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Gu C, Bernstein N, Mittal N, Kurnool S, Schwartz H, Loomba R, Malhotra A. Potential Therapeutic Targets in Obesity, Sleep Apnea, Diabetes, and Fatty Liver Disease. J Clin Med 2024; 13:2231. [PMID: 38673503 PMCID: PMC11050527 DOI: 10.3390/jcm13082231] [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: 03/09/2024] [Revised: 04/07/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Obesity and metabolic syndrome affect the majority of the US population. Patients with obesity are at increased risk of developing type 2 diabetes (T2DM), obstructive sleep apnea (OSA), and metabolic dysfunction-associated steatotic liver disease (MASLD), each of which carry the risk of further complications if left untreated and lead to adverse outcomes. The rising prevalence of obesity and its comorbidities has led to increased mortality, decreased quality of life, and rising healthcare expenditures. This phenomenon has resulted in the intensive investigation of exciting therapies for obesity over the past decade, including more treatments that are still in the pipeline. In our present report, we aim to solidify the relationships among obesity, T2DM, OSA, and MASLD through a comprehensive review of current research. We also provide an overview of the surgical and pharmacologic treatment classes that target these relationships, namely bariatric surgery, the glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon receptor agonists.
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Affiliation(s)
- Christina Gu
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA; (N.B.); (N.M.); (S.K.); (R.L.)
| | - Nicole Bernstein
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA; (N.B.); (N.M.); (S.K.); (R.L.)
| | - Nikita Mittal
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA; (N.B.); (N.M.); (S.K.); (R.L.)
| | - Soumya Kurnool
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA; (N.B.); (N.M.); (S.K.); (R.L.)
| | - Hannah Schwartz
- Weill Cornell Medicine, 1300 York Ave, New York, NY 10065, USA;
| | - Rohit Loomba
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA; (N.B.); (N.M.); (S.K.); (R.L.)
| | - Atul Malhotra
- Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92037, USA; (N.B.); (N.M.); (S.K.); (R.L.)
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Parchani A, Gupta R, Kant R, Saini LK, Gupta R. Evaluation of Hepatic Steatosis and Fibrosis Using Transient Elastography in Patients With Obstructive Sleep Apnea. J Clin Exp Hepatol 2024; 14:101289. [PMID: 38544762 PMCID: PMC10964064 DOI: 10.1016/j.jceh.2023.09.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 09/24/2023] [Indexed: 03/03/2025] Open
Abstract
Objectives Obstructive sleep apnea (OSA) is an independent risk factor for non-alcoholic fatty liver disease. This study was planned to assess proportion of patients with OSA that have hepatic steatosis and fibrosis, as measured by transient elastography, to explore variables influencing their development and to find out the polysomnography parameters that predict the need for transient elastography screening in OSA. Methods Consecutive participants having polysomnography proven OSA were included in the study after screening for eligibility criteria. Data of the polysomnography were scored manually following standard criteria. Participants were subjected to transient elastography (Fibroscan®) and serum investigations after diagnostic polysomnography. The polysomnography, fibroscan®, and laboratory data were tabulated and analyzed. Results A total of 71 participants were enrolled. 16.9% participants had mild OSA, 28.2% had moderate OSA, and remaining participants had severe OSA. Liver steatosis was found in 63.4% participants while hepatic fibrosis was noted in 9.9%. Oxygen desaturation index (ODI), apnea-hypopnea index (AHI), and percentage of sleep spent below 90% oxygen saturation (T90) were significantly associated with the presence of hepatic steatosis and fibrosis. Receiver operating curve (ROC) showed that at the cut-offs of 73 events/hr, 13% and 72.2 events/hr, AHI, T90 and ODI, predicted hepatic fibrosis with area under ROC of 0.960, 0.944, and 0.933, respectively (P < 0.001). Conclusions Patients with OSA are at increased risk for development of hepatic steatosis and fibrosis. ODI, AHI, and T90 during polysomnography predict the presence of underlying hepatic fibrosis.
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Affiliation(s)
- Ashwin Parchani
- Department of Internal Medicine, All India Institute of Medical Sciences, Rishikesh, 249203, India
| | - Ravi Gupta
- Department of Psychiatry, All India Institute of Medical Sciences, Rishikesh, - 249203, India
| | - Ravi Kant
- Department of Internal Medicine, All India Institute of Medical Sciences, Rishikesh, 249203, India
| | - Lokesh K. Saini
- Department of Pulmonary Medicine, All India Institute of Medical Sciences, Rishikesh, 249203, India
| | - Rohit Gupta
- Department of Gastroenterology, All India Institute of Medical Sciences, Rishikesh, 249203, India
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Oh JH, Jun DW. Nonalcoholic fatty liver disease–related extrahepatic complications, associated outcomes, and their treatment considerations. METABOLIC STEATOTIC LIVER DISEASE 2024:101-122. [DOI: 10.1016/b978-0-323-99649-5.00007-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Hany M, Abouelnasr AA, Abdelkhalek MH, Ibrahim M, Aboelsoud MR, Hozien AI, Torensma B. Effects of obstructive sleep apnea on non-alcoholic fatty liver disease in patients with obesity: a systematic review. Int J Obes (Lond) 2023; 47:1200-1213. [PMID: 37696927 PMCID: PMC10663145 DOI: 10.1038/s41366-023-01378-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 08/16/2023] [Accepted: 08/30/2023] [Indexed: 09/13/2023]
Abstract
INTRODUCTION Obesity has been linked to non-alcoholic fatty liver disease (NAFLD), a widespread chronic liver ailment, as well as obstructive sleep apnea (OSA). The development of NAFLD is influenced by repeated intermittent hypoxia, a feature of OSA. METHODS This systematic review (SR) investigated CENTRAL, PubMed, and EMBASE databases. The endpoint of this SR was to assess which OSA-related indicators could predict the presence of NAFLD and the effect of bariatric metabolic surgery (BMS) on improving OSA and NAFLD over time. RESULTS Compared to previous SRs published in 2013, 14 new publications were added to our SR, alongside studies conducted prior to 2013. The SR ultimately included 28 studies (18 cross-sectional and 10 cohort trials). In the majority of studies, significant correlations were observed between OSA, OSA-related outcomes, and NAFLD. However, the apnea-hypopnea index (AHI) alone proved to be an inadequate predictor of NAFLD. Instead, respiratory and metabolic changes were found to alleviate oxidative stress induced by hypoxemia. Six studies involved patients who underwent BMS, with one evaluating patients before and after BMS, revealing associations between increased OSA and NAFLD improvement following BMS. Six months after surgery, 100% of patients in the mild-to-moderate OSA group were free from fatty liver, and an 89% reduction was observed in the severe OSA group. CONCLUSION For the first time, BMS has been tested in treating both OSA and NAFLD pre and postoperative with positive results. Further research, ideally with histological and functional data, is needed to confirm these findings. The SR identified 14 distinct liver outcome tests; however, high heterogeneity and incomplete data precluded a meta-analysis. It is imperative to pay greater attention to the influence of OSA-related factors and uniformity in liver outcomes testing concerning NAFLD. To accomplish this, study designs should be enhanced by incorporating more comprehensive pre- and postoperative evaluations, extending follow-up periods, and employing a more consistent methodology for liver diagnosis in patients with obesity.
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Affiliation(s)
- Mohamed Hany
- Department of Surgery, Medical Research Institute, Alexandria University, Alexandria Governorate, Egypt.
- Madina Women's Hospital (IFSO certified center, European chapter), Alexandria Governorate, Egypt.
| | - Anwar Ashraf Abouelnasr
- Department of Surgery, Medical Research Institute, Alexandria University, Alexandria Governorate, Egypt
| | | | - Mohamed Ibrahim
- Department of Surgery, Medical Research Institute, Alexandria University, Alexandria Governorate, Egypt
| | - Mostafa R Aboelsoud
- Department of Surgery, Medical Research Institute, Alexandria University, Alexandria Governorate, Egypt
| | - Adel Ibrahim Hozien
- Department of Anesthesia and pain management, Medical Research Institute Alexandria University, Alexandria Governorate, Egypt
| | - Bart Torensma
- Leiden University Medical Center (LUMC), Leiden, The Netherlands
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Kurnool S, McCowen KC, Bernstein NA, Malhotra A. Sleep Apnea, Obesity, and Diabetes - an Intertwined Trio. Curr Diab Rep 2023:10.1007/s11892-023-01510-6. [PMID: 37148488 DOI: 10.1007/s11892-023-01510-6] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/18/2023] [Indexed: 05/08/2023]
Abstract
PURPOSE OF REVIEW To synthesize the existing literature regarding the complex interplay between sleep disturbance, obesity, and diabetes. The review emphasizes the three pillars of health being diet, exercise, and sleep, with the notion that if one is ignored, then the other two could suffer. RECENT FINDINGS Sleep deprivation is associated with incident obesity, perhaps mediated by dysregulation in leptin and ghrelin - hormones important in regulation of appetite. Sleep apnea is very common particularly among obese people with type 2 diabetes mellitus. Treatment of sleep apnea has clear symptomatic benefits although its impact on long-term cardiometabolic health is less clear. Sleep disturbance may be an important modifiable risk for patients at risk of cardiometabolic disease. An assessment of sleep health may be an important component of the comprehensive care of patients with obesity and diabetes mellitus.
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Affiliation(s)
- Soumya Kurnool
- UC San Diego Department of Medicine, 9500 Gilman Drive, UC San Diego, La Jolla, CA, 92037, USA
| | - Karen C McCowen
- UC San Diego Department of Medicine, 9500 Gilman Drive, UC San Diego, La Jolla, CA, 92037, USA
| | - Nicole A Bernstein
- UC San Diego Department of Medicine, 9500 Gilman Drive, UC San Diego, La Jolla, CA, 92037, USA
| | - Atul Malhotra
- UC San Diego Department of Medicine, 9500 Gilman Drive, UC San Diego, La Jolla, CA, 92037, USA.
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Jin YX, Wang BY, Wang XL, Yu X, Chen LD, Yang YS, Huang JF. Relationship between Obstructive Sleep Apnea and Liver Abnormalities in Older Patients: A Cross-Sectional Study. Int J Clin Pract 2023; 2023:9310588. [PMID: 36694611 PMCID: PMC9831696 DOI: 10.1155/2023/9310588] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 12/08/2022] [Accepted: 12/17/2022] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Older age is a risk factor for obstructive sleep apnea (OSA), which is associated with the development of nonalcoholic fatty liver disease (NAFLD). We aimed to investigate the correlation between OSA and liver injury among older patients. Study Design. This is a cross-sectional study. METHODS Consecutive older (≥60 years) snoring patients were included. Subjects were divided into no OSA, mild OSA, moderate OSA, and severe OSA groups according to the apnea-hypopnea index (AHI) and were also separated into liver injury and nonliver injury groups based on liver function. Logistic regression analysis was applied to analyze the independent risk factors for liver injury. RESULTS We studied 227 patients (155 male, 72 female). The prevalence of liver injury exhibited an increasing trend among groups with mild-to-severe OSA. In addition, body mass index, AHI, and TG showed significant differences between the liver injury and nonliver injury groups. Logistic regression analysis revealed that AHI and TG were the major contributing factors for liver injury in older patients (adjusted odds ratio [OR] = 1.055, p=0.013, and OR = 1.485, p=0.039, respectively). CONCLUSIONS Older patients with OSA have an increased risk of liver injury and NAFLD, and sleep apnea and high TG are important factors in contributing to the development of liver injury.
