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Obesity (Silver Spring). Author manuscript; available in PMC 2016 July 07. Published in final edited form as: Obesity (Silver Spring). 2016 April ; 24(4): 871–877. doi:10.1002/oby.21409.
The Impact of Obstructive Sleep Apnea on Nonalcoholic Fatty Liver Disease in Patients with Severe Obesity Peter Benotti1, G. Craig Wood1, George Argyropoulos1, Allan Pack2, Brendan T. Keenan2, Xiang Gao3, Glenn Gerhard4, and Christopher Still1
Author Manuscript
1Geisinger
Obesity Institute, Danville, Pennsylvania, USA
2University
of Pennsylvania, Philadelphia, Pennsylvania, USA
3Pennsylvania 4Temple
State University, University Park, Pennsylvania, USA
University, Philadelphia, Pennsylvania, USA
Abstract Objective—Obstructive sleep apnea (OSA) is common among candidates for bariatric surgery. OSA and its associated intermittent hypoxia have been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. A large cohort of bariatric surgery patients was studied in an effort to explore the relationship between OSA severity, hypoxia, metabolic syndrome, and the severity of NAFLD.
Author Manuscript
Methods—Bariatric surgery candidates who underwent both polysomnography and liver biopsy were studied. The severity of OSA as determined by the apnea-hypopnea index (AHI) and parameters of hypoxia was studied in relation to extent of abnormalities of liver histology as measured by the presence of hepatic steatosis, inflammation, and fibrosis. Results—The study cohort included 362 patients with a mean age of 46.2 years and BMI of 49.9 kg/m2. On the basis of AHI, 26% of the cohort had no OSA, 32% mild OSA, 22% moderate OSA, and 20% severe OSA. For the study subjects without metabolic syndrome, positive correlations were found between OSA severity, as measured by AHI, and parameters of hypoxia, with the severity of NAFLD. Conclusions—OSA severity and its accompanying hypoxia are associated with the severity of NAFLD.
Author Manuscript
Introduction Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in the world, affecting 25–30% of the general population and up to 60–70% in obesity (1). NAFLD includes a spectrum of histologic liver alterations, ranging from simple fatty deposition or steatosis to steatosis associated with hepatocellular injury, inflammation, and fibrosis, collectively termed nonalcoholic steatohepatitis (NASH). Steatosis alone is
Correspondence: Peter Benotti ([email protected]). Disclosure: The authors declared no conflict of interest.
Benotti et al.
Page 2
Author Manuscript
generally considered a benign condition, but NASH is an established risk factor for advanced liver disease including cirrhosis, liver failure, and hepatocellular cancer (2). NAFLD is also a risk factor for cardiovascular disease and endothelial dysfunction, and its severity in obesity is directly related to the degree of metabolic dysfunction, extent of visceral fat, insulin resistance, and components of the metabolic syndrome (3). The exact role of NAFLD and how it contributes to the cardiovascular risk associated with obesity and metabolic dysfunction remain unclear.
Author Manuscript Author Manuscript
Obstructive sleep apnea (OSA) is a respiratory disorder characterized by intermittent and recurring collapse of the upper airway during sleep, which results in poor quality and disrupted sleep, daytime somnolence, and chronic intermittent hypoxia (CIH) (4,5). OSA is fairly common, with recent estimates suggesting that 34% of men and 17% of women aged 30–70 have at least mild OSA (apnea-hypopnea index [AHI] ≥ 5) and that an estimated 13% and 6%, respectively, suffer from moderate or severe disease (AHI ≥ 15) (6). The prevalence of OSA increases in direct relationship with increases in body weight and body mass index (BMI) (7). Currently, about 40% of candidates for obesity surgery require treatment for OSA (4,8,9). OSA is also associated with abnormalities of insulin resistance (10) and glucose metabolism (11), and it has been postulated to be a contributor to NAFLD (12–14). A number of recent studies have suggested that the chronic and recurrent hypoxia associated with OSA may contribute to the pathogenesis of NAFLD and NASH (15,16). However, to differentiate the effects of metabolic syndrome and OSA on NAFLD severity in clinical studies has been challenging because these comorbid conditions commonly coexist, especially in severe obesity (17). The relationship between OSA and NAFLD in the absence of metabolic syndrome is unknown. The aim of this study was, therefore, to explore the relationship between OSA and its associated hypoxia on both the extent and severity of changes in liver histology in a large cohort of patients with severe obesity (mean BMI: 49.9 ± 9.4 kg/m2). Furthermore, in order to gain insight into the association between OSA and NAFLD in otherwise metabolically healthy subjects with severe obesity, the cohort was stratified by presence or absence of metabolic syndrome.
