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McGrath MS, Wentworth BJ. The Renin-Angiotensin System in Liver Disease. Int J Mol Sci 2024; 25:5807. [PMID: 38891995 PMCID: PMC11172481 DOI: 10.3390/ijms25115807] [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: 05/04/2024] [Revised: 05/23/2024] [Accepted: 05/25/2024] [Indexed: 06/21/2024] Open
Abstract
The renin-angiotensin system (RAS) is a complex homeostatic entity with multiorgan systemic and local effects. Traditionally, RAS works in conjunction with the kidney to control effective arterial circulation, systemic vascular resistance, and electrolyte balance. However, chronic hepatic injury and resulting splanchnic dilation may disrupt this delicate balance. The role of RAS in liver disease, however, is even more extensive, modulating hepatic fibrosis and portal hypertension. Recognition of an alternative RAS pathway in the past few decades has changed our understanding of RAS in liver disease, and the concept of opposing vs. "rebalanced" forces is an ongoing focus of research. Whether RAS inhibition is beneficial in patients with chronic liver disease appears to be context-dependent, but further study is needed to optimize clinical management and reduce organ-specific morbidity and mortality. This review presents the current understanding of RAS in liver disease, acknowledges areas of uncertainty, and describes potential areas of future investigation.
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Affiliation(s)
- Mary S. McGrath
- Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA;
| | - Brian J. Wentworth
- Division of Gastroenterology & Hepatology, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA
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Kaul NL, Diebolt CM, Meier C, Tschernig T. Transient receptor potential channel 3 in human liver and gallbladder - An investigation in body donors. Ann Anat 2023; 250:152150. [PMID: 37633502 DOI: 10.1016/j.aanat.2023.152150] [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: 06/06/2023] [Revised: 07/13/2023] [Accepted: 07/14/2023] [Indexed: 08/28/2023]
Abstract
Since the discovery of TRP proteins in 1969, during studies of the fruit fly Drosophila melanogaster, interest around them and the subfamily of TRPC channels has remained high. TRPC3 was able to be detected in a number of organs in rodents, such as rats and mice, and also in various human tissues. For the most part, these investigations were carried out using gene expression of TRPC3. Further work has already confirmed the relevance of TRPC3 in the context of neurodegenerative diseases, such as spinocerebellar ataxia, and carcinogenic entities, such as ovarian carcinoma. An association with TRPC3 has also been demonstrated for diseases that affect the liver. In order to confirm the expression of TRPC3 in the human liver, this study uses samples taken from eight (n = 8) fixated human body donors and analyzed with immunohistochemistry. In accordance with the macroscopic anatomy of the organs, six samples (n = 6) of liver tissue and three (n = 3) of gallbladder tissue were obtained. TRPC3 was clearly detected in all liver and gallbladder samples examined. Thus, it is not unlikely that TRPC3 plays a role in the extensive metabolic processes of the liver and could also serve as a target for pharmacological interventions in an imbalance of calcium homeostasis.
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Affiliation(s)
- Nele Leonie Kaul
- Institute of Anatomy and Cell Biology, Saarland University, Medical Campus, Homburg, Saar, Germany
| | - Coline M Diebolt
- Institute of Anatomy and Cell Biology, Saarland University, Medical Campus, Homburg, Saar, Germany
| | - Carola Meier
- Institute of Anatomy and Cell Biology, Saarland University, Medical Campus, Homburg, Saar, Germany
| | - Thomas Tschernig
- Institute of Anatomy and Cell Biology, Saarland University, Medical Campus, Homburg, Saar, Germany.
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Arriola-Montenegro J, Beas R, Cerna-Viacava R, Chaponan-Lavalle A, Hernandez Randich K, Chambergo-Michilot D, Flores Sanga H, Mutirangura P. Therapies for patients with coexisting heart failure with reduced ejection fraction and non-alcoholic fatty liver disease. World J Cardiol 2023; 15:328-341. [PMID: 37576545 PMCID: PMC10415861 DOI: 10.4330/wjc.v15.i7.328] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 06/09/2023] [Accepted: 06/21/2023] [Indexed: 07/25/2023] Open
Abstract
Heart failure with reduced ejection fraction (HFrEF) and nonalcoholic fatty liver disease (NAFLD) are two common comorbidities that share similar pathophysiological mechanisms. There is a growing interest in the potential of targeted therapies to improve outcomes in patients with coexisting HFrEF and NAFLD. This manuscript reviews current and potential therapies for patients with coexisting HFrEF and NAFLD. Pharmacological therapies, including angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, mineralocorticoids receptor antagonist, and sodium-glucose cotransporter-2 inhibitors, have been shown to reduce fibrosis and fat deposits in the liver. However, there are currently no data showing the beneficial effects of sacubitril/valsartan, ivabradine, hydralazine, isosorbide nitrates, digoxin, or beta blockers on NAFLD in patients with HFrEF. This study highlights the importance of considering HFrEF and NAFLD when developing treatment plans for patients with these comorbidities. Further research is needed in patients with coexisting HFrEF and NAFLD, with an emphasis on novel therapies and the importance of a multidisciplinary approach for managing these complex comorbidities.
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Affiliation(s)
- Jose Arriola-Montenegro
- Department of Internal Medicine, University of Minnesota, Minneapolis, MN 55455, United States.
| | - Renato Beas
- Department of Medicine, Indiana University School of Medicine, Indiana, IN 46202, United States
| | | | | | | | | | - Herson Flores Sanga
- Department of Telemedicine, Cardiology, Hospital Nacional Carlos Alberto Seguin Escobedo, Arequipa 8610, Peru
| | - Pornthira Mutirangura
- Department of Medicine, University of Minnesota, Minneapolis, MN 55415, United States
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Eshraghian A, Taghavi A, Nikoupour H, Nikeghbalian S, Malek-Hosseini SA. Angiotensin receptor blockers might be protective against hepatic steatosis after liver transplantation. BMC Gastroenterol 2023; 23:152. [PMID: 37189076 PMCID: PMC10184358 DOI: 10.1186/s12876-023-02781-9] [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: 08/01/2022] [Accepted: 04/23/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND Hepatic steatosis is an increasing complication in liver transplant recipients. Currently, there is no pharmacologic therapy for treatment of hepatic steatosis after liver transplantation. The aim of this study was to determine the association between use of angiotensin receptor blockers (ARB) and hepatic steatosis in liver transplant recipients. METHODS We conducted a case-control analysis on data from Shiraz Liver Transplant Registry. Liver transplant recipients with and without hepatic steatosis were compared for risk factors including use of ARB. RESULTS A total of 103 liver transplant recipients were included in the study. Thirty five patients treated with ARB and 68 patients (66%) did not receive these medications. In univariate analysis, ARB use (P = 0.002), serum triglyceride (P = 0.006), weight after liver transplantation (P = 0.011) and etiology of liver disease (P = 0.008) were associated with hepatic steatosis after liver transplantation. In multivariate regression analysis, ARB use was associated with lower likelihood of hepatic steatosis in liver transplant recipients (OR = 0.303, 95% CI: 0.117-0.784; P = 0.014). Mean duration of ARB use (P = 0.024) and mean cumulative daily dose of ARB (P = 0.015) were significantly lower in patients with hepatic steatosis. CONCLUSION Our study showed that ARB use was associated with reduced incidence of hepatic steatosis in liver transplant recipients.
