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Ates E, My Ong HT, Yu SM, Kim JH, Kang MJ. Comparative Analysis of the Total Proteome in Nonalcoholic Steatohepatitis: Identification of Potential Biomarkers. Mol Cell Proteomics 2025; 24:100921. [PMID: 39894410 PMCID: PMC11910689 DOI: 10.1016/j.mcpro.2025.100921] [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: 06/20/2024] [Revised: 10/06/2024] [Accepted: 11/08/2024] [Indexed: 02/04/2025] Open
Abstract
Nonalcoholic fatty liver disease is a hepatic condition characterized by excessive fat accumulation in the liver with advanced stage nonalcoholic steatohepatitis (NASH), potentially leading to liver fibrosis, cirrhosis, and cancer. Currently, the identification and classification of NASH require invasive liver biopsy, which has certain limitations. Mass spectrometry-based proteomics can detect crucial proteins and pathways implicated in NASH development and progression. We collected the liver and serum samples from choline-deficient, L-amino acid-defined high-fat diet fed NASH C57BL/6J mice and human serum samples to examine proteomic alterations and identify early biomarkers for NASH diagnosis. In-depth targeted multiple reaction monitoring scanning and immunoblotting assays were used to verify the biomarker candidates from mouse liver and serum samples, and enzyme-linked immunosorbent assay (ELISA) was employed to analyze human serum samples. The multiple reaction monitoring analysis of NASH liver revealed 50 proteins with altered expression (21 upregulated and 29 downregulated) that are involved in biological processes such as detoxification, fibrosis, inflammation, and fatty acid metabolism. Ingenuity pathway analysis identified impaired protein synthesis, cellular stress and defense, cellular processes and communication, and metabolism in NASH mouse liver. Immunoblotting analysis confirmed that the expression of proteins associated with fatty acid metabolism (Aldo B and Fasn) and urea cycle (Arg1, Cps1, and Otc) was altered in the mouse liver and serum. Further analysis on human serum samples using ELISA confirmed the increased expression of multiple proteins, including Aldo B, Asl, and Lgals3, demonstrating values of 0.917, 0.979, and 0.965 of area under the curve in NASH diagnosis. These findings offer valuable insights into the molecular mechanisms of NASH and possible diagnostic biomarkers for early detection.
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Affiliation(s)
- Eda Ates
- Center for Advanced Biomolecular Recognition, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea
| | - Hien Thi My Ong
- Center for Advanced Biomolecular Recognition, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea
| | - Seung-Min Yu
- Center for Advanced Biomolecular Recognition, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Ji-Hoon Kim
- Center for Advanced Biomolecular Recognition, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea
| | - Min-Jung Kang
- Center for Advanced Biomolecular Recognition, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, University of Science and Technology, Seoul, Republic of Korea.
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Haghshomar M, Antonacci D, Smith AD, Thaker S, Miller FH, Borhani AA. Diagnostic Accuracy of CT for the Detection of Hepatic Steatosis: A Systematic Review and Meta-Analysis. Radiology 2024; 313:e241171. [PMID: 39499183 DOI: 10.1148/radiol.241171] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2024]
Abstract
Background CT plays an important role in the opportunistic identification of hepatic steatosis. CT performance for steatosis detection has been inconsistent across various studies, and no clear guidelines on optimum thresholds have been established. Purpose To conduct a systematic review and meta-analysis to assess CT diagnostic accuracy in hepatic steatosis detection and to determine reliable cutoffs for the commonly mentioned measures in the literature. Materials and Methods A systematic search of the PubMed, Embase, and Scopus databases (English-language studies published from September 1977 to January 2024) was performed. Studies evaluating the diagnostic accuracy of noncontrast CT (NCCT), contrast-enhanced (CECT), and dual-energy CT (DECT) for hepatic steatosis detection were included. Reference standards included biopsy, MRI proton density fat fraction (PDFF), or NCCT. In several CECT and DECT studies, NCCT was used as the reference standard, necessitating subgroup analysis. Statistical analysis included a random-effects meta-analysis, assessment of heterogeneity with use of the I2 statistic, and meta-regression to explore potential sources of heterogeneity. When available, mean liver attenuation, liver-spleen attenuation difference, liver to spleen attenuation ratio, and the DECT-derived fat fraction for hepatic steatosis diagnosis were assessed. Results Forty-two studies (14 186 participants) were included. NCCT had a sensitivity and specificity of 72% and 88%, respectively, for steatosis (>5% fat at biopsy) detection and 82% and 94% for at least moderate steatosis (over 20%-33% fat at biopsy) detection. CECT had a sensitivity and specificity of 66% and 90% for steatosis detection and 68% and 93% for at least moderate steatosis detection. DECT had a sensitivity and specificity of 85% and 88% for steatosis detection. In the subgroup analysis, the sensitivity and specificity for detecting steatosis were 80% and 99% for CECT and 84% and 93% for DECT. There was heterogeneity among studies focusing on CECT and DECT. Liver attenuation less than 40-45 HU, liver-spleen attenuation difference less than -5 to 0 HU, and liver to spleen attenuation ratio less than 0.9-1 achieved high specificity for detection of at least moderate steatosis. Conclusion NCCT showed high performance for detection of at least moderate steatosis. © RSNA, 2024 Supplemental material is available for this article.
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Affiliation(s)
- Maryam Haghshomar
- From the Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Arkes Family Pavilion, Ste 800, Chicago, IL 60611 (M.H., D.A., S.T., F.H.M., A.A.B.); and Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tenn (A.D.S.)
| | - Dominic Antonacci
- From the Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Arkes Family Pavilion, Ste 800, Chicago, IL 60611 (M.H., D.A., S.T., F.H.M., A.A.B.); and Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tenn (A.D.S.)
| | - Andrew D Smith
- From the Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Arkes Family Pavilion, Ste 800, Chicago, IL 60611 (M.H., D.A., S.T., F.H.M., A.A.B.); and Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tenn (A.D.S.)
| | - Sarang Thaker
- From the Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Arkes Family Pavilion, Ste 800, Chicago, IL 60611 (M.H., D.A., S.T., F.H.M., A.A.B.); and Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tenn (A.D.S.)
| | - Frank H Miller
- From the Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Arkes Family Pavilion, Ste 800, Chicago, IL 60611 (M.H., D.A., S.T., F.H.M., A.A.B.); and Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tenn (A.D.S.)
| | - Amir A Borhani
- From the Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N St. Clair St, Arkes Family Pavilion, Ste 800, Chicago, IL 60611 (M.H., D.A., S.T., F.H.M., A.A.B.); and Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tenn (A.D.S.)
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Barazesh M, Jalili S, Akhzari M, Faraji F, Khorramdin E. Recent Progresses on Pathophysiology, Diagnosis, Therapeutic Modalities,
and Management of Non-alcoholic Fatty Liver Disorder. CURRENT DRUG THERAPY 2024; 19:20-48. [DOI: 10.2174/1574885518666230417111247] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 01/30/2023] [Accepted: 02/06/2023] [Indexed: 01/03/2025]
Abstract
Abstract:
Non-alcoholic fatty liver disease (NAFLD) is currently the utmost common chronic liver
disorder that happens through all age groups and is identified to occur in 14%-30% of the general
population, demonstrating a critical and grossing clinical issue because of the growing incidence of
obesity and overweight. From the histological aspect, it looks like alcoholic liver damage, but it happens in patients who avoid remarkable alcohol usage. NAFLD comprises a broad spectrum, ranging
from benign hepatocellular steatosis to inflammatory nonalcoholic steatohepatitis (NASH), different
levels of fibrosis, and cirrhosis. Patients with NASH are more susceptible to more rapid progression to
cirrhosis and hepatocellular carcinoma. There is no single factor that drives proceeding from simple
steatosis to NASH. However, a combination of multi parameters such as genetic background, gut microflora, intake of high fat/ fructose dietary contents or methionine/choline-deficient diet, and consequently accumulated hepatocellular lipids mainly including triglycerides and also other bio-analytes,
such as free fatty acids, cholesterol, and phospholipids display a crucial role in disease promotion.
NAFLD is related to overweight and insulin resistance (IR) and is regarded as the hepatic presentation
of the metabolic syndrome, an amalgamation of medical statuses such as hyperlipidemia, hypertension, type 2 diabetes, and visceral obesity. Despite the increasing prevalence of this disease, which
imposes a remarkable clinical burden, most affected patients remain undiagnosed in a timely manner,
largely related to the asymptomatic entity of NAFLD patients and the unavailability of accurate and
efficient noninvasive diagnostic tests. However, liver biopsy is considered a gold standard for NAFLD
diagnosis, but due to being expensive and invasiveness is inappropriate for periodic disease screening.
Some noninvasive monitoring approaches have been established recently for NAFLD assessment. In
addition to the problem of correct disease course prediction, no effective therapeutic modalities are
approved for disease treatment. Imaging techniques can commonly validate the screening and discrimination of NAFLD; nevertheless, staging the disease needs a liver biopsy. The present therapeutic approaches depend on weight loss, sports activities, and dietary modifications, although different insulin-sensitizing drugs, antioxidants, and therapeutic agents seem hopeful. This review aims to focus on
the current knowledge concerning epidemiology, pathogenesis, and different biochemical experiments
and imaging modalities applied to diagnose the different grades of NAFLD and its management, as
well as new data about pharmacological therapies for this disorder.
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Affiliation(s)
- Mahdi Barazesh
- School of Paramedical, Gerash University of Medical Sciences, Gerash, Iran
| | - Sajad Jalili
- Department of Orthopedics, School of
Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
| | - Morteza Akhzari
- School of Nursing, Larestan University of
Medical Sciences, Larestan, Iran
| | - Fouzieyeh Faraji
- School of Paramedical, Gerash University of Medical Sciences, Gerash, Iran
| | - Ebrahim Khorramdin
- Department of Orthopedics, School of
Medicine, Ahvaz Jundishapour University of Medical Sciences, Ahvaz, Iran
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Bekheit M, Grundy L, Salih AK, Bucur P, Vibert E, Ghazanfar M. Post-hepatectomy liver failure: A timeline centered review. Hepatobiliary Pancreat Dis Int 2023; 22:554-569. [PMID: 36973111 DOI: 10.1016/j.hbpd.2023.03.001] [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: 04/11/2022] [Accepted: 03/10/2023] [Indexed: 03/29/2023]
Abstract
BACKGROUND Post-hepatectomy liver failure (PHLF) is a leading cause of postoperative mortality after liver surgery. Due to its significant impact, it is imperative to understand the risk stratification and preventative strategies for PHLF. The main objective of this review is to highlight the role of these strategies in a timeline centered way around curative resection. DATA SOURCES This review includes studies on both humans and animals, where they addressed PHLF. A literature search was conducted across the Cochrane Library, Embase, MEDLINE/PubMed, and Web of Knowledge electronic databases for English language studies published between July 1997 and June 2020. Studies presented in other languages were equally considered. The quality of included publications was assessed using Downs and Black's checklist. The results were presented in qualitative summaries owing to the lack of studies qualifying for quantitative analysis. RESULTS This systematic review with 245 studies, provides insight into the current prediction, prevention, diagnosis, and management options for PHLF. This review highlighted that liver volume manipulation is the most frequently studied preventive measure against PHLF in clinical practice, with modest improvement in the treatment strategies over the past decade. CONCLUSIONS Remnant liver volume manipulation is the most consistent preventive measure against PHLF.
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Affiliation(s)
- Mohamed Bekheit
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK; Institute of Medical Sciences, Medical School, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK; Hépatica, Integrated Center of HPB Care, Elite Hospital, Agriculture Road, Alexandria, Egypt.
| | - Lisa Grundy
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK
| | - Ahmed Ka Salih
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK; Institute of Medical Sciences, Medical School, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK
| | - Petru Bucur
- Department of Surgery, University Hospital Tours, Val de la Loire 37000, France
| | - Eric Vibert
- Centre Hépatobiliaire, Paul Brousse Hospital, 12 Paul Valliant Couturier, 94804 Villejuif, France
| | - Mudassar Ghazanfar
- Department of Surgery, NHS Grampian, Foresterhill Health Campus, Ashgrove Road, AB252ZN Aberdeen, UK
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El-Baz AM, El-Ganiny AM, Hellal D, Anwer HM, El-Aziz HAA, Tharwat IE, El-Adawy MA, Helal SEDM, Mohamed MTA, Azb TM, Elshafaey HM, Shalata AA, Elmeligi SM, Abdelbary NH, El-Kott AF, Al-Saeed FA, Salem ET, El-Sokkary MMA, Shata A, Shabaan AA. Valuable effects of lactobacillus and citicoline on steatohepatitis: role of Nrf2/HO-1 and gut microbiota. AMB Express 2023; 13:57. [PMID: 37291355 DOI: 10.1186/s13568-023-01561-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 05/16/2023] [Indexed: 06/10/2023] Open
Abstract
Non-alcoholic steatohepatitis (NASH) is a more dangerous form of chronic non-alcoholic fatty liver disease (NAFLD). In the current investigation, the influence of citicoline on high-fat diet (HFD)-induced NASH was examined, both alone and in combination with Lactobacillus (probiotic). NASH was induced by feeding HFD (10% sugar, 10% lard stearin, 2% cholesterol, and 0.5% cholic acid) to rats for 13 weeks and received single i.p. injection of streptozotocin (STZ, 30 mg/kg) after 4 weeks. Citicoline was given at two dose levels (250 mg and 500 mg, i.p.) at the beginning of the sixth week, and in combination with an oral suspension of Lactobacillus every day for eight weeks until the study's conclusion. HFD/STZ induced steatohepatitis as shown by histopathological changes, elevated serum liver enzymes, serum hyperlipidemia and hepatic fat accumulation. Moreover, HFD convinced oxidative stress by increased lipid peroxidation marker (MDA) and decreased antioxidant enzymes (GSH and TAC). Upregulation of TLR4/NF-kB and the downstream inflammatory cascade (TNF-α, and IL-6) as well as Pentaraxin, fetuin-B and apoptotic markers (caspase-3 and Bax) were observed. NASH rats also had massive increase in Bacteroides spp., Fusobacterium spp., E. coli, Clostridium spp., Providencia spp., Prevotella interrmedia, and P. gingivalis while remarkable drop in Bifidobacteria spp. and Lactobacillus spp. Co-treatment with citicoline alone and with Lactobacillus improve histopathological NASH outcomes and reversed all of these molecular pathological alterations linked to NASH via upregulating the expression of Nrf2/HO-1 and downregulating TLR4/NF-kB signaling pathways. These results suggest that citicoline and lactobacillus may represent new hepatoprotective strategies against NASH progression.
