URSODIOL FOR PRIMARY BILIARY CIRRHOSIS - AASLD

Keith D. Lindor, MD
Cholestatic Disease
Grant Research Support: Axcan, Intercept
Content of the presentation does include discussion of offlabel/investigative
use of medicine(s), medical devices, or procedure(s).
Ursodeoxycholic Acid-PSC

CHOLESTATIC DISEASE
KEITH D. LINDOR, M.D.
MAYO CLINIC
ROCHESTER, MN

UPDATE
• PBC
• PSC
• Complications of cholestasis

PRIMARY BILIARY CIRRHOSIS
• DEFINITION
– Chronic cholestatic liver disease
– Usually affects women (10:1) in middle age
– Chronic, non-destructive lymphocytic cholangitis
– Slowly progressive

EPIDEMIOLOGY OF PBC
Changes Over Time - Prevalence
1970s 1980s 1990s 2000s
Newcastle (1) 180/mil 240/mil
NE England (2) 202/mil 335/mil
Rochester, MN (3)
402/mil
Sheffield (4) 57/mil 136/mil 238/mil
(1) Intl J Epi 1997;26:830-6. (2) Hepatology 1999;30:390-4.
(3) Gastroenterology 2000;199:1631-1636. (4) Hepatology 2001;34:370A.

EPIDEMIOLOGY OF PBC
Changes Over Time - Incidence
Female rate
(95% CI)
Male rate
(95% CI)
Total rate
(95% CI)
1975-1979 4.9 (1.7-8.1) 0 (0-0) 2.5 (0.8-4.2)
1980-1984 3.9 (1.2-6.6) 0.5 (0-1.5) 2.5 (0.9-4.1)
1985-1989 4.4 (1.6-7.2) 1.4 (0-3.3) 3.0 (1.3-4.7)
1990-1995 4.7 (2.2-7.2) 0.8 (0-1.9) 2.8 (1.4-4.3)
Overall 4.5 (3.1-5.9) 0.7 (0.1-1.3) 2.7 (1.9-3.5)
Kim, et al. Gastroenterology 2000;119:1631-1636

PROGNOSTIC MODELS IN PBC
Dickson
et al
Rydning
et al
Christensen
et al
Poupon
et al
Bilirubin X X X X
Age X X
Serum Albumin X X
Prothrombin Time X X
Edema/Ascites X X
Bleeding varices X X
Cirrhosis
IgM
UDCA-treated
Procollagen III
Hyaluronic Acid
X
X
X
X
X

WORSE PROGNOSIS IF:
• ANA +
(Yang W, et al Clin Gastroenterol Hepatol 2004;2:1116-22)
• Anti-centromere +
(Yang W, et al Clin Gastroenterol Hepatol 2004;2:1116-22)
• Gp210 +
(Nakamura M, et al. J Hepatol 2005;42:386-92)

OVERLAP FEATURES
• IgG > 2.0 mg/dL
• ANA/SMA > 1:80
• Interface hepatitis
• Presence of other autoimmune diseases

OUTCOMES
60
50
P

PRIMARY BILIARY CIRRHOSIS
• DIAGNOSIS
– Chronic cholestasis (alkaline phosphatase)
– Antimitochondrial antibody
– Compatible liver biopsy

ROLE OF LIVER BIOPSY IN PBC
• If:
– ⊕AMA (95-98%)
– Alk Phos > 1.5 times normal
– AST < 5 times normal
• Then:
– positive predictive value for PBC > 98%
(sensitivity 80%, specificity 92%)
Zein CO, et al. Clin Gastro and Hepatol 2003;1:89-95.

DIAGNOSIS OF AMA PBC
• Compatible biopsy
• ANA and/or SMA in 95%

NATURAL HISTORY OF PBC
Effects of UDCA
Poupon RE, et al. Hepatology 1999;29:1668-1671.

PREDICTED SURVIVAL RATES
Corpechot C et al. Gastroenterology 2005;128:297-303.

SURVIVAL TO DEATH OR LIVER
TRANSPLANT OF PBC PATIENTS TREATED
WITH UDCA—ALL PATIENTS
Pares A, et al. Gastroenterology 2006;130:715-20

SURVIVAL TO DEATH OR LIVER TRANSPLANT
OF PBC PATIENTS TREATED WITH UDCA—
RESPONDERS (Alk phos. < 40% baseline or normal)
Pares A, et al. Gastroenterology 2006;130:715-20

SURVIVAL TO DEATH OR LIVER TRANSPLANT
OF PBC PATIENTS TREATED WITH UDCA—
NON-RESPONDERS
Pares A, et al. Gastroenterology 2006;130:715-20

COMBINATION THERAPY FOR PBC
• Ursodiol Alone
– biochemical normalization in ~ 1/3
– risk scores or alkaline phosphatase response
predictive (Angulo, et al. Liver 1999;19:119-1121)
– various drugs tried in combination

COMBINATION THERAPY FOR PBC
Ineffective Equivocal or Unknown Promising
Colchicine Corticosteroids Combivir
Cholylsarcosine CellCept Bezafibrate
Methotrexate
Budesonide
Silymarin
Double-dose UDCA

