XXXI Pan American Congress of Gastroenterology

Falk Workshop ‘Digestive Diseases: State-of-the-Art & Daily Practice‘

Santiago de Chile, November 12, 2008

Cholestatic Liver Diseases

Michael Trauner, M.D.
Div. of Gastroenterology & Hepatology
Department of Internal Medicine
Medical University of Graz, Austria
 State-of-the-Art & Daily Practice

• Clinically relevant molecular advances

• Focus on cholangiopathies: PBC, (P)SC
• Intrahepatic cholestasis of pregnancy
• New(ly defined) diseases
• Medical treatment: UDCA & beyond
 Principal Mechanisms & Clinical
Spectrum of Cholestasis
Bland Cholestasis Inflammatory Cholestasis

Drugs
Hormones Alcohol
Cytokines
Drugs Inflammation Viral
Hepatocytes Genetic Sepsis

Small Ducts Bile Duct

Injury Ductopenia (VBDS) PBC

Mechanical Obstruction PSC

• Extraluminal Compression Tu
Large Ducts
• Intraluminal Obstruction

Whitehead et al., Gut 2001; 48: 409 Trauner et al., J Clin Gastro 2005; 39: S111
Bile Secretion
& Cholestasis

Hepatocytes
Canalicular Bile
70%
BSEP

Hereditary
& Acquired Cholestasis
Defects Jaundice

Ductal Bile
Cholangiocytes
30%

Trauner et al., New Engl J Med 1998; 339: 1217

 Hereditary Transport Defects:
A Continuous Spectrum of Liver Diseases
Genetic Diagnosis

Homozygous PFIC Neonates, Infants

(Byler)
Childhood
“Milder“ Mutations BRIC
(Summerskill-Walshe-Tygstrup)

Heterozygous LPAC Adults

Suceptibility ICP, DILD
1/3 Unexplained
Biliary Fibrosis, IAD
MDR3 (Phospholipids)
Cholestasis
BSEP (Bile Acids)
Decompensation by PBC, PSC Modifyer Genes?
2o Injury: FIC1 (Byler)
Hormone (ICP) Ziol et al., Gastro 2008; 135: 131
Drug (DILD), Inflammation Reviewed in: Trauner et al., Sem Liver Dis 2007; 27: 77
Intrahepatic Cholestasis of Pregnancy

• Complex etiology
– Genetic (ABC transporters, FXR)
– Endocrine (estrogen, progesterone)
– Environmental (viral, selenium)
• Diagnostic criteria
– Pruritus in (2nd and) 3rd trimenon
– Serum bile acids > 10 µM (high fetal risk > 40)
– Clinical/biochemical resolution after delivery
Reviews: Lammert et al., J Hepatol 2000; 33: 1012
Pusl & Beuers, Orphanet J Rare Dis 2007; 2: 26
Hay, Hepatology 2008; 47: 1067
Effect of Ursodeoxycholic Acid in ICP

Glantz et al., Hepatology 2005; 42: 1399

Kondrackiene et al., Gastro 2005; 129: 894

Management of Cholestatic Pruritus

• (UDCA: effective only in ICP)

• Cholestyramine: 4 g qid (4hrs UDCA)
• Rifampicin (150-600 mg/d) ~10% Hepatotoxicity
• Central: naltrexone (25-50mg/d), sertraline
• Extracorporeal liver support
• Liver transplantation

Recent Reviews: Bergasa, Clinics in Liver Disease 2008; 12: 219

Kremer et al., Drugs 2008; 68: 2163
 Pregnane X Receptor (PXR) and Constitutive
Androstane Receptor (CAR) Stimulate Adaptation
For renal excretion

Sinusoidal membrane
3 Phase 3
MRP3
MRP4
Phase 1
1 CYP3A11
CYP2B10
Conjugated &
poly-hydroxylated 6-Ethyl-CDCA
Bile acids (Ethichendiol)
Phase II / PBC

2 Phase 2 FXR
Retained UGT1A1
bile acids SULT2A1
PXR CAR
Rifampicin Phenobarbital
Wagner et al., Hepatology 2005; 42: 420
Marschall et al., Gastroenterology 2005 129: 476
 Chronic Cholangiopathies

PBC
Liver
Small duct PSC

PSC

Common bile duct

Duodenum
Courtesy G. Paumgartner
Primary Biliary Cirrhosis (PBC)
Autoimmune
destruction of
Liver small bile ducts

AMA Genetic
- Family risk
Tregs
Common bile duct - Polymorphisms
Environmental
- Infections
Novosphingobium aromaticivorans
- Xenobiotics
Duodenum
Molecular Mimicry
Major Clinical Callenges in PBC

