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 5 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 6 29 events/hour and the median oxygen desaturation during apneic events was 4.6 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.Keywords: hypoxemia; fatty liver disease; metabolic syndrome; sleepdisordered breathing; liver injury Obstructive sleep apnea (OSA) is a complex disorder consisting of upper airway obstruction, chronic intermittent hypoxia (CIH), and sleep fragmentation (1). Epidemiologic studies have demonstrated that OSA is associated with insulin resistance and glucose intolerance, independent of obesity (2-4). Clinical investigations have also shown that OSA results in low-grade systemic inflammation (5, 6). Both insulin resistance and systemic inflammation may contribute to the increased cardiovascular risk in patients with OSA (7-9). Insulin resistance, systemic inflammation, and OSA are particularly prevalent in patients with severe obesity defined as a body mass index (BMI) exceeding 40 kg/m 2 (2, 10-12). While obesity causes systemic inflammation, insulin resistance, and sleep apnea (12-15), sleep apnea may further exacerbate the inflammatory and metabolic disturbances (2, 3, 6). Nevertheless, it is not known whether concomitant OSA is implicated in metabolic dysregulation and systemic inflammation in severe obesity.One of the consequences of obesity and insulin resistance is nonalcoholic fatty liver disease (N...

Liver enzymes in obstructive sleep apnoea syndrome

“…[29] Although there is no single standard cutoff point for abnormal liver function tests levels, the most commonly used criterion is a value of ≥40 U/L for both ALT and AST. [30] Few authors like Polotsky et al [31] and Aron-Wisnewsky et al [32] similar to the present study reported normal range serum ALT and AST values in bariatric population with a BMI >45, regardless of the severity of OSA and NASH. It is worthy to note that liver biopsy of patients in both studies showed evidence of NASH with ballooning and liver fibrosis.…”

Sleep apnoea and metabolic dysfunction

“…Chronic intermittent hypoxia exposure would be the most important pathogenetic mechanism leading to NASH, as shown by studies in animal models [53]. To date, at least two studies have assessed liver morphology in humans in relation to OSA severity [33,54]; both analysed liver biopsies obtained in morbidly obese patients undergoing bariatric surgery and reported a strong association between severity of nocturnal intermittent hypoxia and liver abnormalities (steatosis and fibrosis).…”

Obstructive sleep apnea syndrome should be considered as a cause of nocturia in younger patients without other voiding symptoms

“…3,4 Many studies have demonstrated that OSAS should be diagnosed and treated at an early stage, 5,6 because OSAS can cause serious traffic accidents, 7 long-term hypoxic stress, 8 a pro-inflammatory state, 9 and endothelial dysfunction 10 in various organs. Although some patients with undiagnosed OSAS may visit an otolaryngology department to be treated for their snoring, other patients may visit a psychiatry department for a sense of malaise or a urology department for nocturia or erectile dysfunction.…”