1. Can we predict the progression of your PSC?
Aparna Goel, MD
Stanford University School of Medicine
Liver Transplant Program
June 23, 2018

2. PSC is a highly variable disease
Chronic, slowly progressive cholestatic liver disease with many clinical subtypes
Median survival from time of diagnosis to liver transplantation is years
Clinical subtypes
Classic (large and small) duct
Small duct
Not associated with IBD
Overlap with autoimmune hepatitis
IgG4 cholangiopathy

3. PSC can progress in different ways
Cirrhosis
Chronic cholestasis with cirrhosis
Hepatic decompensation (ascites, encephalopathy, varices)
Infections
- Recurrent cholangitis
Malignancy
Colon cancer
Cholangiocarcinoma
Higher risk of colon and hepatobiliary malignancies regardless of fibrosis stage

4. What can we predict about your PSC?
PSC is difficult to predict
Over the last two decades, several natural history models have been developed to predict the prognosis of an individual person with PSC
These models are constantly being refined as we learn more about how the disease develops and progresses

5. Models to predict outcomes in PSC
Mayo Model
King’s College
Multicenter (Revised Mayo Model)
Swedish
New Mayo Model
1989
1991
1992
1996
2000
Age
Bilirubin
Hepatomegaly
Histologic stage
Albumin
Hemoglobin
Splenomegaly
AST
IBD
ALP
Variceal hemorrhage
Several natural history models were developed in the early 1990s to predict the need for survival and liver transplantation. As you can see, these models had several factors in common. In particular, older age, higher bilirubin, advanced stages of fibrosis on liver biopsy were associated with increased need for liver transplantation or death.
The latest update to the Mayo Model in 2000 was the most favorable as it eliminated the need for a liver biopsy to predict outcomes. Instead, it relies on the presence of variceal hemorrhage as a measure of the severity of underlying liver disease and portal hypertension. This model also eliminated subjectivity that could be associated with the prior prognostic models including hepatomegaly or splenomegaly. The new Mayo model has been validated in an independent set of patients and is currently the most widely used model to estimate survival in PSC in the United States.
Arguably, these models are most useful for predicting outcomes in early stage PSC than classifications of cirrhosis like the Child Pugh score.
Mayo Model – 174 patients at Mayo. MV analysis revealed these factors were most correlated with survival. Asymptomatic patients had a better overall survival compared to symptomatic patients. Median f/u 6 years. (Wiesner R H, Grambsch P M, Dickson E R et al.  Hepatology. 1989; 10(4) )
King’s college – 126 patients with PSC. Cox proportional hazard ratios yielded these variables as most significant (Farrant J M, Hayllar K M, Wilkinson M L et al. Gastroenterology. 1991)
Revised Mayo Model – revised after king’s college model. (Dickson E R, Murtaugh P A, Wiesner R H et al.  Gastroenterology. 1992;  103(6) )
Swedish – 305 patients with PSC. Median follow-up 5 years. (Broome U, Olsson R, Loof L et al.  Gut. 1996;  38(4) )
New Mayo Model – 405 patients, validated with another cohort of 124 patients. Eliminated biopsy (Kim WR, et al. Mayo Clin Proc. 2000 Jul;75(7): )

6. The Mayo Risk Model for PSC
Can estimate survival up to 4 years
R = 0.03 (age [y]) loge (bilirubin [mg/dL]) loge (AST [U/L]) (variceal bleeding [0/1]) – 0.84 (albumin [g/dL])
Kim WR, et al. Mayo Clin Proc. 2000 Jul;75(7):688-94

7. Online calculator: http://www.psc-literature.org/mrscalc.htm
Kim WR, et al. Mayo Clin Proc. 2000 Jul;75(7):688-94

8. Mayo risk score stratifies risk of PSC progression into three groups
Risk score < 0 = low risk
Risk score >0 and <2 = intermediate risk
Risk score > 2 = high risk
Kim WR, et al. Mayo Clin Proc. 2000 Jul;75(7):688-94

9. Limitations of the Mayo Risk Score
Validated to predict short-term outcomes (within 4 years), but what about long term outcomes?
Predicts survival or need for liver transplantation, but not other clinically relevant outcomes such as cholangiocarcinoma or infections