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Affiliation(s)
- Ahad Eshraghian
- Shiraz Transplant Center, Abu-Ali Sina Hospital, 71994-67985, Shiraz, Iran.
| | - Alireza Taghavi
- Shiraz Transplant Center, Abu-Ali Sina Hospital, 71994-67985, Shiraz, Iran
- Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Hamed Nikoupour
- Shiraz Transplant Center, Abu-Ali Sina Hospital, 71994-67985, Shiraz, Iran
- Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saman Nikeghbalian
- Shiraz Transplant Center, Abu-Ali Sina Hospital, 71994-67985, Shiraz, Iran
- Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Seyed Ali Malek-Hosseini
- Shiraz Transplant Center, Abu-Ali Sina Hospital, 71994-67985, Shiraz, Iran
- Shiraz Transplant Center, Abu-Ali Sina Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
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Meng C, Song Z, Zhang L, Geng Y, Sun J, Miao G, Liu P. Effects of losartan in patients with NAFLD: A meta-analysis of randomized controlled trial. Open Life Sci 2023; 18:20220583. [PMID: 36970603 PMCID: PMC10031500 DOI: 10.1515/biol-2022-0583] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 02/18/2023] [Accepted: 02/19/2023] [Indexed: 03/24/2023] Open
Abstract
Losartan has become a hot spot in the treatment of non-alcoholic fatty liver disease (NAFLD) among angiotensin receptor blocker drugs. We sought to conduct a systematic examination and meta-analysis to examine the effects of losartan on patients with NAFLD. We searched for potentially randomized controlled trials in PubMed, Embase, China National Knowledge Infrastructure, Wanfang, and the Cochrane database up to October 09, 2022. We used the Cochrane risk of bias tool to evaluate the study quality. Analysis of subgroups, sensitivity analysis, and publishing bias were explored. The quality of the included studies was moderate to high. Six trials involving 408 patients were included. The meta-analysis demonstrated that aspartate transaminase was significantly affected by losartan therapy (mean difference [MD] = −5.34, 95% confidence interval [CI] [−6.54, −4.13], Z = 8.70, P < 0.01). The meta-analysis subgroup showed that losartan 50 mg once daily could lower the level of alanine aminotransferase (MD = −18.92, 95% CI [−21.18, −16.66], Z = 16.41, P < 0.01). There was no statistically significant difference in serum total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein.
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Affiliation(s)
- Chang Meng
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Zejun Song
- Department of Gastroenterology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, No. 168 Litang Road, Changping District, Beijing, 102218, PR China
| | - Lingnan Zhang
- Department of Cardiology, Affiliated Hospital of Hebei University, Hebei University, 212 Yuhua East Road, Lianchi District, Baoding City, 071000, PR China
| | - Yu Geng
- Department of Cardiology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, NO. 168 Litang Road, Changping District, Beijing102218, P. R. China
| | - Jing Sun
- Department of Critical Care Medicine, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Guobin Miao
- Department of Emergency, Emergency General Hospital, XiBaHe South Road 29, Chaoyang District, Beijing, 100028, PR China
| | - Peng Liu
- Department of Cardiology, Ordos Central Hospital, Ordos School of Clinical Medicine, Inner Mongolia Medical University, 23 Yijinhuoluo West Street, Dongsheng District, Inner Mongolia, 017000, PR China
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Vos MB, Van Natta ML, Blondet NM, Dasarathy S, Fishbein M, Hertel P, Jain AK, Karpen SJ, Lavine JE, Mohammad S, Miriel LA, Molleston JP, Mouzaki M, Sanyal A, Sharkey EP, Schwimmer JB, Tonascia J, Wilson LA, Xanthakos SA. Randomized placebo-controlled trial of losartan for pediatric NAFLD. Hepatology 2022; 76:429-444. [PMID: 35133671 PMCID: PMC9288975 DOI: 10.1002/hep.32403] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 11/18/2021] [Accepted: 12/04/2021] [Indexed: 01/28/2023]
Abstract
BACKGROUND AND AIMS To date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects. APPROACH AND RESULTS The Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double-masked, placebo-controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8-17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty-three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination. Baseline characteristics were similar between groups. The 24-week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = -30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: -23.4 U/l; 95% CI = -41.5, -5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: -7.5 mm Hg; 95% CI = -12.2, -2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group. CONCLUSIONS Losartan did not significantly reduce ALT in children with NAFLD when compared with placebo.
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Affiliation(s)
- Miriam B Vos
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Mark L Van Natta
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Niviann M Blondet
- Division of Pediatric Gastroenterology and Hepatology, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA
| | - Srinivasan Dasarathy
- Division of Gastroenterology, Hepatology and Nutrition, Cleveland Clinic, Cleveland, Ohio, USA
| | - Mark Fishbein
- Department of Pediatrics, Feinberg Medical School of Northwestern University, Chicago, Illinois, USA
| | - Paula Hertel
- Division of Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA
| | - Ajay K Jain
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, St. Louis University, St. Louis, Missouri, USA
| | - Saul J Karpen
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Joel E Lavine
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Columbia University Vagelos College of Physicians and Surgeons, New York, New York, USA
| | - Saeed Mohammad
- Department of Pediatrics, Feinberg Medical School of Northwestern University, Chicago, Illinois, USA
| | - Laura A Miriel
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jean P Molleston
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Indiana University School of Medicine/Riley Hospital for Children, Indianapolis, Indiana, USA
| | - Marialena Mouzaki
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
| | - Arun Sanyal
- Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Emily P Sharkey
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Jeffrey B Schwimmer
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, California, USA
| | - James Tonascia
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Laura A Wilson
- Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Stavra A Xanthakos
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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Bellos I, Pergialiotis V, Perrea DN. Comparative efficacy of fixed-dose statin and antihypertensive agent combinations: A network meta-analysis of randomized controlled trials. Vascul Pharmacol 2021; 141:106900. [PMID: 34343694 DOI: 10.1016/j.vph.2021.106900] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 07/14/2021] [Accepted: 07/26/2021] [Indexed: 01/21/2023]
Abstract
BACKGROUND The concurrent administration of statins and antihypertensive agents has been associated with improved cardiovascular outcomes, although the optimal fixed-dose combination remains unclear. This meta-analysis aims to compare the blood pressure and lipid-lowering effects of various statin and antihypertensive drug combinations. METHODS PubMed, Scopus, Web of Science, CENTRAL and Clinicaltrials.gov were systematically searched from inception to 20 March 2021. Randomized controlled trials evaluating the effects of statin-antihypertensive agent combinations on systolic blood pressure or serum lipids were held eligible. A random-effects frequentist model was applied to provide estimates of mean difference of percentage change. RESULTS Overall, 18 studies were included, comprising 4450 patients. Compared to statin monotherapy no significant difference in the percentage change of low-density lipoprotein cholesterol was achieved by adding any antihypertensive agent. Compared to amlodipine monotherapy, the addition of moderate-intensity statin resulted in a significantly greater percentage reduction of systolic blood pressure (-2.22%, 95% confidence intervals: [-3.82 to -0.62]). Combined high-intensity statin and amlodipine lead to significant increase of high-density lipoprotein cholesterol (8.34%, 95% confidence intervals: [0.73 to 15.95]), while effective triglyceride reduction was achieved by adding amlodipine and telmisartan to high-intensity statin (-14.68%, 95% confidence intervals: [-28.48 to -0.89]). No significant difference of adverse effects was observed. CONCLUSION The present network meta-analysis suggests that the administration of fixed-dose combinations of statins and antihypertensive agents is safe and effective in reducing blood pressure and serum lipids. The optimal dosing strategy to prevent cardiovascular events remains to be determined.
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Affiliation(s)
- Ioannis Bellos
- Laboratory of Experimental Surgery and Surgical Research N.S.Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Greece.
| | - Vasilios Pergialiotis
- Laboratory of Experimental Surgery and Surgical Research N.S.Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Greece
| | - Despina N Perrea
- Laboratory of Experimental Surgery and Surgical Research N.S.Christeas, Athens University Medical School, National and Kapodistrian University of Athens, Greece
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The Tissue Renin-Angiotensin System and Its Role in the Pathogenesis of Major Human Diseases: Quo Vadis? Cells 2021; 10:cells10030650. [PMID: 33804069 PMCID: PMC7999456 DOI: 10.3390/cells10030650] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/09/2021] [Accepted: 03/13/2021] [Indexed: 01/18/2023] Open
Abstract
Evidence has arisen in recent years suggesting that a tissue renin-angiotensin system (tRAS) is involved in the progression of various human diseases. This system contains two regulatory pathways: a pathological pro-inflammatory pathway containing the Angiotensin Converting Enzyme (ACE)/Angiotensin II (AngII)/Angiotensin II receptor type 1 (AGTR1) axis and a protective anti-inflammatory pathway involving the Angiotensin II receptor type 2 (AGTR2)/ACE2/Ang1–7/MasReceptor axis. Numerous studies reported the positive effects of pathologic tRAS pathway inhibition and protective tRAS pathway stimulation on the treatment of cardiovascular, inflammatory, and autoimmune disease and the progression of neuropathic pain. Cell senescence and aging are known to be related to RAS pathways. Further, this system directly interacts with SARS-CoV 2 and seems to be an important target of interest in the COVID-19 pandemic. This review focuses on the involvement of tRAS in the progression of the mentioned diseases from an interdisciplinary clinical perspective and highlights therapeutic strategies that might be of major clinical importance in the future.