Methods Study population
Author Manuscript
Patients enrolled in the bariatric surgery program at the Geisinger Center for Weight Management are offered participation in an IRB approved obesity research program, which involves collection of clinical data during the preoperative preparation phase, as well as liver biopsy at the time of bariatric surgery and subsequent histopathology. The exact details of the electronic extraction of clinical and tissue data for research purposes have been previously described (18). This study was reviewed and approved by the Geisinger Institutional Research Review board. All patients provided their consent for this study. Electronic medical records (EMR) were retrospectively reviewed to identify 362 individuals who underwent bariatric surgery between November 2006 and October 2014 with an intraoperative wedge liver biopsy and had available polysomnography results within the year prior to surgery. Study patients were further analyzed according to age, gender, BMI, and the
Obesity (Silver Spring). Author manuscript; available in PMC 2016 July 07.
Benotti et al.
Page 3
Author Manuscript
presence of diabetes, dyslipidemia, and hypertension, Study patients were stated to have the metabolic syndrome if they had extreme obesity and the presence of any two of the following International Diabetes Federation criteria: elevated triglyceride level; reduced HDL cholesterol level; hypertension; elevated fasting plasma glucose level (19). Analysis of study patients also included liver histology including the presence of steatosis, lobular inflammation, and fibrosis. Sleep study results
Author Manuscript
Bariatric surgery candidates are referred for polysomnography if OSA is suspected on the basis of clinical evaluation. Polysomnography results for study subjects were extracted from clinical sleep reports and any patients who were using continuous positive airway pressure (CPAP) during the polysomnography were excluded from this study. Sleep study results were manually extracted between January 2006 and December 2008 and were available electronically from January 2009 to October 2014. A representative subset of sleep studies occurring after 2009 was chart reviewed by study investigators in order to verify that the electronic data reported agreed with the manually extracted sleep results and that patients using CPAP at time of polysomnography were excluded. The study team and sleep specialists identified a set of sleep-related outcome variables to be included in this analysis. This list was developed after reviewing sleep study reports to determine which data were available during both time periods. These items included:
Author Manuscript
•
AHI: an index used to indicate the severity of sleep apnea, which is defined as the number of apnea and hypopnea events per hour of sleep. An apnea is a pause in breathing lasting 10 or more seconds and associated with a decrease in oxygen saturation. A hypopnea is a reduction in ventilation of ≥ 50% which lasts at least 10 seconds.
•
Oxygen saturation (SaO2) parameters: nadir and mean SaO2 during sleep.
The severity of OSA was defined using the level of AHI (0 foci per 200× field), and the presence of fibrosis (any perisinusoidal fibrosis, portal fibrosis, bridging fibrosis, or cirrhosis) (20).
Obesity (Silver Spring). Author manuscript; available in PMC 2016 July 07.
Benotti et al.
Page 4
Statistical analysis
Author Manuscript Author Manuscript
Demographic characteristics, the presence of metabolic comorbidities, and transaminase levels were compared between levels of NAFLD and OSA severity using ANOVA and chisquare tests. The associations between sleep study measures and results of liver histology were evaluated using logistic regression models that adjusted for age, gender, and BMI. Separate models were conducted using each of the three liver histology outcomes (including steatosis, lobular inflammation, and fibrosis) as the dependent variable. In preliminary analyses, the severity of liver histology (e.g., normal, Grade 1, Grade 2, Grade 3) was evaluated but not presented for simplicity, because the dichotomized outcomes provided results similar to those expressed. For each category of liver histology, separate logistic regression models were conducted for each of the three selected sleep study results including AHI (categorized as none, mild, moderate, and severe), lowest SaO2 (categorized using tertiles), and mean SaO2 (categorized using tertiles). Sensitivity analyses were conducted to verify that the categorized version of the sleep study variables resulted in findings consistent with the continuous versions of the sleep study variables. The above analyses were completed after stratifying the study patients into those with and without Metabolic Syndrome. For each logistic regression model, the corresponding adjusted sleep parameter estimates were used to calculate the predicted probability of steatosis, lobular inflammation, and fibrosis across the categorized sleep variables. Statistical significance was tested using a test of trend across the categorized sleep variables. SAS version 9.4 was used for statistical analyses and P-values
Obesity (Silver Spring). Author manuscript; available in PMC 2016 July 07. Published in final edited form as: Obesity (Silver Spring). 2016 April ; 24(4): 871–877. doi:10.1002/oby.21409.
