Nonalcoholic Fatty Liver Disease
Nonalcoholic fatty liver disease (NAFLD) includes a spectrum of conditions characterized by hepatic fat accumulation in the absence of primary causes, including alcohol abuse. Nonalcoholic steatohepatitis (NASH), in which fat accumulation is accompanied by inflammation, is the most common type of NAFLD and the most common form of liver disease in the US. Clinically, NASH may be indistinguishable from alcoholic hepatitis, but it is most often a subclinical disease.
Genetic predisposition, metabolic syndrome features, and environmental factors are the three main components that drive progressive accumulation of triglycerides in hepatic tissue. Alterations in the delivery of fatty acids to the liver, decreased export of fatty acids from the liver, or impaired oxidation of fatty acids within the liver lead to the observed histologic changes. Insulin resistance is thought to play a key role in disease development by causing alterations in lipid metabolism, leading to increased uptake of fatty acids by the liver and increased oxidation of lipids within it.
Most patients remain asymptomatic, although nonspecific symptoms such as fatigue, malaise, and tenderness of the upper-right abdomen may occur. In more serious cases, the pathologic features resemble those of alcoholic liver disease and may include fibrosis, inflammation, necrosis, and cirrhosis. Hepatocellular carcinoma can develop from cirrhosis caused singularly by NASH, as well as in a fatty liver in the absence of cirrhosis.
Fatty liver disease is particularly prevalent among Latin Americans but is also rapidly increasing in Asian individuals. Other risk factors include:
Age. Most patients are diagnosed in their 40s or 50s, and advancing age increases overall disease risk and risk of complications. However, there has been an increasing prevalence of fatty liver disease in children and young adults.
Obesity, especially abdominal obesity.
States of insulin resistance (typically related to obesity, diabetes mellitus, and metabolic syndrome).
Hyperlipidemia, especially hypertriglyceridemia.
Diet and microbiota. A Western dietary pattern, high in fat and processed fructose, is associated with the metabolic dysfunction seen in NAFLD, specifically lipid dysregulation and insulin resistance. The gut microbiota is increasingly being recognized as contributing to the development of fatty liver via modulation of bile acids and other metabolites that help regulate glucose, lipids and overall energy balance. See Nutritional Considerations below.
Other conditions that may be associated with NAFLD include polycystic ovary syndrome, hypothyroidism, and obstructive sleep apnea. A history of cholecystectomy, independent of risk factors for gallstones, increases risk of NAFLD.
Primary conditions that can lead to hepatic steatosis, and therefore are not necessarily considered NAFLD, include hepatitis C infection, severe or rapid weight loss, total parenteral nutrition, and drugs (e.g., glucocorticoids, synthetic estrogens, and certain pesticides). Acute fatty liver of pregnancy is a life-threatening condition that requires immediate medical attention.
The diagnosis of NAFLD requires all of the following: documentation of hepatic steatosis on imaging or by biopsy, exclusion of overconsumption of alcohol, and exclusion of other causes of hepatic steatosis. Alcoholic liver disease should be ruled out by history, physical examination, and laboratory testing, as necessary.
Laboratory studies that may be helpful in the evaluation include complete blood count, blood chemistry, liver function tests, and coagulation studies.
NASH differs from alcoholic hepatitis in that the alanine aminotransferase is generally greater than the aspartate aminotransferase. The bilirubin level is generally not elevated, but alkaline phosphatase may be up to 2-3 times the upper limit of normal. However, liver function testing is not sufficient to make the diagnosis as these enzymes may be normal even with significant histologic pathology.
It is important to rule out other causes of hepatic steatosis and hepatic inflammation including infection with hepatitis A, B, or C; autoimmune hepatitis; and hemochromatosis.
Ultrasound, CT scan, and MRI may be diagnostic. These tests can identify fatty liver and evaluate for other disorders, including biliary tract disease.
Liver biopsy may be useful if the cause of fatty liver is unclear. Biopsy will also reveal the grade and stage of disease to guide management and estimate prognosis.