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Lin YC, Wang JC, Wu MS, Lin YF, Chen CR, Chen CY, Chen KC, Peng CC. Nifedipine Exacerbates Lipogenesis in the Kidney via KIM-1, CD36, and SREBP Upregulation: Implications from an Animal Model for Human Study. Int J Mol Sci 2020; 21:ijms21124359. [PMID: 32575412 PMCID: PMC7352626 DOI: 10.3390/ijms21124359] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 06/16/2020] [Accepted: 06/17/2020] [Indexed: 12/15/2022] Open
Abstract
Dysregulation of fatty acid oxidation and accumulation of fatty acids can cause kidney injury. Nifedipine modulates lipogenesis-related transcriptional factor SREBP-1/2 in proximal tubular cells by inhibiting the Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) pathway in vitro. However, the mechanisms by which nifedipine (NF) modulates lipotoxicity in vivo are unclear. Here, we examined the effect of NF in a doxorubicin (DR)-induced kidney injury rat model. Twenty-four Sprague–Dawley rats were divided into control, DR, DR+NF, and high-fat diet (HFD) groups. The DR, DR+NF, and HFD groups showed hypertension and proteinuria. Western blotting and immunohistochemical analysis showed that NF significantly induced TNF-α, CD36, SREBP-1/2, and acetyl-CoA carboxylase expression and renal fibrosis, and reduced fatty acid synthase and AMPK compared to other groups (p < 0.05). Additionally, 18 patients with chronic kidney disease (CKD) who received renal transplants were enrolled to examine their graft fibrosis and lipid contents via transient elastography. Low-density lipoprotein levels in patients with CKD strongly correlated with lipid contents and fibrosis in grafted kidneys (p < 0.05). Thus, NF may initiate lipogenesis through the SREBP-1/2/AMPK pathway and lipid uptake by CD36 upregulation and aggravate renal fibrosis in vivo. Higher low-density lipoprotein levels may correlate with renal fibrosis and lipid accumulation in grafted kidneys of patients with CKD.
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Affiliation(s)
- Yen-Chung Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-S.W.); (Y.-F.L.)
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
| | - Jhih-Cheng Wang
- Division of Urology, Department of Surgery, Chi-Mei Medical Center, Tainan City 71004, Taiwan;
- Department of Electric Engineering, Southern Taiwan University of Science and Technology, Tainan City 71005, Taiwan
| | - Mai-Szu Wu
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-S.W.); (Y.-F.L.)
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Yuh-Feng Lin
- Division of Nephrology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan; (M.-S.W.); (Y.-F.L.)
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Division of Nephrology, Department of Internal Medicine, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
| | - Chang-Rong Chen
- International Medical Doctor Program, Vita-Salute San Raffaele University, 20132 Milan, Italy;
| | - Chang-Yu Chen
- Program of Biomedical Sciences, College of Arts and Sciences, California Baptist University, Riverside, CA 92504, USA;
| | - Kuan-Chou Chen
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- TMU-Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan
- Department of Urology, Taipei Medical University-Shuang Ho Hospital, New Taipei City 23561, Taiwan
- Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: (K.-C.C.); (C.-C.P.); Tel.: +886-02-22490088 (K.-C.C.); +886-02-27361661 (C.-C.P.)
| | - Chiung-Chi Peng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;
- Correspondence: (K.-C.C.); (C.-C.P.); Tel.: +886-02-22490088 (K.-C.C.); +886-02-27361661 (C.-C.P.)
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Kodama M, Kanno K, Kishikawa N, Takei H, Nittono H, Tazuma S. Decrease in major secondary bile acid, hyodeoxycholic acid, was the main alteration in hepatic bile acid compositions in a hypertensive nonalcoholic fatty liver disease model. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2019; 26:557-567. [PMID: 31562685 DOI: 10.1002/jhbp.678] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Previous findings on hepatic bile acid compositions in nonalcoholic fatty liver disease (NAFLD) have been inconsistent and complicated. The aim of this study was to investigate the effects of steatosis on hepatic bile acid composition in a hypertensive NAFLD model without obesity and diabetes mellitus and compare hepatic bile acid composition between hypertensive rats with and without steatosis. METHODS Two groups of hypertensive rats were studied: spontaneously hypertensive rats (SHR) fed with a normal diet (SHR-N) or a choline-deficient diet (SHR-CD). Two groups of normotensive rats were studied: Wistar Kyoto rats (WKY) fed a normal diet (WKY-N) or a choline-deficient diet (WKY-CD). Hepatic bile acid analysis was performed using liquid chromatography-electrospray ionization-tandem mass spectrometry. RESULTS Regarding bile acid composition, the hyodeoxycholic acid (HDCA) species in the SHR-CD group showed the largest change in bile acid composition, significantly decreasing to 21.9% of that found in the SHR-N group. In the WKY-CD group, no reduction of HDCA species was observed. CONCLUSIONS We demonstrated that the decrease in HDCA species was the main alteration in a hypertensive NAFLD model. It was suggested that the decrease in HDCA species in the SHR-CD group was caused by dysbiosis.
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Affiliation(s)
- Masanobu Kodama
- Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Keishi Kanno
- Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Nobusuke Kishikawa
- Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Hajime Takei
- Junshin Clinic Bile Acid Institute, Tokyo, Japan
| | | | - Susumu Tazuma
- Department of General Internal Medicine, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
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Ranjbar R, Shafiee M, Hesari A, Ferns GA, Ghasemi F, Avan A. The potential therapeutic use of renin-angiotensin system inhibitors in the treatment of inflammatory diseases. J Cell Physiol 2018; 234:2277-2295. [PMID: 30191985 DOI: 10.1002/jcp.27205] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 07/16/2018] [Indexed: 01/18/2023]
Abstract
Inflammation is a normal part of the immune response to injury or infection but its dysregulation promotes the development of inflammatory diseases, which cause considerable human suffering. Nonsteroidal anti-inflammatory agents are the most commonly prescribed agents for the treatment of inflammatory diseases, but they are accompanied by a broad range of side effects, including gastrointestinal and cardiovascular events. The renin-angiotensin system (RAS) is traditionally known for its role in blood pressure regulation. However, there is increasing evidence that RAS signaling is also involved in the inflammatory response associated with several disease states. Angiotensin II increases blood pressure by binding to angiotensin type 1 (AT1 ) receptor, and direct renin inhibitors, angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) are clinically used as antihypertensive agents. Recent data suggest that these drugs also have anti-inflammatory effects. Therefore, this review summarizes these recent findings for the efficacy of two of the most widely used antihypertensive drug classes, ACE inhibitors and ARBs, to reduce or treat inflammatory diseases such as atherosclerosis, arthritis, steatohepatitis, colitis, pancreatitis, and nephritis.
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Affiliation(s)
- Reza Ranjbar
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Mojtaba Shafiee
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.,Department of Nutrition, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - AmirReza Hesari
- Department of Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Gordon A Ferns
- Division of Medical Education, Brighton & Sussex Medical School, Sussex, UK
| | - Faezeh Ghasemi
- Department of Biotechnology, Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
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12
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Li Y, Xu H, Wu W, Ye J, Fang D, Shi D, Li L. Clinical application of angiotensin receptor blockers in patients with non-alcoholic fatty liver disease: a systematic review and meta-analysis. Oncotarget 2018; 9:24155-24167. [PMID: 29844879 PMCID: PMC5963622 DOI: 10.18632/oncotarget.23816] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Accepted: 10/27/2017] [Indexed: 02/07/2023] Open
Abstract
Objective Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, ranging from simple steatosis to progressive steatohepatitis and cirrhosis. Because of their anti-inflammatory and anti-fibrotic effects, angiotensin receptor blockers (ARBs) are potential therapeutic agents for NAFLD. The present systematic review assessed the effectiveness of ARBs in NAFLD management. Results Accounting for data overlap and exclusion criteria, randomized controlled trial -based and single-arm meta-analyses were conducted for four studies with 362 patients and eight studies with 525 patients, respectively. Although alanine aminotransferase levels were not significantly affected by ARB treatment (standardized mean difference 0.20; 95% confidence interval (CI) [−0.04, 0.44]; P = 0.10), a fixed-effect model revealed a decreasing trend in alanine transaminase levels. Low-density lipoprotein levels were reduced by ARB treatment (MD 5.21; 95% CI [3.01, 7.40]; P < 0.00001), and total cholesterol also decreased in response to ARBs (MD 2.10; 95% CI [−0.37, 4.57]; P = 0.10). However, the fibrosis score and NAFLD activity score were not significantly improved by ARB treatment (MD 0.10; 95% CI [−0.58, 0.78]; P = 0.77) (MD −0.25; 95% CI [−1.05, 0.55]; P = 0.53). Materials and Methods Keywords were used to identify studies in PubMed, EMBASE, CENTRAL, Web of Science and CNKI published up to July 31, 2017. Single-arm and RCT-based meta-analyses of the available data were performed using RevMan (version 5.3). Conclusions Although ARBs significantly decreased plasma low-density lipoprotein and total cholesterol levels, the current evidence is insufficient to support the efficacy of ARBs in managing fibrosis in NAFLD patients.
