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Imajo K, Saigusa Y, Kobayashi T, Nagai K, Nishida S, Kawamura N, Doi H, Iwaki M, Nogami A, Honda Y, Kessoku T, Ogawa Y, Kirikoshi H, Kokubu S, Utsunomiya D, Takahashi H, Aishima S, Sumida Y, Saito S, Yoneda M, Dennis A, Kin S, Andersson A, Nakajima A. Head-to-head comparison among FAST, MAST, and multiparametric MRI-based new score in diagnosing at-risk MASH. Eur Radiol 2025; 35:3599-3609. [PMID: 39638942 DOI: 10.1007/s00330-024-11215-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Revised: 08/14/2024] [Accepted: 10/13/2024] [Indexed: 12/07/2024]
Abstract
OBJECTIVES New scores were developed to identify at-risk metabolic dysfunction-associated steatohepatitis (MASH) using multiparametric MRI (mpMRI). MATERIALS AND METHODS A prospective study was conducted on 176 patients with suspected or diagnosed metabolic dysfunction-associated steatotic liver disease (MASLD) paired with an MR scan, vibration-controlled transient elastography (VCTE), and liver biopsy. Liver stiffness measurement (LSM) using magnetic resonance elastography (MRE), proton density fat fraction (PDFF), and mpMRI-based corrected T1 (cT1) were combined to develop a one-step strategy, named MPcT (MRE + PDFF + cT1, combined score), and a two-step strategy-MRE-based LSM followed by PDFF with cT1 (M-PcT, paired score) for diagnosing at-risk MASH. Each model was categorized using rule-in and rule-out criteria (three categorized analyses). To avoid overfitting, the diagnostic accuracies were evaluated based on 5-fold cross-validation. RESULTS PDFF + cT1 (PcT) had the highest diagnostic performance for severe activity (hepatic inflammation plus ballooning grade ≥ 3) and for NAS ≥ 4 (active MASH). Areas under receiver operating characteristic curves (AUROCs) of M-PcT (0.832) for detecting at-risk MASH were significantly higher than those of Fibroscan-AST (FAST) (0.744, p = 0.017), MRI-AST (MAST) (0.710, p = 0.002), and MPcT (0.695, p < 0.001) in three categorized analysis. Following the rule-in criteria, positive predictive values of M-PcT (84.5%) were higher than those of FAST (73.5%), MAST (70.0%), and MPcT (66.7%). Following the rule-out criteria, negative predictive values of M-PcT (88.7%) were higher than those of FAST (84.0%), MAST (73.9%), and MPcT (84.9%). CONCLUSIONS The two-step strategy, M-PcT (paired score), showed the reliability of rule-in/-out for at-risk MASH, with better predictive performance compared with FAST and MAST (combined score). CLINICAL TRIAL REGISTRATION This study is registered with ClinicalTrials.gov (number, UMIN000012757). KEY POINTS Question There is no mpMRI-based method for detecting as-risk MASH (NAFLD activity score ≥ 4 with fibrosis stage ≥ 2) like FAST and MAST scores. Findings MRE-based LSMs followed by PDFF with cT1 (M-PcT) were more useful in detecting at-risk MASH than the combined score (FAST and MAST). Clinical relevance By combining MRE and PDFF with cT1, it becomes possible to evaluate the pathology of MASH without the need for a liver biopsy, assisting in prognosis prediction and decision-making for treatment options.
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Affiliation(s)
- Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
- Minimally Invasive Surgical and Medical Oncology, Fukushima Medical University, Fukushima, Japan
| | - Yusuke Saigusa
- Department of Biostatistics, Yokohama City University School of Medicine, Kanazawa-ku, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Koki Nagai
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Shinya Nishida
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Nobuyoshi Kawamura
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Hiroyoshi Doi
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Palliative Medicine and Gastroenterology, International University Health and Welfare Narita Hospital, Narita, Japan
| | - Yuji Ogawa
- Department of Gastroenterology, National Hospital Organization Yokohama Medical Center, Yokohama, Japan
| | - Hiroyuki Kirikoshi
- Department of Clinical Laboratory, Yokohama City University Hospital, Yokohama, Japan
| | - Shigehiro Kokubu
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Daisuke Utsunomiya
- Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Shinichi Aishima
- Department of Pathology & Microbiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Yoshio Sumida
- Graduate School of Healthcare Management, International University of Healthcare and Welfare, Minato-ku, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | | | | | | | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
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Chen VL, Vespasiani‐Gentilucci U. Integrating PNPLA3 into clinical risk prediction. Liver Int 2025; 45:e16103. [PMID: 39282715 PMCID: PMC11815612 DOI: 10.1111/liv.16103] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/02/2024] [Accepted: 09/04/2024] [Indexed: 02/05/2025]
Abstract
The PNPLA3-rs738409-G variant was the first common variant associated with hepatic fat accumulation and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Nevertheless, to date, the clinical translation of this discovery has been minimal because it has not yet been clearly demonstrated where the genetic information may play an independent and additional role in clinical risk prediction. In this mini-review, we will discuss the most relevant evidence regarding the potential integration of the PNPLA3 variant into scores and algorithms for liver disease diagnostics and risk stratification, specifically focusing on MASLD but also extending to liver diseases of other etiologies. The PNPLA3 variant adds little in diagnosing the current state of the disease, whether in terms of presence/absence of metabolic dysfunction-associated steatohepatitis or the stage of fibrosis. While it can play an important role in prediction, allowing for the early definition of risk profiles that enable tailored monitoring and interventions over time, this is most valuable when applied to populations with relatively high pre-test probability of having significant fibrosis based on either non-invasive tests (e.g. Fibrosis-4) or demographics (e.g. diabetes). Indeed, in this context, integrating FIB4 with the PNPLA3 genotype can refine risk stratification, though there is still no evidence that genetic information adds to liver stiffness determined by elastography. Similarly, in patients with known liver cirrhosis, knowing the PNPLA3 genotype can play a role in predicting the risk of hepatocellular carcinoma, while more doubts remain about the risk of decompensation.
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Affiliation(s)
- Vincent L. Chen
- Division of Gastroenterology and Hepatology, Department of Internal MedicineUniversity of Michigan Medical SchoolAnn ArborMichiganUSA
| | - Umberto Vespasiani‐Gentilucci
- Research Unit of HepatologyUniversità Campus Bio‐Medico di RomeRomeItaly
- Hepatology and Clinical Medicine UnitFondazione Policlinico Universitario Campus‐Biomedico di RomaRomeItaly
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Maharajan N, Vijayakumar KA, Cho GW. Therapeutic potential of the flavonoid compound Licochalcone D in metabolic dysfunction-associated steatotic liver disease. Biochem Biophys Res Commun 2025; 744:151216. [PMID: 39721362 DOI: 10.1016/j.bbrc.2024.151216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/21/2024] [Accepted: 12/18/2024] [Indexed: 12/28/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent chronic liver disease associated with type 2 diabetes, which doubles the risk of developing this condition. Various flavonoid compounds have a positive effect on lipid metabolism, inflammation, and insulin resistance and can contribute to slowing down the progression of MASLD. In the current study, we investigated the biological effects of Licochalcone D (Lico D), a flavonoid, in a metabolic disease model. Oil Red O staining, quantitative real-time polymerase chain reaction, and western blotting were performed. For in vivo experiments, we used high-fat diet (60 %) plus low-dose streptozotocin (30 mg/kg; 5 days; intraperitoneal)-induced metabolic disease mouse model and evaluated lipid metabolism. We observed that Lico D reduced lipid accumulation and increased lipid metabolism both in vitro and in vivo. Additionally, we identified that the AMP-activated protein kinase and Sirtuin 1 pathways were activated in the mouse liver and hepatic steatosis cell model. In silico analysis revealed that Lico D passes the "Lipinski Rule of Five," which indicates drug-likeness properties. In conclusion, our findings highlight the role of Lico D in improving metabolic dysfunction-associated steatotic liver disease.
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Affiliation(s)
- Nagarajan Maharajan
- Department of Otorhinolaryngology - Head and Neck Surgery, University of Maryland School of Medicine, 21201, Baltimore, MD, USA.
| | - Karthikeyan A Vijayakumar
- Department of Biological Science, College of Natural Sciences, Chosun University, 309 Pilmun-daero, Dong-gu, 61452, Gwangju, South Korea; The Basic Science Institute of Chosun University, Chosun University, 61452, Gwangju, South Korea.
| | - Gwang-Won Cho
- Department of Biological Science, College of Natural Sciences, Chosun University, 309 Pilmun-daero, Dong-gu, 61452, Gwangju, South Korea; The Basic Science Institute of Chosun University, Chosun University, 61452, Gwangju, South Korea; Department of Integrative Biological Science, BK21 FOUR Education Research Group for Age-Associated Disorder Control Technology, Chosun University, 61452, Gwangju, South Korea.
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Giardoglou P, Gavra I, Amanatidou AI, Kalafati IP, Symianakis P, Kafyra M, Moulos P, Dedoussis GV. Development of a Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease Prediction in UK Biobank. Genes (Basel) 2024; 16:33. [PMID: 39858580 PMCID: PMC11765347 DOI: 10.3390/genes16010033] [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: 11/21/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of liver-related morbidity and mortality. Although the invasive liver biopsy remains the golden standard for MASLD diagnosis, Magnetic Resonance Imaging-derived Proton Density Fat Fraction (MRI-PDFF) is an accurate, non-invasive method for the assessment of treatment response. This study aimed at developing a Polygenic Risk Score (PRS) to improve MRI-PDFF prediction using UK Biobank data to assess an individual's genetic liability to MASLD. METHODS We iteratively sequestered 10% of MRI-PDFF samples as a validation set and split the rest of each dataset into base and target partitions, containing GWAS summary statistics and raw genotype data, respectively. PRSice2 was deployed to derive PRS candidates. Based on the frequency of SNP appearances along the PRS candidates, we generated different SNP sets according to variable frequency cutoffs. By applying the PRSs to the validation set, we identified the optimal SNP set, which was then applied to a Greek nonalcoholic fatty liver disease (NAFLD) study. RESULTS Data from 3553 UK Biobank participants yielded 49 different SNP sets. After calculating the PRS on the validation set for every SNP set, an optimal PRS with 75 SNPs was selected (incremental R2 = 0.025, p-value = 0.00145). Interestingly, 43 SNPs were successfully mapped to MASLD-related known genes. The selected PRS could predict traits, like LDL cholesterol and diastolic blood pressure in the UK Biobank, as also disease outcome in the Greek NAFLD study. CONCLUSIONS Our findings provide strong evidence that PRS is a powerful prediction model for MASLD, while it can also be applied on populations of different ethnicity.
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Affiliation(s)
- Panagiota Giardoglou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Ioanna Gavra
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Athina I. Amanatidou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Ioanna Panagiota Kalafati
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42132 Trikala, Greece
| | - Panagiotis Symianakis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Maria Kafyra
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Panagiotis Moulos
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center ‘Alexander Fleming’, 16672 Vari, Greece;
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
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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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Kang YW, Baek YH, Lee JH, Roh YH, Kwon HJ, Moon SY, Son MK, Jeong JS. Assessing the Utility of Acoustic Radiation Force Impulse in the Evaluation of Non-Alcoholic Fatty Liver Disease with Severe Obesity or Steatosis. Diagnostics (Basel) 2024; 14:1083. [PMID: 38893610 PMCID: PMC11171891 DOI: 10.3390/diagnostics14111083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/16/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) encompasses a heterogeneous spectrum ranging from simple steatosis to fibrosis and cirrhosis. Fibrosis, associated with long-term overall mortality and liver-related events, requires evaluation. Traditionally, liver biopsy has been the gold standard for diagnosing fibrosis. However, its invasive nature, potential complications, and sampling variability limit widespread use. Consequently, various non-invasive tests have been developed as alternatives for diagnosing fibrosis in NAFLD patients. AIM This study aimed to compare the accuracy of non-invasive tests (NITs) and evaluate the diagnostic accuracy of acoustic radiation force impulse (ARFI), one of the point shear wave techniques, compared to conventional methods, assessing its effective role in diagnosis. METHODS This is a retrospective study; a total of 136 patients diagnosed with fatty liver disease through ultrasonography were enrolled. The anthropometric data of the patients were collected on the day of admission and blood tests, measurements of ARFI, and a point shear test were conducted using abdominal ultrasound; a biopsy was performed the following day. In addition, we calculated the aspartate aminotransferase-to-platelet ratio index (APRI) index based on four factors (FIB-4) and the NAFLD fibrosis score (NFS). Subsequently, we assessed the diagnostic accuracy of NITs within various subgroups based on the extent of obesity, steatosis, or NAFLD activity score. RESULTS ARFI has been shown to have the highest diagnostic value among various NITs, with AUROC values of 0.832, 0.794, 0.767, and 0.696 for ARFI, APRI, FIB-4, and NFS, respectively. In the morbidly obese subgroup, the AUROC values of ARFI, APRI, FIB-4, and NFS were 0.805, 0.769, 0.736, and 0.674. In the group with severe steatosis or non-alcoholic steatohepatitis (NASH), the AUROC values were 0.679, 0.596, 0.661, and 0.612, respectively, for severe steatosis and 0.789, 0.696, 0.751, and 0.691, respectively, for NASH. CONCLUSIONS In conclusion, ARFI is not affected by various factors and maintains diagnostic accuracy compared to serum NITs. Therefore, we can recommend ARFI as a valuable diagnostic test to screen for advanced fibrosis in patients with NAFLD.
