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Original Research: Sleep Disorders |

Nonalcoholic Fatty Liver Disease, Nocturnal Hypoxia, and Endothelial Function in Patients With Sleep ApneaNonalcoholic Fatty Liver Disease in Sleep Apnea FREE TO VIEW

Caroline Minville, MD; Marie-Noëlle Hilleret, MD; Renaud Tamisier, MD, PhD; Judith Aron-Wisnewsky, MD; Karine Clement, MD, PhD; Candice Trocme, PhD; Jean-Christian Borel, PhD; Patrick Lévy, MD, PhD; Jean-Pierre Zarski, MD, PhD; Jean-Louis Pépin, MD, PhD
Author and Funding Information

From the Institut universitaire de cardiologie et de pneumologie de Québec (Dr Minville), Quebec City, QC, Canada; Département d’Hépato Gastroentérologie (Drs Hilleret and Zarski), Pôle Digidune, CHU de Grenoble, France; Université Joseph Fourier (Drs Minville, Tamisier, Borel, Lévy, and Pépin), INSERM U 1042, Laboratoire HP2, Hypoxie Physiopathologies, Pôle Locomotion, Rééducation et Physiologie, CHU de Grenoble, France; Assistance Publique-Hôpitaux de Paris (Drs Aron-Wisnewsky and Clement), Département Cœur et métabolisme, Centre de Nutrition Humaine, Hôpital Pitié-Salpétrière, Paris 75613, France; INSERM UMRS 872 team 7 Drs Aron-Wisnewsky and Clement), Nutriomique, Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers, Paris 75006, France; and Laboratoire de Biochimie des Enzymes et des Protéines (Dr Trocme), CGD (Institut de Biologie et de Pathologie), CHU de Grenoble, France.

Correspondence to: Jean-Louis Pépin, MD, PhD, Laboratoire EFCR, CHU de Grenoble, BP217X, 38043 Grenoble cedex 09, France; e-mail: jpepin@chu-grenoble.fr


Drs Zarski and Pépin contributed equally to this work.

Funding/Support: This study was supported by the Délégation à la recherche clinique et à l’innovation (DRCI) 2011 in CHU Grenoble and by Agir à dom scientific council grants.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(3):525-533. doi:10.1378/chest.13-0938
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Background:  Nocturnal hypoxia, the hallmark of OSA, is a potential contributing factor for nonalcoholic fatty liver disease (NAFLD). NAFLD severity and its implication in OSA-related endothelial dysfunction have not been investigated in a large, unselected OSA population, including nonobese subjects.

Methods:  Noninvasive blood tests (SteatoTest, NashTest, and FibroTest) were used to evaluate steatosis, nonalcoholic steatohepatitis (NASH), and fibrosis in a large cohort of patients with OSA. In the same group, endothelial function and its links with NAFLD severity were assessed.

Results:  Of the 226 subjects included who were referred for suspicion of OSA (men, 55%; median age, 56 years; median BMI, 34.2 kg/m2 [33% with BMI < 30 kg/m2]), 61.5% exhibited moderate or severe steatosis. By multivariate analysis, independent factors for liver steatosis were, as expected, triglyceride levels (P < .0001) and insulin resistance (P = .0004) as well as nocturnal cumulative time spent < 90% of oxygen saturation (CT90) (P = .01). Thirty-eight percent had borderline or possible NASH (N1 or N2 with NashTest). CT90 was significantly associated with borderline or possible NASH (P = .035) in univariate but not in multivariate analysis. The dose-response relationship between the severity of nocturnal hypoxia and liver injury was established only in morbid obesity and not in lean. Multivariate models showed that steatosis was independently associated with endothelial dysfunction after adjustment for confounders.

Conclusions:  In a large, unselected OSA population, the severity of nocturnal hypoxia was independently associated with steatosis. Preexisting obesity exacerbated the effects of nocturnal hypoxemia. NAFLD is a potential mechanism of endothelial dysfunction in OSA.

Figures in this Article

Nocturnal hypoxia, the hallmark of OSA, is strongly suggested as a contributing factor for nonalcoholic fatty liver disease (NAFLD).1 Although both conditions are associated with higher cardiovascular risk,2,3 it has never been investigated whether NAFLD is among the underlying mechanisms of endothelial dysfunction in patients with OSA.

OSA is a common medical condition characterized by repetitive partial or complete obstruction of the upper airway, causing repetitive nocturnal oxygen desaturation (ie, chronic intermittent hypoxia [CIH]). CIH induces oxidative stress and, consequently, promotes systemic and vascular inflammation, insulin resistance, endothelial dysfunction, and cardiovascular morbidity and mortality.4 Studies in mice and humans have suggested that OSA also leads to liver injury.58 In morbidly obese subjects referred for bariatric surgery, CIH contributes to the severity of liver fibrosis and fibroinflammation independently of obesity.1 However, the consequences of nocturnal hypoxemia on the development of NAFLD remain largely underinvestigated in large populations of less obese or overweight patients with OSA.

OSA has been associated with a higher cardiometabolic risk, and NAFLD might be one of the mechanistic pathways upregulated by CIH and finally leading to poor cardiometabolic outcomes.9 Clinical cardiovascular complications are preceded by both endothelial function impairments and the development of morphologic atherosclerotic changes.10 Digital pulse amplitude augmentation in response to hyperemia (RH-PAT) is one of the validated methods to measure endothelial function, and RH-PAT measurements allow for quantifying cardiovascular risk10 and predicting late adverse cardiovascular events.11,12 The role of NAFLD in OSA-related endothelial dysfunction is largely unexplored.

