0.650-1.692, p = .844)], TM6SF2 rs58542926 [0.721 (0.369-1.411, p = .340)] or MBOAT7 rs641738 [0.885 (0.543-1.439, p = .621)] did not affect the overall mortality. MetS was also a marker of increased risk of CVD mortality (15% vs. 2%, p = .013) while genetic polymorphisms did not affect CVD mortality. In conclusion, MetS, but not the gene polymorphisms studied, predicts increased overall and CVD-specific mortality among NAFLD subjects.
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Affiliation(s)
- Aki Juhani Käräjämäki
- Department of Gastroenterology, Vaasa Central Hospital, Vaasa, Finland.,Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Janne Hukkanen
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Heikki Kauma
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Y Antero Kesäniemi
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Olavi Ukkola
- Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital, University of Oulu, Oulu, Finland
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Arai T, Atsukawa M, Tsubota A, Kawano T, Koeda M, Yoshida Y, Tanabe T, Okubo T, Hayama K, Iwashita A, Itokawa N, Kondo C, Kaneko K, Kawamoto C, Hatori T, Emoto N, Iio E, Tanaka Y, Iwakiri K. Factors influencing subclinical atherosclerosis in patients with biopsy-proven nonalcoholic fatty liver disease. PLoS One 2019; 14:e0224184. [PMID: 31721770 PMCID: PMC6853607 DOI: 10.1371/journal.pone.0224184] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 10/06/2019] [Indexed: 12/12/2022] Open
Abstract
Although the presence of nonalcoholic fatty liver disease (NAFLD) is known to be related to subclinical atherosclerosis, the relationship between the severity of NAFLD and subclinical atherosclerosis is not clear. This study aimed to clarify the factors related to subclinical arteriosclerosis, including the histopathological severity of the disease and PNPLA3 gene polymorphisms, in NAFLD patients. We measured brachial-ankle pulse wave velocity (baPWV) as an index of arterial stiffness in 153 biopsy-proven NAFLD patients. The baPWV values were significantly higher in the advanced fibrosis group than in the less advanced group (median, 1679 cm/s vs 1489 cm/s; p = 5.49×10-4). Multiple logistic regression analysis revealed that older age (≥55 years) (p = 8.57×10-3; OR = 3.03), hypertension (p = 1.05×10-3; OR = 3.46), and advanced fibrosis (p = 9.22×10-3; OR = 2.94) were independently linked to baPWV ≥1600 cm/s. NAFLD patients were categorized into low-risk group (number of risk factors = 0), intermediate-risk group (= 1), and high-risk group (≥2) based on their risk factors, including older age, hypertension, and biopsy-confirmed advanced fibrosis. The prevalence of baPWV ≥1600 cm/s was 7.1% (3/42) in the low-risk group, 30.8% (12/39) in the intermediate-risk group, and 63.9% (46/72) in the high-risk group. Non-invasive liver fibrosis markers and scores, including the FIB-4 index, NAFLD fibrosis score, hyaluronic acid, Wisteria floribunda agglutinin positive Mac-2-binding protein, and type IV collagen 7s, were feasible substitutes for invasive liver biopsy. Older age, hypertension, and advanced fibrosis are independently related to arterial stiffness, and a combination of these three factors may predict risk of arteriosclerosis in NAFLD patients.
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Affiliation(s)
- Taeang Arai
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Masanori Atsukawa
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Akihito Tsubota
- Core Research Facilities for Basic Science, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan
| | - Tadamichi Kawano
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Mai Koeda
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Yuji Yoshida
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Tomohide Tanabe
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Tomomi Okubo
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Korenobu Hayama
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Ai Iwashita
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Norio Itokawa
- Division of Gastroenterology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Chisa Kondo
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Keiko Kaneko
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Chiaki Kawamoto
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
| | - Tsutomu Hatori
- Division of Pathology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Naoya Emoto
- Division of Endocrinology, Nippon Medical School Chiba Hokusoh Hospital, Inzai, Japan
| | - Etsuko Iio
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan
| | - Yasuhito Tanaka
- Department of Virology and Liver Unit, Nagoya City University Graduate School of Medicinal Sciences, Nagoya, Japan
| | - Katsuhiko Iwakiri
- Division of Gastroenterology and Hepatology, Nippon Medical School, Tokyo, Japan
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Lombardi R, Fargion S, Fracanzani AL. Brain involvement in non-alcoholic fatty liver disease (NAFLD): A systematic review. Dig Liver Dis 2019; 51:1214-1222. [PMID: 31176631 DOI: 10.1016/j.dld.2019.05.015] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Revised: 04/21/2019] [Accepted: 05/06/2019] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is associated with high cardiovascular morbidity and mortality which usually is considered to be related to cardiac involvement, while scarce attention is addressed to brain damage. Viceversa NAFLD is associated with asymptomatic brain lesions, alterations in cerebral perfusion and activity, cognitive impairment and brain aging and with increased risk and severity of both ischemic and haemorrhagic stroke. Besides known metabolic risk factors, NAFLD is characterized by a pro inflammatory state, which contributes to atherosclerosis and microglia activation, endothelial dysfunction, pro-coagulant state and platelets activation, which in turn promote both micro and macrovascular damage eventually responsible for clinical and subclinical cerebrovascular alterations. A better knowledge of the association between NAFLD and brain alterations could lead to an improved management of risk factors underpinning both liver and cerebral disease, possibly preventing the progression of asymptomatic brain lesions to clinical cerebrovascular accidents.
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Affiliation(s)
- Rosa Lombardi
- Department of Pathophysiology and Transplantation Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy.
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Cardiovascular Risk in Non-Alcoholic Fatty Liver Disease: Mechanisms and Therapeutic Implications. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16173104. [PMID: 31455011 PMCID: PMC6747357 DOI: 10.3390/ijerph16173104] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/16/2019] [Revised: 08/18/2019] [Accepted: 08/21/2019] [Indexed: 02/06/2023]
Abstract
New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD—in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome—and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.