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Affiliation(s)
- Yating Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Hong Xu
- Department of Orthopaedics, Tianjin Medical University General Hospital, Heping District, Tianjin 300052, People's Republic of China
| | - Wenrui Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Jianzhong Ye
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Daiqiong Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Ding Shi
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University, Hangzhou 31003, People's Republic of China
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13
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Eshraghian A. Current and emerging pharmacological therapy for non-alcoholic fatty liver disease. World J Gastroenterol 2017; 23:7495-7504. [PMID: 29204050 PMCID: PMC5698243 DOI: 10.3748/wjg.v23.i42.7495] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 09/14/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023] Open
Abstract
The main treatment of patients with non-alcoholic fatty liver disease (NAFLD) is life style modification including weight reduction and dietary regimen. Majority of patients are safely treated with this management and pharmacologic interventions are not recommended. However, a subgroup of NAFLD patients with non-alcoholic steatohepatitis (NASH) who cannot achieve goals of life style modification may need pharmacological therapy. One major obstacle is measurement of histological outcome by liver biopsy which is an invasive method and is not recommended routinely in these patients. Several medications, mainly targeting baseline mechanism of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as insulin sensitizing agent and vitamin E as an anti-oxidant have been recommended for treatment of NASH by international guidelines. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet. Several emerging medications are in development for treatment of NASH. Obeticholic acid, liraglutide, elafibranor, cenicriviroc and aramchol have been tested in clinical trials or are completing trials. Here in, current and upcoming medications with promising results in clinical trial for treatment of NAFLD were reviewed.
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Affiliation(s)
- Ahad Eshraghian
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz 71937-11351, Iran
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14
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Stokkeland K, Lageborn CT, Ekbom A, Höijer J, Bottai M, Stål P, Söderberg-Löfdal K. Statins and Angiotensin-Converting Enzyme Inhibitors are Associated with Reduced Mortality and Morbidity in Chronic Liver Disease. Basic Clin Pharmacol Toxicol 2017; 122:104-110. [DOI: 10.1111/bcpt.12844] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Accepted: 07/03/2017] [Indexed: 02/06/2023]
Affiliation(s)
- Knut Stokkeland
- Department of Medicine; Visby Hospital; Visby Sweden
- Department of Medicine Huddinge; Unit of Gastroenterology and Rheumatology; Karolinska Institutet; Stockholm Sweden
| | | | - Anders Ekbom
- Unit of Clinical Epidemiology; Department of Medicine, Solna; Karolinska Institutet; Stockholm Sweden
| | - Jonas Höijer
- Unit of Biostatistics; IMM, Karolinska Institutet; Stockholm Sweden
| | - Matteo Bottai
- Unit of Biostatistics; IMM, Karolinska Institutet; Stockholm Sweden
| | - Per Stål
- Department of Medicine Huddinge; Unit of Gastroenterology and Rheumatology; Karolinska Institutet; Stockholm Sweden
- Unit of Hepatology; Center of Digestive Diseases; Karolinska University Hospital; Stockholm Sweden
| | - Karin Söderberg-Löfdal
- Division of Clinical Pharmacology; Department of Laboratory Medicine; Karolinska Institutet; Stockholm Sweden
- Department of Clinical Pharmacology; Karolinska University Hospital; Stockholm Sweden
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15
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Brea Á, Pintó X, Ascaso JF, Blasco M, Díaz Á, González-Santos P, Hernández-Mijares A, Mantilla T, Millán J, Pedro-Botet J. Enfermedad del hígado graso no alcohólico, asociación con la enfermedad cardiovascular y tratamiento (II). Tratamiento de la enfermedad del hígado graso no alcohólico. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2017; 29:185-200. [DOI: 10.1016/j.arteri.2016.06.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Accepted: 06/28/2016] [Indexed: 12/12/2022]
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Lombardi R, Onali S, Thorburn D, Davidson BR, Gurusamy KS, Tsochatzis E. Pharmacological interventions for non-alcohol related fatty liver disease (NAFLD): an attempted network meta-analysis. Cochrane Database Syst Rev 2017; 3:CD011640. [PMID: 28358980 PMCID: PMC6464620 DOI: 10.1002/14651858.cd011640.pub2] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcohol related fatty liver disease (commonly called non-alcoholic fatty liver disease (NAFLD)) is liver steatosis in the absence of significant alcohol consumption, use of hepatotoxic medication, or other disorders affecting the liver such as hepatitis C virus infection, Wilson's disease, and starvation. NAFLD embraces the full spectrum of disease from pure steatosis (i.e. uncomplicated fatty liver) to non-alcoholic steatohepatitis (NASH), via NASH-cirrhosis to cirrhosis. The optimal pharmacological treatment for people with NAFLD remains uncertain. OBJECTIVES To assess the comparative benefits and harms of different pharmacological interventions in the treatment of NAFLD through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis, and instead, assessed the comparative benefits and harms of different interventions using standard Cochrane methodology. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.com to August 2016. SELECTION CRITERIA We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with NAFLD. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various pharmacological interventions compared with each other or with placebo or no intervention. DATA COLLECTION AND ANALYSIS We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on an available participant analysis with Review Manager. We assessed risk of bias according to the Cochrane risk of bias tool, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS We identified 77 trials including 6287 participants that met the inclusion criteria of this review. Forty-one trials (3829 participants) provided information for one or more outcomes. Only one trial was at low risk of bias in all domains. All other trials were at high risk of bias in one or more domains. Overall, all the evidence was very low quality. Thirty-five trials included only participants with non-alcohol related steatohepatitis (NASH) (based on biopsy confirmation). Five trials included only participants with diabetes mellitus; 14 trials included only participants without diabetes mellitus. The follow-up in the trials ranged from one month to 24 months.We present here only the comparisons of active intervention versus no intervention in which two or more trials reported at least one of the following outcomes: mortality at maximal follow-up, serious adverse events, and health-related quality of life, the outcomes that determine whether a treatment should be used. Antioxidants versus no interventionThere was no mortality in either group (87 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the trial which reported the proportion of people with serious adverse events (87 participants; 1 trial; very low quality evidence). There was no evidence of difference in the number of serious adverse events between antioxidants and no intervention (rate ratio 0.89, 95% CI 0.36 to 2.19; 254 participants; 2 trials; very low quality evidence). None of the trials reported health-related quality of life. Bile acids versus no interventionThere was no evidence of difference in mortality at maximal follow-up (OR 5.11, 95% CI 0.24 to 107.34; 659 participants; 4 trials; very low quality evidence), proportion of people with serious adverse events (OR 1.56, 95% CI 0.84 to 2.88; 404 participants; 3 trials; very low quality evidence), or the number of serious adverse events (rate ratio 1.01, 95% CI 0.66 to 1.54; 404 participants; 3 trials; very low quality evidence) between bile acids and no intervention. None of the trials reported health-related quality of life. Thiazolidinediones versus no interventionThere was no mortality in either group (74 participants; 1 trial; very low quality evidence). None of the participants developed serious adverse events in the two trials which reported the proportion of people with serious adverse events (194 participants; 2 trials; very low quality evidence). There was no evidence of difference in the number of serious adverse events between thiazolidinediones and no intervention (rate ratio 0.25, 95% CI 0.06 to 1.05; 357 participants; 3 trials; very low quality evidence). None of the trials reported health-related quality of life. Source of fundingTwenty-six trials were partially- or fully-funded by pharmaceutical companies that would benefit, based on the results of the trial. Twelve trials did not receive any additional funding or were funded by parties with no vested interest in the results. The source of funding was not provided in 39 trials. AUTHORS' CONCLUSIONS Due to the very low quality evidence, we are very uncertain about the effectiveness of pharmacological treatments for people with NAFLD including those with steatohepatitis. Further well-designed randomised clinical trials with sufficiently large sample sizes are necessary.
