Noninvasive Tests for Liver Fibrosis in the Outpatient Setting

Educational Objectives

The goal of this program is to improve management of liver disease with noninvasive testing. After hearing and assimilating this program, the clinician will be better able to:

1. Adjust scoring of tests for liver fibrosis based on patient age.
2. Use measurements of splenic stiffness in evaluation of portal hypertension.

Summary

Introduction: 33% of persons in the United States have metabolic associated steatotic liver disease (MASLD); ≈2 million Americans may have undiagnosed liver disease; fat and inflammation in the liver leads to non-alcoholic steatohepatitis (NASH) or metabolic associated steatohepatitis (MASH); NASH or MSH may progress to clinically significant fibrosis and cirrhosis; Polaris Observatory hepatitis C virus (HCV) collaborators (2017) — showed a decrease in morbidity and mortality from HCV infections; MASH numbers are increasing; patients with significant liver disease may have normal transaminases; diabetes is an independent predictor of negative outcomes in patients with liver disease; the degree of fibrosis is directly associated with mortality; an inflection point in disease progression may fall between moderate fibrosis (F2) and severe fibrosis (F3); the severity of baseline fibrosis is a determinant in disease progression

Fibrosis-4 (FIB-4) score: used for treatment selection in patients with hepatitis C; variables include age, alanine transaminase (ALT), aspartate transaminase (AST), and platelet counts; it is validated against liver biopsy; FIB-4 <1.3 has a high negative predictive value (NPV) for exclusion of advanced fibrosis; the positive predictive value (PPV) of FIB-4 scores >3.25 is 70%; FIB-4 scores increase with age; most clinical trials feature middle-aged participants; a higher cut-off for identifying advanced fibrosis in the geriatric population is required; the AST to ALT ratio increases with severity of fibrosis

The Enhanced Liver Fibrosis (ELF) score: incorporates hyaluronic acid, tissue inhibitor of metalloproteinases 1 (TIMP-1), and procollagen I carboxy peptide (PIIINP), which are associated with hepatic fibrogenesis; disease targeted organ specific biomarkers help categorize patients as low, medium and high likelihood of advanced fibrosis; the ELF score is validated against liver biopsy, has better PPV than FIB-4, and has prognostic validity in NAFLD progression; however, the ELF test is not available from many hospital laboratories; ELF scores perform similarly to FIB-4 for patients with advanced fibrosis; transient elastography has a slightly better PPV than the ELF score

Transient elastography (TE)(Fibroscan): methodology — probes are placed in the intercostal space; test duration is 10 min; fasting of 3 to 4 hr before the test is necessary because increased visceral blood flow may lead to spurious increases in liver stiffness; the test is non-invasive

Interpretation: results of TE must be interpreted in the setting of ALT; patients with acute hepatitis may have a false positive increase because of increased blood flow and edema; the test is not useful in patients with right heart failure, sleep apnea or fluid overload; alcohol use increases the stiffness of liver by 3 to 4 kPa; TE should not be performed in patients with ascites because the radio frequency waves are dispersed by fluid in the abdomen and do not propagate to the liver; obtaining accurate readings in patients with obesity may be difficult; TE may be used as a surrogate for the severity of liver disease or for staging NASH, MASH and hepatitis C; TE analyzes a larger sample of liver tissue compared with liver biopsy; may be used for prognostication; the test requires 10 consecutive readings of liver stiffness which are consistent (interquartile range <30%); the test is considered unreliable in cases of readings which significantly vary; the clinician may obtain the controlled attenuation parameter (CAP) score with TE

Clinical application: accuracy depends on the population under study; TE has high PPV in groups with high prevalence of advanced fibrosis (30%); the test is less accurate in general practice with lower prevalence (5%); TE is good at ruling out cirrhosis (high NPV) and identifying advanced fibrosis and cirrhosis (good PPV); the CAP score correlates with the amount of fat in the liver or steatosis severity and is measured in dB/m; an improvement in the CAP score with therapy is observed after 3 to 4 mo

Shear wave absolute vibro-elastography (S-WAVE): approved by the Food and Drug Administration; less expensive than TE; features a pad which is placed behind the patient on the right side; the wave travels from posterior to anterior direction; a larger field of tissue is sampled; the device measurements are computerized and measured in kPa; ultrasonography (US) is required to ascertain anatomic location of the probe; five consistent scans are used to obtain reliable results; the device is superior to TE for quantifying the amount of fat in liver tissue; assessment for the severity of fibrosis is similar to TE

