This document discusses non-invasive methods for assessing liver fibrosis as alternatives to liver biopsy. Transient elastography (FibroScan) has been widely adopted due to its simplicity, speed, safety and high degree of accuracy in determining liver cirrhosis. Several blood tests like APRI and Fibrosure can also estimate fibrosis levels but have limitations. Newer techniques like acoustic radiation force impulse imaging and magnetic resonance elastography are presented as promising alternatives. Guidelines now recommend using non-invasive methods first before considering liver biopsy to reduce risk and costs.

1. NORTHWEST AIDS EDUCATION AND TRAINING CENTER

2. Introduction:
• The TE using FibroScan represents one of a range of
noninvasive tools specifically developed for the estimation
of the degree of hepatic fibrosis.
• Several unique features resulted in its rapid uptake in clin
practice, as simplicity, speed of assessment, high degree of
safety &tolerability.
• Currently, > 80 FibroScan machines in Australia.
• No specific guidelines governing the use of these tools or
the interpretation of the results.

3. AASLD Guidelines for Hep C Treatment
 All patients should be
treated
 Highest priority for F3-F4,
extrahepatic disease, pre
and post-txp pts
 High priority is F2, HIV or
HBV coinfection, other liver
dz, PCT, DM, and severe
fatigue
Ghany M, Strader DB, Thomas DL, Seeff LB. Diagnosis, management, and
treatment of hepatitis C: an update. Hepatology 2009; 49:1355-74. Updated July
2014, hepcguidelines.org

4. Liver Biopsy is an Unreliable Gold Standard!
• Sampling error leads to misinterpretation in 10-15% of
cases
– Need at least 2 cm sample, >10 portal triads
– Beware fracturing! Tipoff to cirrhosis
• Can miss the diagnosis of cirrhosis
• Invasive procedure with complications
• Expensive ($2500)
• Poor patient acceptance
• Interpretation has significant inter observer variability
Seeff LB , et al. Clin Gastroenterol Hepatol . 2010;8:877–883.
The French METAVIR Cooperative Study Group . Hepatology . 1994;20:15-20.

5. Blood Tests: Indirect Markers
• Uses commonly obtained laboratory values to estimate
fibrosis and establish overt cirrhosis.
• Prothrombin index
• Platelet Count
• Aspartate aminotransferase
• Alanine aminotransferase

6. Calculating APRI
APRI=AST level (/ULN)
Platelet count (109/L)
x 100

7. Fibrosure
• Includes: age ,gender ,alpha-2-macroglobulin,
haptoglobulin, GGT, apolipoprotein A1, total bilirubin,
& ALT.
• Contraindications for use of the FibroTest method for
fibrosis staging include Gilbert’s disease, acute
hemolysis, extrahepatic cholestasis, post
transplantation, or renal insufficiency, all of which
may lead to inaccurate quantitative predictions.
• Indeterminate in middle fibrotic ranges

8. Direct Markers of Fibrosis
• These include the markers that demonstrate
deposition or removal of extracellular matrix in the
liver.
Glycoproteins-hyaluronic laminin, procollagen
III,IV, matrix metalloproteases(inhibitors), tissue
metallopreotease -1

9. Blood Tests for Liver Fibrosis
Castera, L., Gastroenterology 2012;142: 1293-1302.

10. Radiologic Assessment of Fibrosis
• Ultrasound
• Transient Elastography/Fibroscan
• ARFI-Shear waves
• MRI elastography

11. Ultrasound
• Can assess for nodularity of the liver surface
• If present, >80% PPV
• Coarseness of the parenchyma
• Size of lymph nodes around the hepatic artery, patency
and flow of veins and arteries, spleen size, screen for
hepatocellular carcinoma, and small volume ascites.
• The use of high-frequency ultrasound transducers is
reported to be more reliable than low-frequency
ultrasound in diagnosing cirrhosis.