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A Systematic Review of NAFLD-Associated Extrahepatic Disorders in Youths. J Clin Med 2019; 8:jcm8060868. [PMID: 31213030 PMCID: PMC6617181 DOI: 10.3390/jcm8060868] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Revised: 06/04/2019] [Accepted: 06/13/2019] [Indexed: 02/07/2023] Open
Abstract
Background: There is growing evidence that non-alcoholic fatty liver disease (NAFLD) is a disease affecting not only the liver but also extrahepatic organs. Aim: To investigate whether in youths NAFLD is associated with extrahepatic complications such as subclinical atherosclerosis, cardiac abnormalities, hypertension, type 2 diabetes, decreased bone mineral density, renal dysfunction, obstructive sleep apnea, and polycystic ovary syndrome. Methods: We systematically reviewed PubMed; Scopus; Embase; and the Cochrane Library databases up to 28 February 2019 and assessed the quality of studies using the Newcastle-Ottawa Scale. Results: Thirty-five articles were selected for this systematic review: fifteen (4627 participants) evaluated the association of NAFLD with subclinical atherosclerosis; four (969 participants) with cardiac abnormalities; two (550 participants) with hypertension; four (1328 participants) with diabetes; six (523 participants) with low bone mineral density; two (865 participants) with renal dysfunction; one with obstructive sleep apnea; and one with polycystic ovary syndrome. Most studies found that youths with NAFLD have increased features of subclinical atherosclerosis; as well as of cardiac alterations. Limited data were available to endorse a solid estimate of the prevalence of diabetes; low mineral density and renal dysfunction in the pediatric NAFLD population. Conclusion: NAFLD-related intermediate CVD outcomes can occur and be detected early in young populations.
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Pastore M, Grimaudo S, Pipitone RM, Lori G, Raggi C, Petta S, Marra F. Role of Myeloid-Epithelial-Reproductive Tyrosine Kinase and Macrophage Polarization in the Progression of Atherosclerotic Lesions Associated With Nonalcoholic Fatty Liver Disease. Front Pharmacol 2019; 10:604. [PMID: 31191323 PMCID: PMC6548874 DOI: 10.3389/fphar.2019.00604] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/14/2019] [Indexed: 12/13/2022] Open
Abstract
Recent lines of evidence highlight the involvement of myeloid-epithelial-reproductive tyrosine kinase (MerTK) in metabolic disease associated with liver damage. MerTK is mainly expressed in anti-inflammatory M2 macrophages where it mediates transcriptional changes including suppression of proinflammatory cytokines and enhancement of inflammatory repressors. MerTK is regulated by metabolic pathways through nuclear sensors including LXRs, PPARs, and RXRs, in response to apoptotic bodies or to other sources of cholesterol. Nonalcoholic fatty liver disease (NAFLD) is one of the most serious public health problems worldwide. It is a clinicopathological syndrome closely related to obesity, insulin resistance, and oxidative stress. It includes a spectrum of conditions ranging from simple steatosis, characterized by hepatic fat accumulation with or without inflammation, to nonalcoholic steatohepatitis (NASH), defined by hepatic fat deposition with hepatocellular damage, inflammation, and accumulating fibrosis. Several studies support an association between NAFLD and the incidence of cardiovascular diseases including atherosclerosis, a major cause of death worldwide. This pathological condition consists in a chronic and progressive inflammatory process in the intimal layer of large- and medium-sized arteries. The complications of advanced atherosclerosis include chronic or acute ischemic damage in the tissue perfused by the affected artery, leading to cellular death. By identifying specific targets influencing lipid metabolism and cardiovascular-related diseases, the present review highlights the role of MerTK in NAFLD-associated atherosclerotic lesions as a potential innovative therapeutic target. Therapeutic advantages might derive from the use of compounds selective for nuclear receptors targeting PPARs rather than LXRs regulating macrophage lipid metabolism and macrophage mediated inflammation, by favoring the expression of MerTK, which mediates an immunoregulatory action with a reduction in inflammation and in atherosclerosis.
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Affiliation(s)
- Mirella Pastore
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Stefania Grimaudo
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Rosaria Maria Pipitone
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Giulia Lori
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Chiara Raggi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.,Humanitas Clinical and Research Center, Rozzano, Italy
| | - Salvatore Petta
- Section of Gastroenterology and Hepatology, PROMISE, University of Palermo, Palermo, Italy
| | - Fabio Marra
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Santos RD, Valenti L, Romeo S. Does nonalcoholic fatty liver disease cause cardiovascular disease? Current knowledge and gaps. Atherosclerosis 2019; 282:110-120. [PMID: 30731283 DOI: 10.1016/j.atherosclerosis.2019.01.029] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2018] [Revised: 12/22/2018] [Accepted: 01/18/2019] [Indexed: 12/15/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and includes a spectrum of abnormalities ranging from steatosis to cirrhosis. In this review, we address recent evidence and limitations of studies that evaluated the association of NAFLD with atherosclerotic cardiovascular disease. NAFLD is considered an ectopic fat deposit associated with metabolic (insulin resistance, hyperglycemia and dyslipidemia), inflammatory, coagulation and blood pressure disturbances. Prospective studies have associated NAFLD presence and severity, particularly steatohepatitis and fibrosis, with an increased risk of cardiovascular disease. However, these studies are limited by heterogeneity concerning NAFLD diagnostic criteria and disease severity stratification, as well as by the presence of confounding factors. In addition, genetic variants predisposing to NAFLD, such as the PNPLA3 I148M mutation, were not consistently associated with an increased risk of cardiovascular events. Therefore, currently, it is not possible to prove a causal relation between NAFLD and cardiovascular disease. Furthermore, there is presently no evidence that NAFLD diagnosis can be used as a tool to improve cardiovascular risk stratification and modify treatment. Specific treatments for NAFLD are being developed and must be tested prospectively in adequately designed trials to determine the potential of reducing both hepatic and cardiovascular diseases and to prove whether NAFLD is indeed a cause of atherosclerosis.
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Affiliation(s)
- Raul D Santos
- Hospital Israelita Albert Einstein, Sao Paulo, Brazil; Lipid Clinic Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil.
| | - Luca Valenti
- Università Degli Studi Milano, Fondazione IRCCS Ca' Granda Pad Granelli, Milan, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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Tortora R, Rispo A, Alisi A, Imperatore N, Crudele A, Ferretti F, Nobili V, Miele L, Gerbino N, Caporaso N, Morisco F. PNPLA3 rs738409 Polymorphism Predicts Development and Severity of Hepatic Steatosis but Not Metabolic Syndrome in Celiac Disease. Nutrients 2018; 10:nu10091239. [PMID: 30189691 PMCID: PMC6163162 DOI: 10.3390/nu10091239] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Revised: 08/30/2018] [Accepted: 09/04/2018] [Indexed: 12/24/2022] Open
Abstract
Metabolic syndrome (MS) and hepatic steatosis (HS) have been described in patients with celiac disease (CD) after starting a gluten-free diet (GFD), but data on predictive factors for these conditions are scarce. Recently, the patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 has been identified as a key factor for HS development in the general population. The aim of the study was to evaluate the role of PNPLA3 rs738409 in the development of MS and HS in CD patients after starting GFD. Between June 2014 and September 2016, we consecutively enrolled CD patients with HS, while those without steatosis served as a control group. All patients underwent anthropometric and serologic investigations, ultrasonography (US) to assess the degree and severity of HS, and genotyping of the PNPLA3 rs738409 polymorphism. Finally, 370 subjects were enrolled (136 with and 234 without HS). At genotyping assays, the CC genotype was found in 194 subjects (52.4%), the CG genotype in 138 subjects (37.3%), and the GG genotype in 38 subjects (10.2%). At binary logistic regression, only CG and GG alleles were predictive for the development of HS (odds ratio (OR) 1.97; p < 0.01 for CG and OR 6.9; p < 0.001 for GG). Body mass index (BMI) (OR 3.8; p < 0.001) and waist circumference (OR 2.8; p = 0.03) at CD diagnosis were the only independent factors for the development of MS. Intergroup comparisons showed that the severe grade of HS was more frequently observed in GG than in CC carriers (74% vs. 11.3%, p < 0.001, OR 21.8). PNPLA3 CG and GG carriers with CD have a higher susceptibility to hepatic steatosis, but not to metabolic syndrome. Moreover, patients with GG alleles display more severe forms of HS based on ultrasound.
