The Sleep, Liver Evaluation and Effective Pressure Study (SLEEP)

• Cross Sectional Analysis of NAFLD versus Sleep Apnea Severity Indices (AHI) [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  Cross-sectional analysis will be performed in NAFLD study participants from the JH Hepatology Clinic to examine the relationship between findings on liver biopsy and sleep apnea severity indices. The main predictor variable will be presence/severity of OSA and nocturnal oxyhemoglobin desaturation (assessed by T90%, time w/ oxyhemoglobin desaturation < 90%; Delta SaO2 between baseline and minimal oxyhemoglobin saturation, and standard deviation of nocturnal SaO2). Our primary outcome will be NAFLD activity score on biopsy.
  
  

• Liver Values and MR Indices [ Time Frame: 6 Months ] [ Designated as safety issue: No ]
  Serum ALT and AST activity and MR indices will be measured.
  
  
• Analysis of Variance (ANOVA) in CPAP versus No-CPAP therapy on NAFLD [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  we will test our hypothesis that CPAP therapy improves NAFLD. The main independent variables will be CPAP vs. deferred-CPAP therapy. In a subanalysis, responses in the CPAP treatment group will be compared based on compliance. Compliance with CPAP is defined as using it on > 70% of the days, at least 4 h per night. Our primary outcome will be serum activity of ALT and AST. We will use ANOVA to examine changes in ALT and AST depending on CPAP therapy group and compliance. Secondary outcomes will include the degree of hepatic steatosis and fibrosis, as assessed by MR.
  
  

Nonalcoholic fatty liver disease (NAFLD) is a common disease with a well-established link to obesity and is increasingly prevalent with the concurrent rise in obesity. NAFLD constitutes a disease spectrum from steatosis to cirrhosis and is associated with significant morbidity and mortality. The pathogenesis of NAFLD, especially disease progression, is not well understood. Obesity and insulin resistance play a role as 'a first hit' leading to liver steatosis, but the mechanisms for a 'second hit' triggering progression to steatohepatitis are not known. Based on our Preliminary Data, we propose a novel hypothesis that chronic intermittent hypoxia (CIH) in patients with obstructive sleep apnea (OSA) constitutes a 'second hit' causing progression of NAFLD from steatosis to nonalcoholic steatohepatitis (NASH), a progressive fibrotic disease, in which cirrhosis and liver-related death occur in up to 20% and 12% patients, respectively.

Obstructive sleep apnea (OSA) is characterized by recurrent collapse of the upper airway during sleep, leading to CIH. OSA is a common disease, present in 2% of women and 4% of men in the general US population, but with an increased prevalence of 30-60% in obese populations. Furthermore, CIH has been associated with multiple metabolic complications of OSA independent of obesity, including insulin resistance, dyslipidemia, and atherosclerosis. Previous work in rodent models has demonstrated that intermittent hypoxia (IH) increases: (1) insulin resistance; (2) hepatic steatosis; (3) hepatic levels of SREBP-1 and SCD-1; and (4) hepatic oxidative stress and inflammation Thus, CIH in OSA may contribute to hepatic steatosis, and convert hepatic steatosis to steatohepatitis. To address this hypothesis, we will establish the impact of OSA on NASH in a susceptible cohort of obese human subjects in whom definitive intraoperative liver biopsy will be available to diagnose and stage NAFLD.

Recent evidence in patients with obstructive sleep apnea (OSA) indicates that OSA is associated with NASH. Nevertheless, the prevalence of OSA in patients with biopsy-confirmed NAFLD is unknown and the effect of OSA treatment with CPAP on NASH has never been studied. Our main hypothesis is that the severity of nocturnal intermittent hypoxemia of obstructive sleep apnea (OSA) will be associated with the severity of NAFLD. We will examine NAFLD severity in patients with and without obstructive sleep apnea and examine the effect of CPAP on NAFLD progression in patients with obstructive sleep apnea.

The overall goal is to determine whether OSA is associated with NAFLD and whether CPAP mitigates NAFLD progression. Our primary hypothesis is that the severity of nocturnal intermittent hypoxemia of obstructive sleep apnea (OSA) will be associated with the severity of NAFLD.

• In Specific Aim #1, we will examine NAFLD severity in patients with and without obstructive sleep apnea. We hypothesize that the severity of NAFLD and the presence of NASH will be associated with the presence and severity of OSA.
• In Specific Aim #2, we will examine the effect of CPAP on NAFLD progression in patients with obstructive sleep apnea. We hypothesize that CPAP will decrease markers of hepatic inflammation (serum aminotransferases) in patients with NAFLD, who have moderate or severe OSA. To address this hypothesis, we will enroll patients from the JHMI Hepatology clinic with the diagnosis of NAFLD, who have elevated serum aminotransferases, NAFLD on liver biopsy, and moderate to severe OSA. The effect of CPAP on markers of liver inflammation and serum aminotransferases will be determined, and related to CPAP adherence.