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Recent Advances in Primary Biliary Cirrhosis
Disease Pathways and Potential Targets of Therapy
Ulrich H.W. Beuers, MD Department of Gastroenterology & Hepatology
Tytgat Institute for Liver and Intestinal Research Academic Medical Centre University of Amsterdam
The Netherlands
Primary Biliary Cirrhosis Characteristics
Sex (f:m) 9 : 1 Age 40 - 60 Survival without treatm. 7.5-16 years Cholestatic enzyme pattern AP, γGT
Autoantibodies AMA (anti-PDC-E2)
Sherlock and Summerfield, 1991
Symptoms: • Fatigue • Itch • “Dry eye, dry mouth“ • …
Courtesy of Ulrich H. W. Beuers, MD.
Primary Biliary Cirrhosis
Beuers U, et al. Hepatology. 1998;28:1449-1453.
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Pathogenesis
Primary Biliary Cirrhosis - Pathogenesis -
• Genetic predisposition
• Exogenous factors
• Endogenous factors
Primary Biliary Cirrhosis - Pathogenesis -
• Genetic predisposition Monozygotic twins: >60% PBC Family members: 6% PBC
GWAS*: HLA-DQ-B1, Il12A, Il12B2, STAT4,…
• Exogenous factors
• Endogenous factors
Selmi C, et al. Gastroenterology. 2004;127:485-492.
Hirschfield GM, et al. N Engl J Med. 2009;360:2544-2555.
*GWAS: Genome-wide association study.
Primary Biliary Cirrhosis - Pathogenesis -
• Genetic predisposition
• Exogenous factors
• Endogenous factors
Sequence Homology of the Human Pyruvate Dehydrogenase Complex (PDC-E2208-237) with Bacterial Proteins
Inner lipoyl domain of the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2)
(Left graphic) With permission from Migliaccio C, et al. Hepatology. 2001;33:792-801. (Right graphic) With permission from Selmi C, et al. Hepatology. 2003;38:1250-1257.
Model of AMA Formation and Cholangiocyte Damage in Primary Biliary Cirrhosis
IgA AMA transfer via cholangiocytes
With permission from Rieger R, Gershwin ME. J Autoimmun. 2007;28:76-84.
Primary Biliary Cirrhosis - Pathogenesis -
• Genetic predisposition
• Exogenous factors
• Endogenous factors
Primary Biliary Cirrhosis Characteristics
Sex (f:m) 9 : 1 Age 40 - 60 Survival without treatm. 7.5-16 years Cholestatic enzyme Pattern AP, γGT
Autoantibodies AMA (anti-PDC-E2)
Sherlock and Summerfield, 1991
Signs & symptoms: • Fatigue • Itch • “Dry eye, dry mouth“ • …
Too low HCO3
- ?
Courtesy of Ulrich H.W. Beuers, MD.
Prieto J, et al. Gastroenterology. 1993;105:572-578. Medina JF, et al. Hepatology. 1997;25:12-17. Prieto J, et al. Gastroenterology. 1999;117:167-172. Banales JM, et al. Hepatology. 2012;56:687-697.
Boyer JL. Mechanisms of bile secretion and hepatic transport. In: Andreoli TE, et al, eds. Physiology of Membrane Disorders. 2nd ed. New York: Plenum Publ Corp; 1986:609-636.
Bile Formation in Mice and Men
Contribution to bile formation
Mouse Human0
20
40
60
80
100
Species
appr
ox. c
ontr
ibut
ion
tobi
le fo
rmat
ion
%
Hepatocytes Hepatocytes
%
Cholangio- cytes
(HCO3
-)
Source of bile
Carey MC. Physical-chemical properties of bile acids and their salts. In: Danielsson H, Slövall J, eds. Sterols and Bile Acids. Amsterdam, The Netherlands: Elsevier; 1985:345-403.
Bile Formation in Mice and Men
Boyer JL. Mechanisms of bile secretion and hepatic transport. In: Andreoli TE, et al, eds. Physiology of Membrane Disorders. 2nd ed. New York: Plenum Publ Corp; 1986:609-636.
Contribution to bile formation
Mouse Human0
20
40
60
80
100
Species
appr
ox. c
ontr
ibut
ion
tobi
le fo
rmat
ion
%
Cholangio- cytes
(HCO3
-)
Hepatocytes Hepatocytes
Source of bile
%
Bile composition
Mouse Human0
20
40
60
80
100
Species
appr
ox. c
onju
gatio
n of
bile
aci
ds %
Glycine conjugates
Taurine conjugates
Taurine conjugates
Bile salt composition
%
Bile Formation in Mice and Men
Contribution to bile formation
Mouse Human0
20
40
60
80
100
Species
appr
ox. c
ontr
ibut
ion
tobi
le fo
rmat
ion
%
Cholangio- cytes
(HCO3
-)
Hepatocytes Hepatocytes
Bile composition
Mouse Human0
20
40
60
80
100
Species
appr
ox. c
onju
gatio
n of
bile
aci
ds %
Glycine conjugates
Taurine conjugates
Taurine conjugates
pKa > 4
pKa 1-2
Bile salt composition Source of bile
%
%
Carey MC. Physical-chemical properties of bile acids and their salts. In: Danielsson H, Slövall J, eds. Sterols and Bile Acids. Amsterdam, The Netherlands: Elsevier; 1985:345-403.
