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The spectrum of disorders known as NAFLD is becoming increasingly common. Learn how to spot patients at risk to facilitate early intervention and treatment.
Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent cause of liver disease. NAFLD affects 20% to 30% of the world's population and is the leading cause of abnormal liver enzymes. In the United States, 31% of the total population has NAFLD, with variances in prevalence according to ethnicity, gender, and age. Fatty liver, or the accumulation of triglycerides in the cells of the liver, has long been associated with excessive alcohol intake. However, NAFLD is a type of fatty liver disease that exists in the absence of excessive alcohol consumption (less than 20 g/day for women and less than 30 g/day for men).
Obesity (a body mass index [BMI] of greater than or equal to 30 kg/m2) is a key risk factor for the development of NAFLD, which is found in 75% of obese patients and 91% of morbidly obese patients. NAFLD is also strongly linked to metabolic syndrome; in fact, NAFLD exists in 86% of patients with metabolic syndrome and is often thought of as its hepatic manifestation (see A closer look at metabolic syndrome).
NAFLD occurs in the United States twice as often in men as it does in women. Some studies suggest that estrogen may reduce the risk of developing NAFLD. This disorder occurs in Hispanics more than any other ethnicity, with reported incidence as high as 45%. In White patients, the incidence is lower at 33%. The increased prevalence in Hispanics is believed to be related to a high rate of risk factors in this population, such as obesity, insulin resistance, and type 2 diabetes. NAFLD may occur during childhood; however, the prevalence is known to increase with age, with a peak prevalence noted in those older than age 60.
In this article, we'll take a look at the range of disorders that make up NAFLD, review the clinical signs and symptoms and diagnostic indicators, and examine the recommended treatment modalities.
NAFLD isn't one disorder. It consists of a spectrum of disorders with varying degrees of severity, ranging from simple fatty liver (hepatic steatosis) to nonalcoholic steatohepatitis (NASH). In simple fatty liver there are fatty infiltrates in the liver but no signs of inflammation, cell damage, or fibrosis. In contrast with hepatic steatosis, NASH results in inflammation and scarring of the liver tissue. This scarring can lead to fibrosis and, eventually, cirrhosis (see Stages of NAFLD). Around 20% of patients with hepatic steatosis progress to NASH, and 20% of those with the diagnosis of NASH will develop cirrhosis.
Although there are a number of diagnostic tests that may be useful in identifying NAFLD, currently, a liver biopsy is the only way to make a definitive diagnosis and distinguish between hepatic steatosis and the more advanced disease process, NASH, by identifying inflammation and hepatocellular injury. Hepatocellular injury can manifest as ballooning, apoptosis, or necrosis. Ballooned hepatocytes are enlarged with swollen, pale cytoplasm. The presence of plasma CK-18 fragments is indicative of apoptosis and is one method of identifying NAFLD.
The exact cause of NAFLD isn't known, but what's known is that insulin resistance, which is almost universal in patients with NAFLD, plays a key role in its development. Insulin resistance in fat cells, or adipocytes, results in an increased production of lipase. Lipase breaks down triglycerides into free fatty acids, which are released into the circulation so they can be absorbed by the body. In NAFLD, these free fatty acids are taken up by the cells of the liver (hepatocytes), which results in hepatic steatosis. Lipid-induced mitochondrial dysfunction and oxidative stress in the hepatocytes are factors that are implicated in the progression of simple fatty liver to NASH. Hyperinsulinemia, hepatic iron, leptin, antioxidant deficiencies, and intestinal bacteria are all suspected to be potential oxidative stressors. Damage to the hepatocytes results in inflammation, which can lead to the progression of NAFLD and, eventually, fibrosis.