The diagnosis of NAFLD relies on histopathologic findings and includes a wide spectrum of lesions, including simple steatosis, steatohepatitis, and fibrosis, potentially leading to end-stage cirrhosis. Therefore, liver biopsy represents the gold standard to confirm NAFLD diagnosis and provide prognostic information, yet it is an invasive and costly procedure prone to either minor secondary effects, such as pain, or more severe complications, including a risk of death of 0.01%.13 Notably, there is high sampling variability and high intrapathologist and interpathologist inconsistency.14 Most importantly, facing the actual epidemic of diabetes and obesity15 and the subsequent number of patients at risk for liver alterations, biopsy cannot be considered a practical, efficient, and large-scale tool to identify those at risk for nonalcoholic steatohepatitis (NASH) and advanced fibrosis. To address this issue, less invasive tests have been developed and validated to largely screen NAFLD in at-risk populations (see review by Machado and Cortez-Pinto16). These methods are either biologic tests or physical techniques, such as transient elastography (FibroScan; Echosens). However, FibroScan has some limitations (failure or unreliability) in obese patients, as suggested by Castéra et al.17 Biologic tests prospectively validated by a predetermined scoring system equivalent to that of the METAVIR scoring system appear, then, to be the most appropriate tool in this population.18 The Fibromax patented algorithm19 developed by BioPredictive is a validated, noninvasive tool for NAFLD screening that uses the association of sex, age, weight, height, and numerous serum biomarkers. Fibromax includes SteatoTest (ST), NashTest (NT), and FibroTest (FT) for the noninvasive evaluation of steatosis, NASH, and liver fibrosis, respectively. The aims of this study were (1) to use noninvasive blood tests (ST, NT, and FT) to evaluate steatosis, NASH, and fibrosis in a large cohort of patients with OSA and a wide range of BMI values, including nonobese subjects, and (2) to assess endothelial function by peripheral arterial tone (PAT) as a marker of cardiovascular risk and evaluate its relationship with NAFLD in OSA.

Patients

Figure 1 displays the study flowchart diagram and exclusion criteria. We enrolled 291 adult subjects referred for suspicion of OSA. Women with an alcohol consumption ≥ 20 g/d and men with ≥ 30 g/d were excluded as well as patients with chronic liver disease, including viral hepatitis B or C (confirmed with renewed serologies), and patients on potentially hepatotoxic drug therapy. Patients with obesity-hypoventilation syndrome were excluded. Finally, patients with serious comorbidities, such as heart failure, severe renal impairment, and severe hypertension, were also excluded. Two hundred and twenty-six subjects were included in the study, all of whom had Fibromax analysis as a surrogate of NAFLD. All subjects provided written informed consent approved by the ethical committee at the Grenoble University Hospital (institutional review board numbers 2007-A00472-51 and 38/2006/2).

Laboratory Analysis

Fasting serum samples were obtained from all subjects to be frozen and stored at −80°C until Fibromax analysis (α2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyltransferase, total bilirubin, alanine aminotransferase [ALT], aspartate aminotransferase [AST], fasting blood glucose, triglycerides, and total cholesterol levels). Results were sent anonymously to BioPredictive, blinded to the severity of sleep apnea, and used in the algorithm to obtain Fibromax results.

Fibromax

Fibromax was validated initially in viral hepatitis C,20 chronic hepatitis B,21 and alcoholic liver disease22 and demonstrated good diagnostic ability. In NAFLD, prospective studies have also demonstrated good reliability for prediction of liver abnormalities, including steatosis,23 NASH,24 and fibrosis, in both overweight and obese patients.19

FibroTest:

FT includes α2-macroglobulin, apolipoprotein A1, haptoglobin, γ-glutamyltransferase, and total bilirubin levels, adjusted for age and sex. FT scores range from 0.00 to 1.00, with higher values indicating a greater probability of significant lesions and corresponding to the well-established METAVIR scoring system of stages F0 to F4 (F0, 0.00-0.21; F0-F1, 0.22-0.27; F1, 0.28-0.31; F1-F2, 0.32-0.48; F2, 0.49-0.58; F3, 0.59-0.72; F3-F4, 0.73-0.74; F4, 0.75-1.0).

SteatoTest:

ST combines the components of the FT adjusted for age, sex, height, and weight plus ALT, serum fasting glucose, triglyceride, and cholesterol levels. ST scores range from 0 to 1.00 and can be express by four stages (S0-S4), as follows: S0 (0.00-0.37) = no steatosis; S1 (0.38-0.56) = minimal steatosis (< 5% hepatocytes containing steatosis); S2 (0.57-0.68) = moderate steatosis (6%-32% hepatocytes containing steatosis); and S3-S4 (0.69-1.0) = severe steatosis (> 32% hepatocytes containing steatosis).

NashTest:

NT combines age, sex, and the components of the FT plus weight; height; and AST, serum fasting glucose, triglyceride, and cholesterol levels. Results are given in three categories, as follows: no NASH = 0.25; borderline NASH = 0.50; and NASH = 0.75.