Boyer JL. Mechanisms of bile secretion and hepatic transport. In: Andreoli TE, et al, eds. Physiology of Membrane Disorders. 2nd ed. New York: Plenum Publ Corp; 1986:609-636.
OH HO
COOH
OH HO
COO- HCO3
- H2CO3
• Glycochenodeoxycholic acid induces mucosal injury in mouse gastric mucosa at pH 1 and 3, but not pH 5
Chenodeoxycholic acid Chenodeoxycholate
pKa and pH Determine Protonation, Polarity and Toxicity of Bile Acids
Eastwood GL. Gastroenterology 1975;68:1456-1465. Slide courtesy of Dr. Ulrich Beuers.
Bile Acids, but Not Bile Salts, Invade Cholangiocytes at Low pH
OH HO
COOH
OH HO
COO- HCO3
- H2CO3
Calculated protonation rate of bile salts GCDCA in human H69 cholangiocytes With permission from Hohenester S, et al. Hepatology. 2012;55:173-183. Top graphic courtesy of Dr. Ulrich Beuers.
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
The Cholangiocyte Secretes HCO3- Upon Various Stimuli
Minagawa N, et al. Gastroenterology. 2007;133:1592-1602.
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
Hypothesis: The Biliary HCO3- Umbrella
Bile
Apoptosis
Fibrosing cholangiopathy
Beuers U, et al. Hepatology. 2010;52:1489-1496. Hohenester S, et al. Hepatology. 2012;55:173-183.
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
Defect of the Biliary HCO3- Umbrella in PBC ?
Bile
Apoptosis
Fibrosing cholangiopathy
PBC
Poupon R, et al. J Hepatol. 2008;49:1038-1045.
Prieto J, et al. Gastroenterology. 1993;105:572-578. Medina JF, et al. Hepatology. 1997;25:12-17. Prieto J, et al. Gastroenterology. 1999;117:167-172. Banales JM, et al. Hepatology. 2012;56:687-697.
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
PDC-E2-like Peptides are Aberrantly Expressed on Apoptotic and Senescent Cholangiocytes
Bile
Apoptosis Senescence
Fibrosing cholangiopathy
PBC
Lleo A, et al. Hepatology. 2010;52:987-998. Sasaki M, et al. Liver Int. 2013;33:312-320. van de Graaf S, Beuers U. Liver Int. 2014;34:481-483.
PDC-E2
Primary Biliary Cirrhosis
Beuers U, et al. Hepatology. 1998;28:1449-1453.
?
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Pathogenesis
Beuers U, et al. Hepatology. 1998;28:1449-1453. European Association for the Study of the Liver. J Hepatol. 2009;51:237-267.
Primary Biliary Cirrhosis: Therapy
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Ursodeoxycholic acid (13-15 mg/kg/d)
Pathogenesis
Effect of UDCA on Survival in PBC “Paris I Criteria”
• 10-year survival without transplantation, according to 1-year biochemical response to UDCA: – Responders (n=179): 90% (95% CI: 81% to 95%) – Nonresponders (n=113): 51% (95% CI: 38% to 64%) – p<0.0001; RR, 0.4; 95% CI: 0.3-0.5
Paris I Criteria
• Bilirubin: ≤1 mg/dL • ALP: ≤3 x ULN • AST: ≤2 x ULN
Corpechot C, et al. Hepatology. 2008;48:871-877.
Beuers U, et al. Hepatology. 2010;52:1489-1496. Hohenester S, et al. Hepatology. 2012;55:173-183.
Apoptosis Necrosis
Stimulation of cholangiocellular
secretion
Stimulation of hepatocellular
secretion
Bile acids
Reduction of bile toxicity
Potential Mechanisms and Sites of Action of UDCA in Cholestatic Liver Diseases
Antiapoptotic effects
Biliary HCO3- umbrella
With permission from Beuers U. Nat Clin Pract Gastroenterol Hepatol. 2006;3:318-328.
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
Medina JF, et al. Hepatology. 1997;25:12-17. Prieto J, et al. Gastroenterology. 1999;117:167-172.
UDCA Stimulates Impaired HCO3- Secretion in PBC
Bile
UDCA
Apoptosis Senescence
Fibrosing cholangiopathy
Beuers U, et al. Hepatology. 1998;28:1449-1453. European Association for the Study of the Liver. J Hepatol. 2009;51:237-267.