The patient with NAFLD is often asymptomatic and, for this reason, may go undiagnosed. Often, NAFLD is discovered as part of lab or diagnostic testing for another disorder. A diagnosis of NAFLD must be considered when there's an elevation of liver enzymes in a patient with the risk factors of obesity, diabetes mellitus, or metabolic syndrome. NAFLD is a diagnosis of exclusion and is made after excessive alcohol intake and other possible causes have been eliminated. Possible causes of elevated liver enzymes that need to be considered are medications, viral hepatitis, autoimmune hepatitis, parenteral nutrition, and genetic disorders. It's also important to remember that a patient may have NAFLD concurrently with another form of liver disease.
Some patients with NAFLD may experience pain in the right upper quadrant of the abdomen and abdominal discomfort that results from stretching of the hepatic capsule. Hepatomegaly may be noted on physical examination. However, many patients with NAFLD only experience vague, nonspecific symptoms, such as fatigue, malaise, and nausea.
You may observe the presence of acanthosis nigricans-a dark patch of skin or dark ring that's often noted on the neck and/or axilla of patients with insulin resistance. Patients with insulin resistance may also have central obesity and abdominal striae.
Other findings to be aware of are those found in NASH-related cirrhosis, such as ascites, jaundice, spider angiomas, palmar erythema, and caput medusa.
One indication that something is wrong in the liver is an increase in the liver aminotransferase levels aspartate aminotransferase (AST) and alanine aminotransferase (ALT). NAFLD is the leading cause of abnormal liver enzymes; however, liver aminotransferase levels aren't a conclusive indicator of NAFLD. Although NAFLD is often the cause of elevated aminotransferase levels, the patient with NAFLD may also have normal aminotransferase levels (see Assessing normal liver function).
In NALFD, elevations of AST and ALT are usually mild (mean range, 100 to 200 IU/L) and the AST:ALT ratio is generally less than 1. The diagnosis of NAFLD is made when there's hepatic steatosis present after other potential causes, such as excessive alcohol intake and viral hepatitis, have been excluded based on lab tests, clinical symptoms, and imaging studies.
Alkaline phosphate, gamma-glutamyl transferase, and serum ferritin levels are lab tests that need to be considered for the patient suspected of having NAFLD because they may be elevated in NAFLD. Although an elevated ferritin level may be indicative of advanced fibrosis, it should also prompt testing to rule out hereditary hemochromatosis. Albumin, bilirubin, and platelet levels aren't usually elevated unless the patient has progressed to cirrhosis. Tumor necrosis factor alpha should also be evaluated because it has been shown to correlate with the degree of inflammation and fibrosis seen in NASH.
Recently, a lab test for the plasma biomarker cytokeratin, CK-18, has been used and is showing promise in distinguishing NASH from simple fatty liver. This plasma biomarker can be measured using ELISA. CK-18 fragments are the byproduct of hepatocyte apoptosis and have been found to be elevated in patients with NASH. CK-18 fragments have been noted to decrease in patients with NASH after bariatric surgery and may be used as a valuable tool to assess response to therapy. In one study, CK-18 plasma levels in patients with NASH were compared with those of healthy patients. The plasma levels of patients with NASH ranged from 230 to 549 U/L as compared with 126 to 190 U/L in the healthy individuals.
Considering the relationship between metabolic syndrome and NAFLD, expect to find an elevation of blood glucose and triglyceride levels, and a decrease in high-density lipoprotein (HDL) cholesterol levels, in these patients.
An abdominal ultrasound may be ordered to identify fatty infiltrates in the liver and hepatomegaly when NAFLD is suspected. Fatty infiltrates in the liver will produce increased echogenicity and vascular blurring. However, an ultrasound isn't able to assess the degree of fat accumulation in the liver. Many patients with NAFLD are obese and this can interfere with the accuracy of the ultrasound evaluation.