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Affiliation(s)
- Ahmed M El-Baz
- Department of Microbiology and Biotechnology, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt.
- Department of Microbiology and Biotechnology, Faculty of Pharmacy, Delta University for Science and Technology, International Coastal Road, Gamasa City, Mansoura, Dakahlia, P.O. Box +11152, Egypt.
| | - Amira M El-Ganiny
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, 44519, Zagazig, Egypt
| | - Doaa Hellal
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, 35516, Mansoura, Egypt
| | - Hala M Anwer
- Department of Physiology, Faculty of Medicine, Benha University, Benha, Egypt
| | - Hend A Abd El-Aziz
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Ibrahim E Tharwat
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Mohamed A El-Adawy
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Shehab El-Din M Helal
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Menna Tallah A Mohamed
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Tassnim M Azb
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Hanya M Elshafaey
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - AbdulRahman A Shalata
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Sahar M Elmeligi
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Noran H Abdelbary
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Attalla F El-Kott
- Department of Biology, College of Science, King Khalid University, 61421, Abha, Saudi Arabia
- Department of Zoology, College of Science, Damanhour University, 22511, Damanhour, Egypt
| | - Fatimah A Al-Saeed
- Department of Biology, College of Science, King Khalid University, 61421, Abha, Saudi Arabia
| | - Eman T Salem
- Department of Basic Science, Faculty of Physical Therapy, Horus University-Egypt, 34518, Horus, New Damietta, Egypt
| | | | - Ahmed Shata
- Department of Clinical Pharmacology, Faculty of Medicine, Mansoura University, 35516, Mansoura, Egypt
- Department of Clinical Pharmacy, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
| | - Ahmed A Shabaan
- Department of Pharmacology, Faculty of Pharmacy, Delta University for Science and Technology, 11152, Gamasa, Egypt
- Department of Pharmacology and Toxicology, Faculty of pharmacy, Mansoura University, 35516, Mansoura, Egypt
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6
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El-Baz AM, El-Ganiny AM, Hellal D, Anwer HM, El-Aziz HAA, Tharwat IE, El-Adawy MA, Helal SEDM, Mohamed MTA, Azb TM, Elshafaey HM, Shalata AA, Elmeligi SM, Abdelbary NH, El-kott AF, Al-Saeed FA, Salem ET, El-Sokkary MMA, Shata A, Shabaan AA. Valuable effects of lactobacillus and citicoline on steatohepatitis: role of Nrf2/HO-1 and gut microbiota. AMB Express 2023; 13:57. [DOI: https:/doi.org/10.1186/s13568-023-01561-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 05/16/2023] [Indexed: 05/14/2025] Open
Abstract
AbstractNon-alcoholic steatohepatitis (NASH) is a more dangerous form of chronic non-alcoholic fatty liver disease (NAFLD). In the current investigation, the influence of citicoline on high-fat diet (HFD)-induced NASH was examined, both alone and in combination with Lactobacillus (probiotic). NASH was induced by feeding HFD (10% sugar, 10% lard stearin, 2% cholesterol, and 0.5% cholic acid) to rats for 13 weeks and received single i.p. injection of streptozotocin (STZ, 30 mg/kg) after 4 weeks. Citicoline was given at two dose levels (250 mg and 500 mg, i.p.) at the beginning of the sixth week, and in combination with an oral suspension of Lactobacillus every day for eight weeks until the study’s conclusion. HFD/STZ induced steatohepatitis as shown by histopathological changes, elevated serum liver enzymes, serum hyperlipidemia and hepatic fat accumulation. Moreover, HFD convinced oxidative stress by increased lipid peroxidation marker (MDA) and decreased antioxidant enzymes (GSH and TAC). Upregulation of TLR4/NF-kB and the downstream inflammatory cascade (TNF-α, and IL-6) as well as Pentaraxin, fetuin-B and apoptotic markers (caspase-3 and Bax) were observed. NASH rats also had massive increase in Bacteroides spp., Fusobacterium spp., E. coli, Clostridium spp., Providencia spp., Prevotella interrmedia, and P. gingivalis while remarkable drop in Bifidobacteria spp. and Lactobacillus spp. Co-treatment with citicoline alone and with Lactobacillus improve histopathological NASH outcomes and reversed all of these molecular pathological alterations linked to NASH via upregulating the expression of Nrf2/HO-1 and downregulating TLR4/NF-kB signaling pathways. These results suggest that citicoline and lactobacillus may represent new hepatoprotective strategies against NASH progression.
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Elsayed A, Ismaiel A, Procopio AC, Luzza F, Abenavoli L, Dumitrascu DL. Noninvasive biochemical markers and surrogate scores in evaluating nonalcoholic steatohepatitis. Minerva Med 2022; 113:864-874. [PMID: 35583419 DOI: 10.23736/s0026-4806.22.08185-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The histological features of nonalcoholic steatohepatitis (NASH) are the presence of hepatic steatosis with concomitant inflammation, ballooned hepatocytes, and potential fibrosis, which can lead to liver cirrhosis. To reduce the need for liver biopsy, that is still the gold standard for diagnosing NASH, various noninvasive biomarkers have been investigated. This narrative review summarizes the current knowledge about noninvasive diagnostic biomarkers and scores proposed for patients with NASH. A search was performed in the main medical literature databases. The following search terms were used: NASH, noninvasive biomarkers or NASH scores and panels. We focused only on studies assessing NASH diagnosis or predictive values for biomarkers, panels and scores. Data on their accuracy in predicting NASH were collected. Several panels such as NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4), and FibroMeter presented good predictive values of NASH, with novel proteomics panels such as the NAFLD Fibrosis Protein Panel (NFPP) using mainly the adisintegrin and metalloproteinase with thrombospondin motifs like 2 (ADAMTSL2) that showed an advantage in predicting NASH compared to NFS and FIB-4. Another novel panel, Index of NASH (ION) performed better than cytokeratin 18 (CK-18) in excluding severe fibrosis, but the overall accuracy of ION and CK-18 was modest compared to NFS and FIB-4 as it did not provide any significant advantage. Noninvasive biomarkers are currently unable to replace liver biopsy and histological assessment. However, they may play a key and vital role in triaging patients for liver biopsy, lowering the related financial burden. Future studies are needed to verify the predictive values of the newly emerging tests and panels as well as to find more affordable and reliable noninvasive early diagnostic tools.
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Affiliation(s)
- Abdalla Elsayed
- Department of Internal Medicine, County Emergency Hospital Ilfov, Bucharest, Romania
| | - Abdulrahman Ismaiel
- Second Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania -
| | - Anna C Procopio
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Francesco Luzza
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Ludovico Abenavoli
- Department of Health Sciences, The Magna Græcia University of Catanzaro, Catanzaro, Italy
| | - Dan L Dumitrascu
- Second Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Wang H, Sun R, Yang S, Ma X, Yu C. Association between serum ferritin level and the various stages of non-alcoholic fatty liver disease: A systematic review. Front Med (Lausanne) 2022; 9:934989. [PMID: 35991666 PMCID: PMC9381877 DOI: 10.3389/fmed.2022.934989] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Accepted: 07/18/2022] [Indexed: 12/02/2022] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disorder across the world, and non-invasive evaluation approaches are in need to assess NAFLD disease progression. Serum ferritin has been proposed as one of the biomarkers for NAFLD diagnosis in previous studies. This systematic review aims to identify, report, and synthesize studies that investigated the association of serum ferritin level with the various stages of NAFLD among the adult population. Methods Three databases - MEDLINE, EMBASE, and Scopus - were systematically searched to obtain potentially relevant publications before July 2022. No restrictions were applied to geographical region, study design, publication type and language. The association between serum ferritin level or different ferritin categories and the various stages of NAFLD was the primary outcome of interest. Title and abstract screenings, data extraction and coding, and quality assessment were independently completed by two authors with discrepancies resolved through discussion with a third author. Results Thirty-two studies were included and heterogeneity was considerable. The associations between serum ferritin level and the stages of hepatic steatosis, fibrosis, inflammation and ballooning and the occurrence of non-alcoholic steatohepatitis (NASH) were investigated but inconsistent associations were reported. Most studies identified serum ferritin to be a predictor of advanced NAFLD, while several revealed the opposite end. Conclusions Serum ferritin could be considered to act as a non-invasive biomarker for assessing various stages of NAFLD. Nevertheless, further studies are still in need to confirm its predictive value since this study reported inconsistent associations based on the qualitative synthesis. Systematic Review Registration http://www.crd.york.ac.uk/PROSPERO, identifier: CRD42021275630.
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Affiliation(s)
- Huanqiu Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ruyu Sun
- Institute of Social Medicine, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sisi Yang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Xueqing Ma
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chengbo Yu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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Lavynenko O, Abdul-Ghani M, Alatrach M, Puckett C, Adams J, Abdelgani S, Alkhouri N, Triplitt C, Clarke GD, Vasquez JA, Li J, Cersosimo E, Gastaldelli A, DeFronzo RA. Combination therapy with pioglitazone/exenatide/metformin reduces the prevalence of hepatic fibrosis and steatosis: The efficacy and durability of initial combination therapy for type 2 diabetes (EDICT). Diabetes Obes Metab 2022; 24:899-907. [PMID: 35014145 DOI: 10.1111/dom.14650] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 01/05/2022] [Accepted: 01/06/2022] [Indexed: 12/11/2022]
Abstract
AIM To compare the efficacy of triple therapy (metformin/exenatide/pioglitazone) versus stepwise conventional therapy (metformin → glipizide → glargine insulin) on liver fat content and hepatic fibrosis in newly diagnosed, drug-naïve patients with type 2 diabetes. METHODS Sixty-eight patients completed the 6-year follow-up and had an end-of-study (EOS) FibroScan to provide measures of steatosis (controlled attenuation parameter [CAP] in dB/m) and fibrosis (liver stiffness measurement [LSM] in kPa); 59 had magnetic resonance imaging-proton density fat fraction (MRI-PDFF) to measure liver fat. RESULTS At EOS, HbA1c was 6.8% and 6.0% in triple and conventional therapy groups, respectively (P = .0006). Twenty-seven of 39 subjects (69%) receiving conventional therapy had grade 2/3 steatosis (CAP, FibroScan) versus nine of 29 (31%) in triple therapy (P = .0003). Ten of 39 (26%) subjects receiving conventional therapy had stage 3/4 fibrosis (LSM) versus two of 29 (7%) in triple therapy (P = .04). Conventional therapy subjects had more liver fat (MRI-PDFF) than triple therapy (12.9% vs. 8.8%, P = .03). The severity of steatosis (CAP) (r = 0.42, P < .001) and fibrosis (LSM) (r = -0.48, P < .001) correlated inversely with the Matsuda Index of insulin sensitivity, but not with percentage body fat. Aspartate aminotransferase (AST) to Platelet Ratio Index (APRI), non-alcoholic fatty liver disease fibrosis score (NFS), plasma AST, and alanine aminotransferase (ALT) all decreased significantly with triple therapy, but only the decrease in plasma AST and ALT correlated with the severity of steatosis and fibrosis at EOS. CONCLUSIONS At EOS, subjects with type 2 diabetes treated with triple therapy had less hepatic steatosis and fibrosis versus conventional therapy; the severity of hepatic steatosis and fibrosis were both strongly and inversely correlated with insulin resistance; and changes in liver fibrosis scores (APRI, NFS, Fibrosis-4, and AST/ALT ratio) have limited value in predicting response to therapy.
