What is fibrosis?

Chronic inflammation in the liver produces collagen and extracellular matrix proteins. As the collagen and the extracellular matrix proteins accumulate, scarring occurs. The scarring is called fibrosis. Fibrosis develops over time, and eventually can progress into advanced stages. The most advanced stage of fibrosis is cirrhosis.

How is fibrosis scored?

There are several scoring systems for evaluating chronic hepatitis, and they all include 2 components: inflammatory activity and degree of fibrosis. Commonly used scoring systems are the Knodell score/Histological Activity Index (HAI), the METAVIR score, and the Ishak score (modified Knodell score). The Knodell system has 4 stages of fibrosis and the Ishak system has 6 stages of fibrosis. The METAVIR scoring system has 5 stages of fibrosis, from F0 to F4, as depicted below:

How much time does it take for fibrosis progression to occur?

Fibrosis progression is variable. Not all patients develop fibrosis and those who do may not progress to advanced stages. For those with progressive fibrosis, the rate of progression can be variable. Some patients progress slowly for 20 years and then accelerate in later years. Other patients develop fibrosis within a short period of time and progress quickly, sometimes developing cirrhosis within less than 20 years.

What causes some patients to progress more rapidly or to more advanced stages?

Do all patients with liver disease need to have fibrosis testing?

Fibrosis testing is relevant for the clinical care of patients with chronic liver disease, including hepatitis B, hepatitis C (HCV), non-alcoholic fatty liver disease (NAFLD), co-infections, primary biliary cirrhosis, primary sclerosing cholangitis, and other chronic metabolic diseases of the liver.

• Knowing the severity of fibrosis can help with prognosis and understanding the degree of liver damage.
• More rapid development of fibrosis and more advanced stages of fibrosis are more predictive of cirrhosis, and therefore liver-related illnesses and mortality.
• The severity of liver disease is a factor in determining the urgency for HCV treatment and HBV treatment.
• Understanding the fibrosis stage impacts clinical care decisions. Patients with advanced fibrosis or cirrhosis need more frequent follow up visits and labs, avoidance of some medications, and surveillance for hepatocellular carcinoma (HCC) and gastroesophageal varices.

Common fibrosis terminology

Fibrosis stage ≥ 2 is considered significant fibrosis. "Advanced fibrosis" traditionally refers to stages 3 and 4. The term cirrhosis is reserved for stage 4 disease.

Fibrosis assessment

Until recently, liver biopsy was the only technique available to detect and stage the degree of fibrosis. Today, there are non-invasive options available as well. Get an understanding of the advantages and disadvantages of various assessment approaches by clicking on the options listed below.

The choice of fibrosis test should take into account:

• Availability of the test
• Convenience
• Cost
• Risk to the patient
• Test accuracy

The history, physical exam, routine laboratory tests, and routine abdominal imaging (ultrasound, CT scan, or MRI) will sometimes reveal clear morphological changes of cirrhosis, but are insufficient for determining other stages of fibrosis. The standard alanine aminotransferase (ALT) test for diagnosing chronic liver disease does not identify fibrosis. In some chronic liver diseases, such as HCV, ALT levels do not correlate with the amount of liver tissue damage. Patients with chronic HCV may have persistently normal ALT levels but have significant fibrosis. Conversely, patients may also have elevated ALT levels but no significant fibrosis. Therefore, identifying the presence and degree of liver damage requires testing beyond ALT.

Cirrhosis assessment

Cirrhosis can sometimes be diagnosed based on a combination of physical exam, routine laboratory tests, or routine imaging.

Physical exam findings: enlarged spleen, spider angioma

Laboratory findings: Low platelet count (<140,000/mm3)

Abdominal imaging: Nodularity of the liver, splenomegaly, varices, caudate lobe hypertrophy, portal and splenic vein distension, and ascites are features of cirrhosis

Importantly, the absence of these findings does not rule out cirrhosis or advanced fibrosis. Patients with cirrhosis could also have an unremarkable history and normal physical findings, labs, and imaging.

Can fibrosis scores improve after successful HCV treatment?