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Affiliation(s)
- Yong-Xu Jin
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Fujian Provincial Sleep-Disordered Breathing Clinic Center, Institute of Respiratory Disease, Fujian Medical University, Fuzhou 350005, China
- Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Bi-ying Wang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Fujian Provincial Sleep-Disordered Breathing Clinic Center, Institute of Respiratory Disease, Fujian Medical University, Fuzhou 350005, China
- Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Xiao-li Wang
- Department of Pediatrics, Fujian Provincial Hospital, Gulou District, Fuzhou, Fujian 350001, China
| | - Xing Yu
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Fujian Provincial Sleep-Disordered Breathing Clinic Center, Institute of Respiratory Disease, Fujian Medical University, Fuzhou 350005, China
- Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Li-da Chen
- Department of Respiratory and Critical Care Medicine, Zhangzhou Affiliated Hospital of Fujian Medical University, Xiangcheng, Zhangzhou 363000, China
| | - Yi-song Yang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Fujian Provincial Sleep-Disordered Breathing Clinic Center, Institute of Respiratory Disease, Fujian Medical University, Fuzhou 350005, China
- Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
| | - Jie-feng Huang
- Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Fujian Medical University, Fujian Provincial Sleep-Disordered Breathing Clinic Center, Institute of Respiratory Disease, Fujian Medical University, Fuzhou 350005, China
- Department of Respiratory and Critical Care Medicine, National Regional Medical Center, Binhai Campus of The First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
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Sukahri S, Mohamed Shah FZ, Ismail AI, Koshy M, Johari B, Mohd Razali M, Abdul Rahman TH, Isa MR, Abdul Ghani R. Significantly higher atherosclerosis risks in patients with obstructive sleep apnea and non-alcoholic fatty liver disease. PLoS One 2021; 16:e0253298. [PMID: 34191823 PMCID: PMC8244858 DOI: 10.1371/journal.pone.0253298] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 06/01/2021] [Indexed: 01/11/2023] Open
Abstract
INTRODUCTION There is limited data on the relationship between Obstructive Sleep Apnea (OSA) and Non-Alcoholic Fatty Liver Disease (NAFLD), each associated with increased cardiovascular risk. This study aimed to determine the relationships between severity of OSA, degree of steatosis in NAFLD and cardiovascular risk via CIMT and atherosclerosis markers ie intracellular adhesion molecule-1 (ICAM-1) an Lipoprotein-a (Lp(a)) in a group of patients with OSA. MATERIALS AND METHODS This was a cross-sectional, single center study. A total of 110 subjects between 18 to 65 years of age and diagnosed with OSA following sleep study examinations were recruited. Exclusion criteria included seropositive Hepatitis B or Hepatitis C, and significant alcohol intake. RESULT The prevalence of NAFLD was 81.8%. The mean CIMT (0.08±0.03 vs 0.06±0.01 cm, p = 0.001), ICAM-1 (334.53±72.86 vs 265.46±102.92 ng/mL, p = 0.001) and Lp(a) (85.41±52.56 vs 23.55±23.66 nmol/L, p<0.001) were significantly higher in the NAFLD group compared to the non-NAFLD group. Comparisons between the different groups showed significantly increasing levels of CIMT, ICAM-1 and Lp(a), lowest within the non-NAFLD, followed by the NAFLD 1 and NAFLD 2+3 groups. There was a significant positive correlation between degree of steatosis and the severity of OSA (r = 0.453, p<0.001). Logistic regression analysis revealed that patients with apnea/hypopnea index (AHI) of >30 were 52.77 (CI 6.34, 439.14) times more likely to have NAFLD compared to those with mild AHI (p<0.001). CONCLUSION The prevalence of NAFLD is alarmingly high in this group of OSA patients. The degree of steatosis in patients with NAFLD was significantly correlated with severity of OSA, CIMT measurements, ICAM-1 and Lp(a). Our findings underscore screening for NAFLD in patients with OSA to ensure prompt risk stratification and management.
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Affiliation(s)
- Samshol Sukahri
- Faculty of Medicine, Dept of Internal Medicine, Universiti Teknologi MARA (UiTM), Sg Buloh, Selangor, Malaysia
| | | | - Ahmad Izuanuddin Ismail
- Faculty of Medicine, Dept of Internal Medicine, Universiti Teknologi MARA (UiTM), Sg Buloh, Selangor, Malaysia
| | - Marymol Koshy
- Faculty of Medicine, Dept of Radiology, Universiti Teknologi MARA (UiTM), Sg Buloh, Selangor, Malaysia
| | - Bushra Johari
- Faculty of Medicine, Dept of Radiology, Universiti Teknologi MARA (UiTM), Sg Buloh, Selangor, Malaysia
| | - Mazuin Mohd Razali
- Faculty of Medicine, Dept of Radiology, Universiti Teknologi MARA (UiTM), Sg Buloh, Selangor, Malaysia
| | | | - Mohamad Rodi Isa
- Faculty of Medicine, Dept of Public Health, Universiti Teknologi MARA (UiTM), Sg Buloh, Selangor, Malaysia
| | - Rohana Abdul Ghani
- Faculty of Medicine, Dept of Internal Medicine, Universiti Teknologi MARA (UiTM), Sg Buloh, Selangor, Malaysia
- Laboratory and Forensic Medicine (I-PPerForM), Institute of Pathology, Sg Buloh Campus, Universiti Teknologi MARA (UiTM), Selangor, Malaysia
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The association between obstructive sleep apnea and non-alcoholic steatohepatitis: a retrospective nationwide inpatient sample analysis. Clin Exp Hepatol 2021; 7:25-29. [PMID: 34027112 PMCID: PMC8122103 DOI: 10.5114/ceh.2021.104488] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 10/24/2020] [Indexed: 12/13/2022] Open
Abstract
Aim of the study The primary purpose of this study was to assess the association of obstructive sleep apnea (OSA) and non-alcoholic steatohepatitis (NASH) from a large national inpatient sample database. Material and methods We conducted a retrospective analysis using the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample. OSA and NASH patients were identified using the ICD-10-CM code G47.33 and K75.81. Non-NASH patients (control) were randomly selected and matched by age and gender to each NASH patient in a 4 : 1 ratio. Weighted logistic regression models were used to calculate the association between OSA and NASH in addition to different comorbidities. Results A total of 54,169 participants were included in our analysis; 10,740 cases of NASH were matched to 43,429 controls (non-NASH). NASH was significantly higher in the white population (82.12% vs. 76.64%, p < 0.001). The prevalence of OSA among NASH patients was significantly higher compared to the control group (15.8% vs. 8.9%, adjusted OR: 1.34, 95% CI: 1.14-1.56, p = 0.0003). The prevalence of celiac disease and Crohn’s disease was significantly higher in patients with NASH (0.7% vs. 0.2%, p < 0.0002 and 1.28% vs. 0.76%, p < 0.0001). Multiple comorbidities were significantly elevated in the NASH group compared to the non-NASH group, including diabetes mellitus (DM; 36% vs. 17.6%, p < 0.0001), obesity (36.4% vs. 18.2%, p < 0.0001) and metabolic syndrome (0.86% vs. 0.06%, p < 0.0001). The mortality rate was significantly higher in the NASH group (3.8% vs. 2%, p < 0.0001). Conclusions This is the first study using the ICD-10-CM code with a specific search code for NASH. Our large population database results emphasize that there is a significant association between OSA and NASH.
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Cai H, Bai Z, Ge RL. Hypoxia-inducible factor-2 promotes liver fibrosis in non-alcoholic steatohepatitis liver disease via the NF-κB signalling pathway. Biochem Biophys Res Commun 2021; 540:67-74. [PMID: 33450482 DOI: 10.1016/j.bbrc.2021.01.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 01/01/2021] [Indexed: 12/31/2022]
Abstract
Non-alcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases. Chronic hypoxia is related to the pathogenesis of NASH. HIF-2α is the key gene for lipid metabolism, fibrosis, and inflammation in many cells. To identify the molecular mechanism through which hypoxia exposure increases the morbidity of NASH, the expression level of HIF-2α was analysed and was found to be upregulated in human NASH liver. By constructing the NASH model of chronic hypoxia, the mice were housed at an altitude of 4300 m for 4 and 8 weeks, compared to the control groups that were housed at an altitude of 50 m. Histological studies showed that exposure to hypoxia promoted the activation of NF-κB by upregulating the expression of HIF-2α, as well as that of the genes related to inflammation and fibrosis, thereby promoting the development of NASH both in vivo and in vitro. In summary, hypoxia-exposure could upregulate HIF-2α to aggravate tissue fibrosis and inflammation by upregulating inflammation-related genes and fibrosis-related genes metabolites via the activated NF-κB pathway in NASH. Our results suggest that for NASH patients living at high altitudes, drug therapy could focus on treating tissue fibrosis and inflammation, and thus provides a new strategy for NASH treatment.
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Affiliation(s)
- Hao Cai
- Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, 810001, China; Key Laboratory of High Altitude Medicine(Qinghai University), Ministry of Education, Xining, 810001, China; Key Laboratory for Application of High Altitude Medicine in Qinghai Province, Xining, 810001, PR China; Oncology Department, The Fifth People's Hospital of Qinghai Provincial, Xining, 810000, PR China
| | - Zhenzhong Bai
- Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, 810001, China; Key Laboratory of High Altitude Medicine(Qinghai University), Ministry of Education, Xining, 810001, China; Key Laboratory for Application of High Altitude Medicine in Qinghai Province, Xining, 810001, PR China.
| | - Ri-Li Ge
- Research Center for High Altitude Medicine, Qinghai University Medical College, Xining, 810001, China; Key Laboratory of High Altitude Medicine(Qinghai University), Ministry of Education, Xining, 810001, China; Key Laboratory for Application of High Altitude Medicine in Qinghai Province, Xining, 810001, PR China.
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Shah NM, Malhotra AM, Kaltsakas G. Sleep disorder in patients with chronic liver disease: a narrative review. J Thorac Dis 2020; 12:S248-S260. [PMID: 33214928 PMCID: PMC7642630 DOI: 10.21037/jtd-cus-2020-012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sleep disturbance is a common feature of chronic liver disease (CLD) with impact on health-related quality of life; 60-80% of patients with CLD report subjective poor sleep; frequent presentations of sleep disturbance include insomnia, reduced sleep efficiency, increased sleep latency, reduced time in rapid eye movement (REM) sleep, restless leg syndrome and excessive daytime sleepiness (EDS). Key contributors to sleep disturbance include hepatic encephalopathy (HE) and circadian rhythm imbalance due to altered melatonin metabolism. Specific conditions causing CLD, such as non-alcoholic fatty liver disease (NAFLD), chronic viral hepatitis and primary biliary cholangitis (PBC) result in different types of sleep disturbance, and the treatment of these conditions can often also lead to sleep disturbance. There are currently limited management options for sleep disturbance in CLD. Obstructive sleep apnoea (OSA) is a common condition that causes chronic intermittent hypoxia due to airway collapse during sleep. This chronic intermittent hypoxia appears to contribute to the development of NAFLD. The presence of reactive oxygen species and the overexpression of hypoxia inducible factor 1-alpha secondary to hypoxia may be responsible for the second 'hit' of the 'two-hit' hypothesis of NAFLD. Treatment of the intermittent hypoxia with continuous positive airway pressure therapy has limited efficacy against liver dysfunction. There remain many outstanding areas of investigation in the management of sleep disturbance in CLD, and of liver dysfunction in OSA.
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Affiliation(s)
- Neeraj Mukesh Shah
- Lane Fox Respiratory Service, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Lane Fox Clinical Respiratory Physiology Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Centre for Human and Applied Physiological Sciences (CHAPS), King's College London, London, UK
| | - Akanksha Mimi Malhotra
- Lane Fox Respiratory Service, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Georgios Kaltsakas
- Lane Fox Respiratory Service, St Thomas' Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Lane Fox Clinical Respiratory Physiology Centre, Guy's and St Thomas' NHS Foundation Trust, London, UK.,Centre for Human and Applied Physiological Sciences (CHAPS), King's College London, London, UK
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Barros D, García-Río F. Obstructive sleep apnea and dyslipidemia: from animal models to clinical evidence. Sleep 2020; 42:5204276. [PMID: 30476296 DOI: 10.1093/sleep/zsy236] [Citation(s) in RCA: 85] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 10/02/2018] [Accepted: 11/22/2018] [Indexed: 01/11/2023] Open
Abstract
Lipid metabolism deregulation constitutes the pathogenic basis for the development of atherosclerosis and justifies a high incidence of cardiovascular-related morbidity and mortality. Some data suggest that dyslipidemia may be associated with sleep-disordered breathing, mainly obstructive sleep apnea (OSA), due to alterations in fundamental biochemical processes, such as intermittent hypoxia (IH). The aim of this systematic review was to identify and critically evaluate the current evidence supporting the existence of a possible relationship between OSA and alterations in lipid metabolism. Much evidence shows that, during the fasting state, OSA and IH increase lipid delivery from the adipose tissue to the liver through an up-regulation of the sterol regulatory element-binding protein-1 and stearoyl-CoA desaturase-1, increasing the synthesis of cholesterol esters and triglycerides. In the postprandial state, lipoprotein clearance is delayed due to lower lipoprotein lipase activity, probably secondary to IH-up-regulation of angiopoietin-like protein 4 and decreased activity of the peroxisome proliferator-activated receptor alpha. Moreover, oxidative stress can generate dysfunctional oxidized lipids and reduce the capacity of high-density lipoproteins (HDL) to prevent low-density lipoprotein (LDL) oxidation. In the clinical field, several observational studies and a meta-regression analysis support the existence of a link between OSA and dyslipidemia. Although there is evidence of improved lipid profile after apnea-hypopnea suppression with continuous positive airway pressure (CPAP), the majority of the data come from observational studies. In contrast, randomized controlled trials evaluating the effects of CPAP on lipid metabolism present inconclusive results and two meta-analyses provide contradictory evidence.