12. FibroScan
• Transient elastography examines a large mass
of liver tissue (1 cm diameter by 5 cm in
length) and thus provides a more
representative assessment of the entire
hepatic parenchyma.
• Ultrasound transducer probe that is mounted
on the axis of a vibrator. Vibration is
transmitted toward hepatic tissue, the
vibrations are followed by pulse echo and their
velocities are measured which is related
directly to liver stiffness
• Sensitivities of 84 to 100% and specificities of
91 to 96%. Results limited in those with
ascites, elevated central venous pressure, and
obesity, as fluid and adipose tissue attenuate
the echo waves.

13. ARFI: Acoustic Radiation Forced Impulse
• Acoustic radiation forced impulse (shear waves)
measured in meters/sec
• Easily adaptable to ultrasound machines
• Does not have fluid or obesity limitations
• Better sensitivity than FibroScan, gives 3D picture

14. Transient Elastography Predicts Clinical Outcomes
• N = 667 patients (HCV, 67%; nonalcoholic steatohepatitis,
13%) with liver disease (n = 120 with cirrhosis)
• TE had an area under the receiver operating characteristic
curve of 0.87 for predicting clinical outcome
• High negative predictive value with liver stiffness of 10.5 kPa
for excluding a liver-related clinical outcome such as variceal
bleeding, liver failure, or development of HCC over 2 yrs
Outcomes with TE
cutoff of 10.5 kPa,
%
Sensitivity Specificity PPV NPV
Overall population 95 63 19 99
Cirrhotics only 98 10 27 92
Klibansky DA, et al. J Viral Hepat . 2012;19:e184–e193.

15. Comparison of Blood Tests to Transient
Elastography
Method Advantages Disadvantages
Serum
biomarkers
• Good reproducibility
• High applicability (95%)
• Low cost (~$250) and wide availability
(nonpatented)
• Well validated
• Nonspecific of the liver
• Unable to discriminate between
intermediate stages of fibrosis
• Performance not as good as TE for
cirrhosis
• Results not immediately available
• Cost and limited availability (proprietary)
• Limitations (hemolysis, Gilbert syndrome,
inflammation…) < 5%
Transient
elastography
• Liver stiffness is a genuine physical
property of liver tissue
• Good reproducibility
• Well validated
• High performance for cirrhosis
• User friendly (rapid, results immediately
available; short learning curve)
• Can be performed in the outpatient clinic
• Prognostic value in cirrhosis
•Requires a dedicated device
•Region of interest cannot be chosen
•Unable to discriminate between
intermediate stages of fibrosis
•Low applicability (80%, obesity, ascites,
limited operator experience)
•False positive in case of acute hepatitis,
extrahepatic cholestasis, and congestion
Castera L. Gastroenterology . 2012;142:1293–1302

16. Harborview Evaluation Algorithm
HCV Antibody Positive
(Test all Persons Born 1945-65 or persons with history IDU, Annual Test for Active IDU)
Check HCV RNA
Check HCV Genotype, LFTs & CBC
If APRI .5-1.5 Check Fibrosure or Fibroscan
Vaccinate for HBV/HAV, Counsel on
Transmission Risks and to Avoid Alcohol
Evaluate for Treatment
Patient Counseling on
Transmission and Alcohol, Refer
for Alcohol/Drug Treatment as
Available, Vaccinate for HAV/HBV
Significant Ongoing
Alcohol Abuse or IDU
Positive
Evaluate for Ongoing Alcohol Abuse & IDU
Reevaluate Alcohol/Drug Use &
Potential for Referral at Least Annually
No Active Infection
(Retest Persons with Ongoing
Risk Reinfection Annually)
Negative
No significant Ongoing
Alcohol Abuse or IDU

17. What is the role of the liver biopsy?
• Very useful when diagnosis is uncertain
- -eg, post liver transplant setting, autoimmune hepatitis,
drug-induced hepatitis
• Diminishing role in most patients as noninvasive testing
becomes more accurate and available
• Ultrasound transient elastography may be better test to
predict clinical outcomes
• As treatment becomes less toxic and more effective, there
is less need to stage the patient’s liver disease

