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

• 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.

This research is being done to examine: 1) how common obstructive sleep apnea (OSA) is in patients with non-alcoholic fatty liver disease (NAFLD), 2) whether the severity of OSA is related to the severity of NAFLD, and 3) whether treatment of OSA with continuous positive airway pressure (CPAP) improved NAFLD progression.

OSA is a condition caused by repetitive collapse of throat tissue during sleep that leads to falls in oxygen level and sleep disruption. OSA can be caused by obesity, and especially by fat found in the neck and belly.

NAFLD is a common disease linked to obesity. NAFLD is part of a disease spectrum, which can progress from steatosis (fatty liver) to nonalcoholic steatohepatitis (NASH), a progressive fibrotic disease, in which cirrhosis and liver-related death can occur. Recent evidence in patients with obstructive sleep apnea (OSA) indicates that OSA is associated with NASH. How common OSA is in patients with biopsy-confirmed NAFLD and the effect of OSA treatment with CPAP on NASH is unknown.

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.

• Non Alcoholic Fatty Liver Disease
• Obstructive Sleep Apnea

Inclusion Criteria:

1. Age ≥ 21
2. Recent (≤ 12 months) liver biopsy

3. Elevated levels of alanine aminotransferase (ALT) > 40, aspartate aminotransferase (AST) > 37, and alkaline phosphatase (ALKP) > 120

   • No other cause of liver disease other than NAFLD (as assessed by patient and physician surveys detailed below)

Exclusion Criteria:

Both patients and doctors will be asked to identify potential exclusionary conditions including:

1. Patients with sickle cell anemia, hemoglobinopathies and other hemolytic anemias
2. Known clinical hypersensitivity or a history of asthma or allergic respiratory disorders
3. Advanced renal failure (currently requiring dialysis or with a Glomerular Filtration rate < 30cc/min)
4. Pregnancy
5. History of CPAP treatment for OSA
6. Recent weight loss ≥ 10%
7. Current alcohol use > 20 g/day in women and > 30 g/day in men, or prior use for ≥ 3 consecutive months during the previous 5 years as assessed with the Lifetime Drinking History Questionnaire Viral hepatitis A, B and C
8. Autoimmune hepatitis
9. Hemochromatosis
10. Wilson's disease
11. Alpha-1-antitrypsin deficiency
12. Primary sclerosing cholangitis
13. Cirrhosis of any etiology
14. History of HIV infection and/or HAART therapy
15. Evidence of drug-induced liver injury
16. Use of vitamin E and pioglitazone or another glitazone or metformin
17. Use of systemic steroids for > 10 days during prior 6 months
18. Unstable cardiovascular disease (decompensated CHF, myocardial infarction or revascularization procedures, unstable arrhythmias)
19. Uncontrolled hypertension with BP > 160/100
20. Daytime hypoxemia with SaO2<90%
21. Supplemental oxygen use
22. Presence of any contraindication to MR examinations (see MRI Safety Screening Sheet)
23. History of Metal in the Skull/Eyes
24. Unable to have an MRI Scan
25. Allergy or hypersensitivity reactions to gadolinium or any other ingredients, including benzyl alcohol
26. Severe daytime hypersomnolence as defined by an Epworth Sleepiness Score of greater than 16.
27. Severe sleep apnea as characterized by an apnea-hypopnea index of greater than 80 episodes/hour or an average low SaO2 during sleep disordered breathing episodes below 80%.

Exclusions based on etiology of hepatitis will be assessed by querying both the hepatology list and patient about the above mentioned disorders (#7-15).