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Affiliation(s)
- Raffaella Tortora
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine "Federico II" of Naples, Via S. Pansini 5, 80131 Naples, Italy.
| | - Antonio Rispo
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine "Federico II" of Naples, Via S. Pansini 5, 80131 Naples, Italy.
| | - Anna Alisi
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy.
| | - Nicola Imperatore
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine "Federico II" of Naples, Via S. Pansini 5, 80131 Naples, Italy.
| | - Annalisa Crudele
- Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital-IRCCS, 00165 Rome, Italy.
| | - Francesca Ferretti
- Ferretti: 1. Hepatology, Gastroenterology and Nutrition, "Bambino Gesù" Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
| | - Valerio Nobili
- Ferretti: 1. Hepatology, Gastroenterology and Nutrition, "Bambino Gesù" Children's Hospital, IRCCS, Piazza S. Onofrio 4, 00165 Rome, Italy.
- Pediatric Department, University La Sapienza Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.
| | - Luca Miele
- Department of Internal Medicine and Gastroenterology, Catholic University, 00128 Rome, Italy.
| | - Nicolò Gerbino
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine "Federico II" of Naples, Via S. Pansini 5, 80131 Naples, Italy.
| | - Nicola Caporaso
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine "Federico II" of Naples, Via S. Pansini 5, 80131 Naples, Italy.
| | - Filomena Morisco
- Gastroenterology, Department of Clinical Medicine and Surgery, School of Medicine "Federico II" of Naples, Via S. Pansini 5, 80131 Naples, Italy.
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Petta S, Adinolfi LE, Fracanzani AL, Rini F, Caldarella R, Calvaruso V, Cammà C, Ciaccio M, Di Marco V, Grimaudo S, Licata A, Marrone A, Nevola R, Pipitone RM, Pinto A, Rinaldi L, Torres D, Tuttolomondo A, Valenti L, Fargion S, Craxì A. Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with severe liver fibrosis. J Hepatol 2018; 69:18-24. [PMID: 29505844 DOI: 10.1016/j.jhep.2018.02.015] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 02/14/2018] [Accepted: 02/19/2018] [Indexed: 12/22/2022]
Abstract
BACKGROUND AND AIMS Recent studies suggest an association between hepatitis C virus (HCV) infection and cardiovascular damage, including carotid atherosclerosis, with a possible effect of HCV clearance on cardiovascular outcomes. We aimed to examine whether HCV eradication by direct-acting antiviral agents (DAA) improves carotid atherosclerosis in HCV-infected patients with advanced fibrosis/compensated cirrhosis. MATERIALS AND METHODS One hundred eighty-two consecutive patients with HCV and advanced fibrosis or compensated cirrhosis were evaluated. All patients underwent DAA-based antiviral therapy according to AISF/EASL guidelines. Intima-media thickness (IMT), carotid thickening (IMT ≥1 mm) and carotid plaques, defined as focal thickening of ≥1.5 mm at the level of the common carotid, were evaluated by ultrasonography (US) at baseline and 9-12 months after the end of therapy. Fifty-six percent of patients were male, mean age 63.1 ± 10.4 years, and 65.9% had compensated cirrhosis. One in five had diabetes, 14.3% were obese, 41.8% had arterial hypertension and 35.2% were smokers. At baseline, mean IMT was 0.94 ± 0.29 mm, 42.8% had IMT ≥1 mm, and 42.8% had carotid plaques. RESULTS All patients achieved a 12-week sustained virological response. IMT significantly decreased from baseline to follow-up (0.94 ± 0.29 mm vs. 0.81 ± 0.27, p <0.001). Consistently, a significant reduction in the prevalence of patients with carotid thickening from baseline to follow-up was observed (42.8% vs. 17%, p <0.001), while no changes were reported for carotid plaques (42.8% vs. 47.8%, p = 0.34). These results were confirmed in subgroups of patients stratified for cardiovascular risk factors and liver disease severity. CONCLUSION HCV eradication by DAA improves carotid atherosclerosis in patients with severe fibrosis with or without additional metabolic risk factors. The impact of this improvement in the atherosclerotic burden in terms of reduction of major cardiovascular outcomes is worth investigating in the long term. LAY SUMMARY Hepatitis C virus eradication by direct-acting antiviral agents improves carotid atherosclerosis in patients with advanced fibrosis/compensated cirrhosis. The improvement in intima-media thickness and carotid thickening was confirmed after stratification for severity of liver disease and cardiovascular risk factors. Hepatitis C virus eradication by direct-acting antiviral agents also lead to improvement in glucose homeostasis and increased cholesterol levels.
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Affiliation(s)
- Salvatore Petta
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy.
