xiii falk liver week 2006 - dr. falk pharma · 2017-10-13 · congress short report falk symposia...

Congress Short Report Falk Symposia 155–157

XIII Falk Liver Week 2006Freiburg (Germany), October 6–11, 2006


Text:Dr. Beate FesslerMedical JournalistCologne (Germany)

© Photos: Kai-Uwe Wudtke

1st edition 2007

Leinenweberstr. 5Postfach 652979041 FreiburgGermany

FALK FOUNDATION e.V.

Publisher

© 2007 Falk Foundation e.V.All rights reserved.

Falk Symposium 155

XIX International Bile Acid MeetingBile Acids: Biological Actions and Clinical RelevanceFreiburg, October 6–7, 2006

Falk Symposium 156

Genetics in Liver DiseasesFreiburg, October 8–9, 2006

Falk Symposium 157

Chronic Hepatitis: Metabolic, Cholestatic, Viral and AutoimmuneFreiburg, October 10–11, 2006



2

Scientific Organizers

President:

Falk Symposium 155

Falk Symposium 156

Falk Symposium 157

U. Beuers,Amsterdam

(The Netherlands)

H.E. Blum,Freiburg

(Germany)

D.W. Cox,Edmonton(Canada)

D. Häussinger,Düsseldorf(Germany)

P.L.M. Jansen,Amsterdam

(The Netherlands)

G.A. Kullak-Ublick,Zürich

(Switzerland)

A.M. Diehl,Durham(USA)

M.P. Manns,Hanover

(Germany)

T. Sauerbruch,Bonn

(Germany)

G. Paumgartner,Munich

(Germany)

D. Keppler,Heidelberg(Germany)

U. Leuschner,Frankfurt

(Germany)

A. Stiehl,Heidelberg(Germany)

M. Trauner,Graz

(Austria)


3

Foreword

“Basic research meets clinical research”. Thisstatement summarizes the three scientific sym-posia which were held as part of the XIII FalkLiver Week 2006 in Freiburg, under the presiden-cy of G. Paumgartner, Munich. The participationof nearly 1100 scientists, clinicians and residentdoctors from 57 countries attested to the urgentneed for an exchange between “bench” and“bedside”.At the XIX International Bile Acid Meeting (FalkSymposium 155) participants discussed currentbasic research on metabolism and transport ofbile acids as well as the pathogenesis of bileacid-associated diseases. The therapeutic appli-cation of hydrophilic bile acids was anotherfocus of the organizers U. Beuers, Amsterdam,D. Keppler, Heidelberg, U. Leuschner, Frankfurt,A. Stiehl, Heidelberg, and M. Trauner, Graz.Falk Symposium 156 brought participants up-to-date in the difficult field of genetic liver diseases.The organizers H.E. Blum, Freiburg, D.W. Cox, Ed-monton, D. Häussinger, Düsseldorf, P.L.M. Jansen,

Amsterdam, and G.A. Kullak-Ublick, Zürich, hadput together a program that highlighted thepractical relevance of basic genetic research andillustrated its precise application to everyday clin-ical practice.Last but not least, Falk Symposium 157 concen-trated on chronic hepatitis of metabolic, cholesta-tic, viral and autoimmune origin. Organized byA.M. Diehl, Durham, M.P. Manns, Hanover, andT. Sauerbruch, Bonn, the symposium included in-depth discussion of the latest developments in pathogenesis, diagnosis and treatment ofchronic hepatitis and its sequelae.

5


Page

Falk Symposium 155XIX International Bile Acid MeetingBile Acids: Biological Actions and Clinical RelevanceFreiburg, October 6–7, 2006

• Metabolism of Bile Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

• Hepatobiliary Transport of Bile Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

• Extrahepatic Transport and Actions of Bile Acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

• Nuclear Receptor Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16

• Bile Acids, Cellular Injury, and Disease Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

• Bile Acids, Cellular Injury, and Hepatic Fibrosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

• Bile Acids as Therapeutic Agents: Mechanisms and Actions . . . . . . . . . . . . . . . . . . . . . . 23

• Bile Acids in the Treatment of Cholestatic Liver Diseases . . . . . . . . . . . . . . . . . . . . . . . . . 25

Falk Symposium 156Genetics in Liver DiseasesFreiburg, October 8–9, 2006

• Basic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

• Liver Diseases (Part 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

• Liver Diseases (Part 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Falk Symposium 157Chronic Hepatitis: Metabolic, Cholestatic, Viral and AutoimmuneFreiburg, October 10–11, 2006

• Metabolic and Toxic Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40

• Cholestatic Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

• Viral Hepatitis (Part 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

• Viral Hepatitis (Part 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

• Autoimmune Hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

• Sequelae of Chronic Hepatitis (Part 1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

• Sequelae of Chronic Hepatitis (Part 2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55

• Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

• Presentation of Prizes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58

• Eulogy on the Occasion of Professor Dr. Wolfgang Gerok’s 80th Birthday . . . . . . . . . . . . 60

• Chairpersons, Speakers and Scientific Organizers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63

• Further Congress Short Reports of Falk Symposia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

6

according to D.W. Russel, Dallas. He showed inC273β-HSD-ko mice that the defect leads to ahigh mortality rate within a few days. “The de-fect is fatal”, stated D.W. Russel. The defect canbe corrected and mortality virtually normalized

D.W. Russel

Session 1

High mortality: C273β-HSD defect3β-hydroxy-∆5-C27 steroid oxide reductase(C273β-HSD) is among the enzymes involved inbile acid synthesis. A C273β-HSD defect shouldbe considered as a cause of chronic cholestasis,

Falk Symposium 155XIX International Bile Acid MeetingBile Acids: Biological Actions and Clinical RelevanceFreiburg, October 6–7, 2006

Metabolism of Bile AcidsChair:A.F. Hofmann, La JollaJ. Sjövall, Stockholm

Fig. 1

I Survival rate of C27-3β-HSD-deficient mice (D.W. Russel, Dallas)

Surv

ival

rat

e [%

] –/–, n = 91+ 0.5% Cholic acid

–/–, n = 179+ 0.1% Cholic acid

Age [days]

Congress Short Report Falk Symposium 155

7

by the oral administration of cholic acid at a sufficient concentration (Fig. 1).

