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Which patients with nonalcoholic fatty liver disease should undergo liver biopsy?

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Patients should undergo biopsy to guide management and prognosis if suspected of having steatohepatitis or fibrosis.


Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease in the United States and is the second most common reason for liver transplant.1 It is thought to be the hepatic consequence of systemic insulin resistance and the metabolic syndrome characterized by obesity, dyslipidemia, and type 2 diabetes mellitus.


NAFLD is defined by the accumulation of hepatic fat as evidenced by imaging or histologic study and without a coexisting cause of chronic liver disease or a secondary cause of hepatic steatosis, including significant alcohol use, medications, or an inherited or acquired metabolic state.

NAFLD has two subtypes: nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL is characterized by steatosis, including inflammation, in at least 5% of hepatocytes. NASH is defined by a constellation of features that include steatosis, lobular and portal inflammation, and liver cell injury in the form of hepatocyte ballooning.2

Clinically, it is especially important to distinguish patients with the NASH subtype, as most NAFLD patients have steatosis without necroinflammation or fibrosis and do not require medical therapy.


NAFL carries an excellent prognosis in terms of histologic progression of liver disease, whereas NASH can histologically progress to fibrosis and, in up to 15% of patients, to cirrhosis.3

Progression of fibrosis poses secondary risks, including complications associated with portal hypertension (ascites, variceal hemorrhage, hepatic encephalopathy), end-stage liver disease, and hepatocellular carcinoma. In Western countries, 4% to 22% of cases of hepatocellular carcinoma are attributed to NAFLD.4

In a 2015 meta-analysis, patients with NAFL and stage 0 fibrosis at baseline progressed 1 stage of fibrosis over 14.3 years, whereas patients with NASH and stage 0 fibrosis experienced an accelerated rate of progression, advancing 1 stage of fibrosis over 7.1 years.5 A systematic review of patients with NASH identified age and inflammation on initial liver biopsy as independent predictors of progression to advanced fibrosis.6

Patients with NAFLD have a higher all-cause mortality rate than patients of the same age and sex without NAFLD.7


Initial evaluation of a patient with suspected NAFLD should include a thorough serologic evaluation to exclude coexisting causes of chronic liver disease. Tests include:

  • A viral hepatitis panel
  • Antinuclear antibody (ANA)
  • Antismooth muscle antibody (ASMA)
  • Antimitochondrial antibody (AMA)
  • Iron studies
  • Alpha-1 antitrypsin level
  • Ceruloplasmin level.

Aminotransferase levels and imaging studies (ultrasonography, computed tomography, and magnetic resonance imaging) do not reliably convey the degree of NASH and fibrosis.

Biopsy. Whereas sensitive serologic tests have been introduced to detect and diagnose many causes of liver disease, liver biopsy (trans­jugular or percutaneous) with histologic examination remains the only way to accurately assess the degree of steatosis and, thus, to distinguish NAFL from NASH.2

The Pathology Committee of the NASH Clinical Research Network designed and validated a NAFLD scoring system,8,9 with points allocated for degrees of:

  • Steatosis (0–3)
  • Lobular inflammation (0–2)
  • Hepatocellular ballooning (0–2)
  • Fibrosis (0–4).

A NAFLD Activity Score of less than 3 is consistent with “not NASH,” a score of 3 or 4 with borderline NASH, and a score of 5 or more with NASH.8 However, the diagnosis of NASH is not based on the NAFLD scoring system, but rather on the pathologist’s overall evaluation of the liver biopsy.9

The metabolic syndrome is an established risk factor for steatohepatitis in patients with NAFLD, and its presence in patients with persistently elevated liver biochemical tests may help identify those who would benefit from further diagnostic and prognostic evaluation, including liver biopsy.2,10 In addition, a 2008 study that used a decision-tree modeling system demonstrated that early liver biopsy could provide a survival benefit.11

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