Primary Biliary Cirrhosis: Therapy
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Ursodeoxycholic acid (13-15 mg/kg/d)
Liver transplantation
Pathogenesis
Beuers U, et al. Hepatology. 1998;28:1449-1453.
Primary Biliary Cirrhosis: Future Therapy
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Ursodeoxycholic acid (13-15 mg/kg/d)
Liver transplantation
RCT (Phase 3)
Budesonide ?
Pathogenesis
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
Combined UDCA and Glucocorticoids Upregulate an Alternate AE2 Promoter in Human Liver Cells
Bile
Arenas F, et al. J Clin Invest. 2008;118:695-709.
UDCA + Gluco- corticoid
Apoptosis Senescence
Fibrosing cholangiopathy
Beuers U, et al. Hepatology. 1998;28:1449-1453.
Primary Biliary Cirrhosis: Future Therapy
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Ursodeoxycholic acid (13-15 mg/kg/d)
Liver transplantation
RCT (Phase 3)
Budesonide? norUDCA?
Pathogenesis
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
NorUDCA is a Potent HCO3- Secretagogue in Man and Rodents
Bile
norUDCA
Apoptosis Senescence
Fibrosing cholangiopathy
Hofmann AF, et al. Hepatology. 2005;42:1391-1398. Fickert P, et al. Gastroenterology. 2006;130:465-481. Halibasic E, et al. Hepatology. 2009;49:1972-1981. Denk GU, et al. Hepatology. 2010;52:1758-1768.
Beuers U, et al. Hepatology. 1998;28:1449-1453.
Primary Biliary Cirrhosis: Future Therapy
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Ursodeoxycholic acid (13-15 mg/kg/d)
Liver transplantation
RCT (Phase 3)
Budesonide? norUDCA?
Nuclear receptor agonists? - FXR: obeticholic acid?
RCT (Phase 3)
Pathogenesis
The Farnesoid X Receptor (FXR) Protects Against Toxic Effects of Hydrophobic Bile Acids
MRP2 MDR3
BSEP NTCP
OATP
CFTR
Bile acids
Org. anions
Phospholipids
HCO3
CI CI
FIC1 Aminophospholipids
ABCG5/G8 Cholesterol
FXR
CYP7A1
FXR HCO3-
CA
BSEP: ABCB11 MRP2: ABCC2 MDR3: ABCB4 FIC1: ATP8B1 CA, Carboanhydrase
For details, see: Baghdasaryan A, et al. Mol Asp Med. 2014: epub.
OST α/β
SULT2E1
CYP3A4
UGT2B4
Slide courtesy of Dr. Ulrich Beuers.
The Farnesoid X Receptor (FXR) Protects Against Toxic Effects of Hydrophobic Bile Acids
MRP2 MDR3
BSEP NTCP
OATP
CFTR
Bile acids
Org. anions
Phospholipids
HCO3
CI CI
FIC1 Aminophospholipids
ABCG5/G8 Cholesterol
FXR
CYP7A1
FXR HCO3-
CA
BSEP: ABCB11 MRP2: ABCC2 MDR3: ABCB4 FIC1: ATP8B1 CA, Carboanhydrase
OST α/β
SULT2E1
CYP3A4
UGT2B4
For details, see: Baghdasaryan A, et al. Mol Asp Med. 2014: epub.
Slide courtesy of Dr. Ulrich Beuers.
The Farnesoid X Receptor (FXR) Protects Against Toxic Effects of Hydrophobic Bile Acids
MRP2 MDR3
BSEP NTCP
OATP
CFTR
Bile acids
Org. anions
Phospholipids
HCO3
CI CI
FIC1 Aminophospholipids
ABCG5/G8 Cholesterol
FXR
CYP7A1
FXR HCO3-
CA
BSEP: ABCB11 MRP2: ABCC2 MDR3: ABCB4 FIC1: ATP8B1 CA, Carboanhydrase
OST α/β
SULT2E1
CYP3A4
UGT2B4
For details, see: Baghdasaryan A, et al. Mol Asp Med. 2014: epub.
Slide courtesy of Dr. Ulrich Beuers.
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
FXR Agonists Stimulate Biliary HCO3- Secretion in Rodents
Bile
FXR agonist
Apoptosis Senescence
Fibrosing cholangiopathy
Baghdasaryan A, et al. Hepatology. 2011; 54:1303-1312. Baghdasaryan A, et al. Mol Asp Med. 2014: epub
FXR
Beuers U, et al. Hepatology. 1998;28:1449-1453.
Primary Biliary Cirrhosis: Future Therapy
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Ursodeoxycholic acid (13-15 mg/kg/d)
Liver transplantation
RCT (Phase 3)
Budesonide? norUDCA?
Nuclear receptor agonists? - FXR: obeticholic acid? - PPARα: beza-, fenofibrate?
