NORTHWEST AIDS EDUCATION AND TRAINING CENTER

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.

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

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.

Blood Tests: Indirect Markers

• Uses commonly obtained laboratory values to estimate fibrosis and establish overt cirrhosis.

• Prothrombin index• Platelet Count• Aspartate aminotransferase• Alanine aminotransferase

Calculating APRI

APRI=AST level (/ULN) Platelet count (109/L)

x 100

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

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

Blood Tests for Liver Fibrosis

Castera, L., Gastroenterology 2012;142: 1293-1302.

Radiologic Assessment of Fibrosis

• Ultrasound• Transient Elastography/Fibroscan• ARFI-Shear waves• MRI elastography

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.

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.

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

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.

Comparison of Blood Tests to Transient Elastography

Method Advantages DisadvantagesSerum 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

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 & CBCIf 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

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.