Bile acid transfer across the blood-brain barrierCholesterol is biosynthesized locally in the brain.The blood-brain barrier prevents an exchange of lipoprotein cholesterol with the circulation.However, metabolites of cholesterol with oxi-dized side-chains, namely 24-OH- or 27-OH-cho-lesterol, are able to cross the blood-brain barrier.I. Björkhem, Huddinge, showed that roughly athird of the de novo synthesized cholesterol inthe brain is released into the circulation as resultof excretion of 24-OH-cholesterol. The lateststudies prove that conversely 27-OH-cholesterolfrom the blood is absorbed into the brain. Therelevance of the uptake of 27-OH-cholesterolinto the brain is still unknown, according to I. Björkhem. In human neurons, 27-OH-choles-terol is converted into a C27-steroid acid viaCYP7B1 and released back into the circulation.“This mechanism might be a matter of detoxifi-cation”, stated I. Björkhem.

Conjugated bile acids as regulatorsof glycogen synthaseBile acids have numerous regulatory functions, onwhich interest is increasingly focusing. These func-tions include their ability to activate specific nu-clear receptors such as FXR and PXR and initiatevarious signal transduction chains. P.B. Hylemon,Richmond, showed in rat hepatocytes that con-jugated bile acids activate AKT signal transduc-tion pathways via G protein-coupled receptorsand increase glycogen synthase activity (Fig. 2).“Conjugated bile acids appear to play an impor-tant role in regulating glucose metabolism in theliver”, was the conclusion of P.B. Hylemon. With5-cholesten-3β,25-diol-3-sulfate, S. Ren, Rich-mond, discovered a new sulfonated oxysterol inrat hepatocytes. It appears to be synthesized inthe mitochondria and, as already shown forother oxysterols, it seems to have a regulatoryfunction on cholesterol homeostasis.

I. Björkhem P.B. Hylemon S. Ren

8

Session 1

TCADCASrc

02-

P

ERK

PTP

X

MEK

Shc

Grb2

S0S

RAS

RAFGi

Akt

PDK

PIP3

PI3Kp85

p110

IRS

-1

P

GTP/

GDP

P

P

P

P

Fig. 2

I Function of bile acids in the regulation of glycogen synthesis (P.B. Hylemon, Richmond)

Bile acid-activated

Gi-coupled receptor

Membrane

IR = Insulin receptor

Mitochondrium

Glycogensynthesis

Glycogensynthase GSK3

Nucleus


9

NTCP dephosphorylation preciselylocalizedThe uptake of conjugated bile acids from theblood into the liver takes place essentially via the transporter protein NTCP. Bile acid uptake isstimulated by cAMP which, via the dephosphory-lation of NTCP by activation of protein phos-phatase 2B (Fig. 3), leads to translocation of the enzyme into the basolateral membrane. In

studies on HuH-7 cell lines, M.S. Anwer, NorthGrafton, was able to localize accurately theprocess of dephosphorylation, namely at serine226

of NTCP. This dephosphorylation leads to in-creased retention of NTCP in the basolateralmembrane and hence to increased bile acid uptake. “The relevance of this mechanism incholestatic diseases is being investigated”, stated M.S. Anwer.

Hepatobiliary Transport of Bile AcidsChair:W. Kramer, FrankfurtF.J. Suchy, New York

M.S. Anwer

Session 2

Fig. 3

I Activation of PP2B by cAMP and inhibition by cypermethrin (CM) (M.S. Anwer, North Grafton)

BASAL cAMP

PP

2B

activity (

pm

ol/m

in/m

g)

0

2

4

6

8

10Control

0.5 nM CM

1.0 nM CM

5.0 nM CM *

*

PP2B

act

ivit

y (p

mo

l/min

/mg

)

Control0.5 nM CM1.0 nM CM5.0 nM CM

Prior to Afterstimulation by cAMP

10

Basolateral efflux pumps incholestasisUntil now very little has been known about theefflux of bile acids into the blood in cholestaticdiseases. D. Keppler, Heidelberg, reported thatbasolateral efflux pumps take over when canalic-ular excretion, for example via BSEP, is over-whelmed: MRP3 transports glucuronated bileacids into the bloodstream, MRP4 mainly bileacids and reduced glutathione (Fig. 4). This can lead to a cycle of bile acids between hepatocytes and the circulation. According to D. Keppler, MRP4 is particularly relevant inhereditary cholestasis.

CDCA increases the expression ofOSTα and OSTβIn cholestatic diseases, such as primary biliary cirrhosis (PBC), the heterodimeric transporterprotein OSTα-OSTβ is upregulated in the liver.C.J. Soroka, New Haven, studied the mechanismof upregulation on human HepG2 cells. Shefound that chenodeoxycholic acid (CDCA) in-creases the expression of OSTα and OSTβ in theplasma membrane. The expression of glycosylat-ed, active OSTα in the membrane, however, requires the co-expression of OSTβ. OSTβ couldthus be identified as a “chaperone”, accordingto C.J. Soroka.