RCT (Phase 3)
RCT (Phase 3)
Pathogenesis
HC O3-‐
C l-‐
CFTR
CaCl
C l-‐ C l-‐
S ecretinAC h
ATP
ATP
P2Y AE2
InsP 3
InsP 3 E R
C a++
cAMP
TGR-5
+
C a++
+
P2Y
ATP
C l-‐
C l-‐C l-‐
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3-
HCO3- HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-HCO3
-HCO3
-
HCO3-
HCO3-
HCO3-
HCO3-
M3R
OHHO
COOH
OHHO
COO-
HCO3- H2CO3
Apoptos is
F ibros ing / scleros ing cholangitis
C DC A
B ile
C holang ioc yte
HCO3-‐
H2O + C O2
+ H+
S R
C A
FXR Agonists Stimulate Biliary HCO3- Secretion in Rodents
Bile
PPARα agonist
Apoptosis Senescence
Fibrosing cholangiopathy
Phospholipids Mixed micel formation
Ghonem A, et al. Hepatology. 2014;59:1030-1042.
Beuers U, et al. Hepatology. 1998;28:1449-1453.
Primary Biliary Cirrhosis: Future Therapy
Immune-mediated bile duct
injury
Aggravation of bile duct
injury by hydrophobic
bile acids
Cholestasis with
retention of hydrophobic bile acids in
liver
Liver cell damage,
apoptosis, necrosis, fibrosis, cirrhosis
Liver failure
Ursodeoxycholic acid (13-15 mg/kg/d)
Liver transplantation
RCT (Phase 3)
Budesonide? norUDCA?
Nuclear receptor agonists? - FXR: obeticholic acid? - PPARα: beza-, fenofibrate?
RCT (Phase 3)
RCT (Phase 3)
Pathogenesis
Primary Biliary Cirrhosis Characteristics
Sex (f:m) 9 : 1 Age 40 - 60 Survival without treatm. 7.5-16 years Cholestatic enzyme pattern AP, γGT
Autoantibodies AMA (anti-PDC-E2)
Sherlock and Summerfield, 1991
Symptoms: • Fatigue • Itch • “Dry eye, dry mouth“ • …
Courtesy of Ulrich H.W. Beuers, MD.
Molecular size: <3 kD
Amphiphilic upon protonation: hydrophobicity ↑
No peptide G-protein coupled receptor
Lysophosphatidic acid (LPA)
Kremer AE, et al. Gastroenterology. 2010;139:1008-1018.
Identification of a Neuronal Activator in Serum of Pruritic Patients
*
SMB1
SMB2
*Ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2). Abbreviations: LPC, lysophosphatidylcholine; SMB1, somatomedin B1; SMB2, somatomedin B2. With permission from Nishimasu H, et al. Trends Pharmacol Sci. 2012;33:138-145.
Lysophosphatidic Acid (LPA) is Formed by Autotaxin in Serum
*P <.05. ***P <.001 (ANOVA). With permission from Kremer AE, et al. Hepatology. 2012;56:1391-1400.
Increased Autotaxin (ATX) Activity is Specific for Pruritus of Cholestasis
0
50
100
150
200
beforetherapy(n=18)
aftertherapy(n=18)
p<0.05
Itch
inte
nsity
[%]
0
50
100
150
200
beforetherapy
(n=6)
aftertherapy
(n=6)
p<0.01
Itch
inte
nsity
[%]
0
50
100
150
200
beforetherapy
(n=8)
aftertherapy
(n=8)
p<0.01
Itch
inte
nsity
[%]
0
50
100
150
200
beforetherapy(n=18)
aftertherapy(n=18)
p<0.05
ATX
activ
ity [%
]
0
50
100
150
200
beforetherapy
(n=6)
aftertherapy
(n=6)
p<0.05
ATX
activ
ity [%
]
A B C D
0
50
100
150
200
beforetherapy
(n=8)
aftertherapy
(n=8)
p<0.01
ATX
activ
ity [%
]
Colesevelam-18%
MARS-62%
Nasobiliary Drainage-87%
0
50
100
150
200
beforetherapy
(n=5)
day 3 oftherapy
(n=5)
p<0.005
ATX
activ
ity [%
]
0
50
100
150
200
beforetherapy
(n=5)
day 3 oftherapy
(n=5)
p<0.005
Itch
inte
nsity
[%]
Rifampicin-65%
E F G HColesevelam
-13%MARS-29%
Nasobiliary Drainage-50%
Rifampicin-32%
Itch
Abbreviations: ATX, autotaxin; MARS, molecular absorbance recirculating system. Kremer AE, et al. Hepatology. 2012;56:1391-1400.
Autotaxin Activity Mirrors Therapeutic Efficacy in Pruritus of Cholestasis
-85%
ATX
(n=17) (n=17)
(n=17) (n=17)
Potential Pruritogens in Cholestasis
Accumulate in the systemic circulation
Are secreted into bile
Are (biotrans-)formed in the liver and/or gut
Affect the endogenous serotonergic and
opioidergic system
Autotaxin LPA X
Pruritogens…
Beuers U, et al. Hepatology. 2014. [Epub ahead of print] Slide courtesy of Dr. Ulrich Beuers.