The Impact of Obstructive Sleep Apnea on Nonalcoholic Fatty Liver Disease in Patients with Severe Obesity Peter Benotti1, G. Craig Wood1, George Argyropoulos1, Allan Pack2, Brendan T. Keenan2, Xiang Gao3, Glenn Gerhard4, and Christopher Still1
Author Manuscript
1Geisinger
Obesity Institute, Danville, Pennsylvania, USA
2University
of Pennsylvania, Philadelphia, Pennsylvania, USA
3Pennsylvania 4Temple
State University, University Park, Pennsylvania, USA
University, Philadelphia, Pennsylvania, USA
Abstract Objective—Obstructive sleep apnea (OSA) is common among candidates for bariatric surgery. OSA and its associated intermittent hypoxia have been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis. A large cohort of bariatric surgery patients was studied in an effort to explore the relationship between OSA severity, hypoxia, metabolic syndrome, and the severity of NAFLD.
Author Manuscript
Methods—Bariatric surgery candidates who underwent both polysomnography and liver biopsy were studied. The severity of OSA as determined by the apnea-hypopnea index (AHI) and parameters of hypoxia was studied in relation to extent of abnormalities of liver histology as measured by the presence of hepatic steatosis, inflammation, and fibrosis. Results—The study cohort included 362 patients with a mean age of 46.2 years and BMI of 49.9 kg/m2. On the basis of AHI, 26% of the cohort had no OSA, 32% mild OSA, 22% moderate OSA, and 20% severe OSA. For the study subjects without metabolic syndrome, positive correlations were found between OSA severity, as measured by AHI, and parameters of hypoxia, with the severity of NAFLD. Conclusions—OSA severity and its accompanying hypoxia are associated with the severity of NAFLD.
Author Manuscript
Introduction Nonalcoholic fatty liver disease (NAFLD) is currently the leading cause of chronic liver disease in the world, affecting 25–30% of the general population and up to 60–70% in obesity (1). NAFLD includes a spectrum of histologic liver alterations, ranging from simple fatty deposition or steatosis to steatosis associated with hepatocellular injury, inflammation, and fibrosis, collectively termed nonalcoholic steatohepatitis (NASH). Steatosis alone is
Correspondence: Peter Benotti ([email protected]). Disclosure: The authors declared no conflict of interest.
Benotti et al.
Page 2
Author Manuscript
generally considered a benign condition, but NASH is an established risk factor for advanced liver disease including cirrhosis, liver failure, and hepatocellular cancer (2). NAFLD is also a risk factor for cardiovascular disease and endothelial dysfunction, and its severity in obesity is directly related to the degree of metabolic dysfunction, extent of visceral fat, insulin resistance, and components of the metabolic syndrome (3). The exact role of NAFLD and how it contributes to the cardiovascular risk associated with obesity and metabolic dysfunction remain unclear.
Author Manuscript Author Manuscript
Obstructive sleep apnea (OSA) is a respiratory disorder characterized by intermittent and recurring collapse of the upper airway during sleep, which results in poor quality and disrupted sleep, daytime somnolence, and chronic intermittent hypoxia (CIH) (4,5). OSA is fairly common, with recent estimates suggesting that 34% of men and 17% of women aged 30–70 have at least mild OSA (apnea-hypopnea index [AHI] ≥ 5) and that an estimated 13% and 6%, respectively, suffer from moderate or severe disease (AHI ≥ 15) (6). The prevalence of OSA increases in direct relationship with increases in body weight and body mass index (BMI) (7). Currently, about 40% of candidates for obesity surgery require treatment for OSA (4,8,9). OSA is also associated with abnormalities of insulin resistance (10) and glucose metabolism (11), and it has been postulated to be a contributor to NAFLD (12–14). A number of recent studies have suggested that the chronic and recurrent hypoxia associated with OSA may contribute to the pathogenesis of NAFLD and NASH (15,16). However, to differentiate the effects of metabolic syndrome and OSA on NAFLD severity in clinical studies has been challenging because these comorbid conditions commonly coexist, especially in severe obesity (17). The relationship between OSA and NAFLD in the absence of metabolic syndrome is unknown. The aim of this study was, therefore, to explore the relationship between OSA and its associated hypoxia on both the extent and severity of changes in liver histology in a large cohort of patients with severe obesity (mean BMI: 49.9 ± 9.4 kg/m2). Furthermore, in order to gain insight into the association between OSA and NAFLD in otherwise metabolically healthy subjects with severe obesity, the cohort was stratified by presence or absence of metabolic syndrome.