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Affiliation(s)
- David Barros
- Servicio de Neumología, Hospital Montecelo, Pontevedra, Spain
| | - Francisco García-Río
- Servicio de Neumología, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, Spain.,Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
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Obstructive sleep apnea and liver injury in severely obese patients with nonalcoholic fatty liver disease. Sleep Breath 2020; 24:1515-1521. [PMID: 32002742 DOI: 10.1007/s11325-020-02018-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 12/26/2019] [Accepted: 01/15/2020] [Indexed: 02/08/2023]
Abstract
OBJECTIVES Obstructive sleep apnea (OSA) and nonalcoholic fatty liver disease (NAFLD) are common in subjects with severe obesity. It has been suggested that insulin resistance and systemic inflammation may play a role in the development of nonalcoholic steatohepatitis (NASH), but the mechanisms remain controversial. The aim of this study was to explore the influence of OSA on liver injury and its potential mechanisms in severely obese patients with NAFLD. METHODS Severely obese patients requiring bariatric surgery were consecutively recruited between November 2017 and June 2018. Demographic, biochemical, liver ultrasound, and ambulatory polygraph data were collected. RESULTS One hundred fifty-three subjects with liver ultrasound-verified NAFLD were classified into three groups according to the apnea-hypopnea index (AHI). The level of serum alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) tended to increase with more severe OSA (P = 0.024 and P = 0.004, respectively). In the unadjusted analysis, both ALT and GGT were positively correlated with AHI, oxygen desaturation index, percentage of total sleep time spent with oxyhemoglobin saturation below 90%, male sex, homeostasis model assessment of insulin resistance (HOMA-IR), and total cholesterol, while liver enzymes were negatively related to lowest oxygen saturation. In multiple regression analysis, AHI (odds ratio (OR) = 1.052, P = 0.044) and HOMA-IR (OR = 1.135, P = 0.001) were independent risk factors for an elevated ALT level. High-sensitivity C-reactive protein (hs-CRP) was positively associated with BMI and GGT (r = 0.349 and r = 0.164 (P < 0.05), respectively), and no correlation was found between hs-CRP and AHI or other parameters of hypoxia. hs-CRP and GGT remained significantly correlated after adjusting for confounding parameters (OR = 2.509, P = 0.013). CONCLUSIONS OSA may play a role in liver injury among severely obese individuals with NAFLD. Insulin resistance and systemic inflammation were possible contributing factors in this process.
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13
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Mesarwi OA, Loomba R, Malhotra A. Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease. Am J Respir Crit Care Med 2020; 199:830-841. [PMID: 30422676 DOI: 10.1164/rccm.201806-1109tr] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Recent studies have demonstrated that obstructive sleep apnea (OSA) is associated with the development and evolution of nonalcoholic fatty liver disease (NAFLD), independent of obesity or other shared risk factors. Like OSA, NAFLD is a prevalent disorder associated with major adverse health outcomes: Patients with NAFLD may develop cirrhosis, liver failure, and hepatocellular carcinoma. One major finding that has emerged from these studies is that the OSA-NAFLD association is related to the degree of nocturnal hypoxemia in OSA. Animal models have therefore largely focused on intermittent hypoxia, a key manifestation of OSA, to shed light on the mechanisms by which OSA may give rise to the complex metabolic disturbances that are seen in NAFLD. Intermittent hypoxia leads to tissue hypoxia and can result in oxidative stress, mitochondrial dysfunction, inflammation, and overactivation of the sympathetic nervous system, among many other maladaptive effects. In such models, intermittent hypoxia has been shown to cause insulin resistance, dysfunction of key steps in hepatic lipid metabolism, atherosclerosis, and hepatic steatosis and fibrosis, each of which is pertinent to the development and/or progression of NAFLD. However, many intriguing questions remain unanswered: Principally, how aggressively should the clinician screen for NAFLD in patients with OSA, and vice versa? In this review, we attempt to apply the best evidence from animal and human studies to highlight the relationship between these two disorders and to advocate for further trials aimed at defining these relationships more precisely.
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Affiliation(s)
- Omar A Mesarwi
- 1 Division of Pulmonary, Critical Care, and Sleep Medicine
| | - Rohit Loomba
- 2 Division of Gastroenterology, Department of Medicine, and.,3 Department of Family Medicine and Public Health, University of California San Diego School of Medicine, La Jolla, California
| | - Atul Malhotra
- 1 Division of Pulmonary, Critical Care, and Sleep Medicine
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14
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Samji NS, Verma R, Satapathy SK. Magnitude of Nonalcoholic Fatty Liver Disease: Western Perspective. J Clin Exp Hepatol 2019; 9:497-505. [PMID: 31516266 PMCID: PMC6728535 DOI: 10.1016/j.jceh.2019.05.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2019] [Accepted: 05/07/2019] [Indexed: 12/12/2022] Open
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is continuing to rise worldwide, and it is estimated that this disquieting trend will continue for another 10-15 years before prevalence begins to decrease. NAFLD is the hepatic manifestation of metabolic syndrome. As obesity, diabetes, and other lifestyle-related diseases continue to rise, the spectrum of NAFLD, e.g., nonalcoholic steatohepatitis, liver fibrosis, liver cirrhosis, liver-related morbidity, and mortality, will increase in parallel. Its widespread prevalence and associated economic burden have drawn significant attention, and a multitude of pharmaceutical companies are participating in active research trying to find a "cure". Unfortunately, as of now, no targeted treatment exists to treat this condition, and therefore, emphasis has been on its prevention. The current review focuses on the epidemiology, clinical characteristics, risk factors, and clinical outcomes of NAFLD in Western countries. It is important to understand the magnitude of NAFLD and its risk factors in Western countries where the prevalence of NAFLD has now reached epidemic proportions to identify the best strategy to prevent and possibly control this epidemic.
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Affiliation(s)
- Naga S. Samji
- Tenova Cleveland Hospital, 2305 Chambliss Ave NW, Cleveland, TN, 37311, USA
| | - Rajanshu Verma
- Tenova Cleveland Hospital, 2305 Chambliss Ave NW, Cleveland, TN, 37311, USA
- Division of Transplant Surgery, Department of Surgery, Methodist University Hospital Transplant Institute, University of Tennessee Health Sciences Center, Memphis, TN, 38139, USA
| | - Sanjaya K. Satapathy
- Division of Hepatology and Sandra Atlas Bass Center for Liver Diseases, Northwell Health, Manhasset, NY, 11030, USA
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15
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Abstract
Nonalcoholic fatty liver disease (NAFLD), a disorder of altered metabolic pathways, is increasing worldwide. Recent studies established obstructive sleep apnea (OSA) and chronic intermittent hypoxia (CIH) as NAFLD risk factors. Studies have ascertained that CIH is independently related to NAFLD. Continuous positive airway pressure (CPAP) shows inconsistent results regarding its efficacy in improving NAFLD. Observational, longer duration CPAP therapy studies have shown positive outcomes, whereas shorter duration, randomized controlled trials have shown no benefit. A multifaceted approach to NAFLD management with sufficiently longer duration of CPAP therapy may be beneficial in patients with moderate to severe OSA.
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Affiliation(s)
- Malav P Parikh
- Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, M2 Annex, Cleveland, OH 44114, USA
| | - Niyati M Gupta
- Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, M2 Annex, Cleveland, OH 44114, USA
| | - Arthur J McCullough
- Department of Gastroenterology and Hepatology, Digestive Disease and Surgery Institute, Cleveland Clinic Foundation, 9500 Euclid Ave, M2 Annex, Cleveland, OH 44114, USA; Department of Inflammation and Immunity, Cleveland Clinic Lerner College of Medicine, Case Western University, Cleveland, OH 44195, USA.
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16
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Han J, He Y, Zhao H, Xu X. Hypoxia inducible factor-1 promotes liver fibrosis in nonalcoholic fatty liver disease by activating PTEN/p65 signaling pathway. J Cell Biochem 2019; 120:14735-14744. [PMID: 31009107 DOI: 10.1002/jcb.28734] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 03/11/2019] [Accepted: 03/22/2019] [Indexed: 12/17/2022]
Abstract
Obesity is a major contributor to the development of steatohepatitis and fibrosis from nonalcoholic fatty liver disease (NAFLD). Hypoxia aggravates progression of NAFLD. In mice on high-fat diet (HFD), hepatic steatosis leads to liver tissue hypoxia, evidenced by accumulation of hypoxia inducible factor-1-alpha (HIF-1α), which is a central regulator of the global response to hypoxia. Hepatocyte cell signaling is an important factor in hepatic fibrogenesis. We here hypothesize that HIF-1α knockout in hepatocyte may protect against liver fibrosis. We first found that HFD led to 80% more hepatic collagen deposition than Hif1a-/- hep mice, which was confirmed by a-SMA staining of liver tissue. Body weight and liver weight were similar between groups. We then found the increasing HIF1a expression and decreasing PTEN expression in the mice on HFD and in PA-treated HepG2 cells. Finally, we found that HIF1 mediated PTEN/nfkb-p65 pathway plays an important role in the development of NAFLD to liver fibrosis. Collectively, these results identify a novel HIF1a/PTEN/NF-κ Bp65 signaling pathway in NAFLD, which could be targeted for the therapy.
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Affiliation(s)
- Jie Han
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.,Department of Endocrinology and Metabolism, Qingdao Haici Hospital, Qingdao, Shandong, China
| | - Yaping He
- Department of Emergency, Qingdao Haici Hospital, Qingdao, Shandong, China
| | - Hui Zhao
- Department of Endocrinology and Metabolism, Qingdao Haici Hospital, Qingdao, Shandong, China
| | - Xiaowei Xu
- Department of Endocrinology and Metabolism, Qingdao Haici Hospital, Qingdao, Shandong, China
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17
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Light M, McCowen K, Malhotra A, Mesarwi OA. Sleep apnea, metabolic disease, and the cutting edge of therapy. Metabolism 2018; 84:94-98. [PMID: 28966076 PMCID: PMC5874161 DOI: 10.1016/j.metabol.2017.09.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Revised: 09/11/2017] [Accepted: 09/21/2017] [Indexed: 12/16/2022]
Abstract
Obstructive sleep apnea (OSA) is common, and many cross-sectional and longitudinal studies have established OSA as an independent risk factor for the development of a variety of adverse metabolic disease states, including hypertension, insulin resistance, type 2 diabetes, nonalcoholic fatty liver disease, dyslipidemia, and atherosclerosis. Nasal continuous positive airway pressure (CPAP) has long been the mainstay of therapy for OSA, but definitive studies demonstrating the efficacy of CPAP in improving metabolic outcomes, or in reducing incident disease burden, are lacking; moreover, CPAP has variable rates of adherence. Therefore, the future of OSA management, particularly with respect to limiting OSA-related metabolic dysfunction, likely lies in a coming wave of alternative approaches to endophenotyping OSA patients, personalized care, and defining and targeting mechanisms of OSA-induced adverse health outcomes.
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Affiliation(s)
- Matthew Light
- Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego Department of Medicine, La Jolla, CA, United States.
| | - Karen McCowen
- Division of Endocrinology, UC San Diego Department of Medicine, La Jolla, CA, United States.
| | - Atul Malhotra
- Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego Department of Medicine, La Jolla, CA, United States.
| | - Omar A Mesarwi
- Division of Pulmonary, Critical Care, and Sleep Medicine, UC San Diego Department of Medicine, La Jolla, CA, United States.