| | - Luigi Elio Adinolfi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Francesca Rini
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Rosalia Caldarella
- Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Vincenza Calvaruso
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Calogero Cammà
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Marcello Ciaccio
- Department of Biopathology and Medical Biotechnologies, University of Palermo, Palermo, Italy
| | - Vito Di Marco
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Stefania Grimaudo
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Anna Licata
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
| | - Aldo Marrone
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Riccardo Nevola
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | | | - Antonio Pinto
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Luca Rinaldi
- Department of Medical, Surgical, Neurological, Geriatric, and Metabolic Sciences, University of Campania "Luigi Vanvitelli", 80100 Naples, Italy
| | - Daniele Torres
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Antonino Tuttolomondo
- Sezione di Medicina Interna con Stroke Care, Dipartimento Biomedico di Medicina Interna e Specialistica (Di.Bi.M.I.S), Università di Palermo, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Ca' Granda IRCCS Foundation, Policlinico Hospital, University of Milan, Italy
| | - Antonio Craxì
- Sezione di Gastroenterologia e Epatologia, Di.Bi.M.I.S, Università di Palermo, Italy
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Rüschenbaum S, Schwarzkopf K, Friedrich-Rust M, Seeger F, Schoelzel F, Martinez Y, Zeuzem S, Bojunga J, Lange CM. Patatin-like phospholipase domain containing 3 variants differentially impact metabolic traits in individuals at high risk for cardiovascular events. Hepatol Commun 2018; 2:798-806. [PMID: 30027138 PMCID: PMC6049070 DOI: 10.1002/hep4.1183] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2017] [Revised: 03/14/2018] [Accepted: 03/17/2018] [Indexed: 12/16/2022] Open
Abstract
Single nucleotide polymorphism (SNP) rs738409 C>G in the patatin‐like phospholipase domain containing 3 (PNPLA3) gene results in an amino acid exchange from isoleucin to methionine at position I148M of PNPLA3. The expression of this loss‐of‐function mutation leads to impaired hepatocellular triglyceride hydrolysis and is associated with the development of liver steatosis, fibrosis, and hepatocellular carcinoma. In contrast to these well‐established associations, the relationship of the PNPLA3 rs738409 variant with other metabolic traits is incompletely understood. We therefore assessed the association of the PNPLA3 rs738409 genotype with relevant metabolic traits in a prospective study of patients at high risk for cardiovascular events, i.e., patients undergoing coronary angiography. In a total of 270 patients, known associations of the PNPLA3 rs738409 GG genotype with nonalcoholic steatohepatitis and liver fibrosis were confirmed. In addition, we found an association of the PNPLA3 rs738409 G allele with the presence of diabetes (22% versus 28% versus 58% for CC versus CG versus GG genotype, respectively; P = 0.02). In contrast to its association with nonalcoholic fatty liver disease, liver fibrosis, and diabetes, the minor G allele of PNPLA3 rs738409 was inversely associated with total serum cholesterol and low‐density lipoprotein serum levels (P = 0.003 and P = 0.02, respectively). Finally, there was a trend toward an inverse association between the presence of the PNPLA3 rs738409 G allele and significant coronary heart disease. Comparable trends were observed for the transmembrane 6 superfamily member 2 (TM6SF2) 167 K variant, but the sample size was too small to evaluate this rarer variant. Conclusion: The PNPLA3 rs738409 G allele is associated with liver disease but also with a relatively benign cardiovascular risk profile. (Hepatology Communications 2018;2:798‐806)
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Affiliation(s)
- Sabrina Rüschenbaum
- Department of Internal Medicine 1 J.W. Goethe-University Hospital Frankfurt Germany
| | | | | | - Florian Seeger
- Department of Cardiology St. Elisabeth Hospital Ravensburg Germany
| | - Fabian Schoelzel
- Department of Internal Medicine 1 J.W. Goethe-University Hospital Frankfurt Germany
| | - Yolanda Martinez
- Department of Internal Medicine 1 J.W. Goethe-University Hospital Frankfurt Germany
| | - Stefan Zeuzem
- Department of Internal Medicine 1 J.W. Goethe-University Hospital Frankfurt Germany
| | - Jörg Bojunga
- Department of Internal Medicine 1 J.W. Goethe-University Hospital Frankfurt Germany
| | - Christian M Lange
- Department of Internal Medicine 1 J.W. Goethe-University Hospital Frankfurt Germany
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Abstract
BACKGROUND Recent genome-wide association studies have identified 2 genetic polymorphisms in association with nonalcoholic fatty liver disease (NAFLD): patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), both of which appear to influence the production of very low density lipoprotein (VLDL). The impact of these genetic variations on lipoprotein metabolism in the setting of nonalcoholic steatohepatitis and liver fibrosis are not fully characterized. MATERIALS AND METHODS We measured comprehensive lipoprotein profiles by nuclear magnetic resonance among 170 serially recruited patients in an NAFLD registry, and determined their relationships with PNPLA3 and TM6SF2 genotypes. RESULTS In this cohort, 72% patients had at least 1 allele of either PNPLA3 I148M or TM6SF2 E167K, and 30% carried 2 alleles. In multivariate models adjusting for histologic features of nonalcoholic steatohepatitis and liver fibrosis, PNPLA3 I148M is associated with a decrease in VLDL particle size. Both PNPLA3 I148M and TM6SF2 E167K genotypes were associated with increases in the size of low density lipoprotein (LDL) and high density lipoprotein particles, phenotypes considered atheroprotective. When adjusted for both genotypes, NAFLD activity score, in particular the degree of hepatic steatosis was strongly associated with increases in the size of VLDL particles, the concentration of LDL, especially small LDL particles, and a decrease in the size of high density lipoprotein particles, all of which are linked with a proatherogenic phenotype. CONCLUSIONS PNPLA3 and TM6SF2 are common genetic variants among NAFLD patients and impact lipoprotein profiles in slightly different ways. The interactions between genotypes, hepatic steatosis, and lipoprotein metabolism shed lights on the pathophysiology of NAFLD, and provide opportunities for personalized treatment in the era of emerging NAFLD therapeutics.
