Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis

What is the difference between nonalcoholic fatty liver disease ( NAFLD ) and nonalcoholic steatohepatitis ( NASH ) ?

NAFLD is an umbrella classification for a group of diseases marked by excess accumulation of intrahepatic fat (steatosis), usually as the result of insulin resistance without significant alcohol use (~ 2-3 drinks per day in a man or ~ 1-2 drinks per day in a woman). NASH is a subset of NAFLD, which in addition to hepatic steatosis, has histologic evidence of hepatocyte injury to include lobular inflammation, ballooning degeneration, with or without Mallory hyaline and variable fibrosis.

How does the natural history of isolated fatty liver patients differ from those with NASH?

Whereas isolated fatty liver (the majority of patients with NAFLD) has a generally favorable prognosis with low risk for progression to cirrhosis, the clinical course of NASH patients is more variable. Natural history studies of NASH patients suggest:

• One third of NASH patients show disease (fibrosis) progression.

• One third have disease regression.

• One third have stable disease over a 5- to 10-year period.

How does the mortality of a patient with NAFLD compare with the general population?

All-cause mortality, cancer incidence (mostly hepatocellular carcinoma [HCC]), and type 2 diabetes mellitus are higher in NAFLD patients. Liver-related mortality is comparable to the general population for those with NAFLD who do not have NASH, whereas those with NASH have increased liver-related mortality.

How do patients with NAFLD present?

Patients with NAFLD are often noted to have elevated serum aminotransferases on routine blood work, which prompts a gastroenterology referral. The vast majority of these patients are asymptomatic, although a small but clinically notable fraction of patients complain of right upper quadrant discomfort. This symptom, which can range in presentation from a dull ache to sharp, severe pain, has been attributed to capsular swelling in the setting of hepatomegaly, although it is not always associated with liver enlargement and does not correlate with disease severity. Alkaline phosphatase is less frequently elevated, but can be elevated, particularly in women.

What does the serologic work - up for NAFLD patients show?

Serologic workup is typically negative with normal levels of ceruloplasmin and α ₁ -antitrypsin and negative viral hepatitis panels. Antinuclear antibody and anti–smooth muscle antibody may be positive in up to one third of cases. As a marker of inflammation, serum ferritin may be elevated in NAFLD patients. Ferritin levels more than 1.5 times the upper limit of normal predict more advanced NAFLD histologic findings, although further study to assess for genetic markers of hereditary hemochromatosis or hepatic iron overload (via liver biopsy) should also be considered.

Describe the typical NAFLD patient.

Most patients are overweight, middle-aged adults, although the disease can present in childhood with a rising incidence secondary to the increasing numbers of obese children. There is an even distribution between males and females. The majority of patients already have met criteria for the metabolic syndrome with at least three of the following:

• Increased waist circumference (men, greater than 40 inches; women, greater than 35 inches)

• Fasting serum triglycerides of 150 mg/dL

• High-density lipoprotein of 40 mg/dL in men or 50 mg/dL in women

• Systolic blood pressure of 130 mm Hg

• Diastolic blood pressure of 85 mm Hg

• Fasting glucose of 100 mg/dL

What is the prevalence of NAFLD and NASH?

Although the exact prevalence of NAFLD is unknown, it is easily the most common chronic liver disease in the developed world. Prevalence studies suggest 30% to 40% of the U.S. population has NAFLD. Somewhat lower prevalence rates of 18% to 25% have been noted in non-American populations. Higher prevalence is seen in type 2 diabetic patients, in whom NAFLD prevalence has been documented to be as high as 70% to 75%.

Given the lack of histologic data in most prevalence studies, the rates of NASH within the larger NAFLD population are uncertain, although autopsy data suggest an overall NASH prevalence of 3% to 6%. One prevalence study of middle-aged Texans demonstrated a higher NASH prevalence of 12%, and among morbidly obese patients undergoing bariatric surgery, prevalence rates of 91% for NAFLD and 37% for NASH have been demonstrated.

Are certain ethnic populations at greater risk of NAFLD or NASH?

Preliminary evidence suggests increased prevalence in Hispanic populations and a lower prevalence in African American individuals despite similar rates of comorbid conditions. Asian populations have also been shown to have more advanced disease at a lower body mass index than white counterparts.

How can you distinguish between NAFLD and NASH?

The short answer to this is liver biopsy—it remains the gold standard and is the only test that can provide clear-cut evidence of steatohepatitis. Imaging studies, such as ultrasound (US), computed tomography, and magnetic resonance imaging (MRI), are very good at diagnosing steatosis with upward of 95% sensitivity and 80% specificity, although the accuracy of US is reduced in the morbidly obese. However, these studies are unable to distinguish NASH from isolated fatty liver.

What noninvasive markers are available for either the diagnosis of NASH or fibrosis?

See Box 27-1 . Recent advances that may prove useful are US and MRI transient elastography, which show promise in noninvasively identifying advanced fibrosis (stages 3 and 4).