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Affiliation(s)
- Olga Lavynenko
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Muhammad Abdul-Ghani
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Mariam Alatrach
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Curtiss Puckett
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - John Adams
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Siham Abdelgani
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Naim Alkhouri
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Curtis Triplitt
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Geoffrey D Clarke
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Juan A Vasquez
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Jinqi Li
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Eugenio Cersosimo
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Amalia Gastaldelli
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
| | - Ralph A DeFronzo
- University of Texas Health Science Center and Texas Diabetes Institute, San Antonio, Texas
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10
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Adipose Triglyceride Lipase in Hepatic Physiology and Pathophysiology. Biomolecules 2021; 12:biom12010057. [PMID: 35053204 PMCID: PMC8773762 DOI: 10.3390/biom12010057] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 12/28/2021] [Accepted: 12/28/2021] [Indexed: 12/25/2022] Open
Abstract
The liver is extremely active in oxidizing triglycerides (TG) for energy production. An imbalance between TG synthesis and hydrolysis leads to metabolic disorders in the liver, including excessive lipid accumulation, oxidative stress, and ultimately liver damage. Adipose triglyceride lipase (ATGL) is the rate-limiting enzyme that catalyzes the first step of TG breakdown to glycerol and fatty acids. Although its role in controlling lipid homeostasis has been relatively well-studied in the adipose tissue, heart, and skeletal muscle, it remains largely unknown how and to what extent ATGL is regulated in the liver, responds to stimuli and regulators, and mediates disease progression. Therefore, in this review, we describe the current understanding of the structure–function relationship of ATGL, the molecular mechanisms of ATGL regulation at translational and post-translational levels, and—most importantly—its role in lipid and glucose homeostasis in health and disease with a focus on the liver. Advances in understanding the molecular mechanisms underlying hepatic lipid accumulation are crucial to the development of targeted therapies for treating hepatic metabolic disorders.
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11
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Goyale A, Jain A, Smith C, Papatheodoridi M, Misas MG, Roccarina D, Prat LI, Mikhailidis DP, Nair D, Tsochatzis E. Assessment of non-alcoholic fatty liver disease (NAFLD) severity with novel serum-based markers: A pilot study. PLoS One 2021; 16:e0260313. [PMID: 34813621 PMCID: PMC8610238 DOI: 10.1371/journal.pone.0260313] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 11/06/2021] [Indexed: 12/31/2022] Open
Abstract
Background/Aims Non-alcoholic fatty liver disease (NAFLD) represents a significant public health issue. Identifying patients with simple steatosis from those with non-alcoholic steatohepatitis (NASH) is crucial since NASH is correlated with increased morbidity and mortality. Serum-based markers, including adipokines and cytokines, are important in the pathogenesis and progression of NAFLD. Here we assessed the usefulness of such markers in patients with NAFLD. Methods This prospective, cross-sectional study included 105 adult patients with varying severity of NAFLD. Twelve serum-based markers were measured by 3 biochip platforms and 2 enzyme-linked immunosorbent assay (ELISA) methods. We also developed a NAFLD individual fibrosis index (NIFI) using the serum-based markers mostly correlated with fibrosis severity. Results Sixty-one out of 105 patients were male (58.1%) with mean age was 53.5 years. Higher Interleukin-6 (IL-6) increased (p = 0.0321) and lower Matrix Metalloproteinase-9 (MMP-9) serum levels (p = 0.0031) were associated with higher fibrosis as measured by Fibroscan® in multivariable regression analysis. Using receiver-operating characteristic (ROC) curve analysis for the NIFI, area under the curve for predicting Fibroscan values ≥ 7.2 kPa was 0.77 (95%CI: 0.67, 0.88, p<0.001), with sensitivity of 89.3%, specificity of 57.9% and a positive likelihood ratio of 2.8. Conclusions Increasing fibrosis severity in NAFLD is associated with differential expression of IL-6 and MMP-9. NIFI could be valuable for the prediction of advanced NAFLD fibrosis and potentially help avoid unnecessary interventions such as liver biopsy in low-risk patients.
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Affiliation(s)
- Atul Goyale
- Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom
| | - Anjly Jain
- Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom
| | - Colette Smith
- UCL Research Department of Infection & Population Health, Royal Free Hospital, London, United Kingdom
| | - Margarita Papatheodoridi
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, United Kingdom
| | - Marta Guerrero Misas
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, United Kingdom
| | - Davide Roccarina
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, United Kingdom
| | - Laura Iogna Prat
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, United Kingdom
| | | | - Devaki Nair
- Department of Clinical Biochemistry, Royal Free Hospital, London, United Kingdom
| | - Emmanuel Tsochatzis
- UCL Institute for Liver and Digestive Health, Royal Free Hospital and UCL, London, United Kingdom
- * E-mail:
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12
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Ismaiel A, Dumitrascu DL. Surrogate markers in non-alcoholic steatohepatitis. Med Pharm Rep 2021; 94:S34-S37. [PMID: 38912403 PMCID: PMC11188026 DOI: 10.15386/mpr-2511] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/25/2024] Open
Abstract
BACKGROUND Hepatic steatosis with inflammation, inflated hepatocytes, and potential fibrosis defines non-alcoholic steatohepatitis (NASH), which can possibly lead to liver cirrhosis. Although liver biopsy is still the gold standard for diagnosing NASH, numerous non-invasive surrogate markers have been investigated to reduce the need for this invasive technique. In this review we present several currently assessed biomarkers, scores, and indexes in assessing NASH. METHODS A search in the main medical literature databases was conducted. We searched for observational studies evaluating non-invasive markers, scores, and panels in predicting NASH. RESULTS Several proinflammatory markers, inflammation and apoptosis biomarkers, as well as complex models have been studied in predicting NASH. Proinflammatory markers include C-reactive protein, ferritin, tumor necrosis factor-α, interleukin-6, pentraxin-3, and neutrophil extracellular traps. Inflammation and apoptosis biomarkers include cytokineratin-18, adipocytokines, lipid oxidation panels, plasminogen activator inhibitor-1, and products of free radical-mediated oxidation of linoleic acid. Moreover, several studied complex models such as NashTest, NashTest-2, pairing CK18 fragments with other biomarkers such as ALT and the presence of MetS, the HAIR model, acNASH, NAFIC score, Visceral Adiposity Index have also been studied. CONCLUSION A variety of diagnostic panels have shown good predictive values for diagnosing NASH. Nevertheless, non-invasive surrogate markers are currently unable to replace liver biopsy. However, their clinical significance is mainly in triaging patients for liver biopsy, reducing the financial burden associated with the procedure.
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Affiliation(s)
- Abdulrahman Ismaiel
- 2 Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Dan L Dumitrascu
- 2 Department of Internal Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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13
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Lambrecht J, Tacke F. Controversies and Opportunities in the Use of Inflammatory Markers for Diagnosis or Risk Prediction in Fatty Liver Disease. Front Immunol 2021; 11:634409. [PMID: 33633748 PMCID: PMC7900147 DOI: 10.3389/fimmu.2020.634409] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
In the Western society, non-alcoholic fatty liver disease (NAFLD), characterized by the excessive accumulation of fat in the liver, represents the most common cause of chronic liver disease. If left untreated, approximately 15%-20% of patients with NAFLD will progress to non-alcoholic steatohepatitis (NASH), in which lobular inflammation, hepatocyte ballooning and fibrogenesis further contribute to a distorted liver architecture and function. NASH initiation has significant effects on liver-related mortality, as even the presence of early stage fibrosis increases the chances of adverse patient outcome. Therefore, adequate diagnostic tools for NASH are needed, to ensure that relevant therapeutic actions can be taken as soon as necessary. To date, the diagnostic gold standard remains the invasive liver biopsy, which is associated with several drawbacks such as high financial costs, procedural risks, and inter/intra-observer variability in histology analysis. As liver inflammation is a major hallmark of disease progression, inflammation-related circulating markers may represent an interesting source of non-invasive biomarkers for NAFLD/NASH. Examples for such markers include cytokines, chemokines or shed receptors from immune cells, circulating exosomes related to inflammation, and changing proportions of peripheral blood mononuclear cell (PBMC) subtypes. This review aims at documenting and critically discussing the utility of such novel inflammatory markers for NAFLD/NASH-diagnosis, patient stratification and risk prediction.
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Affiliation(s)
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité University Medicine Berlin, Berlin, Germany
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14
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Duseja A, Chahal GS, Jain A, Mehta M, Ranjan A, Grover V. Association between nonalcoholic fatty liver disease and inflammatory periodontal disease: A case‑control study. J Indian Soc Periodontol 2021; 25:47-54. [PMID: 33642741 PMCID: PMC7904021 DOI: 10.4103/jisp.jisp_45_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2020] [Revised: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Recent evidence suggests an interconnection between chronic periodontal disease and systemic diseases. AIM The aim of this study is to evaluate the possible association between nonalcoholic fatty liver disease (NAFLD) and inflammatory periodontal disease among north Indian population. SETTINGS AND DESIGN Tertiary health care center, cross-sectional case-control observational study. MATERIALS AND METHODS A total of 40 cases, i.e., patients with NAFLD and 40 healthy volunteers were included over a period of 8 months and their periodontal status was compared. The status of their hepatic health was ascertained by anthropometric, imaging, and biochemical evaluation including ultrasound examination of abdomen and transient elastography. STATISTICAL DATA ANALYSIS Paired t-test, multivariate logistic regression analysis using IBM SPSS STATISTICS (version 22.0, Armonk, NY: IBM Corp). RESULTS The study revealed that only 11.9% and 20% of participants had periodontitis, in healthy controls and hepatic disease patients, respectively. A statistically significant difference was observed in clinical parameters of periodontal status, except for malocclusion. Comparative analysis of tumor necrosis factor-α (TNF-α), interleukin-6, C-reactive protein, and cytokeratin-18 revealed differences in mean scores, though statistically nonsignificant. Only aspartate transaminase, number of missing teeth, and bleeding on probing (BOP) were observed with higher odds ratios for hepatic disease patients. Spearman correlation analysis revealed significant positive correlations between TNF-α and BOP, for cases. CONCLUSION Patients with hepatic disease showed a higher prevalence of periodontal disease, worse oral hygiene and periodontal health status compared to healthy individuals.
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Affiliation(s)
- Ajay Duseja
- Department of Hepatology, PGIMER, Panjab University, Chandigarh, India
| | - Gurparkash Singh Chahal
- Department of Periodontology, Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh, India
| | - Ashish Jain
- Department of Periodontology, Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh, India
| | - Manu Mehta
- Department of Hepatology, PGIMER, Panjab University, Chandigarh, India
| | - Aditya Ranjan
- Department of Periodontology, Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh, India
| | - Vishakha Grover
- Department of Periodontology, Dr. Harvansh Singh Judge Institute of Dental Sciences and Hospital, Panjab University, Chandigarh, India
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15
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Godinez-Leiva E, Bril F. Nonalcoholic Fatty Liver Disease (NAFLD) for Primary Care Providers: Beyond the Liver. Curr Hypertens Rev 2020; 17:94-111. [DOI: 10.2174/1573402116999201209203534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 08/20/2020] [Accepted: 09/15/2020] [Indexed: 11/22/2022]
Abstract
Abstract::
Nonalcoholic fatty liver disease (NAFLD) has consolidated as a major public health problem, affecting ~25% of the global population. This percentage is significantly higher in the setting of obesity and/or type 2 diabetes. Presence of NAFLD is associated with severe liver complications, such as nonalcoholic steatohepatitis (NASH; i.e., presence of inflammation and necrosis), cirrhosis and hepatocellular carcinoma. However, the majority of these patients die of cardiovascular disease. For this reason, management of this condition requires a multidisciplinary team, where primary care providers are at center stage. However, important misconceptions remain among primary care providers, preventing them from appropriately approach these patients. Nonalcoholic fatty liver disease should be understood as part of a systemic disease, characterized for abnormal accumulation of fat in tissues other than the adipose tissue. This, in turn, produces dysfunction of those organs or tissues (process sometimes referred to as lipotoxicity). Therefore, due to the systemic nature of this condition, it should not surprise that NAFLD is closely related to other metabolic conditions. In this review, we will focus on the extrahepatic manifestations of NAFLD and its metabolic and cardiovascular implications. We believe these are the most important issues primary care providers should understand, in order to effectively manage these complicated patients. In addition, we have provided a simple and straightforward approach to the diagnosis and treatment of patients with NAFLD and/or NASH. We hope this review will serve as a guide for primary care providers to approach their patients with NAFLD.
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Affiliation(s)
- Eddison Godinez-Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL;, United States
| | - Fernando Bril
- Internal Medicine, Department of Medicine, University of Alabama in Birmingham, Birmingham, AL., United States
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16
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Durazzo M, Marzari L, Bonetto S, Ferro A, Ghigo MC, Belci P, Collo A, Fagoonee S. Noninvasive diagnosis of fibrosis in non-alcoholic fatty liver disease: diagnostic accuracy of different scores. MINERVA GASTROENTERO 2020; 66:301-306. [PMID: 32700500 DOI: 10.23736/s1121-421x.20.02753-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a spectrum of pathologies characterized by liver damage without history of excessive alcohol intake. Advanced fibrosis, generally detected by transient elastography (TE), is the most significant predictor of poor prognosis and mortality among these patients. This study aimed at assessing the accuracy of five noninvasive methods, compared to TE, for the evaluation of severity of liver fibrosis in patients with NAFLD. METHODS The cohort included 41 patients, in whom the result of TE was compared to AST/ALT ratio, BARD Score (Body Mass Index, AST/ALT ratio, diabetes), AST To Platelet Ratio Index (APRI), Fibrosis-4 Index (FIB-4 Index) and NAFLD Fibrosis Score (NFS). RESULTS The severity of fibrosis, assessed by TE, was the following: F0 (absence of fibrosis): 17%, F1 (mild): 39%, F2 (moderate): 17%, F3 (advanced): 10%, F4 (cirrhosis): 17%. Performances of the diagnostic scores were: 49% for AST/ALT ratio, 68% for BARD Score, 73% for APRI, 59% and 71% for the lower and upper cut-off of FIB-4 Index, 61% and 76% for the lower and upper cut-off of NFS. CONCLUSIONS Considering the scores compared to TE, AST/ALT ratio was not enough sensitive, while BARD Score had better diagnostic performance and APRI had a superior accuracy than the formers. However, FIB-4 and NFS were the most useful tests and their performance could be improved through the use of a single cut-off. These findings demonstrated that the most accurate scores, compared to TE, were NFS and FIB-4.