Fibrosis regression has been demonstrated in certain individuals after HBV treatment, HCV treatment, treatment of iron overload, autoimmune hepatitis, and cessation of alcohol. Elimination of the damaging element often improves inflammation and allows for remodeling of the fibrosis. Our understanding of fibrosis regression is evolving and emerging data is encouraging. Importantly, cirrhosis elevates a patient's risk for liver cancer, even after improvement in labs, imaging, or evidence of portal hypertension.

Liver biopsy

Liver biopsy has been the gold standard for the assessment of histologic changes in the liver. In the past, liver biopsy was routinely performed in patients with HCV, particularly before HCV treatment. Liver biopsy is still a very helpful tool for diagnosis of liver disease, and therefore it is important to fully understand the technique and the risks and benefits to patients.

Risks: Liver biopsy carries a small risk of complications. Some of the risks include the following:

• Bleeding requiring transfusion - occurs in less than one in a thousand biopsies.
• Penetration of other organs such as lung, kidney, gallbladder, or intestine - occurs in less than one in a thousand biopsies.
• Fatality - occurs in less than one in ten thousand biopsies

Requirements: If a biopsy is necessary, it should only be performed when the information will be useful for optimal patient care and cannot be obtained in another way. Furthermore, biopsy should only be performed after written informed consent has been obtained.

Procedure: A liver biopsy can usually be safely performed as an outpatient procedure. A physician trained and experienced in the procedure should perform the liver biopsy. Prior to the procedure, patients should discontinue all anticoagulants (e.g., coumadin) for at least one week and should not take aspirin or other non-steroidal anti-inflammatory medicines for about one week (patients can take acetaminophen).

The disadvantages of liver biopsy are that it is invasive, carries risk to the patient, is expensive, and the interpretation is prone to error due to sampling and subjective interpretations. Therefore, it is no longer a routine test for HCV patients and non-invasive tests are preferred for fibrosis staging.

Non-invasive methods of fibrosis assessment

Non-invasive techniques to assess fibrosis refer to any method other than a liver biopsy. Non-invasive methods rely on either blood tests to estimate the risk of advanced fibrosis or newer technology to assess the elasticity of liver tissue. Here we cover the methods currently used in clinical practice. Methods of fibrosis assessment that are not yet integrated into practice or are under investigation are not covered here. An important feature of all non-invasive assessments of liver fibrosis is that the functional parameters of the study are specifically related to the liver disease for which it was developed. Test results must be interpreted based on the liver disease.

FibroSure^®

The blood test "HCV-FibroSure^®" is a panel of six biochemical markers associated with hepatic fibrosis: alpha-2-macroglobulin, haptoglobin, GGT, apolipoprotein A1, total bilirubin, and ALT. The overall FibroSure score is calculated using a proprietary formula that combines the results of all 6 markers in addition to patient age and gender. The FibroSure report includes the results of the individual tests, the computed fibrosis score (which is the most helpful), and an associated fibrosis stage (F0-F4). When compared to liver biopsy, histology results in a sample population in which 38% had significant fibrosis (F2, F3, or F4 by METAVIR), the negative predictive value of clinically significant fibrosis was 91% and the positive predictive value for presence of significant fibrosis was 61%-76%. The presence of some other conditions can make the FibroSure less accurate: Gilbert's disease, acute hemolysis, extrahepatic cholestasis, post transplantation state, or renal insufficiency. Cost is a factor for the FibroSure test as it is expensive. In terms of accuracy, it is most reliable for excluding or confirming cirrhosis but is less reliable for the intermediate fibrosis scores. The identical test is named differently in Europe, where it is referred to as the FibroTest-ActiTest. The major advantage of FibroSure is convenience. The disadvantages are cost, potential influence by other conditions, and poor differentiation between the intermediate stages of fibrosis. FibroSure should only be used in patients with active HCV infection; the test is not reliable in patients without HCV infection and those cured of HCV infection.

APRI

The AST to Platelet Ratio (APRI) test is a calculator tool that inputs routine laboratory values to assess the risk for advanced fibrosis. The APRI does not report on the differing stages of fibrosis. When a cut off of >1.0 is used, the APRI has a sensitivity of 77% and a specificity of 75% for cirrhosis. When a cutoff of >2.0 is used, the APRI has a sensitivity of 48% and a specificity of 94%. The advantages of APRI are convenience and low cost, since it uses routine laboratory tests. The disadvantage is that it cannot discern the specific stage of fibrosis when the score is below the cirrhosis cut-off. The above parameters were developed in a population of patients with active HCV infection.

