Biochemical Markers of Liver Fibrosis for the Evaluation and Management of Liver Disease

Medical Policy: 02.04.15
Original Effective Date: November 2007
Reviewed:
Revised:

This policy applies to all products unless specific contract limitations, exclusions or exceptions apply. Please refer to the member's coverage manual for benefit availability. Managed care guidelines related to referral authorization, and precertification of inpatient hospitalization, home health, home infusion and hospice services apply.

Description:

The stage of fibrosis is the most important single predictor of significant morbidity and mortality in patients with hepatitis C. Liver biopsy is typically recommended prior to the initiation of antiviral therapy, and repeat biopsies may be performed to monitor fibrosis progression. Liver biopsies are analyzed according to a histologic scoring system; the most commonly used one is the Metavir scoring system, which scores fibrosis from F0-F4, with 0 being no activity and 3 or 4 considered severe activity. Treatment is usually indicated if the Metavir score is greater than or equal to F2. However, several limitations to liver biopsy are noted, including its invasive nature, small sample size, and subjective grading system. Regarding small sample size, liver fibrosis can be patchy and thus missed on a biopsy sample, which includes only 1:50,000 of the liver tissue.

A noninvasive alternative to liver biopsy would be particularly helpful, both to initially assess patients and then as a monitoring tool to assess response to therapy. A variety of laboratory tests have been proposed as an alternative to liver biopsy. Laboratory tests can be broadly categorized into indirect and direct markers of liver fibrosis. Indirect markers include liver function tests such as ALT (alanine aminotransferase), AST (aspartate aminotransferase), the ALT/AST ratio (also referred to as the AAR), platelet count and prothrombin index. In recent years there has been growing understanding of the underlying pathophysiology of fibrosis, leading to direct measurement of the factors involved. For example, the central event in the pathophysiology of fibrosis is activation of the hepatic stellate cell. Normally, the stellate cells are quiescent, but are activated in the setting of liver injury, producing a variety of extracellular matrix (ECM) proteins. In normal livers, the rate of ECM production equals its degradation, but in the setting of fibrosis, production exceeds degradation. Metalloproteinases are involved in intracellular degradation of ECM, and a profibrogenic state exists when there is either a down regulation of metalloproteinases or an increase in tissue inhibitors of metalloproteinases (TIMP). Both metalloproteinases and TIMP can be measured in the serum, which directly reflects fibrotic activity. Other direct measures of ECM deposition include hyaluronic acid or alpha-2 macroglobulin.

While many studies of these individual markers or groups of markers in different populations of patients with liver disease have been done, recently there has been interest in analyzing multiple markers using proprietary algorithms to generate a score that categorizes patients according to the Metavir score. It is proposed that these algorithms can be used as an alternative to liver biopsy in patients with liver disease, particularly hepatitis C.

HCV FIBROSURE™ uses a combination of 6 serum biochemical indirect markers of liver function plus age and gender in a patented algorithm to generate a measure of fibrosis and necroinflammatory activity in the liver that correspond to the Metavir scoring system for stage (i.e., fibrosis) and grade (i.e., necroinflammatory activity). The biochemical markers include the readily available measurements of alpha-2 macroglobulin, haptoglobin, gamma glutamyl transpeptidase (GGT), ALT, and apolipoprotein A1. Developed in France, the test has been clinically available in Europe for the past 2 years and is exclusively offered by LabCorp in this country.

FIBROSpect II® uses a combination of 3 markers that directly measure fibrogenesis of the liver, analyzed with a patented algorithm. The markers include hyaluronic acid, TIMP-1, and alpha-2 macroglobulin. FIBROSpect II® is offered exclusively by Prometheus Laboratories.

Policy:

Combined serum markers of hepatic fibrosis, evaluated with algorithms to produce a predictive score, are considered investigational for the evaluation, diagnosis and clinical management of patients with chronic liver disease, including Hepatitis C.

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Procedure Codes and Billing Guidelines:

To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or ICD-9-CM diagnostic codes.

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Selected References:

Snyder N, Nguyen A, Gajula L et al. The APRI may be enhanced by the use of the FIBROSpect II in the estimation of fibrosis in chronic hepatitis C. Clin Chim Acta. 2007 Jun;381(2):119-23. Epub 2007 Mar 19.
Christensen C, Bruden D, Livingston S et al. Diagnostic accuracy of a fibrosis serum panel (FIBROSpect II) compared with Knodell and Ishak liver biopsy scores in chronic hepatitis C patients. J Viral Hepat. 2006;13(10):652-58.
Zaman A, Rosen HR, Ingram K et al. Assessment of FIBROSpect II to detect hepatic fibrosis in chronic hepatitis C patients. Am J Med. 2007;120(3):280-14.
Patel K, Gordon SC, Jacobson I et al. Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients.
Lu LG, Zeng MD, Wan MB et al. Grading and staging of hepatic fibrosis, and its relationship with noninvasive diagnostic parameters. World J Gastroenterol. 2003;9(11):2574-2578.
Schiavon LL, Schiavon JL, Filho RJ et al. Simple blood tests as noninvasive markers of liver fibrosis in hemodialysis patients with chronic hepatitis C virus infection. Hepatology. 2007 Aug;46(2):307-14.
Myers RP, Ratziu V, Imbert-Bismut F et al. Biochemical markers of liver fibrosis: a comparison with historical features in patients with chronic hepatitis C. Am J Gastroenterol. 2002 Sep;97(9):2419-25.
Bourliere M, Penaranda G, Renou C et al. Validation and comparison of indexes for fibrosis and cirrhosis prediction in chronic hepatitis C patients: proposal for a pragmatic approach classification without liver biopsies. J Viral Hepat. 2006 Oct;13(10):659-70.
Lackner C, Struber G, Liebl B et al. Comparison and validation of simple noninvasive tests for the prediction of fibrosis in chronic hepatitis C. Hepatology. 2005 Jun;41(6):1376-82.

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New information or technology that would be relevant for Wellmark to consider when this policy is next reviewed may be submitted to:

Wellmark Blue Cross and Blue Shield
Medical Policy Analyst
Station 304
636 Grand Ave
Des Moines, Iowa 50309

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