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NAFLD, Sleep Apnea and Hypopnea Syndrome

These are obesity-related conditions

As obesity rates are rising, NPs and PAs are seeing numerous patients with obesity-related conditions. Two such conditions, non-alcoholic fatty liver disease (NAFLD) and obstructive sleep apnea and hypopnea syndrome (OSAHS), historically have been considered distinct conditions that happen to share similar clinical features and risk factors. But recent studies have identified a cause-and-effect association between OSAHS and NAFLD that has implications for screening, diagnosis, education and treatment.

Nonalcoholic Fatty Liver Disease   

In the absence of excessive alcohol intake, uncomplicated hepatic steatosis, or fat deposition within the liver parenchyma, can evolve into nonalcoholic steatohepatitis (NASH).1 NASH can progress to fibrosis and, eventually, cirrhosis of the liver; these conditions fall within the continuum of NAFLD.1 Liver cirrhosis, regardless of its etiology, has the potential to further progress to liver failure (requiring transplant) or to hepatocellular carcinoma.1

Since its initial identification in the early 1950s, NAFLD has become the most common chronic liver disease. It now affects 30% of the general population and 60% to 70% of patients who have diabetes or are obese. The increasing rates are in direct proportion to the obesity epidemic.2

Patients with NAFLD may present with complaints of daytime sleepiness, fatigue or indistinct right upper quadrant discomfort.1,3 Some may complain of impaired memory or concentration, and/or postural dizziness, falls or syncope.4 Many patients with NAFLD, however, are asymptomatic and their condition is only uncovered by incidental mild liver enzyme elevations.1

NAFLD is a diagnosis of exclusion. Evaluation of the patient with liver dysfunction begins with an accurate, thorough history and serum analysis to rule out other liver diseases (hepatitis B and C, iron studies, ceruloplasmin, alpha 1 antitrypsin and autoimmune markers). At this juncture, alcoholic steatohepatitis may be ruled out only when less than 20 g/day of alcohol is consumed.1 Histologically, NAFLD and alcoholic disease appear much alike; imaging studies may merely reveal fat deposition in the liver. Therefore, definitive diagnosis is achieved by liver biopsy in exclusive combination with the absence of alcohol use.1

Sleep Apnea

Unexplained excessive daytime sleepiness, along with a minimum of five obstructive breathing events (apnea or hypopnea) per hour, is typically present in obstructive sleep apnea and hypopnea syndrome.5 Between 3% and 6% of the middle aged population has OSAHS and, like NAFLD, it is becoming more prevalent with the obesity epidemic.5 Additional symptoms identified in OSAHS include impaired vigilance, cognition and driving; depression; disturbed, unrefreshing sleep and nocturnal choking; loud snoring; and hypertension.5 The gold standard diagnostic test for OSAHS is polysomnography.6


NAFLD and OSAHS may be considered related based on their similar symptoms of daytime sleepiness and cognitive impairment along with the prominent risk factor of obesity. These conditions additionally share common clinical predictors: central obesity; hyperlipidemia; metabolic syndrome, insulin resistance and type 2 diabetes.5,7 A more distinct connection between NAFLD and hypoxia associated with OSAHS is emerging.

Compared to other organs, the liver is markedly more susceptible to damage from hypoxia, possibly owing to the liver's narrow difference in arterial and venous partial pressures of oxygen within the organ's circulatory system.8 Animal studies have demonstrated the damaging effects of hypoxia on liver gene expression. In response to 32 days of progressive hypoxia in mice, Baze and colleagues observed altered expression of hepatic genes commonly associated with lipid and carbohydrate metabolism, angiogenesis, immune response and protein amino acid phosphorylation.9 Many of the 580 genes that demonstrated altered expression are known to commonly respond to acute injury, indicating the significance of short-term hypoxic events.9 Similarly, in order to isolate the effects of hypoxia on the liver, Piguet and colleagues examined mice that lacked a tumor suppressant gene. The researchers compared the effects of exposing the study group to hypoxia (10% oxygen) and the control group to room air (21% oxygen) for 7 days.10 The hypoxic mice showed worsening steatosis and necroinflammation in the liver, along with increased serum glucose and triglycerides and decreased insulin sensitivity.10 This suggests that hypoxia alone accentuates the progression of NASH via upregulation of the expression of lipogenic genes, downregulation of the expression of genes associated with lipid metabolism, and decreased insulin sensitivity.10