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18
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Trzepizur W, Boursier J, Le Vaillant M, Ducluzeau PH, Dubois S, Henni S, Abraham P, Aubé C, Calès P, Gagnadoux F. Increased liver stiffness in patients with severe sleep apnoea and metabolic comorbidities. Eur Respir J 2018; 51:13993003.00601-2018. [PMID: 29880653 DOI: 10.1183/13993003.00601-2018] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 05/01/2018] [Indexed: 02/06/2023]
Abstract
The goal of this study was to assess the relationship between the severity of obstructive sleep apnoea (OSA) and liver stiffness measurement (LSM), one of the most accurate noninvasive screening tools for liver fibrosis in nonalcoholic fatty liver disease.The study included 147 patients with at least one criterion for the metabolic syndrome, assessed by polysomnography for suspected OSA. LSM was performed using transient elastography (FibroScan). Significant liver disease and advanced liver fibrosis were defined as LSM ≥7.3 and ≥9.6 kPa, respectively.23 patients were excluded because of unreliable LSM. Among 124 patients, 34 (27.4%) had mild OSA, 38 (30.6%) had moderate OSA and 52 (42.0%) had severe OSA. LSM values were 7.3- <9.6 kPa in 18 (14.5%) patients and ≥9.6 kPa in 15 (12.1%) patients. A dose-response relationship was observed between OSA severity and LSM values (p=0.004). After adjustment for age, sex, metabolic syndrome and insulin resistance, severe OSA was associated with an increased risk of LSM ≥7.3 kPa (OR 7.17, 95% CI 2.51-20.50) and LSM ≥9.6 kPa (OR 4.73, 95% CI 1.25-17.88).In patients with metabolic comorbidities, severe OSA is independently associated with increased liver stiffness, which may predispose to a higher risk of significant liver disease and poorer prognosis.
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Affiliation(s)
- Wojciech Trzepizur
- Dépt de Pneumologie, Centre Hospitalier Universitaire, Angers, France.,INSERM UMR 1063, Université d'Angers, Angers, France
| | - Jérôme Boursier
- Dépt d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire, Angers, France.,Laboratoire HIFIH, EA3859, Université d'Angers, Angers, France
| | - Marc Le Vaillant
- Institut de Recherche en Santé Respiratoire des Pays de la Loire, Beaucouzé, France
| | - Pierre-Henri Ducluzeau
- Unité d'Endocrinologie-Diabétologie-Nutrition, Pole de Médecine, Centre Hospitalier Universitaire, Tours, France
| | - Séverine Dubois
- INSERM UMR 1063, Université d'Angers, Angers, France.,Dépt d'Endocrinologie, Diabétologie et Nutrition, Centre Hospitalier Universitaire, Angers, France
| | - Samir Henni
- Dépt de Médecine du Sport et Explorations Fonctionnelles Vasculaires, Centre Hospitalier Universitaire, Angers, France.,Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers, Angers, France
| | - Pierre Abraham
- Dépt de Médecine du Sport et Explorations Fonctionnelles Vasculaires, Centre Hospitalier Universitaire, Angers, France.,Institut MITOVASC, UMR CNRS 6015, INSERM 1083, Université d'Angers, Angers, France
| | - Christophe Aubé
- Laboratoire HIFIH, EA3859, Université d'Angers, Angers, France.,Dépt de Radiologie, Centre Hospitalier Universitaire, Angers, France
| | - Paul Calès
- Dépt d'Hépato-Gastroentérologie, Centre Hospitalier Universitaire, Angers, France.,Laboratoire HIFIH, EA3859, Université d'Angers, Angers, France
| | - Frédéric Gagnadoux
- Dépt de Pneumologie, Centre Hospitalier Universitaire, Angers, France.,INSERM UMR 1063, Université d'Angers, Angers, France
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19
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Bajantri B, Lvovsky D. A Case of Concomitant Obstructive Sleep Apnea and Non-Alcoholic Steatohepatitis Treated With CPAP Therapy. Gastroenterology Res 2018; 11:252-259. [PMID: 29915639 PMCID: PMC5997478 DOI: 10.14740/gr1033w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Accepted: 05/09/2018] [Indexed: 12/12/2022] Open
Abstract
Obstructive sleep apnea syndrome is a disorder of sleep breathing that is a result of recurrent and intermittent hypoxia during sleep induced by the repeated partial or complete collapse of the upper airway, eventually causing chronic intermittent hypoxia. Non-alcoholic fatty liver disease is divided into non-alcoholic fatty liver and non-alcoholic steatohepatitis. Animal and human studies showed that obesity is associated with chronic liver hypoxia, even in the presence of systemic normoxia causing inflammation and release of cytokines. A "two-hit" model has been proposed. The first hit is characterized by insulin resistance and excess hepatic lipid accumulation secondary to abnormal fatty acid metabolism. Oxidative stress and inflammation are thought to comprise the second hit. Gold standard for the diagnosis of non-alcoholic steatohepatitis is a liver biopsy. Many clinical scores and non-invasive tools are used for the diagnosis of non-alcoholic steatohepatitis. Conservative management with lifestyle modifications including diet, exercise and weight loss remains the therapy of choice today. We present a case report of a 39-year-old man who was diagnosed with concomitant non-alcoholic steatohepatitis and severe obstructive sleep apnea. He was started treatment with continuous positive airway pressure and demonstrated excellent adherence to therapy for 6 years, with concomitant obstructive sleep apnea and non-alcoholic steatohepatitis which reversed with prolonged optimal continuous positive airway pressure therapy. Physical examination remained unremarkable except for morbid obesity. His abdominal girth, as well as body mass index, remained unchanged. After 6 years of optimal continuous positive airway pressure therapy, liver enzymes and relevant lipid panel normalized, suggesting reversal of non-alcoholic steatohepatitis.
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Affiliation(s)
- Bharat Bajantri
- Division of Pulmonary Critical Care, Department of Medicine, Bronx Care Health System, Bronx, NY 10457, USA
| | - Dmitry Lvovsky
- Division of Pulmonary Critical Care, Department of Medicine, Bronx Care Health System, Bronx, NY 10457, USA.,Division of Pulmonary and Critical Care Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA
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20
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Enezi A, Al-Jahdali F, Ahmed A, Shirbini N, Harbi A, Salim B, Ali Y, Abdulrahman A, Khan M, Khaleid A, Hamdan AJ. Symptoms of Daytime Sleepiness and Sleep Apnea in Liver Cirrhosis Patients. Ann Hepatol 2018; 16:591-598. [PMID: 28611264 DOI: 10.5604/01.3001.0010.0304] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
UNLABELLED Background/propose. Sleep disturbance and excessive daytime sleepiness (EDS) have been reported in patients with hepatic cirrhosis with no hepatic encephalopathy (HE). The objective of this study was to evaluate daytime sleepiness and risk of obstructive sleep apnea (OSA) among liver cirrhosis patients. MATERIAL AND METHODS A cross-sectional study was conducted at King Abdulaziz Medical City (KAMC)-Riyadh over a period of six months, using a structured questionnaire that investigated: 1) Sleep patterns and daytime sleepiness using the Epworth Sleeping Scale (ESS), and 2) The risk for sleep apnea using the Berlin Questionnaire (BQ). We enrolled patients with a confirmed diagnosis of liver cirrhosis who were being followed at the hepatology and pre-liver transplant clinics. RESULTS We enrolled 200 patients with liver cirrhosis, 57.5% of whom were male. The mean age was 60 (± SD 12.2). The reported prevalence of EDS, OSA, and both EDS and OSA were 29.5%, 42.9%, and 13.6%, respectively. The prevalence of EDS was higher in patients with Hepatitis-C and patients with DM, who experienced short sleep duration. We did not find any association between the severity of liver disease and EDS or OSA as measured by Child-Pugh scores (CPS). CONCLUSIONS The risk of OSA and EDS is high among liver cirrhosis patients. Those patients with cirrhosis secondary to Hepatitis C are at higher risk of EDS and OSA. Both EDS and OSA affect patients designated as CPS Class A more frequently than patients designated as CPS Class B.
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Affiliation(s)
- Abdullah Enezi
- College of Medicine. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Fares Al-Jahdali
- College of Medicine. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Anwar Ahmed
- College of Public Health and Health Informatics. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Nahid Shirbini
- Department of Medicine, Pulmonary Division, and Sleep Disorders Center. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Abdullah Harbi
- Department of Medicine, Pulmonary Division, and Sleep Disorders Center. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Baharoon Salim
- Department of Medicine, Pulmonary Division, and Sleep Disorders Center. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Yosra Ali
- College of Public Health and Health Informatics. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Aljumah Abdulrahman
- Departments of Hepatobiliary Surgery and Liver Transplantation. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Mohd Khan
- College of Medicine. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Abdullah Khaleid
- Departments of Hepatobiliary Surgery and Liver Transplantation. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Al-Jahdali Hamdan
- Department of Medicine, Pulmonary Division, and Sleep Disorders Center. King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
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21
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Hepatocellular Carcinoma in Obesity: Finding a Needle in the Haystack? ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1061:63-77. [DOI: 10.1007/978-981-10-8684-7_6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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22
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Benedict M, Zhang X. Non-alcoholic fatty liver disease: An expanded review. World J Hepatol 2017; 9:715-732. [PMID: 28652891 PMCID: PMC5468341 DOI: 10.4254/wjh.v9.i16.715] [Citation(s) in RCA: 504] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2016] [Revised: 02/08/2017] [Accepted: 04/18/2017] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) encompasses the simple steatosis to more progressive steatosis with associated hepatitis, fibrosis, cirrhosis, and in some cases hepatocellular carcinoma. NAFLD is a growing epidemic, not only in the United States, but worldwide in part due to obesity and insulin resistance leading to liver accumulation of triglycerides and free fatty acids. Numerous risk factors for the development of NAFLD have been espoused with most having some form of metabolic derangement or insulin resistance at the core of its pathophysiology. NAFLD patients are at increased risk of liver-related as well as cardiovascular mortality, and NAFLD is rapidly becoming the leading indication for liver transplantation. Liver biopsy remains the gold standard for definitive diagnosis, but the development of noninvasive advanced imaging, biochemical and genetic tests will no doubt provide future clinicians with a great deal of information and opportunity for enhanced understanding of the pathogenesis and targeted treatment. As it currently stands several medications/supplements are being used in the treatment of NAFLD; however, none seem to be the "magic bullet" in curtailing this growing problem yet. In this review we summarized the current knowledge of NAFLD epidemiology, risk factors, diagnosis, pathogenesis, pathologic changes, natural history, and treatment in order to aid in further understanding this disease and better managing NAFLD patients.
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Affiliation(s)
- Mark Benedict
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
| | - Xuchen Zhang
- Mark Benedict, Xuchen Zhang, Department of Pathology, Yale University School of Medicine, New Haven, CT 06510, United States
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23
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Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease. PLoS One 2016; 11:e0168572. [PMID: 28030556 PMCID: PMC5193414 DOI: 10.1371/journal.pone.0168572] [Citation(s) in RCA: 76] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/03/2016] [Indexed: 12/21/2022] Open
Abstract
Background Obstructive sleep apnea (OSA) is associated with the progression of non-alcoholic fatty liver disease (NAFLD) to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1), a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis. Methods Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep) were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2) or normoxia (16% O2) for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking. Results Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03), which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia. Conclusions Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver tissue hypoxia in hepatic steatosis. HIF-1 is necessary for collagen cross-linking in an in vitro model of fibrosis.
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24
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Obstructive Sleep Apnea Is Associated with Liver Damage and Atherosclerosis in Patients with Non-Alcoholic Fatty Liver Disease. PLoS One 2015; 10:e0142210. [PMID: 26672595 PMCID: PMC4682677 DOI: 10.1371/journal.pone.0142210] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Accepted: 10/19/2015] [Indexed: 12/12/2022] Open
Abstract
Background/Aims We assessed whether obstructive sleep apnea (OSA) and nocturnal hypoxemia are associated with severity of liver fibrosis and carotid atherosclerosis in patients with biopsy-proven NAFLD and low prevalence of morbid obesity. Secondary aim was to explore the association of OSA and hypoxemia with NASH and severity of liver pathological changes. Methods Consecutive patients (n = 126) with chronically elevated ALT and NAFLD underwent STOP-BANG questionnaire to estimate OSA risk and ultrasonographic carotid assessment. In patients accepting to perform cardiorespiratory polygraphy (PG, n = 50), OSA was defined as an apnea/hypopnea index ≥5. A carotid atherosclerotic plaque was defined as a focal thickening >1.3 mm. Results Prevalence of high OSA risk was similar in patients refusing or accepting PG (76% vs 68%, p = 0.17). Among those accepting PG, overall OSA prevalence was significantly higher in patients with F2-F4 fibrosis compared to those without (72% vs 44%; p = 0.04). Significant fibrosis was independently associated with mean nocturnal oxygen saturation (SaO2)<95% (OR 3.21, 95%C.I. 1.02–7.34; p = 0.04). Prevalence of OSA tended to be higher in patients with, than in those without, carotid plaques (64% vs 40%; p = 0.08). Carotid plaques were independently associated with %time at SaO2<90% >1 (OR 6.30, 95%C.I. 1.02–12.3; p = 0.01). Conclusions In NAFLD patients with chronically elevated ALT at low prevalence of morbid obesity, OSA was highly prevalent and indexes of SaO2 resulted independently associated with severity of liver fibrosis and carotid atherosclerosis. These data suggest to consider sleep disordered breathing as a potential additional therapeutic target in severe NAFLD patients.