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Liver and Cardiovascular Damage in Patients With Lean Nonalcoholic Fatty Liver Disease, and Association With Visceral Obesity. Clin Gastroenterol Hepatol 2017; 15:1604-1611.e1. [PMID: 28554682 DOI: 10.1016/j.cgh.2017.04.045] [Citation(s) in RCA: 152] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 04/07/2017] [Accepted: 04/21/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Lean nonalcoholic fatty liver disease (NAFLD) is defined as NAFLD that develops in patients with a body mass index (BMI) less than 25 kg/m2. We investigated the differences between lean NAFLD and NAFLD in overweight and obese persons, factors associated with the severity of liver and cardiovascular disease, and the effects of visceral obesity. METHODS We performed a retrospective cohort study of 669 consecutive patients with biopsy-proven NAFLD seen at 3 liver centers in Italy. We collected anthropometric, clinical, and biochemical data, as well as information on carotid atherosclerosis (artery intima-media thickness and plaque), liver histology (nonalcoholic steatohepatitis [NASH] and fibrosis), insulin resistance, and diabetes. Overweight was defined as a BMI of 25 to 29.9 kg/m2, and obese was defined as a BMI of 30 kg/m2 or greater. Patients were assigned to groups based on waist circumference, a marker of visceral obesity (low: men, <94 cm, women <80 cm; medium: men, 94-102 cm, women 80-88 cm; or high: men >102 cm, women >88 cm). DNA samples were analyzed for the rs738409 C>G (I148M in PNPLA3), the rs58542926 C>T (E167K in TM6SF2), and single-nucleotide polymorphisms. Variables in men and women were analyzed using chi-squared analysis and the Mann-Whitney or Kruskal-Wallis tests. Multiple linear or logistic regression analyses were adjusted for all the variables of clinical relevance or statistically significant at univariate analyses. The primary outcome was the difference in liver and cardiovascular disease between lean NAFLD and NAFLD in overweight and obese persons. Secondary outcomes were effects of visceral obesity, based on waist circumference, on hepatic, vascular, and metabolic features. RESULTS Significantly lower proportions of patients with lean NAFLD (143 patients; 43 women; mean age, 46 ± 13 y) had hypertension (P = .001), diabetes (P = .0001), and metabolic syndrome (P = .0001) than overweight or obese patients with NAFLD (526 patients; 149 women; mean age, 49 ± 12 y). Significantly lower proportions of patients with lean NAFLD had NASH (17% vs 40% of obese or overweight patients with NAFLD; P = .0001), fibrosis of F2 or higher (17% vs 42%; P = .0001), or carotid plaques (27% vs 39%; P = .03). Patients with lean NAFLD had significantly thinner carotid intima-media (0.74 ± 0.1 mm) than obese or overweight patients with NAFLD (0.84 ± 0.3 mm; P = .0001). There was no significant difference in the proportions of patients with rs738409 C>G in PNPLA3, but a significantly greater proportion of patients with lean NAFLD carried rs58542926 C>T in TM6SF2 (4%) than obese or overweight individuals with NAFLD (0.3%; P = .001). Of the 143 patients with lean NAFLD, 27 had grade 3 steatosis, 24 had a lobular inflammation score greater than 2, 10 had a ballooning score of 2, and 25 had a fibrosis score of 2 or higher. In patients with lean NAFLD, the only variable associated independently with NASH and a fibrosis score of 2 or higher was rs738409 C>G in PNPLA3. Patients with lean NAFLD and a medium waist circumference had a significantly higher risk of diabetes (odds ratio, 11; 95% confidence interval [CI], 1.2-106; P = .03) than overweight or obese patients with a similar waist circumference (odds ratio, 1.3; 95% CI, 0.4-4.2; P = .6). Lean and overweight or obese patients with high waist circumferences had significant increases in risk compared with patients with low and medium circumference and diabetes, hypertension, and fibrosis scores of 2 or higher. CONCLUSIONS In a retrospective study of patients with lean NAFLD vs obese or overweight persons with NAFLD, we found 20% of patients with lean NAFLD to have NASH, fibrosis scores of 2 or higher, and carotid atherosclerosis. Lean patients with rs738409 C>G in PNPLA3 should be monitored for liver disease progression; studies including large series of patients with lean NAFLD will clarify the possible role of TM6SF2 polymorphisms.
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Lonardo A, Nascimbeni F, Targher G, Bernardi M, Bonino F, Bugianesi E, Casini A, Gastaldelli A, Marchesini G, Marra F, Miele L, Morisco F, Petta S, Piscaglia F, Svegliati-Baroni G, Valenti L, Bellentani S. AISF position paper on nonalcoholic fatty liver disease (NAFLD): Updates and future directions. Dig Liver Dis 2017; 49:471-483. [PMID: 28215516 DOI: 10.1016/j.dld.2017.01.147] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 01/08/2017] [Accepted: 01/10/2017] [Indexed: 02/07/2023]
Abstract
This review summarizes our current understanding of nonalcoholic fatty liver disease (NAFLD), a multi-factorial systemic disease resulting from a complex interaction between a specific genetic background and multiple environmental/metabolic "hits". The role of gut microbiota, lipotoxicity, inflammation and their molecular pathways is reviewed in-depth. We also discuss the epidemiology and natural history of NAFLD by pinpointing the remarkably high prevalence of NAFLD worldwide and its inherent systemic complications: hepatic (steatohepatitis, advanced fibrosis and cirrhosis), cardio-metabolic (cardiovascular disease, cardiomyopathy, arrhythmias and type 2 diabetes) and neoplastic (primary liver cancers and extra-hepatic cancers). Moreover, we critically report on the diagnostic role of non-invasive biomarkers, imaging techniques and liver biopsy, which remains the reference standard for diagnosing the disease, but cannot be proposed to all patients with suspected NAFLD. Finally, the management of NAFLD is also reviewed, by highlighting the lifestyle changes and the pharmacological options, with a focus on the innovative drugs. We conclude that the results of ongoing studies are eagerly expected to lead to introduce into the clinical arena new diagnostic and prognostic biomarkers, prevention and surveillance strategies as well as to new drugs for a tailored approach to the management of NAFLD in the individual patient.
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Lonardo A, Ballestri S, Targher G. "Not all forms of NAFLD were created equal". Do metabolic syndrome-related NAFLD and PNPLA3-related NAFLD exert a variable impact on the risk of early carotid atherosclerosis? Atherosclerosis 2017; 257:253-255. [PMID: 28126321 DOI: 10.1016/j.atherosclerosis.2017.01.008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2016] [Accepted: 01/12/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Amedeo Lonardo
- Azienda USL, Nuovo Ospedale Sant'Agostino Estense di Baggiovara, Modena, Italy.
| | | | - Giovanni Targher
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Italy
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Jaruvongvanich V, Wirunsawanya K, Sanguankeo A, Upala S. Nonalcoholic fatty liver disease is associated with coronary artery calcification: A systematic review and meta-analysis. Dig Liver Dis 2016; 48:1410-1417. [PMID: 27697419 DOI: 10.1016/j.dld.2016.09.002] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 08/20/2016] [Accepted: 09/04/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is associated increased cardiovascular events and mortality. Coronary artery calcium scanning (CAC) is the robust predictor of coronary events in the asymptomatic individuals. Several recent studies have investigated the association between NAFLD and this surrogate marker. Thus, we conducted a systematic review and meta-analysis to better characterize the association between NAFLD and CAC. METHODS MEDLINE and EMBASE were searched through May 2016. Primary outcome was the association between NAFLD and CAC. Pooled odds ratio (OR) and 95% confidence interval (CI) from multivariable-adjusted estimates were calculated using a random-effects model. The between-study heterogeneity of effect-size was quantified using the Q statistic and I2. RESULTS Data were extracted from 16 studies (all cross-sectional studies) involving 16,433 NAFLD patients and 41,717 controls. NAFLD is significantly associated with CAC score >0 and CAC score >100 with pooled OR of 1.41 (95%CI 1.26-1.57, Pheterogeneity=0.07, I2=66%) and 1.24 (95%CI 1.02-1.52, Pheterogeneity=0.10, I2=42%). CONCLUSIONS NAFLD is associated with increased coronary artery calcification independent of traditional risk factors. The assessment of coronary artery calcium may be useful in identifying NAFLD patients at risk of future cardiovascular events.