Accumulate in the systemic circulation
Are secreted into bile
Affect the endogenous serotonergic and
opioidergic system
X Rifampicin
Naltrexone Sertraline
Cholestyramine
Nasobiliary drainage
Pruritogens…
Rifampicin Albumin dialysis etc.
Pathogenesis of Pruritus in Cholestasis Targets for Interventional Therapies: Summary
Autotaxin LPA
Are (biotrans-)formed in the liver and/or gut
Beuers U, et al. Hepatology. 2014. [Epub ahead of print] Slide courtesy of Dr. Ulrich Beuers.
Challenges and New Opportunities in the Clinical Management of PBC
David E.J. Jones, MD, PhD Dean of Research and Innovation
Newcastle University Newcastle upon Tyne, United Kingdom
Survival Is Still Significantly Impaired in PBC in the UDCA Era
Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Jones DE, et al. J Hepatol. 2010;53:911-917.
Transplant-free survival of all NE1-25 cohort PBC patients vs case controls
Suboptimal Therapy in PBC—What Are the Potential Causes?
l Drugs are not as effective as we think they are and/or our biomarkers of response don’t accurately predict real response
l Effectiveness may not be as universal as we think it is l Drugs are effective but we aren’t using them optimally l Drugs are effective but aren’t actually getting to people l Some combination of the above
Abbreviations: PBC, primary biliary cirrhosis.
Suboptimal Therapy in PBC—What Are the Potential Causes?
l In UK-PBC national cohort, 20% of PBC patients are not treated with ursodeoxycholic acid (UDCA)
l Significant percentage of patients are treated with doses in 10- to 12-mg/kg range
l Some issues with adherence (weight gain, nausea, hair loss?)
l Simple and consistent message is needed about UDCA
Abbreviations: PBC, primary biliary cirrhosis.
UDCA Is an Effective Therapy in PBC
Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Poupon RE, et al. Gastroenterology. 1997;113:884-890.
Criteria for “Response” to UDCA in PBC
Paris Criteria
• Bilirubin ≤1 mg/dL + AST ≤2 x ULN +ALP ≤3 x ULN after 12/12 UDCA at 13-15 mg/kg
• Responder: 96% survival vs 99% control population at 5 years
• Nonresponder: 69% survival vs 68% Mayo Predicted Survival
• ALP decrease by 40% or normalized After 12/12 UDCA at 13-15 mg/kg
Barcelona Criteria
Issues
• Reciprocity • “Virtual” controls (the 65-year-old woman paradox) • Generalizability • Dichotomizes a continuous variable
Abbreviations: ALP, alkaline phosphatase; AST, aspartate aminotransferase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Corpechot C, et al. Hepatology. 2008;48:871-877.
Criteria for “Response” to UDCA in PBC Early-Stage Patients
70
10 11
76
8 20
53
5 16
86
1
18
71
7 17
0
20
40
60
80
100
Rate of biochemical response
Adverse outcome in responders
Adverse outcome in nonresponders
Barcelona Paris I Paris II Rotterdam Toronto
Patie
nts (
%)
• Early stage defined as normal albumin and bilirubin • Paris II criteria: ALT and ALP ≤1.5 x ULN after medical therapy
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; NS, not significant; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal. Corpechot C, et al. J Hepatol. 2011;55:1361-1367.
P = NS for Barcelona, Paris I, Rotterdam, and Toronto; P <.05 for Paris II.
Criteria Chi-‐square statistic P-‐valueBarcelona 7.3 6.73E-‐03Paris I 106 <1E-‐16Toronto 24.2 8.78E-‐07Paris II 45.7 1.40E-‐11
RESULTS: Log-‐rank test for time free from LT for PBC, PBC-‐related death or Bilirubin ≥ 100µmol/L
Abbreviations: LT, liver transplant; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Carbone M, et al. Gastroenterology. 2013;144:560-569.e7.
UDCA-Response Criteria in the UK-PBC Patient Cohort—Independent Validation
Responders Nonresponders
Factors Predicting Outcome in PBC in the UK-PBC Patient Cohort
Mul%variate %me-‐to-‐event analysis (baseline variables only) Variable Es%mate SE HR L95 U95 P Baseline Sodium -‐0.086 0.035 0.918 0.857 0.983 0.014 Crea7nine -‐0.0158 0.005 0.984 0.975 0.994 0.001 LN Bilirubin 1.407 0.15 4.085 3.046 5.477 <2e-‐16 LN (AST or ALT ra7o) -‐0.53 0.164 0.588 0.427 0.811 0.001 LN ALP 0.477 0.152 1.611 1.195 2.172 0.002 Platelets -‐0.004 0.002 0.996 0.993 0.999 0.006
Mul%variate %me-‐to-‐event analysis (including "Paris I response" at 12 months) Variable Es%mate SE HR L95 U95 P Baseline Sodium -‐0.076 0.031 0.927 0.871 0.986 0.016 LN Bilirubin 1.157 0.139 3.181 2.423 4.177 <2e-‐16 LN (AST or ALT ra7o) -‐0.455 0.165 0.634 0.459 0.877 0.006 Platelets -‐0.003 0.001 0.997 0.994 0.999 0.020 12 months Treatment failure 2.124 0.308 8.361 4.574 15.278 5.10E-‐12
Cox Proportionate Hazards Model: Time-to-Event Analysis
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; HR, hazard ratio; LN, natural log; PBC, primary biliary cirrhosis; SE, standard error. Carbone M, et al. J Hepatol. 2013;58:S43-S44. Abstract 99. Slide courtesy of David E. J. Jones, MD, PhD.