Endothelial Dysfunction as Measured by PAT

PAT, as measured by EndoPAT (Itamar Medical), is a noninvasive method to assess vasodilation in the index fingertip after 5 min of ischemia. It is based on a finger pneumo-optic plethysmograph measuring volume changes at the fingertip related to arterial blood flow. Two finger probes were put on the index fingers of both hands and inflated with uniform pressure (near diastolic BP). Subjects were comfortably settled in the supine position in a quiet room with neutral temperature. The reactive hyperemia test consisted of three consecutive 5-min recordings: Resting baseline was recorded during 5 min, and arterial flow was interrupted for 5 min by inflating an arm cuff to 60 mm Hg above systolic pressure and then suddenly deflated for 5 min for a postocclusion recording. Results can be interpreted in different ways by using the direct PAT value; the natural logarithm of the PAT (lnPAT); or, as recently published, the RH-PAT index.25 The RH-PAT index was calculated as the lnPAT of the average amplitude of the PAT signal after 90 to 120 s deflation divided by the average amplitude of the PAT signal during the 210 s prior to cuff inflation.

Sleep Studies

The diagnosis of OSA was made after full polysomnography (RemLogic [Embla Systems] and Coherence [Deltamed SA] systems) following international recommendations. Details have been previously published.26,27

Statistical Analysis

The relationship between Fibromax results (prospectively scored with a predetermined scoring system equivalent to the METAVIR scoring system) and severity of nocturnal hypoxemia were analyzed with logistic regressions. The FT model was adjusted for BMI. In univariate logistic regression, when continuous variables were not log-linear, a new variable was created from the quartiles, tertiles, or median value.

Colinearity was assessed by Pearson or Spearman coefficient or Cramér V2. Independent parameters were included in the multivariate model when significance was ≤ 0.2 in the univariate model. A backward selection was used for the multivariate model. An unpaired t test or Mann-Whitney U test was used for comparisons between variables, depending on validation of normal distribution and equality of variance, for continuous variables. Normality of the data was checked by tests of skewness and kurtosis, and equality of variance was examined by Levene test.

Results were considered statistically significant at P < .05. Statistical analysis was performed with SAS version 9.1.3 (SAS Institute Inc) software.

Study Flowchart

A total of 226 subjects (101 women [45%]) were included in this study (Fig 1). Population characteristics are presented in Table 1. There was a large distribution in BMI values (median [Q1-Q3], 34.2 [28.2-39.9] kg/m2), with 33% of the population being normal weight or overweight (BMI < 30 kg/m2), and 55.2% of the included subjects fulfilled the criteria of metabolic syndrome as defined by National Cholesterol Education Program/Adult Treatment Panel III guidelines.28 After sleep studies, 31 subjects did not have sleep-related breathing disorders.

Table Graphic Jump Location
Table 1 —Patient Characteristics

Data are presented as mean ± SD, No., or %. AHI = apnea-hypopnea index; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT90 = nocturnal cumulative time spent < 90% of oxygen saturation; GGT = γ-glutamyl transferase; HDL = high-density lipoprotein; HT = hypertension; ODI = oxygen desaturation index; Spo2 = oxygen saturation as measured by pulse oximetry; TG = triglyceride; TST = total sleep time.

Fatty Liver Diseases and Association With Metabolic Phenotypes and Nocturnal Hypoxia

As defined by an ST ≥ S2, 61.5% of the subjects exhibited moderate or severe steatosis. In this group, C-reactive protein values were significantly higher than in those with ST < S2 (6.64 ± 8.15 vs 3.2 ± 4.52 when ST < S2, P = .0002) (Table 2).

Table Graphic Jump Location
Table 2 —Fibromax Results

In univariate analysis (Table 3), moderate or severe steatosis was associated with higher BMI (P < .0001), abdominal circumference (P < .0001), systolic BP (P = .01), triglyceride levels (P < .0001), and levels of insulin resistance surrogates (homeostasis of model of assessment-insulin resistance [HOMA-IR] index) (P < .0001). Moderate or severe steatosis was also associated with the occurrence of metabolic syndrome (P < .0001) and nocturnal hypoxia, which was true both when hypoxia was expressed as nocturnal cumulative time spent < 90% of oxygen saturation (CT90) (P = .0001) and when looking at tertiles of 3% oxygen desaturation index (n = 157, P < .0009).

Table Graphic Jump Location
Table 3 —SteatoTest Univariate Analysis

Data are presented as mean ± SD, No., or % unless otherwise indicated. HOMA-IR = homeostasis of model of assessment-insulin resistance index; Sao2 = arterial oxygen saturation. See Table 1 legend for expansion of other abbreviations.

a 

Significant P < .05.

b 

Global test.

c 

Comparison between second and first tertiles.

d 

Comparison between third and first tertiles.

In multivariate analysis, triglyceride levels (P < .0001), insulin resistance (HOMA-IR > 3) (P = .0004), and CT90 (P = .01) remained independent factors for liver steatosis (Table 4). Thirty-eight percent of the subjects showed possible or probable NASH (N1 or N2 with NT). C-reactive protein values were significantly higher in those meeting borderline or possible NASH criteria (5.76 ± 6.39 vs 4.93 ± 7.50 without NASH, P < .01). In univariate analysis, CT90 was significantly associated with borderline or possible NASH (P = .035), as was abdominal circumference (P < .0001), triglyceride levels (P < .0001), markers of insulin resistance (HOMA-IR > 3) (P = .009), and metabolic syndrome (P < .0001). However, in multivariate analysis, nocturnal hypoxia did not remain an independent factor (Table 4).

