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

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 17- 21 years Clinical subtypes Classic (large and small) duct Small duct Not associated with IBD Overlap with autoimmune hepatitis IgG4 cholangiopathy

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

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

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) 430-436) 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) 1893-1901) Swedish – 305 patients with PSC. Median follow-up 5 years. (Broome U, Olsson R, Loof L et al.  Gut. 1996;  38(4) 610-615) 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):688-94.)

The Mayo Risk Model for PSC Can estimate survival up to 4 years R = 0.03 (age [y]) + 0.54 loge (bilirubin [mg/dL]) + 0.54 loge (AST [U/L]) + 1.24 (variceal bleeding [0/1]) – 0.84 (albumin [g/dL]) Kim WR, et al. Mayo Clin Proc. 2000 Jul;75(7):688-94

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

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

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

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

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

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].

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 1.4-2.5, and 1.5, 95% CI 1.1-2.1, respectively) was associated with transplant-free survival independently of the Mayo risk score (hazard ratio = 1.3, 95% CI 1.1-1.6, and 1.6, 95% CI 1.2-2.1, respectively).  Vesterhus M, et al. Hepatology. 2015 Jul;62(1):188-97

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!

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 2010. 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. 2014 Apr;146(4):970-9

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. 2014 Apr;146(4):970-9

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. 2018 May 9. doi: 10.1002/hep.30085. [Epub ahead of print]

PREsTo incorporates 9 variables Eaton JE, et al. Hepatology. 2018 May 9. doi: 10.1002/hep.30085. [Epub ahead of print]

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

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)