Just How Effective Is UDCA in PBC? The Conventional Model
l 79.7% of UDCA-treated patients are UDCA-
responsive (Paris I) l 797 beneficiaries per 1000 patients in UK-PBC
cohort l UDCA is highly effective!
BUT l Significant proportion of patients meet response
criteria before therapy is commenced
Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.
Just How Effective Is UDCA in PBC?
80% 20%
74%
80%
1000 patients
800 UDCA-treated 200 UDCA-untreated
640 responders 160 nonresponders
20%
474 “respond” without therapy 166 true responders
UDCA has a beneficial effect in 166/1000 patients with PBC in the UK-PBC cohort For every 100 genuine responders, there are 96 genuine nonresponders
Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Slide courtesy of David Jones, MD.
Treatment Failure in the UK-PBC Patient Cohort
>50% of patients in the UK-PBC patient cohort who presented before the age of 50 have failed primary therapy (in a state of UDCA nonresponse or already transplanted) by the time of study
Abbreviation: UDCA, ursodeoxycholic acid. With permission from Pells G, et al. J Hepatol. 2013;59:67-73.
Potential Mechanisms for UDCA Nonresponse in PBC and Possible Options for Therapeutic Advance
l Different severity or nature of immune response – Targeted immunosuppression (biologics)
l Different bile pool/microbiota – “Second-line” bile acid therapies
l Different biliary epithelial response – Biliary epithelial protectant agents
l Pre-existing fibrosis/cirrhosis – Earlier diagnosis allowing treatment window for UDCA! – Antifibrotics
Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.
Challenges for Trial Design for Second-Line Therapy in PBC
• Definition of the “at-risk” population requiring second-line therapy
• Outcome measures (do UDCA response criteria apply to other therapies?)
• Lack of relevant biomarkers • Impossibility of carrying out a hard endpoints trial due to
prolonged disease • Difficulty in performing a histology-based trial (acceptability
and lack of scoring systems)
Abbreviations: PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.
Drugs Under Evaluation for PBC
l Rituximab (B-cell depletion) l Fibrates (PPAR-α agonists) l Obeticholic acid (6-ethyl chenodeoxycholic acid,
FXR agonist) l Nor-ursodeoxycholic acid (bicarbonate “umbrella,”
anti-inflammatory, anti-fibrotic)
Abbreviations: FXR, farnesoid X receptor; PBC, primary biliary cirrhosis; PPAR, peroxisome proliferator-activated receptor.
Biochemical Effects of Rituximab in Patients with PBC and an Incomplete Response to UDCA
l Open-label study of rituximab treatment in patients with PBC and incomplete responses to UDCA (n = 6)
l Rituximab was well tolerated and associated with reductions in serum immunoglobulins (IgA; IgM) and antimitochondrial antibodies
l Significant reductions in serum ALP levels were observed up to 36 weeks following rituximab treatment
Abbreviations: ALP, alkaline phosphatase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Tsuda M, et al. Hepatology. 2012;55:512-521.
Fenofibrate Improves Liver Biochemistry Values in PBC Patients
l Peroxisome proliferator-activated receptor (PPAR)-α agonist, fibric acid derivative
l PPAR-α activity – Regulation of bile acid synthesis and detoxification – Modulates phospholipid secretion, which helps protect bile duct
epithelium by formation of micelles l Open-label study to evaluate efficacy and safety of fenofibrate in
patients with PBC and incomplete response to UDCA (n = 20) l ALP levels decreased significantly; rebound in ALP levels occurred
following fenofibrate discontinuation l Contraindicated in patients with hepatic or severe renal disfunction,
including PBC Abbreviations: ALP, alkaline phosphatase; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. Levy C, et al. Hepatology. 2009;50(suppl 4):995A-996A. Zollner G, Trauner M. Br J Pharmacol. 2009;156:7-27. Tricor PI. 2010. Abbott Laboratories.
FXR-Agonism as a Therapeutic Option in PBC—Properties of Obeticholic Acid
Shared Properties with Ursodeoxycholic Acid (UDCA) l Choleresis l Antiapoptosis l Antioxidant
Additional Direct Properties l Induced bile acid detoxification l Induced bile acid conjugation l Suppressed bile acid synthesis l Modified bile acid transport
Additional Indirect Properties (via GI release of FGF-19) l Suppressed bile acid synthesis
Could “UDCA nonresponse” addressed by OCA be a manifestation of indirect actions?
