Hepatitis; Staging Liver Fibrosis: Liver Biopsy, Imaging and Biomarkers

AGA Perspectives August/September 2011

Staging Liver Fibrosis: Liver Biopsy, Imaging and Biomarkers

Nezam H. Afdhal, MD

Chief of Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

The staging of liver fibrosis has important implications for disease prognosis and treatment decisions for diseases such as viral hepatitis B and C (HCV), autoimmune liver diseases, and NAFLD. I believe the most important aspect of fibrosis staging is to diagnose or exclude cirrhosis; since this has major implications for patient outcomes, I recommend instituting radiological screening every six months for hepatocellular carcinoma and endoscopy to rule out portal hypertension.1

Traditional staging has been with liver biopsy to give a numerical stage, which is arbitrary and most accurate at the level of no fibrosis (stage zero) or cirrhosis. In-betweenstages are prone to problems of sampling error, inadequate biopsy size and interobserver variability. I usually tell my patients that the accuracy of biopsy is 80 percent and that a one-stage error with a risk of both understaging and overstaging is possible. The other critical point about biopsy staging is that the clinician and the patient should realize that fibrosis staging scores were initially designed for use in clinical trials for viral hepatitis, and aside from stage four (cirrhosis), the clinical significance of lesser stages has not been validated in many liver diseases. Since many factors are associated with highly individually variable fibrosis progression, I am not comfortable with a single biopsy as the only method to stage progression risk over time.

The extensive interest in developing noninvasive tests has resulted in alternatives to biopsy that can be used in clinical practice.2 These alternatives have benefits in terms of cost, risk and patient convenience. Clinically applicable non-invasive tests include radiological studies, elastography and serum markers. The most extensive validation of these non-invasive tests has been for hepatitis C.

These tests are not focused on exact staging of disease, but rather on dividing patients into categories of mild fibrosis (metavir stage zero to one) versus significant fibrosis (greater than or equal to metavir stage two) and cirrhosis. They perform extremely well, as does biopsy, for excluding significant disease and for diagnosing cirrhosis with areas under the receiver operating characteristic curve (AUC) of 0.85 to 0.95.

Standard radiological imaging may show features of cirrhosis with splenomegaly, nodular liver and varices, and can be enhanced by elastography, both MR- and ultrasoundbased. I will usually accept radiological features of cirrhosis to make the diagnosis and will not perform a liver biopsy. Elastography is not widely used in the U.S., but studies have shown a strong correlation of liver stiffness to the stage of liver fibrosis. Elastography can characterize patients as having either no or minimal portal fibrosis versus bridging fibrosis and cirrhosis.3 They are useful for cirrhosis where the AUC is 0.95, and I recommend them, if available, for my patients.

Ultrasound-based elastography can be performed in the office and gives the liver stiffness in kilopascals, which can then be used to inform the patient of the relative risk of significant fibrosis or cirrhosis. Recently, two U.S. studies have shown that elevated liver stiffness has been associated with both the presence of esophageal varices and an increased risk of adverse clinical outcomes over a three-year period.4, 5MR elastography is also an excellent technique for determining liver stiffness, but is not widely available, and requires an MR scanner, significantly more time and expense.6

Serological tests for staging liver disease are the most widely available tests in the U.S. and can help me in clinical decision making.2 These tests can be used to determine the probability of no or mild fibrosis from advanced disease and cirrhosis. The available tests include HepaScore® and FibroSure™, and both use a linear scale that correlates with the stage of fibrosis.7 Each test measures multiple fibrosis markers in serum; then, using a mathematical algorithm, gives a score, which can be used to determine the probability of disease. I find these tests useful when I do not need exact staging of disease, but wish to see if my patient has mild disease, such as in a young patient with HCV and no clinical risk factors for advanced fibrosis, or when a patient has clinical or radiological features of cirrhosis and I wish to confirm this without biopsy.
Staging of liver fibrosis can now be performed with a variety of complimentary tests. Since fibrosis staging is an inexact science, I frequently recommend combining these tests to most accurately stage disease. As more well validated non-invasive tests for staging fibrosis become widely available, the overall need for liver biopsy for clinical decision making will regress, making clinical care safer and more convenient for our patients.

1. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838-51.
2. Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology. 2008;134(6):1670-8.
3. Cohen EB, Afdhal NH. Ultrasound-based hepatic elastography:origins, limitations, and applications. J Clin Gastroenterol. 2010;44(9):637-45.
4. Pritchett S, Cardenas A, Manning D, Curry M, Afdhal NH. The optimal cut-off for predicting large oesophageal varices using transient elastography is disease specific. J Viral Hepat 2011:18;75-80.
5. Klibansky DA, Mehta SH, Curry M, Nasser I, Challies T, Afdhal NH. Transient Elastography for predicting clinical outcomes in patients with chronic liver disease In Press, J Viral Hepat 2011.
6. Talwalkar JA, Yin M, Fidler JL, Sanderson SO, Kamath PS, Ehman RL. Magnetic resonance imaging of hepatic fibrosis: emerging clinical applications. Hepatology. 2008;47:332-4.
7. Becker L, Salameh W, Sferruzza A, Zhang K, Chen R, Malik R, Reitz R, Nasser I, Afdhal NH. Validation of Hepascore, compared to simple indices of fibrosis, in US patients with chronic hepatitis C virus infection. Clin Gastroenterol Hepatol. 2009;7:696-701.
8. Krauskopf MS. 2009 C5 Summit Presentation. 2009.

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