• Identification of patients at risk for cirrhosis

• Optimize treatment (non-responders)
• Extrahepatic manifestations &
complications
– Pruritus, fatigue, cognitive dysfunction
– Cardiovascular risk, osteoporosis
– Associated immune disorders
PBC – A Variably Progressive Disease
Number of Bile Ducts

• Subclinical PBC (AMA+) Cholestasis

• Non-progressive PBC (AP, GGT)
(asymptomatic)
Jaundice
• Slowly progressive PBC
(Bilirubin)
• Liver histology
(+ symptoms)
• Sp100, gp210
• Rapidly progressive PBC • Albumin, bili
(premature ductopenic) • NR to UDCA
Liver-
Cirrhosis

Duration (Years – Decades)

cm
Excellent Prognosis in PBC Patients with
Biochemical Response to UDCA
Responder Non-Responder

Pares et al., Gastroenterology 2006; 130: 715

Pathogenesis and Therapeutic Targets in PBC
Immune-mediated Bile Duct Injury

Aggravation of Duct Lesion by

Cytotoxic Bile (Salts) Treat early (stages)

Cholestasis with Retention of Ursodeoxycholic

Bile Salts in Hepatocytes Acid (UDCA)
13-15 mg/kg/d
Necrosis, Apoptosis,
Fibrosis, Cirrhosis

Liver Failure Paumgartner & Beuers, Hepatology 2002; 36: 525

Beuers, Nature Clin Pract Gastro Hep 2006; 3: 318
Excellent Prognosis in PBC Patients with
Biochemical Response to UDCA

Responder

Suboptimal
33(-61)%
Responder

Corpechot et al., Hepatology 2008; 48: 871

 Pathogenesis and Therapeutic Targets in PBC
Anti-Retroviral? Antibiotic?
Tamoxifen? Methotrexate
Immunologic Bile Duct Injury Raloxifen?
CSA, MMF
Anti-CD20 (Rituximab)?
Thalidomide, Sulindac
Azathioprine
Aggravation of Duct Lesion by Fibrates?
Statins?
Predniso(lo)ne
Cytotoxic Bile Salts Budesonide

Combination Therapy
Cholestasis with Retention of
Bile Salts in Hepatocytes Ursodeoxycholic
Acid (UDCA)

Necrosis, Apoptosis, Colchicine, Silymarin

Fibrosis, Cirrhosis D- Penicillamine

Recent Review:
Liver Failure Silveira & Lindor
LTx Clin Liver Dis 2008; 12: 425
 Clinical and Molecular Effects of
UDCA/Budesonide Combination Therapy
Clinical Effect (de novo) Molecular Synergism (AE2)

Caveat:
Portal HT
Cirrhosis GR

Rautiainen et al., Hepatology 2005; 41: 747 Arenas et al., J Clin Invest 2008; 118: 695
Bile Secretion
& Cholestasis

Hepatocytes

BSEP

Poupon et al., J Hepatol 2008 online

Primary Biliary
Cholangiocytes Cirrhosis
Ae2 Knockout Mouse
Salas et al., Gastro 2008
Lazaridis et al., Gastro 2004
Trauner et al., New Engl J Med 1998
 Primary Sclerosing Cholangitis (PSC)

Small Duct PSC

Liver

Gut-primed T cells
Obliterative fibrosis
of bile ducts
LPS

Colitis (~75%) • Right-sided

• Oligo-symptom.
• Backwash ileitis
• Rectal sparing Common bile duct
• CRC (5x>UC)
Loftus et al., Gut 2005
MRC ERC
Duodenum Berstad et al., Clin Gastroerol Hepatol 2006
Prognosis: Small vs. Large Duct

Small-duct PSC
(5%)

Very rare

Malignancy Large-duct PSC

• CCC (15%) (95%)
• Colorectal
• Pancreas, HCC
Bergquist et al., J Hepatol 2002; 36: 321 Angulo et al., Hepatology 2002; 35: 1494
Major Clinical Callenges in PSC

• Disease heterogeneity (mixed bag?)

• Lack of effective medical treatment
• Malignancy (screening, treatment)
MRCP FISH
LTx

Extrahepatic

Malhi & Gores, J Hepatol 2006; 45: 856

Gores et al., J Hepatol 2007; 47: 454
 Immunological
Mechanisms Cytokines
Transport
Defects
Atypical pANCA
CD4-pos. Infiltrates Toxic Bile

Ineffective in PSC:
• Immunosuppressants
• Anti-inflammatory
• Anti-fibrotics
• Antibiotics
Fibrogenesis

IBD

Intestinal Ischemia
Translocation PAMPs (LPS…)

