1. Biomarkers & Imaging John E. Eaton MD
Division of Gastroenterology and Hepatology
Mayo Clinic College of Medicine and Science
Rochester MN USA

2. Objectives Define the term “Biomarker”
Implications of biomarkers for individual patients & drug development
Overview of select non-radiographic & magnetic resonance imaging based biomarkers used in clinical practice
*Did not include information about cholangiocarcinoma biomarkers but happy to discuss in Q&A if questions

3. Biomarkers Definition (FDA)
An objective measured indicator of normal biology, pathologic process or response to therapy

4. Importance of Biomarkers in PSC
Clinical practice
Diagnostic & prognostic
Necessity for clinical trials & drug approval
Biomarkers as surrogate endpoints
Used in clinical trials as substitute for a direct measure of how a patient feels, functions or survives
Useful when disease is rare and clinical events uncommon

5. Predictive Biomarkers & Surrogate Endpoints Medicines Crystal Ball…ideally
∆ Surrogate endpoint (predictive biomarker)
Intervention
Group A
PSC patients
∆ Clinical Outcome
Ex., liver transplant
No ∆ Surrogate endpoint (predictive biomarker)
No intervention
Group B
PSC patients
No ∆ Clinical Outcome
Ex., liver transplant
Time

6. Potential Diagnostic & Prognostic Biomarkers Hot area for research evolving rapidly!
Cholestasis
Alkaline phosphatase
GGT
Total bilirubin
Serum bile acids C4
Prognostic scores (PREsTo, MELD, Mayo PSC Risk, UK PSC Risk)
Cholangiogram
MRCP based (ANALI, MRCP+)
ERCP based (Amsterdam score)
Fibrosis & Portal HTN
Histology
Elastography
Spleen Length
ELF score
APRI
proC3
Prognostic scores (PREsTo, Mayo PSC Risk, UK PSC Risk)
Immune System
Histology
MRI based assessment of inflammation
VAP 1
Cytokines

7. Diagnostic & Prognostic Biomarkers in Clinical Practice
Cholestasis
Alkaline phosphatase
GGT
Total bilirubin
Serum bile acids C4
Prognostic scores (PREsTo) MELD, Mayo PSC Risk, UK PSC Risk
Cholangiogram
MRCP based (ANALI, MRCP+)
ERCP based (Amsterdam score)
Fibrosis & Portal HTN
Histology
Elastography
Spleen Length
ELF score
APRI
proC3
Prognostic scores (PREsTo), Mayo PSC Risk, UK PSC Risk
Immune System
Histology
MRI based assessment of inflammation

8. Serum Alkaline Phosphatase (SAP)
Enzyme in multiple organs
Liver, intestine, bone, placenta, kidney
Normal or < 1.5 x ULN improved outcomes
After 7 years 15% normal SAP versus 35% abnormal SAP developed serious complication
Used as primary or secondary surrogate endpoint in most PSC trials
I would also look at this as 65% of patients with an abnormal alkaline phosphatase DON’T have a bad outcome after 7 years…we can do better at predicting outcomes
Al Mamari S, et al. J Hepatol 2013
Stanich P, et al. Dig Liver Dis 2011

9. SAP alone is suboptimal biomarker
Lacks specificity
60% of patients with SAP >1.5 x ULN no liver related complications over 10 years
Normal SAP common
Rate of normalizing 5% per year
55% re-develop an abnormal SAP within 2 years
Wide individual fluctuations
SAP varied by 12% during 96 week simtuzumab trial
Changes not associated with outcomes
Reasons for these fluctuations are typically not apparent.
Al Mamari S, et al. J Hepatol 2013
Stanich P, et al. Dig Liver Dis 2011
Eaton JE, et al. AASLD submitted 2019
Trivedi PJ, EASL 2019

10. PSC Risk Estimate Tool (PREsTo) Novel model created using artificial intelligence
9 variables
Eaton JE, et al. Hepatology 2018