Table Graphic Jump Location
Table 4 —Multivariate Analysis

SBP = systolic BP. See Table 1 legend for expansion of other abbreviations.

a 

Backward regression.

b 

Significant P < .05.

c 

Global test.

d 

Comparison between second and first tertiles.

e 

Comparison between third and first tertiles.

f 

F0 vs > F0.

In univariate analysis, liver fibrosis (FT > F0) was associated with older age (P < .0001), male sex (P = .0001), higher insulin resistance (HOMA-IR > 3) (P = .049), and metabolic syndrome (P = .02). No association was found between liver fibrosis and nocturnal hypoxia. Age, sex, and fasting glycemic or diabetic status were independent factors for fibrosis in multivariate analysis (Table 4).

Of note, a dose-response relationship between nocturnal hypoxia and the severity of steatosis and NASH was observed solely in the upper BMI tertile (Figs 2A, 2B). In the highest tertile of BMI, the relationship between CT90 and moderate or severe steatosis remained significant, even after adjusting for BMI in this specific tertile, confirming that the interaction between higher CT90 and moderate to severe steatosis was not simply mediated by higher BMI.

Figure Jump LinkFigure 2. A and B, Steatosis and Nash among BMI and severity of hypoxia tertiles. Lower and upper limits are shown in brackets. Mean ± SD of BMI in kg/m2 in every tertile. CT90 = nocturnal cumulative time spent < 90% of oxygen saturation; Nash = nonalcoholic steatohepatitis.Grahic Jump Location
Fatty Liver Disease: Relationship With Endothelial Function and BP

Endothelial function was more severely impaired in subjects with moderate or severe steatosis (ST ≥ S2 vs ST < S2) (lnPAT, 0.72 ± 0.23 vs 0.79 ± 0.22, respectively; P = .04) and borderline or possible NASH (N1, N2 vs N0) (RH-PAT, 0.49 ± 0.29 vs 0.61 ± 0.34, respectively; P = .01). Office systolic BP was also significantly more elevated in those with moderate or severe steatosis and borderline or possible NASH (P = .01 and P = .004, respectively, unadjusted P values). We have implemented univariate and multivariate models in which the dependent variable was RH-PAT and independent variables were age, sex, BMI, waist circumference, a measure of OSA severity (apnea-hypopnea index or CT90) and a measure of NAFLD (NASH and steatosis). The different models showed that steatosis was independently associated with RH-PAT after adjusting for confounders and beyond the usual risk factors (Tables 5, 6). This relationship was not significant in multivariate analysis for NASH.

Table Graphic Jump Location
Table 5 —Univariate Analysis for RH-PAT

RH-PAT = pulse amplitude augmentation in response to hyperemia. See Table 1 legend for expansion of other abbreviations.

a 

Significant P < .05.

Table Graphic Jump Location
Table 6 —Multivariate Analysis for RH-PAT

See Table 1 and 5 legends for expansion of abbreviations.

a 

Significant P < .05.

To our knowledge, this study is the first to investigate the prevalence and severity of NAFLD using noninvasive blood tests in a large group of patients with OSA and a wide range of BMI values. We demonstrate a dose-response relationship between the severity of nocturnal hypoxia and liver injury only in the highest tertile of BMI (> 37.8 kg/m2) but not in lean subjects with OSA. Finally, in sleep apnea, severe hepatic steatosis and borderline or possible NASH were associated with higher cardiovascular risk as demonstrated by elevated BP and more severe endothelial dysfunction.

Hepatic steatosis develops in a context of an imbalance between triglyceride afflux in the liver due to concomitant increased supply (coming from diet, de novo lipogenesis, and adipose tissue) and decreased degradation (through impaired β-oxidation).29,30 In mouse studies, CIH increases the expression of key lipogenic transcription factors (eg, sterol regulatory element binding protein-1c, peroxisome proliferator-activated receptor γ, acetyl-CoA carboxylase 1 and 2), suggesting an induction of de novo lipogenesis.3133 Furthermore, CIH is responsible for increased circulating triglyceride levels through decreased lipoprotein lipase activity in adipose tissue and decreased clearance of triglyceride-rich lipoproteins.34 Finally, CIH decreases the liver gene expression of peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase 1, which are both involved in β-oxydation.35 Altogether, these mechanisms may account for the independent role we found between nocturnal hypoxia and the occurrence of hepatic steatosis as observed in multivariate analysis (P = .01).