PSC as Immune-mediated
Gut-primed T cells Inflammatory “Disease“
 Treatment of PSC with UDCA
Placebo - Controlled Trials
Prevention of Beuers Stiehl Lindor Mitchell Olsson
CRC (& CCC?) (n=14) (n=20) (n=105) (n=26) (n=110)

Dose (mg/kg/d) 13 -15 10 -12 13 -15 20 17-23

Serum liver tests + + + + -

Histology (+) (+) - +

Cholangiography + -

Survival - -

Reviewed in: Pusl & Beuers, WJG 2006; 12: 3487

Paumgartner & Pusl, Clin Liver Dis 2008; 12: 53
 High-dose UDCA in PSC

• Pilot study promising (30 mg/kg/d, 2 y)

– Biochemistry, Mayo risk score improved
• Recent RCT (28-30 mg/kg/d, 3 y) negative
– 76 vs. 74 pts
– Biochemistry improved
– Varices, histological progression RR x 2.2
– Death, transplant RR x 3.3
Only established Rx
(80% survival / 10y)
Cullen et al., J Hepatol 2008; 48: 792
Lindor et al., AASLD 2008 (LB Abstract #2)
 UDCA Combined with Endoscopic Treatment of
Strictures Improves Survival of Patients with PSC

100 UDCA + Endoscopic Treatment

Probability
of 80 Survival predicted by
Survival Mayo Model
60
• Dilatation
40 • Short term stenting
Patients at risk • Antibiotic coverage
20 n=61 55 41 33 • Brushing
24 20 & 14biopsy

0
0 20 40 60 80 100
Months
Stiehl et. al., J Hepatol 1997
 norUDCA Reverses Sclerosing
Cholangitis in Mdr2 -/- (KO) Mice
H&E pv
bd pv pv
bd
pv bd bd
bd

WTWT
(+/+) KO (-/-) KO+UDCA KO+norUDCA
(U/L) (U/L)
ALT 800,0
† AP †
800 500500
700,0 450

600,0
600 * 400400
* 350
500,0
300300 *
400,0
400
250
‡
0 1 300,0
2 3 Months ‡ 200200
150
200,0
200
100,0
Rx 100100
50

0,0 0
1 2 3 4 1 2 3 4

W
T
KO DCA CA
W
T
KO DCA CA Conjugation
p<0.05
D D
+U orU UDCA +U norUDCA
orU * vs. WT
KO +n KO +n † vs. KO
K O K O ‡ vs. KO
Fickert et al., Gastroenterology 2006; 130: 465-81
 Sclerosing Cholangitis
Gossard et al. Am J Gastro 2005

• Primary
– Immune-mediated (gut?)
• Secondary
– Bacterial, recurrent pyogenic cholangitis
– IgG4-associated cholangitis Bile Duct Cast in Rapidly
Progressive SC after Sepsis
– Posttraumatic, sepsis, burns
– Ischemic cholangitis
– AIDS cholangiopathy
– Portal biliopathy

Abdalian & Heathcote, Hepatology 2006; 44: 1063

 IgG4-associated Cholangitis

• Synonyms
– Autoimmune pancreatitis-associated SC
– Sclerosing pancreato-cholangitis
• Clinical presentation: 75% acute jaundice
• Diagnostic test
– IgG4 > 140mg/dL, (plasma cells), imaging
– DDx: 9% of PSC have elevated IgG4
• Therapy
– Steroids, (azathioprine, MMF)
Björnsson et al., Hepatology 2007; 45: 1547
Ghazale et al., Gastroenterology 2008; 134: 706
IgG4-associated Cholangitis

90%

Björnsson et al., Hepatology 2007; 45: 1547

 IgG4-associated Cholangitis

• Clinical presentation: 75% acute jaundice

• Diagnostic tests
– IgG4 > 140 mg/dL, ( + plasma cells on [L]Bx )
– Imaging (MRCP, ERCP)
• Therapy
– Steroids, (azathioprine, MMF)

Björnsson et al., Hepatology 2007; 45: 1547

Umemura et al., Hepatology 2007; 46: 463
Ghazale et al., Gastroenterology 2008; 134: 706
IgG4-associated Cholangitis
Before After Steroids (3m)

Ghazale et al., Gastroenterology 2008; 134: 706

 Overlap-Syndromes

AIH 10% PBC

10% rare
Abdalian et al.,
Hepatology 2008; 47: 949

10%

IgG4-assoc.
Cholangitis PSC
Mendes et al., Am J Gastro 2006; 101: 2070
 Summary & Conclusions

• Better understanding of pathogenesis of

cholestasis & cholangiopathies
• “New“ cholangiopathies: IgG4, Sepsis
• UDCA basis of therapy
• New bile acid derivatives (norUDCA,
6-ECDCA) on horizon
• Nuclear receptors as therapeutic targets
 University Hospital Graz

Thank you for your attention!