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Cakmak E, Duksal F, Altinkaya E, Acibucu F, Dogan OT, Yonem O, Yilmaz A. Association Between the Severity of Nocturnal Hypoxia in Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Damage. HEPATITIS MONTHLY 2015; 15:e32655. [PMID: 26834793 PMCID: PMC4719120 DOI: 10.5812/hepatmon.32655] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/23/2015] [Revised: 09/20/2015] [Accepted: 09/22/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Obstructive sleep apnea (OSA) is a major disease that can cause significant mortality and morbidity. Chronic intermittent hypoxia is a potential causal factor in the progression from fatty liver to nonalcoholic steatohepatitis. OBJECTIVES This study evaluated the association between the degree of liver steatosis and severity of nocturnal hypoxia. PATIENTS AND METHODS In this study, between December 2011 and December 2013, patients with ultrasound-diagnosed NAFLD evaluated by standart polysomnography were subsequentally recorded. Patients with alcohol use, viral hepatitis and other chronic liver diseases were excluded. We analyzed polysomnographic parameters, steatosis level and severity of obstructive sleep apnea (OSA) in consideration of body mass index (BMI), biochemical tests and ultrasonographic liver data of 137 subjects. Patients with sleep apnea and AHI scores of < 5, 5 - 14, 15 - 29 and ≥30 are categorized as control, mild, moderate and severe, respectively. RESULTS One hundred and thirty-seven patients (76 women, 61 men) with a mean age of 55.75 ± 10.13 years who underwent polysomnography were included in the study. Of 118 patients diagnosed with OSA, 19 (16.1%) had mild OSA, 39 (33.1%) moderate OSA and 60 (50.8%) severe OSA. Nineteen cases formed the control group. Apnea/hypopnea index and oxygen desaturation index (ODI) values were significantly higher in moderate and severe non-alcoholic fatty liver disease (NAFLD) compared to the non-NAFLD group. Mean nocturnal SpO2 values were significantly lower in mild NAFLD and severe NAFLD compared to the non-NAFLD group. Lowest O2 saturation (LaSO2) was found low in mild, moderate and severe NAFLD compared to the non-NAFLD group in a statistically significant manner. CONCLUSIONS We assessed polysomnographic parameters of AHI, ODI, LaSO2 and mean nocturnal SpO2 levels, which are especially important in the association between NAFLD and OSAS. We think that it is necessary to be attentive regarding NAFLD development and progression in patients with OSA whose nocturnal hypoxia is severe.
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Affiliation(s)
- Erol Cakmak
- Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
- Corresponding Author: Erol Cakmak, Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, P. O. Box: 58140, Sivas, Turkey. Tel: +90-3464444458, Fax: +90-3462239530, E-mail:
| | - Faysal Duksal
- Department of Chest Diseases, Sivas Numune Hospital, Sivas, Turkey
| | - Engin Altinkaya
- Department of Gastroenterology, Kayseri Training and Research Hospital, Kayseri, Turkey
| | - Fettah Acibucu
- Department of Endocrinology, Sivas Numune Hospital, Sivas, Turkey
| | - Omer Tamer Dogan
- Department of Chest Diseases, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
| | - Ozlem Yonem
- Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
| | - Abdulkerim Yilmaz
- Department of Gastroenterology, Cumhuriyet University Faculty of Medicine, Sivas, Turkey
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Li J, Zhang YL, Chen R, Wang Y, Xiong KP, Huang JY, Han F, Liu CF. Elevated Serum Liver Enzymes in Patients with Obstructive Sleep Apnea-hypopnea Syndrome. Chin Med J (Engl) 2015; 128:2983-7. [PMID: 26608975 PMCID: PMC4795259 DOI: 10.4103/0366-6999.168943] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND Obstructive sleep apnea-hypopnea syndrome (OSAS) is associated with elevated liver enzymes and fatty liver. The purpose of this study was to measure serum liver enzyme levels in patients evaluated by polysomnography (PSG) and the factors associated with liver injury in OSAS patients. METHODS All patients referred to PSG for evaluation of sleep apnea symptoms between June 2011 and November 2014 were included in this study. Demographic data and PSG parameters were recorded. Serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase levels were systematically measured. OSAS patients were divided into mild, moderate, and severe groups according to the apnea-hypopnea index (AHI) values of 5-14 events/h, 15-29 events/h, and ≥30 events/h. RESULTS A total of 540 patients were enrolled in this study; among these patients, 386 were male. Elevated liver enzymes were present in 42.3% of OSAS patients (32.4% in mild/moderate group; 51.0% in severe group) and 28.1% patients without OSAS. Patients with OSAS had higher body mass index (BMI) (P < 0.01). In the bivariate correlation, the liver enzymes level was negatively correlated with age and the lowest arterial oxygen saturation (SaO 2 ), and was positively correlated with BMI, oxygen desaturation index, percent of total time with oxygen saturation level <90% (TS90%), AHI, total cholesterol (TC), and triglyceride (TG). In logistic regression analysis, Age, BMI, TS90%, TC, and TG were included in the regression equation. CONCLUSIONS Our data suggest that OSAS is a risk factor for elevated liver enzymes. The severity of OSAS is correlated with liver enzyme levels; we hypothesize that hypoxia is one of main causes of liver damage in patients with OSAS.
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Affiliation(s)
- Jie Li
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Yan-Lin Zhang
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Rui Chen
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Yi Wang
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Kang-Ping Xiong
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Jun-Ying Huang
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Fei Han
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
| | - Chun-Feng Liu
- Department of Neurology and Sleep Center, Second Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215004, China
- Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215123, China
- Beijing Key Laboratory for Parkinson's Disease, Beijing 100053, China
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Mesarwi OA, Shin MK, Drager LF, Bevans-Fonti S, Jun JC, Putcha N, Torbenson MS, Pedrosa RP, Lorenzi-Filho G, Steele KE, Schweitzer MA, Magnuson TH, Lidor AO, Schwartz AR, Polotsky VY. Lysyl Oxidase as a Serum Biomarker of Liver Fibrosis in Patients with Severe Obesity and Obstructive Sleep Apnea. Sleep 2015; 38:1583-91. [PMID: 26085300 DOI: 10.5665/sleep.5052] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Indexed: 12/12/2022] Open
Abstract
STUDY OBJECTIVES Obstructive sleep apnea (OSA) is associated with the progression of nonalcoholic fatty liver disease (NAFLD). We hypothesized that the hypoxia of OSA increases hepatic production of lysyl oxidase (LOX), an enzyme that cross-links collagen, and that LOX may serve as a biomarker of hepatic fibrosis. DESIGN Thirty-five patients with severe obesity underwent liver biopsy, polysomnography, and serum LOX testing. A separate group with severe OSA had serum LOX measured before and after 3 mo of CPAP or no therapy, as did age-matched controls. LOX expression and secretion were measured in mouse hepatocytes following exposure to hypoxia. SETTING The Johns Hopkins Bayview Sleep Disorders Center, and the Hypertension Unit of the Heart Institute at the University of São Paulo Medical School. MEASUREMENTS AND RESULTS In the bariatric cohort, the apnea-hypopnea index was higher in patients with hepatic fibrosis than in those without fibrosis (42.7 ± 30.2 events/h, versus 16.2 ± 15.5 events/h; P = 0.002), as was serum LOX (84.64 ± 29.71 ng/mL, versus 45.46 ± 17.16 ng/mL; P < 0.001). In the sleep clinic sample, patients with severe OSA had higher baseline LOX than healthy controls (70.75 ng/mL versus 52.36 ng/mL, P = 0.046), and serum LOX decreased in patients with OSA on CPAP (mean decrease 20.49 ng/mL) but not in untreated patients (mean decrease 0.19 ng/mL). Hypoxic mouse hepatocytes demonstrated 5.9-fold increased LOX transcription (P = 0.046), and enhanced LOX protein secretion. CONCLUSIONS The hypoxic stress of obstructive sleep apnea may increase circulating lysyl oxidase (LOX) levels. LOX may serve as a biomarker of liver fibrosis in patients with severe obesity and nonalcoholic fatty liver disease.
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Affiliation(s)
- Omar A Mesarwi
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Mi-Kyung Shin
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Luciano F Drager
- Hypertension Unit, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil
| | - Shannon Bevans-Fonti
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Jonathan C Jun
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Nirupama Putcha
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | | | - Rodrigo P Pedrosa
- Sleep Laboratory, Pulmonary Division, University of São Paulo Medical School, São Paulo, Brazil
| | - Geraldo Lorenzi-Filho
- Sleep Laboratory, Pulmonary Division, University of São Paulo Medical School, São Paulo, Brazil
| | - Kimberley E Steele
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michael A Schweitzer
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Thomas H Magnuson
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Anne O Lidor
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Alan R Schwartz
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Vsevolod Y Polotsky
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
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Corey KE, Misdraji J, Gelrud L, King LY, Zheng H, Malhotra A, Chung RT. Obstructive Sleep Apnea Is Associated with Nonalcoholic Steatohepatitis and Advanced Liver Histology. Dig Dis Sci 2015; 60:2523-8. [PMID: 25840922 PMCID: PMC4499481 DOI: 10.1007/s10620-015-3650-8] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 03/26/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnea (OSA) are growing in prevalence in the USA. Existing data on the relationship between OSA and NAFLD are conflicting and limited by the use of various histologic definitions of nonalcoholic steatohepatitis (NASH). Using a robust definition of NASH in a large, well-characterized cohort, we sought to evaluate whether OSA was associated with NASH and advanced fibrosis. METHODS Two hundred and thirteen subjects undergoing weight loss surgery were queried for OSA and then underwent liver biopsy. NASH was defined, as recommended by the American Association for the Study of Liver Disease, by the presence of all of the following: >5 % macrovesicular steatosis, lobular inflammation, and hepatocyte ballooning. NAFLD activity score (NAS) was also determined for each subject. RESULTS Subjects with OSA had significantly higher alanine and aspartate aminotransferase levels than subjects without OSA (ALT 54.1 vs. 37.7 U/L, P = 0.0007; AST 31.7 vs. 20.5 U/L, P = 0.0007). OSA was associated with the presence of NASH, and this remained significant after adjusting for age, gender, race, and diabetes mellitus (P = 0.03 OR 2.01; 95 %, 1.05-3.87). Steatosis grade, lobular inflammation grade, NAS score, and fibrosis stage were all significantly associated with the presence of OSA and remained so after adjustment. CONCLUSIONS OSA is associated with elevated aminotransferase levels, the presence of NASH, and advanced NASH histology. Further studies are needed to evaluate the impact of OSA treatment on NASH.
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Affiliation(s)
- Kathleen E Corey
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA
,Harvard Medical School, Boston, MA
| | - Joseph Misdraji
- Department of Pathology, Massachusetts General Hospital, Boston, MA
,Harvard Medical School, Boston, MA
| | - Lou Gelrud
- Department of Internal Medicine, Bon Secours Richmond Health System, Richmond, VA
| | - Lindsay Y. King
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA
| | - Hui Zheng
- MGH Biostatistics Center, Massachusetts General Hospital, Boston, MA
,Harvard Medical School, Boston, MA
| | - Atul Malhotra
- Department of Pulmonary and Critical Care Medicine, University of California San Diego, San Diego, CA
| | - Raymond T Chung
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA
,Harvard Medical School, Boston, MA
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Drager LF, Polotsky VY, O'Donnell CP, Cravo SL, Lorenzi-Filho G, Machado BH. Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea. Am J Physiol Heart Circ Physiol 2015; 309:H1101-11. [PMID: 26232233 DOI: 10.1152/ajpheart.00094.2015] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Accepted: 07/22/2015] [Indexed: 12/17/2022]
Abstract
Obstructive sleep apnea (OSA) is known to be independently associated with several cardiovascular diseases including hypertension, myocardial infarction, and stroke. To determine how OSA can increase cardiovascular risk, animal models have been developed to explore the underlying mechanisms and the cellular and end-organ targets of the predominant pathophysiological disturbance in OSA-intermittent hypoxia. Despite several limitations in translating data from animal models to the clinical arena, significant progress has been made in our understanding of how OSA confers increased cardiovascular risk. It is clear now that the hypoxic stress associated with OSA can elicit a broad spectrum of pathological systemic events including sympathetic activation, systemic inflammation, impaired glucose and lipid metabolism, and endothelial dysfunction, among others. This review provides an update of the basic, clinical, and translational advances in our understanding of the metabolic dysfunction and cardiovascular consequences of OSA and highlights the most recent findings and perspectives in the field.
