Fatty liver disease—a condition in which a person has increased amounts of fat in the liver—often has few or no symptoms until its later stages. As a result, it can progress from simple fatty infiltration into the liver (steatosis), to fatty infiltration with inflammation, to inflammation with fibrous scarring of the liver (steatohepatitis) in its final stages. Liver failure can result if the fibrous scarring in the liver is widespread (cirrhosis). Not all people with fatty liver disease inevitably develop cirrhosis and liver failure. Often fatty liver disease can be reversed if the underlying cause or risk factor is eliminated. Alcohol abuse is the most common cause of fatty liver disease, but nonalcoholic factors can also result in a fatty liver. Fatty liver disease that is not due to alcohol abuse is called nonalcoholic fatty liver disease (NAFLD). Some risk factors for NAFLD are obesity, type 2 adult-onset diabetes, and a high fat diet. In recent years, several studies have indicated that obstructive sleep apnea (OSA) may also be a risk factor for NAFLD.
THE ROOTS OF NAFLD
Normally, 5% of the liver is fat. In people with NAFLD, fat may make up 10% to 40% of the liver. Liver function becomes increasingly impaired as the amount of fat increases. Inflammation and scarring in NAFLD can further impair liver function. Why increased amounts of fat accumulate in the liver is unknown.
Some research has focused on genetic and metabolic factors with interesting findings. For example, variations in certain genes may make a person more susceptible to developing NAFLD. In an animal study,1 mice genetically bred for a mutation in the gene that encodes mitochondrial trifunctional protein (MTP) ultimately develop steatosis and insulin resistance as they age. MTP plays a role in the breakdown of fatty acids in a hepatocyte (ie, liver cell). MTP produced by the mutated gene, however, impairs the breakdown of these molecules, thereby allowing them to remain in the cell and induce steatosis. In a human study, Valenti and associates2 compared the prevalence of two polymorphisms (238 and 308) of the tumor necrosis factor-alpha (TNF-alpha) gene in 99 NAFLD subjects. The gene encodes TNF-alpha, a protein that plays a role in tissue inflammation and insulin resistance. People with NAFLD tend to have increased levels of TNF-alpha. Valenti found that the prevalence of the 238 polymorphism was greater in subjects with NAFLD than in the controls (31% versus 15% in controls). Additionally, the researchers noted that nearly all of the subjects had insulin resistance but those who had the TNF-alpha polymorphisms had a higher insulin resistance index (IRI, the value of which is obtained by multiplying the fasting insulin level by the fasting glucose level and dividing the product by 22.5; the greater the index value, the greater the insulin resistance).
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Scientists3 believe that insulin resistance develops before steatosis occurs in the liver. Normally, insulin blocks the metabolism of fat molecules in adipose tissue. When adipose tissue becomes insulin resistant, fat cells can not fully respond to the effects of insulin and therefore the cells convert fat molecules into glycerol and fatty acids. This results in high levels of these molecules circulating in the blood.4 Excessive amounts of the molecules ultimately travel to the liver where they interfere with its ability to metabolize fat properly. This sets the stage for steatosis in the liver.
Hepatocytes normally synthesize fatty acids from glucose. Once synthesized, one or more fatty acid molecules may be joined with glycerol to form a fat molecule. A fat molecule may be a monoglyceride, a diglyceride, or a triglyceride. Triglycerides are transported out of the liver to fat and muscle tissue. Excessive amounts of fatty acids transported from the blood to a hepatocyte damage the cell, thereby interfering with its ability to synthesize fatty acids and metabolize fat. As a result, fat molecules and triglyceride levels remain high, which may then contribute to type 2 diabetes and obesity, in addition to damaging liver tissue.