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Affiliation(s)
- Rosa Lombardi
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUKNW3 2QG
| | - Simona Onali
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUKNW3 2QG
| | - Douglas Thorburn
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUKNW3 2QG
| | - Brian R Davidson
- Royal Free Campus, UCL Medical SchoolDepartment of SurgeryPond StreetLondonUKNW3 2QG
| | | | - Emmanuel Tsochatzis
- Royal Free Hospital and the UCL Institute of Liver and Digestive HealthSheila Sherlock Liver CentreLondonUKNW3 2QG
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17
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Srivastava A, Adams-Huet B, Vega GL, Toto RD. Effect of losartan and spironolactone on triglyceride-rich lipoproteins in diabetic nephropathy. J Investig Med 2016; 64:1102-8. [PMID: 27388615 PMCID: PMC4975815 DOI: 10.1136/jim-2016-000102] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/16/2016] [Indexed: 12/28/2022]
Abstract
Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) can improve dyslipidemia in patients with diabetes and albuminuria. Whether combined ACEi+ARB or ACEi+mineralocorticoid receptor blockade improves dyslipidemia is not known. We hypothesized long-term administration of either losartan 100 mg or spironolactone 25 mg once daily added onto lisinopril 80 mg once daily would improve dyslipidemia in diabetic nephropathy (DN). We measured lipid levels, very-low-density (V), intermediate-density (I), low-density (LDL), high-density (HDL) lipoprotein, LDL particle size with their respective cholesterol (C) and apolipoprotein B levels (ApoB), and urine albumin/creatinine ratio (UACR) at 12-week interval during a 48-week randomized, double-blind placebo-controlled trial in 81 patients with DN. Plasma lipids and lipoprotein C were analyzed enzymatically and Apo B was determined chemically. Data were analyzed by mixed model repeated measures. ΔUACR differed among treatment arms (placebo −24.6%, los −38.2%, spiro −51.6%, p=0.02). No correlation existed between ΔUACR and ΔTG or any of the lipid or lipoprotein measurements. Compared with placebo losartan, but not spironolactone, decreased TG (−20.9% vs +34.3%, p<0.01), V+I C(−18.8% vs +21.3%, p<0.01), and V+I-ApoB (−13.2% vs +21%, p<0.01). There were no significant changes in body weight, HbA1c or other lipoprotein variables. We conclude losartan improves dyslipidemia in patients with DN. We speculate the mechanism improved clearance of VLDL and remnant lipoproteins.
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Affiliation(s)
- Anand Srivastava
- Division of Renal Medicine, Brigham &Women's Hospital, Boston, Massachusetts, USA
| | - Beverley Adams-Huet
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Gloria L Vega
- Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Robert D Toto
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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18
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Michopoulos S, Chouzouri VI, Manios ED, Grapsa E, Antoniou Z, Papadimitriou CA, Zakopoulos N, Dimopoulos AM. Untreated newly diagnosed essential hypertension is associated with nonalcoholic fatty liver disease in a population of a hypertensive center. Clin Exp Gastroenterol 2016; 9:1-9. [PMID: 26834493 PMCID: PMC4716740 DOI: 10.2147/ceg.s92714] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Purpose Recent studies have demonstrated that hypertension (HTN) is associated with nonalcoholic fatty liver disease (NAFLD) in treated hypertensive patients. The aim of this study was to investigate the association between newly diagnosed essential HTN and NAFLD in untreated hypertensive patients. Patients and methods A consecutive series of 240 subjects (143 hypertensives and 97 normotensives), aged 30–80 years, without diabetes mellitus were enrolled in the study. Subjects with 24-hour systolic blood pressure (SBP) values ≥130 mmHg and/or diastolic BP values ≥80 mmHg were defined as hypertensives. NAFLD was defined as the presence of liver hyperechogenicity on ultrasound. Results Body mass index (P=0.002) and essential HTN (P=0.016) were independently associated with NAFLD in the multivariate logistic regression model. Furthermore, the multivariate analysis revealed that morning SBP (P=0.044) was independently associated with NAFLD. Conclusion Untreated, newly diagnosed essential HTN is independently associated with NAFLD. Ambulatory BP monitoring could be used for the diagnosis of essential HTN in patients with NAFLD.
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Affiliation(s)
- Spyros Michopoulos
- Department of Clinical Therapeutics, Medical School of Athens, Alexandra Hospital, Athens, Greece
| | - Vasiliki I Chouzouri
- Department of Clinical Therapeutics, Medical School of Athens, Alexandra Hospital, Athens, Greece
| | - Efstathios D Manios
- Department of Clinical Therapeutics, Medical School of Athens, Alexandra Hospital, Athens, Greece
| | - Eirini Grapsa
- Nephrology Department, Medical School of Athens, Aretaieio Hospital, Athens, Greece
| | - Zoi Antoniou
- Department of Clinical Therapeutics, Medical School of Athens, Alexandra Hospital, Athens, Greece
| | | | - Nikolaos Zakopoulos
- Department of Clinical Therapeutics, Medical School of Athens, Alexandra Hospital, Athens, Greece
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19
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Derosa G, Mugellini A, Pesce RM, D'Angelo A, Maffioli P. Perindopril and barnidipine alone or combined with simvastatin on hepatic steatosis and inflammatory parameters in hypertensive patients. Eur J Pharmacol 2015; 766:31-6. [PMID: 26407654 DOI: 10.1016/j.ejphar.2015.09.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2015] [Revised: 09/15/2015] [Accepted: 09/18/2015] [Indexed: 02/06/2023]
Abstract
UNLABELLED The aim of this study was to evaluate the effects of perindopril or barnidipine alone or combined with simvastatin on metabolic parameters and hepatic steatosis degree. One hundred and forty nine mild to moderate hypertensive, normocholesterolemic, overweight or obese outpatients with hepatic steatosis were enrolled. They were treated with perindopril 5mg/day, or barnidipine, 20mg/day, for 6 months; subsequently simvastatin, 20mg/day was added to both treatments for further 6 months. Blood pressure variation was recorded. Patients also underwent an ultrasound examination, at baseline and after 6, and 12 months. We also assessed: fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, adiponectin (ADN), tumor necrosis factor-α (ΤΝF-α), interleukin-6 (IL-6), high-sensitivity C reactive protein (Hs-CRP). Both perindopril and barnidipine reduced blood pressure, with barnidipine being more effective. Barnidipine, but not perindopril, slightly decreased total cholesterol and triglycerides after 6 months compared to baseline; lipid profile improved in both groups when simvastatin was added. Regarding inflammatory parameters, barnidipine reduced TNF-a, IL-6, and Hs-CRP, both in monotherapy, and after simvastatin addition. Hepatic steatosis parameters improved only when simvastatin was added. We can conclude that barnidipine better reduced blood pressure compared to perindopril and inflammatory parameters. Regarding hepatic steatosis parameters, only the addition of simvastatin improved them. REGISTRATION NUMBER NCT02064218, ClinicalTrials.gov.
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Affiliation(s)
- Giuseppe Derosa
- Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; Center for the Study of Endocrine-Metabolic Pathophysiology and Clinical Research, University of Pavia, Pavia, Italy; Laboratory of Molecular Medicine, University of Pavia, Pavia, Italy.
| | - Amedeo Mugellini
- Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Rosa M Pesce
- Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Angela D'Angelo
- Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; Laboratory of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Pamela Maffioli
- Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy; PhD School in Experimental Medicine, University of Pavia, Pavia, Italy
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20
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Abstract
Lifestyle modifications and optimization of the management of cardiometabolic comorbidities are currently the mainstay of treatment for patients with nonalcoholic fatty liver disease. Pharmacotherapy to halt or reverse hepatic histological injury and prevent the development of end-stage liver disease is specifically offered to patients with nonalcoholic steatohepatitis (NASH) and those with advanced fibrosis. In this review, the authors discuss the state of the art of various pharmacological agents for NASH. The efficacy of vitamin E and pioglitazone is reasonably well established in a selected group of patients with NASH. Current data do not offer convincing evidence for efficacy of pentoxifylline, long-chain polyunsaturated fatty acids, angiotensin receptor blockers, metformin, or ursodeoxycholic acid. They also discuss the state of several emerging agents for treating NASH including the farsenoid X receptor ligand, obeticholic acid.