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Affiliation(s)
- Luciano F Drager
- Hypertension Unit, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil; Hypertension Unit, Renal Division, University of São Paulo Medical School, São Paulo, Brazil;
| | - Vsevolod Y Polotsky
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christopher P O'Donnell
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Sergio L Cravo
- Department of Physiology, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil
| | - Geraldo Lorenzi-Filho
- Sleep Laboratory, Pulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil; and
| | - Benedito H Machado
- Department of Physiology, School of Medicine of Ribeirao Preto, University of São Paulo, São Paulo, Brazil
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Agrawal S, Duseja A, Aggarwal A, Das A, Mehta M, Dhiman RK, Chawla Y. Obstructive sleep apnea is an important predictor of hepatic fibrosis in patients with nonalcoholic fatty liver disease in a tertiary care center. Hepatol Int 2015; 9:283-91. [PMID: 25788200 DOI: 10.1007/s12072-015-9615-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 02/17/2015] [Indexed: 12/17/2022]
Abstract
BACKGROUND The association of obstructive sleep apnea (OSA) with nonalcoholic fatty liver disease (NAFLD) has only been studied in selected subgroups such as the morbidly obese. We aimed to determine the prevalence and effect of OSA on NAFLD and vice versa in unselected patients attending the outpatient department. METHODS OSA was diagnosed by polysomnography, done in patients having symptoms of OSA, in patients with NAFLD attending the liver clinic. Polysomnography-proven patients with OSA attending the chest clinic were evaluated for NAFLD by ultrasonography. Anthropometry, liver function tests, metabolic syndrome evaluation and transient elastography were performed in all patients. RESULTS Three (3%; 95% CI 1.03-8.45%) out of 100 patients with NAFLD (mean age 41 ± 11 years) had symptomatic OSA. Of 23 patients with OSA (mean age 46 ± 12 years,), 3 (13%) had mild, 5 (22%) moderate and 15 (65%) severe OSA. Twenty-one (91.3%; 95% CI 73.2-97.6%) patients with OSA had NAFLD, while raised hepatic transaminase levels were seen in seven (30.4%; 95% CI 15.6-50.9%). Body mass index (OR 1.21, 95% CI 1.02-1.44) and male gender (OR 4.79, 95% CI 1.12-20.48) were significant independent predictors of OSA in NAFLD. The apnea-hypopnea index (OR 1.084, 95% CI 1.002-1.172), a marker of OSA severity, was the only significant independent predictor of significant fibrosis in patients with NAFLD. CONCLUSIONS Prevalence of symptomatic OSA in patients with NAFLD is low and is predicted by male gender and obesity. Prevalence of NAFLD in patients with OSA is very high. Significant hepatic fibrosis in patients with NAFLD is predicted by OSA independent of obesity and metabolic syndrome.
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Affiliation(s)
- Swastik Agrawal
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India,
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da Rosa DP, Forgiarini LF, e Silva MB, Fiori CZ, Andrade CF, Martinez D, Marroni NP. Antioxidants inhibit the inflammatory and apoptotic processes in an intermittent hypoxia model of sleep apnea. Inflamm Res 2014; 64:21-9. [PMID: 25380745 DOI: 10.1007/s00011-014-0778-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2014] [Revised: 09/18/2014] [Accepted: 09/22/2014] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Sleep apnea causes intermittent hypoxia (IH). We aimed to investigate the proteins related to oxidative stress, inflammation and apoptosis in liver tissue subjected to IH as a simulation of sleep apnea in conjunction with the administration of either melatonin (MEL, 200 μL/kg) or N-acetylcysteine (NAC, 10 mg/kg). METHODS Seventy-two adult male Balb-C mice were divided: simulation of IH (SIH), SIH + MEL, SIH + NAC, IH, IH + MEL and IH + NAC. The animals were subjected to simulations of sleep apnea for 8 h a day for 35 days. The data were analyzed with ANOVA and Tukey tests with the significance set at p < 0.05. RESULTS In IH, there was a significant increase in oxidative stress and expression of HIF-1a. In addition, we observed increase in the activation levels of NF-kB. This increase may be responsible for the increased expression of TNF-alpha and iNOS as well as the significant increase of VEGF signaling and expression of caspase-3 and caspase-6, which suggests an increase in apoptosis. In the groups treated with antioxidants, the analysis showed that the enzyme activity and protein levels were similar to those of the non-simulated group. CONCLUSIONS Thus, we show that IH causes liver inflammation and apoptosis, which may be protected with either MEL or NAC.
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Affiliation(s)
- Darlan Pase da Rosa
- Programa de Pós-Graduação Medicina, Ciências Médicas, Universidade Federal do Rio Grande do Sul, UFRGS, Porto Alegre, RS, CEP 90670-001, Brazil,
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Suzuki T, Shinjo S, Arai T, Kanai M, Goda N. Hypoxia and fatty liver. World J Gastroenterol 2014; 20:15087-15097. [PMID: 25386057 PMCID: PMC4223242 DOI: 10.3748/wjg.v20.i41.15087] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2013] [Revised: 02/14/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The liver is a central organ that metabolizes excessive nutrients for storage in the form of glycogen and lipids and supplies energy-producing substrates to the peripheral tissues to maintain their function, even under starved conditions. These processes require a considerable amount of oxygen, which causes a steep oxygen gradient throughout the hepatic lobules. Alcohol consumption and/or excessive food intake can alter the hepatic metabolic balance drastically, which can precipitate fatty liver disease, a major cause of chronic liver diseases worldwide, ranging from simple steatosis, through steatohepatitis and hepatic fibrosis, to liver cirrhosis. Altered hepatic metabolism and tissue remodeling in fatty liver disease further disrupt hepatic oxygen homeostasis, resulting in severe liver hypoxia. As master regulators of adaptive responses to hypoxic stress, hypoxia-inducible factors (HIFs) modulate various cellular and organ functions, including erythropoiesis, angiogenesis, metabolic demand, and cell survival, by activating their target genes during fetal development and also in many disease conditions such as cancer, heart failure, and diabetes. In the past decade, it has become clear that HIFs serve as key factors in the regulation of lipid metabolism and fatty liver formation. This review discusses the molecular mechanisms by which hypoxia and HIFs regulate lipid metabolism in the development and progression of fatty liver disease.
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Bhatt SP, Guleria R. Sleep apnea and fatty liver disease: The growing link and management issues. World J Respirol 2014; 4:11-18. [DOI: 10.5320/wjr.v4.i2.11] [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] [Received: 11/12/2013] [Revised: 12/27/2013] [Accepted: 03/17/2014] [Indexed: 02/06/2023] Open
Abstract
Obstructive sleep apnea (OSA) is associated with metabolic, cardiovascular and neuropsychological disorders, with substantial morbidity and economic costs. OSA has been estimated to affect 4%-11% of the population, depending on age. Obesity is a significant risk factor for OSA. Non alcoholic fatty liver disease (NAFLD) has emerged as an integral component of the metabolic syndrome, with insulin resistance as the central pathogenic feature. Estimates based on imaging and autopsy studies suggest that about 20%-30% of adults in the United States and other Western countries have NAFLD. Evidence now suggests that NAFLD is independently correlated to insulin resistance regardless of adiposity. Some authors have suggested that OSA may be another contributor to NAFLD development. In complex diseases, several or many different genes interact with environmental factors in determining disease presence or its phenotype. Individual genes only have a small effect on disease risk and can therefore be very difficult to identify. The genetic and hormonal determinants of OSA and NAFLD have received little attention. A wide variety of intermediate phenotypes and genes are involved in OSA and NAFLD which makes this syndrome genetically complex. Various adipokines, the most important of which are leptin, adiponectin, tumor necrosis factor-alpha, resistin and interleukin-6, have a key role in NAFLD and OSA. Some studies have suggested that oxidative stress may also contribute to the development of NAFLD and OSA. Lifestyle intervention, insulin sensitizer drugs and bariatric surgery aim to improve metabolic syndrome, OSA and NAFLD but need further investigation.
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Sookoian S, Pirola CJ. Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis. Obes Surg 2014. [PMID: 23740153 DOI: 10.1007/s11695-13-0981-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND Obstructive sleep apnea (OSA) is associated with the cluster of clinical conditions that comprise the metabolic syndrome, including nonalcoholic fatty liver disease (NAFLD). Our primary purpose was to estimate the effect of OSA on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Our secondary purpose was to investigate the potential influence of OSA on histological severity of NAFLD to explore whether chronic intermittent hypoxia is associated with inflammation and fibrosis. METHODS Our literature search identified 11 studies, from which we extracted information about numbers of control subjects and OSA patients, and ALT, AST, and NAFLD. RESULTS From a total of 668 OSA patients and 404 controls, we found that the standardized difference in mean values of ALT and AST levels in patients with OSA was significantly different from that in the controls. Meta-regression showed that the association was independent of body mass index and type 2 diabetes. Fatty liver was associated with OSA in five studies with 400 subjects. OSA was significantly associated with liver fibrosis in 208 subjects, but not with lobular inflammation. CONCLUSIONS Routine assessment of liver enzymes and liver damage should be implemented in OSA patients because they have an increase of 13.3% of ALT and 4.4% of AST levels, and a 2.6-fold higher risk of liver fibrosis when they have NAFLD, which is 2.6 times more frequent in OSA patients.
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Affiliation(s)
- Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina,
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Sookoian S, Pirola CJ. Obstructive sleep apnea is associated with fatty liver and abnormal liver enzymes: a meta-analysis. Obes Surg 2014; 23:1815-25. [PMID: 23740153 DOI: 10.1007/s11695-013-0981-4] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Obstructive sleep apnea (OSA) is associated with the cluster of clinical conditions that comprise the metabolic syndrome, including nonalcoholic fatty liver disease (NAFLD). Our primary purpose was to estimate the effect of OSA on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Our secondary purpose was to investigate the potential influence of OSA on histological severity of NAFLD to explore whether chronic intermittent hypoxia is associated with inflammation and fibrosis. METHODS Our literature search identified 11 studies, from which we extracted information about numbers of control subjects and OSA patients, and ALT, AST, and NAFLD. RESULTS From a total of 668 OSA patients and 404 controls, we found that the standardized difference in mean values of ALT and AST levels in patients with OSA was significantly different from that in the controls. Meta-regression showed that the association was independent of body mass index and type 2 diabetes. Fatty liver was associated with OSA in five studies with 400 subjects. OSA was significantly associated with liver fibrosis in 208 subjects, but not with lobular inflammation. CONCLUSIONS Routine assessment of liver enzymes and liver damage should be implemented in OSA patients because they have an increase of 13.3% of ALT and 4.4% of AST levels, and a 2.6-fold higher risk of liver fibrosis when they have NAFLD, which is 2.6 times more frequent in OSA patients.
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Affiliation(s)
- Silvia Sookoian
- Department of Clinical and Molecular Hepatology, Institute of Medical Research A Lanari-IDIM, University of Buenos Aires-National Council of Scientific and Technological Research (CONICET), Ciudad Autónoma de Buenos Aires, Argentina,
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Pulixi EA, Tobaldini E, Battezzati PM, D'Ingianna P, Borroni V, Fracanzani AL, Maggioni M, Pelusi S, Bulgheroni M, Zuin M, Fargion S, Montano N, Valenti L. Risk of obstructive sleep apnea with daytime sleepiness is associated with liver damage in non-morbidly obese patients with nonalcoholic fatty liver disease. PLoS One 2014; 9:e96349. [PMID: 24763757 PMCID: PMC3999268 DOI: 10.1371/journal.pone.0096349] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Accepted: 04/06/2014] [Indexed: 12/19/2022] Open
Abstract
Background A high prevalence of obstructive sleep apnea syndrome (OSAS) has been reported in severely obese patients with nonalcoholic fatty liver disease (NAFLD), but few studies have evaluated OSAS in non-morbidly obese NAFLD patients. Aims To determine the prevalence of risk for OSAS with or without daytime sleepiness in non-morbidly obese patients with NAFLD and evaluate the association with the severity of liver damage. Methods We considered 159 consecutive patients with histological NAFLD and body mass index (BMI) <35 Kg/m2, and 80 controls without ultrasonographic steatosis matched for age, sex, and BMI. OSAS risk was determined by positivity for Berlin questionnaire (BQ), and daytime sleepiness by the Sleepness Epworth Scale (ESS). Liver damage was evaluated according to the NAFLD activity score. Results In NAFLD patients, BQ alone was positive in 39 (25%), ESS in 8 (5%), and both in 13 (8%, OSAS with sleepines); p = ns vs. controls without steatosis. In NAFLD patients at risk for OSAS with (but not in those without) sleepiness, we observed a higher prevalence of nonalcoholic steatohepatitis (NASH; 11/13, 85% vs. 72/146, 49%; p = 0.018), and of clinically significant fibrosis (stage>1; 9/13, 69% vs. 39/146, 27%; p = 0.003). At multivariate logistic regression analysis, OSAS with sleepiness was strongly associated with NASH and fibrosis>1 independently of known clinical risk factors such as age, gender, BMI, diabetes, and ALT levels (OR 7.1, 95% c.i. 1.7–51, p = 0.005 and OR 14.0, 95% c.i. 3.5–70, p = 0.0002, respectively). Conclusions A proportion of NAFLD patients without severe obesity is at risk for OSAS with daytime sleepiness, which is associated with the severity of liver damage independently of body mass and other cofactors.