A computed tomography scan or magnetic resonance imaging may also be used to detect hepatic steatosis but, as with ultrasound, these scans are unable to differentiate between simple fatty liver and NASH. For this reason, a liver biopsy-although invasive-continues to be the gold standard for the diagnosis of NAFLD. A liver biopsy is able to differentiate NAFLD from other liver diseases (drug induced hepatoxicity, Wilson disease, and autoimmune hepatitis) and identify the level of inflammation and fibrosis that's present in NASH. The presence of steatosis in more than 5% of the liver cells is indicative of fatty liver disease.
A NAFLD activity score (NAS) was developed to help diagnose and monitor NAFLD. NAS is a total of scores (0 to 8) assigned for steatosis (0 to 3), hepatocellular ballooning (0 to 2), and lobular inflammation (0 to 3). Although there isn't a value of NAS that's used reliably to identify the presence of NASH, most patients with NASH have a NAS score of greater than or equal to 5.
The goal of treatment for the patient with NAFLD is to limit the progression of the disease to fibrosis and cirrhosis. Related to the strong relationship that exists between NAFLD and metabolic syndrome, treatment is focused on managing obesity, insulin resistance, hypertension, and dyslipidemia. Many of these factors can be improved with lifestyle modification. Patient adherence to lifestyle modification is often sustained when family members adopt the same lifestyle changes.
Controlling obesity, which is defined as a BMI of greater than 30, is an important component in the treatment of NAFLD. Weight loss, with the goal of reducing weight by 5% to 10% of the total body weight, has been shown to decrease hepatic steatosis, improve liver enzyme levels, and prevent the progression of NAFLD to fibrosis and cirrhosis. A correlation has been established between a reduction in body fat and a decrease in liver fat.
Some experts recommend bariatric surgery for patients with NAFLD who are unable to lose weight because 20% of patient with NASH will develop cirrhosis. A decrease in visceral fat associated with bariatric surgery is an added benefit that has been shown to improve insulin resistance. Rapid weight loss (more than 3.5 lb [1.6 kg]/week) should be avoided because it can result in worsening of hepatic inflammation and fibrosis; slow, gradual weight loss is recommended.
Insulin resistance can also be improved with weight loss and exercise. A diet that's low in saturated fats and high in fiber should be encouraged. Medications, such as metformin and thiazolidinedione, may be indicated to improve insulin sensitivity. Metformin is recommended for NAFLD patients who are obese and have type 2 diabetes because it lowers hepatic glucose production and promotes the uptake of glucose in muscles. In patients with NASH, thiazolidinedione has been shown to both improve insulin sensitivity and decrease liver tissue inflammation. It's important to be aware of the possible adverse reactions to thiazolidinedione, including weight gain, heart failure, pulmonary edema, and anemia.
In addition to teaching patients with NAFLD about diet and exercise, it's important to stress that they need to avoid drinking alcohol and taking unnecessary medications due to their potential hepatotoxic effects.
Although there are no medications indicated specifically for the treatment of NAFLD, medications for the management of metabolic syndrome are often used. However, many of these medications are contraindicated in patients with hepatic impairment. Statins, fibrates, and angiotensin II receptor antagonists, which are used to treat hypertension and dyslipidemia, need to be used with caution. Statins aren't contraindicated in patients with NAFLD as one might suspect. The control of lipids can help control fatty changes that result in inflammation. These medications should be started in low dosages and titrated carefully to prevent liver toxicity. Because NAFLD can alter the metabolism of statin drugs, it's important to assess for signs of myotoxicity, such as muscle pain, muscle weakness, and dark urine.
Another medication used to treat patients with NAFLD who don't have diabetes is the antioxidant vitamin E. The use of vitamin E in patients with diabetes hasn't been studied and isn't recommended at this time. Vitamin E, 800 IU daily, has been shown to reverse the oxidative stress on hepatocytes associated with NASH and improve aminotransferase levels and liver histology. However, vitamin E should be used with caution because some research has shown an increased risk of prostate cancer related to its use.
New information is emerging that suggests coffee consumption (300 to 500 g of caffeine/day) is beneficial in the reduction of inflammation and fibrosis.