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Affiliation(s)
- Samer Gawrieh
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana
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21
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Czaja MJ. A new mechanism of lipotoxicity: Calcium channel blockers as a treatment for nonalcoholic steatohepatitis? Hepatology 2015; 62:312-4. [PMID: 25904459 PMCID: PMC4482768 DOI: 10.1002/hep.27858] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/07/2022]
Affiliation(s)
- Mark J. Czaja
- Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY
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Lonardo A, Ballestri S, Targher G, Loria P. Diagnosis and management of cardiovascular risk in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2015; 9:629-650. [PMID: 25327387 DOI: 10.1586/17474124.2015.965143] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is increasingly recognized as an important cardiovascular risk (CVR) factor. This is a narrative clinical review aimed at answering how diagnosis and management of CVR should be conducted in the individual patient with NAFLD. To this end, the authors performed an extensive search of the existing literature on PubMed (1993-2014) using pertinent keywords. To date, CVR among patients with NAFLD might be assessed with the Framingham risk score equation or other risk calculators, to be adapted to the true CVR in the specific population being assessed; however, the use of these CVR calculators needs to be validated by future studies in larger cohorts of NAFLD patients of various ethnic backgrounds in order to substantiate their clinical relevance as a foundation for the primary prevention of cardiovascular diseases in this group of patients. Early and aggressive drug treatment of CVR should be started in NAFLD patients with a history of cardiovascular events, established diabetes or who are at high (calculated) CVR. Whether such an aggressive pharmacological approach is also justified in patients with NAFLD, who are at intermediate or low CVR, remains debatable. Currently, there are no clinical trials showing that the treatment of NAFLD per se (either associated or unassociated with traditional CVR factors) will result in decreased risk of cardiovascular events. Accordingly, drug treatment should be better individualized, aiming at correcting all the coexisting cardio-metabolic risk factors of the individual patient with NAFLD. To this end, an overview of the lifestyle interventions and the available drugs is offered, emphasis being conveyed to statins and metformin, which promise to cover worrying complications of NAFLD such as the risk of developing hepatocellular carcinoma.
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Affiliation(s)
- Amedeo Lonardo
- Department of Medicine, Division of Internal Medicine, Pavullo Hospital, Pavullo 41026, Italy
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Trovato FM, Catalano D, Musumeci G, Trovato GM. 4Ps medicine of the fatty liver: the research model of predictive, preventive, personalized and participatory medicine-recommendations for facing obesity, fatty liver and fibrosis epidemics. EPMA J 2014; 5:21. [PMID: 25937854 PMCID: PMC4417534 DOI: 10.1186/1878-5085-5-21] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 11/24/2014] [Indexed: 12/13/2022]
Abstract
Relationship between adipose tissue and fatty liver, and its possible evolution in fibrosis, is supported by clinical and research experience. Given the multifactorial pathogenesis of non-alcoholic fatty liver disease (NAFLD), treatments for various contributory risk factors have been proposed; however, there is no single validated therapy or drug association recommended for all cases which can stand alone. Mechanisms, diagnostics, prevention and treatment of obesity, fatty liver and insulin resistance are displayed along with recommendations and position points. Evidences and practice can get sustainable and cost-benefit valuable outcomes by participatory interventions. These recommendations can be enhanced by comprehensive research projects, addressed to societal issues and innovation, market appeal and industry development, cultural acceptance and sustainability. The basis of participatory medicine is a greater widespread awareness of a condition which is both a disease and an easy documented and inclusive clue for associated diseases and unhealthy lifestyle. This model is suitable for addressing prevention and useful for monitoring improvement, worsening and adherence with non-invasive imaging tools which allow targeted approaches. The latter include health psychology and nutritional and physical exercise prescription expertise disseminated by continuous medical education but, more important, by concrete curricula for training undergraduate and postgraduate students. It is possible and recommended to do it by early formal teaching of ultrasound imaging procedures and of practical lifestyle intervention strategies, including approaches aimed to healthier fashion suggestions. Guidelines and requirements of research project funding calls should be addressed also to NAFLD and allied conditions and should encompass the goal of training by research and the inclusion of participatory medicine topics. A deeper awareness of ethics of competences in health professionals and the articulation of knowledge, expertise and skills of medical doctors, dieticians, health psychologists and sport and physical exercise graduates are the necessary strategy for detectin a suboptimal health status and achieving realistically beneficial lifestyle changes. “The devil has put a penalty on all things we enjoy in life. Either we suffer in health or we suffer in soul or we get fat” (Albert Einstein); the task of medical research and intervention is to make possible to enjoy life also without things that make sufferance in health and souls and which excessively increase body fat.
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Affiliation(s)
- Francesca Maria Trovato
- Department of Clinical and Experimental Medicine, Internal Medicine Division, School of Medicine, University of Catania, Via S. Sofia, 78-95123 Catania, Italy
| | - Daniela Catalano
- Department of Clinical and Experimental Medicine, Internal Medicine Division, School of Medicine, University of Catania, Via S. Sofia, 78-95123 Catania, Italy
| | - Giuseppe Musumeci
- Department of Biomedical and Biotechnological Sciences, Human Anatomy and Histology Section, School of Medicine, University of Catania, Via S. Sofia, 87-95123 Catania, Italy
| | - Guglielmo M Trovato
- Department of Clinical and Experimental Medicine, Internal Medicine Division, School of Medicine, University of Catania, Via S. Sofia, 78-95123 Catania, Italy
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Arab JP, Candia R, Zapata R, Muñoz C, Arancibia JP, Poniachik J, Soza A, Fuster F, Brahm J, Sanhueza E, Contreras J, Cuellar MC, Arrese M, Riquelme A. Management of nonalcoholic fatty liver disease: an evidence-based clinical practice review. World J Gastroenterol 2014; 20:12182-201. [PMID: 25232252 PMCID: PMC4161803 DOI: 10.3748/wjg.v20.i34.12182] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2013] [Revised: 03/27/2014] [Accepted: 04/27/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To build a consensus among Chilean specialists on the appropriate management of patients with nonalcoholic fatty liver disease (NAFLD) in clinical practice. METHODS NAFLD has now reached epidemic proportions worldwide. The optimal treatment for NAFLD has not been established due to a lack of evidence-based recommendations. An expert panel of members of the Chilean Gastroenterological Society and the Chilean Hepatology Association conducted a structured analysis of the current literature on NAFLD therapy. The quality of the evidence and the level of recommendations supporting each statement were assessed according to the recommendations of the United States Preventive Services Task Force. A modified three-round Delphi technique was used to reach a consensus among the experts. RESULTS A group of thirteen experts was established. The survey included 17 open-ended questions that were distributed among the experts, who assessed the articles associated with each question. The levels of agreement achieved by the panel were 93.8% in the first round and 100% in the second and third rounds. The final recommendations support the indication of lifestyle changes, including diet and exercise, for all patients with NAFLD. Proven pharmacological therapies include only vitamin E and pioglitazone, which can be used in nondiabetic patients with biopsy-proven nonalcoholic steatohepatitis (the progressive form of NAFLD), although the long-term safety and efficacy of these therapies have not yet been established. CONCLUSION Current NAFLD management is rapidly evolving, and new pathophysiology-based therapies are expected to be introduced in the near future. All NAFLD patients should be evaluated using a three-focused approach that considers the risks of liver disease, diabetes and cardiovascular events.
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Musso G, Gambino R, Tabibian JH, Ekstedt M, Kechagias S, Hamaguchi M, Hultcrantz R, Hagström H, Yoon SK, Charatcharoenwitthaya P, George J, Barrera F, Hafliðadóttir S, Björnsson ES, Armstrong MJ, Hopkins LJ, Gao X, Francque S, Verrijken A, Yilmaz Y, Lindor KD, Charlton M, Haring R, Lerch MM, Rettig R, Völzke H, Ryu S, Li G, Wong LL, Machado M, Cortez-Pinto H, Yasui K, Cassader M. Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis. PLoS Med 2014; 11:e1001680. [PMID: 25050550 PMCID: PMC4106719 DOI: 10.1371/journal.pmed.1001680] [Citation(s) in RCA: 512] [Impact Index Per Article: 46.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Accepted: 06/12/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD. METHODS AND FINDINGS English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05) and incidence (HR 2.12, 95% CI 1.42-3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14-8.61) and incidence (HR 3.29, 95% CI 2.30-4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies. CONCLUSION The presence and severity of NAFLD are associated with an increased risk and severity of CKD. Please see later in the article for the Editors' Summary.
