Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity

Abstract

Rationale: Obstructive sleep apnea is associated with insulin resistance and liver injury. It is unknown whether apnea contributes to insulin resistance and steatohepatitis in severe obesity.

Objectives: To examine whether sleep apnea and nocturnal hypoxemia predict the severity of insulin resistance, systemic inflammation, and steatohepatitis in severely obese individuals presenting for bariatric surgery.

Methods: We performed sleep studies and measured fasting blood glucose, serum insulin, C-reactive protein, and liver enzymes in 90 consecutive severely obese individuals, 75 women and 15 men, without concomitant diabetes mellitus or preexistent diagnosis of sleep apnea or liver disease. Liver biopsies (n = 20) were obtained during bariatric surgery.

Measurements and main results: Obstructive sleep apnea with a respiratory disturbance index greater than 5 events/hour was diagnosed in 81.1% of patients. The median respiratory disturbance index was 15 +/- 29 events/hour and the median oxygen desaturation during apneic events was 4.6 +/- 1.8%. All patients exhibited high serum levels of C-reactive protein, regardless of the severity of apnea, whereas liver enzymes were normal. Oxygen desaturation greater than 4.6% was associated with a 1.5-fold increase in insulin resistance, according to the homeostasis model assessment index. Histopathology data suggested that significant nocturnal desaturation might predispose to hepatic inflammation, hepatocyte ballooning, and liver fibrosis. Fasting blood glucose levels and steatosis scores were not affected by nocturnal hypoxia. There was no relationship between the respiratory disturbance index and insulin resistance or liver histopathology.

Conclusions: Hypoxic stress of sleep apnea may be implicated in the development of insulin resistance and steatohepatitis in severe obesity.

Figure 1.

Fasting serum glucose, serum insulin, and the homeostasis model assessment (HOMA) index in severely obese individuals with obstructive sleep apnea (OSA). The HOMA index was calculated as fasting serum insulin (μU/ml) × fasting blood glucose (mmol/L)/22.5 (33). (A) Comparison of patients with the respiratory disturbance index (RDI) less than 15 per hour and greater than 15 per hour (n = 45 per group). (B) Comparison of patients with average fall in oxyhemoglobin saturation during apneic events (ΔSa_O2) less than 4.6% and at least 4.6% (n = 45 per group).

Figure 2.

(A) Representative image of liver without inflammation in an individual without OSA Macrovesicular hepatic steatosis is evident, but inflammation is absent (hematoxylin–eosin; original magnification, ×100). (B) Representative image of liver in an individual with OSA and severe nocturnal oxyhemoglobin desaturation. Macrovesicular hepatic steatosis is evident, and lobular inflammation is present (arrows) (hematoxylin–eosin; original magnification, ×100). (C) Representative image of liver without pericellular fibrosis in an individual without OSA (Masson trichrome; original magnification, ×100). (D) Representative image of liver in an individual with OSA and severe nocturnal oxyhemoglobin desaturation. Prominent pericellular perisinusoidal fibrosis is present. Collagen depositions are stained blue and have a chicken-wire appearance (Masson trichrome; original magnification, ×100).

Figure 3.

Relationships between hepatic histopathology and the severity of OSA as measured by respiratory disturbance index (RDI < 15 events/h or > 15 events/h) and average fall in oxyhemoglobin saturation during apneic events (ΔSa_O2 < 4.6% and ≥ 4.6%). (A) Hepatic lobular inflammation score; (B) hepatocyte ballooning score; (C) nonalcoholic fatty liver disease (NAFLD) activity score defined as the sum of steatosis, lobular inflammation, and ballooning scores (32); (D) hepatic fibrosis score; and (E) body mass index (BMI). *P < 0.05 between the group of patients with RDI less than 15 events/hour, ΔSa_O2 less than 4.6% and the group of patients with RDI greater than 15 events/hour, ΔSa_O2 at least 4.6% or more.