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Affiliation(s)
- Edoardo Alessandro Pulixi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milano, Italy
| | - Eleonora Tobaldini
- Department of Biomedical and Clinical Sciences “L. Sacco”, Division of Medicine and Pathophysiology, Università degli Studi di Milano, Ospedale Luigi Sacco, Milano, Italy
| | - Pier Maria Battezzati
- Department of Health Sciences, Università degli Studi di Milano, Division of Medicine and Gastroenterology and Liver Unit, Ospedale San Paolo, Milano, Italy
| | - Paola D'Ingianna
- Department of Health Sciences, Università degli Studi di Milano, Division of Medicine and Gastroenterology and Liver Unit, Ospedale San Paolo, Milano, Italy
| | - Vittorio Borroni
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milano, Italy
| | - Anna Ludovica Fracanzani
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milano, Italy
| | - Marco Maggioni
- Pathology, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milano, Italy
| | - Serena Pelusi
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milano, Italy
| | - Mara Bulgheroni
- Department of Biomedical and Clinical Sciences “L. Sacco”, Division of Medicine and Pathophysiology, Università degli Studi di Milano, Ospedale Luigi Sacco, Milano, Italy
| | - Massimo Zuin
- Department of Health Sciences, Università degli Studi di Milano, Division of Medicine and Gastroenterology and Liver Unit, Ospedale San Paolo, Milano, Italy
| | - Silvia Fargion
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milano, Italy
| | - Nicola Montano
- Department of Biomedical and Clinical Sciences “L. Sacco”, Division of Medicine and Pathophysiology, Università degli Studi di Milano, Ospedale Luigi Sacco, Milano, Italy
- International Clinical Research Center, St. Anne University Hospital, Brno, Czech Republic
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Policlinico di Milano, Milano, Italy
- * E-mail:
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Sundaram SS, Sokol RJ, Capocelli KE, Pan Z, Sullivan JS, Robbins K, Halbower AC. Obstructive sleep apnea and hypoxemia are associated with advanced liver histology in pediatric nonalcoholic fatty liver disease. J Pediatr 2014; 164:699-706.e1. [PMID: 24321532 PMCID: PMC4014349 DOI: 10.1016/j.jpeds.2013.10.072] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 09/25/2013] [Accepted: 10/24/2013] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To determine whether obstructive sleep apnea (OSA) and/or nocturnal hypoxemia are associated with the severity of liver injury in patients with pediatric nonalcoholic fatty liver disease (NAFLD). STUDY DESIGN Obese children aged 10-18 years with liver biopsy-proven NAFLD were enrolled. Demographic, clinical, and laboratory data were collected, polysomnography was performed, and liver histology was scored. Subjects were divided into those with OSA/hypoxemia and those without OSA/hypoxemia for analysis. RESULTS Of 25 subjects with NAFLD, OSA/hypoxemia was present in 15 (60%) (mean age, 12.8 ± 1.9 years; 68% male; 88% Hispanic; mean body mass index z-score, 2.3 ± 0.3). Subjects with and without OSA/hypoxemia had similar levels of serum aminotransferases, serum lipids, and inflammatory and insulin resistance markers. Although there were no differences between groups in the histological severity of steatosis, inflammation, ballooning degeneration, NAFLD activity score, or histological grade, subjects with OSA/hypoxemia had significantly more severe hepatic fibrosis. Moreover, oxygen saturation nadir during polysomnography was related to hepatic fibrosis stage (r = -0.49; P = .01) and aspartate aminotransferase level (r = 0.42; P < .05). Increasing percentage of time with oxygen saturation ≤90% was related to NAFLD inflammation grade (r = 0.44; P = .03), degree of hepatic steatosis (r = -0.50; P = .01), NAFLD activity score (r = 0.42; P = .04), aspartate aminotransferase level (r = 0.56; P = .004), and alanine aminotransferase level (r = 0.44; P = .03). CONCLUSION Moderate OSA/hypoxemia is common in pediatric patients with biopsy-proven NAFLD. OSA and the severity/duration of hypoxemia are associated with biochemical and histological measures of NAFLD severity.
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Affiliation(s)
- Shikha S. Sundaram
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children’s Hospital Colorado and University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO
| | - Ronald J. Sokol
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children’s Hospital Colorado and University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO
| | | | - Zhaoxing Pan
- Department of Biostatistics and Informatics, Colorado School of Public Health, Aurora, CO
| | - Jillian S. Sullivan
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children’s Hospital Colorado and University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO
| | - Kristen Robbins
- Section of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children’s Hospital Colorado and University of Colorado School of Medicine, Anschutz Medical Campus, Aurora, CO
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Yu J, Shen J, Sun TT, Zhang X, Wong N. Obesity, insulin resistance, NASH and hepatocellular carcinoma. Semin Cancer Biol 2013; 23:483-91. [PMID: 23876851 DOI: 10.1016/j.semcancer.2013.07.003] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2013] [Accepted: 07/12/2013] [Indexed: 02/06/2023]
Abstract
Epidemiological and clinical data have clearly demonstrated that non-alcoholic steatohepatitis (NASH) predisposes risk to the development of hepatocellular carcinoma (HCC). NASH is the liver manifestation of metabolic syndrome, which constellates obesity, insulin resistance and dyslipidemia. Although the percentage of patients diagnosed annually with NASH-associated HCC is still relatively low, this number signifies a large population due to the rapidly increasing incidence of obesity and diabetes globally. Fundamental studies on lipid storage, regulation of adipose factors, inflammatory cytokine recruitments and oxidative stress have provided insights into NASH as well as metabolic syndrome. Recent evidence also indicates the significant role of genetic factors in contributing to the pathogenesis of NASH and induced hepatic malignancy. In this review, we attempt to collate current research on NASH biology that lead to our understandings on how metabolic disorders may intersect with cancer development. We also discuss study models that have supported discoveries of molecular and cellular defects, and offered a perspective on therapeutic developments. These studies have collectively increased our knowledge on the complex signaling pathways involved in NASH and cancer, and provided the foundation for improved clinical management of patients with metabolic diseases.
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Affiliation(s)
- Jun Yu
- Institute of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China; Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
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Musso G, Cassader M, Olivetti C, Rosina F, Carbone G, Gambino R. Association of obstructive sleep apnoea with the presence and severity of non-alcoholic fatty liver disease. A systematic review and meta-analysis. Obes Rev 2013; 14:417-31. [PMID: 23387384 DOI: 10.1111/obr.12020] [Citation(s) in RCA: 182] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 01/08/2013] [Accepted: 01/09/2013] [Indexed: 02/06/2023]
Abstract
Obstructive sleep apnoea syndrome (OSAS) and non-alcoholic fatty liver disease (NAFLD) are common in clinical practice. NAFLD encompasses simple steatosis and non-alcoholic steatohepatitis (NASH): both confer an increased risk of cardiovascular disease and diabetes; NASH increases also liver-related risk. Growing experimental evidence connects chronic intermittent hypoxia of OSAS to NAFLD. We reviewed English and non-English articles and international meeting abstracts through December 2012. Observational studies were included if they assessed OSAS by polysomnography and NAFLD by histological, radiological or biochemical criteria. Two reviewers evaluated retrieved articles by appropriate quality scores. Main outcomes were pooled using random- or fixed-effects models. The effect of age, sex and body mass index (BMI) on effect estimates was assessed by meta-regression. Eighteen cross-sectional studies (2,183 participants) were included. Pooled odds ratios (ORs) of OSAS for the presence of NAFLD, as defined by histology, radiology, and AST or ALT elevation, were 2.01(95% CI: 1.36-2.97), 2.99(1.79-4.99), 2.36(1.46-3.82) and 2.60(1.88-3.61), respectively. Pooled ORs of OSAS for NASH, fibrosis-any stage, or advanced fibrosis in biopsy-proven NAFLD patients were 2.37(1.59-3.51), 2.16(1.45-3.20) and 2.30(1.21-4.38). The magnitude and direction of effects were unaffected by age, sex and BMI. In conclusion, OSAS is associated with an increased risk of NAFLD, NASH and fibrosis. OSAS patients should be screened for the presence and severity of NAFLD.
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Affiliation(s)
- G Musso
- Gradenigo Hospital, Turin, Italy.
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da Rosa DP, Forgiarini LF, Baronio D, Feijó CA, Martinez D, Marroni NP. Simulating sleep apnea by exposure to intermittent hypoxia induces inflammation in the lung and liver. Mediators Inflamm 2012; 2012:879419. [PMID: 23226929 PMCID: PMC3513737 DOI: 10.1155/2012/879419] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2012] [Revised: 10/15/2012] [Accepted: 10/28/2012] [Indexed: 12/25/2022] Open
Abstract
Sleep apnea is a breathing disorder that results from momentary and cyclic collapse of the upper airway, leading to intermittent hypoxia (IH). IH can lead to the formation of free radicals that increase oxidative stress, and this mechanism may explain the association between central sleep apnea and nonalcoholic steatohepatitis. We assessed the level of inflammation in the lung and liver tissue from animals subjected to intermittent hypoxia and simulated sleep apnea. A total of 12 C57BL/6 mice were divided into two groups and then exposed to IH (n = 6) or a simulated IH (SIH) (n = 6) for 35 days. We observed an increase in oxidative damage and other changes to endogenous antioxidant enzymes in mice exposed to IH. Specifically, the expression of multiple transcription factors, including hypoxia inducible factor (HIF-1α), nuclear factor kappa B (NF-κB), and tumor necrosis factor (TNF-α), inducible NO synthase (iNOS), vascular endothelial growth factor (VEGF), and cleaved caspase 3 were shown to be increased in the IH group. Overall, we found that exposure to intermittent hypoxia for 35 days by simulating sleep apnea leads to oxidative stress, inflammation, and increased activity of caspase 3 in the liver and lung.
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Affiliation(s)
- Darlan Pase da Rosa
- Ciências Médicas, Programa de Pós-Graduação em Medicina, Universidade Federal do Rio Grande do Sul (UFRGS), 90035-903 Porto Alegre, RS, Brazil.
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Mirrakhimov AE, Polotsky VY. Obstructive sleep apnea and non-alcoholic Fatty liver disease: is the liver another target? Front Neurol 2012; 3:149. [PMID: 23087670 PMCID: PMC3473309 DOI: 10.3389/fneur.2012.00149] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 10/01/2012] [Indexed: 12/15/2022] Open
Abstract
Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH). OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD). NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH), liver fibrosis, and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1) IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA) flux into the liver; (2) IH up-regulates lipid biosynthetic pathways in the liver; (3) IH induces oxidative stress in the liver; (4) IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.
