December 2009 Issue

Nonalcoholic Fatty Liver Disease — Strategies for Prevention and Treatment of an Emerging Condition
By Christen C. Cooper, MS, RD
Today’s Dietitian
Vol. 11 No. 12 P. 28

The prevalence of nonalcoholic fatty liver disease (NAFLD), a condition once thought to affect mainly overweight postmenopausal women, is increasing among people of all ages. According to a review in the November/December issue of the Journal of Clinical Gastroenterology, NAFLD is believed to be one of the most common forms of liver disease worldwide, and its prevalence is growing in proportion to the rapid rise in obesity. Experts believe this condition may currently affect 20% to 40% of individuals in industrialized Western countries, representing a problem with a wide physical and financial impact.1

To recommend lifestyle changes that can help clients prevent or manage NAFLD, we must first understand the disease’s origins, stages, and types.

NAFLD: An Overview
When we think of liver disease, we usually think of severe problems such as cirrhosis or conditions requiring liver transplants. But there are less severe forms brought on by lifestyle factors that, when left unchecked, can progress to more severe levels. After all, the liver is a complex organ with key roles in the metabolism of fats, carbohydrates, and proteins. Fats may pose the most taxing work since the liver must metabolize, store, manufacture, and package fat into lipoproteins for delivery to body cells.

A healthy liver can readily handle a lifetime’s worth of dietary fat, but a failing liver cannot. The liver can be overtaxed by excess dietary fat. Triglycerides can build up in hepatocytes if the liver’s mitochondrial beta-oxidation and very–low-density lipoprotein production are insufficient to handle the fatty acid load.2 Over time, this fat accumulation can lead to scarring, inflammation, fibrosis, and cirrhosis—the progressive stages of NAFLD.

A technical review of NAFLD published in the November 2002 issue of Gastroenterology describes this condition’s principal histologic feature as excess fat within hepatocytes that displaces the nucleus to the edge of the cell. Additional features, such as inflammation and degeneration in specific liver regions, may be present in some, but not all, patients.3

NAFLD is currently classified into two types: hepatic steatosis and nonalcoholic steatohepatitis (NASH). Hepatic steatosis is a reversible condition in which large vacuoles of triglyceride fat accumulate in the liver cells, causing nonspecific inflammation. Most people with this condition experience few, if any, symptoms, and it does not usually lead to scarring or serious liver damage. The majority of patients with NAFLD have this type.

NASH is the more severe, progressive form that involves not only fat accumulation (steatosis) in the liver but also inflammation. Steatohepatitis can lead to fibrosis and eventually to cirrhosis, which is severe scarring that can lead to liver failure.

Theories From the Experts
Why is NAFLD’s prevalence rising? Many experts believe it’s because people are becoming fatter. Research has shown that the risk of NAFLD is directly associated with and proportional to the degree of obesity, particularly truncal obesity.1,4

Some experts have suggested that the rising prevalence of NAFLD may simply reveal better detection and not necessarily an increase in prevalence. Today, many individuals, especially those considering statin therapy for hypercholesterolemia, undergo bloodwork that tests liver enzyme levels. With these data, physicians can more readily detect and diagnose NAFLD.

Still other experts, including most of those whose data were reported in the current Journal of Clinical Gasteroenterology review, believe that the real culprit behind NAFLD is not excess body fat but insulin resistance. In individuals who are insulin resistant, serum glucose builds up, raising insulin levels. This hyperinsulinemia, in turn, raises serum triglycerides. Insulin may also play a role in fatty liver disease by inhibiting lipolysis of fat in body cells and blocking mitochondrial beta-oxidation in the liver, stimulating the synthesis of new fatty acids from glucose. In other words, hyperinsulinemia leaves the liver with an abundance of materials for making fats but nowhere to ship them once they are made. Thus, the liver begins to preferentially esterify the fatty acids into triglycerides, which then accumulate, leading to steatosis and eventually to fatty liver disease.2

Some experts combine obesity, insulin resistance, and related factors and call NAFLD a “multi-hit” condition. This theory makes NAFLD the “hepatic component” of metabolic syndrome, a condition characterized not only by obesity and insulin resistance but also by hyperinsulinemia, diabetes, and hypertension.1,5 Although researchers do not entirely understand it on a molecular level, metabolic syndrome has strong clinical associations with NAFLD. There is considerable research to suggest that NAFLD is associated with diabetes and progressive liver fibrosis and that NASH is associated with obesity and type 2 diabetes.1,2