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Affiliation(s)
- Yeo Wool Kang
- Department of Internal Medicine, Dong-A University College of Medicine, 32 Daeshingongwonro, Seo-gu, Busan 49201, Republic of Korea; (Y.W.K.); (J.H.L.); (S.Y.M.)
| | - Yang Hyun Baek
- Department of Internal Medicine, Dong-A University College of Medicine, 32 Daeshingongwonro, Seo-gu, Busan 49201, Republic of Korea; (Y.W.K.); (J.H.L.); (S.Y.M.)
| | - Jong Hoon Lee
- Department of Internal Medicine, Dong-A University College of Medicine, 32 Daeshingongwonro, Seo-gu, Busan 49201, Republic of Korea; (Y.W.K.); (J.H.L.); (S.Y.M.)
| | - Young Hoon Roh
- Department of General Surgery, Dong-A University College of Medicine, 32 Daeshingongwonro, Seo-gu, Busan 49201, Republic of Korea;
| | - Hee Jin Kwon
- Department of Radiology, Dong-A University College of Medicine, 1,3-ga Dongdaesindong, Seo-gu, Busan 49201, Republic of Korea;
| | - Sang Yi Moon
- Department of Internal Medicine, Dong-A University College of Medicine, 32 Daeshingongwonro, Seo-gu, Busan 49201, Republic of Korea; (Y.W.K.); (J.H.L.); (S.Y.M.)
| | - Min Kook Son
- Department of Physiology, Dong-A University College of Medicine, 32 Daeshingongwonro, Seo-gu, Busan 49201, Republic of Korea;
| | - Jin Sook Jeong
- Department of Pathology, Dong-A University College of Medicine, 32 Daeshingongwonro, Seo-gu, Busan 49201, Republic of Korea;
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Imajo K, Saigusa Y, Kobayashi T, Nagai K, Nishida S, Kawamura N, Doi H, Iwaki M, Nogami A, Honda Y, Kessoku T, Ogawa Y, Kirikoshi H, Yasuda S, Toyoda H, Hayashi H, Kokubu S, Utsunomiya D, Takahashi H, Aishima S, Kim BK, Tamaki N, Saito S, Yoneda M, Loomba R, Nakajima A. M-PAST score is better than MAST score for the diagnosis of active fibrotic nonalcoholic steatohepatitis. Hepatol Res 2023; 53:844-856. [PMID: 37237426 PMCID: PMC10792544 DOI: 10.1111/hepr.13927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 04/26/2023] [Accepted: 05/05/2023] [Indexed: 05/28/2023]
Abstract
BACKGROUND Clinical trials enroll patients with active fibrotic nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease [NAFLD] activity score ≥ 4) and significant fibrosis (F ≥ 2); however, screening failure rates are high following biopsy. We developed new scores to identify active fibrotic NASH using FibroScan and magnetic resonance imaging (MRI). METHODS We undertook prospective primary (n = 176), retrospective validation (n = 169), and University of California San Diego (UCSD; n = 234) studies of liver biopsy-proven NAFLD. Liver stiffness measurement (LSM) using FibroScan or magnetic resonance elastography (MRE), controlled attenuation parameter (CAP), or proton density fat fraction (PDFF), and aspartate aminotransferase (AST) were combined to develop a two-step strategy-FibroScan-based LSM followed by CAP with AST (F-CAST) and MRE-based LSM followed by PDFF with AST (M-PAST)-and compared with FibroScan-AST (FAST) and MRI-AST (MAST) for diagnosing active fibrotic NASH. Each model was categorized using rule-in and rule-out criteria. RESULTS Areas under receiver operating characteristic curves (AUROCs) of F-CAST (0.826) and M-PAST (0.832) were significantly higher than those of FAST (0.744, p = 0.004) and MAST (0.710, p < 0.001). Following the rule-in criteria, positive predictive values of F-CAST (81.8%) and M-PAST (81.8%) were higher than those of FAST (73.5%) and MAST (70.0%). Following the rule-out criteria, negative predictive values of F-CAST (90.5%) and M-PAST (90.9%) were higher than those of FAST (84.0%) and MAST (73.9%). In the validation and UCSD cohorts, AUROCs did not differ significantly between F-CAST and FAST, but M-PAST had a higher diagnostic performance than MAST. CONCLUSIONS The two-step strategy, especially M-PAST, showed reliability of rule-in/-out for active fibrotic NASH, with better predictive performance compared with MAST. This study is registered with ClinicalTrials.gov (number, UMIN000012757).
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Affiliation(s)
- Kento Imajo
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Yusuke Saigusa
- Department of Biostatistics, Yokohama City University School of Medicine, Yokohama, Japan
| | - Takashi Kobayashi
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Koki Nagai
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Shinya Nishida
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Nobuyoshi Kawamura
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Hiroyoshi Doi
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Michihiro Iwaki
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Asako Nogami
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yasushi Honda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takaomi Kessoku
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yuji Ogawa
- Department of Gastroenterology, National Hospital Organization Yokohama Medical Center, Yokohama, Japan
| | - Hiroyuki Kirikoshi
- Department of Clinical Laboratory, Yokohama City University Hospital, Yokohama, Japan
| | - Satoshi Yasuda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Hidenori Toyoda
- Department of Gastroenterology and Hepatology, Ogaki Municipal Hospital, Gifu, Japan
| | - Hideki Hayashi
- Department of Gastroenterology and Hepatology, Gifu Municipal Hospital, Gifu, Japan
| | - Shigehiro Kokubu
- Department of Gastroenterology, Shin-yurigaoka General Hospital, Kawasaki, Japan
| | - Daisuke Utsunomiya
- Department of Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Saga, Japan
| | - Beom Kyung Kim
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Nobuharu Tamaki
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Satoru Saito
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masato Yoneda
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Rohit Loomba
- NAFLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Atsushi Nakajima
- Department of Gastroenterology and Hepatology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Anwar SD, Foster C, Ashraf A. Lipid Disorders and Metabolic-Associated Fatty Liver Disease. Endocrinol Metab Clin North Am 2023; 52:445-457. [PMID: 37495336 DOI: 10.1016/j.ecl.2023.01.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/28/2023]
Abstract
Dyslipidemia has been linked metabolic-associated fatty liver disease (MAFLD). Several genes and transcription factors involved in lipid metabolism can increase susceptibility to MAFLD. Multiple parallel 'hits' have been proposed for developing hepatic steatosis, NASH, and MAFLD, including insulin resistance and subsequent free fatty acid excess, de novo lipogenesis, and excessive hepatic triglyceride and cholesterol deposition in the liver. This lead to defective beta-oxidation in the mitochondria and VLDL export and increased inflammation. Given the significant cardiovascular risk, dyslipidemia associated with MAFLD should be managed by lifestyle changes and lipid-lowering agents such as statins, fenofibrate, and omega-3 fatty acids, with judicious use of insulin-sensitizing agents, and adequate control of dysglycemia.
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Affiliation(s)
- Shima Dowla Anwar
- Department of Pediatrics, Boston Children Hospital, Harvard Medical School, Boston, MA, USA
| | - Christy Foster
- University of Alabama at Birmingham, 1601, 4th Avenue South, CPP M 30, Birmingham, AL 35233, USA
| | - Ambika Ashraf
- University of Alabama at Birmingham, 1601, 4th Avenue South, CPP M 30, Birmingham, AL 35233, USA.
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9
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Zhang X, Cai Y, Yao Z, Chi H, Li Y, Shi J, Zhou Z, Sun L. Discovery of novel OXM-based glucagon-like peptide 1 (GLP-1)/glucagon receptor dual agonists. Peptides 2023; 161:170948. [PMID: 36646385 DOI: 10.1016/j.peptides.2023.170948] [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: 11/06/2022] [Revised: 01/09/2023] [Accepted: 01/11/2023] [Indexed: 01/15/2023]
Abstract
Novel glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have improved efficacy over GLP-1R mono-agonists in treating type 2 diabetes (T2DM) and obesity. Here, we describe the discovery of a novel oxyntomodulin (OXM) based GLP-1R/GCGR dual agonist with potent and balanced potency toward GLP-1R and GCGR. The lead peptide OXM-7 was obtained via stepwise rational design and long-acting modification. In ICR and db/db mice, OXM-7 exhibited prominent acute and long-acting hypoglycemic effects. In diet-induced obesity (DIO) mice, twice-daily administration of OXM-7 produced significant weight loss, normalized lipid metabolism, and improved glucose control. In DIO-nonalcoholic steatohepatitis (NASH) mice, OXM-7 treatment significantly reversed hepatic steatosis, and reduced serum and hepatic lipid levels. These preclinical data suggest the therapeutic potential of OXM-7 as a novel anti-diabetic, anti-steatotic and/or anti-obesity agent.
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Affiliation(s)
- Xiaolong Zhang
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Yuchen Cai
- School of Engineering, China Pharmaceutical University, Nanjing 210009, Jiangsu, PR China
| | - Zhihong Yao
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China
| | - Heng Chi
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Yan Li
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Jingjing Shi
- Food and Pharmaceutical Research Institute, Jiangsu Food & Pharmaceutical Science College, Huaian 223003, Jiangsu, PR China
| | - Zhongbo Zhou
- School of Pharmacy, Youjiang Medical University for Nationalities, 98 Chengxiang Road, Baise 533000, Guangxi, PR China.
| | - Lidan Sun
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, College of Medicine, Jiaxing University, Jiaxing 314001, Zhejiang, PR China.
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10
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Shi YW, Fan JG. Surveillance of the progression and assessment of treatment endpoints for nonalcoholic steatohepatitis. Clin Mol Hepatol 2023; 29:S228-S243. [PMID: 36521452 PMCID: PMC10029951 DOI: 10.3350/cmh.2022.0401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/08/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022] Open
Abstract
Nonalcoholic steatohepatitis (NASH) is an aggressive form of nonalcoholic fatty liver disease (NAFLD) characterized by steatosis-associated inflammation and liver injury. Without effective treatment or management, NASH can have life-threatening outcomes. Evaluation and identification of NASH patients at risk for adverse outcomes are therefore important. Key issues in screening NASH patients are the assessment of advanced fibrosis, differentiation of NASH from simple steatosis, and monitoring of dynamic changes during follow-up and treatment. Currently, NASH staging and evaluation of the effectiveness for drugs still rely on pathological diagnosis, despite sample error issues and the subjectivity associated with liver biopsy. Optimizing the pathological assessment of liver biopsy samples and developing noninvasive surrogate methods for accessible, accurate, and safe evaluation are therefore critical. Although noninvasive methods including elastography, serum soluble biomarkers, and combined models have been implemented in the last decade, noninvasive diagnostic measurements are not widely applied in clinical practice. More work remains to be done in establishing cost-effective strategies both for screening for at-risk NASH patients and identifying changes in disease severity. In this review, we summarize the current state of noninvasive methods for detecting steatosis, steatohepatitis, and fibrosis in patients with NASH, and discuss noninvasive assessments for screening at-risk patients with a focus on the characteristics that should be monitored at follow-up.
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Affiliation(s)
- Yi-wen Shi
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
| | - Jian-Gao Fan
- Center for Fatty Liver, Department of Gastroenterology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai, China
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11
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Sulaiman SA, Dorairaj V, Adrus MNH. Genetic Polymorphisms and Diversity in Nonalcoholic Fatty Liver Disease (NAFLD): A Mini Review. Biomedicines 2022; 11:106. [PMID: 36672614 PMCID: PMC9855725 DOI: 10.3390/biomedicines11010106] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Revised: 12/13/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common liver disease with a wide spectrum of liver conditions ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The prevalence of NAFLD varies across populations, and different ethnicities have specific risks for the disease. NAFLD is a multi-factorial disease where the genetics, metabolic, and environmental factors interplay and modulate the disease's development and progression. Several genetic polymorphisms have been identified and are associated with the disease risk. This mini-review discussed the NAFLD's genetic polymorphisms and focusing on the differences in the findings between the populations (diversity), including of those reports that did not show any significant association. The challenges of genetic diversity are also summarized. Understanding the genetic contribution of NAFLD will allow for better diagnosis and management explicitly tailored for the various populations.
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Affiliation(s)
- Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Jalan Yaa’cob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; (V.D.); (M.N.H.A.)