Magnetic resonance elastography (MRE): considered the gold standard of non-invasive tests; requires specific scanners; not widely available; shear waves are passed through the liver; a large volume of tissue may be sampled; may be used to quantify the amount of fat in the liver; the liver stiffness is measured in kPa; the margin of error is small; normal stiffness is <2.6, mild to moderate fibrosis is 2.6 to 3.6, and advanced fibrosis is >3.6; MRE is able to predict decompensation, varices, cancer, and mortality; Kim et al (2023) — performed a multi-center study to predict hepatic decompensation using MRE; 10 patients had variceal bleeding; ascites was the most common complication, and 2 patients had hepatic encephalopathy; predictors of clinical outcomes included age, MRE value, albumin level, AST, and platelets

Guideline recommendations: clinicians must rule out other causes (eg, hepatitis C) in patients with suspected fatty liver; the first calculator to be used is the FIB-4 scoring; patients with low FIB-4 can be evaluated again after 1 to 2 yr; the second test to order is TE or MRE; MRE provides the most accurate information; clinicians may narrow down the differential diagnoses based on results of TE or MRE; several tools are available to stratify the risk for individual patients; a splenic stiffness test may be done at the same time as a liver stiffness test; a separate probe with a different frequency is used to assess splenic stiffness; US is used to localize the spleen; splenic stiffness measurements correlate better than liver stiffness measurements with clinically significant portal hypertension

Readings

Åberg F, Danford CJ, Thiele M, et al. A dynamic aspartate-to-alanine aminotransferase ratio provides valid predictions of incident severe liver disease. Hepatol Commun. 2021;5(6):1021-1035. Published 2021 Mar 8. doi:10.1002/hep4.1700. View Article; Basu R, Noureddin M, Clark JM. Nonalcoholic fatty liver disease: Review of management for primary care providers. Mayo Clin Proc. 2022;97(9):1700-1716. doi:10.1016/j.mayocp.2022.04.005. View Article; Duarte-Rojo A, Patel K, Rockey DC. Noninvasive assessment of liver fibrosis and portal hypertension. Curr Opin Gastroenterol. 2024;40(3):148-155. doi:10.1097/MOG.0000000000001019. View Article; Hinkson A, Lally H, Gibson H, et al. Meta-analysis: Enhanced liver fibrosis test to identify hepatic fibrosis in chronic liver diseases. Aliment Pharmacol Ther. 2023;57(7):750-762. doi:10.1111/apt.17385. View Article; Inadomi C, Takahashi H, Ogawa Y, et al. Accuracy of the Enhanced Liver Fibrosis test, and combination of the Enhanced Liver Fibrosis and non-invasive tests for the diagnosis of advanced liver fibrosis in patients with non-alcoholic fatty liver disease. Hepatol Res. 2020;50(6):682-692. doi:10.1111/hepr.13495. View Article; Kim BK, Bergstrom J, Loomba R, et al. Magnetic resonance elastography-based prediction model for hepatic decompensation in NAFLD: A multicenter cohort study. Hepatology. 2023;78(6):1858-1866. doi:10.1097/HEP.0000000000000470. View Article; Reiberger T. The value of liver and spleen stiffness for evaluation of portal hypertension in compensated cirrhosis. Hepatol Commun. 2022;6(5):950-964. doi:10.1002/hep4.1855. View Article; Shearer JE, Jones R, Parker R, et al. The natural history of advanced chronic liver disease defined by transient elastography. Clin Gastroenterol Hepatol. 2023;21(3):694-703.e8. doi:10.1016/j.cgh.2022.03.015. View Article; Wong YJ, Urias E, Song MW, et al. Combination of Fibrosis-4, liver-stiffness measurement, and Fibroscan-AST score to predict liver-related outcomes in nonalcoholic fatty liver disease. Hepatol Commun. 2023;7(10):e0244. Published 2023 Sep 22. doi:10.1097/HC9.0000000000000244. View Article; Younossi ZM, Felix S, Jeffers T, et al. Performance of the enhanced liver fibrosis test to estimate advanced fibrosis among patients with nonalcoholic fatty liver disease. JAMA Netw Open. 2021;4(9):e2123923. Published 2021 Sep 1. doi:10.1001/jamanetworkopen.2021.23923. View Article.

Disclosures

For this program, the following relevant financial relationships were disclosed and mitigated to ensure that no commercial bias has been inserted into this content: Dr. Fontana has received grants and research support from Takeda Pharmaceuticals North America and Kezar Life Sciences, and has been on the data and safety monitoring board at Vedanta Biosciences. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Fontana was recorded at the 26th Annual Liver Disease Wrap-Up, held on December 9, 2023, in Plymouth, MI, and presented by the University of Michigan Medical School. For information on upcoming CME activities from this presenter, please visit medschool.umich.edu/offices/cme. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.25 CE contact hours.

Lecture ID:

FP722502

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.