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Affiliation(s)
- Marilena Durazzo
- Department of Medical Sciences, University of Turin, Turin, Italy -
| | - Letizia Marzari
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Silvia Bonetto
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Arianna Ferro
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Maria C Ghigo
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Paola Belci
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Alessandro Collo
- Department of Medical Sciences, University of Turin, Turin, Italy
| | - Sharmila Fagoonee
- Institute for Biostructures and Bioimages (CNR), Molecular Biotechnology Center, Turin, Italy
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El-Boghdady NA, Kamel MA, El-Shamy RM. Omeprazole and Spirulina Platensis Ameliorate Steatohepatitis in Experimental Nonalcoholic Fatty Liver Disease. Metab Syndr Relat Disord 2020; 18:426-434. [DOI: 10.1089/met.2019.0129] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Affiliation(s)
- Noha A. El-Boghdady
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Maher A. Kamel
- Biochemistry Department, Medical Research Institute, Alexandria University, Alexandria, Egypt
| | - Rouaina M. El-Shamy
- Biochemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt
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18
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Serum visfatin level as a noninvasive marker for nonalcoholic fatty liver disease in children and adolescents with obesity: relation to transient elastography with controlled attenuation parameter. Eur J Gastroenterol Hepatol 2020; 32:1008-1016. [PMID: 31834057 DOI: 10.1097/meg.0000000000001608] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Obesity is associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). Visfatin is an adipokine produced by visceral fat tissue and liver cells. Transient elastography with controlled attenuation parameter (CAP) noninvasively assesses liver fibrosis and steatosis. AIM To measure visfatin level in 80 children and adolescents with obesity as a potential biomarker for NAFLD and assess its relation to transient elastography. METHODS Abdominal ultrasound, liver stiffness and CAP measurements were performed for all patients. Fasting lipid profile, fasting blood glucose, insulin level, liver and kidney functions, coagulation profile and serum visfatin levels were assessed. RESULTS Among patients with obesity, 31 (38.8%) had NAFLD and 16 (20%) patients had elevated alanine aminotransferase (ALT), while 9 (11.2%) had both NAFLD and elevated ALT. Transient elastography showed that 12.5% had fibrosis stage F1, 2.5% had F2 and another 2.5% had F3 while none had F4. Using CAP, 23.8, 13.8 and 17.5% had S1, S2 and S3, respectively. Serum visfatin levels were significantly elevated in all patients compared with nonobese controls. Higher visfatin levels were found among patients with dyslipidemia, NAFLD, elevated ALT and steatosis defined by CAP. Serum visfatin was related to the degree of fibrosis and steatosis. Visfatin cutoff value 18 ng/mL could significantly detect the presence of NAFLD with 83.9% sensitivity and 81.4% specificity. Serum visfatin was positively correlated to BMI, waist circumference, waist/hip ratio, ALT, total cholesterol, liver stiffness and CAP. CONCLUSIONS Visfatin could be a promising serum biomarker for monitoring liver disease among pediatric patients with obesity.
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Lv X, Dong Y, Hu L, Lu F, Zhou C, Qin S. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the management of nonalcoholic fatty liver disease (NAFLD): A systematic review. Endocrinol Diabetes Metab 2020; 3:e00163. [PMID: 32704576 PMCID: PMC7375121 DOI: 10.1002/edm2.163] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 04/19/2020] [Accepted: 05/23/2020] [Indexed: 12/18/2022] Open
Abstract
There are no licensed drugs for nonalcoholic fatty liver disease (NAFLD), and there is a lack of consensus on the best outcome measures for controlled trials. This systematic review aimed to evaluate the efficacy of GLP-1 RAs in the management of NAFLD, the degree of heterogeneity in trial design and the robustness of conclusions drawn from these clinical trials. We searched publication databases and clinical trial registries through 2 November 2019 for clinical trials with NAFLD. We evaluated improvements in histological findings, noninvasive markers of hepatic steatosis, inflammation, and fibrosis, insulin resistance and anthropometric measures. Our final analysis included 24 clinical trials, comprising 6313 participants with a mean duration of 37 weeks. Four clinical trials, including RCT (n = 1), single-arm studies (n = 2) and case series studies (n = 1), used biopsy-confirmed liver histological change as their end-points. The remaining studies (n = 20) used surrogate end-points. GLP-1 RAs were effective for the improvement in hepatic inflammation, hepatic steatosis and fibrosis. More importantly, GLP-1 RAs showed promise in improving the histological features of NASH. In addition, 8 ongoing trials were identified. In this systematic review of published and ongoing clinical trials of the efficacy of GLP-1RAs for NAFLD, we found that GLP-1 RAs are effective for hepatic steatosis and inflammation, with the potential to reverse fibrosis. Further prospective studies of sufficient duration using histological end-points are needed to fully assess the efficacy of GLP-1 RAs in the management of NAFLD.
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Affiliation(s)
- Xiaodan Lv
- Department of EndocrinologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Yongqiang Dong
- Department of Thyroid SurgeryThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Lingling Hu
- Department of EndocrinologyNingbo Medical Center Lihuili Eastern HospitalZhejiangChina
| | - Feiyu Lu
- Department of PaediatricsThe First Hospital of Jilin UniversityChangchunChina
| | - Changyu Zhou
- Department of Gastroenterology and HepatologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
| | - Shaoyou Qin
- Department of Gastroenterology and HepatologyChina‐Japan Union Hospital of Jilin UniversityChangchunChina
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Okamoto K, Koda M, Okamoto T, Onoyama T, Miyoshi K, Kishina M, Matono T, Kato J, Tokunaga S, Sugihara T, Hiramatsu A, Hyogo H, Tobita H, Sato S, Kawanaka M, Hara Y, Hino K, Chayama K, Murawaki Y, Isomoto H. Serum miR-379 expression is related to the development and progression of hypercholesterolemia in non-alcoholic fatty liver disease. PLoS One 2020; 15:e0219412. [PMID: 32106257 PMCID: PMC7046274 DOI: 10.1371/journal.pone.0219412] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
Introduction Non-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker. Methods Eighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control. One patient was excluded due to low RT-PCR signal. Results Compared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, low-density-lipoprotein cholesterol and non-high-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism–related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379. Conclusions Serum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.
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Affiliation(s)
- Kinya Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
- * E-mail:
| | - Masahiko Koda
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Toshiaki Okamoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takumi Onoyama
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Kenichi Miyoshi
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Manabu Kishina
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Tomomitsu Matono
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Jun Kato
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Shiho Tokunaga
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Takaaki Sugihara
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Akira Hiramatsu
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Hideyuki Hyogo
- Department of Gastroenterology and Hepatology, JA Hiroshima General Hospital, Hatsukaichi, Hiroshima, Japan
| | - Hiroshi Tobita
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Shuichi Sato
- Department of Gastroenterology and Hepatology, Shimane University School of Medicine, Izumo, Shimane, Japan
| | - Miwa Kawanaka
- Department of General Internal Medicine 2, General Medical Center, Kawasaki Medical School, Okayama, Okayama, Japan
| | - Yuichi Hara
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Kurashiki, Okayama, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima, Japan
| | - Yoshikazu Murawaki
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
| | - Hajime Isomoto
- Second Department of Internal Medicine, Tottori University School of Medicine, Yonago, Tottori, Japan
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Bredemolic Acid Ameliorates Selected Liver Function Biomarkers in a Diet-Induced Prediabetic Rat Model. Can J Gastroenterol Hepatol 2020; 2020:2475301. [PMID: 32149046 PMCID: PMC7053450 DOI: 10.1155/2020/2475301] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 12/21/2019] [Accepted: 01/06/2020] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Prediabetes is an intermediary hyperglycaemic state that precedes type 2 diabetes mellitus (T2DM) in which abnormal metabolism of glucose and lipids occurs in organs such as the liver. Evidence has shown that, about 70% of T2DM patients develop hepatic dysfunction which is found to begin during the prediabetic stage. Bredemolic acid, a pentacyclic triterpene, has been found to improve insulin sensitivity in diet-induced prediabetic rats. The effects of this compound on liver function, however, are unknown. This study was therefore designed to investigate the effects of BA on liver function in high fat-high carbohydrate (HFHC) diet-induced prediabetic rats. METHODS Thirty-six (36) male rats that weigh 150 g-180 g were divided into two groups, the non-prediabetic (n = 6) and the prediabetic groups (n = 6) and the prediabetic groups (n = 6) and the prediabetic groups (. RESULTS The induction of prediabetes resulted in increased release of liver enzymes (AST and ALT), increased liver glycogen and triglyceride, lipid peroxidation, and decreased sterol regulatory element-binding protein (SREBP1c) and antioxidant enzymes. However, the administration of BA decreased liver enzyme concentrations, decreased hepatic oxidative stress, and improved antioxidant enzymes such as SOD and GPx. CONCLUSION BA administration improved liver function in diet-induced prediabetic rats in the presence or absence of dietary intervention.
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Bril F, McPhaul MJ, Caulfield MP, Clark VC, Soldevilla-Pico C, Firpi-Morell RJ, Lai J, Shiffman D, Rowland CM, Cusi K. Performance of Plasma Biomarkers and Diagnostic Panels for Nonalcoholic Steatohepatitis and Advanced Fibrosis in Patients With Type 2 Diabetes. Diabetes Care 2020; 43:290-297. [PMID: 31604692 DOI: 10.2337/dc19-1071] [Citation(s) in RCA: 133] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2019] [Accepted: 09/10/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVE The 2019 Standards of Medical Care in Diabetes suggested that patients with nonalcoholic fatty liver disease (NAFLD) should be evaluated for liver fibrosis. However, the performance of noninvasive clinical models/scores and plasma biomarkers for the diagnosis of nonalcoholic steatohepatitis (NASH) and advanced fibrosis has not been carefully assessed in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS In this cross-sectional study, patients (n = 213) had a liver MRS, and those with a diagnosis of NAFLD underwent a percutaneous liver biopsy. Several noninvasive clinical models/scores and plasma biomarkers were measured to identify NASH and advanced fibrosis (NASH: ALT, cytokeratin-18, NashTest 2, HAIR, BARD, and OWLiver; advanced fibrosis: AST, fragments of propeptide of type III procollagen [PRO-C3], FIB-4, APRI, NAFLD fibrosis score, and FibroTest). RESULTS None of the noninvasive tools assessed for the diagnosis of NASH in patients with T2DM had an optimum performance (all areas under the curve [AUCs] <0.80). Of note, none of the panels or biomarkers was able to outperform plasma ALT (AUC 0.78 [95% CI 0.71-0.84]). Performance was better to diagnose advanced fibrosis, in which plasma PRO-C3, AST, and APRI showed better results than the other approaches (AUC 0.90 [0.85-0.95], 0.85 [0.80-0.91], and 0.86 [0.80-0.91], respectively). Again, none of the approaches did significantly better than plasma AST. Sequential use of plasma AST and other noninvasive tests may help in limiting the number of liver biopsies required to identify patients with advanced fibrosis. CONCLUSIONS Performance of noninvasive clinical models/scores and plasma biomarkers for the diagnosis of NASH or advanced fibrosis was suboptimal in patients with T2DM. Combination of multiple tests may provide an alternative to minimize the need for liver biopsies to detect fibrosis in these patients.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
- Internal Medicine, Department of Medicine, University of Florida, Gainesville, FL
| | | | | | - Virginia C Clark
- Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL
| | | | - Roberto J Firpi-Morell
- Division of Gastroenterology, Hepatology and Nutrition, University of Florida, Gainesville, FL
| | - Jinping Lai
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
| | - Dov Shiffman
- Quest Diagnostics Nichols Institute, San Juan Capistrano, CA
| | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
- Division of Endocrinology, Diabetes and Metabolism, Malcom Randall VA Medical Center, Gainesville, FL
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Baandrup Kristiansen MN, Veidal SS, Christoffersen C, Feigh M, Vrang N, Roth JD, Erickson M, Adorini L, Jelsing J. Validity of biopsy-based drug effects in a diet-induced obese mouse model of biopsy-confirmed NASH. BMC Gastroenterol 2019; 19:228. [PMID: 31883514 PMCID: PMC6935483 DOI: 10.1186/s12876-019-1149-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Accepted: 12/17/2019] [Indexed: 02/07/2023] Open
Abstract
Background Compounds in clinical development for nonalcoholic steatohepatitis (NASH) improve liver histopathology in diet-induced obese mouse models of biopsy-confirmed NASH. Since the biopsy section used for histopathological evaluation represents only < 1% of the whole mouse liver, we evaluated how well biopsy-based quantitative image analyses correlate to stereology-based whole-liver quantitative changes upon drug treatment. Methods Male leptin-deficient Lepob/Lepob mice were fed the Amylin liver NASH (AMLN) diet for 16 weeks before stratification into treatment groups using a biopsy-based evaluation of type I collagen αI (col1a1) levels. Mice were treated for 8 weeks with either vehicle (PO, QD), liraglutide (0.4 mg/kg, SC, QD), elafibranor (30 mg/kg, PO, QD) or INT-767 (10 mg/kg, PO, QD). Terminal quantitative histological assessment of liver lipid (hematoxylin-eosin staining), inflammation (galectin-3 immunohistochemistry (IHC); gal-3), and fibrosis (col1a1 IHC) was performed on terminal liver biopsies and compared with stereologically sampled serial sections spanning the medial, left and right lateral lobe of the liver. Results The distribution of liver lipid and fibrosis was markedly consistent across lobes, whereas inflammation showed some variability. While INT-767 and liraglutide significantly reduced total liver weight by 20 and 48%, respectively, elafibranor tended to exacerbate hepatomegaly in Lepob/Lepob-NASH mice. All three compounds markedly reduced biopsy-based relative liver lipid content. Elafibranor and INT-767 significantly reduced biopsy-based relative gal-3 levels (P < 0.001), whereas INT-767 and liraglutide tended to reduce relative col1a1 levels. When changes in liver weight was accounted for, both INT-767 and liraglutide significantly reduced biopsy-based total col1a1 content. Although minor differences in absolute and relative liver lipid, inflammation and fibrosis levels were observed across lobes, the interpretation of drug-induced effects were consistent with biopsy-based conclusions. Notably, the incorporation of changes in total liver mass revealed that liraglutide’s efficacy reached statistical significances for all analyzed parameters. Conclusions In conclusion, in-depth analyses of liver homogeneity demonstrated that drug-induced improvement in liver biopsy-assessed histopathology is representative for overall liver effects assessed using stereology. Importantly, these findings reveal how changes in whole-liver mass should be considered to provide a deeper understanding of apparent drug treatment efficacy in preclinical NASH studies.