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12
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Yu S, Jiang J, Li Q, Liu X, Wang Z, Yang L, Ding L. Schisantherin A alleviates non-alcoholic fatty liver disease by restoring intestinal barrier function. Front Cell Infect Microbiol 2022; 12:855008. [PMID: 36132991 PMCID: PMC9483129 DOI: 10.3389/fcimb.2022.855008] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Accepted: 08/02/2022] [Indexed: 01/21/2023] Open
Abstract
Background Non-alcoholic fatty liver disease (NAFLD) is intricately linked to dysregulation of the gut–liver axis, and correlated with intestinal inflammation and barrier disruption. Objectives To investigate the protective effects and possible molecular mechanism of Schisantherin A (Sin A) in a high-fat diet (HFD) induced NAFLD mouse model. Methods HFD-fed NAFLD mice were treated with the vehicle and 80 mg/kg Sin A every day for 6 weeks. The gut permeability of the NAFLD mice was assessed by intestinal permeability assays in vivo and transepithelial electrical resistance (TEER) measurements in vitro were also used to evaluate the function of the gut barrier. TLR4 inhibitor was then used to investigate the impact of Sin A in the LPS- TLR4 signaling pathway. Alternatively, the composition of the microbiome was assessed using 16S rRNA amplification. Finally, the experiment of antibiotic treatment was performed to elucidate the roles of the gut microbiome mediating Sin A induced metabolic benefits in the NAFLD mice. Results We found that Sin A potently ameliorated HFD-induced hepatic steatosis and inflammation, alleviated gut inflammation, and restored intestinal barrier function. We also observed that Sin A improved gut permeability and reduced the release of lipopolysaccharide (LPS) into circulation and further found that Sin A can suppress LPS-TLR4 signaling to protect against HFD-induced NAFLD. Sin A treatment altered the composition of the microbiome in NAFLD mice compared to vehicle controls. Conclusions Sin A is an effective and safe hepatoprotective agent against HFD-induced NAFLD by partly ameliorating gut inflammation, restoring intestinal barrier function, and regulating intestinal microbiota composition.
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Affiliation(s)
- Shenglan Yu
- Shanghai Key Laboratory of Complex Prescription and Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Phamcological Research Department, Shanghai Research and Development Center for Standardization of Traditional Chinese Medicines, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiarui Jiang
- Shanghai Key Laboratory of Complex Prescription and Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Phamcological Research Department, Shanghai Research and Development Center for Standardization of Traditional Chinese Medicines, Shanghai, China
| | - Qinqin Li
- Shanghai Key Laboratory of Complex Prescription and Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Phamcological Research Department, Shanghai Research and Development Center for Standardization of Traditional Chinese Medicines, Shanghai, China
| | - Xuan Liu
- Research and Development Department, Xuzhou Wanwusheng Pharmaceutical Co., Ltd., Xuzhou, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription and Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Phamcological Research Department, Shanghai Research and Development Center for Standardization of Traditional Chinese Medicines, Shanghai, China
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription and Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Phamcological Research Department, Shanghai Research and Development Center for Standardization of Traditional Chinese Medicines, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- *Correspondence: Lili Ding, ; Li Yang,
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription and Ministry of Education Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Phamcological Research Department, Shanghai Research and Development Center for Standardization of Traditional Chinese Medicines, Shanghai, China
- *Correspondence: Lili Ding, ; Li Yang,
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Advance of Serum Biomarkers and Combined Diagnostic Panels in Nonalcoholic Fatty Liver Disease. DISEASE MARKERS 2022; 2022:1254014. [PMID: 35811662 PMCID: PMC9259243 DOI: 10.1155/2022/1254014] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/31/2022] [Accepted: 06/02/2022] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) affects approximately 25-30% population worldwide, which progresses from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma, and has complications such as cardiovascular events. Liver biopsy is still the gold standard for the diagnosis of NAFLD, with some limitations, such as invasive, sampling deviation, and empirical judgment. Therefore, it is urgent to develop noninvasive diagnostic biomarkers. Currently, a large number of NAFLD-related serum biomarkers have been identified, including apoptosis, inflammation, fibrosis, adipokines, hepatokines, and omics biomarkers, which could effectively diagnose NASH and exclude patients with progressive fibrosis. We summarized serum biomarkers and combined diagnostic panels of NAFLD, to provide some guidance for the noninvasive diagnosis and further clinical studies.
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14
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Park J, Kwon HJ, Sohn W, Cho JY, Park SJ, Chang Y, Ryu S, Kim BI, Cho YK. Risk of liver fibrosis in patients with prediabetes and diabetes mellitus. PLoS One 2022; 17:e0269070. [PMID: 35653399 PMCID: PMC9162349 DOI: 10.1371/journal.pone.0269070] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 05/13/2022] [Indexed: 11/18/2022] Open
Abstract
The aim of this study was to assess the risk of liver fibrosis in those with no glucose intolerance, prediabetes, or diabetes. A cross-sectional study was conducted based on a cohort from a health examination program which included a magnetic resonance elastography (MRE). Participants were classified into three groups according to glucose tolerance: no glucose intolerance, prediabetes, and diabetes mellitus. Liver fibrosis was evaluated by liver stiffness measurement (LSM) value using two-dimensional real-time MRE. The risk of significant liver fibrosis was compared among three groups. A total of 2,090 subjects were included: no glucose intolerance (n = 889); prediabetes (n = 985); and diabetes (n = 216). Mean values of LSM in those with no glucose intolerance, prediabetes, and diabetes were 2.37 ± 0.43 kPa, 2.41 ± 0.34 kPa, and 2.65 ± 0.70 kPa, respectively (p<0.001). Proportions of significant fibrosis (LSM ≥2.97 kPa) in no glucose intolerance, prediabetes, and diabetes groups were 3.1%, 4.4%, and 16.7%, respectively (p<0.001). Compared with those with no glucose intolerance, those with diabetes had higher risk of significant fibrosis (adjusted odds ratio [aOR]: 3.02, 95% confidence interval [CI]: 1.57–5.81, p<0.001). However, there was no difference between prediabetes and no glucose intolerance (aOR: 1.05, 95% CI: 0.59–1.86, p = 0.876). A subgroup analysis also showed that prediabetes, unlike diabetes, was not associated with significant fibrosis in subjects with or without liver disease. Diabetes, but not prediabetes, is a risk factor for significant liver fibrosis. This finding is consistent regarldess of the pressence of liver disease.
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Affiliation(s)
- Jongsin Park
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Heon-Ju Kwon
- Department of Radiology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Won Sohn
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- * E-mail:
| | - Ju-Yeon Cho
- Department of Internal Medicine, Chosun University Hospital, Gwang-Ju, Republic of Korea
| | - Soo Jin Park
- Department of Surgery, Wonkwang University Sanbon Hospital, Gunpo, Korea
| | - Yoosoo Chang
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Seungho Ryu
- Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- Department of Clinical Research Design and Evaluation, SAIHST, Sungkyunkwan University, Seoul, Republic of Korea
| | - Byung Ik Kim
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yong Kyun Cho
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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15
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Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Eat Weight Disord 2022; 27:1603-1619. [PMID: 34914079 PMCID: PMC9123074 DOI: 10.1007/s40519-021-01287-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 07/29/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the past years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato, the Società Italiana di Diabetologia and the Società Italiana dell'Obesità reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure and Istituto Superiore di Sanità. Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources.Level of evidence Level of evidence of recommendations for each PICO question were reported according to available evidence.
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16
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Cholongitas E, Tsilingiris D, Diamantopoulou P, Mastrogianni E, Tentolouris A, Karagiannakis D, Moyssakis I, Papatheodoridis GV, Tentolouris N. Association of cardiovascular factors in diabetic patients with non-alcoholic fatty liver disease. Hormones (Athens) 2022; 21:133-145. [PMID: 34716911 DOI: 10.1007/s42000-021-00334-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 10/19/2021] [Indexed: 02/07/2023]
Abstract
PURPOSE To evaluate the association between severity of hepatic steatosis/fibrosis with clinical, laboratory, and echocardiographic characteristics, including visceral obesity and type 2 diabetes mellitus (T2DM)-related micro- and macrovascular complications in diabetic patients with non-alcoholic fatty liver disease (NAFLD). METHODS We studied 60 consecutive NAFLD outpatients with T2DM, recording several demographic and clinical characteristics, trunk and visceral fat, cardiac ultrasound, and micro- and macrovascular complications of diabetes mellitus including microalbuminuria, diabetic peripheral neuropathy, peripheral vascular disease, and cardiac autonomic function. Severity of steatosis and fibrosis was evaluated with abdominal ultrasound and liver stiffness measurements, respectively. RESULTS Twenty-three (41%) of the patients had grade 1 steatosis and mean liver stiffness was 7.5 ± 3 kPa. After applying Bonferroni correction for multiple comparisons, ferritin concentration was the only factor significantly different between patients with mild (grade 1) compared to those with moderate/severe (grade 2/3) steatosis and showed good discriminative ability for the presence of moderate/severe steatosis (AUC: 0.74, sensitivity 88%, specificity 48%, PPV 74%, and NPV 72%). In addition, waist circumference was the only factor associated with the presence of significant fibrosis (≥ F2) with very good discriminative ability (AUC: 0.77, sensitivity 89%, specificity 45%, PPV 75%, and NPV 70%). CONCLUSION Specific clinical and laboratory characteristics, which may be determined via widely accessible and noninvasive techniques, were associated with severity of diabetics NAFLD, taking into account echocardiographic characteristics, visceral obesity, and T2DM-related systemic complications.
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Affiliation(s)
- Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National, Laiko General Hospital, Kapodistrian University of Athens, Agiou Thoma 17, 11527, Athens, Greece.
| | - Dimitrios Tsilingiris
- First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiota Diamantopoulou
- First Department of Internal Medicine, Medical School of National, Laiko General Hospital, Kapodistrian University of Athens, Agiou Thoma 17, 11527, Athens, Greece
| | - Elpida Mastrogianni
- First Department of Internal Medicine, Medical School of National, Laiko General Hospital, Kapodistrian University of Athens, Agiou Thoma 17, 11527, Athens, Greece
| | - Anastasios Tentolouris
- First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Dimitrios Karagiannakis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - George V Papatheodoridis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Tentolouris
- First Department of Propaedeutic Internal Medicine, Medical School, Laiko General Hospital, National and Kapodistrian University of Athens, Athens, Greece
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Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Dig Liver Dis 2022; 54:170-182. [PMID: 34924319 DOI: 10.1016/j.dld.2021.04.029] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 03/22/2021] [Accepted: 04/21/2021] [Indexed: 12/11/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.
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18
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Segura-Azuara NDLÁ, Varela-Chinchilla CD, Trinidad-Calderón PA. MAFLD/NAFLD Biopsy-Free Scoring Systems for Hepatic Steatosis, NASH, and Fibrosis Diagnosis. Front Med (Lausanne) 2022; 8:774079. [PMID: 35096868 PMCID: PMC8792949 DOI: 10.3389/fmed.2021.774079] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD), formerly known as nonalcoholic fatty liver disease, is the most prevalent liver disorder worldwide. Historically, its diagnosis required biopsy, even though the procedure has a variable degree of error. Therefore, new non-invasive strategies are needed. Consequently, this article presents a thorough review of biopsy-free scoring systems proposed for the diagnosis of MAFLD. Similarly, it compares the severity of the disease, ranging from hepatic steatosis (HS) and nonalcoholic steatohepatitis (NASH) to fibrosis, by contrasting the corresponding serum markers, clinical associations, and performance metrics of these biopsy-free scoring systems. In this regard, defining MAFLD in conjunction with non-invasive tests can accurately identify patients with fatty liver at risk of fibrosis and its complications. Nonetheless, several biopsy-free scoring systems have been assessed only in certain cohorts; thus, further validation studies in different populations are required, with adjustment for variables, such as body mass index (BMI), clinical settings, concomitant diseases, and ethnic backgrounds. Hence, comprehensive studies on the effects of age, morbid obesity, and prevalence of MAFLD and advanced fibrosis in the target population are required. Nevertheless, the current clinical practice is urged to incorporate biopsy-free scoring systems that demonstrate adequate performance metrics for the accurate detection of patients with MAFLD and underlying conditions or those with contraindications of biopsy.
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19
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Marchesini G, Bugianesi E, Burra P, Marra F, Miele L, Alisi A, Vajro P, Masarone M, Petta S, Persico M, Svegliati-Baroni G, Valenti L, Federici M, Purrello F, Sasso FC, Targher G, Busetto L, Petroni ML, Santini F, Cammà C, Colli A. Non-alcoholic fatty liver disease in adults 2021: A clinical practice guideline of the Italian Association for the Study of the Liver (AISF), the Italian Society of Diabetology (SID) and the Italian Society of Obesity (SIO). Nutr Metab Cardiovasc Dis 2022; 32:1-16. [PMID: 34924246 DOI: 10.1016/j.numecd.2021.04.028] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 04/28/2021] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a common and emerging liver disease in adults, paralleling the epidemic of obesity and diabetes, and leading to worrisome events (hepatocellular carcinoma and end-stage liver disease). In the last years, mounting evidence added insights about epidemiology, natural history, diagnosis and lifestyle-based or drug treatment of NAFLD. In this rapidly evolving scenario, members of the Associazione Italiana per lo Studio del Fegato (AISF), the Società Italiana di Diabetologia (SID) and the Società Italiana dell'Obesità (SIO) reviewed current knowledge on NAFLD. The quality of the published evidence is graded, and practical recommendations are made following the rules and the methodology suggested in Italy by the Centro Nazionale per l'Eccellenza delle cure (CNEC) and Istituto Superiore di Sanità (ISS). Whenever possible, recommendations are placed within the context the Italian Healthcare system, with reference to specific experience and local diagnostic and management resources. Level of evidence: Level of evidence of recommendations for each PICO question were reported according to available evidence.