The patient with NAFLD may be asymptomatic. However, assess for the presence of right upper quadrant pain, fatigue, and malaise-the most common symptoms associated with NAFLD-and plan interventions to alleviate these symptoms.
Carefully evaluate all medications taken by the patient and identify any medications that can worsen hepatic steatosis, including amiodarone, methotrexate, steroids, tetracycline, tamoxifen, estrogen, and valproic acid.
The teaching plan for the patient with NAFLD needs to focus on lifestyle modification. A plan for improved nutrition and weight loss is essential. Weight loss, along with exercise, has been shown to decrease the progression of NAFLD and improve liver histology as reflected by improved NAS scores. The amount of weight lost has been shown to correlate with a reduction in liver fat.
Calorie restriction is needed for weight loss, along with limiting fats and the amount of carbohydrates to 40% to 45% of the daily intake of calories. It's recommended that patients with NAFLD gradually reduce weight at a rate of 1 to 2 lb/week.
Research has shown that fructose and trans-fatty acids found in processed oils are associated with insulin resistance. Recognizing the relationship between NAFLD and insulin resistance, patient teaching should include educating the patient to avoid these foods.
The patient should receive education on the benefit of establishing a regular exercise program to prevent disease progression. Exercise improves insulin sensitivity in muscles. Achieving the goal of a regular exercise program (3 to 5 days/week for 20 to 30 minutes) is often difficult for the patient with NAFLD due to fatigue, a common symptom of NAFLD.
In addition to lifestyle modification, the patient with diabetes and NAFLD should be encouraged to maintain tight glucose control to slow the progression of NAFLD.
It's important that patients with risk factors for NAFLD be evaluated for this increasingly common disorder. The rate of incidence in individuals who are obese is high, and it's expected that the incidence of NAFLD will continue to increase as obesity continues to rise.
The implications for not diagnosing and treating NAFLD are serious. NAFLD is emerging as one of the leading causes of cirrhosis in the United States. Cirrhosis can eventually lead to liver failure, hepatocellular carcinoma, and death. Early detection is important to stop liver damage and decrease liver-related mortality. We also shouldn't overlook that the relationship between NAFLD and metabolic syndrome makes NAFLD a significant risk factor for cardiovascular disease-one more reason to be aware of and manage NAFLD aggressively. It should be noted that the most common cause of death in patients with NAFLD is cardiovascular disease.
Historically, chronic liver disease has been associated with excessive alcohol consumption. NAFLD is becoming recognized as the most common cause of chronic liver disease. With the increasing prevalence of NAFLD, you can expect to care for patients with this disease. By recognizing patients who have risk factors and providing them with education on NAFLD, you can make a difference.
* Viral hepatitis
* Autoimmune hepatitis
* Wilson disease
* Acute pancreatitis
* Biliary tract obstruction
* Primary biliary cirrhosis
* Alpha-1 antitrypsin deficiency
* Chronic alcohol abuse
* Fatty liver
* Hepatic carcinoma
* Muscle injury
* Congestive heart failure
* Cardiac arrhythmias
* Liver tumors
* Hepatotoxic medications
* NAFLD is the leading cause of abnormal liver enzymes.
* NAFLD occurs in people who drink little or no alcohol.
* NAFLD is known as the hepatic manifestation of metabolic syndrome.
* NAFLD occurs in Hispanics more than any other population.
* NAFLD consists of a spectrum of disorders.
* NAFLD is a leading cause of cirrhosis.
* Patients with NAFLD may be asymptomatic.
* The gold standard for the diagnosis of NAFLD is a liver biopsy.
* The goal of treatment for NAFLD is to limit the progression from simple fatty liver to NASH.
* The mainstay of treatment for NAFLD is lifestyle modification.
American Liver Foundation:http://www.liverfoundation.org
National Digestive Disease Information Clearinghouse:http://digestive.niddk.nih.gov/ddiseases/pubs/nash
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