10. Serum alkaline phosphatase
Useful biomarker and perhaps a surrogate marker of disease outcomes
139 patients in Oxford PSC database. Improvement in SAP to below 1.5 ULN is associated with better outcome and reduced risk of CCA in PSC. This was comparable to the achievement of complete normalization of SAP
Al MS, et al. J Hepatol 2013;58(2):329–34

11. Reduced serum alkaline phosphatase is associated with lower rate of PSC progression
Alkaline phosphatase reduced
The longterm follow-up analysis of 198 patients in the 5-year trial of UDCA (n = 97 on UDCA and n = 101 on placebo) performed in 2009–2010 is particularly informative regarding the long-term safety and efficacy of UDCA at doses of 17–23 mg/kg per day.
While actuarial survival did not differ between patients randomized to the UDCA or placebo arms of the trial, the cumulative probability of surviving for 10 years was significantly increased in “responders” to UDCA, defined as a reduction of ALP either to normal or by ≥40% from baseline after 1 year in the trial
Response: normal or ≥40% reduction in ALP after 1 year in the trial (P = .033)
Alkaline phosphatase not reduced
Lindstrom L, et al. Clin Gastroenterol Hepatol 2013;11(7):841–6

12. UK-PSC consortium of 1700 patients showed that alkaline phosphatase is a valuable tool for prognosis
Factors associated with increased risk of liver transplantation
Elevated alkaline phosphatase
>2x normal at diagnosis
>1.5x normal one year after diagnosis
>2x normal two years after diagnosis
Favorable factors that decrease risk of liver transplantation
Small-duct PSC
PSC limited to the liver without extra-hepatic bile duct changes
Goode et al. EASL 2015 [Abstract #80].

13. Enhanced Liver Fibrosis (ELF) panel can also predict survival without transplantation
Direct marker of fibrosis based on three circulating markers
hyaluronic acid
tissue inhibitor of metalloproteinases-1 (TIMP-1)
propeptide of type III procollagen (PIIINP)
No liver biopsy required
305 patients
In multivariate Cox regression analysis in both panels, ELF score (hazard ratio = 1.9, 95% CI , and 1.5, 95% CI , respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI , and 1.6, 95% CI , respectively). 
Vesterhus M, et al. Hepatology Jul;62(1):188-97

14. Transient Elastography (Fibroscan®)
LSM: liver stiffness measure
Cut-off values: ≥F2 of 8.6 kPa and F4 of 14.4 kPa
Dramatic change in survival if > 18.5
Also helpful longitudinal changes over time!

15. Liver stiffness measurement may serve as a marker for disease progression and prognosis
percutaneous liver biopsy specimens from 73 consecutive patients with PSC from January 2005 to December Patients underwent VCTE no more than 6 months after the biopsy specimens were collected. 
≥F1, ≥F2, ≥F3, and F4 were 7.4 kPa, 8.6 kPa, 9.6 kPa, and 14.4 kPa, respectively. 
Corpechot C, et al. Gastroenterology Apr;146(4):970-9

16. Change in liver stiffness over time is an important prognostic marker
Change in LSM over time also provide important prognostic information
Corpechot C, et al. Gastroenterology Apr;146(4):970-9

17. PSC Risk Estimate Tool (PREsTo): a new model based on machine learning to estimate risk of hepatic decompensation from PSC
19 potential models were studied and utilized 2,500 decision trees
Derived from 509 subjects and validated in an international cohort of 278 patients
Performs well compared to Mayo Risk Score and MELD scores
Can be used over time to re-assess risk of decompensation
The model was derived using 509 subjects from a multicenter North American cohort and validated in an international multicenter cohort (n=278)
Eaton JE, et al. Hepatology May 9. doi: /hep [Epub ahead of print]

18. PREsTo incorporates 9 variables
Eaton JE, et al. Hepatology May 9. doi: /hep [Epub ahead of print]

19. Ascites, varices, encephalopathy
Progression of PSC
Cirrhosis
Ascites, varices, encephalopathy
Malignancy
Infections
Tools to predict progression/ need for transplant:
Mayo Risk Score
Serum Alkaline Phosphatase
Enhanced Liver Fibrosis score
Fibroscan
PREsTo

20. The future is promising
PSC is a highly variable disease with clinical heterogeneity
We are moving toward optimizing how we measure the status of PSC and predict its future course for patients
Blood tests of inflammation
Blood tests of fibrosis (scars)
Imaging tests (MRIs)