18. Summary
• There is no perfect one test solution
• Serum markers good at ends but soft in middle
• More powerful if several tests used together such as 2
biomarker tests or one biomarker and elastography.
• Stay tuned for MRI elastography

19. Practicalities of (TE)
• 1. TE should be performed according to a standardized
protocol consistent with existing guidelines with the patient
in the supine position, right arm in full abduction.
• 2. The reference site of LSM is the midaxillary line in the
first intercostal space below the liver dullness upper limit.
The phase of respiration may be relevant &should be taken
into account.
• 3. The patient should fast for at least 2 h prior to the
procedure.
• 4. The M probe is suitable for most patients, but ideally, the
XL probe should be used for patients with a SCD of > 25
mm.

20. Practicalities of (TE)
• 5. A reliable assessment must include an IQR/M of ≤ 0.30 &a minimum of
10 valid shots.
• 6. TE can be performed in a reliable way by both physicians &
technicians, but a learning curve is apparent& operator experience is a
factor determining accuracy, may require > 500 examinations.
• 7. Result interpretation should be mindful of the error inherent to both
liver biopsy & noninvasive technologies such as TE. LSM is a guide to
severity of fibrosis&ideally, results should be expressed in terms of
probability rather than certainty. We recommended against using terms
such as “normal” or “no fibrosis” due to the overlap between early
fibrosis stages; “no or minimal fibrosis” would be more accurate.
Consistent with most investigations and diagnostic tests, LSMs need to
be considered in light of the clinical context&interpreted accordingly.
• 8. TE/other noninvasive tools & liver biopsy should be used in an
integrated way to allow safe, accurate& timely evaluation of patients.

21. Practicalities of (TE)
• 9. Reporting should include detail required for independent analysis of
the quality of the test & ideally include anatomical site of assessment,
probe type, number of valid shots, median LSM,IQR & IQR/M, fasting
status& ALT.

22. TE in chronic hepatitis C (CHC):
• 1. TE provides additional information to the clinician to assist in
establishing treatment priorities & clinical decision making, provided
that consideration is given to factors adversely affect its performance.
• 2. For patients not undergoing a liver biopsy, TE or another validated
noninvasive technique should be performed in all with HCV infection.
• 3. TE performed every 1–2 years for patients undergoing surveillance
while awaiting CHC therapy.
• 4. For significant fibrosis (≥ F2) the proposed existing cutoffs (6.8–8.8
kPa) have a high positive predictive value (PPV:83–97%) but variable
negative predictive value (NPV: 23–85%) & therefore a higher LSM is
better at confirming the presence of ≥ F2 rather than excluding it.
• Many factors limit TE ability to distinguish F1 from F2;limitations of liver
biopsy itself particularly for this early stage of liver fibrosis.
• 5. For advanced fibrosis (≥ F3), a cut-off ranging from 8.9–10.8 kPa has
a PPV and NPV of 71–89% and 78–95% respectively.

23. TE in chronic hepatitis C (CHC):
• 6. For cirrhosis, the proposed existing cut-offs (11.9–14.8 kPa) offer a
PPV ranging from 52-85%, so LSM above these cut-offs may not, on its
own, be enough to confirm cirrhosis,but associated with a high NPV (≥
95%) & therefore function well for the exclusion of cirrhosis.
• 7. Treatment decisions should not be solely based on LSM.
• 8. Current guidelines recommend avoiding response-guided therapy in
genotype 1 patients with cirrhosis, although there is no data regarding
the use of TE assessment in the determination of CHC treatment
duration&decision needs to be individualized.
• 9. TE may overestimate the degree of hepatic fibrosis in patients with
early stage disease & ALT elevation,so interpretation of TE should be
made in conjunction with knowledge of the ALT& TE should be
interpreted with caution in patients with a markedly elevated ALT.
• 10. There is evidence suggesting that TE may improve the prognostic
stratification of patients with cirrhosis beyond that offered by biopsy or
Child–Pugh /model for MELD score.