Weight loss is essential for overweight patients with NAFLD. Even modest weight loss (~ 5% of body weight) may have significant beneficial effects by alleviating diabetes and hypertension. Diet changes are particularly important. Use of pharmacologic weight loss agents may be beneficial. Severely obese patients (body mass index > 35 kg/m2) may consider surgical options, such as gastric bypass.
Exercise may be beneficial, with or without associated weight loss.
Diabetes mellitus in NAFLD patients should be treated as appropriate. Insulin-sensitizing drugs, thiazolidinediones in particular, reduce steatosis. However, this class of medications has significant side effects and is not indicated in the routine treatment of NAFLD. While it does help modulate blood sugar, metformin has not been found to improve NASH. A newer class of diabetes and weight loss drugs, GLP-1 agonists (semaglutide, liraglutide), have promising data for decreasing fibrosis progression and/or leading to histologic resolution of NASH. Treatment of hyperlipidemia with statins is safe in NASH and may decrease the progression of disease.
Vitamin E is an antioxidant and has been found to improve histologic score and liver transaminase levels in patients with NASH. In a joint statement issued in 2012, the American Association for the Study of Liver Diseases, the American Gastroenterological Association, and the American College of Gastroenterology suggest vitamin E (800 mg daily) as first-line pharmacotherapy for nondiabetic patients with biopsy-proven NASH.
Rarely, patients with advanced disease may require liver transplantation.
All patients without documented immunity should receive hepatitis A and hepatitis B vaccinations, along with the pneumococcal vaccine, which is indicated for all individuals with chronic liver disease.
NAFLD is in most cases the result of obesity, particularly the abdominal variety known to be involved in the promotion of insulin resistance. Although this can occur with excessive weight gain from any cause (except for lean body mass), NAFLD is more easily promoted with diets high in saturated fat and refined carbohydrates (e.g., high fructose corn syrup). Healthful dietary patterns and the intake of unsaturated fats are protective against NAFLD, while a Western diet increases the risk for this disease due to its high content of bioavailable iron and saturated fat content. Certain dietary supplements (omega-3 fatty acids, probiotics, vitamin E, and milk thistle) may be helpful as well.
Weight loss. Between 20-60% of adults with a body mass index (BMI) ≥ 30 kg/m2 have NAFLD, and this number is even larger for children with a BMI ≥ 30 kg/m2. According to a number of investigations, consumption of excess fructose (as found in beverages sweetened with high fructose corn syrup) is a suspected contributor to NAFLD and is associated with a greater degree of fibrosis in patients with extant NAFLD. Through its metabolism to uric acid, fructose ultimately depletes hepatocyte adenosine triphosphate, causing enhanced hepatic lipogenesis, mitochondrial generation of oxygen radicals, endothelial dysfunction, and pro-inflammatory cytokine secretion. High amounts of high fructose corn syrup are also known to promote de novo lipogenesis, and this, as with all methods of carbohydrate overconsumption, is the pathway most increased in patients with NAFLD. Nevertheless, the current consensus states that excess weight gain per se is responsible for causing NAFLD, rather than an excess of specific macronutrients.
Weight loss of at least 7% is sufficient to reduce hepatic inflammation and steatosis; however, a loss of 10% or more provides the greatest degree of improvement. Improvement in NAFLD has been shown with weight loss regardless of the type of diet used, though a combination of diet and exercise may be more effective because the latter reduces intrahepatic fat regardless of weight loss. Previous concerns that rapid weight loss (exceeding ~ 1 lb per week in children and ~ 3.5 lb per week in adults) could worsen NAFLD symptoms appear to be unfounded for the overwhelming majority of patients. Although the American College of Gastroenterology, the American Gastroenterological Association, and the American Association for the Study of Liver Diseases do not yet consider weight loss surgery an established option for NASH treatment, reviews have concluded that nearly all bariatric surgery patients have consistent improvement of steatosis, inflammation, and fibrosis and have no disease progression.
