Intended for US healthcare professionals only.
Intended for US healthcare professionals only.
Take a
closer look
at noninvasive
tests
Identifying patients with Advanced Fibrosis is a changing landscape.
While biopsy has long been the standard, it’s an imperfect standard.1,2 However, there are a range of noninvasive tests (NITs) that can identify the presence of Advanced Fibrosis.
Let’s take a look at what makes NITs a viable alternative when testing for Advanced Fibrosis.
BIOPSY HAS TRADITIONALLY BEEN USED FOR IDENTIFICATION OF Advanced Fibrosis BUT IS ASSOCIATED WITH NUMEROUS LIMITATIONS2-7
Only analyzes 1/50,000 of the liver and interpretation may differ between pathologists, therefore serial biopsies may provide inconsistent findings2,4-6
Costly procedure4 which may require additional cost and time of an interventional radiologist7
Invasive procedure with a risk of rare but life-threatening complications, not ideal for monitoring patients over time2,4,8
Patient concerns related to the invasive nature of biopsy, as well as the potential for pain, discomfort, and complications2,8
According to claims data, ~7% of patients newly diagnosed with NASH (without cirrhosis) received a liver biopsy in the prior 12 months9*
LIVER BIOPSY IS AN IMPERFECT REFERENCE STANDARD FOR THE IDENTIFICATION OF ADVANCED FIBROSIS1,2
AUROC for detection of Advanced Fibrosis in paired biopsies from 51 patients: 0.87 (95% CI: 0.7–0.95)1
Absence of Advanced Fibrosis1†‡
Sensitivity of 85%
15% of patients with Advanced
Fibrosis are missed
Presence of Advanced Fibrosis1†‡
Specificity of 89%
11% of patients are wrongly diagnosed
with Advanced Fibrosis
In a study of patients with Advanced Fibrosis (n=17) , diagnosis would have been missed in 35% of patients if only one liver biopsy were analyzed1†‡
Interobserver concordance rates of <67% show that the interpretation of liver biopsy results can vary among trained pathologists10§
Based on paired biopsies assessed with Brunt scores 3 and 4. Brunt scores 3 and 4 defined in publication as ‘bridging fibrosis’.
Study to assess the sampling error of liver biopsy and its impact on diagnosis and stage of NASH. Patients with NAFLD (n=51) underwent percutaneous liver biopsy with 2 samples collected. The agreement between paired biopsy specimens was assessed by the percentage of discordant results and by the Kappa reliability test.
The study investigated interobserver agreement for scores of liver fibrosis in 65 biopsy specimens from patients with mixed liver disease etiologies. Concordance between three pathologists was analysed. Bivariate weighted κ for Ishak staging ranged from 0.57–0.67, and for NASH CRN staging ranged from 0.47–0.59.
NONINVASIVE TESTS OFFER ALTERNATIVE WAYS TO DETERMINE THE DEGREE OF FIBROSIS
NITs ARE REPRODUCIBLE, WIDELY AVAILABLE, AND RELATIVELY LOW-COST2,11-13
Safe and simple way to support disease monitoring over time11
May be cost effective as opposed to biopsy11
Assess the level — e.g. absence or presence — of fibrosis12
Sequential use of NITs may increase the number of patients identified with Advanced Fibrosis13
COMMONLY USED NITs
NITs use different approaches to determine liver fibrosis4:
1
Simple Scores
Use Information from standard liver tests and patient data4
2
Proprietary
Serum
Tests
Test biomarkers associated with fibrosis stage4
3
Imaging Techniques
Focus on liver stiffness4
NITs are an area of active research and learning continues to evolve.
All third-party trademarks referenced herein are the property of their respective owners. For general information and educational purposes only and is not a substitute for professional advice. Intercept makes no representation or warranty of any kind, express or implied, regarding the accuracy, adequacy, validity, reliability, availability or completion of the information provided or the tests described herein. Please contact labs and NIT manufacturers for specific information and limitations regarding tests.
List of NITs provided above is not exhaustive.
WHAT MAKES A GOOD NIT?
A good NIT is both sensitive and specific in determining the presence of Advanced Fibrosis.16
Use of two cut-off values can maximize sensitivity and specificity compared to the use of a single cut-off value.2
Lower
cut-off value
Upper
cut-off value
Absence of Advanced Fibrosis
Indeterminate
Presence of Advanced Fibrosis
An acceptable NIT also has an AUROC value closer to 1.016¶
If a patient falls in between these two cut-offs, in the indeterminate zone, a second NIT may be conducted.2,13,17,18
THE USE OF A SECOND NIT for patients in the indeterminate zone COULD INCREASE THE NUMBER OF PATIENTS IDENTIFIED WITH ADVANCED FIBROSIS2,13,17,18
The sequential use of NITs maintains sensitivity and specificity
while decreasing the number of patients in the indeterminate zone.2,13,17,18
Adapted from Younossi ZM et al. Presented at: AASLD; November 9–13, 2018; San Francisco, United States; Abstract LB-10.