Abbreviations: FCF-19, fibroblast growth factor 19; FXR, farnesoid X receptor; GI, gastrointestinal; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid.
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase II Data in PBC Patients on Stable UDCA
*Primary efficacy endpoint was percent change in plasma ALP from pretreatment values; patients with a placebo-subtracted ALP reduction of ≥10% were defined as responders. Abbreviations: ET, end of treatment; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid. With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.
Patie
nts R
espo
ndin
g (%
)
Day 85/ET
Placebo 10 mg 50 mg0
20
40
60
80
10 mg50 mg
Placebo
p <0.0001 p = 0.0017
0%
70%
44%
Dose
% S
ubjec
ts
Placebo OCA 10 mg OCA 50 mg
OCA 50 mg
OCA 10 mg
Patie
nts R
espo
ndin
g (%
)*
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase II Data
Abbreviations: ET, end of treatment; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis. With permission from Mason AL, et al. Hepatology. 2010:52(suppl S1):357A.
Placebo 10mg 50mg0
10
20
30
40
50
Placebo10mg50mg
%Pa
tient
s With
draw
ing
D
ue to
Pru
ritu
s (%
)
Placebo OCA 10 mg OCA 50 mg
OCA 50 mg OCA 10 mg
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III (POISE)
M9 Screening
1 to 8 weeks
Entry ALP ≥1.67 x ULN
and/or bilirubin > ULN
but <2 x ULN
N = 216
Positive Response • ALP <1.67 x ULN and bilirubin WNL,
and ≥15% ALP reduction
Continue pre-study UDCA
All Patients (N = 180) Long-term Safety Extension
5 years OCA Rx OCA 10 mg
Placebo
12 Months M12
& LTSE Visit 1
M6 W2 0
OCA 5 mg OCA 10 mg
M3
Abbreviations: ALP, alkaline phosphatase; FXR, farnesoid X receptor; LTSE, long-term safety extension; OCA, obeticholic acid; PBC, primary biliary cirrhosis; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; WNL, within normal limits. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
*P <.0001 vs placebo; P-values obtained using Cochran-Mantel-Haenszel stratified by randomization strata factor. Abbreviations: ALP, alkaline phosphatase; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis; ULN, upper limit of normal. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III Data (POISE)
R e s p o n d e rs (% )
0
2 0
4 0
6 0P la c e b o (n = 7 3 )
T it ra te d O C A (n = 7 0 )
1 0 m g O C A (n = 7 3 )
1 2 m o n th s6 m o n th s
*
***
Primary Endpoint: Proportion of subjects achieving ALP <1.67 x ULN with bilirubin ≤ ULN
and ≥15% reduction in ALP
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III Data (POISE)
Time (months)
LS M
ean
(SE)
Δ in
ALP
(U/L
)fro
m B
asel
ine
-200
-150
-100
-50
0 Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)
0 6 12
P <.0001 vs placebo for all post baseline values of titrated OCA and 10 mg OCA groups. Abbreviations: ALP, alkaline phosphatase; FXR, farnesoid X receptor; LS, least squares; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III Data (POISE)
Time (months)
LS M
ean
(SE)
Δ in
ALT
(U/L
)fro
m b
asel
ine
-40
-30
-20
-10
0 Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)
0 6 12
P <.0001 vs placebo for all post baseline values of titrated OCA and 10 mg OCA groups. Abbreviations: ALT, alanine aminotransferase; FXR, farnesoid X receptor; LS, least squares; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III Data (POISE)
Time (months)
LS M
ean
(SE)
Δ in
Dire
ct B
ilirub
in( µ
mol
/L) f
rom
Bas
elin
e
-2
-1
0
1
2
3Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)
0 6 12
*
*
*
* *
**
*
*P <.05 vs placebo. Abbreviations: FXR, farnesoid X receptor; LS, least squares; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III Data (POISE)
Placebo (n=73)
Titrated OCA (n=70)
10 mg OCA (n=73)
D/C due to pruritus, n (%) 0 1 (1%) 7 (10%) TEAEs without pruritus, n (%) 66 (90%) 62 (89%) 63 (86%) TEAE pruritus, n (%) 28 (38%) 39 (56%) 50 (68%) SAEs, n (%) 3 (4%) 11 (16%) 8 (11%)
Abbreviations: D/C, discontinuation; FXR, farnesoid X receptor; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SAE, serious adverse event; TEAE, treatment-emergent adverse effect. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
*p<0.05 vs placebo for LS mean change VAS score range: 0= no pruritus, 100= severe pruritus
T im e (m o n th s )
S c o re (m m )
0
1 0
2 0
3 0
4 04 0
1 0 0
P la c e b o (n = 7 3 )
0 6 1 2
T itra te d O C A (n = 7 0 )1 0 m g O C A (n = 7 3 )
* **
Pruritus Visual Analog Scale Score
Cholestyramine Placebo: 11% Titration OCA: 19% 10 mg OCA: 26%
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III Data (POISE)
Time (months)
Mea
n (S
E) L
DL C
hole
ster
ol(m
mol
/L)
3.0
3.2
3.4
3.6
3.8
4.0Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)
0 6 12
Abbreviations: FXR, farnesoid X receptor; OCA, obeticholic acid; LDL, low density lipoprotein; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
FXR-Agonism as a Therapeutic Option in PBC—Obeticholic Acid (INT-747)
Phase III Data (POISE)
Time (months)
Mea
n (S
E) H
DL C
hole
ster
ol(m
mol
/L)
1.0
1.5
2.0
2.5Placebo (n=73)Titrated OCA (n=70)10 mg OCA (n=73)
0 6 12
Abbreviations: FXR, farnesoid X receptor; HDL, high density lipoprotein; OCA, obeticholic acid; PBC, primary biliary cirrhosis; SE, standard error. With permission from Nevens F, et al. J Hepatol. 2014:60(suppl): Abstract 0168.
