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    Fibrosis-4 (FIB-4) Index for Liver Fibrosis

    Noninvasive estimate of liver scarring in HCV and HBV patients, to assess need for biopsy.
    When to Use
    Why Use
    • Patients with any known risk factors for liver disease, including chronic hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD) and the cholestatic and metabolic liver diseases.
    • Patients with known liver fibrosis should have their fibrosis trended over time to evaluate for progression or stabilization.
    • Liver fibrosis often progresses non-linearly, so it is important to be able to re-assess fibrosis trends in individual patients over time, and invasive re-assessments carry significant risk to patients. FIB-4 allows for non-invasive liver fibrosis assessment.
    • FIB-4 was developed in patients with HIV and HCV co-infection.
    • FIB-4 was developed to correlate with Ishak levels of fibrosis (by biopsy) with 3 levels:
      • 0-2 (mild fibrosis)
      • 3-4 (moderate fibrosis)
      • 5-6 (severe fibrosis/cirrhosis)
    • While liver biopsy is the gold standard for the diagnosis of liver fibrosis, it is not ideal; biopsy only evaluates a minute portion of the liver itself, so sampling errors can occur. Liver biopsy also comes with substantial morbidity.
    • Liver fibrosis often progresses non-linearly, so it is important to be able to re-assess fibrosis trends in individual patients over time.
    • It is critical that tests to identify liver cirrhosis are highly sensitive, as patients with the disease require screening for hepatocellular carcinoma (HCC) and gastroesophageal varices.
    • The FIB-4 Index was shown to be superior to 7 other noninvasive markers of fibrosis in patients with NAFLD, including the NAFLD Fibrosis Score (Shah 2009).
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    Creator Insights
    Dr. Richard Sterling

    From the Creator

    How did you develop a clinical interest in liver disease? Was there a particular clinical experience or patient encounter you had?

    I first became interested in liver disease while getting my master’s in biochemistry at the University of Texas, Austin while focusing on intermediary metabolism. My decision to become a hepatologist was also influenced in large part due to my interactions with my chairman of medicine, Dr. Willis Maddrey, while a student at Jefferson Medical College.

    What pearls, pitfalls and/or tips do you have for users of the FIB-4? Do you know of cases when it has been applied, interpreted, or used inappropriately?

    While FIB-4 offers an easy and essentially free assessment of liver fibrosis, it is not without limitations. It was developed in a cohort of subjects that did not include the young or very old, so it may not perform as well in those populations given that age is in the numerator. Furthermore, inclusion of age makes it less reliable to use longitudinally.  Because AST is also in the numerator, it may overestimate fibrosis in those with alcohol use. Lastly, the cut offs for HCV are different than those with NASH or HBV.

    How do you use the FIB-4 in your own clinical practice?

    As with any biomarker, we are really asking two questions. First, does my patient have no fibrosis, in which case they might not need urgent treatment and can be followed conservatively? Second, does my patient have advanced fibrosis which might need additional testing, such as ultrasound to screen for hepatocellular carcinoma and endoscopy to screen for varices? Those with advanced fibrosis are also a priority for treatment. We use FIB-4 as an initial assessment. In chronic HCV, when combined with APRI, it has excellent negative predictive value for excluding advanced fibrosis. The positive predictive value is less clear.  Those with FIB-4 >1.5 and/or APRI >0.5 often go on to liver elastography.

    There are no data on the use of FIB-4 in someone who has been treated with a direct-acting antiviral (DAA) and achieved sustained virologic response (SVR). Because AST and ALT often normalize with SVR, unless there is underlying non-alcoholic fatty liver disease (NAFLD), I would not expect FIB-4 or APRI to be increased unless the patient had low platelets. That also goes for liver elastography, where most improvements are related to reductions in inflammation and not necessarily fibrosis.   

    How is the landscape of hepatitis C virus (HCV) management changing since the advent of DAAs? Should HCV patients on the transplant list be treated before transplantation? Will the disease be eradicated someday?

    The development of DAA and non-invasive assessments of liver disease severity have dramatically changed how we approach and manage chronic HCV. The overall safety and tolerability of DAA also have expanded the patient population who we can treat. Those with compensated cirrhosis or MELD <15 have similar high SVR compared to those without cirrhosis although they may require longer treatment or addition of ribavirin to the DAA. Data also suggests that those with mild decompensation (MELD 15-20) can be treated successfully although a percentage may worsen. In this group, we often evaluate for liver transplant first.  In those with more severe decompensation (MELD >20), treatment should be done in liver transplant centers with expertise in managing these patients. There is a MELD score beyond which treatment may be safe and beneficial, but that is center specific. When deciding on HCV treatment in someone on the transplant list, the patient must be made aware that their MELD score may improve to the point where they no longer have the same priority (MELD purgatory) and that if they are SVR, they may not be eligible for a HCV positive organ which might also prolong their wait. With increased use of DAA, NASH is becoming the most common indication for liver transplantation.

    There are some data suggesting a link between DAAs and development of HCC (e.g. Reig et al 2016) - or at least no decrease in HCC risk (e.g. Conti et al 2016), which seems counterintuitive. What are your thoughts on this?

    After the initial reports on an increased risk of developing HCC post SVR with DAA, I have followed the literature carefully.  Fortunately, several large cohort studies have not shown an increased rate of HCC after SVR with DAAs. This was also true at our center. That being said, it is important to screen for HCC prior to starting DAA in any patient with advanced fibrosis and continue surveillance after SVR.

    Where are there deficits in research in liver disease? Any research in the pipeline that you're particularly interested in?

    There are few challenging treatment populations remaining in HCV.  Many of the factors that were negative predictors to SVR (black race, HIV coinfection, cirrhosis, steatosis, IL-28B) are no longer important. Those with genotype 3, especially if cirrhosis and prior non-response to treatment and those with mild decompensated cirrhosis have excellent, but somewhat lower SVR. The groups that remains a challenge where we need new therapies are those with decompensation and renal significant dysfunction and the rare patient who fails our current DAA regimens. Lastly, we now recognize that there is a chance of HBV reactivation in those treated with DAAs. Although this seems limited to those who are HBsAg positive, rare cases of HBV reactivation have been reported in those with past exposure to HBV (core antibody positive) and surface antigen negative.  The mechanism of this rare event needs further study.

    About the Creator

    Richard K. Sterling, MD, is a professor and the chief of hepatology at Virginia Commonwealth University. His research interests include liver transplantation, HIV-HCV coinfection, acute and chronic liver disease, viral hepatitis C and B, and other hepatic pathologies.

    To view Dr. Richard Sterling's publications, visit PubMed

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    About the Creator
    Dr. Richard Sterling
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