Session 2

D. Keppler C.J. Soroka

Fig. 4

I Hepatobiliary transport in humans (D. Keppler, Heidelberg)

NTCP

OCT1

ATP

ATP

ATP

ATP

ATP

OATP1B1

ATP ATP

OAT2

MDR3

MRP2

MRP3

MRP4 MRP6

BSEP ATP

ATP

ABCG5+G8

ABCG2 (BCRP)

MDR1

OATP1B3

OATP2B1

OST +

OrganicanionsHCO3

–

Bile acidsNa+

Organiccations

Organicanions

ConjugatesGSH

Lipid cations

CholesterolPhospholipids

Sulfoconjugates

Bile acids

Organic anionsBile acids + GSHProstanoidsUrate

GlucuronosidesBile acids

Blood

Hepatocyte


11

Protective mechanism in PFIC 2 and 3: downregulation of NTCPIn PFIC 2 and 3, where there is an underlying ge-netic defect for BSEP (ABCB11) or MDR3 (ABCB4),the transport systems OATP1B1 and B3 as wellas NTCP, which transport bile acids from theblood into the hepatocytes, are downregulated.This is ultimately a protective mechanism, R. Kubitz, Düsseldorf, explained. The sinusoidalefflux pump MRP3, by contrast, is normally ex-pressed. “It is only upregulated when there is an MRP2 defect”, according to R. Kubitz. UnlikeMRP4, which is upregulated in PFIC. The conclu-sion of R. Kubitz is: The downregulation of NTCPand OATP is a direct protective mechanism, the

upregulation of MRP4 a compensatory mecha-nism to protect the hepatic parenchyma cells. A possible cause of the hepatotoxicity of drugs is an influence on the transporter proteins of or-ganic anions and bile acids, such as OATP, NTCPand BSEP. K. Maeda, Tokyo, demonstrated inhibi-tion of these transporter proteins for the PPARγ-agonist troglitazone. This might explain the he-patotoxic effect of this substance.

R. Kubitz K. Maeda

12

ASBT expression determinescholangiocyte sensitivityThe sensitivity of cholangiocytes to bile acid sig-nals is largely determined by the expression ofthe sodium-dependent apical bile acid transporterASBT, which is localized to the apical membraneof large intrahepatic bile ducts, among other

sites. “Bile acids function like hormones, ASBT asreceptors”, according to G.D. LeSage, Houston.Via activation of PKC and an increased calciumlevel, secretion but also proliferation and differ-entiation are stimulated (Fig. 5).

Extrahepatic Transport and Actions of Bile AcidsChair:J.L. Boyer, New HavenP.J. Meier-Abt, Basel

G.D. LeSage

Session 3

Fig. 5

I Bile acids function as hormones and ASBT functions as receptors in cholangiocytes (G.D. LeSage, Houston)

FXR

PKC

Ca+2

Secretion

Proliferation

Differentiation

PKC

PI3K

Ca 2+

ASBT

SecretionProliferationDifferentiation

ASBT expression determinescholangiocyte sensitivity tobile acid signaling

Control

TC 1 week

Bile acid fed rat model

Bile acid


13

MRP3: secondary role in bile acidtransportTransport of bile acids from the intestine into theportal circulation is regulated by numerous trans-porter proteins on the basolateral and apicalmembrane. P.A. Dawson, Winston-Salem, stud-ied the importance of the apical transporterASBT and the basolateral transporter MRP3 in ko mice. It was found that MRP3 is of rather secondary importance. For instance, the fecal excretion of bile acids increases in ASBT-ko mice,

but not in MRP3-ko mice (Fig. 6). According to P.A. Dawson, MRP3 plays a rather secondaryrole. He also showed that OSTα-OSTβ is overex-pressed in MRP3-deficient mice. His conclusion:“OSTα-OSTβ is more relevant than MRP3.”

Therapeutic use: inhibiting orblocking ASBT expressionSpecifically influencing ASBT expression mightbe of therapeutic use, according to B.L. Shneider,New York. For instance, in inflammatory intesti-nal diseases there is repression of ASBT with de-pletion of the bile acid pool, an increased bileacid concentration in the colon and hence an increased risk of inflammatory exacerbation. Inthis case, induction of ASBT could be consid-ered. Conversely, blockade of ASBT expressionwould be conceivable in hypercholesterolemia orcholestasis. Here B.L. Shneider referred particu-larly to Byler’s disease (Fig. 7), which is associat-ed with upregulation of ASBT in the ileum andthe cholangiocytes.

P.A. Dawson B.L. Shneider

Fig. 6

I Fecal bile acid excretion in Asbt and Mrp3null mice (P.A. Dawson, Winston-Salem)

0

20

40

60

80

100

120

140

160

+/+ -/- +/+ -/-

Asbtincreased > 10-fold

Mrp3increased

~ 14%

p < 0.0001

p > 0.3

Feca

l bile

aci

d e

xcre

tio

n(µ

mo

l/day

per

100

g B

W)

14

Regulation of hepatic bile acid syn-thesis via bile acid-FXR interactionWhen orally administered bile acids bind to thenuclear receptor FXR, a negative feedback mecha-nism leads to inhibition of bile acid synthesis in theliver by means of FGF-19 activation, M. Rudling,Huddinge, explained. In concrete terms this meansthat, if bile acids are given orally, the serum-FGF19levels rise and bile acid synthesis is reduced.

Session 3

M. Rudling

Fig. 7

I Molecular mechanism of FIC1 (B.L. Shneider, New York)

BA FXR

ILBP

BSEP

SHP

ASBT

RAR

FIC1 Transcriptionalactivation


15

“Osmosignal”: DCA controls fluidcontent in the colonDeoxycholic acid (DCA) influences chloride secre-tion in the colon in a concentration-dependentway and hence influences osmosis, explained S.J. Keely, Dublin. In patients with bile acid mal-absorption, such as in short bowel syndrome, inflammatory bowel disease or microscopic colitis,DCA stimulates chloride and fluid secretion inthe colon. This causes diarrhea. The result is thatpathophysiologically raised DCA concentrationsincrease chloride secretion. By contrast, physio-logical DCA concentrations result in inhibition of chloride secretion, as S.J. Keely showed. Hisconclusion: DCA is an “osmosignal” which controls the fluid content of the feces.