¶The AUROC (Area Under the Receiver Operating Characteristic curve) gives an average performance of a model (NIT) along all sensitivity thresholds. The higher the AUROC (or the closer to 1.0 or similar) the better the model is at distinguishing between patients with disease and no disease.16
UTILIZATION OF A SECOND NIT FOR PATIENTS IN THE INDETERMINATE ZONE FOLLOWING A SINGLE NIT
Utilization of NITs sequentially may…
…generally
maintain
sensitivity
and
specificity2
…detect up
to five times
more cases
of Advanced
Fibrosis and
cirrhosis13
…reduce the
rate of
indeterminate
results
to as
low as 20%2,19
However, when
two NITs are utilized
sequentially,
the misclassification
rate also
increases slightly2
RECENT GUIDELINES RECOGNIZE THE VALUE OF NITs
NITs have prognostic value in predicting both mortality and liver-related complications in patients with NAFLD/NASH and other chronic liver diseases.4
“There has been significant
interest in developing clinical prediction rules and noninvasive biomarkers for identifying SH [steatohepatitis]”3
“All individuals in target patient risk groups# undergo a 2-tier process to assess for clinically significant liver fibrosis. The first tier involves using simple, nonproprietary fibrosis scores such as FIB-4. The second tier relies on an imaging-based test for LSM, depending on the initial FIB-4 score.”18
#Target risk groups include patients with type 2 diabetes, 2 or more metabolic risk factors, or an incidental finding of hepatic steatosis or elevated aminotransferases. Metabolic risk factors include central obesity (waist circumference with ethnicity-specific cut-offs; raised serum triglycerides (≥150 mg/dL, or specific treatment for hypertriglyceridemia); reduced serum high-density lipoprotein cholesterol (<40 mg/dL in men, <50 mg/dL in women or specific treatment); hypertension (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg, or specific treatment); and raised fasting plasma glucose (100-125 mg/dL [prediabetes]).
GET TO KNOW YOUR NITs
Fibrosis 4 (FIB-4) can determine the presence of Advanced Fibrosis2,13
FIB-4 cut-off scores and accuracy for measurement of Advanced Fibrosis2*
<1.3
≥2.67
Absence of Advanced Fibrosis
Presence of Advanced Fibrosis
FIB-4 can be easily calculated in office with a simple blood test and online calculator21
FIB-4 test results are based on age, hence the accuracy of the test may vary according to age.
NAFLD Fibrosis Score (NFS) can determine the presence of Advanced Fibrosis
NFS cut-off scores and accuracy for measurement of Advanced Fibrosis2*
<-1.445
≥0.676
Absence of Advanced Fibrosis
Presence of Advanced Fibrosis
NFS can be easily calculated in office with a simple blood test and
online calculators3*
Calculator available at: https://www.mdcalc.com
NFS test results are based on age, hence the accuracy of the test may vary according to age.
Aspartate Aminotransferase/Platelet Ratio Index (APRI) can exclude
Advanced Fibrosis
APRI cut-off scores and accuracy for measurement of Advanced Fibrosis24*
<0.57
>0.84
Absence of Advanced Fibrosis
Presence of Advanced Fibrosis
Caution needed with false positives, particularly in patients with acute hepatitis.4
May be more useful to exclude, rather than determine, Advanced Fibrosis.15
APRI can be easily calculated in office with a simple blood test and online
The study population included patients with histological findings consistent with NAFLD.
FibroSure® can determine the presence of Advanced Fibrosis
FibroSure® cut-off scores and accuracy for measuring Advanced Fibrosis26,27†
≤0.31
>0.58
Early or No Fibrosis
Presence of Advanced Fibrosis
FibroSure® is distributed by LabCorpTM in the US.
False positives can arise from haemolysis, Gilbert syndrome, cholestasis and inflammation due to increased levels of α2-macroglobulin and haptoglobin.11
In patients with hepatitis C.