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20
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Prevalence of non-alcoholic fatty liver disease (NAFLD) in a cohort of patients with type 2 diabetes: the PHIGNA-DM2 study. NUTR HOSP 2022; 39:1012-1018. [DOI: 10.20960/nh.03969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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21
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Dorairaj V, Sulaiman SA, Abu N, Abdul Murad NA. Nonalcoholic Fatty Liver Disease (NAFLD): Pathogenesis and Noninvasive Diagnosis. Biomedicines 2021; 10:15. [PMID: 35052690 PMCID: PMC8773432 DOI: 10.3390/biomedicines10010015] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/20/2021] [Accepted: 12/20/2021] [Indexed: 12/14/2022] Open
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) or metabolic associated fatty liver disease (MAFLD), as it is now known, has gradually increased. NAFLD is a disease with a spectrum of stages ranging from simple fatty liver (steatosis) to a severe form of steatosis, nonalcoholic steatohepatitis (NASH), which could progress to irreversible liver injury (fibrosis) and organ failure, and in some cases hepatocellular carcinoma (HCC). Although a liver biopsy remains the gold standard for accurate detection of this condition, it is unsuitable for clinical screening due to a higher risk of death. There is thus an increased need to find alternative techniques or tools for accurate diagnosis. Early detection for NASH matters for patients because NASH is the marker for severe disease progression. This review summarizes the current noninvasive tools for NAFLD diagnosis and their performance. We also discussed potential and newer alternative tools for diagnosing NAFLD.
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Affiliation(s)
| | - Siti Aishah Sulaiman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia (UKM), Kuala Lumpur 56000, Malaysia; (V.D.); (N.A.); (N.A.A.M.)
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22
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Anti-inflammatory diet consumption reduced fatty liver indices. Sci Rep 2021; 11:22601. [PMID: 34799655 PMCID: PMC8604894 DOI: 10.1038/s41598-021-98685-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Accepted: 08/30/2021] [Indexed: 01/07/2023] Open
Abstract
The aim of this study was to assess the association between dietary inflammatory index (DII) and non-invasive markers of liver status in adults. This cross-sectional study was performed on 8520 adults, recruited in Ravansar Non-Communicable Diseases (RaNCD) cohort study, western Iran. The DII score was calculated based on participants’ dietary intakes obtained from Food Frequency Questionnaire (FFQ). Fatty Liver Index (FLI) score was calculated by anthropometric measurements and some non-invasive markers of liver status. Linear regression models were applied to estimate the associations and adjust the possible confounding factors. A greater DII score was significantly associated with higher energy intake, body mass index (BMI), body fat mass (BFM), blood pressure, and FLI (P < 0.001). Participants with the highest DII score had a significantly higher consumption saturated fat, trans fat and red meat than those in the lowest quartile (P < 0.001). After adjustments of age and sex, participants in the highest quartile of the DII score had a greater risk of FLI (β: 0.742, 95% CI: 0.254, 0.601). More pro-inflammatory diet in participants was associated with a higher FLI. The DII score was positively associated with non-invasive liver markers. Thus, having an anti-inflammatory diet can help balance liver enzymes, reduce obesity, and decrease fatty liver.
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23
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Chang E, Chang JS, Kong ID, Baik SK, Kim MY, Park KS. Multidimensional Biomarker Analysis Including Mitochondrial Stress Indicators for Nonalcoholic Fatty Liver Disease. Gut Liver 2021; 16:171-189. [PMID: 34420934 PMCID: PMC8924798 DOI: 10.5009/gnl210106] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Revised: 06/15/2021] [Accepted: 06/22/2021] [Indexed: 11/22/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is accompanied by a complex and multifactorial pathogenesis with sequential progressions from inflammation to fibrosis and then to cancer. This heterogeneity interferes with the development of precise diagnostic and prognostic strategies for NAFLD. The current approach for the diagnosis of simple steatosis, steatohepatitis, and cirrhosis mainly consists of ultrasonography, magnetic resonance imaging, elastography, and various serological analyses. However, individual dry and wet biomarkers have limitations demanding an integrative approach for the assessment of disease progression. Here, we review diagnostic strategies for simple steatosis, steatohepatitis and hepatic fibrosis, followed by potential biomarkers associated with fat accumulation and mitochondrial stress. For mitochondrial stress indicators, we focused on fibroblast growth factor 21 (FGF21), growth differentiation factor 15 (GDF15), angiopoietin-related growth factor and mitochondrial-derived peptides. Each biomarker may not strongly indicate the severity of steatosis or steatohepatitis. Instead, multidimensional analysis of different groups of biomarkers based on pathogenic mechanisms may provide decisive diagnostic/prognostic information to develop a therapeutic plan for patients with NAFLD. For this purpose, mitochondrial stress indicators, such as FGF21 or GDF15, could be an important component in the multiplexed and contextual interpretation of NAFLD. Further validation of the integrative evaluation of mitochondrial stress indicators combined with other biomarkers is needed in the diagnosis/prognosis of NAFLD.
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Affiliation(s)
- Eunha Chang
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jae Seung Chang
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In Deok Kong
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Kyu-Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
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24
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Alqahtani SA, Schattenberg JM. Nonalcoholic fatty liver disease: use of diagnostic biomarkers and modalities in clinical practice. Expert Rev Mol Diagn 2021; 21:1065-1078. [PMID: 34346799 DOI: 10.1080/14737159.2021.1964958] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The global burden of liver disease is increasing, and nonalcoholic fatty liver disease (NAFLD) is among the most common chronic liver diseases in Asia, Europe, North and South America. The field of noninvasive diagnostic and their role in staging, but also predicting outcome is evolving rapidly. There is a high-unmet need to stage patients with NAFLD and to identify the subset of patients at risk of progression to end-stage liver disease. AREAS COVERED The review covers all established diagnostic blood-based and imaging biomarkers to stage and grade NAFLD. Noninvasive surrogate scores are put into perspective of the available evidence and recommended use. The outlook includes genetics, combined algorithms, and artificial intelligence that will allow clinicians to guide and support the management in both early and later disease stages. EXPERT OPINION In the future, these diagnostics tests will help clinicians to establish patient care pathways and support the identification of relevant subgroups for monitoring and pharmacotherapy. In addition, researchers will be guided to better understand available scores and support the development of future prediction systems. These will likely include multiparametric aspects of the disease and machine learning algorithms will refine their use and integration with large datasets.
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Affiliation(s)
- Saleh A Alqahtani
- Liver Transplantation Unit, King Faisal Specialist Hospital & Research Center, Riyadh, Saudi Arabia.,Division Of Gastroenterology And Hepatology, Johns Hopkins University, Baltimore, USA
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department Of Medicine, University Medical Center, Mainz, Germany
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25
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Brito MDF, Torre C, Silva-Lima B. Scientific Advances in Diabetes: The Impact of the Innovative Medicines Initiative. Front Med (Lausanne) 2021; 8:688438. [PMID: 34295913 PMCID: PMC8290522 DOI: 10.3389/fmed.2021.688438] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/02/2021] [Indexed: 12/16/2022] Open
Abstract
Diabetes Mellitus is one of the World Health Organization's priority diseases under research by the first and second programmes of Innovative Medicines Initiative, with the acronyms IMI1 and IMI2, respectively. Up to October of 2019, 13 projects were funded by IMI for Diabetes & Metabolic disorders, namely SUMMIT, IMIDIA, DIRECT, StemBANCC, EMIF, EBiSC, INNODIA, RHAPSODY, BEAT-DKD, LITMUS, Hypo-RESOLVE, IM2PACT, and CARDIATEAM. In general, a total of €447 249 438 was spent by IMI in the area of Diabetes. In order to prompt a better integration of achievements between the different projects, we perform a literature review and used three data sources, namely the official project's websites, the contact with the project's coordinators and co-coordinator, and the CORDIS database. From the 662 citations identified, 185 were included. The data collected were integrated into the objectives proposed for the four IMI2 program research axes: (1) target and biomarker identification, (2) innovative clinical trials paradigms, (3) innovative medicines, and (4) patient-tailored adherence programmes. The IMI funded projects identified new biomarkers, medical and research tools, determinants of inter-individual variability, relevant pathways, clinical trial designs, clinical endpoints, therapeutic targets and concepts, pharmacologic agents, large-scale production strategies, and patient-centered predictive models for diabetes and its complications. Taking into account the scientific data produced, we provided a joint vision with strategies for integrating personalized medicine into healthcare practice. The major limitations of this article were the large gap of data in the libraries on the official project websites and even the Cordis database was not complete and up to date.
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Affiliation(s)
| | - Carla Torre
- Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.,Laboratory of Systems Integration Pharmacology, Clinical & Regulatory Science-Research Institute for Medicines (iMED.ULisboa), Lisbon, Portugal
| | - Beatriz Silva-Lima
- Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.,Laboratory of Systems Integration Pharmacology, Clinical & Regulatory Science-Research Institute for Medicines (iMED.ULisboa), Lisbon, Portugal
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26
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Amerikanou C, Kanoni S, Kaliora AC, Barone A, Bjelan M, D'Auria G, Gioxari A, Gosalbes MJ, Mouchti S, Stathopoulou MG, Soriano B, Stojanoski S, Banerjee R, Halabalaki M, Mikropoulou EV, Kannt A, Lamont J, Llorens C, Marascio F, Marascio M, Roig FJ, Smyrnioudis I, Varlamis I, Visvikis‐Siest S, Vukic M, Milic N, Medic‐Stojanoska M, Cesarini L, Campolo J, Gastaldelli A, Deloukas P, Trivella MG, Francino MP, Dedoussis GV. Effect of Mastiha supplementation on NAFLD: The MAST4HEALTH Randomised, Controlled Trial. Mol Nutr Food Res 2021; 65:e2001178. [DOI: 10.1002/mnfr.202001178] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 01/28/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Charalampia Amerikanou
- Department of Nutrition and Dietetics, School of Health Science and Education Harokopio University Athens Greece
| | - Stavroula Kanoni
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UK
| | - Andriana C. Kaliora
- Department of Nutrition and Dietetics, School of Health Science and Education Harokopio University Athens Greece
| | | | - Mladen Bjelan
- Faculty of Medicine University of Novi Sad Novi Sad Serbia
| | - Giuseppe D'Auria
- Sequencing and Bioinformatics Service Fundació per al Foment de la Investigació Sanitària i Biomèdica de la Comunitat Valenciana (FISABIO‐Salut Pública) Avda. Catalunya 21 València 46020 Spain
- CIBER en Epidemiología y Salud Pública Av. Monforte de Lemos 3–5 Madrid 28029 Spain
| | - Aristea Gioxari
- Department of Nutrition and Dietetics, School of Health Science and Education Harokopio University Athens Greece
| | - María José Gosalbes
- CIBER en Epidemiología y Salud Pública Av. Monforte de Lemos 3–5 Madrid 28029 Spain
- Joint Research Unit in Genomics and Health Fundació per al Foment de la Investigació Sanitària i Biomèdica de la Comunitat Valenciana (FISABIO) and Institut de Biologia Integrativa de Sistemes (Universitat de València / Consejo Superior de Investigaciones Científicas) Avda. Catalunya 21 València 46020 Spain
| | | | | | - Beatriz Soriano
- Biotechvana, Parc Científic Universitat de València Paterna Valencia Spain
| | - Stefan Stojanoski
- Faculty of Medicine University of Novi Sad Novi Sad Serbia
- Centre for Imaging Diagnostics Oncology Insitute of Vojvodina Sremska Kamenica Serbia
| | | | - Maria Halabalaki
- Division of Pharmacognosy and Natural Products Chemistry Department of Pharmacy National and Kapodistrian University of Athens Athens Greece
| | - Eleni V. Mikropoulou
- Division of Pharmacognosy and Natural Products Chemistry Department of Pharmacy National and Kapodistrian University of Athens Athens Greece
| | - Aimo Kannt
- Sanofi Research and Development Industriepark Hoechst Frankfurt 65926 Germany
- Institute of Clinical Pharmacology Goethe University Frankfurt Frankfurt 60590 Germany
- Fraunhofer Institute for Translational Medicine and Pharmacology ITMP Frankfurt 60596 Germany
| | - John Lamont
- Randox Laboratories Limited, Crumlin, Co. Antrim Northern Ireland UK
| | - Carlos Llorens
- Biotechvana, Parc Científic Universitat de València Paterna Valencia Spain
| | | | | | - Francisco J. Roig
- Biotechvana, Parc Científic Universitat de València Paterna Valencia Spain
- Facultad de Ciencias de la Salud Universidad San Jorge Zaragoza 50830 Spain
| | | | - Iraklis Varlamis
- Department of Informatics and Telematics Harokopio University Athens Greece
| | | | - Milan Vukic
- Department of Food Technology, Faculty of Technology Zvornik University of East Sarajevo Zvornik 75400 Bosnia and Herzegovina
| | - Natasa Milic
- Faculty of Medicine University of Novi Sad Novi Sad Serbia
| | - Milica Medic‐Stojanoska
- Faculty of Medicine University of Novi Sad Novi Sad Serbia
- Clinic for Endocrinology, Diabetes and Metabolic Diseases Clinical Centre of Vojvodina Novi Sad Serbia
| | - Lucia Cesarini
- Division of Hepatology and Gastroenterology Niguarda Ca' Grande Hospital Milan Italy
| | | | - Amalia Gastaldelli
- Cardiometabolic Risk Unit Institute of Clinical Physiology, CNR Pisa Italy
| | - Panos Deloukas
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry Queen Mary University of London London EC1M 6BQ UK
- Centre for Genomic Health, Life Sciences Queen Mary University of London London UK
| | - Maria Giovanna Trivella
- Institute of Clinical Physiology CNR Milan Italy
- Cardiometabolic Risk Unit Institute of Clinical Physiology, CNR Pisa Italy
| | - M. Pilar Francino
- CIBER en Epidemiología y Salud Pública Av. Monforte de Lemos 3–5 Madrid 28029 Spain
- Joint Research Unit in Genomics and Health Fundació per al Foment de la Investigació Sanitària i Biomèdica de la Comunitat Valenciana (FISABIO) and Institut de Biologia Integrativa de Sistemes (Universitat de València / Consejo Superior de Investigaciones Científicas) Avda. Catalunya 21 València 46020 Spain
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education Harokopio University Athens Greece
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Chrysavgis L, Papatheodoridi AM, Chatzigeorgiou A, Cholongitas E. The impact of sodium glucose co-transporter 2 inhibitors on non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2021; 36:893-909. [PMID: 33439540 DOI: 10.1111/jgh.15202] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/29/2020] [Accepted: 07/23/2020] [Indexed: 12/13/2022]
Abstract
Affecting one fourth of the global population, non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disorder. It encompasses the simple liver fat accumulation to more progressive steatosis, inflammation, and fibrosis characterized as non-alcoholic steatohepatitis (NASH) and in some cases cirrhosis and hepatocellular carcinoma. NAFLD regularly coexists with metabolic disorders, such as obesity and mostly type 2 diabetes mellitus (T2DM). A relatively new class of antidiabetic drugs, the sodium glucose co-transporter 2 (SGLT2) inhibitors exert their action by increasing the urinary glucose and calorie excretion leading to ameliorated plasma glucose levels and lower bodyweight. Recently, several animal studies and human clinical trial have emphasized the possible beneficial impact of SGLT2 inhibitors on NAFLD and its progression to NASH. In this present review, we summarize the current literature regarding the efficacy of the aforementioned category of drugs on anthropometric, laboratory, and histological features of patients with NAFLD. Conclusively, as SGLT2 inhibitors seem to be an appealing therapeutic opportunity for NAFLD management, we identify the open issues and questions to be addressed in order to clarify the impact in choosing antidiabetic medication to treat NAFLD patients associated with T2DM.
