2012-05-23 20:42:56 UTC

Should We Routinely Do Liver Biopsy in NAFLD Patients?

May 23, 2012


Rohit Loomba, MD, MHSc

Assistant Professor of Clinical Medicine, Division of Gastroenterology; Assistant Adjunct Professor, Division of Epidemiology, University of California at San Diego, La Jolla


One in every three adult Americans is afflicted by NAFLD. Estimates are that 10 to 20 percent of these individuals have a progressive form of NAFLD termed nonalcoholic steatohepatitis (NASH). NASH is characterized histologically by hepatocellular injury, steatosis and lobular inflammation with or without peri-sinusoidal fibrosis on liver biopsy in individuals who drink little or no alcohol. Patients with NASH, as distinguished from patients with only steatosis (NAFLD), can progress to advanced fibrosis and cirrhosis, and are at risk of death from liver disease. NASH is now the third leading indication for liver transplant in the U.S., and its prevalence is expected to rise in the coming decades.

In this brief commentary, I will discuss the specific issues that impact a practicing gastroenterologist when he or she sees a patient with suspected NASH. Given that NASH is a clinico-pathologic entity, a liver biopsy is essential to make this diagnosis. However, whether a liver biopsy must be performed to establish the diagnosis remains controversial, even among academic hepatologists at large referral centers.

My approach is to weigh the indications for and against performing a liver biopsy for each individual patient. One extreme position would be to biopsy all patients with NAFLD to see whether NASH was present. However, it is clearly impractical to biopsy all 80 million Americans who are estimated to have NAFLD. Our health-care system has neither the capacity nor the resources to afford such a policy.

On the other extreme, some physicians prefer not to biopsy any patient with fatty liver because they are not sure what to do once they find that the histology indicates that NASH is present, although it may provide important prognostic information. Currently, there are no therapies approved by the FDA for the treatment of NASH. However, limited but well-controlled studies suggest that therapies such as vitamin E and pioglitazone unequivocally induce improvement in liver histology in NASH.

Additionally, intensive lifestyle modifications — weight loss and exercise — have been shown to reverse NASH. Furthermore, liver biopsy can help identify patients who have advanced fibrosis. The risk of hepatocellular carcinoma (HCC) in patients with NASH cirrhosis is 2 to 3 percent per year, which is substantial. Therefore, biopsy is not only important for determining the need for therapy, but also to determine the need for HCC surveillance. Finally, findings on liver biopsy have prognostic significance. Patients who have ballooning and/or Mallory bodies and/or fibrosis on liver biopsy have up to a 25 percent risk of progression to cirrhosis over 10 years of follow-up. When patients are counseled appropriately with prognostic information, there is a greater likelihood of success with lifestyle interventions.


Indications for liver biopsy in patients with NAFLD with negative work-up for other etiologies for elevated serum transaminases*

  1. Presence of metabolic syndrome
  2. Presence of Type 2 diabetes

Physical exam (anecdotal evidence)

  1. Enlarged left lobe of the liver
  2. Hard liver on exam

Biochemical and laboratory tests (strong evidence)

  1. AST > ALT, especially in the setting of low platelet count and/or albumin
  2. Elevated ferritin with high-fasting insulin and fasting plasma glucose in the absence of diabetes

Other special clinical context for a low threshold for biopsy (either strong evidence or emerging)

  1. Older adults (higher rates of fibrosis on biopsy)
  2. Family history of diabetes (emerging)
  3. Increased NAFLD fibrosis score (NAFLDscore.com)

Role of genetic testing for NASH prior to performing a liver biopsy

  1. Uncertain at this time and not recommended

Role of non-invasive biomarkers prior to performing a liver biopsy

  1. Emerging but uncertain at this time and not recommended*These recommendations are based upon Dr. Loomba’s clinical approach to NAFLD based upon current evidence, and do not represent the view of any society or research consortia.

In my opinion, the appropriate strategy should be guided by two main principles: patient preference and the pre-test probability of having NASH and/or advanced fibrosis on liver biopsy based upon available clinical parameters. A good medical history, physical examination and a thorough assessment of routinely available clinical and biochemical laboratory tests can help identify patients who are at increased risk of having NASH and/or advanced fibrosis.

Several studies have shown that the presence of metabolic syndrome and diabetes are the two most important risk factors for the finding of NASH on liver biopsy in NAFLD patients. The accompanying table provides a simplified list of indications for liver biopsy in patients with elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) who have fatty liver on imaging, assuming a negative work-up for viral hepatitis, auto-immune liver disease, drug-induced liver injury, and other etiologies for abnormal liver tests. Liver biopsy is also helpful in excluding other causes of abnormal liver tests such as iron overload and alpha-1-antitrypsin deficiency. A careful physical exam can suggest cirrhosis if the left lobe of the liver is palpable or the liver is hard on palpation. Elevated levels of ALT and AST (especially if AST-to-ALT ratio is 0.8 or higher), and lower platelet count and albumin levels are associated with NASH

and/or advanced fibrosis on biopsy. Emerging data suggest that older adults have increased risk of NASH as well as advanced fibrosis. Family history of diabetes is an emerging risk factor of NASH, especially among non-diabetics. Genetic markers and non-invasive biomarkers are undergoing intense investigations, but none are ready for primetime.

Unless there are contraindications to a liver biopsy, all NAFLD patients who are referred to a liver clinic with diabetes and/or metabolic syndrome should be offered a liver biopsy evaluation. Patients with elevated aminotransferase levels and an AST-to-ALT ratio greater than or equal to 0.8, especially in the setting of low serum albumin and/or platelet count, may have advanced fibrosis or cirrhosis. These are the highest risk patients within the spectrum of NAFLD, and further evaluation with a liver biopsy is desirable.

Dr. Loomba is an AGA Research Foundation Research Scholar Award recipient. He received the 2009 Designated Research Scholar Award in Geriatric Gastroenterology.

Dr. Loomba receives research support from Daiichi Sankyo Inc. He is also a member of AASLD’s Annual Meeting Education Committee as well as the American Liver Foundation’s Board of Directors.

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