S.J. Keely

16

Insulin regulates CYP7A1 expressionvia transcription factorsHow does insulin regulate the gene expressionof CYP7A1, the decisive enzyme in bile acid synthesis, in humans? This question was exam-ined by J.Y.L. Chiang, Rootstown, in studies onhuman hepatocytes. He showed that insulin hasa concentration-dependent effect on CYP7A1expression. In physiological concentrations thehormone induces CYP7A1 expression, whereashigh insulin concentrations result in inhibition of CYP7A1 expression. The insulin effect onCYP7A1 is mediated by the insulin-regulatingtranscription factors FoxO1 and SREBP, which inhibit the human CYP7A1. Thus, high insulinconcentrations appear to activate SREBP-1c andthereby to inhibit CYP7A1 expression by an in-teraction with HNF4-α. Bile acid-like hormones,known as dafachonic acids, also function as li-gands for the nuclear orphan receptor DAF-12 of C. elegans, stressed D.J. Mangelsdorf, Dallas.Among others, they influence reproduction andlife expectancy.

FXR: central role in bile acid transportThe nuclear receptor FXR is mainly involved inthe regulation of hepatic and intestinal bile acidtransport. Induced by bile acids, FXR activatesBSEP, the bile acid efflux pump in hepatocytes,as well as the heteromeric transporter proteinOSTα-OSTβ in hepatocytes and enterocytes. The expression of the transporter proteins NTCPand ASBT is reduced by interaction of SHP with the glucocorticoid receptor, explained G.A. Kullak-Ublick, Zürich (Fig. 8). The expres-sion of ASBT can be induced by dexamethasoneand inhibited by the anti-glucocorticoid RU486.

Nuclear Receptor RegulationChair:D.J. Mangelsdorf, DallasD.W. Russel, Dallas

J.Y.L. Chiang

G.A. Kullak-Ublick

D.J. Mangelsdorf

Session 4


17

Fig. 8

I Divergent regulation of bile acid uptake and efflux systems (G.A. Kullak-Ublick, Zürich)

Bile acidsbile acid flux

ASBT

FXR RXR

OST OST

BSEP

NTCP

FXR RXR

Bile acids

SHP

GR GR

FXR RXR

SHP

GR GR

FXR RXR

RXRRAR

Bile acid efflux

Blood

Enterocytebasolateralmembrane

Hepatocytebasolateralmembrane

Enterocyteapicalmembrane Hepatocyte

canalicularmembrane

Blood

Bilecanaliculus

Intestinal lumen

Bile acid uptake

Bile acid efflux

Bile acid uptake

Bile acidflux

Bileacids

Bileacids

18

Regulation of bile acid homeostasisvia FGF15Bile acid homeostasis in the liver and gallbladderin mice is regulated via FXR by activation ofFGF15, an orthologue of human FGF19, via theFGFR4 receptor at the liver cell (Fig. 9). S. Kliewer,Dallas, showed that FGF15 suppresses the ex-pression of CYP7A1 in the liver via an SHP-medi-ated mechanism, and FGF15-ko mice have in-creased CYP7A1 expression with corresponding-ly increased bile acid synthesis.

Kupffer cells and SE cells expressTGR5Bile acids are also ligands for the recently discov-ered G protein-coupled receptor TGR5. V. Keitel,Düsseldorf, showed with the aid of antibodiesthat TGR5 is also expressed by liver cells: bothKupffer cells (KC) and sinusoidal endothelial cells (SEC). Bile acids increased intracellular cAMPin isolated SEC and KC. According to V. Keitel,this result suggests that both cell types responddirectly to bile acids via TGR5.

Session 4

V. KeitelS. Kliewer

Fig. 9

I FGF15 regulates bile acid homeostasis (S. Kliewer, Dallas)

FGFR4

SHP

FXR RXRSHP

CYP7A1

FGF15

FXR RXRFGF

FGF

Intestine

What else does FGF15 do?

Bile acids

Liver


19

TLCS induces hepatocyte apoptosisvia CD95 activationInduction of the apoptosis of hepatocytes by hy-drophobic bile acids is discussed as a basic causeof liver damage in the context of cholestasis. D. Häussinger, Düsseldorf, showed that pro-apop-totic, hydrophobic bile salts such as taurolitho-cholate-3-sulfate (TLCS) in hepatocytes lead toactivation of CD95 with subsequent apoptosis.In the process, they induce generation of ROS,mediated via NADPH-oxidase, and this leads toEGFR-mediated phosphorylation of CD95. Theactivation of NADPH oxidase via phosphorylationof the NADPH oxidase subunit p47phox seems tobe an important step: TLCS-induced ROS forma-tion is absent in hepatocytes of p47phox-ko mice.According to studies on human liver cells by

C. Rust, Munich, the most important hydrophobichuman bile acid, glycochenodeoxycholic acid(GCDCA), induces apoptosis independently ofFas/CD95 and caspase 8. A Fas/CD95-independ-ent, direct effect on mitochondrial metabolism is under discussion.

Increased malignancy in BSEP deficiency?R.J. Thompson, London, revealed the importanceof physiological bile acid transport. For instance,a deficiency of BSEP is associated with severe liverdiseases, possibly even a higher malignancy rate.He reported on 13 BSEP-deficient patients withHCC and 2 BSEP-deficient patients with cholan-giocarcinoma. Missense mutations appear to bethe decisive genetic defect.