MAKING THE CONNECTION
The prevalence of type 2 diabetes, obesity, and a high triglyceride level is greater in people with NAFLD and in people with OSA than in people without either of these disorders. Since these factors are common to both NAFLD and OSA, several researchers have recently investigated whether there could be an association between NAFLD and OSA. Epidemiological studies indicate that there may be. Canadian researchers Harminder Singh and associates5 found that about 50% of patients with NAFLD (which includes both steatosis and steatohepatitis) had symptoms of OSA. Similarly, Kallwitz and colleagues6 found that 51% of subjects with OSA had NAFLD. French scientists Florence Tanne and coworkers7 found that 20% of OSA subjects had elevated liver enzymes, which can indicate NAFLD-related liver injury. Several of Tanne’s OSA subjects voluntarily underwent a liver biopsy. Through this test, Tanne was able to gain a more accurate idea of the extent of liver injury in this group. Of the biopsied group, 67% had evidence of fatty infiltration with inflammation and 39% had evidence of inflammation with fibrotic scarring in the liver.
The association of NAFLD with OSA may be related to the pathophysiology of OSA. OSA involves repeated episodes of complete or partial upper airway closure during sleep, causing a cessation in breathing. The obstruction occurs because muscles supporting upper airway tissues relax too much during sleep, thereby allowing the tissues to collapse into and block the upper airway. The obstruction restricts airflow, and as a result, the blood oxygen level falls. Low blood oxygen levels ultimately trigger an arousal so that the person can take some fast, deep breaths in order to restore the oxygen level to normal. Once the oxygen level is restored, the person resumes sleep. However, on resuming sleep, OSA can recur. Repeated episodes of hypoxia or frequent arousals from sleep may set the stage for or worsen the progression of NAFLD.
MAKING MATTERS WORSE
Some scientists believe that the intermittent episodes of OSA-induced hypoxia during sleep8 may result in increased levels of TNF-alpha and other inflammatory substances,9 which then may damage the liver. When OSA occurs in a person who has NAFLD, the level of TNF-alpha (which may already be elevated due to NAFLD) may be further elevated, worsening the inflammation and scarring that are occurring with NAFLD.
High levels of cortisol have been noted in people with OSA and in people with NAFLD. Some research10,11 suggests that increased levels of cortisol may worsen the progression of NAFLD in people who also have OSA. Cortisol is a steroid that regulates carbohydrate, lipid, and protein metabolism. Chronically high levels of cortisol can contribute to obesity, impaired glucose control, insulin resistance, and type 2 diabetes. Some researchers believe that apnea-induced arousals from sleep can induce a transient surge in cortisol secretion, which in turn may explain the increased levels of cortisol noted in people with OSA.12,13 High levels of cortisol may then contribute to liver damage by excessively stimulating glucose release from the liver and increasing fatty acid mobilization in the liver.
Recent research suggests that treating OSA might reduce or slow the rate of liver injury in NAFLD. In a 2008 University of Louisville pediatric study with obese/overweight children, Kheirandish-Gozal and colleagues14 found that 32.4% of them had elevated liver enzymes (eg, aminotransferase), indicating that they had NAFLD. Of this group, 91.3% also had OSA. Treating sleep apnea reduced the liver enzyme levels in 76% of the children. In an adult study, Chin and associates15 measured the levels of the liver enzymes aspartate aminotransferase and alanine aminotransferase in men with OSA before and after starting CPAP treatment. Before treatment, the aspartate aminotransferase level was approximately 14% higher in the morning (after a sleep period) than before the sleep period. After beginning CPAP treatment, the morning level of aspartate aminotransferase dropped by approximately 66% from its presleep level and the morning level of alanine aminotransferase dropped by 60% from its presleep level. Chin and associates then followed up with the subjects after 1 month and after 6 months of CPAP treatment. They found that the reduction in liver enzyme levels remained. They concluded that CPAP treatment may be helpful in reducing elevated enzyme levels in people with both NAFLD and OSA. Despite such encouraging results, the researchers caution that more studies are needed to determine to what extent OSA treatment can delay or prevent the development of NAFLD in children and adults.
Most people who have NAFLD are unaware of it since symptoms such as fatigue, weight loss, and weakness usually do not appear until the disease is advanced or cirrhosis is present. Nonalcoholic steatohepatitis (NASH), the more serious form of NAFLD, is the third leading cause of cirrhosis in America (with hepatitis C being the second and alcohol abuse, the first).16 As the prevalence of obesity rises, liver transplants are increasingly being performed for people who have NASH. Eliminating or treating factors associated with NAFLD such as a high fat diet and obesity can reverse NAFLD in its early stages and possibly prevent its progression to NASH.
