Obstructive Sleep Apnea and Non-Alcoholic Fatty Liver Disease (NAFLD)-Clinical Implications
Introduction: Obstructive sleep apnea (OSA) syndrome is a common sleep disorder and is characterized by episodes of complete or partial airway obstruction during sleep caused by repeated pharyngeal collapse. It is manifested by snoring, choking, frequent awakenings, disrupted sleep and excessive daytime sleepiness.(1) OSA has implications beyond disrupted sleep. There is intermittent hypoxia and sympathetic stimulation. This disorder is being increasingly recognized as an independent risk factor for cardiac, neurologic and metabolic disorders and peri-operative morbidities. There is poor awareness of this disorder both among medical professionals and in society at large. (2)
Non-alcoholic fatty liver disease (NAFLD) is closely associated with obesity,type 2 diabetes mellitus, hypertension and hyperlipidemia. NAFLD by this association places the subject at higher risk for these co-morbidities and also for progressive liver disease.
Recently intense interest has been generated on this association since management of the core issue may give better treatment options.
Prevalence of OSA
Studies have shown that 4% of men and 2% of women more than 50 years of age suffer from symptomatic OSA.(3) Studies in the early nineties have shown the prevalence of sleep disordered breathing, defined as apnea hypopnea score of 5 or higher, was 9 % for women and 24% for men.4 They also stated that 2% of women and 4% of men in middle aged work force met with a minimal diagnostic criterion for sleep apnea syndrome (an apnea hypopnea score of (5) or higher and daytime hypersomnolence). Recent reports suggest the prevalence of moderate to severe OSA (> 15 events/hour) at 23.4% in women and 49.7% in men aged 40 years or older. (5) The prevalence of OSA increases with aging. (6,7) The prevalence of obesity is increasing and so is the prevalence of OSA since obesity is a risk factor for OSA. However, OSA can occur in lean individuals due to craniofacial features.(8)
Prevalence of NAFLD
There is a high prevalence of both NAFLD and Non-alcoholic Steatohepatitis (NASH). The global prevalence of NAFLD is estimated to be 25.2%. Highest prevalence is observed in the Middle East and South America (31.8 % and 30.4% respectively). The prevalence rates in North America, Europe and Asia are 24.1%, 23.7%, and 27.4% respectively.(9) It can be said that these high prevalence rates are being driven by the global epidemic of diabetes and obesity.
NAFLD is a common cause for incidental abnormal liver tests. Ultrasonography abdomen done for other reasons often shows the presence of fatty liver of various grades. NAFLD has a multifactorial pathologic basis. Many mechanisms can cause fatty infiltration, inflammation, oxidative stress and progressive fibrosis. Simple steatosis generally represents a benign condition. It has a non-progressive clinical course. The group of patients who suffer NASH have more severe fibrosis and are at a higher risk for progressing to liver disease complications such as liver cancer and decompensated liver cirrhosis. The association of NAFLD with metabolic and cardiovascular disorders makes them more vulnerable to consequences of these disorders.
The link between OSA and NAFLD:
Umbro Iliaro et al(10) recently in a review highlighted several observations and evidence which go to show the close association of OSA with NAFLD
1.Insulin resistance occupies a central stage in the pathogenesis of metabolic syndrome. It also plays an important role in the first stage of fatty infiltration.(11) OSA is an independent risk factor for metabolic syndrome.(12)
2. Chronic oxidative stress is a major player triggering the progression of simple steatosis to NASH. This is a result of imbalance of between pro-oxidant and anti-oxidant chemicals that lead to liver cell damage. (13,14)
It is well known that intermittent hypoxia in OSA results in oxidative stress and inflammation which is responsible for many of its consequences. In OSA, due to hypoxic environment, there is an increased adipose tissue lipolysis, oxidative stress, inflammation and liver fibrosis. (15) The chronic intermittent hypoxia may be linked with the pathogenesis and severity of NAFLD.(16)
3. The association seems to be independent of co-existing co-morbidities such as visceral fat or metabolic syndrome. Yue et al (17) demonstrated the association independent from visceral fat level in subjects with mean BMI of 24.7/m2 particularly in those with short sleep duration or excessive daytime sleepiness.
4. Severity of NAFLD is associated with an increase in OSA severity.(10)
5. Continuous Positive Airway Pressure is the most accepted mode of therapy treating OSA. Chen et al (17) reported a statistically significant increase in liver steatosis and serum aminotransferase with increasing severity with increasing OSA severity and a significant decrease in both ALT and AST levels just after 3 months of CPAP treatment. Several other workers have also observed this response. CPAP usage also improves insulin sensitivity which therefore can correct the core issue of insulin resistance.
Conclusion
In conclusion, a strong association exists between OSA and NAFLD. Recognizing OSA in clinical practice is therefore important. A polysomnography is required to diagnose OSA. Usage of CPAP/BIPAP as required, while sleeping, is highly rewarding as it corrects the basic problem. These findings and observations have implications in management of patients of NAFLD.
References:
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14. Del Ben M, Polimeni L, Carnevale R, Bartimoccia S, Nocella C, Baratta F, Loffredo L, Pignatelli P, Violi F, Angelico F. NOX2-generated oxidative stress is associated with severity of ultrasound liver steatosis in patients with non- alcoholic fatty liver disease. BMC Gastroenterol 2014; 14: 81.
15.Parathath S, Mick SL, Feig JE, Joaquin V, Grauer L, Habiel DM, Gassmann M, Gardner LB, Fisher EA. Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism. Circ Res 2011; 109:1141-1152.
16. Savransky V, Nanayakkara A, Vivero A, Li J, Bevans S, Smith PL, Torbenson MS, Polotsky VY. Chronic intermittent hypoxia predisposes to liver injury. Hepatology 2007; 45: 1007-1013.
17.Yu JH, Ahn JH, Yoo HJ, Seo JA, Kim SG, Choi KM, Baik SH, Choi DS, Shin C, Kim NH. Obstructive sleep apnea with excessive daytime sleepiness is associated with non-alcoholic fatty liver disease regardless of visceral fat. Korean J Intern Med 2015; 30: 846-855
18.Chen LD, Zhang LJ, Lin XJ, Qi JC, Li H, Wu Z, Xu QZ, Huang YP, Lin L. Association between continuous positive airway pressure and serum aminotransferases in patients with obstructive sleep apnea.Eur Arch Otorhinolaryngol 2018; 275: 587-594
Dr. S. Ramnathan Iyer, MD (Medicine), FRCP (Glasgow),FICP,FGSI,FISDA,FISH, Consultant Physician- Sleep Medicine, Geriatric Medicine, Diabetes, Ambika Clinics - Dombivli ( East) Dist Thane and Kharghar (Navi Mumbai), Visiting Consultant Sleep Medicine- Godrej Memorial Hospital, Vikhroli (East) Mumbai.
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