Bile Acids, Cellular Injury, and Disease MechanismsChair:M. Trauner, GrazU. Beuers, Amsterdam

D. Häussinger C. Rust

R.J. Thompson

Session 5

20

UDCA in ICP: reduction of sulfatedprogesterone metabolitesIn pregnant women with intrahepatic cholestasis,ursodeoxycholic acid (UDCA) relieves itching,even in severe stages of the disease. In these patients, not only blood levels of bile acids are in-creased, but they also have high concentrations

of sulfated progesterone metabolites. Based on data from the Swedish ICP (intrahepaticcholestasis of pregnancy) study, H.-U. Marschall,Huddinge, outlined the influence of UDCA anddexamethasone on metabolite formation. Urinesamples from 40 pregnant women with ICPwere analyzed. They received either placebo for3 weeks, UDCA for 3 weeks or dexamethasonefor 1 week and placebo for 2 weeks. While thelevels remained unchanged on placebo and dexa-methasone, UDCA led to a significant improve-ment in itching with a simultaneous reduction ofprogesterone metabolite concentrations by 53%(Fig. 10). H.-U. Marschall speculated that theUDCA effect, at least in ICP, might be due to increased biliary excretion of the progesteronemetabolites.

Session 5

H.-U. Marschall

Fig. 10

I Treatment of intrahepatic cholestasis of pregnancy (ICP) with ursodeoxycholicacid (UDCA) (H.-U. Marschall, Huddinge)

n=5

0

20

40

60

80

100

0 1 2 3

0

200

400

600

800

1000

[%]

Pruritus scores vs. urinary pregnanediol disulfates

[mm] [µM]

UDCA treatment [weeks]

Vis

ible

an

alo

gu

e


21

FXR ligands and norUDCA againstfibrosisHepatic stellate cells (HSC) express FXR to a highdegree. Their activation leads to a reduction ofHSC proliferation. S. Fiorucci, Perugia, found evi-dence that FXR ligands might offer a new strate-gy for the treatment or prevention of fibrosis inliver diseases. In rat models, the expression of fi-brotic markers in the liver could be reduced withFXR ligands. In an immunological fibrosis model,the development of fibrosis could be prevented.

This seems to involve a “cross-talk” with otherreceptors, such as PPARγ or PXR. P. Fickert, Graz,showed in a fibrosis model with Mdr2-ko micethat hydrophilic bile acids, such as UDCA, butparticularly norUDCA (Fig. 11), induce antifibroticeffects. Whether this is a direct effect or whetherthe bile acids act indirectly via an influence onreactive epithelial cells in the bile ducts “still hasto be explained”, according to P. Fickert.

Bile Acids, Cellular Injury, and Hepatic FibrosisChair:D. Häussinger, DüsseldorfP.L.M. Jansen, Amsterdam

P. FickertS. Fiorucci

Session 6

Fig. 11

I norUDCA reverses biliary fibrosis in Mdr2 –/– (ko) mice (P. Fickert, Graz)

WTWT

100

200

*

300

‡

400

*

Fickert et al., Gastroenterology 2006; 130: 465

KO KO+norUDCAKO+UDCA

bd = bile ductpv = portal vein

Sirius red

Hydroxyproline(µg/g Liver)

p < 0.5* vs. WT‡ vs. KO

WT KO KO + UDCA

KO + norUDCA

22

EGFR inhibitors inhibit bile acid-induced HSC proliferationBile acids are crucially involved in the cell death ofhepatocytes and the fibrotic process. H. Moshage,Groningen, established that, in cholestasis, bileacids such as GCDCA (glycochenodeoxycholicacid) induce death of hepatocytes. On the otherhand, HSCs are not killed by bile acids becausethey lack the bile acid transporter NTCP neces-sary for induction of apoptosis (Fig. 12). Via the

activation of EGFR, they stimulate ERK, PKC andp70S6K and thereby the proliferation of HSC.This offers opportunities for antifibrotic treat-ment. With EGFR inhibitors such as AG1478, thebile acid-induced signals can be inhibited andHSC proliferation blocked. Y. Zhang, Tsukuba,also showed that bile acids increase the motilityof HSC, evidence that induction takes place viap38/JNK.

Session 6

Fig. 12

I NTCP is required for bile acid-induced apoptosis (H. Moshage, Groningen)

0

10000

20000

30000

40000

Con FasCon Fas

HepG2-ntcp HepG2

GCDCA

GCDCA

Caspase-3activity (AFU)

H. Moshage Y. Zhang


23

UDCA derivatives: promising resultsin animal modelsUrsodeoxycholic acid is currently the only treat-ment option for primary sclerosing cholangitis(PSC). One alternative might be the more hy-drophilic norUDCA. M. Trauner, Graz, presentedanimal experiments with norUDCA, a chemicallyproduced derivative in which the side-chain isshortened by a methylene group. Furthermore, it is more resistant to conjugation reactions andis excreted largely unchanged in the bile. Thecholehepatic shunt, which leads to bicarbonate-rich choleresis among other things, is high. In

the cholangiopathy model with Mdr2–/– mice,the sclerosing cholangitis was reversible within 4 weeks on norUDCA. UDCA is also known tohave a chemopreventive effect in relation tocolonic and cholangiocarcinomas. UDC disul-fate (SUDC) seems to be even more effective, as K.D.R. Setchell, Cincinnati, showed in theazoxymethane (AOM)-induced animal model ofcolonic carcinoma. The Fischer rats were eitherfed normally or received additionally UDCA orSUDC. The tumor incidence was lowest onSUDC (Fig. 13). 73% of the animals developed a tumor in the control group, 53% on UDCA

Bile Acids as Therapeutic Agents:Mechanisms and ActionsChair:G.P. van Berge Henegouwen, UtrechtA. Stiehl, Heidelberg

M. Trauner K.D.R. Setchell

Session 7

Fig. 13

I Macroscopic appearance of rat colons (K.D.R. Setchell, Cincinnati)

Rat colon: AOM-treated and SUDC-fed

Rat colon: saline only, no carcinogen (control)

Rat colon: AOM-treated

Tumors

24

and 47% on SUDC. K.D.R. Setchell found differ-ences in the composition of the bile acids in thecolon. While SUDC was excreted virtually un-changed, UDCA was metabolized to lithocholicacid. SUDC is now being tested in a phase Ihuman trial.