Moderate, F1–F2 and F2–bridging fibrosis with few septa.25
Enhanced Liver Fibrosis (ELFTM) can determine the presence of Advanced Fibrosis
ELFTM cut-off scores and accuracy for measurement of Advanced Fibrosis28,30
<7.7
≥9.8
Early or No Fibrosis
Presence of Advanced Fibrosis
All third-party trademarks referenced herein are the property of their respective owners.
AUROC and cut-off values for identifying presence vs absence of Advanced Fibrosis
from a study of patients with various liver disease etiologies.30
Transient Elastography (e.g. FIBROSCAN®) can determine the presence of Advanced Fibrosis
FibroScan® cut-off scores and accuracy for measurement of Advanced Fibrosis32
<7.9 kPa
≥9.6 kPa
Absence of Advanced Fibrosis
Presence of Advanced Fibrosis
Transient Elastography (e.g. FibroScan®) measures liver stiffness, which correlates with fibrosis33
Measures liver stiffness
over an area estimated to be 100x greater than that of liver biopsy33
Failure to obtain readings
is more likely in patients with a high BMI (>30 kg/m2), however, use of XL probe may help overcome this limitation33
Over-estimation of fibrosis
can occur in cases of hepatitis, cholestasis, liver congestion and if mass lesions are present in the liver34
Magnetic Resonance Elastography (MRE) can determine the presence of Advanced Fibrosis
MRE cut-off scores and accuracy for measurement of advanced fibrosis36
<2.97
>3.62
Early or No Fibrosis
Presence of Advanced Fibrosis
MRE is recognized by the American Association for the Study of Liver Diseases, or AASLD, as clinically useful for the identification of Advanced Fibrosis in patients with NAFLD.3
MRE has been shown to be both sensitive and specific when identifying different stages of liver fibrosis33
Unlike other NITs and liver biopsy, MRE estimates the average degree of fibrosis throughout the entire liver33
Limitations include the high cost of the equipment and the level of expertise required to interpret results33
Moderate is classified as patients with fibrosis staging of F2.
MRE image indicates Advanced Fibrosis (F3) – liver stiffness 6.1 kPa. Adapted from Venkatesh SK et al. J Magn Reson Imaging. 2013;37:544–555.
References: 1. Ratzui V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898-1906. 2. Anstee QM, Lawitz EJ, Alkhouri N, et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology. 2019;70(5):1521-1530. 3. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328-357. 4. European Association for Study of Liver. EASL-ALEH clinical practice guidelines: non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63(1):237-264. 5. Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD; American Association for the Study of Liver Diseases. Liver biopsy. Hepatology. 2009;49(3):1017-1044. 6. Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(2):475-485. 7. Diehl AM, Day C. Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis. N Engl J Med. 2017;23;377(21):2063-2072. 8. Leoni S, Tovoli F, Napoli L, Serio I, Ferri S, Bolondi L. Current guidelines for the management of non-alcoholic fatty liver disease: A systematic review with comparative analysis. World J Gastroenterol. 2018;24(30):3361-3373. 9. Data on File [US-NAS-MED-00826]. 10. Pavlides M, Birks J, Fryer E, et al. Interobserver variability in histologic evaluation of liver fibrosis using categorical and quantitative scores. Am J Clin Pathol. 2017;147(4):364-369. 11. Tapper EB, Sengupta N, Hunink MG, Afdhal NH, Lai M. Cost-effective evaluation of nonalcoholic fatty liver disease with NAFLD fibrosis score and vibration controlled transient elastography. Am J Gastroenterol. 2015;110(9):1298-1304. 12. Lucero C, Brown RS Jr. Noninvasive measures of liver fibrosis and severity of liver disease. Gastroenterol Hepatol (NY). 2016;12(1):33-40. 13. Srivastava A, Gailer R, Tanwar S, et al. Prospective evaluation of a primary care referral pathway for patients with non-alcoholic fatty liver disease. J Hepatol. 2019;71(2):371-378. 14. Alkhouri N, McCullough AJ. Noninvasive diagnosis of NASH and liver fibrosis within the spectrum of NAFLD. Gastroenterol Hepatol (NY). 2012;8(10):661-668. 15. Atay K, Alan O, Canbakan B, et al. Evaluation of non-invasive diagnostic methods as indicators of fibrosis in patients with nonalcoholic fatty liver disease. Biomedical Research. 2017;28(2):565-570. 16. Bewick V, Cheek L, Ball J. Statistics review 13: receiver operating characteristic curves. Crit Care. 2004;8(6):508-512. 17. Younossi ZM, et al. Presented at: AASLD; November 9–13, 2018; San Francisco, California; Abstract LB-10. 18. Kanwal F, Shubrook JH, Adams LA, et al. Clinical care pathway for the risk stratification and management of patients with nonalcoholic fatty liver disease. Gastroenterology. 