Use of non-invasive tests for liver fibrosis

Authors:

By Shirley Jiang MD (biography, no disclosures) and Hin Hin Ko MD FRCPC (biography and disclosures)

Disclosures and mitigating statements: Dr. Ko: Intercept Pharmaceuticals: Advisory board/speaker honoraria/clinical investigator. Mitigating potential bias: no relevant disclosures for this article.

What care gaps or frequently asked questions I have noticed

All liver etiologies that cause inflammation in the liver can lead to fibrosis over time i.e. alcohol, fatty liver, hepatitis B, C, autoimmune and metabolic liver disease, etc. While liver biopsy is crucial in determining the stage of liver fibrosis in chronic liver disease, it is not the most accessible or appropriate test in most general practice settings. This is because liver biopsy is resource-intensive, invasive, and prone to sampling error. Non-invasive tests (NITs) for liver fibrosis, on the other hand, are more widely available and applicable to different liver conditions. NITs can be a useful tool in general practice to stratify high-risk patients who may require further investigations and referral to specialist care.

Data that answers these questions or gaps

Non-invasive tests ((NITs) can be applied to all liver etiologies, including viral hepatitis,¹ non-alcoholic fatty liver disease (NAFLD),² alcoholic liver disease,³ autoimmune hepatitis,⁴ and cholestatic liver disease.⁵ NITs are comprised of serum fibrosis scores and elastography techniques.

1. Serum scores
   Serum scores require only basic blood work and can be accessed through simple online calculators, such as MDcalc (see “Additional reading” links below). Interpretation of serum scores requires consideration of clinical context; for example, acute hepatitis can elevate serum aminotransferases leading to falsely elevated fibrosis scores. Serum scores are most reliable at the extreme stages of fibrosis (i.e. presence or absence of cirrhosis).² Commonly used fibrosis scores include:
   • Fibrosis-4 score: FIB-4 is calculated based on age, platelet count, AST and ALT. With a lower cut-off value of <1.45, the negative predictive value (NPV) to exclude advanced fibrosis is 90%. An upper cut-off of >3.25 has a positive predictive value (PPV) of 65% for advanced fibrosis, with a specificity of 97%. Originally developed for viral hepatitis patients, this score is the most validated and commonly used for any liver etiology.⁶ For NAFLD, a lower cut-off of FIB-4 <1.3 is recommended for increased sensitivity.^2,7,8 Please see the FIB-4 calculator here.
   • NAFLD fibrosis score: NFS is calculated based on age, platelets, AST:ALT ratio, albumin level, BMI, and presence of impaired fasting glucose or diabetes. A lower cut-off of -1.455 excludes fibrosis with an NPV of 88% and upper cut-off of 0.676 can diagnose advanced fibrosis with PPV 82%. Utilizing NFS to stratify NAFLD patients at high risk of fibrosis has been shown to avoid biopsy in 75% of patients.⁹ Please see the NFS calculator here.
   • AST-to-platelet ratio (APRI): Utilizing only AST and platelets, this score is more accessible though it has lower sensitivity and specificity: an upper cut-off score of >1 has a sensitivity of 76% and 72% for predicting cirrhosis.¹⁰ In NAFLD, an upper cut-off of APRI >0.8 is recommended for increased diagnostic accuracy.¹¹ Please see the APRI calculator here.
   • Composite scores: Commercial scores include the FibroTest® or Enhanced Liver Fibrosis (ELF) score, however, these scores are under patent and limited in accessibility.