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Affiliation(s)
- Maria Nicoline Baandrup Kristiansen
- Gubra Aps, Hoersholm, Denmark.,Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | | | - Christina Christoffersen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Department of Clinical Biochemistry, Bispebjerg Hospital and Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
| | | | | | | | - Mary Erickson
- Intercept Pharmaceuticals, San Diego, California, USA
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Bril F, Leeming DJ, Karsdal MA, Kalavalapalli S, Barb D, Lai J, Rabe M, Cusi K. Use of Plasma Fragments of Propeptides of Type III, V, and VI Procollagen for the Detection of Liver Fibrosis in Type 2 Diabetes. Diabetes Care 2019; 42:1348-1351. [PMID: 31221701 DOI: 10.2337/dc18-2578] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2018] [Accepted: 04/19/2019] [Indexed: 02/05/2023]
Abstract
OBJECTIVE This study assessed the utility of plasma fragments of propeptides of type III (PRO-C3), V (PRO-C5), and VI (PRO-C6) procollagen for the detection of liver fibrosis in patients with type 2 diabetes mellitus (T2DM). RESEARCH DESIGN AND METHODS Patients with T2DM (n = 191) underwent an oral glucose tolerance test, a liver 1H-MRS, and a liver biopsy when indicated. PRO-C3, PRO-C5, and PRO-C6 were blindly assessed. RESULTS PRO-C3 performed well for the diagnosis of moderate-to-advanced (area under the receiver operating characteristic curve [AUROC] 0.81 [95% CI 0.74-0.88]) and advanced (AUROC 0.88 [0.80-0.95]) fibrosis in T2DM patients. Its performance was similar to that of AST to platelet ratio index (APRI) (AUROC 0.83 and 0.87, respectively) and Fibrosis-4 (FIB-4) (AUROCs 0.83 and 0.86, respectively) scores. Use of PRO-C5 and PRO-C6 did not improve the accuracy to detect liver fibrosis. After 18 months, PRO-C3 changes were associated with changes in fibrosis stages. CONCLUSIONS PRO-C3 performed well for the detection of fibrosis in T2DM patients and showed promising results for prediction of histological changes in fibrosis stage with treatment.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
- Malcom Randall Veterans Administration Medical Center, Gainesville, FL
| | | | | | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Jinping Lai
- Department of Pathology, Immunology and Laboratory Medicine, University of Florida, Gainesville, FL
| | - Matthew Rabe
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL
- Malcom Randall Veterans Administration Medical Center, Gainesville, FL
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Culafic M, Vezmar Kovacevic S, Dopsaj V, Stulic M, Vlaisavljevic Z, Miljkovic B, Culafic D. A Simple Index for Nonalcoholic Steatohepatitis-HUFA-Based on Routinely Performed Blood Tests. ACTA ACUST UNITED AC 2019; 55:medicina55060243. [PMID: 31163711 PMCID: PMC6631799 DOI: 10.3390/medicina55060243] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Revised: 05/28/2019] [Accepted: 05/30/2019] [Indexed: 02/06/2023]
Abstract
Background and objectives: Data suggests that nearly 30% of the general population have steatosis and up to 5% of this population develops nonalcoholic steatohepatitis (NASH). Liver biopsy is still considered to be the gold standard for the diagnosis of NASH. Great effort is being made toward the identification of sensitive diagnostic tests that do not involve invasive procedures to address a common concern in patients with the nonalcoholic fatty liver disease—whether they have NASH or simple steatosis. We aimed to investigate the independent predictors and develop a non-invasive, easy-to-perform, low-cost set of parameters that may be used in clinical practice to differentiate simple steatosis from NASH. Methods: А cross-sectional study of nonalcoholic fatty liver disease (NAFLD) patients divided into two groups: group I—simple steatosis (SS) and group II—biopsy-proven NASH. Strict inclusion criteria and stepwise analysis allowed the evaluation of a vast number of measured/estimated parameters. Results: One hundred and eleven patients were included—82 with simple steatosis and 29 with biopsy-proven NASH. The probability of NASH was the highest when homeostatic model assessment of insulin resistance (HOMA-IR) was above 2.5, uric acid above 380 µmol/L, ferritin above 100 µg/L and ALT above 45 U/L. An acronym of using first letters was created and named the HUFA index. This combined model resulted in an area under the receiver operator characteristic curve (AUROC) of 0.94, provided sensitivity, specificity, positive predictive value and a negative predictive value for NASH of 70.3%, 95.1%, 83.1% and 90.0%, respectively. Conclusion: We suggest a simple non-invasive predictive index HUFA that encompasses four easily available parameters (HOMA-IR, uric acid, ferritin and ALT) to identify patients with NASH, which may reduce the need for a liver biopsy on a routine basis in patients with NAFLD.
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Affiliation(s)
- Milica Culafic
- Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia.
- Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
| | - Sandra Vezmar Kovacevic
- Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia.
| | - Violeta Dopsaj
- Department of Medical Biochemistry, Clinical Centre of Serbia, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia.
| | - Milos Stulic
- Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
| | - Zeljko Vlaisavljevic
- Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
| | - Branislava Miljkovic
- Department of Pharmacokinetics and Clinical Pharmacy, Faculty of Pharmacy, University of Belgrade, 11000 Belgrade, Serbia.
| | - Djordje Culafic
- Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, 11000 Belgrade, Serbia.
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Choi JW, Lee CH, Park JS. Comparison of laboratory indices of non-alcoholic fatty liver disease for the detection of incipient kidney dysfunction. PeerJ 2019; 7:e6524. [PMID: 30867987 PMCID: PMC6410686 DOI: 10.7717/peerj.6524] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 01/26/2019] [Indexed: 12/19/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely linked to insulin resistance and related adverse health outcomes. We investigated the non-invasive index of NAFLD that has the best performance in estimating the renal manifestations of metabolic disturbances. This nation-wide, cross-sectional study included 11,836 subjects, using various non-invasive assessments comprising routinely measured clinical and laboratory variables. The subjects were native Koreans aged 20 years or older and had no diabetes, history of liver or kidney disease. All participants were divided into quintiles according to their fibrosis-4 (FIB-4) results. Participants in the highest quintile were more hypertensive and obese with greater glycemic exposure, poor lipid profiles, and impaired kidney function, than those in the other quintiles. Multiple logistic regression, adjusted for age, sex, smoking, systolic blood pressure, white blood cell, platelet, fasting plasma glucose, and triglyceride, demonstrated that FIB-4, the hepatic steatosis index, the aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio, Gholam’s model for non-alcoholic steatohepatitis, and the BARD score were independently associated with kidney dysfunction. ROC curve analysis revealed that FIB-4 (AUC = 0.6227, 95% CI [0.5929–0.6526], p = 0.0258) was the most precise in predicting kidney dysfunction. Our findings suggest that FIB-4 may be a favorable screening tool for the renal manifestation of hepatic metabolic disturbances.
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Affiliation(s)
- Jong Wook Choi
- Department of Internal Medicine, Konkuk University Chungju Hospital, Chungju, Republic of Korea
| | - Chang Hwa Lee
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
| | - Joon-Sung Park
- Department of Internal Medicine, Hanyang University College of Medicine, Seoul, Republic of Korea
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ANXA2, PRKCE, and OXT are critical differentially genes in Nonalcoholic fatty liver disease. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2019; 12:131-137. [PMID: 31191837 PMCID: PMC6536018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
AIM Identification of prominent genes which are involved in onset and progress of steatosis stage of Nonalcoholic fatty liver disease (NAFLD) is the aim of this study. BACKGROUND NAFLD is characterized by accumulation of lipids in hepatocytes. The patients with steatosis (the first stage of NAFLD) will come across nonalcoholic steatohepatitis (NASH) and finally hepatic cirrhosis. There is correlation between cirrhosis and hepatic cancer. However, ultrasonography is used to diagnose NAFLD, biopsy is the precise diagnostic method. METHODS Gene expression profiles of 14 steatosis patients and 14 controls are retrieved from gene expression omnibus (GEO) and after statistical validation top 250 differentially expressed genes (DEGs) were determined. The characterized DEGs were included in network analysis and the central DEGs were identified. Gene ontology (GO) performed by ClueGO analysis of DEGs to determine critical biological terms. Role of prominent DEGs in steatosis is discussed in details. RESULTS Numbers of 31 significant DEGs including 20 up-regulated and 11 down-regulated ones were determined. Nine biological groups including 27 terms were recognized. Negative regulation of low-density lipoprotein particle receptor catabolic process, TRAM-dependent toll-like receptor signaling pathway, and regulation of hindgut contraction which were related to ANXA2, PRKCE, and OXT respectively were determined as critical biological term groups and DEGS. CONCLUSION Deregulation of ANXA2, PRKCE, and OXT is a critical event in steatosis. It seems these three genes are suitable biomarker to diagnosis of steatosis.
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28
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Bril F, Millán L, Kalavalapalli S, McPhaul MJ, Caulfield MP, Martinez-Arranz I, Alonso C, Ortiz Betes P, Mato JM, Cusi K. Use of a metabolomic approach to non-invasively diagnose non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. Diabetes Obes Metab 2018. [PMID: 29527789 DOI: 10.1111/dom.13285] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS To assess the utility of existing metabolomics scores to classify liver disease in patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS A total of 220 patients with T2DM were recruited. Patients underwent routine laboratory tests, liver proton magnetic resonance spectroscopy (1 H-MRS), a 75-g oral glucose tolerance test, and liver biopsy if 1 H-MRS findings indicated non-alcoholic fatty liver disease. A serum sample was blindly provided to OWL Metabolomics on which to run the OWLiver Care and OWLiver tests. RESULTS When compared with liver biopsy, the OWLiver Care and OWLiver tests had a suboptimal performance in patients with T2DM (areas under the receiver-operating characteristic [AUROC] curve both <0.70). Given the discordance of these results in this heterogeneous, multiethnic cohort compared with those of a previous report in predominantly white patients without diabetes, we examined the influence of age, ethnicity and other variables on test performance. A specific subset of patients was selected to mirror the characteristics of the population used for the development of this model (ie, white patients without T2DM). Among white patients with good glycaemic control (glycated haemoglobin <53mmol/mol [or <7%]) and without cirrhosis, the AUROC curve was significantly improved (0.79 [CI 95%: 0.68-0.90]). Among white patients with lower insulin resistance (homeostatic model assessment of insulin resistance <3) and without cirrhosis, the AUROC was even higher: 0.87 (CI 95%: 0.76-0.97). CONCLUSIONS There is a great need to develop non-invasive approaches to diagnose non-alcoholic steatohepatitis in patients with T2DM; models originally developed for patients without diabetes cannot be directly applied to patients with T2DM.