Preventing gallstones with ezetimibeThe cholesterol absorption inhibitor ezetimibe canprevent the formation of cholesterol gallstonesand, because of the reduced cholesterol concen-tration in the liver, can also prevent disturbed

motility of the gallbladder. This was demonstrat-ed by D.Q.-H. Wang, Boston, in an animal modelon C57L mice on a lithogenic diet (Fig. 14). Fur-thermore, he showed that ezetimibe reduces theexpression of NPC1L1, which regulates choles-terol absorption in the intestine.Taurin-conjugated UDCA has an anticholestaticeffect. U. Beuers, Amsterdam, showed in isolat-ed rat livers that this effect in TLCA-inducedcholestasis is controlled by the activation of asignaling pathway dependent on PKC and PKA.“It is a cooperative effect”, U. Beuers stated.

Session 7

D.Q.-H. Wang U. Beuers

Fig. 14

I A dose-dependent reduction in gallstone prevalence rates by ezetimibe (D.Q.-H. Wang, Boston)

Gal

lsto

ne

pre

vale

nce

[%

]

Nostones

Ezetimibe [µg/day]

100

80

60

40

20

00 2 10 20


25

UDCA in PSC: on the way to optimal doseUDCA at higher doses than the 10–15 mg/kgBW/day, which has hitherto been the usualdosage, improves not only the liver values andthe liver histology in PSC. It also appears tolengthen the survival time, according to resultsof various current studies. A Scandinavian studypublished one year ago, which treated PSC pa-tients for five years either with UDCA at dailydoses of 17–23 mg/kg BW or placebo, showed a marked difference in the combined endpointof death/transplantation of 7.2% on UDCA versus 10% on placebo, explained K.D. Lindor,Rochester. The lack of statistical significance ledR.W. Chapman, Oxford, to conclude that the

study was “underpowered”, the dose was stilltoo low and the duration of the study too short.He presented results from a currently completed,double-blind, placebo-controlled trial whichcompared the effect of 10, 20 and 30 mgUDCA/kg BW with placebo. The results over 4years show a significantly higher survival prob-ability (Mayo Risk Score) on the highest UDCAdose (Fig. 15). However, R.W. Chapman conced-ed, this is again only a small study. K.D. Lindor is hoping for clarity from the NIH-sponsored,large-scale study with 150 PSC patients lasting 5 years, in which UDCA doses of 28–30 mg/kgBW/day are being studied. The focus is also onthe chemopreventive effect on colonic dysplasiaand carcinomas.

Bile Acids in the Treatment ofCholestatic Liver DiseasesChair:H.-U. Marschall, HuddingeU. Leuschner, Frankfurt

R.W. ChapmanK.D. Lindor

Session 8

Fig. 15

I High-dose UDCA in PSC (R.W. Chapman, Oxford)

Differences in survival probabilities from baseline to end of the study3,5

3

2,5

2

1,5

1

0,5

0

1 year 2 years 3 years 4 years

All patients10 mg/kg20 mg/kg30 mg/kg

Surv

ival

pro

bab

iliti

es

26

Prognosis-defining in PSC: SXRpolymorphismsThe nuclear receptor SXR plays a key role in thedetoxification of hydrophobic bile acids, forwhich an important role in the pathogenesis ofPSC is also under discussion. SXR is able to pro-tect against liver damage caused by cholestasis,explained T.H. Karlsen, Oslo. In PSC patients,polymorphisms in the SXR gene appear to havean influence on the prognosis. T.H. Karlsenshowed in 327 Scandinavian PSC patientsthrough a median follow-up of 8.5 years thatpolymorphisms have a negative influence on thepatients’ survival (Fig. 16).

Cholangiocarcinoma in PSC: low incidence on UDCAIn patients with PSC, UDCA not only reduces the risk of colonic carcinoma. A preventive effectin relation to cholangiocarcinoma has also beendescribed on several occasions. A. Stiehl, Heidel-berg, presented data from a survey which in-cluded 150 PSC patients receiving UDCA therapybetween 1987 and 2005. The mean treatmentperiod was 6.7 years. A total of 5 patients onUDCA developed cholangiocarcinoma. The inci-dence is 2.9%, and hence lower than in compa-rable studies on the course of PSC. Furthermore,the incidence decreases as the duration of treat-ment increases. In all patients CCA was associat-ed with colitis and a dominant stenosis, stressedA. Stiehl.

Session 8

T.H. Karlsen A. Stiehl

Fig. 16

I Effect of SXR polymorphisms on survival in PSC: Kaplan-Meier analysis (T.H. Karlsen, Oslo)

Cu

mu

lati

ve s

urv

ival

Time [years]

Median 3.6 vs. 13.6 years (p = 0.004)

SXR polymorphism

All patients withouthomozygotes

Homozygotes


27

Polymorphisms influence the individual response to drugsHow a patient responds to a drug therapy differsfrom individual to individual. As well as age, gen-der, comorbidities and polypharmacy, genetic fac-tors also play a role because they can greatly in-fluence the pharmacokinetics and pharmacody-namics of an active substance, G.A. Kullak-Ublick,Zürich, explained. A familiar example is the poly-morphism in the TPMT gene, which significantlyinfluences the metabolism of azathioprine andhence its risk for side-effects. The 1457T>C polymorphism in the BSEP gene is seen as a risk factor for drug-induced cholestasis. In prin-ciple, genetic changes in a wide variety of en-zymes can influence pharmacokinetics (Fig. 17).G.A. Kullak-Ublick therefore called for strategiesto be developed, such as gene expression analy-ses, in order to identify genes relevant to a drug.