2. Elastography
   Elastography involves transmitting an acoustic wave through liver parenchyma and measuring the velocity of propagation to estimate degree of fibrosis. Elastography is a non-invasive, point-of-care test that only takes a few minutes to perform. However, it is limited by availability of costly instruments and trained operators, thus more commonly used in specialized centres. Techniques include:
   • Transient elastography (TE; Fibroscan®): A specialized probe is used to determine the degree of fibrosis, expressed as the Liver Stiffness Measure (LSM) in kPa. TE can also assess attenuation of the ultrasound wave to provide the Controlled Attenuation Parameter (CAP), which corresponds to degree of liver steatosis. As the measured liver volume is 100 times larger than a core biopsy sample, it can provide a more representative assessment of the parenchyma.¹² Sensitivity and specificity for advanced fibrosis are 86.3% and 87.5%, respectively.¹³ Typically, for most liver diseases, an approximate cut-off of LSM <7 kPa suggests absent or minimal fibrosis and >14 kPa correlates with advanced fibrosis or cirrhosis, with NPV >90% for advanced fibrosis. Falsely elevated readings can be seen with non-fasting state, acute hepatitis, cholestasis, hepatic congestion, hepatic mass, and excessive alcohol intake. Accuracy of the readings can also be affected by the presence of ascites or obesity (BMI >35kg/m2).
   • Shear wave elastography (SWE): Conducted with a conventional ultrasound probe, allowing for simultaneous ultrasound image guidance to generate a 2D map of liver stiffness. SWE can better propagate through fluid and subcutaneous tissue, making it more precise in cases of ascites or extreme obesity compared to TE. SWE may be more accurate than TE but currently has less validation studies and lacks established quality criteria.¹⁴
   • Magnetic resonance elastography (MRE): Utilizing MR to determine shear wave propagation, MRE is considered the most accurate technique but is resource-intensive and currently mostly used in a research setting.¹⁵

What I recommend (Practice Tips)

For general practice, non-invasive tests (NITs) can be utilized for excluding advanced fibrosis to aid in risk stratification for specialist referral. NITs do not replace clinical assessment and should always be interpreted according to clinical context, including other investigations, and within its limitations. Liver biopsy, as determined by the specialist, remains the gold standard for cases of diagnostic uncertainty, discordant NITs, and for definitively establishing fibrosis stage.¹⁶

For patients with low likelihood of advanced liver fibrosis, clinicians can begin with a FIB-4 score or APRI score for any liver etiology. For FIB-4 scores less than 1.45 (or 1.3 for suspected NAFLD), it is very unlikely that the patient has advanced fibrosis and continued follow-up/monitoring with their primary care provider is likely appropriate, barring other clinical concerns. If suspicion for liver fibrosis remains high, other causes leading to falsely low scores should be considered (such as clinical conditions affecting serum parameters) and if no confounders are found, referral to the specialist can be considered for more confirmative testing.

Conversely, if the FIB-4 score is greater than 3.25 (with 97% specificity for advanced fibrosis) or APRI is greater than 1 (or 0.8 for suspected NAFLD), referral to the specialist should be considered for confirmation and management of advanced liver fibrosis.

Intermediate results should be clarified with sequential testing, i.e. transient elastography or shear wave elastography, depending on the resource availability. If advanced fibrosis is confirmed on subsequent tests, specialist involvement would be beneficial in helping to manage the underlying liver condition.

Utilizing non-invasive scores and liver stiffness measurements can improve recognition of advanced liver fibrosis, reduce unnecessary liver biopsy and specialist referral, and potentially lead to health system savings.^18,19

Resources

1. Angulo P. NAFLD (non-alcoholic fatty Liver Disease) FIBROSIS SCORE. MDCalc. (View). Accessed September 2, 2021.
2. Sterling R. Fibrosis-4 (fib-4) index for liver fibrosis. MDCalc. (View). Accessed September 2, 2021.