According to this theory, the first “hit” is the collection of fat in hepatic parenchyma due to insulin resistance, which leads to hyperinsulinemia. The second hit is the liver’s response to this stress—the release of reactive oxygen species and cytokines. The oxidative stress, in turn, leads to peroxidation of membrane lipids and the production of additional proinflammatory cytokines. The condition can progress to fibrogenesis and then to hepatocyte damage. In about 20% of cases, the inflammation of NASH ends with cirrhosis or even hepatic carcinoma.3

Treatment and Prevention
Many scientists believe that the first step in preventing and treating NAFLD is achieving and maintaining a healthy weight. Individuals can most directly avoid insulin resistance and metabolic syndrome, conditions closely linked to NAFLD, by staying trim. Those at risk for NAFLD should lose weight through improvements in both diet and physical activity, since both types of lifestyle modification shows promise for combating the disease.

The National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases recommend that individuals who are overweight lose up to 10% of body weight through regular exercise and dieting. Research shows that a weight reduction of 10% or more is effective for ameliorating aminotransferase activities and decreasing liver size, as well as improving insulin sensitivity and cardiovascular risk profiles.6

Some hepatologists recommend that patients lose weight by trimming calories from saturated and total fat and by increasing fiber and polyunsaturated fatty acid intake. This dietary pattern can help patients feel full while consuming a diet that is designed to lower insulin resistance.3,6 There is also some evidence that reducing dietary cholesterol and controlling protein intake may help control NAFLD, according to an article in the July issue of Hepatology, but this research is preliminary.

Some experts believe that because obesity’s role in NAFLD is profound, the sooner body weight is reduced, the healthier the liver will become. Such experts recommend that individuals with a body mass index of greater than 35 consider gastric bypass surgery or another aggressive means of weight loss. This recommendation was once in question, however, since many of the first reports of NAFLD and deaths from fatty liver-induced morbidity and mortality came from jejunoileal bypass patients.3

Research suggests that newer bariatric surgery procedures do not harm the liver and that over time, postsurgical abnormalities in liver enzymes tend to normalize. However, rapid weight loss with or without surgery may lead to fatty liver since it spurs the liver to produce endogenous fatty acids to make up for the fat missing from the diet.3 This is a concern that merits further exploration within NAFLD research.

Another concern is that there are no clinical guidelines for monitoring liver function during weight loss in NAFLD patients, nor are there any solid data on how different rates of weight loss affect liver function. Liver enzyme and liver function monitoring should be made standard procedures to ensure the safety of studying dietary modifications for NAFLD. These procedures would be especially prudent for treating NAFLD in children, since healthy liver function and nutritional adequacy are indispensable for proper growth and development.

Lifestyle Research
The current body of research suggests that the best way to prevent and treat NAFLD is to combine a healthful diet with regular exercise to achieve a healthy weight. Exercise is important for achieving and maintaining weight loss, and it also reduces the risk of the conditions linked to NAFLD: type 2 diabetes, insulin resistance, hypertension, dyslipidemia, impaired fasting glucose, and metabolic syndrome.3 Exercise also increases the oxidative capacity of muscle cells and increases the use of fat as energy, thereby keeping excess fat from being stored in the liver.1

A recent Australian study involving 141 patients with NAFLD reported the impact of an exercise intervention on liver function. The patients were assigned to a low-intensity group that received three physical activity counseling sessions, a moderate-intensity group with six sessions, a high-intensity group with six sessions and ongoing telephone support, and a control group that received only an initial counseling session. The goal for participants in all groups was to increase physical activity to at least 30 minutes per day, five days per week (for a total of 150 minutes per week). All participants were fitness tested after three months.

Those who exercised at least 60 minutes per week had significant improvement in all liver enzymes, as well as in glucose, insulin resistance, cholesterol, and triglyceride levels. Yet, those who exercised for more than 60 minutes per week saw no significant additional improvements in enzyme profiles, suggesting that even modest exercise can help prevent NAFLD.