Identification of disease genes:problem of genetic heterogeneityH. Omran, Freiburg, outlined various strategiesto identify disease genes. Possible candidategenes can be approached by means of positionalcloning or via functional information. The mostsuccessful approach is to combine both strate-gies. Another possibility is computer-assistedanalysis. The greatest problem is genetic hetero-geneity, stressed H. Omran.

Session 1

Falk Symposium 156Genetics in Liver DiseasesFreiburg, October 8–9, 2006

Basic AspectsChair:H.E. Blum, FreiburgD. Häussinger, Düsseldorf

H. OmranG.A. Kullak-Ublick

28

Session 1

Fig. 17

I Genetic polymorphisms in drug metabolism (G.A. Kullak-Ublick, Zürich)

Wild type

Mutation

Time

Time

Co

nce

ntr

atio

nC

on

cen

trat

ion

Congress Short Report Falk Symposium

29

HCC: prognosis by DNA microarrayThe method of gene expression analyses basedon DNA microarray is increasingly used in researchof liver diseases. By means of microarray analy-sis, S. Thorgeirsson, Bethesda, worked out a sub-classification of HCC dependent on the gene ex-pression of the tumor cells. Based on the geneexpression pattern, he was able to identify twosubclasses, cluster A and cluster B, with differentprognoses. He also filtered out a subclass of patients with signs of hepatoblast (HB) gene ex-pression. Tumor cells with this HB subtype ap-pear to have a higher probability of metastasiz-ing. Comparing the survival probability, HB-posi-tive patients had the worst prognosis (Fig. 18).

Gallstones: polygenetic factors andenvironmental influencesWhether a patient develops gallstones also de-pends on genetic factors. In rare cases it is a mat-ter of monogenetic defects, on the ABCB4 orCFTR1 gene, for instance. “As a rule, polygenet-ic factors and environmental influences interactin the development of gallstones,” according toF. Lammert, Bonn. He referred to the only studyto date on polygenetically induced cholelithiasisas part of the San Antonio Family Diabetes/Gall-bladder Study (SAFDGS). A correlation was foundwith various defects on chromosome 1p, someof which correspond to the localization of thelithogenic gene in mouse models.

156

S. Thorgeirsson F. Lammert

Fig. 18

I Three subclasses of HCC patients (S. Thorgeirsson, Bethesda)

Pro

bab

ility Cluster B & HB– patients

N = 56 (29 death)

Cluster A & HB– patientsN = 35 (24 death)

Cluster A & HB+ patientsN = 22 (21 death)

Survival [months]

30

Spontaneous virus elimination inhepatitis: a question of individualgeneticsThe genetic conditions of the patient essentiallydetermine the natural history of viral hepatitisand the patient’s response to any antiviral thera-py. “The outcome after acute infection dependson the immune response of the individual”, R. Thimme, Freiburg, emphasized. Once again itis a question of the individual genes. A few stud-ies have shown that polymorphisms in variousgenes, for example TNF-α, CCR5, interleukin orCTLA4 polymorphisms, influence viral clearanceor elimination. Virus-specific CD8 T cell respons-es play a crucial role in successful elimination ofhepatitis C. Certain human leucocyte antigens(HLA) class I alleles are also associated with sig-nificantly higher spontaneous virus eliminationafter HCV infection. The strongest associationwas found for the HLA-B27 allele, R. Thimmestressed: “This effect is HCV-specific.”

β-catenin signaling in hepatoblas-tomas: Localization determines proliferationHepatoblastomas (HB) are the most common pediatric liver tumors and they affect childrenunder 3 years of age in more than 90% of cases.However, they are still rare with an incidence of1/1,000,000 children/year. Around 5% have ge-netic causes, 95% occur sporadically. Histologi-cally hepatoblastomas are heterogeneous withepithelial cells in different stages of development.It is also known that β-catenin mutations arefound in more than 50% of HBs. M.-A. Buendia,Paris, analyzed more than 100 HB samples from18 centers in France. She found an “extremelyhigh rate of β-catenin mutations” of 78%. Geneexpression analysis of 25 primary HBs identifiedtwo clusters. The β-catenin signaling was activat-ed in both clusters (C1 and C2), the decisive dif-ference is the localization of the β-catenin pro-tein: for C1 in fetal tissue, for C2 in embryonictissue. C2 tumors had a higher proliferativeindex than C1 tumors.

Session 1

M.-A. BuendiaR. Thimme


31

Hereditary hemochromatosis (HH):clinical and pathophysiological entityThe most common form of hemochromatosis iscaused by pathogenic mutations on the “he-mochromatosis gene” HFE. Mutations on thegene for transferrin receptor 2 (TfR2) also lead to avery similar pathology, according to A. Pietrangelo,Modena. In juvenile, hereditary hemochromato-sis, the mutation on the gene for hemojuvelin,which controls the transcription of hepcidin, ismost prominent. Hepcidin is a protein that regu-lates iron transfer from the enterocytes andmacrophages into the circulation. The geneticdefect in the formation of hepcidin already leadsto iron overload in the body during youth. A. Pietrangelo stressed that low hepcidin levelsare also measured with mutations on the HFEand TfR2 gene. He referred to recent reportswhere, in juvenile hemochromatosis, similar clini-

cal pictures arose in patients with mutations onthe HFE or TfR2 gene. He concluded that a largenumber of genotypes can trigger the clinical pic-ture of hereditary hemochromatosis. He askedfor hereditary hemochromatosis to be seen as aclinical and pathophysiological entity which canbe triggered by various mutations on the knownHH genes.