Studies of isocaloric diets have favored low-fat, high-carbohydrate regimens over low-carbohydrate, high-fat diets, showing a decrease in liver fat in the former and an increase in the latter. While studies of hypocaloric diets initially found a benefit of very low-carbohydrate (i.e., ketogenic) regimens over standard low-calorie diets in terms of reduced steatosis, these benefits were not maintained roughly 3 months later.
Replace saturated fats with polyunsaturated and monounsaturated types.Various types of diets have been compared regarding both the causes and treatment for NAFLD. Saturated fat has a significantly greater ability to promote NAFLD when compared with unsaturated fats, while both polyunsaturated and monounsaturated fats reduce liver fat content. Differences between how these fats affect the liver are thought to derive in part from the fact that the unsaturated fats more easily undergo beta-oxidation while suppressing lipogenic genes.
A healthy dietary pattern. Although research in this area needs further clarification, existing data have shown two trends. The first is the ability of a Western dietary pattern, high in saturated fat and refined carbohydrates, to significantly increase the risk for NAFLD (by roughly 60%). The second is the association of healthy diets (high in whole grains, fruits, vegetables, and legumes) with a significantly lower risk for this disease.
Although clinical trials have not yet evaluated the effect of low-fat, high-fiber vegetarian diets on NAFLD, these diets nevertheless can help achieve the aims required to prevent or improve this disease. Plant-based diets typically cause weight loss, can lower the concentrations of blood fats (e.g., triglycerides) that contribute to NAFLD, and are also associated with reduced insulin resistance and greater antioxidant protection, compared with omnivorous diets. Plant-based diets have somewhat less iron bioavailability, and vegetarians have lower body-iron stores. This is significant in that excess iron storage has been found in roughly one-third of NAFLD patients, and evidence suggests that this worsens the clinical course in these individuals.
Alcohol avoidance. Although alcohol intake in individuals with a BMI ≥ 30 clearly increases the risk for NAFLD, the evidence is lacking in persons with a BMI < 30, in whom light to moderate drinking is associated with a lower risk for NAFLD.
Omega-3 fatty acid supplements. At a median dose of 4 g/day, omega-3 supplements reduced steatosis, insulin resistance, and inflammation, while enhancing lipid oxidation and decreasing endogenous lipid production in patients with NAFLD.
Probiotic supplementation. Intestinal dysbiosis exists in NAFLD and influences its progression to NASH. Most studies with probiotics in patients with NAFLD have found decreases in aminotransferases levels and hepatic steatosis after short-term interventions, and another review found significant decreases in insulin resistance, total cholesterol, and TNF-α.
Monitor for low vitamin D levels. Vitamin D affects free fatty acid metabolism through certain peroxisome proliferator-activated receptors (PPAR-γ) and through reducing hepatocyte inflammation. Patients with NAFLD were roughly 25% more likely to be vitamin D deficient, when compared with controls.
Vitamin E supplements. Studies in pediatric populations with NAFLD have revealed that low vitamin E intakes are associated with a higher grade of hepatic steatosis, and that vitamin E supplements led to an improvement in liver enzymes and histology. In adults, vitamin E supplements (800 IU/day) combined with either ursodeoxycholic acid or pioglitazone are an effective treatment for NAFLD.
Milk thistle. Controlled clinical trials have shown that the active ingredients in milk thistle (silymarin and silybin) reduce liver enzymes, increase the production of antioxidant enzymes, and may decrease insulin resistance. Some of these, moreover, have demonstrated increased effectiveness with coadministration of vitamin E.
Patients on total parenteral nutrition. Patients receiving total parenteral nutrition are at risk for developing fatty liver due to a lack of choline. This is now considered an essential nutrient. Choline requirements are influenced by estrogen status and genetic variation.
See Basic Diet Orders chapter.
Hepatitis A and B vaccines, if not immune.
What to Tell the Family
In many cases, fatty liver disease is responsive to diet changes, along with medications that address the elevations in weight, blood fats, and insulin resistance associated with this condition. Family members can assist the patient by participating in and encouraging a low-fat, high-fiber diet suitable for safe and gradual weight loss, along with appropriate exercise. These measures may help the patient avoid more serious liver damage, and family members are likely to benefit as well. See Obesity chapter.
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