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Weingarten TN, Mantilla CB, Swain JM, Kendrick ML, Oberhansley JM, Burcham RJ, Ribeiro TC, Watt KD, Schroeder DR, Narr BJ, Sprung J. Nonalcoholic steatohepatitis in bariatric patients with a diagnosis of obstructive sleep apnea. Obes Facts 2012; 5:587-96. [PMID: 22986647 PMCID: PMC6902219 DOI: 10.1159/000342677] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2011] [Accepted: 02/12/2012] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE To study a possible association between obstructive sleep apnea (OSA) severity, managed with noninvasive ventilation, and nonalcoholic steatohepatitis (NASH) in bariatric surgical patients. METHODS Medical records of 218 bariatric surgical patients who underwent liver biopsy were reviewed. OSA severity was determined from preoperative polysomnography (apnea-hypopnea index (AHI) ≤ 15 no/mild OSA vs. AHI ≥ 16 moderate/severe OSA). Patients diagnosed with OSA were prescribed noninvasive ventilation. Patients were categorized according to liver histopathology into 3 groups: (i) no liver disease or simple steatosis, (ii) mild NASH (steatosis with necroinflammation and mild fibrosis (stage 0-1)), and iii) advanced NASH (steatosis with necroinflammation and more advanced fibrosis (stage ≥ 2)). RESULTS 125 patients (57%) had no/mild OSA, and 93 (43%) had moderate/severe OSA. There was no difference in serum aminotransferases between patients by OSA severity classification. There was a high prevalence of hepatic histopathological abnormalities: 84% patients had steatosis, 57% had necroinflammation, 34% had fibrotic changes, and 14% had advanced NASH. There was no association between severity of NASH and severity of OSA. CONCLUSIONS There is no association between stage of steatohepatitis and OSA severity among morbidly obese patients managed with noninvasive ventilation.
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Affiliation(s)
| | | | | | | | | | | | - Tarsila C.R. Ribeiro
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Department of Medicine, Gastroenterology Center, University Hospital of the Federal University of Juiz de Fora, Juiz de Fora, Minas Gerais, Brazil
| | - Kymberly D. Watt
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Darrell R. Schroeder
- Health Sciences Research, Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Bradly J. Narr
- Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA
| | - Juraj Sprung
- Department of Anesthesiology, Mayo Clinic, Rochester, MN, USA
- *Juraj Sprung, MD, PhD, Department of Anesthesiology, College of Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905 (USA), Tel. +1 507 2553298, E-Mail
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Chronic intermittent hypoxia: a breath of fresh air in the understanding of NAFLD pathogenesis. J Hepatol 2012; 56:20-2. [PMID: 21925128 DOI: 10.1016/j.jhep.2011.09.002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2011] [Accepted: 09/07/2011] [Indexed: 12/20/2022]
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Aron-Wisnewsky J, Minville C, Tordjman J, Lévy P, Bouillot JL, Basdevant A, Bedossa P, Clément K, Pépin JL. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol 2012; 56:225-33. [PMID: 21703181 DOI: 10.1016/j.jhep.2011.04.022] [Citation(s) in RCA: 188] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2010] [Revised: 04/05/2011] [Accepted: 04/19/2011] [Indexed: 12/14/2022]
Abstract
BACKGROUND & AIMS Morbid obesity is frequently associated with low grade systemic inflammation, increased macrophage accumulation in adipose tissue (AT), obstructive sleep apnea (OSA), and nonalcoholic fatty liver disease (NAFLD). It has been suggested that chronic intermittent hypoxia (CIH) resulting from OSA could be an independent factor for early stage of NAFLD in addition to other well-recognized factors (dyslipidemia or insulin resistance). Moreover, macrophage accumulation in AT is associated with local hypoxia in fat tissue. We hypothesized that the association between CIH and morbid obesity could exert additional specific deleterious effects both in the liver and adipose tissues. METHODS One hundred and one morbidly obese subjects were prospectively recruited and underwent bariatric surgery during which a liver needle biopsy as well as surgical subcutaneous and omental AT biopsies were obtained. Oxygen desaturation index (ODI) quantified the severity of nocturnal CIH. RESULTS Histopathologic analysis of liver biopsies demonstrated that NAFLD lesions (ballooning of hepatocytes, lobular inflammation), NAFLD activity score (NAS), and fibrosis were significantly more severe in patients with the highest ODI tertile (p values ≤0.001 for all hepatic lesions). In multivariate analysis, after adjustment for age, obesity, and insulin resistance status, CIH remained independently associated with hepatic fibrosis, fibroinflammation, and NAS. By contrast, no association was found between CIH, macrophage accumulation, and adipocytes size in both subcutaneous and omental adipose tissue. CONCLUSIONS In morbidly obese patients, CIH was strongly associated with more severe liver injuries but did not worsen obesity induced macrophage accumulation in adipose tissue depots.
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Affiliation(s)
- Judith Aron-Wisnewsky
- Assistance Publique-Hôpitaux de Paris, Endocrinology and Nutrition Department, and Center of Human Nutrition (CRNH), Pitié-Salpétrière Hospital, Paris 75613, France
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Drager LF, Jun JC, Polotsky VY. Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metab 2010; 24:843-51. [PMID: 21112030 PMCID: PMC3011976 DOI: 10.1016/j.beem.2010.08.011] [Citation(s) in RCA: 167] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obstructive sleep apnea (OSA) is recurrent obstruction of the upper airway leading to sleep fragmentation and intermittent hypoxia (IH) during sleep. There is growing evidence from animal models of OSA that IH is independently associated with metabolic dysfunction, including dyslipidemia and insulin resistance. The precise mechanisms by which IH induces metabolic disturbances are not fully understood. Over the last decade, several groups of investigators developed a rodent model of IH, which emulates the oxyhemoglobin profile in human OSA. In the mouse model, IH induces dyslipidemia, insulin resistance and pancreatic endocrine dysfunction, similar to those observed in human OSA. Recent reports provided new insights in possible mechanisms by which IH affects lipid and glucose metabolism. IH may induce dyslipidemia by up-regulating lipid biosynthesis in the liver, increasing adipose tissue lipolysis with subsequent free fatty acid flux to the liver, and inhibiting lipoprotein clearance. IH may affect glucose metabolism by inducing sympathetic activation, increasing systemic inflammation, increasing counter-regulatory hormones and fatty acids, and causing direct pancreatic beta-cell injury. IH models of OSA have improved our understanding of the metabolic impact of OSA, but further studies are needed before we can translate recent basic research findings to clinical practice.
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Affiliation(s)
- Luciano F Drager
- Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA
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Abstract
Obstructive sleep apnea (OSA) is a complex disorder that consists of upper airway obstruction, chronic intermittent hypoxia and sleep fragmentation. OSA is well known to be associated with hypoxia, insulin resistance and glucose intolerance, and these factors can occur in the presence or absence of obesity and metabolic syndrome. Although it is well established that insulin resistance, glucose intolerance and obesity occur frequently with non-alcoholic fatty liver disease (NAFLD), it is now becoming apparent that hypoxia might also be important in the development of NAFLD, and it is recognized that there is increased risk of NAFLD with OSA. This review discusses the association between OSA, NAFLD and cardiovascular disease, and describes the potential role of hypoxia in the development of NAFLD with OSA.
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Feng SZ, Tian JL, Zhang Q, Wang H, Sun N, Zhang Y, Chen BY. An experimental research on chronic intermittent hypoxia leading to liver injury. Sleep Breath 2010; 15:493-502. [PMID: 20582634 DOI: 10.1007/s11325-010-0370-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2009] [Revised: 05/18/2010] [Accepted: 05/18/2010] [Indexed: 01/21/2023]
Abstract
PURPOSE Sleep apnea-hypopnea syndrome and its chronic intermittent hypoxia component may cause multi-system-targeted injury. The latest finding shows that liver is one of the injured organs. The purpose of the study is to observe the dynamic process of the influence that chronic intermittent hypoxia plays on rat liver enzyme, hepatic histology, and ultrastructure based on lipid disorders. METHODS A total of 72 male Wistar rats were randomly divided into three groups. The control group was fed with a regular chow diet, the high fat group with a high fat diet, and the high fat plus intermittent hypoxia group with a high fat diet with a 7-h/day intermittent hypoxia treatment. Changes were observed in rat liver enzyme, hepatic histology, and ultrastructure of the three groups on the third, sixth, and ninth weeks, respectively. The liver paraffin sections were detected with myeloperoxidase. RESULTS The liver function and structure of the control group were found to be normal; the liver enzyme level of the high fat group was significantly higher than that of the control group on the sixth and ninth weeks; and the liver enzyme level of the high fat plus intermittent hypoxia group was significantly higher than that of the control group and the high fat group on the third, sixth, and ninth weeks (all P < 0.01). Observed by a light microscope and a transmission electron microscope, the high fat group and the high fat plus intermittent hypoxia group were all characterized by nonalcoholic fatty liver disease: the high fat group was characterized by simple fatty liver on the third and sixth weeks and by steatohepatitis on the ninth week; the damage of the high fat plus intermittent hypoxia group was significantly more severe than that of the high fat group in all the monitoring points, characterized by steatohepatitis on the sixth week and by obvious liver fibrosis on the ninth week; the myeloperoxidase level of the high fat plus intermittent hypoxia group was significantly higher than that of the control group and the high fat group (all P < 0.01). CONCLUSIONS Under the conditions of high fat and intermittent hypoxia, the injury to the liver function, hepatic histology, and ultrastructure is more severe than that of the high fat group. The injury mainly was characterized by nonalcoholic fatty liver disease and becomes more severe with increased exposure time. Oxidative stress may play an important role in the mechanism.
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Affiliation(s)
- Shu-zhi Feng
- Department of Gerontology, Tianjin Medical University General Hospital, Tianjin, China
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Nonalcoholic Fatty Liver Disease Associated with Obstructive Sleep Apnea: Just a Coincidence? Obes Surg 2010; 20:1536-43. [DOI: 10.1007/s11695-010-0212-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease in the Western world, is tightly associated with obesity and metabolic syndrome. NAFLD entails an increased cardiometabolic and liver-related risk, the latter regarding almost exclusively non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD. Pathogenetic models encompass altered hepatic lipid partitioning and adipokine action, increased oxidative stress, free fatty acid lipotoxicity. On this basis, lifestyle-, drug- or surgically induced weight loss, insulin sensitizers, antioxidants, lipid-lowering drugs have been evaluated in NAFLD/NASH. Most trials are small, of short duration, nonrandomized, without histological end points, thus limiting assessment of long-term safety and efficacy of proposed treatments. All NAFLD patients should be evaluated for their metabolic, cardiovascular and liver-related risk. Liver biopsy remains the gold standard for staging NAFLD, but non-invasive methods are under intense development. Weight loss through lifestyle intervention is the initial approach, because of established efficacy on NAFLD-associated cardiometabolic abnormalities, and to emerging benefits on necroinflammation and overall disease activity in NASH. Bariatric surgery warrants further evaluation before it can be routinely considered in morbidly obese NASH. Larger- and longer-duration randomized trials assessing safety and benefits of drugs on patient-oriented outcomes are needed before pharmacological treatment can be routinely recommended for NASH.
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Affiliation(s)
- G Musso
- Gradenigo Hospital, Turin, Italy.
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Shpirer I, Copel L, Broide E, Elizur A. Continuous positive airway pressure improves sleep apnea associated fatty liver. Lung 2010; 188:301-7. [PMID: 20066542 DOI: 10.1007/s00408-009-9219-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2009] [Accepted: 12/21/2009] [Indexed: 02/06/2023]
Abstract
Treatment of sleep apnea can improve liver enzyme abnormalities in patients with nonalcoholic fatty liver disease. However, the effect of continuous positive airway pressure therapy for sleep apnea on liver fat accumulation was not assessed. Liver biopsy is the "gold standard" for determining and quantifying liver fat accumulation; however, obtaining two separate liver biopsies is challenging. We examined, using a newly described computerized tomography method to quantify liver fat accumulation, whether treatment of sleep apnea improves liver steatosis. In a prospective cohort study, patients diagnosed with obstructive sleep apnea, at Assaf Harofeh Medical Center's sleep laboratory, were identified. Patients completed a questionnaire and underwent blood tests for liver enzymes and lipid profile, and computed tomography scans to determine the liver attenuation index. Patients with liver attenuation index <or=-10 (correlating with histological macrovesicular steatosis >or=30%) were treated with continuous positive airway pressure for 2-3 years. Subsequently, patients underwent repeat blood tests and tomography scans. Of 47 patients who were analyzed, 16 had a low liver attenuation index (<or=-10). Patients with moderate-severe sleep apnea had worse liver attenuation index compared with patients with mild sleep apnea despite comparable body mass index and triglycerides levels. Patients who were compliant with 2-3 years of continuous positive airway pressure treatment demonstrated significant improvement in the mean liver attenuation index, whereas noncompliant patients did not. Patients with nonalcoholic fatty-liver disease may benefit from identification and treatment for obstructive sleep apnea because treatment may improve liver steatosis.
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Affiliation(s)
- Isaac Shpirer
- Institute of Pulmonary Medicine, Assaf Harofeh Medical Center, Zerifin, Israel
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