Other researchers have found compelling relationships between hypoxia and liver dysfunction. Reinke et al exposed study groups of lean and obese mice to intermittent and sustained hypoxia and found the following: large delta oxygen level swings in the liver but not in the muscle or adipose tissue following hypoxia; lower oxygen levels at baseline among obese subjects; all forms of hypoxia led to insulin resistance in lean and obese subjects; and obesity led to severe systemic inflammation that overtook and concealed the metabolic effects of hypoxia, aside from insulin resistance.11 In another lean animal study, chronic intermittent hypoxia led to mild liver injury secondary to oxidative stress and excessive glycogen accumulation, but not to severe injury as with steatohepatitis and fibrosis.12

Human studies have yielded similar results. Kallwitz et al followed 85 patients who had a sleep study followed by liver biopsy at the time of obesity surgery. They found that 84 had histologic evidence of NAFLF and 51% had OSAHS.13 A greater number of patients with OSAHS also had elevated alanine transferase levels (13/39) versus those without OSAHS (3/34) (P = 0.01).13 Shpirer et al demonstrated that radiologic changes (per computed tomography) indicative of moderate to severe steatosis were associated with more severe sleep apnea, as measured by apnea-hypopnea index and nocturnal hypoxemia.14 This investigation also revealed that 3 years of adherence to continuous positive airway pressure (CPAP) therapy partially reversed these changes in most patients and normalized them in some.14

In nonobese patients with OSAHS, Tatsumi and Saibara demonstrated a risk of progressive liver disease in the presence of liver fat accumulation.15 Likewise, Turkay et al found a 71% prevalence of OSAHS in patients with NAFLD vs. 36% prevalence in those without.16 After adjusting for body mass index, weight and insulin resistance, the investigators found that apnea/hypopnea and oxygen desaturation were independent predictors of NAFLD.16

And most recently, Aron-Wisnewsky et al observed a dose-response relationship between the time and severity of nocturnal hypoxia and the severity of hepatic lesions found on biopsy.17 After adjusting for other risk factors, insulin resistance, steatosis, ballooning of hepatocytes, lobular inflammation and fibrosis were distinctly positively correlated with more severe oxygen desaturation upon multivariate analysis.17 Both the human and animal studies present evidence of a causal link between OSAHS and NAFLD that warrants research attention.


It is important to recognize the overlap of OSAHS and NAFLD because these conditions are becoming increasingly prevalent. Clinical findings of either condition should prompt investigation for the other. The patient known to have OSAHS should be monitored for declining liver function over time, and precaution should be taken when considering any therapy known to have liver side effects. Previously, given the knowledge available, the mainstay of treatment for NAFLD has been weight loss and exercise, which is difficult to achieve and maintain.1 Recent research indicates a positive association between liver injury and OSAHS, as well as possible attenuation of liver damage following CPAP. The patient diagnosed with OSAHS should be educated about the consequences of untreated OSAHS and assisted to obtain and become adherent with CPAP therapy. CPAP therapy helps the patient achieve restful sleep to decrease daytime sleepiness, improves insulin sensitivity and may potentially reduce liver steatosis. Furthermore, the patient who is rested and energized is more likely to achieve success with weight loss and exercise goals, further enhancing the positive effects on the liver.

Pamela Martin is an adult nurse practitioner at Lutheran Senior Services in Columbia, Mo. She has completed a disclosure statement and reports no relationships related to this article.


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DL, et al, eds. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill; 2012: 2603-2606.

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10. Piguet AC, et al. Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN. Clin Sci. 2009;118(6):401-410.

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12. Savransky V, et al. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol. 2007;293(4):G871-G877.

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16. Turkay C, et al. Influence of obstructive sleep apnea on fatty liver disease: role of chronic intermittent hypoxia. Respir Care. 2012; 57(2): 244-249.

17. Aron-Wisnewsky J, et al. Chronic intermittent hypoxia is a major trigger for non-alcoholic fatty liver disease in morbid obese. J Hepatology. 2012;56(1): 225-233.



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