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Affiliation(s)
- Veeravich Jaruvongvanich
- Department of Internal Medicine, University of Hawaii, Honolulu, HI, USA; Department of Medicine, King Chulalongkorn Memorial Hospital, Bangkok, Thailand.
| | | | - Anawin Sanguankeo
- Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA; Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
| | - Sikarin Upala
- Department of Internal Medicine, Bassett Medical Center and Columbia University College of Physicians and Surgeons, Cooperstown, NY, USA; Department of Preventive and Social Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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Fracanzani AL, Pisano G, Consonni D, Tiraboschi S, Baragetti A, Bertelli C, Norata GD, Dongiovanni P, Valenti L, Grigore L, Tonella T, Catapano A, Fargion S. Epicardial Adipose Tissue (EAT) Thickness Is Associated with Cardiovascular and Liver Damage in Nonalcoholic Fatty Liver Disease. PLoS One 2016; 11:e0162473. [PMID: 27627804 PMCID: PMC5023162 DOI: 10.1371/journal.pone.0162473] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Accepted: 08/23/2016] [Indexed: 12/20/2022] Open
Abstract
Background and Aims Epicardial adipose tissue (EAT) has been proposed as a cardiometabolic and hepatic fibrosis risk factor in patients with non alcoholic fatty liver disease (NAFLD). Aim of this study was to evaluate the role of EAT in NAFLD by analyzing 1) the association between EAT, the other metabolic parameters and the severity of steatosis 2) the relationship between cardiovascular (cIMT, cplaques, E/A), liver (presence of NASH and significant fibrosis) damage and metabolic risk factors including EAT 3) the relationship between EAT and genetic factors strongly influencing liver steatosis. Methods In a cross-sectional study, we considered 512 consecutive patients with NAFLD (confirmed by biopsy in 100). EAT, severity of steatosis, carotid intima-media thickness (cIMT) and plaques were evaluated by ultrasonography and results analysed by multiple linear and logistic regression models. Variables independently associated with EAT (mm) were female gender (p = 0.003), age (p = 0.001), BMI (p = 0.01), diastolic blood pressure (p = 0.009), steatosis grade 2 (p = 0.01) and 3 (p = 0.04), fatty liver index (p = 0.001) and statin use (p = 0.03). Variables independently associated with carotid IMT were age (p = 0.0001), hypertension (p = 0.009), diabetes (p = 0.04), smoking habits (p = 0.04) and fatty liver index (p = 0.02), with carotid plaques age (p = 0.0001), BMI (p = 0.03), EAT (p = 0.02),) and hypertension (p = 0.02), and with E/A age (p = 0.0001), diabetes (p = 0.005), hypertension (p = 0.04) and fatty liver index (p = 0.004). In the 100 patients with available liver histology non alcoholic steatohepatitis (NASH) was independently associated with EAT (p = 0.04) and diabetes (p = 0.054) while significant fibrosis with EAT (p = 0.02), diabetes (p = 0.01) and waist circumference (p = 0.05). No association between EAT and PNPLA3 and TM6SF2 polymorphisms was found. Conclusion In patients with NAFLD, EAT is associated with the severity of liver and vascular damage besides with the known metabolic risk factors.
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Affiliation(s)
- Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
- * E-mail:
| | - Giuseppina Pisano
- Department of Pathophysiology and Transplantation, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | - Dario Consonni
- Epidemiology Unit, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | - Silvia Tiraboschi
- Department of Pathophysiology and Transplantation, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | - Andrea Baragetti
- Department of Pharmacological and Biomolecular Sciences, University of Milan and Centro Studi Aterosclerosi Milan, Milan, Italy
| | - Cristina Bertelli
- Department of Pathophysiology and Transplantation, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | - Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, University of Milan and Centro Studi Aterosclerosi Milan, Milan, Italy
| | - Paola Dongiovanni
- Department of Pathophysiology and Transplantation, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
| | | | - Tatiana Tonella
- Cardiovascular Medicine Unit, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, Milan, Italy
| | - Alberico Catapano
- Department of Pharmacological and Biomolecular Sciences, University of Milano, and Multimedica IRCCS, Milan, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Ca’ Granda Foundation IRCCS Maggiore Policlinico Hospital, University of Milan, Milan, Italy
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Posadas-Sánchez R, López-Uribe ÁR, Posadas-Romero C, Pérez-Hernández N, Rodríguez-Pérez JM, Ocampo-Arcos WA, Fragoso JM, Cardoso-Saldaña G, Vargas-Alarcón G. Association of the I148M/PNPLA3 (rs738409) polymorphism with premature coronary artery disease, fatty liver, and insulin resistance in type 2 diabetic patients and healthy controls. The GEA study. Immunobiology 2016; 222:960-966. [PMID: 27615511 DOI: 10.1016/j.imbio.2016.08.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 07/20/2016] [Accepted: 08/23/2016] [Indexed: 12/19/2022]
Abstract
The aim of this study was to evaluate the potential use of the I148M/PNPLA3 (rs738409) gene polymorphism as a susceptibility marker for premature coronary artery disease (pCAD) and/or cardiovascular risk factors in Mexican type 2 diabetes mellitus patients (T2DM). The polymorphism was genotyped by 5' exonuclease TaqMan assays in a group of 2572 subjects (1103 with pCAD and 1469 healthy controls) belonging to the Genetics of Atherosclerotic Disease (GEA) Mexican Study. Anthropometric and biochemical measurements were performed in all individuals. The association between the I148M/PNPLA3 (rs738409) gene polymorphism with pCAD and other metabolic and cardiovascular risk factors was evaluated using logistic regression analysis under different statistical approaches including dominant, recessive, heterozygous, additive, and co-dominant models. The polymorphism was not associated with pCAD in the whole group of participants, however, when patients and controls were divided into those with and without T2DM, under additive model, the polymorphism was associated with the presence of pCAD only in patients with T2DM (OR=1.20, 95% CI: 1.01-1.42, Padd=0.042). On the other hand, under several models adjusted for age, gender, body mass index and T2DM, the polymorphism was associated with increased risk of fatty liver and elevated levels of alanine transaminase (ALT) in the whole group of pCAD patients and controls. In the control group, the polymorphism was associated with insulin resistance and coronary artery calcification (CAC) score≥10 under several models. The results suggest that the I148M/PNPLA3 (rs738409) polymorphism is associated with the presence of pCAD in T2DM patients and with some cardiometabolic parameters. The association detected with CAC in the control group indicates that this polymorphism could be a marker for subclinical atherosclerosis.