Clinician Awareness Is a Challenge for Effective Therapy in PBC
Abbreviations: gastro, gastroenterologist; hep, hepatologist; PBC, primary biliary cirrhosis Bodenheimer HC, et al. J Hepatol. 2014:60(suppl): Abstract P399. Slide courtesy of David E. J. Jones, MD, PhD.
80
65
0
20
40
60
80
100
Heps Gastros
Competence: “Highly Competent”
Early Diagnosis/Treatment
88 87
Heps Gastros
Early Diagnosis
Practice Performance: “Always/Often”
76 65
Heps Gastros
Early Treatment
Res
pond
ers (
%)
Clinician Competence in and Use of Response Criteria for Assessing Treatment Response
in PBC
Abbreviations: gastro, gastroenterologist; hep, hepatologist; PBC, primary biliary cirrhosis Bodenheimer HC, et al. J Hepatol. 2014:60(suppl): Abstract P399. Slide courtesy of David E. J. Jones, MD, PhD.
76
42
0
20
40
60
80
100
Heps Gastros
Practice Performance: “Always/Often”
36 30
0
20
40
60
80
100
Heps Gastros
Competence: “Highly Competent”
Res
pond
ers (
%)
Effect of Untreated or Suboptimally Treated PBC on Disease Progression/Mortality
Abbreviations: gastro, gastroenterologist; hep, hepatologist; PBC, primary biliary cirrhosis Bodenheimer HC, et al. J Hepatol. 2014:60(suppl): Abstract P399. Slide courtesy of David E. J. Jones, MD, PhD.
74
55 64
38
0
20
40
60
80
100
Heps Gastros Heps Gastros
Competence: “Highly Competent”
Effect on Disease Progression
Res
pond
ers (
%)
Causes of Suboptimal Treatment
Overall Health Status and Quality of Life Are Also Impaired in PBC, UK-PBC
Cohort Data (n = 2300)
l 35% of primary biliary cirrhosis (PBC) patients report perceived QOL impairment vs 6% of healthy controls (P <.0001)
l 46% of PBC patients rated their perceived health status as fair or poor vs 15% of healthy controls (P <.0001)
l In terms of change over time, 49% of PBC patients reported their health as worse compared with the previous year vs 14% of healthy controls (P <.0001)
Mells GF, et al. Hepatology. 2013;58:273-283.
Individual Symptom Domain Impacts UK-PBC Cohort Data (n = 2300)
Con PBC11
22
33
44
55p<0.0001
45%
PBC-
40 F
atig
ue D
omai
n
With permission from Mells GF, et al. Hepatology. 2013;58:273-283.
Individual Symptom Domain Impacts UK-PBC Cohort Data (n = 2300)
l Fatigue is important symptom with significant impact on patient – Fatigue had its greatest impact on perceived QOL when
accompanied by symptoms of social dysfunction
– 89% of patients with severe fatigue and poor QOL had symptoms of impaired social function compared with 11% of patients with severe fatigue and no QOL impairment (P <.0001)
l Critical issue is how patients adapt and cope with fatigue as this will ultimately affect impact of fatigue on QOL
l Disease management should ultimately target both the underlying biology of the disease as well as symptoms
Mells GF, et al. Hepatology. 2013;58:273-283.
Reaching the Goal—What We Need to do to Improve PBC Care
l Improve community, patient, and first responder awareness of the disease and its presentations
l Improve physician awareness of the need for therapy with UDCA and assessment of response
l Systematic approach to management with triage built in for high-risk/nonresponding patients
l Systematic approach to the evaluation of second-line therapy and implementation into stratified management pathways
l Improved awareness of, assessment of, and treatment of symptoms in PBC using systematic approaches