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DESCRIPTIONMultianalyte serum assays with algorithmic analysis are being evaluated as a substitute for biopsy in the screening, evaluation, and monitoring of patients with chronic liver disease. Several commercially available tests are proposed to detect fibrosis, steatosis (fatty liver), or steatohepatitis (fatty liver with inflammation) in patients with hepatitis C, alcoholic liver disease, and non-alcoholic fatty liver disease.
Biopsy for Chronic Liver Disease. The diagnosis of non-neoplastic liver disease is often made from needle biopsy samples. In addition to establishing a disease etiology, liver biopsy can determine the degree of inflammation present and can stage the degree of fibrosis. The degree of inflammation and fibrosis may be assessed by different scoring schemes. Most of these scoring schemes grade inflammation from 0-4 (with 0 being no or minimal inflammation and 4 being severe) and fibrosis from 0-4 (with 0 being no fibrosis and 4 cirrhosis). There are several limitations to liver biopsy, including its invasive nature, small tissue sample size, and subjective grading system. Regarding small tissue sample size, liver fibrosis can be patchy and thus missed on a biopsy sample, which includes only 0.002% 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.
Hepatitis C. Infection with the hepatitis C virus can lead to permanent liver damage. Liver biopsy is typically recommended prior to the initiation of antiviral therapy. Repeat biopsies may be performed to monitor fibrosis progression. Liver biopsies are analyzed according to a histologic scoring system; the most commonly used one for hepatitis C is the Metavir scoring system, which scores the presence and degree of inflammatory activity and fibrosis. The fibrosis is graded from F0-F4, with a Metavir score of F0 signifying no fibrosis and F4 signifying cirrhosis (which is defined as the presence throughout the liver of fibrous septa that subdivide the liver parenchyma into nodules (ancytod represents the final and irreversible form of disease). The stage of fibrosis is the most important single predictor of morbidity and mortality in patients with hepatitis C. Biopsies for hepatitis C are also evaluated according to the degree of inflammation present, referred to as the grade or activity level. For example, the Metavir system includes scores for necroinflammatory activity ranging from A0 to A3 (A0=no activity, A1=minimal activity, A2=moderate activity, A3=severe activity).
Alcoholic Liver Disease (ALD). ALD is the leading cause of liver disease in most Western countries. Histologic features of ALD usually include steatosis, alcoholic steatohepatitis (ASH), hepatocyte necrosis,Mallory bodies (tangled proteins seen in degenerating hepatocytes), a large polymorphonuclear inflammatory infiltrate, and, with continued alcohol abuse, fibrosis and possibly cirrhosis. The grading of fibrosis is similar to the scoring system used in hepatitis C. The commonly used Laënnec scoring system uses grades 0-4, with 4 being cirrhosis.
Non-alcoholic Fatty Liver Disease (NAFLD). NAFLD is defined as a condition that pathologically resembles ALD but occurs in patients who are not heavy users of alcohol. It may be associated with a variety of conditions, including obesity, diabetes, and dyslipidemia. The characteristic feature of NAFLD is steatosis. At the benign end of the spectrum of the disease, there is usually no appreciable inflammation, hepatocyte death, or fibrosis. In contrast, non-alcoholic steatohepatitis (NASH), which shows overlapping histologic features with ALD, is an intermediate form of liver damage, and liver biopsy may show steatosis, Mallory bodies, focal inflammation, and degenerating hepatocytes. NASH can progress to fibrosis and cirrhosis. A variety of histological scoring systems have been used to evaluate NAFLD. The NAFLD activity score (NAS) system for NASH includes scores for steatosis (0-3), lobular inflammation (0-3), and ballooning (0-2). Cases with scores of 5 or greater are considered NASH, while cases with scores of 3 and 4 are considered borderline (probable or possible) NASH. The grading of fibrosis is similar to the scoring system used in hepatitis C. The commonly used Laënnec scoring system uses grades 0-4, with 4 being cirrhosis.
Non-invasive Alternatives to Liver Biopsy. A variety of non-invasive laboratory tests are being evaluated as an alternative to liver biopsy. Biochemical 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.
HCV FibroSure™ (FibroTest™) 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, bilirubin, y-glutamyl transpeptidase (GGT), ALT, and apolipoprotein A1. Developed in France, the test has been clinically available in Europe under the name FibroTest™ since 2003 and is exclusively offered by LabCorp in the U.S. as HCV FibroSure™.
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.
ASH FibroSURE™ (ASH Test) uses a combination of 10 serum biochemical markers of liver function together with age, gender, height, and weight in a proprietary algorithm and is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and alcoholic steatohepatitis (ASH). The biochemical markers include alpha-2 macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name ASH Test™ and is exclusively offered by LabCorp in the U.S. as ASH FibroSure™.
NASH FibroSURE™ (NASH Test) uses a proprietary algorithm of the same 10 biochemical markers of liver function in combination with age, gender, height, and weight and is proposed to provide surrogate markers for liver fibrosis, hepatic steatosis, and NASH. The biochemical markers include alpha-2 macroglobulin, haptoglobin, apolipoprotein A1, bilirubin, GGT, ALT, AST, total cholesterol, triglycerides, and fasting glucose. The test has been available in Europe under the name NASH Test™ and is exclusively offered by LabCorp in this country as NASH FibroSure™.
POLICYMultianalyte assays with algorithmic analyses are considered investigational for the diagnosis or monitoring of patients with chronic liver disease.
POLICY GUIDELINESInvestigative service is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized by certifying boards and/or approving or licensing agencies or published peer review criteria as standard, effective medical practice for the treatment of the condition being treated and as such therefore is not considered medically necessary.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
09/27/2012: New policy added.
09/16/2014: Policy reviewed; description updated. Policy statement unchanged. Sources section updated to change "2.01.84" to "2.04.41."
SOURCE(S)Blue Cross Blue Shield Association policy # 2.04.41
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.