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Affiliation(s)
| | - Ángel René López-Uribe
- Endocrinology Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Carlos Posadas-Romero
- Endocrinology Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Nonanzit Pérez-Hernández
- Molecular Biology Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | | | | | - José Manuel Fragoso
- Molecular Biology Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | | | - Gilberto Vargas-Alarcón
- Molecular Biology Department, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
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Lonardo A, Sookoian S, Pirola CJ, Targher G. Non-alcoholic fatty liver disease and risk of cardiovascular disease. Metabolism 2016; 65:1136-1150. [PMID: 26477269 DOI: 10.1016/j.metabol.2015.09.017] [Citation(s) in RCA: 165] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Revised: 08/17/2015] [Accepted: 09/19/2015] [Indexed: 02/06/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver diseases worldwide, causing considerable liver-related mortality and morbidity. During the past decade, it has also become increasingly evident that NAFLD is a multisystem disease that affects many extra-hepatic organ systems, including the heart and the vascular system. In this updated clinical review, we discuss the rapidly expanding body of clinical and epidemiological evidence that supports a strong association of NAFLD with cardiovascular diseases (CVDs) and other functional and structural myocardial abnormalities. We also discuss some recently published data that correlate NAFLD due to specific genetic polymorphisms with the risk of CVDs. Finally, we briefly examine the assessment tools for estimating the global CVD risk in patients with NAFLD as well as the conventional and the more innovative pharmacological approaches for the treatment of CVD risk in this group of patients.
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Affiliation(s)
- Amedeo Lonardo
- Outpatient Liver Clinic and Division of Internal Medicine, Department of Biomedical, Metabolic and Neural Sciences, NOCSAE, Baggiovara, Azienda USL and University of Modena and Reggio Emilia, Modena, Italy
| | - Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos J Pirola
- Department of Molecular Genetics and Biology of Complex Diseases, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Scientific and Technical Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy.
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An BQ, Lu LL, Yuan C, Xin YN, Xuan SY. Leptin Receptor Gene Polymorphisms and the Risk of Non-Alcoholic Fatty Liver Disease and Coronary Atherosclerosis in the Chinese Han Population. HEPATITIS MONTHLY 2016; 16:e35055. [PMID: 27257426 PMCID: PMC4888499 DOI: 10.5812/hepatmon.35055] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/27/2015] [Revised: 01/26/2016] [Accepted: 02/05/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Leptin receptor (LEPR) polymorphisms have been reported to be associated with lipid metabolism and insulin resistance in various populations. However, whether LEPR polymorphisms are associated with the risks of non-alcoholic fatty liver disease (NAFLD) and coronary atherosclerosis in the Chinese Han population remains unknown. OBJECTIVES To investigate the association of LEPR polymorphisms at Q223R and K109R with the risks of NAFLD and coronary atherosclerosis in the Chinese Han population. PATIENTS AND METHODS Genotypes of LEPR Q223R and K109R were determined by polymerase chain reaction followed by sequencing in patients with NAFLD (n = 554), coronary atherosclerosis (n = 421), and healthy controls (n = 550). Serum lipid profiles were determined using biochemical methods. Pearson's χ(2) test was used to check for Hardy-Weinberg equilibrium and to analyze the distributions of genotypes' alleles between groups. Baseline characteristics were analyzed using student's t-test, paired-samples t-test, or the χ(2) test where appropriate. RESULTS The LEPR Q223R A allele significantly reduced the risks of both NAFLD and coronary atherosclerosis (OR = 0.683, 95% CI: 0.527 - 0.884, P = 0.004 and OR = 0.724, 95% CI: 0.548 - 0.955, P = 0.022, respectively). Compared to controls, no significant differences in the genotype and allele frequencies of K109R were found in the NAFLD and coronary atherosclerosis populations, respectively. However, there was a significantly increased risk of coronary atherosclerosis in NAFLD patients who carried the K109R A allele (OR = 2.283, 95% CI: 1.556 - 3.348, P < 0.001). CONCLUSIONS LEPR Q223R polymorphisms may confer a significant risk of NAFLD and coronary atherosclerosis. The A allele in the K109R polymorphism might be considered an independent risk factor for coronary atherosclerosis in NAFLD patients.
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Affiliation(s)
- Bai-Quan An
- Department of Gastroenterology, Qingdao Municipal College, Nanjing Medical University, Qingdao, Shandong Province, China
| | - Lin-Lin Lu
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Central Laboratories, Qingdao Municipal Hospital, Qingdao, China
| | - Chen Yuan
- Department of Gastroenterology, Qingdao Municipal College, Nanjing Medical University, Qingdao, Shandong Province, China
| | - Yong-Ning Xin
- Department of Gastroenterology, Qingdao Municipal College, Nanjing Medical University, Qingdao, Shandong Province, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
- Corresponding Authors: Yong-Ning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China. Tel: +86-53288905289, Fax: +86-53288905293, E-mail: ; Shi-Ying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China. Tel: +86-53288905289, Fax: +86-53288905293, E-mail:
| | - Shi-Ying Xuan
- Department of Gastroenterology, Qingdao Municipal College, Nanjing Medical University, Qingdao, Shandong Province, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
- Corresponding Authors: Yong-Ning Xin, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China. Tel: +86-53288905289, Fax: +86-53288905293, E-mail: ; Shi-Ying Xuan, Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China. Tel: +86-53288905289, Fax: +86-53288905293, E-mail:
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Xia MF, Ling Y, Bian H, Lin HD, Yan HM, Chang XX, Li XM, Ma H, Wang D, Zhang LS, Wang SS, Wu BJ, He WY, Zhao NQ, Gao X. I148M variant of PNPLA3 increases the susceptibility to non-alcoholic fatty liver disease caused by obesity and metabolic disorders. Aliment Pharmacol Ther 2016; 43:631-642. [PMID: 26765961 DOI: 10.1111/apt.13521] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 09/23/2015] [Accepted: 12/16/2015] [Indexed: 12/28/2022]
Abstract
BACKGROUND The patatin-like phospholipase 3 (PNPLA3) rs738409 gene polymorphism is an important genetic determinant of non-alcoholic fatty liver disease (NAFLD). However, the associations between liver fat and metabolic traits in rs738409 G allele carriers and the allelic influence on this association have not been fully studied. AIM To investigate the influence of the PNPLA3 gene polymorphism on the association of liver fat with serum metabolic factors and carotid atherosclerosis. METHODS Liver fat was measured by quantitative ultrasound in 4300 subjects in the Shanghai Changfeng community and analysed for its association with obesity and metabolic factors in individuals with the PNPLA3 CC, CG and GG genotypes. RESULTS Non-alcoholic fatty liver disease occurred in 37.9% and 28.8% of the subjects with the GG and CC genotypes respectively (P < 0.001). Liver fat was significantly associated with body mass index, waist circumference, serum triglycerides, high-density lipoprotein cholesterol, fasting blood glucose and insulin in the PNPLA3 rs738409 G allele carriers (P < 0.001). Compared with the CC homozygotes, the GG homozygotes presented higher liver fat and liver fibrosis scores despite their better metabolic status (comparison of regression line slopes, P < 0.05). An increase in liver fat was accompanied by a significant increase in the average and maximum carotid intima-media thickness in subjects with the PNPLA3 CC genotype but not in those with the GG genotype. CONCLUSIONS PNPLA3 rs738409 G allele carriers were found to be more susceptible to the metabolic-related hepatic steatosis, and developed NAFLD and liver fibrosis despite presenting relatively better metabolic statuses and lower risks for carotid atherosclerosis.