APRI = [(AST (IU/L)/AST_ULN (IU/L))x100]/ platelet count (10⁹/L)

FIB-4

The Fibrosis-4 (FIB-4) test is a calculator tool that also inputs routine laboratory values in addition to age to predict cirrhosis. When the cutoff is set at <1.45, the FIB-4 has a negative predictive value of 90% and sensitivity of 70% for ruling out advanced fibrosis. When the cutoff is set at >3.25, the FIB-4 has a positive predictive value of 65% and a specificity of 97% for the diagnosis of cirrhosis. The advantages of the FIB-4 are the convenience and the low cost as the test is based on AST, ALT, platelet count, and age. Similar to the APRI, the test is unable to determine the specific fibrosis stage. It is very useful for ruling in cirrhosis, but less useful for determining other fibrosis stages. There is a large indeterminant range (1.45<X<3.25) where the results are unable to rule in mild fibrosis or rule out advanced fibrosis, requiring additional methods for assessment. These FIB4 parameters are best validated in patients with active HCV infection.

FIB-4= age (yr) x AST (IU/L)/platelet count (10⁹/L) x [ALT (IU/L)1/2]

Platelet count

For identification of cirrhosis, a platelet count of 140-155 x 10⁹ cells/L is associated with a specificity of 87% and a sensitivity of 78%.

Radiologic tests

Transient Elastography (FibroScan^®)

Transient elastography (TE) is an ultrasound-based method that measures the velocity of an elastic shear wave moving through the liver. This measurement directly correlates to tissue stiffness. Stiffer livers have faster shear wave propagation. The results are reported in kilopascals (kPa) from 2.5 - 75 kPa and a normal value is approximately 5 kPa. For diagnosing significant fibrosis (F≥2), it has an estimated sensitivity of 70 percent and an estimated specificity of 84 percent. For diagnosing cirrhosis, the sensitivity and specificity are estimated to be 87 and 91 percent, respectively.

The test is performed by using a piston that is used to lightly push the skin over an intercostal space, resulting in a shear wave that travels through the liver. Measurements of the shear wave speed are then taken along the direction of the ultrasound beam.

The advantages of TE include its very rapid results, highly accurate, is non-invasive, reproducible, and is relatively easy to train technicians. The disadvantages include the need for dedicated equipment, moderate expense, and limited accuracy in patients with obesity. FibroScan was FDA approved in 2013.

There are different cutoff values for the diagnosis of cirrhosis in patients with chronic HBV and chronic HCV using transient elastography. In patients with HCV, the cutoff values for cirrhosis are 11-14 kPa; in patients with chronic HBV, the cutoff values for cirrhosis are 9.0-10 kPa.

Acoustic Radiation Force Impulse

Acoustic Radiation Force Impulse (ARFI) is an alternative to transient elastography. APRI is also an ultrasound-based method that measures shear wave speeds, producing similarly accurate and rapid results. ARFI generates the shear waves differently and takes different measurements.

Additional resources

Some organizations outside the VA have published recommendations on the preferred test for fibrosis staging.

• World Health Organization (WHO) guidelines
  The updated WHO guidelines for HCV management and treatment address the assessment of liver fibrosis and cirrhosis. WHO recommends APRI or FIB-4 tests for assessment of hepatic fibrosis rather than other methods such as elastography or FibroSure/FibroTest, as these tests require more resources.
• American Association for the Study of Liver Diseases (AASLD) guidelines
  The AASLD guidelines for HCV management recommend performing fibrosis evaluation but do not recommend a preference for any specific test. The report states that, "Evaluation for advanced fibrosis using liver biopsy, imaging, and/or noninvasive markers is recommended for all persons with HCV infection, to facilitate an appropriate decision regarding HCV treatment strategy and to determine the need for initiating additional measures for the management of cirrhosis (eg, hepatocellular carcinoma screening)."

Summary table