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Affiliation(s)
- Lampros Chrysavgis
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
| | | | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School of National and Kapodistrian University of Athens, Athens, Greece
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany
| | - Evangelos Cholongitas
- First Department of Internal Medicine, Medical School of National and Kapodistrian University, General Hospital of Athens "Laiko", Athens, Greece
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28
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Mouskeftara T, Goulas A, Ioannidou D, Ntenti C, Agapakis D, Assimopoulou A, Gika H. A Study of Blood Fatty Acids Profile in Hyperlipidemic and Normolipidemic Subjects in Association with Common PNPLA3 and ABCB1 Polymorphisms. Metabolites 2021; 11:metabo11020090. [PMID: 33557317 PMCID: PMC7915980 DOI: 10.3390/metabo11020090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 01/28/2021] [Accepted: 01/29/2021] [Indexed: 01/06/2023] Open
Abstract
Adiponutrin (patatin-like phospholipase domain-containing 3; PNPLA3), encoded in humans by the PNPLA3 gene, is a protein associated with lipid droplet and endoplasmic reticulum membranes, where it is apparently involved in fatty acid redistribution between triglycerides and phospholipids. A common polymorphism of PNPLA3 (I148M, rs738409), linked to increased PNPLA3 presence on lipid droplets, is a strong genetic determinant of non-alcoholic fatty liver disease (NAFLD) and of its progression. P-glycoprotein (Pgp, MDR1—multidrug resistance protein 1, ABCB1—ATP-binding cassette sub-family B member 1), encoded by the ABCB1 gene, is another membrane protein implicated in lipid homeostasis and steatosis. In the past, common ABCB1 polymorphisms have been associated with the distribution of serum lipids but not with fatty acids (FA) profiles. Similarly, data on the effect of PNPLA3 I148M polymorphism on blood FAs are scarce. In this study, a gas chromatography-flame ionization detection (GC-FID) method was optimized, allowing us to analyze twenty FAs (C14: 0, C15: 0, C15: 1, C16: 0, C16: 1, C17: 0, C17: 1, C18: 0, C18: 1cis, C18: 2cis, C20: 0, C20: 1n9, C20: 2, C20: 3n6, C20: 4n6, C20: 5, C23: 0, C24: 0, C24: 1 and C22: 6) in whole blood, based on the indirect determination of the fatty acids methyl esters (FAMES), in 62 hyperlipidemic patients and 42 normolipidemic controls. FA concentrations were then compared between the different genotypes of the rs738409 and rs2032582 (ABCB1 G2677T) polymorphisms, within and between the hyperlipidemic and normolipidemic groups. The rs738409 polymorphism appears to exert a significant effect on the distribution of blood fatty acids, in a lipidemic and fatty acid saturation state-depending manner. The effect of rs2032582 was less pronounced, but the polymorphism did appear to affect the relative distribution of blood fatty acids between hyperlipidemic patients and normolipidemic controls.
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Affiliation(s)
- Thomai Mouskeftara
- Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Biomic AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), 57001 Thessaloniki, Greece
| | - Antonis Goulas
- Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.G.); (D.I.); (C.N.)
| | - Despoina Ioannidou
- Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.G.); (D.I.); (C.N.)
| | - Charikleia Ntenti
- Laboratory of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece; (A.G.); (D.I.); (C.N.)
| | - Dimitris Agapakis
- Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
| | - Andreana Assimopoulou
- Natural Products Research Center of Excellence (NatPro-AUTH), Center for Interdisciplinary Research and Innovation (CIRI-AUTH), 57001 Thessaloniki, Greece;
- Laboratory of Organic Chemistry, School of Chemical Engineering, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Helen Gika
- Laboratory of Forensic Medicine and Toxicology, School of Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece;
- Biomic AUTh, Center for Interdisciplinary Research and Innovation (CIRI-AUTH), 57001 Thessaloniki, Greece
- Correspondence:
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29
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Reply. Clin Gastroenterol Hepatol 2021; 19:413-414. [PMID: 33248097 DOI: 10.1016/j.cgh.2020.04.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
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30
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Luukkonen PK, Qadri S, Lehtimäki TE, Juuti A, Sammalkorpi H, Penttilä AK, Hakkarainen A, Orho-Melander M, Arola J, Yki-Järvinen H. The PNPLA3-I148M Variant Confers an Antiatherogenic Lipid Profile in Insulin-resistant Patients. J Clin Endocrinol Metab 2021; 106:e300-e315. [PMID: 33064150 DOI: 10.1210/clinem/dgaa729] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/14/2020] [Indexed: 02/08/2023]
Abstract
CONTEXT The I148M (rs738409-G) variant in PNPLA3 increases liver fat content but may be protective against cardiovascular disease. Insulin resistance (IR) amplifies the effect of PNPLA3-I148M on liver fat. OBJECTIVE To study whether PNPLA3-I148M confers an antihyperlipidemic effect in insulin-resistant patients. DESIGN Cross-sectional study comparing the impact of PNPLA3-I148M on plasma lipids and lipoproteins in 2 cohorts, both divided into groups based on rs738409-G allele carrier status and median HOMA-IR. SETTING Tertiary referral center. PATIENTS A total of 298 obese patients who underwent a liver biopsy during bariatric surgery (bariatric cohort: age 49 ± 9 years, body mass index [BMI] 43.2 ± 6.8 kg/m2), and 345 less obese volunteers in whom liver fat was measured by proton magnetic resonance spectroscopy (nonbariatric cohort: age 45 ± 14 years, BMI 29.7 ± 5.7 kg/m2). MAIN OUTCOME MEASURES Nuclear magnetic resonance profiling of plasma lipids, lipoprotein particle subclasses and their composition. RESULTS In both cohorts, individuals carrying the PNPLA3-I148M variant had significantly higher liver fat content than noncarriers. In insulin-resistant and homozygous carriers, PNPLA3-I148M exerted a distinct antihyperlipidemic effect with decreased very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL) particles and their constituents, and increased high-density lipoprotein particles and their constituents, compared with noncarriers. VLDL particles were smaller and LDL particles larger in PNPLA3-I148M carriers. These changes were geometrically opposite to those due to IR. PNPLA3-I148M did not have a measurable effect in patients with lower IR, and its effect was smaller albeit still significant in the less obese than in the obese cohort. CONCLUSIONS PNPLA3-I148M confers an antiatherogenic plasma lipid profile particularly in insulin-resistant individuals.
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Affiliation(s)
- Panu K Luukkonen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
- Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut
| | - Sami Qadri
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Tiina E Lehtimäki
- HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
| | - Anne Juuti
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Henna Sammalkorpi
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Anne K Penttilä
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Antti Hakkarainen
- HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
| | | | - Johanna Arola
- Department of Pathology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
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31
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Ramos LF, Silva CM, Pansa CC, Moraes KCM. Non-alcoholic fatty liver disease: molecular and cellular interplays of the lipid metabolism in a steatotic liver. Expert Rev Gastroenterol Hepatol 2021; 15:25-40. [PMID: 32892668 DOI: 10.1080/17474124.2020.1820321] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Non-alcoholic fatty liver disease (NAFLD) affects ~25% of world population and cases have increased in recent decades. These anomalies have several etiologies; however, obesity and metabolic dysfunctions are the most relevant causes. Despite being considered a public health problem, no effective therapeutic approach to treat NAFLD is available. For that, a deep understanding of metabolic routes that support hepatic diseases is needed. AREAS COVERED This review covers aspects of the onset of NAFLD. Thereby, biochemistry routes as well as cellular and metabolic effects of the gut microbiota in body's homeostasis and epigenetics are contextualized. EXPERT OPINION Recently, the development of biological sciences has generated innovative knowledge, bringing new insights and perspectives to clarify the systems biology of liver diseases. A detailed comprehension of epigenetics mechanisms will offer possibilities to develop new therapeutic and diagnostic strategies for NAFLD. Different epigenetic processes have been reported that are modulated by the environment such as gut microbiota, suggesting strong interplays between cellular behavior and pathology. Thus, a more complete description of such mechanisms in hepatic diseases will help to clarify how to control the establishment of fatty liver, and precisely describe molecular interplays that potentially control NAFLD.
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Affiliation(s)
- Letícia F Ramos
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Caio M Silva
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Camila C Pansa
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
| | - Karen C M Moraes
- Molecular Biology Laboratory, Departamento de Biologia Geral e Aplicada, Universidade Estadual Paulista "Júlio de Mesquita Filho" - Campus Rio Claro, Instituto de Biociências , Rio Claro, Brazil
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Surlin P, Didilescu AC, Lazar L, Arsenie CC, Camen A, Popescu DM, Gheorghe DN, Osiac E, Rogoveanu I. Evaluation Through the Optical Coherence Tomography Analysis of the Influence of Non-Alcoholic Fatty Liver Disease on the Gingival Inflammation in Periodontal Patients. Diabetes Metab Syndr Obes 2021; 14:2935-2942. [PMID: 34234491 PMCID: PMC8254560 DOI: 10.2147/dmso.s310314] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 05/13/2021] [Indexed: 01/23/2023] Open
Abstract
PURPOSE The purpose of this ex vivo study is to exhibit the inflammatory changes that occur within the gingival tissue by using optical coherence tomography (OCT) in periodontal patients with non-alcoholic fatty liver disease (NAFLD) and if NAFLD could influence the local periodontal inflammation. PATIENTS AND METHODS Gingival tissue samples obtained from patients were divided into three groups - P (periodontitis), NAFLD+P (NAFLD+periodontitis) and H (healthy) groups - and were scanned using an OCT light beam, in order to perform a qualitative and quantitative analysis of images. The value of average pixel density has been associated with the degree of inflammation. RESULTS The highest average pixel density was found in patients from the H group, while the lowest value of average pixel density was recorded in gingival tissue samples collected from patients with NAFLD+P. The image assessments from NAFLD+P group delivered lower values of average pixel density than those of P group, suggesting a possible influence of this disease on the inflammatory tissular changes produced by periodontal disease. CONCLUSION After comparing the OCT analysis results obtained for the three groups of patients, we can consider that NAFLD may be an aggravating factor for the inflammation of periodontal disease.