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Affiliation(s)
- M-F Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
| | - Y Ling
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
| | - H Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
| | - H-D Lin
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
| | - H-M Yan
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
| | - X-X Chang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
| | - X-M Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - H Ma
- Department of Geriatrics, Zhongshan Hospital, Fudan University, Shanghai, China
| | - D Wang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - L-S Zhang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
| | - S-S Wang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - B-J Wu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - W-Y He
- Department of Ultrasonography, Zhongshan Hospital, Fudan University, Shanghai, China
| | - N-Q Zhao
- Department of Health Statistics and Social Medicine, School of Public Health, Fudan University, Shanghai, China
| | - X Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
- Institute of Chronic Metabolic Diseases, Fudan University, Shanghai, China
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Yuan C, Lu L, An B, Jin W, Dong Q, Xin Y, Xuan S. Association Between LYPLAL1 rs12137855 Polymorphism With Ultrasound-Defined Non-Alcoholic Fatty Liver Disease in a Chinese Han Population. HEPATITIS MONTHLY 2015; 15:e33155. [PMID: 26977168 PMCID: PMC4772303 DOI: 10.5812/hepatmon.33155] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/14/2015] [Revised: 10/09/2015] [Accepted: 10/17/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent genome-wide association studies (GWAS) identified that gene Lysophospholipase-like 1 (LYPLAL1) rs12137855 associated with non-alcoholic fatty liver disease (NAFLD). No research has been performed regarding the association between LYPLAL1 and NAFLD in China. OBJECTIVES The aim of the present study was to investigate the association between the gene LYPLAL1 rs12137855 and NAFLD, and the effect on serum lipid profiles in a Chinese Han population. PATIENTS AND METHODS LYPLAL1 rs12137855 gene was genotyped in 184 patients with NAFLD and 114 healthy controls using sequencing and polymerase chain reaction analysis (PCR). We tested serum lipid profiles using biochemical methods. RESULTS No significant differences in genotype and allele frequencies of LYPLAL1 rs12137855 was found between the NAFLD group and the controls group (P > 0.05). Subjects with the variant LYPLAL1 rs12137855 CC genotype had a higher mean weight, body mass index (BMI) and low density lipoprotein (LDL). CONCLUSIONS Our results showed for the first time that LYPLAL1 gene is not associated with a risk of NAFLD development in the Chinese Han population. The variant carriers of overall subjects significantly increased weight, BMI and LDL.
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Affiliation(s)
- Chen Yuan
- Department of Gastroenterology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
| | - Linlin Lu
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Central Laboratories, Qingdao Municipal Hospital, Qingdao, China
| | - Baiquan An
- Department of Gastroenterology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Wenwen Jin
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Quanjiang Dong
- Central Laboratories, Qingdao Municipal Hospital, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Yongning Xin
- Department of Gastroenterology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
- Digestive Disease Key Laboratory of Qingdao, Qingdao, China
- Department of Gastroenterology, Qingdao Municipal Hospital, Qingdao, China
| | - Shiying Xuan
- Department of Gastroenterology, Qingdao Municipal Hospital, Nanjing Medical University, Qingdao, China
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Kahali B, Halligan B, Speliotes EK. Insights from Genome-Wide Association Analyses of Nonalcoholic Fatty Liver Disease. Semin Liver Dis 2015; 35:375-91. [PMID: 26676813 PMCID: PMC4941959 DOI: 10.1055/s-0035-1567870] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is caused by hepatic steatosis, which can progress to nonalcoholic steatohepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma in the absence of excessive alcohol consumption. Nonalcoholic fatty liver disease will become the number one cause of liver disease worldwide by 2020. Nonalcoholic fatty liver disease is correlated albeit imperfectly with obesity and other metabolic diseases such as diabetes, hyperlipidemia, and cardiovascular disease, but exactly how having one of these diseases contributes to the development of other metabolic diseases is only now being elucidated. Development of NAFLD and related metabolic diseases is genetically influenced in the population, and recent genome-wide association studies (GWASs) have discovered genetic variants that associate with these diseases. These GWAS-associated variants cannot only help us to identify individuals at high risk of developing NAFLD, but also to better understand its pathophysiology so that we can develop more effective treatments for this disease and related metabolic diseases in the future.
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Affiliation(s)
- Bratati Kahali
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Brian Halligan
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
| | - Elizabeth K. Speliotes
- Division of Gastroenterology, Department of Internal Medicine, Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan
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Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver disease: A comprehensive review. World J Gastroenterol 2015; 21:11088-11111. [PMID: 26494964 PMCID: PMC4607907 DOI: 10.3748/wjg.v21.i39.11088] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2015] [Revised: 06/11/2015] [Accepted: 09/02/2015] [Indexed: 02/06/2023] Open
Abstract
In the Western world, nonalcoholic fatty liver disease (NAFLD) is considered as one of the most significant liver diseases of the twenty-first century. Its development is certainly driven by environmental factors, but it is also regulated by genetic background. The role of heritability has been widely demonstrated by several epidemiological, familial, and twin studies and case series, and likely reflects the wide inter-individual and inter-ethnic genetic variability in systemic metabolism and wound healing response processes. Consistent with this idea, genome-wide association studies have clearly identified Patatin-like phosholipase domain-containing 3 gene variant I148M as a major player in the development and progression of NAFLD. More recently, the transmembrane 6 superfamily member 2 E167K variant emerged as a relevant contributor in both NAFLD pathogenesis and cardiovascular outcomes. Furthermore, numerous case-control studies have been performed to elucidate the potential role of candidate genes in the pathogenesis and progression of fatty liver, although findings are sometimes contradictory. Accordingly, we performed a comprehensive literature search and review on the role of genetics in NAFLD. We emphasize the strengths and weaknesses of the available literature and outline the putative role of each genetic variant in influencing susceptibility and/or progression of the disease.
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