Just as notable, participants who received the largest amount of counseling increased physical activity the most and those who received the lowest amount of guidance exercised the least. This suggests that counseling and support that gets people moving, even to a small extent, is a good investment for those at risk of NAFLD. The study also found that fitness levels improved in those who exercised, regardless of weight loss, also suggesting that counseling should focus on increasing physical activity.7

Additionally, participation in the intervention groups made individuals more likely to adhere to recommended lifestyle changes. Individuals assigned to the moderate and intense counseling groups were nine times more likely to increase exercise by one hour per week than those assigned to the control group, and 96% of those participants remained involved until follow-up evaluation.7 This shows that lifestyle programs can be successful in helping people control NAFLD, even if the changes they enforce are difficult and abrupt.

Another recent study by Kittichai Promrat, MD, of Brown University published in the November 2008 issue of Hepatology demonstrated that combination lifestyle therapy can also help improve liver chemistry and histology in patients with fatty liver. Thirty-one overweight or obese patients with NASH were randomized to either 48 weeks of intensive lifestyle modification, a combination group, or a control group that received no intervention. The goal of both intervention arms was a 7% to 10% weight loss.

The intensive lifestyle modification group cut calories to 1,000 to 1,500 per day and fat to less than 25% of total calories. Participants in the combination group received the same calorie guidelines but had the additional goal of working up to 200 minutes of moderate-intensity physical activity per week. Practically all liver disease parameters improved in the intervention group participants, including weight (9.3% average loss), transaminase (eg, alanine aminotransferase) levels, degrees of hepatic steatosis, inflammation, and other markers of liver damage.

A German study that appeared in the September issue of Gut involved 50 patients diagnosed with NAFLD and 120 patients without NAFLD at risk for metabolic diseases. Both groups received weight-loss counseling and instructions to moderately increase aerobic activity. At the 8.7-month follow-up, both the treatment and control groups exhibited overall decreases in total, subcutaneous abdominal, and visceral fat, as well as improved fitness levels. NAFLD completely resolved in 20 patients. The strongest predictive factor for change in liver fat was baseline fitness level, which proved to have an effect greater than and independent from baseline total fat and baseline visceral fat levels.

Other Potential Therapies
Results from a number of small studies suggest that other therapies may be useful for treating either the first or second hit of NAFLD. Studies suggest that the first hit of NAFLD may be treated with cytoprotective agents such as ursodeoxycholic acid and taurine, as well as the lipid-lowering agent gemfibrozil. Antidiabetic drugs such as metformin, troglitazone, and pioglitazone have also conferred some first-hit benefits in small studies.2,8

In terms of attacking the second hit, vitamin E supplementation has offered encouraging results, particularly among children with NAFLD. Additionally, silymarin, which is a milk thistle extract, appears to be effective for treating NAFLD in some individuals, although there is no evidence of its safety or effectiveness. And antibiotics or probiotics, which alter the bowel flora, are other potential weapons against the second hit, since they help control cytokine load.9

Future Directions
The growing body of research on NAFLD seems to suggest that obesity, insulin resistance, or perhaps all of the components of metabolic syndrome may underlie the rising rates of NAFLD. We know that fatty liver disease can occur in patients who receive total parenteral nutrition. A valuable nutritional therapy, total parenteral nutrition can lead to hepatobiliary sequelae, which are usually nonprogressive. Numerous studies describe this problem as a substrate imbalance and a high percentage of calories from carbohydrates, leading to insulin release and fat accumulation in the liver.2 (This article focuses on NAFLD and NASH from lifestyle factors rather than on fatty liver caused by total parenteral nutrition.)

An important goal of future NAFLD research will be to explore the specific pathways by which obesity-related conditions such as diabetes, hypertriglyceridemia, and insulin resistance may injure the liver.3 Studies show that NAFLD is associated not only with insulin resistance but also with increased free fatty acids, increased fatty acid beta-oxidation, and increased hepatic lipid peroxidation.10 Some research indicates that there may be additional factors at work in promoting fatty liver disease. Leptin, for instance, may play a role not only in insulin resistance but also in the development of liver fibrogenesis.3