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Affiliation(s)
- Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
- Division of Endocrinology, Diabetes, and Metabolism, Malcom Randall Veterans Administration Medical Center, Gainesville, Florida
| | | | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
| | - Michael J McPhaul
- Quest Diagnostics Nichols Institute, San Juan Capristano, California
| | | | | | | | | | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, Florida
- Division of Endocrinology, Diabetes, and Metabolism, Malcom Randall Veterans Administration Medical Center, Gainesville, Florida
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Neonatal intake of oleanolic acid attenuates the subsequent development of high fructose diet-induced non-alcoholic fatty liver disease in rats. J Dev Orig Health Dis 2018; 9:500-510. [PMID: 29792584 DOI: 10.1017/s2040174418000259] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Dietary manipulations during the early postnatal period are associated with the development of metabolic disorders including non-alcoholic fatty liver disease (NAFLD) or long-term protection against metabolic dysfunction. We investigated the potential hepatoprotective effects of neonatal administration of oleanolic acid (OA), a phytochemical, on the subsequent development in adulthood, of dietary fructose-induced NAFLD. Male and female suckling rats (n=112) were gavaged with; distilled water (DW), OA (60 mg/kg), high fructose solution (HF; 20% w/v) and OA+HF (OAHF) for 7 days. The rats were weaned onto normal rat chow on day 21 up to day 55. From day 56, half of the rats in each treatment group were continued on plain water or HF as drinking fluid for 8 weeks. Hepatic lipid accumulation and hepatic histomorphometry were then determined. Fructose consumption in adulthood following neonatal fructose intake (HF+F) caused a 47-49% increase in hepatic lipid content of both male and female rats (P<0.05). However, fructose administered in adulthood only, caused a significant increase (P<0.05) in liver lipid content in females only. NAFLD activity scores for inflammation and steatosis were higher in the fructose-fed rats compared with other groups (P<0.05). Steatosis, low-grade inflammation and fibrosis were observed in rats that received HF+F. NAFLD area fraction for fibrosis was three times higher in rats that received fructose neonatally and in adulthood compared with the rats in the negative control group (P<0.05). Treatment with OA during a critical window of developmental plasticity in rats prevented the development of fructose-induced NAFLD.
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Cozzani E, Rosa GM, Burlando M, Parodi A. Psoriasis as a cardiovascular risk factor: updates and algorithmic approach. GIORN ITAL DERMAT V 2018; 153:659-665. [PMID: 29683293 DOI: 10.23736/s0392-0488.18.06040-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Although psoriasis is predominantly a chronic inflammatory skin disorder, it has been known to be associated with cardiovascular disease. Patients with psoriasis, particularly with moderate to severe forms, present an increased rate of cardiovascular mortality, myocardial infarction and stroke. However the pathophysiology of the relationship between psoriasis and cardiovascular risk and comorbidities has not yet completely known. Chronic inflammation may be considered a solid link between psoriasis and related cardiovascular events. Several cytokines and inflammatory cells play a pivotal role in the development of psoriatic lesions, resulting in angiogenesis and endothelial dysfunction. Furthermore, the imbalance between oxidative stress and antioxidant mechanisms in psoriatic patients may contribute to explain the pathogenesis of increased reactive oxygen species and the formation of atherosclerotic plaque. Other mechanistic pathways which may be involved in this relationship include cardiovascular effects of medications, a common genetic background and a higher prevalence of cardiovascular risk factors, which are often under-diagnosed and under-treated in psoriatic patients. Indeed, the early detection of specific markers of cardiovascular impairment, such as N-terminal pro B-type natriuretic peptide, homocysteine and YKL-40, may enable psoriatic patients at higher cardiovascular risk to be identified as soon as possible. This review examines the increased cardiovascular risk profile and high prevalence of cardiovascular disease associated with psoriasis, focusing on pathogenic links between psoriasis and atherosclerosis, serological markers of cardiovascular involvement and the implications of antipsoriatic therapies on cardiovascular risk and proposes a flow chart, that every dermatologist should follow to screen psoriatic patients.
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Affiliation(s)
- Emanuele Cozzani
- Department of Dermatology, San Martino Policlinic, University of Genoa, Genoa, Italy -
| | - Gian Marco Rosa
- Department of Cardiology, San Martino Policlinic, University of Genoa, Genoa, Italy
| | - Martina Burlando
- Department of Dermatology, San Martino Policlinic, University of Genoa, Genoa, Italy
| | - Aurora Parodi
- Department of Dermatology, San Martino Policlinic, University of Genoa, Genoa, Italy
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Joo SK, Kim W, Kim D, Kim JH, Oh S, Lee KL, Chang MS, Jung YJ, So YH, Lee MS, Bae JM, Kim BG. Steatosis severity affects the diagnostic performances of noninvasive fibrosis tests in nonalcoholic fatty liver disease. Liver Int 2018; 38:331-341. [PMID: 28796410 DOI: 10.1111/liv.13549] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Accepted: 07/30/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Nonalcoholic fatty liver disease (NAFLD) includes a wide spectrum of heterogeneous metabolic subtypes. This study compared the diagnostic performances of noninvasive fibrosis tests in predicting advanced fibrosis among patients with NAFLD and examined the effects of the subgroups on their diagnostic performances. METHODS Three hundred fifteen patients with biopsy-proven NAFLD were prospectively enrolled. Acoustic radiation force impulse imaging (ARFI) was performed to obtain liver stiffness measurements (LSMs). The aspartate aminotransferase-to-alanine aminotransferase ratio (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis 4 index (FIB-4), NAFLD fibrosis score (NFS) and BARD score were calculated. The diagnostic performances of noninvasive fibrosis tests were evaluated using the area under the receiver operating characteristic curve (AUROC). RESULTS Fibrosis 4 index (FIB-4) showed the highest AUROC for advanced fibrosis (0.866; 95% CI, 0.811-0.922). AUROC subgroup analyses were performed to assess the effects of the subgroups on diagnostic performance. For patients with advanced fibrosis, the APRI, BARD, FIB-4 and NFS AUROCs were significantly different among the radiological steatosis grades. Additionally, the AUROC of ARFI tended to decrease with increasing radiological steatosis severity. FIB-4 and NFS showed significantly lower AUROCs for advanced fibrosis in obese NAFLD than in nonobese NAFLD (P = .002 and P < .001 respectively). However, only radiological steatosis severity was independently associated with advanced fibrosis in multivariable analysis. CONCLUSIONS Steatosis severity may affect the diagnostic performances of noninvasive fibrosis tests in patients with NAFLD. The application of different tools should be tailored for various NAFLD subgroups to optimize noninvasive fibrosis assessments.
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Affiliation(s)
- 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
| | - 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
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Jung Ho Kim
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Sohee Oh
- Department of Biostatistics, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Kook Lae Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, 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
| | - Yong Jin Jung
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Young Ho So
- Department of Radiology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Myoung Seok Lee
- Department of Radiology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University College of Medicine, Seoul Metropolitan Government Boramae Medical Center, Seoul, Korea
| | - Byeong Gwan 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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Yoo W, Gjuka D, Stevenson HL, Song X, Shen H, Yoo SY, Wang J, Fallon M, Ioannou GN, Harrison SA, Beretta L. Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid. PLoS One 2017; 12:e0189965. [PMID: 29244873 PMCID: PMC5731750 DOI: 10.1371/journal.pone.0189965] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Accepted: 12/05/2017] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD) NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn’t affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.
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Affiliation(s)
- Wonbeak Yoo
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Donjeta Gjuka
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Heather L. Stevenson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Xiaoling Song
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America
| | - Hong Shen
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Suk Young Yoo
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Jing Wang
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
| | - Michael Fallon
- Division of Gastroenterology, The University of Texas Health Science Center at Houston, Houston, Texas, United States of America
| | - George N. Ioannou
- Division of Gastroenterology, Veterans Affairs Puget Sound Health Care System and University of Washington, Seattle, Washington, United States of America
| | - Stephen A. Harrison
- Department of Medicine, Brooke Army Medical Center, San Antonio, Texas, United States of America
| | - Laura Beretta
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America
- * E-mail:
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Lee TY, Wu JC, Yu SH, Lin JT, Wu MS, Wu CY. The occurrence of hepatocellular carcinoma in different risk stratifications of clinically noncirrhotic nonalcoholic fatty liver disease. Int J Cancer 2017; 141:1307-1314. [PMID: 28509327 DOI: 10.1002/ijc.30784] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 04/18/2017] [Accepted: 04/26/2017] [Indexed: 01/04/2025]
Abstract
Nonalcoholic fatty liver disease (NAFLD) may be a cause of hepatocellular carcinoma (HCC), but its high prevalence challenges current surveillance strategies. We aimed to evaluate HCC incidences in different risk stratifications for noncirrhotic NAFLD. Using Taiwan's National Health Insurance Research Database, we located 31,571 patients with NAFLD between the years 1998 and 2012. After excluding other causes of hepatitis, underlying cirrhosis or malignancy, 18,080 patients were recruited for final analysis. Cumulative incidences of HCC were analyzed after adjusting for competing mortality. With a median follow-up duration of 6.32 years in the study cohort, the 10-year cumulative incidence of HCC was 2.73% [95% confidence interval (CI): 1.69-3.76%]. Hepatoprotectant was used as a surrogate marker for elevated serum alanine transaminase (ALT). After adjusting for age, gender, hypertension, hypercholesterolemia, diabetes mellitus, gout, statin use, metformin use and aspirin use, elevated ALT was independently associated with an increased HCC risk [hazard ratio (HR) 6.80, 95% CI: 3.00-15.42; p < 0.001]. Multivariate stratified analysis verified this association in all subgroups (HR> 1.0). Moreover, increased age (HR 1.08 per year, 95% CI: 1.05-1.11) and statin use (HR 0.29, 95% CI: 0.12-0.68) were also identified as independent risk factors. The 10-year cumulative HCC incidence was highest in older (age >55 years) patients with ALT elevation (12.41%, 95% CI: 5.99-18.83%), but lowest in younger patients without ALT elevation (0.36%, 95% CI: 0-1.08%). The incidence of HCC was relatively low in patients with clinically noncirrhotic NAFLD, however, HCC risk was significantly increased in older patients experiencing an elevated serum ALT.
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Affiliation(s)
- Teng-Yu Lee
- Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
- Department of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Jaw-Ching Wu
- Institute of Clinical Medicine and Genomic Research Center, National Yang-Ming University, Taipei, Taiwan
- Translational Research Division, Medical Research Department, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Shi-Hang Yu
- Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Jaw-Town Lin
- School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
- Department of Internal Medicine, E-Da Hospital/I-Shou University, Kaohsiung, Taiwan
- Center for Health Policy Research and Development, National Health Research Institutes, Miaoli, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Chun-Ying Wu
- Division of Gastroenterology & Hepatology, Taichung Veterans General Hospital, Taichung, Taiwan
- Faculty of Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan
- College of Public Health and Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan
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Sharma DL, Lakhani HV, Klug RL, Snoad B, El-Hamdani R, Shapiro JI, Sodhi K. Investigating Molecular Connections of Non-alcoholic Fatty Liver Disease with Associated Pathological Conditions in West Virginia for Biomarker Analysis. ACTA ACUST UNITED AC 2017; 8. [PMID: 29177105 PMCID: PMC5701750 DOI: 10.4172/2155-9899.1000523] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a disease characterized by a steatosis of the liver that may progress to more serious pathological conditions including: nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis. As the prevalence of NAFLD has increased worldwide in recent years, pathophysiology and risk factors associated with disease progression of NAFLD are at the focus of many studies. NAFLD is related to and shares common serum biomarkers with cardiovascular disease (CVD), type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome (MetS). West Virginia (WV) is a state with some of the highest rates of CVD, obesity and diabetes mellitus. As NAFLD is closely related to these diseases, it is of particular interest in WV. Currently there is no cost-effective, standardized method used clinically to detect NAFLD prior to the onset of reversible complications. At this time, the diagnosis of NAFLD is made with costly radiologic studies and invasive biopsy. These studies are only diagnostic once changes to hepatic tissue have occurred. The diagnosis of NAFLD by traditional methods may not allow for successful intervention and may not be readily available in areas with already sparse medical resources. In this literature review, we identify a list of biomarkers common among CVD, T2DM, obesity, MetS and NAFLD. From this research we propose the following biomarkers are good candidates for inclusion in a panel of biomarkers for the early detection of NAFLD: adiponectin, AST, ALT, apo-B, CK18, CPS1, CRP, FABP-1, ferritin, GGT, GRP78, HDL-C, IGF-1, IL-1β, 6, 8, 10, IRS-2PAI-1, leptin, lumican, MDA SREBP-1c and TNF-α. Creating and implementing a biomarker panel for the early detection and attenuation of NAFLD, prior to the onset of irreversible complication would provide maximum benefit and decrease the disease burden on the patients and healthcare system of WV.
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Affiliation(s)
- Dana L Sharma
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Hari Vishal Lakhani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rebecca L Klug
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Brian Snoad
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Rawan El-Hamdani
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Joseph I Shapiro
- Department of Internal Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Komal Sodhi
- Department of Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
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von Loeffelholz C, Lieske S, Neuschäfer-Rube F, Willmes DM, Raschzok N, Sauer IM, König J, Fromm M, Horn P, Chatzigeorgiou A, Pathe-Neuschäfer-Rube A, Jordan J, Pfeiffer AFH, Mingrone G, Bornstein SR, Stroehle P, Harms C, Wunderlich FT, Helfand SL, Bernier M, de Cabo R, Shulman GI, Chavakis T, Püschel GP, Birkenfeld AL. The human longevity gene homolog INDY and interleukin-6 interact in hepatic lipid metabolism. Hepatology 2017; 66:616-630. [PMID: 28133767 PMCID: PMC5519435 DOI: 10.1002/hep.29089] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Revised: 12/15/2016] [Accepted: 01/19/2017] [Indexed: 12/17/2022]
Abstract
UNLABELLED Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY. CONCLUSION Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616-630).