References

1. de Lédinghen V, Vergniol J, Barthe C, et al. Non-invasive tests for fibrosis and liver stiffness predict 5-year survival of patients chronically infected with hepatitis B virus. Aliment Pharmacol Ther. 2013;37(10):979-988. doi:10.1111/apt.12307. (View)
2. Younossi ZM, Noureddin M, Bernstein D, et al. Role of Noninvasive Tests in Clinical Gastroenterology Practices to identify patients with nonalcoholic steatohepatitis at high risk of adverse outcomes: expert panel recommendations. Am J Gastroenterol. 2021;116(2):254-262. doi:10.14309/ajg.0000000000001054. (View with CPSBC or UBC)
3. Moreno C, Mueller S, Szabo G. Non-invasive diagnosis and biomarkers in alcohol-related liver disease. J Hepatol. 2019;70(2):273-283. doi:10.1016/j.jhep.2018.11.025. (View with CPSBC or UBC)
4. Wu S, Yang Z, Zhou J, et al. Systematic review: diagnostic accuracy of non-invasive tests for staging liver fibrosis in autoimmune hepatitis. Hepatol Int. 2019;13(1):91-101. doi:10.1007/s12072-018-9907-5. (Request with CPSBC or view UBC)
5. Corpechot C, Carrat F, Poujol-Robert A, et al. Noninvasive elastography-based assessment of liver fibrosis progression and prognosis in primary biliary cirrhosis. Hepatology. 2012;56(1):198-208. doi:10.1002/hep.25599. (View)
6. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325. doi:10.1002/hep.21178. (View)
7. Sun W, Cui H, Li N, et al. Comparison of FIB-4 index, NAFLD fibrosis score and BARD score for prediction of advanced fibrosis in adult patients with non-alcoholic fatty liver disease: A meta-analysis study. Hepatol Res. 2016;46(9):862-870. doi: 10.1111/hepr.12647. (Request with CPSBC or view UBC)
8. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67(1):6-19. doi:10.1136/gutjnl-2017-314924. (View)
9. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854. doi:10.1002/hep.21496. (View)
10. Lin Z-H, Xin Y-N, Dong Q-J, et al. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011;53(3):726-736. doi:10.1002/hep.24105. (View)
11. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010;59(9):1265-1269. doi:10.1136/gut.2010.216077. (View)
12. Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48(5):835-847. doi:10.1016/j.jhep.2008.02.008. (View with CPSBC or UBC)
13. Li Y, Huang Y-S, Wang Z-Z, et al. Systematic review with meta-analysis: the diagnostic accuracy of transient elastography for the staging of liver fibrosis in patients with chronic hepatitis B. Aliment Pharmacol Ther. 2016;43(4):458-469. doi:10.1111/apt.13488. (View)
14. Cassinotto C, Boursier J, Lédinghen V de, et al. Liver stiffness in nonalcoholic fatty liver disease: A comparison of supersonic shear imaging, FibroScan, and ARFI with liver biopsy. Hepatology. 2016;63(6):1817-1827. doi:10.1002/hep.28394. (View)
15. Hsu C, Caussy C, Imajo K, et al. Magnetic resonance vs transient elastography analysis of patients with nonalcoholic fatty liver disease: A systematic review and pooled analysis of individual participants. Clin Gastroenterol Hepatol. 2019;17(4):630-637.e8. doi:10.1016/j.cgh.2018.05.059. (View)
16. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63(1):237-264. doi:10.1016/j.jhep.2015.04.006. (View with CPSBC or UBC).
17. Xiao G, Zhu S, Xiao X, Yan L, Yang J, Wu G. Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: A meta‐analysis. Hepatology. 2017;66(5):1486-1501. doi:10.1002/hep.29302. (View).
18. Vilar-Gomez E, Lou Z, Kong N, Vuppalanchi R, Imperiale TF, Chalasani N. Cost Effectiveness of Different Strategies for Detecting Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Based on United States Health Care System. Clin Gastroenterol Hepatol. 2020;18(10):2305-2314.e12. doi:10.1016/j.cgh.2020.04.017. (Request with CPSBC or view UBC)
19. Shaheen AA, Riazi K, Medellin A, et al. Risk stratification of patients with nonalcoholic fatty liver disease using a case identification pathway in primary care: a cross-sectional study. CMAJ Open. 2020;8(2):E370-E376. doi:10.9778/cmajo.20200009. (View)

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