Importantly, most of the previous studies addressing the relationship between OSA and liver injury have been done in morbidly obese patients undergoing bariatric surgery,36 thus, limiting the generalization of the findings. In other works, liver biopsy specimens used to assess the severity of NAFLD were merely performed in patients with elevated liver enzymes.5 Yet, liver enzymes lack sensitivity for the proper diagnosis of NAFLD and fibrosis.1,37 Moreover, in a normal or overweight population, there is hardly any information regarding liver injury associated with nocturnal hypoxemia. Previous studies in both adults38,39 and children40 using liver ultrasound imaging, abnormal liver enzyme levels, or both have found a link between nocturnal hypoxia and NAFLD in nonbariatric patients. Because the association of OSA and obesity may magnify liver injuries, liver lesions were hypothesized as less severe in obese than in morbidly obese patients with OSA, and we actually confirmed this hypothesis (Figs 2A, 2B). Obesity in the context of insulin resistance leads to numerous metabolic abnormalities, among which is an elevation of plasma free fatty acids. This leads to lipid accumulation in both muscle and liver, thus, increasing the already existing insulin resistance and possibly worsening liver injury. In diet-induced obese mice, intermittent hypoxia exposure favors a shift from obesity-related microvesicular hepatic steatosis to more severe hepatic injury, as seen by macrovesicular steatosis and lobular inflammation development.41 In these mice, CIH increased liver triglyceride content and proinflammatory cytokine levels and induced severe oxidative stress in the liver with a fivefold increase in lipid peroxidation. These results in obese rodents are completely in accordance with the dose-response relationship between the severity of intermittent hypoxia and liver lesions that we previously reported in morbidly obese patients.1 By contrast, in lean mice, CIH had only a minimal impact on liver lipid peroxidation, whereas liver triglyceride content and inflammation were not affected.41 Leptin is elevated in obesity, and leptin induction of inducible nitric oxide synthase and nicotinamide adenine dinucleotide phosphate oxidase has recently been demonstrated to cause peroxynitrite-mediated oxidative stress, thus, activating Kupffer cells and the progression of NAFLD in obese mice.42 Collectively, our actual study and previous animal data suggest that associated or preexisting obesity is required for nocturnal hypoxemia to trigger a shift from already existing hepatic steatosis to an inflammatory and fibrogenic response in the liver.35

The endothelium is the key regulator of vascular homeostasis. Alteration in endothelial function precedes the development of morphologic atherosclerotic changes and afterward, clinical complications.10 Digital RH-PAT is one of the validated methods used to measure endothelial function, allowing for quantifying cardiovascular risk43 and predicting late adverse cardiovascular events.11,12 Numerous studies have demonstrated an association among OSA, atherosclerosis, and coronary artery disease independent of age, sex, and BMI.44 A variety of pathophysiologic mechanisms are involved in OSA-related cardiovascular complications, including increased sympathetic tone, impaired regulation of coagulation, impaired glucose metabolism,45,46 and endothelial dysfunction. Systemic inflammation and oxidative stress are believed to play key roles in the development of these pathways.47 There is growing evidence that NAFLD may confer increased cardiometabolic risk with major adverse cardiovascular outcomes independently of traditional cardiovascular risk factors.3 It was previously reported that flow-mediated vasodilation is progressively more severely altered from simple steatosis to NASH,48 thus, confirming the graded association of cardiovascular risk with severity of NAFLD. An association between NAFLD and coronary plaques has also been reported,49 more recently with thickening of left ventricular walls and concentric remodeling at the heart level.50 The present study is the first to our knowledge to demonstrate that beyond sympathetic activity and inflammation, NAFLD is one additional pathway for endothelial dysfunction that could subsequently contribute to adverse cardiometabolic consequences of OSA.

In a large unselected OSA population with a wide range of BMI values, the severity of nocturnal hypoxia is independently associated with the severity steatosis. This study establishes that preexisting obesity exacerbates the effects of nocturnal hypoxemia and that NAFLD is one of the mechanisms involved in endothelial dysfunction in OSA. The prognostic interest of a systematic and large-scale evaluation by noninvasive biomarkers of NAFLD in severe OSA deserves further study. An improvement in liver enzyme levels after adenotonsillectomy has been demonstrated in obese children with OSA.51 Conversely, in adult OSA, Kohler et al52 did not find any differences between 4 weeks of therapeutic CPAP and sham CPAP in AST and ALT levels. The study was presumably negative because a large proportion of patients with OSA had normal or minimally elevated enzyme levels at baseline and there was not enough room for improvement. Additionally, CPAP adherence was not as optimal, and 4 weeks of CPAP therapy might not be sufficient to achieve improvement in liver function. Future randomized controlled trials are needed to assess whether effective vs sham CPAP treatment is able to improve liver injury and endothelial function in patients with coexisting OSA and NAFLD.

Author contributions: Drs Zarski and Pépin had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Minville: contributed to the study conception and design, data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Hilleret: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Tamisier: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Aron-Wisnewsky: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Clement: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Trocme: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Borel: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Lévy: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Zarski: contributed to the data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Dr Pépin: contributed to the study conception and design, data analysis and interpretation, drafting of the manuscript, and review of the manuscript for important intellectual content.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Tamisier has received consulting fees from Respicardia, Inc; unrestricted research funds from ResMed Foundation, Agiradom, Orkyn, Fondation de la recherche medicale, and Direction de la recherche Clinique du CHU de Grenoble; and lecture fees from HealthID, Inc; Périmètre, SA; American Thoracic Society; and European Respiratory Society. Drs Minville, Hilleret, Aron-Wisnewsky, Clement, Trocme, Borel, Lévy, Zarski, and Pépin have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Role of sponsors: The sponsors had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.

Other contributions: The authors thank Nathalie Arnol, MSc, and Sonia Dias-Domingos, MSc (INSERM U1042, HP2 Laboratory, CHU de Grenoble, France) for statistical analyses and Sylvie Larrat, MD, for collaboration and the completion of virologic analysis.