THERAPY FOR PBC -
CURRENT RECOMMENDATIONS
– Ursodiol at 13-15 mg/kg/day
– initiate slowly
– Consider for suboptimal responders
experimental therapeutic trials with other agents

HEPATOCELLULAR CANCER RISK
IN PBC
• 18 Patients among 2000 over 25 years
• Multivariate Analysis
O.R P
Age 1.6

PRIMARY SCLEROSING CHOLANGITIS
• OVERVIEW
– Diagnosis
– Natural history/prognosis
– Management of PSC complications
– Management
– surgical/endoscopic
– medical
– liver transplantation

PRIMARY SCLEROSING CHOLANGITIS
• DEFINITION
– Chronic cholestatic liver disease
– Unknown etiology, frequently associated with
IBD in ¾
– Diffuse inflammation and fibrosis of biliary tree
– Usually leads to biliary cirrhosis and portal
hypertension

PRIMARY SCLEROSING CHOLANGITIS
• DIAGNOSIS
– ERCP most commonly used
– Percutaneous cholangiography infrequently
used
– Magnetic resonance cholangiography emerging
• non-invasive
• no radiation
• cost-effective

PRIMARY SCLEROSING CHOLANGITIS
• DIFFERENTIAL DIAGNOSIS
– Choledocholithiasis
– Previous biliary surgical trauma
– Cholangiocarcinoma
– Metastatic involvement (rare)
– HIV
– Caustic strictures
– Ischemic stricture post transplant

PRIMARY SCLEROSING CHOLANGITIS
• LIVER BIOPSY
– Role of liver biopsy being defined
– May help prognostically
• not used in some models
– May help exclude other diseases
– In setting of cholestasis and IBD with normal
cholangiogram
• small-duct PSC may be diagnosed

PRIMARY SCLEROSING CHOLANGITIS
• Small-duct PSC
– 5% of PSC
– Normal cholangiogram but biopsy showing PSC
– Can progress to classic PSC

SURVIVAL IN PSC –
SMALL DUCT VS. LARGE
Bjornsson E, et al. Gastroenterology 2008;134:975-80

PRIMARY SCLEROSING CHOLANGITIS
• Natural History
– progressive
– median survival 12-17 years

PSC SURVIVAL IN OLMSTED
COUNTY MINNESOTA
Bambha K, et al. Gastro 2003;125:1364-1369.

PRIMARY SCLEROSING CHOLANGITIS
• Specific Therapy
– surgical therapy seldom used
– dilation for complications
– medical

PRIMARY SCLEROSING CHOLANGITIS
Management of specific complications
• Dominant biliary strictures
– uncommon
– cytology insensitive for cancer
• other methods (DIA & FISH) being evaluated
– long-term stents may cause problems
– dilatation alone seems preferable

PRIMARY SCLEROSING CHOLANGITIS
Specific Therapy
• Medical therapy tested to date
Penicillamine Colchicine Mycophenolate Mofetil
Cyclosporine Methotrexate Silymarin
Pentoxifylline Budesonide Tacrolimus
Nicotine Pirfenidone Ursodeoxycholic acid
Azathioprine Etanercept
_____ = possible benefit

AUTOIMMUNE PANCREATITIS/
CHOLANGITIS IN PSC
• IgG4 elevated in 9% PSC patients
• These patients may be more steroid
responsive.

COMPARISON OF CHOLANGIOGRAM
Band-like
stricture
BETWEEN PSC AND SC WITH AIP
Segmental
stricture
PSC SC with AIP P Value
++ -

HIGH DOSE URSO IN PSC
Primary Endpoints UDCA Placebo
Death 3 4
Liver Transplant 9 3
Minimal Listing Criteria for Liver 12 10
Transplant
Cirrhosis 5 3
Esophageal and/or Gastric Varices 14 6
Cholangiocarcinoma 2 1

PRIMARY SCLEROSING CHOLANGITIS
Management of specific complications
• Cholangiocarcinoma
– may occur in 7-15%
– incidence 0.5 to 1% per year
– Smoking and IBD risks
– Also at risk for liver cell, pancreatic, and colon
cancer

Incidence of Cholangiocarcinoma
Cumulative incidence of
cholangiocarcinoma (%)
10
7.5
5
2.5
0
0 2 4 6
Years since PSC diagnosis

COLON CANCER/IBD/PSC
50%
PSC/CUC
CUC
Risk %
31%
9%
2%
5%
10%
10 Years 20 Years 25 Years
Broome, et al. Hepatology 1995;22:1404-8.

LIVER TRANSPLANTATION
Cholestatic Liver Disease
• Liver transplantation
– Survival
1 year 90-97%
5 years 85-88%
– Problems with rejection, infection, recurrence,
colon cancer with PSC

CONCLUSIONS
• PBC treated with UDCA – 13-15 mg/kg/d
• PSC – no known effective therapy
– dilations for strictures
• Malignancy can complicate both PBC &
PSC
• Complications of cholestasis can be
managed