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Affiliation(s)
- Christian von Loeffelholz
- Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, and Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, 01774, Germany
| | - Stefanie Lieske
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany
- Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, 14558, Germany
| | | | - Diana M. Willmes
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany
| | - Nathanael Raschzok
- General, Visceral, and Transplantation Surgery, Charité – University School of Medicine, Berlin, 10117, Germany
| | - Igor M. Sauer
- General, Visceral, and Transplantation Surgery, Charité – University School of Medicine, Berlin, 10117, Germany
| | - Jörg König
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, 91054, Germany
| | - Martin Fromm
- Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität, Erlangen-Nürnberg, 91054, Germany
| | - Paul Horn
- Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Friedrich Schiller University, and Department of Anesthesiology and Intensive Care, Jena University Hospital, Jena, 01774, Germany
| | - Antonis Chatzigeorgiou
- Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Dresden, TUD, Germany
| | | | - Jens Jordan
- Institute for Clinical Pharmacology, Hannover Medical School, 30625 Hannover, Germany
| | - Andreas F. H. Pfeiffer
- Department of Endocrinology, Diabetes and Nutrition, Charité – University School of Medicine, Berlin, 10117, Germany
- German Centre for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Geltrude Mingrone
- Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE1 8WA, UK
- Catholic University of Rome, Department of Internal Medicine, Rome, Italy
| | - Stefan R. Bornstein
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany
- Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE1 8WA, UK
- German Centre for Diabetes Research (DZD e.V.), Neuherberg, Germany
| | - Peter Stroehle
- Max Planck Institute for Metabolism Research, Excellence cluster on cellular stress responses in aging associated diseases (CECAD), Cologne, 5093, Germany
| | - Christoph Harms
- Charité-Universitätsmedizin Berlin, Center for Stroke Research, Department of Experimental Neurology, Charitéplatz 1, 10117 Berlin, Germany
| | - F. Thomas Wunderlich
- Max Planck Institute for Metabolism Research, Excellence cluster on cellular stress responses in aging associated diseases (CECAD), Cologne, 5093, Germany
| | - Stephen. L. Helfand
- Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA
| | - Michel Bernier
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Rafael de Cabo
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA
| | - Gerald I. Shulman
- Department of Internal Medicine, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Dresden, TUD, Germany
| | - Gerhard. P. Püschel
- Lehrstuhl für Biochemie der Ernährung, Universität Potsdam, Potsdam, 14558, Germany
| | - Andreas. L. Birkenfeld
- Section of Metabolic Vascular Medicine, Medical Clinic III, Dresden University School of Medicine, Paul Langerhans Institute Dresden (PLID), TU Dresden,01307 Germany
- Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE1 8WA, UK
- German Centre for Diabetes Research (DZD e.V.), Neuherberg, Germany
- Competence Center for Metabolic Vascular Medicine, GWT-TU Dresden, Germany
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Caira S, Iannelli A, Sciarrillo R, Picariello G, Renzone G, Scaloni A, Addeo P. Differential representation of liver proteins in obese human subjects suggests novel biomarkers and promising targets for drug development in obesity. J Enzyme Inhib Med Chem 2017; 32:672-682. [PMID: 28274171 PMCID: PMC6009959 DOI: 10.1080/14756366.2017.1292262] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
The proteome of liver biopsies from human obese (O) subjects has been compared to those of nonobese (NO) subjects using two-dimensional gel electrophoresis (2-DE). Differentially represented proteins were identified by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry (MS)-based peptide mass fingerprinting (PMF) and nanoflow-liquid chromatography coupled to electrospray-tandem mass spectrometry (nLC-ESI-MS/MS). Overall, 61 gene products common to all of the liver biopsies were identified within 65 spots, among which 25 ones were differently represented between O and NO subjects. In particular, over-representation of short-chain acyl-CoA dehydrogenase, Δ(3,5)-Δ(2,4)dienoyl-CoA isomerase, acetyl-CoA acetyltransferase, glyoxylate reductase/hydroxypyruvate reductase, fructose-biphosphate aldolase B, peroxiredoxin I, protein DJ-1, catalase, α- and β-hemoglobin subunits, 3-mercaptopyruvate S-transferase, calreticulin, aminoacylase 1, phenazine biosynthesis-like domain-containing protein and a form of fatty acid-binding protein, together with downrepresentation of glutamate dehydrogenase, glutathione S-transferase A1, S-adenosylmethionine synthase 1A and a form of apolipoprotein A-I, was associated with the obesity condition. Some of these metabolic enzymes and antioxidant proteins have already been identified as putative diagnostic markers of liver dysfunction in animal models of steatosis or obesity, suggesting additional investigations on their role in these syndromes. Their differential representation in human liver was suggestive of their consideration as obesity human biomarkers and for the development of novel antiobesity drugs.
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Affiliation(s)
- Simonetta Caira
- a Proteomics and Mass Spectrometry Laboratory , ISPAAM, National Research Council , Naples , Italy
| | - Antonio Iannelli
- b Département de Chirurgie Digestive , Centre Hospitalier Universitarie de Nice , Nice , France
| | - Rosaria Sciarrillo
- c Dipartimento di Scienze e Tecnologie , Università degli Studi del Sannio , Benevento , Italy
| | | | - Giovanni Renzone
- a Proteomics and Mass Spectrometry Laboratory , ISPAAM, National Research Council , Naples , Italy
| | - Andrea Scaloni
- a Proteomics and Mass Spectrometry Laboratory , ISPAAM, National Research Council , Naples , Italy
| | - Pietro Addeo
- e Service de Chirurgie Hépatique, Pancréatique, Biliaire et Transplantation, Pôle des Pathologies Digestives, Hépatiques et de la Transplantation, Hôpital de Hautepierre , Université de Strasbourg, Hôpitaux Universitaires de Strasbourg , Strasbourg , France
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Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2016; 4:50-61. [PMID: 28344991 PMCID: PMC5363319 DOI: 10.1016/j.omtm.2016.11.004] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/07/2016] [Accepted: 11/15/2016] [Indexed: 12/14/2022]
Abstract
Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation of liver macrophages are suggested to be essential to disease progression. In the present study, we show that a low dose of an anti-CD163-IgG-dexamethasone conjugate targeting the hemoglobin scavenger receptor CD163 in Kupffer cells and other M2-type macrophages has a profound effect on liver inflammatory changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone conjugated to a control IgG did not have this effect but instead exacerbated liver lipid accumulation. The low-dose anti-CD163-IgG-dexamethasone conjugate displayed no apparent systemic side effects. In conclusion, macrophage targeting by antibody-directed anti-inflammatory low-dose glucocorticoid therapy seems to be a promising approach for safe treatment of fructose-induced liver inflammation.
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Salman AAA, Aboelfadl SAE, Heagzy MAE. New Era for Usage of Serum Liver Enzymes as A Promising Horizon for the Prediction of Non-Alcoholic Fatty Liver Disease. Open Access Maced J Med Sci 2016; 4:348-352. [PMID: 27703554 PMCID: PMC5042614 DOI: 10.3889/oamjms.2016.092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Revised: 07/30/2016] [Accepted: 07/30/2016] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Liver histology remains the gold standard for assessing non-alcoholic fatty liver disease (NAFLD). Noninvasive serological markers and radiological methods have been developed to evaluate steatosis to avoid biopsy. AIM To put cutoff value for liver enzymes that could predict non-alcoholic steatohepatitis (NASH). PATIENTS AND METHODS This study was conducted on 54 patients (with NAFLD diagnosed by the US). Patients were subjected to history, physical, anthropometric measurements, investigations including liver enzymes, abdominal US, and liver biopsy. According to biopsy results, patients were subdivided according to NASH development. Also, biopsy results were correlated to the levels of liver enzymes. RESULTS Forty-seven patients who were suspected to have NAFLD by sonar were confirmed by biopsy. There was a significant correlation between steatosis degree in biopsy and sonar. Correlation study between steatosis in biopsy and ALT level showed highly significant positive correlation. Correlation study between steatosis in biopsy on one side & AST and GGT on the other side showed significant positive correlation. Cutoff value for detection of NASH using ALT & AST & and GGT were 50.5, 56, 60.5 respectively with sensitivity = 95.5, 90.5, 86.4 % and specificity = 93.8, 100, 87.5%. CONCLUSION Cut off values of liver enzymes can be combined with abdominal sonar to predict NASH.
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Petrick A, Benotti P, Wood GC, Still CD, Strodel WE, Gabrielsen J, Rolston D, Chu X, Argyropoulos G, Ibele A, Gerhard GS. Utility of Ultrasound, Transaminases, and Visual Inspection to Assess Nonalcoholic Fatty Liver Disease in Bariatric Surgery Patients. Obes Surg 2016; 25:2368-75. [PMID: 26003548 DOI: 10.1007/s11695-015-1707-6] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is common in adults with extreme obesity and can impact long-term health and survival. Liver biopsy is the only accurate test for diagnosis and staging, but is invasive and costly. Non-invasive testing offers an attractive alternate, but the overall accuracy remains a significant issue. This study was conducted to determine the accuracy and clinical utility of pre-operative ultrasound and liver transaminase levels, as well as intra-operative hepatic visual inspection, for assessing presence of NAFLD as confirmed by hepatic histology. METHODS Data was collected prospectively from 580 morbidly obese adult patients who underwent Roux-en-Y gastric bypass surgery with intraoperative wedge biopsy between January 2004 and February 2009. Complete data for ultrasound, ALT and AST levels, and documented visual inspection was available for 513 patients. RESULTS The prevalence of NAFLD was 69 % and that of NASH was 32 %. The individual non-invasive clinical assessments demonstrated low sensitivity, specificity, and accuracy for detecting the presence of steatosis, steatohepatitis, or fibrosis. The combination of normal or abnormal results for all tests improved predictive utility. Abnormal tests with all three assessments had a sensitivity of 95-98 % and a specificity of 28-48 % for major histologic findings in NAFLD/NASH. Normal tests with all three assessments had a sensitivity of 12-22 % and a specificity of 89-97 % for major histologic findings in NAFLD/NASH. CONCLUSIONS Although individual clinical tests for NAFLD have limited accuracy, the use of combined clinical tests may prove useful.
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Affiliation(s)
| | - Peter Benotti
- Geisinger Obesity Research Institute, Danville, PA, USA.
| | - G Craig Wood
- Geisinger Obesity Research Institute, Danville, PA, USA
| | | | | | | | - David Rolston
- Geisinger Obesity Research Institute, Danville, PA, USA
| | - Xin Chu
- Geisinger Obesity Research Institute, Danville, PA, USA
| | | | - Anna Ibele
- Geisinger Obesity Research Institute, Danville, PA, USA
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Erçin CN, Doğru T, Çelebi G, Gürel H, Genç H, Sertoğlu E, Bağci S. The relationship between blood urea nitrogen levels and metabolic, biochemical, and histopathologic findings of nondiabetic, nonhypertensive patients with nonalcoholic fatty liver disease. Turk J Med Sci 2016; 46:985-91. [PMID: 27513394 DOI: 10.3906/sag-1502-144] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 09/13/2015] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND/AIM Nonalcoholic fatty liver disease (NAFLD) is known as the most common cause of chronic liver disease. It is accepted that the leading cause of death in patients with NAFLD is from coronary events. Blood urea nitrogen (BUN) was used as a prognostic indicator for cardiovascular disease. We aimed to investigate the relationship between BUN levels and metabolic, biochemical, and histopathologic findings of nondiabetic patients with NAFLD. MATERIALS AND METHODS A total of 195 male patients with biopsy proven NAFLD and 82 healthy controls with normal liver and renal function tests and normal abdominal ultrasonography were enrolled in the study. BUN levels were reviewed retrospectively. RESULTS The mean BUN levels of patients and controls were 13.07 (11.3-15.41) and 13.31 (10.97-15.87) mg/dL respectively. Patients were grouped as simple steatosis (n = 33, 16.9%), borderline nonalcoholic steatohepatitis (n = 64, 32.8%), and nonalcoholic steatohepatitis (n = 98, 50.3%), and the BUN levels of the histologic subgroups were 13.14 ± 2.89, 14.34 ± 3.04, and 13.71 ± 3.21 mg/dL, respectively. We could not find any differences between the patient group and control group with respect to BUN levels. CONCLUSION Our findings showed that there was no relationship between BUN levels and metabolic, biochemical, and histopathologic findings of patients with NAFLD. Further investigations, including in patients with late stages of NAFLD, are required.