ALT

alanine aminotransferase

AST

aspartate aminotransferase

CIH

chronic intermittent hypoxia

CT90

nocturnal cumulative time spent < 90% of oxygen saturation

FT

FibroTest

HOMA-IR

homeostasis of model of assessment-insulin resistance index

lnPAT

natural logarithm of peripheral arterial tone

NAFLD

nonalcoholic fatty liver disease

NASH

nonalcoholic steatohepatitis

NT

NashTest

PAT

peripheral arterial tone

RH-PAT

pulse amplitude augmentation in response to hyperemia

ST

SteatoTest

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Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology. 2010;51(3):828-835. [PubMed]
 
Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24(2):289-293. [CrossRef] [PubMed]
 
Poynard T, Lassailly G, Diaz E, et al; FLIP Consortium. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PLoS ONE. 2012;7(3):e30325. [CrossRef] [PubMed]
 
Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357(9262):1069-1075. [CrossRef] [PubMed]
 
Myers RP, Tainturier MH, Ratziu V, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol. 2003;39(2):222-230. [CrossRef] [PubMed]
 
Naveau S, Raynard B, Ratziu V, et al. Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease. Clin Gastroenterol Hepatol. 2005;3(2):167-174. [CrossRef] [PubMed]
 
Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol. 2005;4:10. [CrossRef] [PubMed]
 
Poynard T, Ratziu V, Charlotte F, et al; LIDO Study Group; CYTOL Study Group. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:34. [CrossRef] [PubMed]
 
Rubinshtein R, Kuvin JT, Soffler M, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31(9):1142-1148. [CrossRef] [PubMed]
 
Argod J, Pépin JL, Lévy P. Differentiating obstructive and central sleep respiratory events through pulse transit time. Am J Respir Crit Care Med. 1998;158(6):1778-1783. [CrossRef] [PubMed]
 
Berry RB, Budhiraja R, Gottlieb DJ, et al; American Academy of Sleep Medicine; Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. J Clin Sleep Med. 2012;8(5):597-619. [PubMed]
 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421. [PubMed]
 
Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332(6037):1519-1523. [CrossRef] [PubMed]
 
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52(2):774-788. [CrossRef] [PubMed]
 
Piguet AC, Stroka D, Zimmermann A, Dufour JF. Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN. Clin Sci (Lond). 2010;118(6):401-410. [CrossRef]
 
Savransky V, Jun J, Li J, et al. Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. Circ Res. 2008;103(10):1173-1180. [CrossRef] [PubMed]
 
Li J, Thorne LN, Punjabi NM, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res. 2005;97(7):698-706. [CrossRef] [PubMed]
 
Drager LF, Li J, Shin MK, et al. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur Heart J. 2012;33(6):783-790. [CrossRef] [PubMed]
 
Musso G, Olivetti C, Cassader M, Gambino R. Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms. Semin Liver Dis. 2012;32(1):49-64. [CrossRef] [PubMed]
 
Mishra P, Nugent C, Afendy A, et al. Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis. Liver Int. 2008;28(8):1080-1086. [CrossRef] [PubMed]
 
Kunde SS, Lazenby AJ, Clements RH, Abrams GA. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology. 2005;42(3):650-656. [CrossRef] [PubMed]
 
Norman D, Bardwell WA, Arosemena F, et al. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. Sleep. 2008;31(1):121-126. [PubMed]
 
Türkay C, Ozol D, Kasapoğlu B, Kirbas I, Yıldırım Z, Yiğitoğlu R. Influence of obstructive sleep apnea on fatty liver disease: role of chronic intermittent hypoxia. Respir Care. 2012;57(2):244-249. [PubMed]
 
Verhulst SL, Jacobs S, Aerts L, et al. Sleep-disordered breathing: a new risk factor of suspected fatty liver disease in overweight children and adolescents? Sleep Breath. 2009;13(2):207-210. [CrossRef] [PubMed]
 
Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring). 2011;19(11):2167-2174. [CrossRef] [PubMed]
 
Chatterjee S, Ganini D, Tokar EJ, et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental nonalcoholic steatohepatitis. J Hepatol. 2013;58(4):778-784. [CrossRef] [PubMed]
 
Hamburg NM, Keyes MJ, Larson MG, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008;117(19):2467-2474. [CrossRef] [PubMed]
 
Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010;122(4):352-360. [CrossRef] [PubMed]
 
Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med. 2002;165(5):677-682. [CrossRef] [PubMed]
 
Harsch IA, Schahin SP, Radespiel-Tröger M, et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2004;169(2):156-162. [CrossRef] [PubMed]
 
Lavie L, Lavie P. Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Eur Respir J. 2009;33(6):1467-1484. [CrossRef] [PubMed]
 
Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42(2):473-480. [CrossRef] [PubMed]
 
Assy N, Djibre A, Farah R, Grosovski M, Marmor A. Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology. 2010;254(2):393-400. [CrossRef] [PubMed]
 
Hallsworth K, Hollingsworth KG, Thoma C, et al. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J Hepatol. 2013;58(4):757-762. [CrossRef] [PubMed]
 
Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest. 2008;133(1):92-99. [CrossRef] [PubMed]
 
Kohler M, Pepperell JC, Davies RJ, Stradling JR. Continuous positive airway pressure and liver enzymes in obstructive sleep apnoea: data from a randomized controlled trial. Respiration. 2009;78(2):141-146. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 2. A and B, Steatosis and Nash among BMI and severity of hypoxia tertiles. Lower and upper limits are shown in brackets. Mean ± SD of BMI in kg/m2 in every tertile. CT90 = nocturnal cumulative time spent < 90% of oxygen saturation; Nash = nonalcoholic steatohepatitis.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Patient Characteristics

Data are presented as mean ± SD, No., or %. AHI = apnea-hypopnea index; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CT90 = nocturnal cumulative time spent < 90% of oxygen saturation; GGT = γ-glutamyl transferase; HDL = high-density lipoprotein; HT = hypertension; ODI = oxygen desaturation index; Spo2 = oxygen saturation as measured by pulse oximetry; TG = triglyceride; TST = total sleep time.

