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Hepatitis, Liver Enzymes and Fibrosis Progression

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Repeated studies prove that those with chronic hepatitis must be evaluated directly for fibrosis progression. Although your doctor or peers may single out a normal ALT from a liver panel as good news, discover why this measurement provides little information about liver fibrosis.

Although chronic hepatitis causes relatively minor symptoms by itself, those with chronic Hepatitis B or C run the risk of developing fibrosis. As fibrosis worsens, it may lead to permanent scarring of the liver. Known as cirrhosis, this permanent liver injury is the tenth leading cause of death in the United States. As one of the markers of a person’s liver health, measuring liver enzymes sparks some controversy. While elevated levels of the liver enzyme, alanine aminotransferase, is often measured as an indicator of liver injury, it may not accurately reflect fibrosis progression.

Chronic viral hepatitis is a relatively common problem; worldwide, an estimated 350 million individuals are chronically infected with Hepatitis B (HBV) and 170 million are chronically infected with Hepatitis C (HCV). To monitor the health of patients with chronic hepatitis, there are two primary components of the liver that attending physicians evaluate: necro-inflammatory activity and fibrosis:

  1. Necro-inflammation – This refers to liver cell inflammation and cell death.
  2. Fibrosis – This refers to the hardening of liver tissue.

Alanine Aminotransferase

The laboratory findings most correlated with necro-inflammation are measurements of the liver enzymes, aspartate and alanine aminotransferases. In particular, alanine aminotransferases (ALT) is released into the bloodstream when the liver incurs damage. Traditionally, a panel of liver blood tests including ALT is used to evaluate whether or not a person’s liver function is deteriorating. Although this measurement is used ceremoniously by physicians, there appears to be little correlation between the aminotransferases and fibrosis. An increasing amount of evidence suggests that, while ALT is a standard sign of liver inflammation, it is not a good reflection of fibrosis progression.

Very high levels of ALT (more than 10 times the highest normal level) are usually due to acute viral hepatitis. In acute hepatitis, ALT levels typically stay high for about one to two months, but can take as long as three to six months to come back to normal. ALT levels are usually not as high in chronic hepatitis, often less than four times the highest normal level. In cases of chronic hepatitis, ALT levels often vary between normal and slightly increased, so doctors will typically order this test frequently to detect a pattern. In some liver diseases, especially when the bile ducts are blocked, a person has cirrhosis, and when other types of liver cancer are present, ALT may be close to normal levels.

Measuring Fibrosis

The feature that best correlates with the likelihood of developing cirrhosis is fibrosis. To evaluate the extent of fibrosis, physicians rely on the liver biopsy or more recently approved comparable methods:

  • Liver Biopsy – Riddled with complications, liver biopsy is an expensive, invasive procedure with a considerable risk of complications (particularly bleeding) and a small chance of death. Since chronic hepatitis does not affect the liver uniformly, the extent of fibrosis may vary from one part of the liver to another. Also, because a liver biopsy samples only one small part of the liver, it can easily miss a fibrotic area. Even with adequate-sized samples, cirrhosis is estimated to be missed in 15 – 30 percent of liver biopsies. Even with these drawbacks, a liver biopsy is still considered to be the gold standard of measuring fibrosis.
  • Transient Elastography – An alternative to a liver biopsy, transient elastography (FibroScan) is a non-invasive method of evaluating liver tissue. By measuring a low-frequency sound wave as it moves along the liver, this test records the speed with which the sound wave moves and correlates it with the degree of liver fibrosis. The stiffer (more fibrotic) the tissue, the faster the sound wave moves. Using ultrasound technology, this test is quick and painless. The primary drawbacks for using transient elastography are that, at this time, it cannot be used with patients who have ascites or who are obese.
  • Serum Markers – The other leading alternative to liver biopsy is using serum markers to test the degree of liver fibrosis. Currently licensed in the United States and several European countries, FibroTest measures the levels of five components in the blood: bilirubin, gamma-glutamyltranspeptidase (GGT), haptoglobin, alpha 2-macroglobulin and apoliprotein A1. By computing these five components, a mathematical formula produces a score, which correlates with the degree of fibrosis in the liver. Another liver serum marker test used specifically for those with HCV is Fibrosure. By carefully combining the measurements of six liver-related chemicals in the blood with age and sex, a Fibrosure test determines the degree of inflammation and fibrosis in the liver.

ALT and Liver Injury

While measuring ALT may accurately reflect liver inflammation, more and more evidence is showing it to be unreliable for determining liver fibrosis.

  1. As reported in the December 2000 Journal of Hepatology, researchers aimed to determine whether normal ALT is associated with liver injury in patients with chronic HBV who were undergoing biopsy. After tabulating the results, the authors of this study concluded that “there is significant fibrosis and inflammation in 37 percent of patients with persistently normal ALT levels.”
  2. In another 2000 study, Pennsylvania researchers evaluated the advisability of utilizing ALT elevation as the basis for recommending liver biopsy in adults co-infected with HIV and HCV. The authors of this study reported that, while biopsy-proven fibrosis was evident in all patients with abnormal ALTs, 80 percent of those with normal ALTs also had fibrosis. These findings showed that 80 percent of co-infected patients for whom biopsy may have been deemed inappropriate based on normal ALT levels, had significant liver pathology consistent with chronic HCV infection.
  3. Presented at the 2007 American Association for the Study of Liver Diseases, H. Gui and colleagues announced their aim to identify predictors of significant histological findings in chronic HBV with normal ALT and low viral load. The researchers found that 23.7 percent of HBV patients with significant liver inflammation and fibrosis had persistently normal ALT levels – regardless of HBeAg status or viral load levels. Based on their findings, the researchers advised that, “Liver biopsy be considered in chronic Hepatitis B patients with persistently normal ALT and detectable viral load, even low viral load, especially in those older than age 40 years and [with] higher ALT within 0.75-1 x ULN.”

Although ALT levels are repeatedly measured during a person with chronic hepatitis’s doctor visits, these numbers should not be cause for alarm or relief. Although elevated levels of this enzyme usually correlate with hepatic inflammation, they don’t appear to give much information about the progression of fibrosis. At this point in time, it appears that the only way to measure fibrosis is by using one of the tests designed directly for that purpose: a biopsy, transient electrography or serum marker fibrosis tests.


Dufour, Robert, D., Assessment of Liver Fibrosis: Can Serum Become the Sample of Choice?, Clinical Chemistry, January 2005.

Hoffman-Terry, M., Reed J., Correlation of ALT with Degree of Liver Damage by Biopsy in HIV/HCV Coinfected Adults, Intersci. Conference of Antimicrobial Agents and Chemotherapy, September 2000.

www.hivandhepatitis.com, Chronic Hepatitis B Patients May Have Significant Liver Disease Despite Normal ALT, Liz Highleyman, hivandhepatitis.com, December 2007.

www.hivandhepatitis.com, Clinical Significance of Persistently Normal ALT in Chronic Hepatitis B Patients, hivandhepatitis.com, 2008.

www.labtestsonline.org, ALT: The Test, American Association for Clinical Chemistry, 2008.

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