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Affiliation(s)
- Petra Surlin
- Department of Periodontology, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Andreea Cristiana Didilescu
- Department of Embryology, Faculty of Dental Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania
| | - Luminita Lazar
- George Emil Palade University of Medicine, Pharmacy, Science and Technology of Târgu Mureş, Targu-Mures, Romania
| | - Cristian Cosmin Arsenie
- Doctoral School, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- Correspondence: Cristian Cosmin Arsenie Doctoral School, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş St., Craiova, 200349, RomaniaTel +40 351 443 557 Email
| | - Adrian Camen
- Department of Oral Surgery, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Dora Maria Popescu
- Department of Periodontology, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
- Dora Maria Popescu Department of Periodontology, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, 2 Petru Rareş St., Craiova, 200349, RomaniaTel +40 351 443 557 Email
| | - Dorin Nicolae Gheorghe
- Department of Periodontology, Faculty of Dental Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Eugen Osiac
- Department of Biophysics, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - Ion Rogoveanu
- Department of Gastroenterology, Faculty of Medicine, University of Medicine and Pharmacy of Craiova, Craiova, Romania
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Wang J, Zheng J, Ren X, Wang S, Wang G, Hu B, Yang H, Liu H. Integrative analysis of hepatic metabolomic and transcriptomic data reveals potential mechanism of nonalcoholic steatohepatitis in high-fat diet-fed mice. J Diabetes 2020; 13:390-401. [PMID: 33022884 DOI: 10.1111/1753-0407.13120] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 09/30/2020] [Accepted: 10/04/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Due to the complex pathogenesis, the molecular mechanism of nonalcoholic steatohepatitis (NASH) remains unclear. In this study, we aimed to reveal the comprehensive metabolic and signaling pathways in the occurrence of NASH. METHODS C57BL/6 mice were treated with high-fat diet for 4 months to mimic the NASH phenotype. After the treatment, the physiochemical parameters were evaluated, and the liver tissues were prepared for untargeted metabolomic analysis with ultraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Then, three relevant Gene Expression Omnibus (GEO) datasets were selected for integrative analysis of differentiated messenger RNA and metabolites. RESULTS The levels of phosphatidylethanolamine (PE) (16:1(9Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, and sphingomyelin (SM) (d18:0/12:0) were significantly increased, and the content of adenosine was severely reduced in NASH mice. The integrated interpretation of transcriptomic and metabolomic data indicated that the glycerophospholipid metabolism and necroptosis signaling were evidently affected in the development of NASH. The high level of SM (d18:0/12:0) may be related to the expression of acid sphingomyelinase (ASMase), and the elevated arachidonic acid was coordinated with the upregulation of cytosol phospholipase A2 (cPLA2) in the necroptosis pathway. CONCLUSIONS In summary, the inflammatory response, necroptosis, and glycerophospholipid may serve as potential targets for mechanistic exploration and clinical practice in the treatment of NASH.
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Affiliation(s)
- Jinhua Wang
- Jiangsu Province Blood Center, Nanjing, China
| | - Junping Zheng
- College of Life Sciences, Wuchang University of Technology, Wuhan, China
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Xianghui Ren
- North China Institute of Computer Technology, Beijing, China
| | - Shaojiang Wang
- North China Institute of Computer Technology, Beijing, China
- Knowledge Engineering Lab, Department of Computer Science and Technology, Tsinghua University, Beijing, China
| | - Guizhou Wang
- School of Economics and Management, University of Chinese Academy of Sciences, Beijing, China
| | - Baifei Hu
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Huabing Yang
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
| | - Hongtao Liu
- College of Life Sciences, Wuchang University of Technology, Wuhan, China
- School of Basic Medical Sciences, Hubei University of Chinese Medicine, Wuhan, China
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Koo BK, Joo SK, Kim D, Lee S, Bae JM, Park JH, Kim JH, Chang MS, Kim W. Development and Validation of a Scoring System, Based on Genetic and Clinical Factors, to Determine Risk of Steatohepatitis in Asian Patients with Nonalcoholic Fatty Liver Disease. Clin Gastroenterol Hepatol 2020; 18:2592-2599.e10. [PMID: 32062042 DOI: 10.1016/j.cgh.2020.02.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 01/28/2020] [Accepted: 02/07/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There are no biomarkers of nonalcoholic steatohepatitis (NASH) that are ready for routine clinical use. We investigated whether an analysis of PNPLA3 and TM6SF2 genotypes (rs738409 and rs58542926) can be used to identify patients with nonalcoholic fatty liver disease (NAFLD), with and without diabetes, who also have NASH. METHODS We collected data from the Boramae registry in Korea on 453 patients with biopsy-proven NAFLD with sufficient clinical data for calculating scores. Patients enrolled from February 2014 through March 2016 were assigned to cohort 1 (n = 302; discovery cohort) and patients enrolled thereafter were assigned to cohort 2 (n = 151; validation cohort). DNA samples were obtained from all participants and analyzed for the PNPLA3 rs738409 C>G, TM6SF2 rs58542926 C>T, SREBF2 rs133291 C>T, MBOAT7-TMC4 rs641738 C>T, and HSD17B13 rs72613567 adenine insertion (A-INS) polymorphisms. We used multivariable logistic regression analyses with stepwise backward selection to build a model to determine patients' risk for NASH (NASH PT) using the genotype and clinical data from cohort 1 and tested its accuracy in cohort 2. We used the receiver operating characteristic (ROC) curve to compare the diagnostic performances of the NASH PT and the NASH scoring systems. RESULTS We developed a NASH PT scoring system based on PNPLA3 and TM6SF2 genotypes, diabetes status, insulin resistance, and levels of aspartate aminotransferase and high-sensitivity C-reactive protein. NASH PT scores identified patients with NASH with an area under the ROC (AUROC) of 0.859 (95% CI, 0.817-0.901) in cohort 1. In cohort 2, NASH PT scores identified patients with NASH with an AUROC of 0.787 (95% CI, 0.715-0.860), which was significantly higher than the AUROC of the NASH score (AUROC, 0.729; 95% CI, 0.647-0.812; P = .007). The AUROC of the NASH PT score for detecting NASH in patients with NAFLD with diabetes was 0.835 (95% CI, 0.776-0.895) and in patients without diabetes was 0.809 (95% CI, 0.757-0.861). The negative predictive value of the NASH PT score <-0.785 for NASH in patients with NAFLD with diabetes reached 0.905. CONCLUSIONS We developed a scoring system, based on polymorphisms in PNPLA3 and TM6SF2 and clinical factors that identifies patients with NAFLD, with or without diabetes, who have NASH, with an AUROC value of 0.787. This system might help clinicians better identify NAFLD patients at risk for NASH.
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Affiliation(s)
- Bo Kyung Koo
- Division of Endocrinology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Sae Kyung Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, California
| | - Seonhwa Lee
- Department of Bio-convergence Engineering, Korea University, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Jeong Hwan Park
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Jung Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Mee Soo Chang
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Won Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea.
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Rosato V, Masarone M, Aglitti A, Persico M. The diagnostic conundrum in non-alcoholic fatty liver disease. EXPLORATION OF MEDICINE 2020. [DOI: 10.37349/emed.2020.00018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver alteration worldwide. It encompasses a spectrum of disorders that range from simple steatosis to a progressive form, defined non-alcoholic steatohepatitis (NASH), that can lead to advanced fibrosis and eventually cirrhosis and hepatocellular carcinoma. On liver histology, NASH is characterized by the concomitant presence of significant fat accumulation and inflammatory reaction with hepatocellular injury. Until now, liver biopsy is still required to differentiate simple steatosis from NASH and evaluate the degree of liver fibrosis. Unfortunately, this technique has well-known limitations, including invasiveness and expensiveness. Moreover, it may be biased by sampling error and intra- or inter-observed variability. Furthermore, due to the increasing prevalence of NAFLD worldwide, to program a systematic screening with liver biopsy is not imaginable. In recent years, different techniques were developed and validated with the aim of non-invasively identifying NASH and assess liver fibrosis degrees. The non-invasive tests range from simple blood-tests analyses to composite scores and complex imaging techniques. Nevertheless, even if they could represent cost-effective strategies for diagnosing NASH, advanced fibrosis and cirrhosis, their accuracy and consequent usefulness are to be discussed. With this aim, in this review the authors summarize the current state of non-invasive assessment of NAFLD. In particular, in addition to the well-established tests, the authors describe the future perspectives in this field, reporting the latest tests based on OMICS, gut-miocrobioma and micro-RNAs. Finally, the authors provide an accurate assessment of how these non-invasive tools perform in clinical practice depending on the clinical context, with the aim of giving the clinicians a useful tool to try to resolve the diagnostic conundrum of NAFLD.
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Affiliation(s)
- Valerio Rosato
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Mario Masarone
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Andrea Aglitti
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
| | - Marcello Persico
- Internal Medicine and Hepatology Unit, Department of Medicine, Surgery and Odontostomatology “Scuola Medica Salernitana”- University of Salerno, Street Salvador Allende, 43, Fisciano, 84084 Campania, Italy
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A composite biomarker using multiparametric magnetic resonance imaging and blood analytes accurately identifies patients with non-alcoholic steatohepatitis and significant fibrosis. Sci Rep 2020; 10:15308. [PMID: 32943694 PMCID: PMC7499258 DOI: 10.1038/s41598-020-71995-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Accepted: 08/21/2020] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is major health burden lacking effective pharmacological therapies. Clinical trials enrol patients with histologically-defined NAFLD (non-alcoholic fatty liver disease) activity score (NAS) ≥ 4 and Kleiner-Brunt fibrosis stage (F) ≥ 2; however, screen failure rates are often high following biopsy. This study evaluated a non-invasive MRI biomarker, iron-corrected T1 mapping (cT1), as a diagnostic pre-screening biomarker for NASH. In a retrospective analysis of 86 biopsy confirmed NAFLD patients we explored the potential of blood and imaging biomarkers, both in isolation and in combination, to discriminate those who have NAS ≥ 4 and F ≥ 2 from those without. Stepwise logistic regression was performed to select the optimal combination of biomarkers, diagnostic accuracy was determined using area under the receiver operator curve and model validated confirmed with and fivefold cross-validation. Results showed that levels of cT1, AST, GGT and fasting glucose were all good predictors of NAS ≥ 4 and F ≥ 2, and the model identified the combination of cT1-AST-fasting glucose (cTAG) as far superior to any individual biomarker (AUC 0.90 [0.84–0.97]). This highlights the potential utility of the composite cTAG score for screening patients prior to biopsy to identify those suitable for NASH clinical trial enrolment.
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Qadri S, Lallukka-Brück S, Luukkonen PK, Zhou Y, Gastaldelli A, Orho-Melander M, Sammalkorpi H, Juuti A, Penttilä AK, Perttilä J, Hakkarainen A, Lehtimäki TE, Orešič M, Hyötyläinen T, Hodson L, Olkkonen VM, Yki-Järvinen H. The PNPLA3-I148M variant increases polyunsaturated triglycerides in human adipose tissue. Liver Int 2020; 40:2128-2138. [PMID: 32386450 DOI: 10.1111/liv.14507] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 04/23/2020] [Accepted: 05/02/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS The I148M variant in PNPLA3 is the major genetic risk factor for non-alcoholic fatty liver disease (NAFLD). The liver is enriched with polyunsaturated triglycerides (PUFA-TGs) in PNPLA3-I148M carriers. Gene expression data indicate that PNPLA3 is liver-specific in humans, but whether it functions in adipose tissue (AT) is unknown. We investigated whether PNPLA3-I148M modifies AT metabolism in human NAFLD. METHODS Profiling of the AT lipidome and fasting serum non-esterified fatty acid (NEFA) composition was conducted in 125 volunteers (PNPLA3148MM/MI , n = 63; PNPLA3148II , n = 62). AT fatty acid composition was determined in 50 volunteers homozygous for the variant (PNPLA3148MM , n = 25) or lacking the variant (PNPLA3148II , n = 25). Whole-body insulin sensitivity of lipolysis was determined using [2 H5 ]glycerol, and PNPLA3 mRNA and protein levels were measured in subcutaneous AT and liver biopsies in a subset of the volunteers. RESULTS PUFA-TGs were significantly increased in AT in carriers versus non-carriers of PNPLA3-I148M. The variant did not alter the rate of lipolysis or the composition of fasting serum NEFAs. PNPLA3 mRNA was 33-fold higher in the liver than in AT (P < .0001). In contrast, PNPLA3 protein levels per tissue protein were three-fold higher in AT than the liver (P < .0001) and nine-fold higher when related to whole-body AT and liver tissue masses (P < .0001). CONCLUSIONS Contrary to previous assumptions, PNPLA3 is highly abundant in AT. PNPLA3-I148M locally remodels AT TGs to become polyunsaturated as it does in the liver, without affecting lipolysis or composition of serum NEFAs. Changes in AT metabolism do not contribute to NAFLD in PNPLA3-I148M carriers.
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Affiliation(s)
- Sami Qadri
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Susanna Lallukka-Brück
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Panu K Luukkonen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - You Zhou
- Minerva Foundation Institute for Medical Research, Helsinki, Finland.,Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | | | - Henna Sammalkorpi
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Anne Juuti
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Anne K Penttilä
- Department of Gastrointestinal Surgery, Abdominal Center, Helsinki University Hospital, Helsinki, Finland
| | - Julia Perttilä
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Antti Hakkarainen
- HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
| | - Tiina E Lehtimäki
- HUS Medical Imaging Center, Helsinki University Hospital, Helsinki, Finland
| | - Matej Orešič
- Department of Chemistry, Örebro University, Örebro, Sweden
| | | | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.,National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
| | - Vesa M Olkkonen
- Minerva Foundation Institute for Medical Research, Helsinki, Finland
| | - Hannele Yki-Järvinen
- Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland
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Paul J. Recent advances in non-invasive diagnosis and medical management of non-alcoholic fatty liver disease in adult. EGYPTIAN LIVER JOURNAL 2020. [DOI: 10.1186/s43066-020-00043-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Abstract
Background
Number of non-alcoholic fatty liver disease (NAFLD) cases is increasing over time due to alteration of food habit, increase incidence of metabolic syndrome, and lack of exercise. Liver biopsy is the test for diagnosis and staging of NAFLD, but nowadays several biochemical markers, scoring systems, and imaging studies are available to diagnose and stage NAFLD which is linked to end-stage liver disease, hepatocellular cancer, and elevated cardiovascular- and cancer-related morbidity and mortality. Therefore urgent diagnosis and management are required to avoid complications related to NAFLD. This review summarizes recent advances in diagnosis and medical management of non-alcoholic fatty liver disease.