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Affiliation(s)
- Cemal Nuri Erçin
- Department of Gastroenterology, Gülhane Military Medical Academy, Ankara, Turkey
| | - Teoman Doğru
- Department of Gastroenterology, Gülhane Military Medical Academy, Ankara, Turkey
| | - Gürkan Çelebi
- Department of Gastroenterology, Gülhane Military Medical Academy, Ankara, Turkey
| | - Hasan Gürel
- Department of Gastroenterology, Gülhane Military Medical Academy, Ankara, Turkey
| | | | - Erdim Sertoğlu
- Anıttepe Military Dispensary, Medical Biochemistry, Ankara, Turkey
| | - Sait Bağci
- Department of Gastroenterology, Gülhane Military Medical Academy, Ankara, Turkey
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Non-Alcoholic Steatohepatitis: Limited Available Treatment Options but Promising Drugs in Development and Recent Progress Towards a Regulatory Approval Pathway. Drugs 2016. [PMID: 26201461 PMCID: PMC4532706 DOI: 10.1007/s40265-015-0437-3] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is increasing world-wide in parallel to the increase of the obesity epidemic. Insulin resistance (IR) and the accumulation of triglyceride-derived toxic lipid metabolites play a key role in its pathogenesis. Multiple biomarkers are being evaluated for the non-invasive diagnosis of NASH. However, a percutaneous liver biopsy is still the gold standard method; the minimal diagnostic criteria include the presence of >5 % macrovesicular steatosis, inflammation, and liver cell ballooning. Several pharmaceutical agents have been evaluated for the treatment of NASH; however, no single therapy has been approved so far. Due to the increasing prevalence and the health burden, there is a high need to develop therapeutic strategies for patients with NASH targeting both those with early-stage disease as well as those with advanced liver fibrosis. There are unique challenges in the design of studies for these target populations. Collaborative efforts of health authorities, medical disease experts, and the pharmaceutical industry are ongoing to align options for a registrational pathway. Several companies pursuing different mechanisms of action are nearing the end of phase II with their candidates. This manuscript reviews those compounds with a variety of mode of actions that have been evaluated and/or are currently being tested with the goal of achieving a NAFLD/NASH indication.
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Marcuccilli M, Chonchol M. NAFLD and Chronic Kidney Disease. Int J Mol Sci 2016; 17:562. [PMID: 27089331 PMCID: PMC4849018 DOI: 10.3390/ijms17040562] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Revised: 03/25/2016] [Accepted: 03/28/2016] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in developed countries and it is now considered a risk factor for cardiovascular disease. Evidence linking NAFLD to the development and progression of chronic kidney disease (CKD) is emerging as a popular area of scientific interest. The rise in simultaneous liver-kidney transplantation as well as the significant cost associated with the presence of chronic kidney disease in the NAFLD population make this entity a worthwhile target for screening and therapeutic intervention. While several cross-sectional and case control studies have been published to substantiate these theories, very little data exists on the underlying cause of NAFLD and CKD. In this review, we will discuss the most recent publications on the diagnosis of NAFLD as well new evidence regarding the pathophysiology of NAFLD and CKD as an inflammatory disorder. These mechanisms include the role of obesity, the renin-angiotensin system, and dysregulation of fructose metabolism and lipogenesis in the development of both disorders. Further investigation of these pathways may lead to novel therapies that aim to target the NAFLD and CKD. However, more prospective studies that include information on both renal and liver histology will be necessary in order to understand the relationship between these diseases.
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Affiliation(s)
- Morgan Marcuccilli
- Division of Renal Diseases and Hypertension, University of Colorado Hospital, Aurora, CO 80045, USA.
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, University of Colorado Denver, 13199 East Montview Boulevard, Suite 495, Aurora, CO 80045, USA.
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Renelus B, Foster T. Noninvasive evaluation of nonalcoholic fatty liver disease. Clin Liver Dis (Hoboken) 2016; 7:45-47. [PMID: 31041027 PMCID: PMC6490259 DOI: 10.1002/cld.538] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 01/03/2016] [Accepted: 02/24/2016] [Indexed: 02/04/2023] Open
Affiliation(s)
- Benjamin Renelus
- Morehouse School of Medicine Internal Medicine Residency Program
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Ganzetti G, Campanati A, Molinelli E, Offidani A. Psoriasis, non-alcoholic fatty liver disease, and cardiovascular disease: Three different diseases on a unique background. World J Cardiol 2016; 8:120-131. [PMID: 26981209 PMCID: PMC4766264 DOI: 10.4330/wjc.v8.i2.120] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 09/04/2015] [Accepted: 12/18/2015] [Indexed: 02/06/2023] Open
Abstract
Psoriasis is a chronic inflammatory immune-mediated skin disease, frequently associated with systemic comorbidities. According to recent data, patients with psoriasis show a greater prevalence of metabolic syndrome, which confers a higher cardiovascular risk. The link between these pathological conditions appears to be a chronic low-grade inflammatory status. The aim of this review is to focus on the multiple epidemiological and physio-pathogenetic aspects linking non-alcoholic fatty liver disease, psoriasis, and cardiovascular disease.
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Yoshimura K, Okanoue T, Ebise H, Iwasaki T, Mizuno M, Shima T, Ichihara J, Yamazaki K. Identification of novel noninvasive markers for diagnosing nonalcoholic steatohepatitis and related fibrosis by data mining. Hepatology 2016; 63:462-73. [PMID: 26390046 DOI: 10.1002/hep.28226] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2015] [Accepted: 09/15/2015] [Indexed: 02/06/2023]
Abstract
UNLABELLED It is important that patients with nonalcoholic steatohepatitis (NASH) are diagnosed and treated early to prevent serious complications, such as liver cirrhosis or hepatocellular carcinoma. However, current methods for NASH diagnosis are invasive given that they rely on liver biopsy, making early diagnosis difficult. In this study, we developed novel noninvasive markers for the diagnosis of NASH and NASH-related fibrosis. A total of 132 Japanese patients with nonalcoholic fatty liver disease were included in this study. Blood samples were collected, and 261 biomolecules were quantified in serum. Using cluster and pathway analyses, we identified biomolecule modules connected to biological events that occur with disease progression to NASH. The modules were used as variables for diagnosis, leading to a NASH diagnostic marker associated with two biological events, that is, protective response to hepatic steatosis and hepatitis-causing innate immune response. Regarding the NASH-related fibrosis marker, immunological responses to hepatocyte injury were identified as a biological event. To develop diagnostic markers for NASH and NASH-related fibrosis, specific biomolecules were selected from each biomolecule module. The former marker was obtained by averaging the levels of four biomolecules, whereas the latter was obtained by averaging the levels of two biomolecules. Both markers achieved a diagnostic accuracy of almost 0.9 of the area under the receiver operating characteristic curve, and the latter exhibited equivalent performance in an independent group of 62 prospectively recruited patients. CONCLUSION We developed highly accurate markers for the diagnosis of both NASH and NASH-related fibrosis (i.e., FM-NASH index and FM-fibro index, respectively). These markers may be used as an alternative diagnostic tool to liver biopsy.
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Affiliation(s)
- Keito Yoshimura
- Genomic Science Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan
| | - Takeshi Okanoue
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Hayao Ebise
- Genomic Science Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan
| | - Tsuyoshi Iwasaki
- Genomic Science Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan
| | - Masayuki Mizuno
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Toshihide Shima
- Department of Gastroenterology and Hepatology, Saiseikai Suita Hospital, Osaka, Japan
| | - Junji Ichihara
- Genomic Science Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan
| | - Kazuto Yamazaki
- Genomic Science Laboratories, Sumitomo Dainippon Pharma Co., Ltd., Osaka, Japan
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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease. Nat Commun 2015; 5:3083. [PMID: 24419221 DOI: 10.1038/ncomms4083] [Citation(s) in RCA: 410] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 12/10/2013] [Indexed: 02/07/2023] Open
Abstract
Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis.
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Fu L, Bruckbauer A, Li F, Cao Q, Cui X, Wu R, Shi H, Zemel MB, Xue B. Interaction between metformin and leucine in reducing hyperlipidemia and hepatic lipid accumulation in diet-induced obese mice. Metabolism 2015; 64:1426-34. [PMID: 26303871 DOI: 10.1016/j.metabol.2015.07.006] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Revised: 06/18/2015] [Accepted: 07/13/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Leucine stimulates Sirt1 and AMPK signaling in vitro and in vivo. Since metformin converges on the same pathway, we have tested the ability of leucine to amplify the effects of metformin on AMPK-mediated hepatic lipid metabolism in diet-induced-obese insulin-resistant mice. METHODS Mice were fed high leucine (24 g/kg diet) with or without sub-therapeutic levels of metformin (0.05-0.50 g/kg diet) or therapeutic levels of metformin (1.5 g/kg diet; ~300 mg/kg body weight). RESULTS High-fat diet produced a 10-fold increase in inguinal fat pad weight and 25% increase in liver weight, histologically confirmed as steatosis. The leucine-metformin combinations reduced fat pad mass, normalized liver weight, liver and plasma lipids and inflammatory markers (interleukin 6, interleukin 1 beta, tumor necrosis factor alpha, monocyte chemotactic protein-1, C-reactive protein) comparable to the effects of therapeutic metformin. Moreover, the highest sub-therapeutic levels of metformin with leucine exerted significantly greater effects than therapeutic levels of metformin and fully reversed hepatic steatosis. These effects were mediated by upregulation of hepatic AMPK and associated changes in lipogenic gene expression (fatty acid synthase, stearoyl CoA desaturase, acetyl CoA carboxylase) in the liver. CONCLUSION A low-dose leucine-metformin combination exerts comparable effects on adiposity to therapeutic doses of metformin and fully reverses hepatic steatosis in diet-induced-obese mice.
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Affiliation(s)
- Lizhi Fu
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Antje Bruckbauer
- NuSirt Biopharma Inc., 3835 Cleghorn Ave, Nashville, TN 37215, USA
| | - Fenfen Li
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Qiang Cao
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Xin Cui
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Rui Wu
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Hang Shi
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA
| | - Michael B Zemel
- NuSirt Biopharma Inc., 3835 Cleghorn Ave, Nashville, TN 37215, USA
| | - Bingzhong Xue
- Center for Obesity Reversal, Department of Biology, Georgia State University, 24 Peachtree Center Avenue, Atlanta, GA 30303, USA.
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Abstract
OBJECTIVE Because the prevalence of obesity in children is increasing, the frequency of pediatric nonalcoholic fatty liver disease (NAFLD) is growing. A reliable noninvasive biomarker for monitoring progression of liver fibrosis would be useful. In cirrhotic persons serum bile acid (BA) levels are significantly elevated. We hypothesized that BA levels and composition in pediatric NAFLD vary depending on the stage of fibrosis. METHODS Children with NAFLD were compared with controls and classified by stages of fibrosis (NAFLD-F0, n = 27; NAFLD-F≥1, n = 65) based on liver-biopsy findings. Fasted metabolic and cholestasis status was assessed by several blood tests. BA profiles were measured by tandem mass spectrometry and compared with healthy controls (n = 105). RESULTS Compared with controls, all of the NAFLD patients were overweight and showed significantly elevated glucose, insulin, aspartate transaminase, and alanine transaminase levels. Total serum BAs were lower in nonfibrotic NAFLD children than in a control cohort (1.73 vs 3.6 μmol/L) because low glycine-conjugated BA levels were incompletely compensated by increases in taurine-conjugated or unconjugated BA. In patients with fibrotic NAFLD, BA levels were lower than in controls (2.45 vs 3.6 μmol/L) but higher than in nonfibrotic patients (2.45 vs 1.73 μmol/L), and the BA pattern resembled that of healthy controls. Fibroblast growth factor 19 levels were significantly lower in both NAFLD groups than in controls (P ≤ 0.001) and were positively correlated with ursodeoxycholic acid levels. CONCLUSIONS Our data indicate that serum BA levels decrease in early NAFLD and increase during progression to fibrosis. Given that BA levels are increased in cirrhotic adults, we postulate a continuous rise as NAFLD advances. BA may have a value as a noninvasive biomarker in pediatric NAFLD progression.
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Letters to the Editor. Menopause 2015; 22:797-8. [DOI: 10.1097/gme.0000000000000497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Enomoto H, Bando Y, Nakamura H, Nishiguchi S, Koga M. Liver fibrosis markers of nonalcoholic steatohepatitis. World J Gastroenterol 2015; 21:7427-7435. [PMID: 26139988 PMCID: PMC4481437 DOI: 10.3748/wjg.v21.i24.7427] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Revised: 04/27/2015] [Accepted: 05/07/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver injury. NAFLD includes a wide range of clinical conditions from simple steatosis to nonalcoholic steatohepatitis (NASH), advanced fibrosis, and liver cirrhosis. The histological findings of NASH indicate hepatic steatosis and inflammation with characteristic hepatocyte injury (e.g., ballooning degeneration), as is observed in the patients with alcoholic liver disease. NASH is considered to be a potentially health-threatening disease that can progress to cirrhosis. A liver biopsy remains the most reliable diagnostic method to appropriately diagnose NASH, evaluate the severity of liver fibrosis, and determine the prognosis and optimal treatment. However, this invasive technique is associated with several limitations in routine use, and a number of biomarkers have been developed in order to predict the degree of liver fibrosis. In the present article, we review the current status of noninvasive biomarkers available to estimate liver fibrosis in the patients with NASH. We also discuss our recent findings on the use of the glycated albumin-to-glycated hemoglobin ratio, which is a new index that correlates to various chronic liver diseases, including NASH.
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