Methods Study population
Author Manuscript
Patients enrolled in the bariatric surgery program at the Geisinger Center for Weight Management are offered participation in an IRB approved obesity research program, which involves collection of clinical data during the preoperative preparation phase, as well as liver biopsy at the time of bariatric surgery and subsequent histopathology. The exact details of the electronic extraction of clinical and tissue data for research purposes have been previously described (18). This study was reviewed and approved by the Geisinger Institutional Research Review board. All patients provided their consent for this study. Electronic medical records (EMR) were retrospectively reviewed to identify 362 individuals who underwent bariatric surgery between November 2006 and October 2014 with an intraoperative wedge liver biopsy and had available polysomnography results within the year prior to surgery. Study patients were further analyzed according to age, gender, BMI, and the
Obesity (Silver Spring). Author manuscript; available in PMC 2016 July 07.
Benotti et al.
Page 3
Author Manuscript
presence of diabetes, dyslipidemia, and hypertension, Study patients were stated to have the metabolic syndrome if they had extreme obesity and the presence of any two of the following International Diabetes Federation criteria: elevated triglyceride level; reduced HDL cholesterol level; hypertension; elevated fasting plasma glucose level (19). Analysis of study patients also included liver histology including the presence of steatosis, lobular inflammation, and fibrosis. Sleep study results
Author Manuscript
Bariatric surgery candidates are referred for polysomnography if OSA is suspected on the basis of clinical evaluation. Polysomnography results for study subjects were extracted from clinical sleep reports and any patients who were using continuous positive airway pressure (CPAP) during the polysomnography were excluded from this study. Sleep study results were manually extracted between January 2006 and December 2008 and were available electronically from January 2009 to October 2014. A representative subset of sleep studies occurring after 2009 was chart reviewed by study investigators in order to verify that the electronic data reported agreed with the manually extracted sleep results and that patients using CPAP at time of polysomnography were excluded. The study team and sleep specialists identified a set of sleep-related outcome variables to be included in this analysis. This list was developed after reviewing sleep study reports to determine which data were available during both time periods. These items included:
Author Manuscript
•
AHI: an index used to indicate the severity of sleep apnea, which is defined as the number of apnea and hypopnea events per hour of sleep. An apnea is a pause in breathing lasting 10 or more seconds and associated with a decrease in oxygen saturation. A hypopnea is a reduction in ventilation of ≥ 50% which lasts at least 10 seconds.
•
Oxygen saturation (SaO2) parameters: nadir and mean SaO2 during sleep.
The severity of OSA was defined using the level of AHI (0 foci per 200× field), and the presence of fibrosis (any perisinusoidal fibrosis, portal fibrosis, bridging fibrosis, or cirrhosis) (20).
Obesity (Silver Spring). Author manuscript; available in PMC 2016 July 07.
Benotti et al.
Page 4
Statistical analysis
Author Manuscript Author Manuscript
Demographic characteristics, the presence of metabolic comorbidities, and transaminase levels were compared between levels of NAFLD and OSA severity using ANOVA and chisquare tests. The associations between sleep study measures and results of liver histology were evaluated using logistic regression models that adjusted for age, gender, and BMI. Separate models were conducted using each of the three liver histology outcomes (including steatosis, lobular inflammation, and fibrosis) as the dependent variable. In preliminary analyses, the severity of liver histology (e.g., normal, Grade 1, Grade 2, Grade 3) was evaluated but not presented for simplicity, because the dichotomized outcomes provided results similar to those expressed. For each category of liver histology, separate logistic regression models were conducted for each of the three selected sleep study results including AHI (categorized as none, mild, moderate, and severe), lowest SaO2 (categorized using tertiles), and mean SaO2 (categorized using tertiles). Sensitivity analyses were conducted to verify that the categorized version of the sleep study variables resulted in findings consistent with the continuous versions of the sleep study variables. The above analyses were completed after stratifying the study patients into those with and without Metabolic Syndrome. For each logistic regression model, the corresponding adjusted sleep parameter estimates were used to calculate the predicted probability of steatosis, lobular inflammation, and fibrosis across the categorized sleep variables. Statistical significance was tested using a test of trend across the categorized sleep variables. SAS version 9.4 was used for statistical analyses and P-values