Main text
Recently published studies from PubMed, Red Cross, Copernicus, and also various previous studies were reviewed. We have discussed various non-invasive methods for detection of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis (NASH), and hepatic fibrosis. Non pharmacological therapies for NAFLD, indications, and approved medications for NAFLD and other commonly used non-approved medications have been discussed in this review article.
Conclusions
Multiple non-invasive tests are available for diagnosis of NAFLD, and its different stages however gold standard test is liver biopsy. NALFD without NASH and significant fibrosis is treated by lifestyle modifications which include moderate to vigorous exercise and diet modification. To improve hepatic steatosis, minimum of 3–5% of body weight loss is necessary, but > 7–10% weight reductions is required for histological improvement in NASH and fibrosis. Pharmacotherapy is indicated when patient is having NASH with significant fibrosis.
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Validation of a Non-Laboratory Based Screening Tool for Predicting Non-Alcoholic Fatty Liver Disease in an Egyptian Setting. Am J Med Sci 2020; 360:662-677. [PMID: 32739036 DOI: 10.1016/j.amjms.2020.06.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 05/02/2020] [Accepted: 06/18/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disorder in more than 20% of the general population worldwide. Several combinations of non-invasive factors and scoring models were investigated as indicators of NAFLD. This study aimed to validate and adapt an established fatty liver score, which allows the identification of NAFLD based on routinely available clinical and laboratory data. MATERIALS AND METHODS The study cohort comprised 190 adults seeking health check-up at the out-patient clinic of a tertiary care hospital in Alexandria, Egypt. Anthropometric, clinical, and laboratory data were recorded and the status of fatty liver was diagnosed by abdominal ultrasound. A logistic regression model was built to determine the predictors of NAFLD. The performance of the derived risk scores was compared to other existing models. RESULTS Obesity (60.0%), metabolic syndrome (42.6%), and NAFLD (56.8%) were predominant features among the study population. Smoking [OR (95% CI) = 4.4 (0.9-21.4)], obesity [OR (95% CI) = 4.0 (1.7-9.7)], hypertension [OR (95% CI) = 2.4 (1.03-5.5)], elevated serum total cholesterol [OR (95% CI) = 4.8 (1.8-13.1)], triglycerides [OR (95% CI) = 11.8 (2.3-661.02)], and ALT [OR (95% CI) = 4.8 (1.8-13.1)] were multivariate predictors of NAFLD. A NAFLD screening questionnaire with values applicable for Egyptians was adapted from an existing model after validation. A total score ≥7 was suggestive of NAFLD [AUC = 0.810 (0.749-0.871); sensitivity = 87.0%; specificity = 62.2%; PPV = 75.2%; NPV = 78.5%]. CONCLUSIONS NAFLD can be sufficiently predicted among apparently healthy Egyptians by a tempted simple and non-invasive scoring index although external validation is warranted.
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Gerhardt F, Petroff D, Blank V, Böhlig A, van Bömmel F, Wittekind C, Berg T, Karlas T, Wiegand J. Biopsy rate and nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD). Scand J Gastroenterol 2020; 55:706-711. [PMID: 32476514 DOI: 10.1080/00365521.2020.1766554] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background: Licensed therapies for nonalcoholic fatty liver disease (NAFLD) do not yet exist, but clinical trials are testing treatment options. Inclusion criteria often require liver biopsy showing fibrosis (F2/3) or cirrhosis (F4) and nonalcoholic steatohepatitis (NASH). However, histological criteria pose a serious obstacle for recruitment.Aims: Characterize the relevance of liver biopsies in the selection of patients with NAFLD.Methods: Patients between 2013 and 2018 with the ICD-10 code K76.0 were analyzed. Fibrosis was defined by the NASH clinical research network (CRN) fibrosis staging system, NASH by a NAFLD activity score (NAS) ≥4. Predictive factors were determined by logistic regression.Results: Liver biopsy was performed in 87/638 (13.6%) patients (49% female, age 52.5 ± 14.0, BMI 30.4 ± 5.9 kg/m2). Fibrosis stage F0/F1/F2/F3/F4 was observed in N = 7/47/7/17/9, an NAS ≥4 in N = 27. Fibrosis stage F2/F3 and F4 along with NAS ≥4 was found in 1.7% and 0.5% of cases. Liver stiffness measurement, LSM (OR 2.3 per doubling of value; CI 1.3-4.4, p = .005) and FIB-4 (OR 2.3 per doubling of value; CI 1.2-4.4, p = .012) were significant predictors for fibrosis ≥ F2. Predictive factors for NASH were not identified.Conclusion: The biopsy rate in NAFLD patients is low and fibrosis ≥ F2 along with NAS ≥4 only present in a few cases. Transient elastography and FIB-4 are useful to select patients at risk for fibrosis for liver biopsy.
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Affiliation(s)
- Florian Gerhardt
- Clinic and Polyclinic of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany
| | - David Petroff
- Clinical Trial Center Leipzig, University of Leipzig, Leipzig, Germany
| | - Valentin Blank
- Clinic and Polyclinic of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany.,Integrated Research and Treatment Center Adiposity Diseases, University of Leipzig, Leipzig, Germany
| | - Albrecht Böhlig
- Clinic and Polyclinic of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany
| | - Florian van Bömmel
- Clinic and Polyclinic of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany
| | | | - Thomas Berg
- Clinic and Polyclinic of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Karlas
- Clinic and Polyclinic of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany
| | - Johannes Wiegand
- Clinic and Polyclinic of Oncology, Gastroenterology, Hepatology, Pneumology and Infectious Diseases, University Hospital Leipzig, Leipzig, Germany
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Lee BW, Lee YH, Park CY, Rhee EJ, Lee WY, Kim NH, Choi KM, Park KG, Choi YK, Cha BS, Lee DH. Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus: A Position Statement of the Fatty Liver Research Group of the Korean Diabetes Association. Diabetes Metab J 2020; 44:382-401. [PMID: 32431115 PMCID: PMC7332334 DOI: 10.4093/dmj.2020.0010] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Accepted: 02/24/2020] [Indexed: 12/14/2022] Open
Abstract
This clinical practice position statement, a product of the Fatty Liver Research Group of the Korean Diabetes Association, proposes recommendations for the diagnosis, progression and/or severity assessment, management, and follow-up of non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus (T2DM). Patients with both T2DM and NAFLD have an increased risk of non-alcoholic steatohepatitis (NASH) and fibrosis and a higher risk of cardiovascular diseases and diabetic complications compared to those without NAFLD. With regards to the evaluation of patients with T2DM and NAFLD, ultrasonography-based stepwise approaches using noninvasive biomarker models such as fibrosis-4 or the NAFLD fibrosis score as well as imaging studies such as vibration-controlled transient elastography with controlled attenuation parameter or magnetic resonance imaging-proton density fat fraction are recommended. After the diagnosis of NAFLD, the stage of fibrosis needs to be assessed appropriately. For management, weight reduction achieved by lifestyle modification has proven beneficial and is recommended in combination with antidiabetic agent(s). Evidence that some antidiabetic agents improve NAFLD/NASH with fibrosis in patients with T2DM is emerging. However, there are currently no definite pharmacologic treatments for NAFLD in patients with T2DM. For specific cases, bariatric surgery may be an option if indicated.
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Affiliation(s)
- Byung Wan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Cheol Young Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eun Jung Rhee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Won Young Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Nan Hee Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Keun Gyu Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yeon Kyung Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Bong Soo Cha
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea.
| | - Dae Ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea.
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42
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Åberg F, Puukka P, Salomaa V, Männistö S, Lundqvist A, Valsta L, Perola M, Färkkilä M, Jula A. Risks of Light and Moderate Alcohol Use in Fatty Liver Disease: Follow-Up of Population Cohorts. Hepatology 2020; 71:835-848. [PMID: 31323122 DOI: 10.1002/hep.30864] [Citation(s) in RCA: 113] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 07/09/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The effects of alcohol use in nonalcoholic fatty liver disease are unclear. We investigated the impact of alcohol use in fatty liver disease on incident liver, cardiovascular, and malignant disease, as well as death. APPROACH AND RESULTS Our study comprised 8,345 persons with hepatic steatosis (fatty liver index >60) who participated in health-examination surveys (FINRISK 1992-2012 or Health 2000), with available data on baseline alcohol intake. Main exclusions were baseline clinical liver disease, viral hepatitis, ethanol intake >50 g/day, and current abstainers. Data were linked with national registers for hospital admissions, malignancies, and death regarding liver, cardiovascular, and malignant disease, as well as all-cause death. Adjustment were for multiple confounders. Alcohol consumption showed a dose-dependent risk increase for incident advanced liver disease and malignancies. Consuming 10-19 g/day of alcohol in general or 0-9 g/day as nonwine beverages doubled the risk for advanced liver disease compared to lifetime abstainers. In contrast, alcohol intake up to 49 g/day was associated with a 22%-40% reduction of incident cardiovascular disease (CVD). We observed a J-shaped association between alcohol intake and all-cause death with a maximal risk reduction of 21% (95% confidence interval, 5%-34%) at alcohol intake of 0-9 g/day compared to lifetime abstainers. However, these benefits on CVD and mortality were only observed in never smokers. Alcohol intake >30 g/day yielded increased risk estimates for mortality compared to lifetime abstainers. In a subpopulation with longitudinal data, alcohol intake remained stable over time in >80% of subjects. CONCLUSIONS Even low alcohol intake in fatty liver disease is associated with increased risks for advanced liver disease and cancer. Low to moderate alcohol use is associated with reduced mortality and CVD risk but only among never smokers.
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Affiliation(s)
- Fredrik Åberg
- Transplantation and Liver Surgery Clinic, Helsinki University Hospital, Helsinki University, Helsinki, Finland.,The Transplant Institute, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Pauli Puukka
- National Institute for Health and Welfare, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Veikko Salomaa
- National Institute for Health and Welfare, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Satu Männistö
- National Institute for Health and Welfare, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Annamari Lundqvist
- National Institute for Health and Welfare, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Liisa Valsta
- National Institute for Health and Welfare, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Markus Perola
- National Institute for Health and Welfare, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Martti Färkkilä
- Clinic of Gastroenterology, Helsinki University and Helsinki University Hospital, Helsinki, Finland
| | - Antti Jula
- National Institute for Health and Welfare, Helsinki University and Helsinki University Hospital, Helsinki, Finland
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Romeo S, Sanyal A, Valenti L. Leveraging Human Genetics to Identify Potential New Treatments for Fatty Liver Disease. Cell Metab 2020; 31:35-45. [PMID: 31914377 DOI: 10.1016/j.cmet.2019.12.002] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 10/07/2019] [Accepted: 12/06/2019] [Indexed: 02/08/2023]
Abstract
Fatty liver disease (FLD), including its more severe pathologies, namely steatohepatitis, hepatocarcinoma, and cirrhosis, is the most common cause of chronic liver disease worldwide and is projected to become the leading cause of hepatocellular carcinoma and end-stage liver disease. FLD is heterogeneous with multiple etiologies and diverse histological phenotypes, so therapies will ultimately need to be individualized for relevant targets. Inherited factors contribute to FLD, and most of the genetic variation influencing liver disease development and progression is derived from genes involved in lipid biology, including PNPLA3, TM6SF2, GCKR, MBOAT7, and HSD17B13. From this point of view, we focus in this perspective on how human molecular genetics of FLD have highlighted defects in hepatic lipid handling as a major common mechanism of its pathology and how this insight could be leveraged to treat and prevent its more serious complications.
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Affiliation(s)
- Stefano Romeo
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Cardiology Department, Sahlgrenska University Hospital, Gothenburg, Sweden.
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda, Pad Marangoni, Milan, Italy.
