Non-alcoholic fatty liver disease, or NAFLD, is the buildup of excess fat in the liver that is unrelated to alcohol consumption. It begins with simple fatty liver and can progress to life-threatening liver cirrhosis, in which the liver is loaded with scar tissue and can no longer function properly. NAFLD is the most common form of liver disease in the developed world.
In the United States, at least 30 percent of adults and as much as 10 percent of children older than 2 have NAFLD. With obesity as a common comorbidity, the prevalence of NAFLD has doubled in the last two decades and may soon surpass hepatitis C infection as the leading cause for liver transplantation in the U.S.
The Disease Spectrum
NAFLD is a non-specific title describing several variations of the disease with differing levels of severity. In simple NAFLD, there are no symptoms, only steatosis, which is an excess of triglycerides in the liver. As many as 30 percent of people with NAFLD will progress to non-alcoholic steatohepatitis, or NASH, a severe form of fatty liver characterized by inflammation. There often are no symptoms related to NASH, though some sufferers complain of fatigue or discomfort in the upper right abdomen. Many people with NASH go on to develop fibrosis or scarring of the liver. As fibrosis progresses, cirrhosis develops, which can lead to progressive chronic liver failure, liver cancer and death.
Risk Factors and Causes
NAFLD is more common in people who have obesity or Type 2 diabetes. At least half of people with Type 2 diabetes and approximately 90 percent of people with body mass indices of 35 or higher have some form of NAFLD. Insulin resistance is common among these conditions and often is expressed as metabolic syndrome.
NAFLD is widely considered the liver manifestation of metabolic syndrome. Insulin resistance leads to excess free fatty acids in the blood stream and increased fat deposition in the liver. Furthermore, metabolic abnormalities spur the liver to produce and store high amounts of fatty acids. Most people with NAFLD have at least one feature of metabolic syndrome, and about one-third have all five features: elevated blood sugar levels, high blood pressure, low HDL cholesterol levels, elevated triglyceride levels and increased waist circumference.
Additional risk factors for NAFLD include high cholesterol levels, polycystic ovary syndrome, sleep apnea and underactive thyroid. These conditions share risk factors and complications such as weight gain, inactivity, diabetes and poor diet.
Less common causes of NAFLD include medications, infections, genetic disorders affecting metabolism, malnutrition and rapid weight loss.
NAFLD Progression and Cardiovascular Complications
Progression of patients throughout the spectrum of NAFLD is not well-defined. Continued or worsening insulin resistance likely plays a role in the advancement of liver abnormalities, as do oxidative stress and inflammation. Zachary Henry, MD, assistant professor of gastroenterology and hepatology at the University of Virginia, notes that for most of his patients, as metabolic syndrome worsens, so does NAFLD. To make matters worse, the progression to NASH may cause a vicious cycle of increased insulin resistance and faster progression through the NAFLD spectrum.
Not all patients progress in a typical fashion. “There are subsets of patients that likely have a genetic predisposition to progress regardless of metabolic syndrome,” Henry says.
Heart disease is the top killer among people with NAFLD, especially for those who have progressed to NASH. It is unclear if this is an association related to metabolic disturbances or if liver abnormalities cause heart complications. Research suggests NAFLD may lead to heart disease by contributing to blood vessel dysfunction, systemic inflammation, oxidative stress, and worsening cholesterol and triglyceride levels.
Screening for and Diagnosing NAFLD
Screening starts with a blood test to measure liver enzymes, but diagnosis requires imaging of the liver, typically by ultrasound. Health care providers frequently order imaging tests for patients with elevated liver enzymes in the presence of high-risk conditions such as Type 2 diabetes, metabolic syndrome, obstructive sleep apnea and a BMI of 35 or higher. However, the disorder likely is under-diagnosed because many patients with NAFLD have normal liver enzyme levels. Henry favors imaging everyone at high risk, but because this puts a heavy burden on the health care system, many providers order diagnostic procedures only when liver enzymes are elevated.
A liver biopsy is necessary to learn if a patient has simple steatosis or if the disease has progressed to NASH, fibrosis or cirrhosis. Under a microscope, the sampled liver tissue looks identical whether the patient has fatty liver from alcohol consumption, insulin resistance or some other reason. The diagnosis of NAFLD is made by ruling out excessive alcohol intake.
Treatment of NAFLD
There currently are no FDA-approved medications for treating NAFLD. The treatment trifecta is weight loss, healthful eating and physical activity — the same lifestyle interventions that treat other conditions associated with insulin resistance.
Inspiring difficult lifestyle changes for a condition without symptoms is challenging, but early intervention can prevent progression and even reverse NAFLD, says Kristin Kirkpatrick, MS, RD, LD, manager of Wellness Nutrition Services at Cleveland Clinic and author of Skinny Liver (Da Capo Press 2017). The key, she says, is to learn what motivates each individual and to focus on comorbid conditions such as elevated blood sugar levels.
WEIGHT LOSS. As with other conditions related to insulin resistance, even moderate weight loss improves NAFLD. At the University of Virginia Health System, Mary Lou Perry, MS, RDN, CDE, works with a multidisciplinary team to encourage healthful lifestyle habits and weight loss of 7 percent to 10 percent of starting weight. Perry notes that the degree of improvement is proportional to the amount of weight lost. However, rapid weight loss of more than 3.5 pounds weekly, with its greater flux of fatty acids to the liver, may worsen inflammation in NASH and accelerate disease progression.
HEALTHFUL EATING. Research has not identified an ideal diet or macronutrient distribution for the treatment of NAFLD. Thus, following recommendations of the 2015-2020 Dietary Guidelines for Americans is reasonable. One option gaining traction among health professionals is a Mediterranean-style diet. In a small crossover study, a Mediterranean-style diet produced greater reversal of both insulin resistance and liver fat content compared to a low-fat, high-carbohydrate diet even without a change in weight.
The following food items deserve special attention because they affect the progression of the disease or because patients frequently ask about them:
Alcohol: Moderate alcohol intake is associated with less heart disease and greater insulin sensitivity. However, it is unknown if these benefits extend to patients with NAFLD or if small amounts of alcohol are harmful. The American Liver Foundation and some physicians advise people with NAFLD to completely avoid alcohol. In the absence of clear guidelines, patients with NAFLD should adhere to the American Heart Association’s defined daily limits of one drink for women and two drinks for men.
Coffee: Limited data suggests coffee consumption may reduce the severity of NAFLD through anti-inflammatory and antioxidant properties.
Green tea: With its rich polyphenol content, researchers propose that drinking green tea may improve NAFLD. However, there have been no randomized controlled studies in humans.
Sugar-sweetened beverages: Research suggests drinking sugary beverages is associated with greater risk of NAFLD.
Dietary supplements: There is little evidence for the use of dietary supplements in treating NAFLD. Vitamin E shows some promise, but other studies link vitamin E supplements to increased mortality. Although some people may try unproven therapies such as milk thistle and green tea extract, unsupervised dietary and herbal supplements cause 20 percent of liver toxicity cases.
PHYSICAL ACTIVITY. Both cardiovascular exercise and strength training improve insulin resistance and NAFLD. Without clear exercise guidelines for this condition, it is prudent to work toward federal recommendations of achieving at least 150 minutes of moderate-intensity aerobic activity and two full-body strength training sessions weekly.