Table Graphic Jump Location
Table 2 —Fibromax Results
Table Graphic Jump Location
Table 3 —SteatoTest Univariate Analysis

Data are presented as mean ± SD, No., or % unless otherwise indicated. HOMA-IR = homeostasis of model of assessment-insulin resistance index; Sao2 = arterial oxygen saturation. See Table 1 legend for expansion of other abbreviations.

a 

Significant P < .05.

b 

Global test.

c 

Comparison between second and first tertiles.

d 

Comparison between third and first tertiles.

Table Graphic Jump Location
Table 4 —Multivariate Analysis

SBP = systolic BP. See Table 1 legend for expansion of other abbreviations.

a 

Backward regression.

b 

Significant P < .05.

c 

Global test.

d 

Comparison between second and first tertiles.

e 

Comparison between third and first tertiles.

f 

F0 vs > F0.

Table Graphic Jump Location
Table 5 —Univariate Analysis for RH-PAT

RH-PAT = pulse amplitude augmentation in response to hyperemia. See Table 1 legend for expansion of other abbreviations.

a 

Significant P < .05.

Table Graphic Jump Location
Table 6 —Multivariate Analysis for RH-PAT

See Table 1 and 5 legends for expansion of abbreviations.

a 

Significant P < .05.

References

Aron-Wisnewsky J, Minville C, Tordjman J, et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatol. 2012;56(1):225-233. [CrossRef] [PubMed]
 
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Bhatia LS, Curzen NP, Calder PC, Byrne CD. Non-alcoholic fatty liver disease: a new and important cardiovascular risk factor? Eur Heart J. 2012;33(10):1190-1200. [CrossRef] [PubMed]
 
Baguet JP, Barone-Rochette G, Tamisier R, Levy P, Pépin JL. Mechanisms of cardiac dysfunction in obstructive sleep apnea. Nat Rev Cardiol. 2012;9(12):679-688. [CrossRef] [PubMed]
 
Tanné F, Gagnadoux F, Chazouillères O, et al. Chronic liver injury during obstructive sleep apnea. Hepatology. 2005;41(6):1290-1296. [CrossRef] [PubMed]
 
Jouët P, Sabaté JM, Maillard D, et al. Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study. Obes Surg. 2007;17(4):478-485. [CrossRef] [PubMed]
 
Tatsumi K, Saibara T. Effects of obstructive sleep apnea syndrome on hepatic steatosis and nonalcoholic steatohepatitis. Hepatol Res. 2005;33(2):100-104. [CrossRef] [PubMed]
 
Savransky V, Nanayakkara A, Vivero A, et al. Chronic intermittent hypoxia predisposes to liver injury. Hepatology. 2007;45(4):1007-1013. [CrossRef] [PubMed]
 
Pépin JL, Tamisier R, Lévy P. Obstructive sleep apnoea and metabolic syndrome: put CPAP efficacy in a more realistic perspective. Thorax. 2012;67(12):1025-1027. [CrossRef] [PubMed]
 
Deanfield JE, Halcox JP, Rabelink TJ. Endothelial function and dysfunction: testing and clinical relevance. Circulation. 2007;115(10):1285-1295. [PubMed]
 
Rubinshtein R, Kuvin JT, Soffler M, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31(9):1142-1148. [CrossRef] [PubMed]
 
Flammer AJ, Anderson T, Celermajer DS, et al. The assessment of endothelial function: from research into clinical practice. Circulation. 2012;126(6):753-767. [CrossRef] [PubMed]
 
Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol. 1986;2(2):165-173. [CrossRef] [PubMed]
 
Ratziu V, Charlotte F, Heurtier A, et al; LIDO Study Group. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898-1906. [CrossRef] [PubMed]
 
The Lancet. Time for action in New York on non-communicable diseases. Lancet. 2011;378(9795):961. [CrossRef] [PubMed]
 
Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013;58(5):1007-1019. [CrossRef] [PubMed]
 
Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology. 2010;51(3):828-835. [PubMed]
 
Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group. Hepatology. 1996;24(2):289-293. [CrossRef] [PubMed]
 
Poynard T, Lassailly G, Diaz E, et al; FLIP Consortium. Performance of biomarkers FibroTest, ActiTest, SteatoTest, and NashTest in patients with severe obesity: meta analysis of individual patient data. PLoS ONE. 2012;7(3):e30325. [CrossRef] [PubMed]
 
Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357(9262):1069-1075. [CrossRef] [PubMed]
 
Myers RP, Tainturier MH, Ratziu V, et al. Prediction of liver histological lesions with biochemical markers in patients with chronic hepatitis B. J Hepatol. 2003;39(2):222-230. [CrossRef] [PubMed]
 
Naveau S, Raynard B, Ratziu V, et al. Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease. Clin Gastroenterol Hepatol. 2005;3(2):167-174. [CrossRef] [PubMed]
 