2021;161(5):1657-1669. 19. Chan WK, Treeprasertsuk S, Goh GB, et al. Optimizing use of non-alcoholic fatty liver disease fibrosis scare, fibrosis-4 score, and liver stiffness measurement to identify patients with advanced fibrosis. Clin Gastroenterol Hepatol. 2019;17(12):2570-2580. 20. Srivastava A, Jong S, Gola A, et al. Cost-comparison analysis of FIB-4, ELF and fibroscan in community pathways for non-alcoholic fatty liver disease. BMC Gastroenterol 2019;19(1):122. 21. Fibrosis-4 calculator. Available at: https://www.mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis. Accessed October 2022. 22. Angulo P, Bugianesi E, Bjornsson ES, et al. Simple noninvasive systems predict long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology. 2013;145:782–789. 23. Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-1273. 24. Siddiqui MS, Yamada G, Vuppalanchi R, et al. Diagnostic accuracy of noninvasive fibrosis models to detect change in fibrosis stage. Clin Gastroenterol Hepatol. 2019;17(9):1877-1885. 25. Kruger FC, Daniels CR, Kidd M, et al. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J. 2011;101(7):477-480. 26. Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3(1):8. 27. LabCorp NASH FibroSure sample report. Available at: https://files.labcorp.com/testmenu-d8/sample_reports/550140.pdf. Accessed October 2022. 28. Siemens Healthineers. ELFTM instructions for use. Available at: https://doclib.siemens-healthineers.com/rest/v1/view?document-id=728561. Accessed October 2022. 29. Siemens Healthineers. FDA Grants Marketing Authorization to Siemens Healthineers ELFTM Test for NASH Prognostic Assessment. Available at: https://www.siemens-healthineers.com/en-us/press-room/press-releases/fdamarketingauthorizationelfnash.html. Accessed October 2022. 30. Day J, Patel P, Parkes J, Rosenberg W. Derivation and performance of standardized Enhanced Liver Fibrosis (ELFTM) test thresholds for the detection and prognosis of liver fibrosis. J Appl Lab Med. 2019;3(5):815-826. 31. Mikolasevic I, Orlic L, Franjic N, Hauser G, Stimac D, Milic S. Transient elastography (FibroScan®) with controlled attenuation parameter in the assessment of liver steatosis and fibrosis in patients with nonalcoholic fatty liver disease - Where do we stand? World J Gastroenterol. 2016;22(32):7236-7251. 32. Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010;51(2):454-462. 33. Grandison GA, Angulo P. Can NASH be diagnosed, graded, and staged noninvasively? Clin Liver Dis. 2012;16(3):567-585. 34. Kemp W, Roberts S. FibroScan® and transient elastography. Aust Fam Physician. 2013;42(7):468-471. 35. Boursier J, Vergniol J, Guillet A, et al. Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease. J Hepatol. 2016;65(3):570–578. 36. 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.
FIB-4 score may predict long-term outcomes
Cumulative probability of death/liver transplantation is related to FIB-4 score22,23
Charts are illustrative and not comparative due to differing patient populations described in the studies
FIB-4, fibrosis-4
NFS may predict long-term outcomes
Cumulative probability of death/liver transplantation is related to NFS22,23
Charts are illustrative and not comparative due to differing patient populations described in the studies
NAFLD, nonalcoholic fatty liver disease; NFS, NAFLD fibrosis score.
APRI may predict long-term outcomes
Cumulative probability of death/liver transplantation is related to APRI score22,23
Charts are illustrative and not comparative due to differing patient populations described in the studies
APRI, aspartate aminotransferase/platelet ratio index
ELFTM score may predict long-term liver-related outcomes23,30
Cumulative probability of liver-related events is related to ELFTM score1*
Charts are illustrative and not comparative due to differing patient populations described in the studies
All third-party trademarks referenced herein are the property of their respective owners.
*Kaplan–Meier survival curves for survival free of liver-related events including complications of portal hypertension, liver cancer, liver transplantation, and death for patients with ELFTM scores in the ranges <7.70, 7.7–9.79, 9.80–11.29, and ≥11.30
ELFTM, enhanced liver fibrosis; IFU, instructions for use
Fibrosis stage measured by Transient Elastography
is predictive of mortality
Cumulative probability of death is related to Transient Elastography score23,35
Charts are illustrative and not comparative due to differing patient populations described in the studies
LSM, liver stiffness measurement; TE, transient elastography
