Cirrhosis represents the final stage of liver fibrosis, characterized by the destruction of the liver's structural integrity. Various factors can lead to this condition, including alcohol-related disease, non-alcoholic fatty liver disease (NAFLD), chronic viral hepatitis, and cholestatic liver disease. Nonalcoholic fatty liver disease (NAFLD) stands as the predominant contributor to chronic liver disease, and it is intricately linked to a systemic condition that includes obesity, insulin resistance (IR), type 2 diabetes mellitus (T2D), hypertension, and atherogenic dyslipidemia. In contrast, nonalcoholic steatohepatitis (NASH), which has a higher likelihood of progressing to advanced fibrosis stages, is distinguished by the presence of active hepatocyte injury and inflammation alongside steatosis.

Detecting liver fibrosis at an early stage, before clinical symptoms emerge, is crucial for preventing cirrhosis. Although liver biopsy is considered the gold standard for staging fibrosis, it comes with notable drawbacks, such as invasiveness, high cost, and potential complications like pain, infection, and peritoneal bleeding. Additionally, fibrosis distribution within the liver tissue varies, and a diagnosis is based on a small 15 mm biopsy specimen, which represents just a fraction of the entire liver. Consequently, the accuracy of histological evaluation relies heavily on the pathologist's experience. The diagnosis and assessment of liver fibrosis stage are essential for evaluating the risk of cirrhosis and guiding its treatment. Consequently, there is a rising interest in non-invasive markers that could provide viable and cost-effective alternatives for both patients and healthcare professionals.

In general, noninvasive laboratory tests can be categorized into two groups: (1) fibrosis-4 (fib-4) index score, NAFLD fibrosis score (NFS), and aspartate aminotransferase-platelet ratio index score, using routinely collected laboratory and clinical data to calculate a risk score; and (2) blood-based tests that utilize direct biomarkers associated with fibrogenesis and cytolysis, which is enhanced liver fibrosis (ELF). Fib-4 was discussed before [1], and the ELF test is focused on this scientific short. The ELF test comprises three components, which are type III procollagen peptide (PIIINP), hyaluronic acid (HA), and tissue inhibitor of metalloproteinase-1 (TIMP1).

In a prospective longitudinal cohort study involving 3,012 adults, researchers compared the outcomes before and after the introduction of a two-step care pathway. They found that utilizing the FIB-4 and ELF tests led to an impressive 88% reduction in unnecessary specialist referrals. Furthermore, it resulted in a fourfold increase in the detection of individuals who were likely to have advanced fibrosis [2]. In another large study involving 829 patients with NAFLD, the ELF test demonstrates strong performance in recognizing individuals with NAFLD who have an elevated risk of advanced fibrosis. Combining this test with the fib-4 score could provide a reliable clinical tool for determining the presence or absence of advanced fibrosis in patients with NAFLD [3].

In the most recently published AACE guidelines, it is recommended that after establishing the presence of NAFLD, it becomes crucial to stratify the risk of fibrosis. The initial recommended test is the FIB-4, which often effectively distinguishes individuals with low and high risks of liver fibrosis. Nevertheless, a significant portion of individuals may fall into a 'gray zone' where the risk is uncertain, necessitating additional testing to determine whether referral to a liver specialist is warranted. The second recommended blood test is the ELF test, which should provide risk assessment for most individuals. Those with a low risk of cirrhosis can be managed within primary care and/or endocrinology clinics, whereas individuals with an indeterminate to high risk of liver fibrosis should be referred to a liver specialist, facilitating a multidisciplinary approach to their care [4].

These biomarkers offer significant benefits, including less invasiveness compared to liver biopsy, simple application through routine laboratory tests, excellent reproducibility across various laboratories, and the ability to assess the pathophysiological progression. Nevertheless, they come with several drawbacks, such as the inability to distinguish between intermediate stages, a lack of liver-specificity in most cases, susceptibility to interference from comorbidities, and often limited analytical accuracy.

References

  1. Ask the Expert - Focus on FibroTest. https://www.myadlm.org/cln/articles/2022/julyaugust/focus-on-fibrotest
  2. Ankur Srivastava, Ruth Gailer, Sudeep Tanwar, Paul Trembling, Julie Parkes, Alison Rodger, Deepak Suri, Douglas Thorburn, Karen Sennett, Sarah Morgan, Emmanuel A Tsochatzis, William Rosenberg. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol. 2019 Aug;71(2):371-378. doi: 10.1016/j.jhep.2019.03.033.
  3. Zobair M Younossi, Sean Felix, Thomas Jeffers, Elena Younossi, Fatema Nader, Huong Pham, Arian Afendy, Rebecca Cable, Andrei Racila, Zahra Younoszai, Brian P Lam, Pegah Golabi, Linda Henry, Maria Stepanova. Performance of the Enhanced Liver Fibrosis Test to Estimate Advanced Fibrosis Among Patients With Nonalcoholic Fatty Liver Disease. JAMA Netw Open. 2021 Sep 1;4(9):e2123923. doi: 10.1001/jamanetworkopen.2021.23923.
  4. Kenneth Cusi, Scott Isaacs, Diana Barb, Rita Basu, Sonia Caprio, W Timothy Garvey, Sangeeta Kashyap, Jeffrey I Mechanick, Marialena Mouzaki, Karl Nadolsky, Mary E Rinella, Miriam B Vos, Zobair Younossi. American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings: Co-Sponsored by the American Association for the Study of Liver Diseases (AASLD). Endocr Pract. 2022 May;28(5):528-562. doi: 10.1016/j.eprac.2022.03.010.