Poynard T, Ratziu V, Naveau S, et al. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol. 2005;4:10. [CrossRef] [PubMed]
 
Poynard T, Ratziu V, Charlotte F, et al; LIDO Study Group; CYTOL Study Group. Diagnostic value of biochemical markers (NashTest) for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol. 2006;6:34. [CrossRef] [PubMed]
 
Rubinshtein R, Kuvin JT, Soffler M, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J. 2010;31(9):1142-1148. [CrossRef] [PubMed]
 
Argod J, Pépin JL, Lévy P. Differentiating obstructive and central sleep respiratory events through pulse transit time. Am J Respir Crit Care Med. 1998;158(6):1778-1783. [CrossRef] [PubMed]
 
Berry RB, Budhiraja R, Gottlieb DJ, et al; American Academy of Sleep Medicine; Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. J Clin Sleep Med. 2012;8(5):597-619. [PubMed]
 
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106(25):3143-3421. [PubMed]
 
Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332(6037):1519-1523. [CrossRef] [PubMed]
 
Neuschwander-Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatology. 2010;52(2):774-788. [CrossRef] [PubMed]
 
Piguet AC, Stroka D, Zimmermann A, Dufour JF. Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN. Clin Sci (Lond). 2010;118(6):401-410. [CrossRef]
 
Savransky V, Jun J, Li J, et al. Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. Circ Res. 2008;103(10):1173-1180. [CrossRef] [PubMed]
 
Li J, Thorne LN, Punjabi NM, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res. 2005;97(7):698-706. [CrossRef] [PubMed]
 
Drager LF, Li J, Shin MK, et al. Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur Heart J. 2012;33(6):783-790. [CrossRef] [PubMed]
 
Musso G, Olivetti C, Cassader M, Gambino R. Obstructive sleep apnea-hypopnea syndrome and nonalcoholic fatty liver disease: emerging evidence and mechanisms. Semin Liver Dis. 2012;32(1):49-64. [CrossRef] [PubMed]
 
Mishra P, Nugent C, Afendy A, et al. Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis. Liver Int. 2008;28(8):1080-1086. [CrossRef] [PubMed]
 
Kunde SS, Lazenby AJ, Clements RH, Abrams GA. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women. Hepatology. 2005;42(3):650-656. [CrossRef] [PubMed]
 
Norman D, Bardwell WA, Arosemena F, et al. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. Sleep. 2008;31(1):121-126. [PubMed]
 
Türkay C, Ozol D, Kasapoğlu B, Kirbas I, Yıldırım Z, Yiğitoğlu R. Influence of obstructive sleep apnea on fatty liver disease: role of chronic intermittent hypoxia. Respir Care. 2012;57(2):244-249. [PubMed]
 
Verhulst SL, Jacobs S, Aerts L, et al. Sleep-disordered breathing: a new risk factor of suspected fatty liver disease in overweight children and adolescents? Sleep Breath. 2009;13(2):207-210. [CrossRef] [PubMed]
 
Drager LF, Li J, Reinke C, Bevans-Fonti S, Jun JC, Polotsky VY. Intermittent hypoxia exacerbates metabolic effects of diet-induced obesity. Obesity (Silver Spring). 2011;19(11):2167-2174. [CrossRef] [PubMed]
 
Chatterjee S, Ganini D, Tokar EJ, et al. Leptin is key to peroxynitrite-mediated oxidative stress and Kupffer cell activation in experimental nonalcoholic steatohepatitis. J Hepatol. 2013;58(4):778-784. [CrossRef] [PubMed]
 
Hamburg NM, Keyes MJ, Larson MG, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation. 2008;117(19):2467-2474. [CrossRef] [PubMed]
 
Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation. 2010;122(4):352-360. [CrossRef] [PubMed]
 
Punjabi NM, Sorkin JD, Katzel LI, Goldberg AP, Schwartz AR, Smith PL. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med. 2002;165(5):677-682. [CrossRef] [PubMed]
 
Harsch IA, Schahin SP, Radespiel-Tröger M, et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med. 2004;169(2):156-162. [CrossRef] [PubMed]
 
Lavie L, Lavie P. Molecular mechanisms of cardiovascular disease in OSAHS: the oxidative stress link. Eur Respir J. 2009;33(6):1467-1484. [CrossRef] [PubMed]
 
Villanova N, Moscatiello S, Ramilli S, et al. Endothelial dysfunction and cardiovascular risk profile in nonalcoholic fatty liver disease. Hepatology. 2005;42(2):473-480. [CrossRef] [PubMed]
 
Assy N, Djibre A, Farah R, Grosovski M, Marmor A. Presence of coronary plaques in patients with nonalcoholic fatty liver disease. Radiology. 2010;254(2):393-400. [CrossRef] [PubMed]
 
Hallsworth K, Hollingsworth KG, Thoma C, et al. Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease. J Hepatol. 2013;58(4):757-762. [CrossRef] [PubMed]
 
Kheirandish-Gozal L, Sans Capdevila O, Kheirandish E, Gozal D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest. 2008;133(1):92-99. [CrossRef] [PubMed]
 
Kohler M, Pepperell JC, Davies RJ, Stradling JR. Continuous positive airway pressure and liver enzymes in obstructive sleep apnoea: data from a randomized controlled trial. Respiration. 2009;78(2):141-146. [CrossRef] [PubMed]
 
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