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Affiliation(s)
| | - Roberto Gambino
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
| | - James H. Tabibian
- Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota, United States of America
| | - Mattias Ekstedt
- Division of Gastroenterology and Hepatology, Linköping University, Linköping, Sweden
| | - Stergios Kechagias
- Division of Cardiovascular Medicine, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Masahide Hamaguchi
- Department of Experimental Immunology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Rolf Hultcrantz
- Departments of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Hannes Hagström
- Departments of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Seung Kew Yoon
- Division of Hepato-Gastroenterology, Department of Internal Medicine, Kangnam St. Mary Hospital, Catholic University Medical College, Seoul, Korea
| | | | - Jacob George
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, New South Wales, Australia
| | - Francisco Barrera
- Storr Liver Unit, Westmead Millennium Institute, University of Sydney and Department of Gastroenterology and Hepatology, Westmead Hospital, Westmead, New South Wales, Australia
| | - Svanhildur Hafliðadóttir
- Dept of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbrau, Reykjavik, Iceland
| | - Einar Stefan Björnsson
- Dept of Gastroenterology and Hepatology, Landspitali University Hospital, Hringbrau, Reykjavik, Iceland
| | - Matthew J. Armstrong
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Laurence J. Hopkins
- Centre for Liver Research and NIHR Biomedical Research Unit in Liver Disease, Institute of Biomedical Research, University of Birmingham, Birmingham, United Kingdom
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - An Verrijken
- Department of Endocrinology, Diabetology and Metabolism, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium
| | - Yusuf Yilmaz
- Department of Gastroenterology, Marmara University, School of Medicine, Istanbul, Turkey
| | - Keith D. Lindor
- Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota, United States of America
| | - Michael Charlton
- Division of Gastroenterology and Hepatology Mayo Clinic, Rochester, Minnesota, United States of America
| | - Robin Haring
- Institute of Clinical Chemistry and Laboratory Medicine, Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany
| | - Markus M. Lerch
- Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Rainer Rettig
- Institute of Physiology, Ernst-Moritz-Arndt-University Medicine Greifswald, Karlsburg, Germany
| | - Henry Völzke
- Institute for Community Medicine, Ernst-Moritz-Arndt University Medicine Greifswald, Greifswald, Germany
| | - Seungho Ryu
- Department of Occupational and Environmental Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University, School of Medicine, Seoul, Republic of Korea
| | - Guolin Li
- College of Life Sciences, Hunan Normal University, Changsha, China
| | - Linda L. Wong
- John A. Burns School of Medicine at University of Hawaii, Transplant Institute, Hawaii Medical Center, Honolulu, Hawaii, United States of America
| | - Mariana Machado
- Department of Gastroenterology, University Hospital of Santa Maria, Institute of Molecular Medicine, Lisbon, Portugal
| | - Helena Cortez-Pinto
- Department of Gastroenterology, University Hospital of Santa Maria, Institute of Molecular Medicine, Lisbon, Portugal
| | - Kohichiroh Yasui
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Japan
| | - Maurizio Cassader
- Dept. of Medical Sciences, San Giovanni Battista Hospital, University of Turin, Turin, Italy
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Rouabhia S, Milic N, Abenavoli L. Metformin in the treatment of non-alcoholic fatty liver disease: safety, efficacy and mechanism. Expert Rev Gastroenterol Hepatol 2014; 8:343-9. [PMID: 24580044 DOI: 10.1586/17474124.2014.894880] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease etiology worldwide. It encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis. Although the physiopathology of NAFLD is partly known. Insulin-resistance plays a central role in the development and progression of NAFLD. Several studies have indicated that metformin, as an insulin sensitizer, effectively improves NAFLD and its related metabolic status. Metformin was effective in reducing enzyme levels in the short period, but very limited and controversial information are available on liver histology. Larger randomized controlled trials of sufficient duration using clearly defined histological endpoints are needed to fully assess the efficacy of this drug in modifying the natural history of NAFLD.
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Affiliation(s)
- Samir Rouabhia
- Department of Internal Medicine, University Hospital Center Touhami Benfis, Batna, Algeria
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Derosa G, Cicero AFG, Carbone A, Querci F, Fogari E, D'Angelo A, Maffioli P. Different aspects of sartan + calcium antagonist association compared to the single therapy on inflammation and metabolic parameters in hypertensive patients. Inflammation 2014; 37:154-62. [PMID: 24018781 DOI: 10.1007/s10753-013-9724-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
This study aims to evaluate the effects of an angiotensin receptor blocker (ARB)/calcium channel blocker combination on blood pressure control, lipid profile, insulin sensitivity, and inflammation markers. We randomized 276 hypertensive patients to olmesartan 20 mg, amlodipine 10 mg, or a single pill containing an olmesartan/amlodipine combination 20/5 mg for 12 months. We evaluated the following: body weight, systolic and diastolic blood pressure, fasting plasma glucose, fasting plasma insulin (FPI), M value, lipid profile, adiponectin (ADN), high sensitivity C-reactive protein (Hs-CRP), monocyte chemoattractant protein-1 (MCP-1), and macrophage migration inhibitory factor-1β (MIP-1β). Olmesartan/amlodipine combination better reduced blood pressure, FPI, homeostasis model assessment index, and increased M value and ADN compared to olmesartan and amlodipine monotherapies. Olmesartan/amlodipine significantly decreased Hs-CRP, MCP-1, and MIP-1β. In this multicenter, randomized, double-blind, clinical study, ARB/calcium antagonist combination resulted to be more effective than single monotherapies in reducing blood pressure, in improving insulin sensitivity, and in reducing inflammation parameters in patients with stage I essential hypertension.
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Affiliation(s)
- Giuseppe Derosa
- Department of Internal Medicine and Therapeutics, University of Pavia, Fondazione IRCCS Policlinico S. Matteo, P.le C. Golgi 2, 27100, Pavia, Italy,
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Matthew Morris E, Fletcher JA, Thyfault JP, Rector RS. The role of angiotensin II in nonalcoholic steatohepatitis. Mol Cell Endocrinol 2013; 378:29-40. [PMID: 22579612 PMCID: PMC12063499 DOI: 10.1016/j.mce.2012.04.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Accepted: 04/30/2012] [Indexed: 01/18/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is now considered the most prevalent chronic liver disease, affecting over 30% of the US adult population. NAFLD is strongly linked to insulin resistance and is considered the hepatic manifestation of the metabolic syndrome. Activation of the renin-angiotensin-aldosterone system (RAAS) is known to play a role in the hypertension observed in the metabolic syndrome and also is thought to play a central role in insulin resistance and NAFLD. Angiotensin II (AngII) is considered the primary effector of the physiological outcomes of RAAS signaling, both at the systemic and local tissue level. Herein, we review data describing the potential involvement of AngII-mediated signaling at multiple levels in the development and progression of NAFLD, including increased steatosis, inflammation, insulin resistance, and fibrosis. Additionally, we present recent work on the potential therapeutic benefits of RAAS and angiotensin II signaling inhibition in rodent models and patients with NAFLD.
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Affiliation(s)
- E Matthew Morris
- Department of Internal Medicine - Division of Gastroenterology and Hepatology, University of Missouri, MO, United States; Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65201, United States.
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Ultrasonography modifications of visceral and subcutaneous adipose tissue after pioglitazone or glibenclamide therapy combined with rosuvastatin in type 2 diabetic patients not well controlled by metformin. Eur J Gastroenterol Hepatol 2013; 25:1113-22. [PMID: 23524525 DOI: 10.1097/meg.0b013e3283608317] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIM To compare pioglitazone or glibenclamide alone and in combination with rosuvastatin on hepatic steatosis in type 2 diabetic patients. MATERIALS AND METHODS After 3 months of metformin, patients were randomized to add pioglitazone 15 mg twice a day or glibenclamide 5 mg twice a day for 6 months, and then rosuvastatin 5 mg was added for other 6 months. Patients underwent an ultrasound examination for evaluation of steatosis degree, subcutaneous adipose tissue, and visceral adipose tissue diameter, an euglycemic hyperinsulinemic clamp, and blood sample collection for evaluation of glycemic control, fasting plasma insulin, lipid profile, adipocytokines at randomization, and after 6 and 12 months. RESULTS Both pioglitazone and glibenclamide improved glycemic control. Pioglitazone reduced fasting plasma insulin, whereas glibenclamide increased it. Pioglitazone increased the glucose infusion rate compared with glibenclamide. Pioglitazone, but not glibenclamide, improved the lipid profile, and, when rosuvastatin was added, there was a greater improvement with pioglitazone and rosuvastatin. Adiponectin was increased by pioglitazone (+0.5 μg/ml), with a further increase (+0.4 μg/ml) when rosuvastatin was added. A significant decrease in leptin (-3.1 ng/ml) and interleukin-6 (-0.4 pg/ml) was found only with pioglitazone; a similar trend (-2.5 ng/ml and -0.3 pg/ml, respectively) was maintained after the addition of rosuvastatin.Rosuvastatin+pioglitazone decreased tumor necrosis factor-α (-0.3 ng/ml) and were superior to glibenclamide+rosuvastatin in reducing high-sensitivity C-reactive protein (-0.4 mg/l).Pioglitazone decreased ultrasound parameters, and the addition of rosuvastatin further decreased them both compared with randomization and glibenclamide. CONCLUSION Pioglitazone was more effective than glibenclamide in improving inflammation and hepatic steatosis indices.