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44
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Lin SY, Lin CL, Chen WS, Lin CC, Lin CH, Hsu WH, Hsu CY, Kao CH. Association Between Alcoholic Cirrhosis and Hemorrhagic Stroke: A Nationwide Population-based Study. Alcohol Alcohol 2019; 54:302-309. [PMID: 30957143 DOI: 10.1093/alcalc/agz025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Revised: 02/27/2019] [Accepted: 03/11/2019] [Indexed: 02/07/2023] Open
Abstract
AIMS This study investigated whether patients with alcoholic cirrhosis have a high risk of hemorrhagic stroke. METHODS In this study, 17,094 patients diagnosed with cirrhosis between 2000 and 2010 were identified using the Taiwan National Health Insurance claims data. Identified patients were randomly selected and propensity score matched with individuals without cirrhosis according to age, sex, comorbidities and index year. RESULTS The overall incidence rate of stroke was 4.41 and 12.1 per 1000 person-years in the chronic liver disease and cirrhosis (CLDC) with hepatitis B virus (HBV) or hepatitis C virus (HCV) cohort and the alcoholic CLDC cohort, respectively. The alcoholic CLDC cohort exhibited a 4.53-fold higher risk of hemorrhagic stroke (adjusted subhazard ratio [aSHR] = 4.53, 95% confidence interval [CI] = 3.05-6.71) than did the non-CLDC cohort, and the CLDC with HBV or HCV cohort exhibited a 1.40-fold higher risk of hemorrhagic stroke (aSHR = 1.40, 95% CI = 1.10-1.78) than did the non-CLDC cohort. The alcoholic CLDC cohort and the CLDC with HBV or HCV cohort showed an aSHR of 1.80 (95% CI = 1.36-2.40) and 0.95 (95% CI = 0.83-1.07) for ischemic stroke, respectively, compared with the non-CLDC cohort. CONCLUSION Alcoholic patients with CLDC had a higher risk of hemorrhagic stroke compared with non-alcoholic patients with CLDC and patients without CLDC.
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Affiliation(s)
- Shih-Yi Lin
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taiwan.,Division of Nephrology and Kidney Institute, China Medical University Hospital, Taichung, Taiwan
| | - Cheng-Li Lin
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
| | - Wei-Shan Chen
- Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
| | - Cheng-Chieh Lin
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taiwan.,Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chih-Hsueh Lin
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taiwan.,Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Wu-Huei Hsu
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taiwan.,Division of Pulmonary and Critical Care Medicine, China Medical University Hospital and China Medical University, Taichung, Taiwan
| | - Chung Y Hsu
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taiwan
| | - Chia-Hung Kao
- Graduate Institute of Biomedical Sciences and School of Medicine, College of Medicine, China Medical University, Taiwan.,Department of Nuclear Medicine, China Medical University Hospital, Taichung, Taiwan.,Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
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45
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Dhamija E, Paul SB, Kedia S. Non-alcoholic fatty liver disease associated with hepatocellular carcinoma: An increasing concern. Indian J Med Res 2019; 149:9-17. [PMID: 31115369 PMCID: PMC6507546 DOI: 10.4103/ijmr.ijmr_1456_17] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer in world and third largest cause of cancer-related deaths. The last few decades have witnessed the emergence of non-viral causes of HCC, the most important being non-alcoholic fatty liver disease (NAFLD). NAFLD ranges from simple steatosis in the absence of excessive alcohol intake to non-alcoholic steatohepatitis (NASH) with or without cirrhosis. About 3-15 per cent of the obese patients with NASH progress to cirrhosis and about 4-27 per cent of NASH with cirrhosis patients transform to HCC. It is also known that HCC can develop de novo in patients with NASH without the presence of cirrhosis. Yearly cumulative incidence of NASH-related HCC is low (2.6%) compared to four per cent of viral-HCC. NAFLD has been associated with risk factors such as metabolic syndrome, insulin resistance, altered gut flora and persistent inflammation. Due to alarming rise in metabolic diseases, both in the developing as well as the developed world, it is expected that the incidence of NAFLD/NASH-HCC would rise manifold in future. No definite guidelines have been drawn for surveillance and management of NAFLD/NASH-associated HCC. It is thus important to discuss the entity of HCC in NAFLD at length with special focus on its epidemiology, risk factors, pathophysiology, diagnosis, clinical presentation and prevention.
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Affiliation(s)
- Ekta Dhamija
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Shashi Bala Paul
- Department of Radiodiagnosis, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Kedia
- Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India
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46
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Caussy C, Ajmera VH, Puri P, Li-Shin Hsu C, Bassirian S, Mgdsyan M, Singh S, Faulkner C, Valasek MA, Rizo E, Richards L, Brenner DA, Sirlin CB, Sanyal AJ, Loomba R. Serum metabolites detect the presence of advanced fibrosis in derivation and validation cohorts of patients with non-alcoholic fatty liver disease. Gut 2019; 68:1884-1892. [PMID: 30567742 PMCID: PMC8328048 DOI: 10.1136/gutjnl-2018-317584] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Revised: 10/22/2018] [Accepted: 11/29/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Non-invasive and accurate diagnostic tests for the screening of disease severity in non-alcoholic fatty liver disease (NAFLD) remain a major unmet need. Therefore, we aimed to examine if a combination of serum metabolites can accurately predict the presence of advanced fibrosis. DESIGN This is a cross-sectional analysis of a prospective derivation cohort including 156 well-characterised patients with biopsy-proven NAFLD and two validation cohorts, including (1) 142 patients assessed using MRI elastography (MRE) and(2) 59 patients with biopsy-proven NAFLD with untargeted serum metabolome profiling. RESULTS In the derivation cohort, 23 participants (15%) had advanced fibrosis and 32 of 652 analysed metabolites were significantly associated with advanced fibrosis after false-discovery rate adjustment. Among the top 10 metabolites, 8 lipids (5alpha-androstan-3beta monosulfate, pregnanediol-3-glucuronide, androsterone sulfate, epiandrosterone sulfate, palmitoleate, dehydroisoandrosterone sulfate, 5alpha-androstan-3beta disulfate, glycocholate), one amino acid (taurine) and one carbohydrate (fucose) were identified. The combined area under the receiver operating characteristic curve (AUROC) of the top 10 metabolite panel was higher than FIB--4 and NAFLD Fibrosis Score (NFS) for the detection of advanced fibrosis: 0.94 (95% CI 0.897 to 0.982) versus 0.78 (95% CI0.674 to 0.891), p=0.002 and versus 0.84 (95% CI 0.724 to 0.929), p=0.017, respectively. The AUROC of the top 10 metabolite panel remained excellent in the independent validation cohorts assessed by MRE or liver biopsy: c-statistic of 0.94 and 0.84, respectively. CONCLUSION A combination of 10 serum metabolites demonstrated excellent discriminatory ability for the detection of advanced fibrosis in an derivation and two independent validation cohorts with greater diagnostic accuracy than the FIB-4-index and NFS. This proof-of-concept study demonstrates that a non-invasive blood-based diagnostic test can provide excellent performance characteristics for the detection of advanced fibrosis.
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Affiliation(s)
- Cyrielle Caussy
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Université Lyon 1, Hospices Civils de Lyon, Lyon, California, France
| | - Veeral H Ajmera
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Puneet Puri
- Virginia Commonwealth University, Richmond, Virginia, USA
| | | | - Shirin Bassirian
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Mania Mgdsyan
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Seema Singh
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Claire Faulkner
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Mark A Valasek
- Department of Pathology, University of California at San Diego, La Jolla, California, USA
| | - Emily Rizo
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - Lisa Richards
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA
| | - David A Brenner
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, La Jolla, California, USA
| | - Claude B Sirlin
- Liver Imaging Group, Department of Radiology, University of California, San Diego, La Jolla, California, USA
| | - Arun J Sanyal
- Virginia Commonwealth University, Richmond, Virginia, USA
| | - Rohit Loomba
- NAFLD Research Center, Department of Medicine, La Jolla, California, USA,Division of Gastroenterology, Department of Medicine, La Jolla, California, USA,Division of Epidemiology, Department of Family and Preventive Medicine, University of California at San Diego, La Jolla, California, USA
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Povsic M, Wong OY, Perry R, Bottomley J. A Structured Literature Review of the Epidemiology and Disease Burden of Non-Alcoholic Steatohepatitis (NASH). Adv Ther 2019; 36:1574-1594. [PMID: 31065991 PMCID: PMC6824389 DOI: 10.1007/s12325-019-00960-3] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Non-Alcoholic Steatohepatitis (NASH) is a chronic, progressive disease characterized by fatty liver and liver cell injury, advancing to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Diagnosis involves liver biopsy; however, as a result of its high cost and invasiveness, NASH remains underdiagnosed, and accurate burden of disease (BoD) data are lacking. Our aim was to understand the epidemiological and BoD landscape in NASH and identify knowledge gaps. METHODS The Ovid search engine was used to conduct a structured review, following quality systematic principles. It included publications that reported on epidemiology, quality of life (QoL) and BoD outcomes in NASH adults. Searches were limited to English language studies published between January 2007 and September 2017. Additional grey literature searches were conducted. A total of 53 references were selected; 38 were peer-reviewed and 15 were grey literature sources. RESULTS NASH is estimated to affect 3-5% of the global population, most suffering from several comorbidities. Advancing fibrosis drives clinical outcomes, with approximately 20% of patients developing cirrhosis and/or HCC, the latter being a leading cause of death in NASH. A recent model predicted the 15-year survival of advanced fibrosis patients at F3 and F4 as 51.0% and 28.4%, respectively. The limited data consistently show that NASH patients experience significantly poorer QoL and higher costs compared to non-NASH patients. CONCLUSION This first broad-ranging examination of NASH literature revealed a paucity of evidence, with poor-quality, small studies found. The overwhelming impact of NASH and its patient and healthcare burden is evident. Further evidence is needed to improve our understanding of NASH, especially as fibrosis stages advance. FUNDING Gilead Science Inc.
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48
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Boyle M, Anstee QM. Nonalcoholic Fatty Liver Disease. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 4E 2019:523-546. [DOI: 10.1002/9781119211419.ch35] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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49
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Coffee prevents fatty liver disease induced by a high-fat diet by modulating pathways of the gut-liver axis. J Nutr Sci 2019; 8:e15. [PMID: 31037218 PMCID: PMC6477661 DOI: 10.1017/jns.2019.10] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2018] [Revised: 02/25/2019] [Accepted: 02/27/2019] [Indexed: 02/07/2023] Open
Abstract
Coffee consumption is inversely associated with the risk of non-alcoholic fatty liver disease (NAFLD). A gap in the literature still exists concerning the intestinal mechanisms that are involved in the protective effect of coffee consumption towards NAFLD. In this study, twenty-four C57BL/6J mice were divided into three groups each receiving a standard diet, a high-fat diet (HFD) or an HFD plus decaffeinated coffee (HFD+COFFEE) for 12 weeks. Coffee supplementation reduced HFD-induced liver macrovesicular steatosis (P < 0·01) and serum cholesterol (P < 0·001), alanine aminotransferase and glucose (P < 0·05). Accordingly, liver PPAR- α (P < 0·05) and acyl-CoA oxidase-1 (P < 0·05) as well as duodenal ATP-binding cassette (ABC) subfamily A1 (ABCA1) and subfamily G1 (ABCG1) (P < 0·05) mRNA expressions increased with coffee consumption. Compared with HFD animals, HFD+COFFEE mice had more undigested lipids in the caecal content and higher free fatty acid receptor-1 mRNA expression in the duodenum and colon. Furthermore, they showed an up-regulation of duodenal and colonic zonulin-1 (P < 0·05), duodenal claudin (P < 0·05) and duodenal peptide YY (P < 0·05) mRNA as well as a higher abundance of Alcaligenaceae in the faeces (P < 0·05). HFD+COFFEE mice had an energy intake comparable with HFD-fed mice but starting from the eighth intervention week they gained significantly less weight over time. Data altogether showed that coffee supplementation prevented HFD-induced NAFLD in mice by reducing hepatic fat deposition and metabolic derangement through modification of pathways underpinning liver fat oxidation, intestinal cholesterol efflux, energy metabolism and gut permeability. The hepatic and metabolic benefits induced by coffee were accompanied by changes in the gut microbiota.
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Key Words
- ABCA1, ATP-binding cassette subfamily A1
- ABCG1, ATP-binding cassette subfamily G1
- ACOX1, acyl-CoA oxidase 1
- ALT, alanine aminotransferase
- FFAR, free fatty acid receptor
- Gut microbiota
- Gut permeability
- HFD+COFFEE, HFD plus decaffeinated coffee
- HFD, high-fat diet
- LXR-α, liver X receptor-α
- Metabolic syndrome
- NAFLD, non-alcoholic fatty liver disease
- Non-alcoholic steatohepatitis
- PYY, peptide YY
- Polyphenols
- SD, standard diet
- ZO-1, zonulin-1
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Castera L, Friedrich-Rust M, Loomba R. Noninvasive Assessment of Liver Disease in Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2019; 156:1264-1281.e4. [PMID: 30660725 PMCID: PMC7505052 DOI: 10.1053/j.gastro.2018.12.036] [Citation(s) in RCA: 999] [Impact Index Per Article: 166.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 12/02/2018] [Accepted: 12/24/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is estimated to afflict approximately 1 billion individuals worldwide. In a subset of NAFLD patients, who have the progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH), it can progress to advanced fibrosis, cirrhosis, hepatocellular carcinoma, and liver-related morbidity and mortality. NASH is typically characterized by a specific pattern on liver histology, including steatosis, lobular inflammation, and ballooning with or without peri-sinusoidal fibrosis. Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice.
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Affiliation(s)
- Laurent Castera
- Department of Hepatology, Hôpital Beaujon, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1149, University of Paris-VII, Clichy, France.
| | - Mireen Friedrich-Rust
- Department of Internal Medicine 1, Division of Gastroenterology, Hepatology, Goethe University Hospital, Frankfurt, Germany
| | - Rohit Loomba
- Nonalcoholic Fatty Liver Disease Research Center, Division of Gastroenterology, Department of Medicine, University of California at San Diego, La Jolla, California
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