Researchers will also explore potential causes such as obstructive sleep apnea and its upregulation of hepatic cytochrome P450 E21. One small study by Kheirandish-Gozal et al published in Chest in 2008 examined the effects of obstructive sleep apnea on the liver in children. The results showed that serum transaminase levels in most patients normalized without much change in body weight after the obstructive sleep apnea was treated. More research on the connections between oxygenation of the hepatic tissues and NAFLD, as well as on treating conditions that often occur along with fatty liver disease, would help individuals avoid NAFLD with early treatments.4

Research on the ethnic breakdown of NAFLD is another area of exploration. Liver disease appears to be clustered in families. Some data show that Mexican Americans are more likely to have NAFLD and African Americans are less likely compared with non-Hispanic whites.3 Advances in nutrigenetics may provide windows into the insulin, glucose, fat, and hormonal interactions that may contribute to fatty liver disease.

Whatever its histopathology, NAFLD is taking on a new importance in hepatology as scientists search beyond alcohol abuse for answers about the causes, preventive options, and potential treatments for severe liver disease. With a generation of children who are at higher risk for obesity than previous generations, it is critical to discover and treat the roots of NAFLD. At present, dietitians can help clients attack NAFLD even before the first hit by encouraging them to eat a heart-healthy diet rich in antioxidants. We can also recommend exercise as part of a plan for not only preventing NAFLD but also for total body well-being.

— Christen C. Cooper, MS, RD, is a Pleasantville, N.Y.-based freelance health and nutrition writer. She has worked in healthcare consulting in Latin America and the United States and holds a master’s degree in nutrition education from Teachers College, Columbia University.

 

Current Recommendations for Nutrition and Exercise Therapy
• If the patient is overweight, lose 10% of baseline body weight.

• Reduce daily calories by enough to promote a 1- to 2-lb weekly weight loss but no more.

• Reduce saturated fats (less than 7% of total calories).

• Reduce total fat intake to 30% of total calories or less.

• Increase fiber intake.

• Exercise regularly to help with weight loss and increase insulin sensitivity.

• If body mass index is greater than 35, consider weight-loss surgery. If the patient undergoes surgery, closely monitor liver enzymes and function during rapid weight loss.

• In individuals with diabetes, bring hemoglobin A1C levels to less than 7%.

 

Recommended Steps for Diagnosing NAFLD1,3
• Screen for preexisting medical conditions such as hepatitis C.

• Estimations of alcohol consumption (clinical evaluation, family interviews, aspartate aminotransferase/alanine aminotransferase ratio, as a score of greater than 2 increases the possibility of alcoholic liver disease instead of NAFLD)

• Biomarkers of liver disease (serum aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase)

• Liver function tests (serum bilirubin, albumin, prothrombin time)

• Imaging (sonography, CT scan, MRI), though imaging does not distinguish between simple fatty liver and more serious cases

• Liver biopsy (This is performed if clinical circumstances are highly suggestive of NAFLD and if the cost and risks of the biopsy seem to be worth the information that could guide treatment decisions.)

 

References
1. American Gastroenterological Association. American Gastroenterological Association medical position statement: Nonalcoholic fatty liver disease. Gastroenterology. 2002;123(5):1702-1704.

2. Fong DG, Nehra V, Lindor KD, Buchman AL. Metabolic and nutritional considerations in nonalcoholic fatty liver. Hepatology. 2000;32(1):3-10.

3. Sanyal AJ, American Gastroenterological Association. AGA technical review on nonalcoholic fatty liver disease. Gastroenterology. 2002;123(5):1705-1725.

4. Younossi ZM, Dielh AM, Ong JP. Nonalcoholic fatty liver disease: An agenda for clinical research. Hepatology. 2002;35(4):746-752.

5. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology. 2003;37(4):917-923.

6. Executive summary of the clinical guidelines on the identification, evaluation and treatment of overweight and obesity in adults. Arch Intern Med. 1998;158(17):1855-1867.

7. St George A, Bauman A, Johnston A, et al. Independent effects of physical activity in patients with nonalcoholic fatty liver disease. Hepatology. 2009;50(1):68-76.

8. McAvoy NC, Ferguson JW, Campbell IW, Hayes PC. Nonalcoholic fatty liver disease: Natural history, pathogenesis, and treatment: Other potential therapies. British Journal of Diabetes & Vascular Disease. 2006;6(6):251-260.

9. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference. Hepatology. 2003;37(5):1202-1219.

10. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120(5):1183-1192.

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