11. PREsTo Accurately Predicts Hepatic Decompensation
Eaton JE, et al. Hepatology 2018

12. PREsTo In Action https://rtools.mayo.edu/PRESTO_calculator/ Person 2
Age (years) 20 45
SAP x ULN
1.3
1.7
AST 40 90
Total Bilirubin
1.0
3.0
Albumin
4.0
3.5
Sodium
140
136
Hemoglobin
14.5
12.5
Platelets x109
300
180
PSC duration (years) 2 15
70%
Person 2
Person 1 3%

13. Role of Magnetic Resonance Imaging Studies
Diagnosis of PSC
Monitoring for complications
ERCP triage & roadmap for endoscopist
Measurement of liver stiffness (magnetic resonance elastography, MRE)

14. MRCP/MRE
Picture also illustrates that PSC is a patchy disease that does not impact the liver and bile ducts in a uniform manner.
T2, DWI, Arterial enhancement and delayed phase images and MRE
MRCP (A) showing multiple strictures including R. posterior duct stricture (arrow). Corresponding sequences showing hyperintensity due to inflammation/fibrosis with focal ↑ liver stiffness (MRE, F) with mild atrophy and compensatory left lobe hypertrophy.

15. MRI/MRCP Downsides MRI/MRCP intolerance (relatively uncommon) Cost
Claustrophobia, incompatible devices
Cost
Quality & access may vary
Gadolinium contrast agent
Helpful if concerned for malignancy but not mandatory
Gadolinium may deposit in tissue after repeated exposure
No adverse clinical effects in humans/animals to date
Selective use in gadolinium
Avoid in renal failure

16. Elastography Magnetic Resonance Elastography & Transient elastography (Fibroscan)
Conceptual Framework
Speed at which vibration wave travels through tissue is related to tissue stiffness.
Tissue stiffness=surrogate for fibrosis
Nonfibrotic causes of increased stiffness
Acute inflammation
Acute biliary obstruction
Example, “dominant strictures” in PSC
Heart failure

17. Magnetic Resonance Elastography (MRE)
-90
+90
Displacement (mm)
Shear Stiffness (kPa)) 10 4 6 8 2 10
+90
Reproducible
Predicts fibrosis stage
Predicts outcomes:
Low risk <4.5 kPa
Medium kPa
Higher risk > 6.0 kPa 4
Displacement (mm)
-90
Imaging time: 11-16s/slice
Active Driver
Acoustic waves at 60Hz
Eaton JE, et al. J Gastroenterol Hepatol 2016
Eaton JE, et al. submitted 2019

18. Fibroscan (transient elastography)
Accurately predicts stage of fibrosis
Associated with outcomes in PSC
Corpechot C, et al. Gastroenterology 2014

19. MRE versus Fibroscan (transient elastography)
Lower failure rate
Samples larger volume
Can detect complications
When MRCP performed no added cost or much time
Widely available
Done at bedside
Cheaper & easier if MRCP not required
MRE
Fibroscan

20. Appearance of bile ducts, liver & stiffness important MRCP prognostic score (ANALI) + Elastography
Components of ANALI score:
Intrahepatic bile duct dilation
“Dysmorphy” (i.e., atrophy, cirrhotic appearing liver)
Presence of portal hypertension
% adverse outcome
LS=liver stiffness
Cazzagon N, et al. EASL 2019

21. Quantitative Biliary Metrics
Sophisticated & elegant appearing software that measures aspects of the biliary tree and individual duct segments. Unresolved questions: is this technology reproducible, does it provide prognostic information, are changes over time associated with changes in disease course
Areas of uncertainty
Prognostic value
Reproducibility & accuracy

22. Summary
Biomarkers are an objective measurement of normal or disease process
Accurate biomarkers that can serve as surrogate endpoints in clinical trials essential step for drug development & approval
Diagnostic & prognostic biomarkers useful for routine care
Key biomarkers to be familiar with as patients are liver tests (examples, alkaline phosphatase, total bilirubin), prognostic scores (example, PREsTo), MRI/MRCP & elastography