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Results from a 12 months, randomized, clinical trial comparing an olmesartan/amlodipine single pill combination to olmesartan and amlodipine monotherapies on blood pressure and inflammation. Eur J Pharm Sci 2013; 51:26-33. [PMID: 23999037 DOI: 10.1016/j.ejps.2013.08.031] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2013] [Revised: 08/03/2013] [Accepted: 08/21/2013] [Indexed: 01/26/2023]
Abstract
AIM Hypertension affects nearly 1 in 3 adults in the United States, and it is an important modifiable risk factor for coronary artery disease, heart failure, renal failure, and stroke. The aim of this study was to evaluate the effects of a fixed-dose olmesartan/amlodipine combination on blood pressure control, lipid profile, insulin sensitivity, and inflammation compared to singles monotherapies. METHODS We randomized 276 hypertensive patients to olmesartan 20 mg, amlodipine 10mg or a single pill containing a fixed-dose olmesartan/amlodipine combination 20/5mg for 12 months. We evaluated: body weight, body mass index (BMI), systolic and diastolic blood pressure (SBP and DBP), fasting plasma glucose (FPG), fasting plasma insulin (FPI), lipid profile, omentin, chemerin, high sensitivity C-reactive protein (Hs-CRP). At baseline, and after 6 and 12 months, patients underwent an euglycemic, hyperinsulinemic clamp to assess insulin sensitivity (M value). RESULTS Olmesartan/amlodipine combination was more effective than amlodipine or olmesartan in reducing blood pressure. Olmesartan/amlodipine combination, but not amlodipine, decreased FPG after 12 months. Olmesartan/amlodipine combination better decreased FPI and HOMA index and increased M value compared to olmesartan and amlodipine monotherapies. Olmesartan/amlodipine significantly decreased chemerin and omentin compared to olmesartan and amlodipine. CONCLUSION Other than to be more effective in reducing blood pressure, olmesartan/amlodipine single pill combination gave also a major increase of insulin sensitivity and a decrease of inflammatory markers compared to single monotherapies.
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Derosa G, Cicero AFG, Carbone A, Querci F, Fogari E, D'Angelo A, Maffioli P. Evaluation of safety and efficacy of a fixed olmesartan/amlodipine combination therapy compared to single monotherapies. Expert Opin Drug Saf 2013; 12:621-9. [DOI: 10.1517/14740338.2013.816674] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Williams KH, Shackel NA, Gorrell MD, McLennan SV, Twigg SM. Diabetes and nonalcoholic Fatty liver disease: a pathogenic duo. Endocr Rev 2013; 34:84-129. [PMID: 23238855 DOI: 10.1210/er.2012-1009] [Citation(s) in RCA: 171] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recent data increasingly support a complex interplay between the metabolic condition diabetes mellitus and the pathologically defined nonalcoholic fatty liver disease (NAFLD). NAFLD predicts the development of type 2 diabetes and vice versa, and each condition may serve as a progression factor for the other. Although the association of diabetes and NAFLD is likely to be partly the result of a "common soil," it is also probable that diabetes interacts with NAFLD through specific pathogenic mechanisms. In particular, through interrelated metabolic pathways currently only partly understood, diabetes appears to accelerate the progression of NAFLD to nonalcoholic steatohepatitis, defined by the presence of necroinflammation, with varying degrees of liver fibrosis. In the research setting, obstacles that have made the identification of clinically significant NAFLD, and particularly nonalcoholic steatohepatitis, difficult are being addressed with the use of new imaging techniques combined with risk algorithms derived from peripheral blood profiling. These techniques are likely to be used in the diabetes population in the near future. This review examines the pathogenic links between NAFLD and diabetes by exploring the epidemiological evidence in humans and also through newer animal models. Emerging technology to help screen noninvasively for differing pathological forms of NAFLD and the potential role of preventive and therapeutic approaches for NAFLD in the setting of diabetes are also examined.
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Affiliation(s)
- K H Williams
- Sydney Medical School and the Bosch Institute, The University of Sydney, Sydney, New South Wales 2006, Australia
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Abstract
PURPOSE OF REVIEW This article reviews the mechanisms leading to the development of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) and the effects of hypoglycaemic and lipid-lowering therapies on NAFLD/NASH. RECENT FINDINGS The interaction of lipogenesis, fatty acid oxidation, inflammation, endoplasmic reticulum stress and hepatic insulin resistance contribute to the pathogenesis of NAFLD/NASH. Few large scale clinical trials exist with biopsy or magnetic resonance endpoints as opposed to ultrasonographic and transaminase endpoints. Trial evidence that exists supports the utility of weight loss, metformin, thiazolidinediones, fibrates, niacin, ezetimibe and statins in improving the steatosis component of NAFLD/NASH though with less or minimal effects on the fibrotic component of NASH. SUMMARY Hypoglycaemic and lipid-lowering therapies may have a role in the treatment of NAFLD/NASH but large scale endpoint trials remain to be performed.
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Affiliation(s)
- Anthony S Wierzbicki
- Department of Metabolic Medicine/Chemical Pathologyemical Pathology, Guy's and St. Thomas' Hospitals, London, UK.
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Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 2012; 55:885-904. [PMID: 22278337 DOI: 10.1007/s00125-011-2446-4] [Citation(s) in RCA: 486] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2011] [Accepted: 12/02/2011] [Indexed: 12/13/2022]
Abstract
AIMS/HYPOTHESIS Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to non-alcoholic steatohepatitis (NASH): NAFLD causes an increased risk of cardiovascular disease, diabetes and liver-related complications (the latter confined to NASH). The effect of proposed treatments on liver disease, glucose metabolism and cardiovascular risk in NAFLD is unknown. We reviewed the evidence for the management of liver disease and cardio-metabolic risk in NAFLD. METHODS Publications through November 2011 were systematically reviewed by two authors. Outcomes evaluated though standard methods were: histological/radiological/biochemical features of NAFLD, variables of glucose metabolism and cardiovascular risk factors. Seventy-eight randomised trials were included (38 in NASH, 40 in NAFLD): 41% assessed post-treatment histology, 71% assessed glucose metabolism and 88% assessed cardiovascular risk factors. Lifestyle intervention, thiazolidinediones, metformin and antioxidants were most extensively evaluated. RESULTS Lifestyle-induced weight loss was safe and improved cardio-metabolic risk profile; a weight loss ≥7% improved histological disease activity, but was achieved by <50% patients. Statins and polyunsaturated fatty acids improved steatosis, but their effects on liver histology are unknown. Thiazolidinediones improved histological disease activity, glucose, lipid and inflammatory variables and delayed fibrosis progression. Pioglitazone also improved blood pressure. Weight gain (up to 4.8%) was common. Antioxidants yielded mixed histological results: vitamin E improved histological disease activity when administered for 2 years, but increased insulin resistance and plasma triacylglycerols. CONCLUSIONS/INTERPRETATION Weight loss is safe, and improves liver histology and cardio-metabolic profile. For patients not responding to lifestyle intervention, pioglitazone improves histological disease activity, slows fibrosis progression and extensively ameliorates cardio-metabolic endpoints. Further randomised controlled trials (RCTs) of adequate size and duration will assess long-term safety and efficacy of proposed treatments on clinical outcomes.
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Affiliation(s)
- G Musso
- Gradenigo Hospital, C.so Regina Margherita 8, Turin, Italy.
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