24. TE in chronic hepatitis B (CHB):
• 1. TE (or alternative tests) recommended as the initial investigation for
determination of hepatic fibrosis in CHB not undergoing liver biopsy.
• 2. TE (or alternative tests) are recommended for patients who start
treatment without liver biopsy in order to establish a baseline LSM.
• TE has a higher NPV than PPV &so better at excluding cirrhosis than
confirming it.
• 3. Assessment of fibrosis is only one of several factors determining
management decisions, treatment recommendations& follow-up, so TE
should be interpreted as part of specialist care &not recommended for
isolated use in PHC to determine suitability for trt or specialist referral.
• 4. BZ elevated ALT associated with viral flares, so sensible to measure
liver stiffness where practical, once the elevation of ALT has
subsided&testing of ALT around the time of LSM is recommendedB Z
necroinflammation can contribute to stiffness & result in an
overestimation of fibrosis stage.

25. Conclusions:
• The absence of mandatory liver biopsies in the management of HBV /
HCV has removed a significant barrier to treatment of these conditions,
but, in turn, has presented new challenges for the patient & clinician in
the assessment of liver fibrosis.
• NIV assessment of liver fibrosis has become widely accepted as a
clinically useful investigation in the assessment of patients with chronic
liver diseases who have not or do not wish to have a liver biopsy as part
of a formal histological assessment.
• Regardless of the technique used to assess liver fibrosis (either liver
biopsy or noninvasive tools such as TE) one must remain cognizant of
the potential limitations and margin for error&incorrect staging,so
assessment of liver fibrosis should not become overly reliant on a
single assessment, but in a clinically appropriate manner &in
conjunction with the clinical situation.

26. Conclusions:
• TE is used as the initial NIV tool in the assessment of patients with HCV
/ HBV to establish management priorities.
• Where results are incongruous with the clinical situation or where the
interpretation results in a significant deviation in clinical management, a
second INV tool or a liver biopsy would be a reasonable approach.
• Where TE able to produce reliable & reproducible LSMs, TE performed
on a 1–2 yearly basis for the majority of our patients undergoing clinic
follow-up particularly in patients with a high baseline LSM or
comorbidities in order to identify/treat more aggressive diseases.
• This area requires further clarification &economic estimations.
• The future research will help to define the role TE &other NIV tools have
in predicting patient outcomes as HCC development, hepatic
decompensation & survival& likely that the merits of new or alternative
techniques such as SWE / ARFI will become clearer with time.

28. Introduction:
Liver biopsy was the gold standard for the assessment of liver fibrosis for many
decades.
Now, liver biopsy has been partially replaced by NI methods for the assessment
of liver fibrosis, esp in chronic viral hepatitis.
NI methods implemented in several guidelines for assessment of liver fibrosis
but indications for liver biopsy remain.
Many different elastography techniques have emerged&currently all large
ultrasonography companies offer an elastography technique integrated in their
machines.
Results from one elastography technique cannot simply be transferred to
another & interpretation using liver histology as a reference is challenging.

35. Conclusions:
NI imagings evaluated for the assessment of liver fibrosis,
showing good diagnostic accuracies for stage F≥2 fibrosis
&excellent diagnostic accuracies for liver cirrhosis.
Most use TE, followed by point SWE, 2D SWE &MRE.
Comparable results revealedthat larger ROI used in point &
2D SWE possibly has an advantage over TE; but these
techniques require more operator training &expertise.
The advantage of point & 2D SWE being integrated in
conventional U/S systems — enabling HCC surveillance with
the same machine.
At present, quality criteria & evidence is most for TE.
NI tests is implemented in national/int guidelines, reducing
liver biopsies performed for fibrosis staging.
For individual patient care, prognostic studies are of great
importance &already published for S. markers &TE.