Physicians are often unaware of the increased prevalence of OSA in people with NAFLD. As a result, patients with NAFLD may have undiagnosed OSA, which may hasten the progression of inflammation and fibrosis. Physicians may need to consider testing their NAFLD patients for OSA. Treating OSA in patients with NAFLD could potentially spare them the more serious consequences of NASH.
Regina Patrick, RPSGT, is a contributing writer for Sleep Review. She can be reached at firstname.lastname@example.org.
- Ibdah JA, Perlegas P, Zhao Y, et al. Mice heterozygous for a defect in mitochondrial trifunctional protein develop hepatic steatosis and insulin resistance. Gastroenterology. 2005;128(5):1381–1390.
- Valenti L, Fracanzani AL, Dongiovanni P, et al. Tumor necrosis factor alpha promoter polymorphisms and insulin resistance in nonalcoholic fatty liver disease. Gastroenterology. 2002;122(2):274–280.
- Balistreri WF. Digestive Disease Week 2006: nonalcoholic fatty liver disease—insights and controversies. Medscape (Internal Medicine). www.medscape.com/viewarticle/536326. Accessed October 15, 2008.
- Fromenty B, Robin MA, Igoudjil A, Mansouri A, Pessayre D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab. 2004;30(2):121–138.
- Singh H, Pollock R, Uhanova J, Kryger M, Hawkins K, Minuk GY. Symptoms of obstructive sleep apnea in patients with nonalcoholic fatty liver disease. Dig Dis Sci. 2005;50(12):2338–2343.
- Kallwitz ER, Herdegen J, Madura J, Jakate S, Cotler SJ. Liver enzymes and histology in obese patients with obstructive sleep apnea. J Clin Gastroenterol. 2007;41(10):918–921.
- Tanne F, Gagnadoux F, Chazouilleres O, et al. Chronic liver injury during obstructive sleep apnea. Hepatology. 2005; 41(6):1290–1296.
- Tam CS, Wong M, Tam K, Aouad L, Waters KA. The effect of acute intermittent hypercapnic hypoxia treatment on IL-6, TNF-a, and CRP levels in piglets. Sleep. 2007;30(6):723–727.
- Vgontzas AN, Zoumakis E, Lin HM, Bixler EO, Trakada G, Chrousos GP. Marked decrease in sleepiness in patients with sleep apnea by Etanercept, a tumor necrosis factor-alpha antagonist. J Clin Endocrinol Metab. 2004;89(9):4409–4413.
- Bratel T, Wennlund A, Carlstrom K. Pituitary reactivity, androgens and catecholamines in obstructive sleep apnoea. Effects of continuous positive airway pressure (CPAP). Respir Med. 1999;93:1–7.
- Spath-Schwalbe E, Gofferje M, Kern W, Born J, Fehm HL. Sleep disruption alters nocturnal ACTH and cortisol secretory patterns. Biol Psychiatry. 1991;29(6):575–584.
- Dadoun F, Darmon P, Achard V, et al. Effect of sleep apnea syndrome on the circadian profile of cortisol in obese men. Am J Physiol Endocrinol Metab. 2007;293:E466–E474.
- Trakada G, Chrousos G, Pejovic S, Vgontzas A. Sleep apnea and its association with the stress system, inflammation, insulin resistance and visceral obesity. Sleep Med Clin. 2007;2(2):251–261.
- Kheirandish-Gozal L, Sans Capdevila O, Kheirandish I, Gozal D. Elevated serum aminotransferase levels in children at risk for obstructive sleep apnea. Chest. 2008;133(1):92–99.
- Chin K, Nakamura T, Takahashi K, et al. Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients. Am J Med. 2003;114(5):370–376.
- National Institute of Diabetes and Digestive and Kidney Diseases. National Digestive Diseases Information Clearinghouse (NDDIC). Nonalcoholic steatohepatitis. NIH Publication No. 07–4921. November 2006. digestive.niddk.nih.gov/ddiseases/pubs/nash/index.htm. Accessed October 15, 2008.