Wilson’s disease: DNA diagnosispossible and usefulAccording to D.W. Cox, Edmonton, Wilson’s dis-ease is still a diagnostic challenge. Traditional di-agnosis is difficult, because most patients do notshow all the typical symptoms, such as Kayser-Fleischer rings, lower ceruloplasmin or high uri-nary excretion of copper (Fig. 19): “Sometimesonly one symptom appears, which is only slight.”This is why gene analysis lends itself to substan-tiating any suspicion. Mutations on the gene for the ATP7B protein are under consideration. D.W. Cox identified 291 mutations, “most com-monly missense mutations”. At least one muta-tion on the ATP7B gene was found in 98% ofthe patients, who were studied because of typicalclinical symptoms and biochemical signs. “Thisshows the high effectiveness of DNA analysis inpatients with an uncertain diagnosis”. D.W. Coxfurther stressed the need to screen patients’families by DNA analysis. This is because, if drugintervention is started early, the patients’ chancesare good and the need for liver transplantation isminimal. As a treatment strategy for Wilson’s

Liver Diseases (Part 1)Chair:P.L.M. Jansen, AmsterdamW. Stremmel, Heidelberg

A. Pietrangelo

D.W. Cox E.A. Roberts

Session 2

32

disease, E.A. Roberts, Toronto, proposed thechelator trientine, which is better tolerated thanpenicillamine. Another possibility is the use ofzinc, which inhibits the absorption of copperfrom the enterocytes. For patients with severeliver disease, E.A. Roberts advocated the combi-

nation of trientine and zinc, distributed duringthe day at intervals of 5–6 hours. For initialmonotherapy, zinc may be superior to penicil-lamine, as shown by a randomized comparativeclinical trial involving a total of 67 patients.

Session 2

Fig. 19

I Transport of copper in humans (D.W. Cox, Edmonton)

Oral intake(1.5–3 mg/24 h)

Intestinal absorption

Plasma albumin

(rapid clearance)

Menkes disease(X chromosome)

Other tissues,proteins:BrainEyeKidneyEnzymes

Urine

LiverMT apoceruloplasminCu (I) (chromosome 3)

Wilson’s disease(chromosome 13)

Biliary excretion(1–3 mg/24 h)

CeruloplasminOther proteins

– Cytochrome oxidase– Dopa β mono oxygenase– Lysyl oxidase– Superoxide dismutase

Iron mobilization

Fe (II)

Fe (III)


33

α1-antitrypsin deficiency: Hepaticsymptoms usually follow a mildcourseIn a survey conducted in Sweden from 1972 to 1974, T. Sveger, Malmö, stated, neonatalcholestasis was found in 11% of children withα1-antitrypsin deficiency with homozygous PiZZ.In the majority of children, hepatic symptomsfollowed a rather mild course. The liver enzymeswere elevated in 50%, but returned to normalwith increasing age. Only a small proportion ofpatients die from the consequences of neonatalcholestasis. “But don’t forget the lungs,“ T. Svegerstressed. Smoking status is the key here. 30-year-old PiZZ patients who do not smoke had normallung function.

Acute porphyria: induction via nuclear receptorsNeurovisceral attacks in acute porphyrias areassociated with elevated δ-aminolevulinic acidlevels. They are induced by drugs, calorie restric-tion, hormones, but also by infections and alco-hol. U.A. Meyer, Basel, explained that these fac-tors upregulate ALAS-1 (aminolevulinic acid syn-thase) on transcription level. Studies in miceshowed an increase in hepatic ALAS-1 caused byphenobarbital and bile acids, but also as a reac-tion to hunger. These effects are controlled vianuclear receptors. Medicines induce the ALAS-1increase by means of CAR and PXR (Fig. 20), thebile acids via FXR and hunger via PGC-1α.

156

T. Sveger U.A. Meyer

Fig. 20

I Xenosensors CAR and PXR mediate drug induction of ALAS-1 (U.A. Meyer, Basel)

CAR/PXR ALAS1

- 16kb

CYP3A

CYP2B

UGT1A1

Drug

Negative feedback regulation of ALAS-1 by heme amplifies the response to drugs of ALAS-1 in acute porphyrias

ALAS-1

34

UDCA: beneficial effect on hepatopathy in CFThere is liver involvement in about a third of children with cystic fibrosis (CF). According to C. Colombo, Milan, the only available treatmentoption is ursodeoxycholic acid (UDCA). In a ran-domized, controlled trial a significant improve-

ment in the biochemical parameters was achieved.Furthermore, she referred to data from the ItalianUDCA Study Group, which followed up 50 CFpatients for 14 years receiving long-term treat-ment with UDCA between 1990 and 2004. Theincidence of compensated cirrhosis remained un-changed at 43.4% and 45.3%. Only two patientsdeveloped ascites. A total of 15 patients died,only one of them because of a hepatic complica-tion. C. Colombo’s conclusion: UDCA appears tohave a beneficial effect on the progression of theliver disease. In addition, liver disease in the con-text of CF does not increase mortality, especiallyif the patients are treated with UDCA.

Session 2

C. Colombo


35

Genetic cholestasis: well character-ized by phenotype and genotypeGenotypes and phenotypes of progressive famil-ial intrahepatic cholestasis (PFIC) type 1, 2 and 3are well characterized, according to P.L.M. Jansen,Amsterdam. The type-related genetic changeslead to a defect of bile acid transporter proteinsin the canalicular membrane. In type 1, muta-tions on the ATP8B1 gene lead to an FIC1 defectwith low γGT levels, intermittent cholestasis andsevere pruritus. Type 2 is characterized by a BSEPdefect based on mutations in the ABCB11 genewith low γGT levels, permanent cholestasis andsevere pruritus. In type 3, based on ABCB4 gene

mutations, there is an MDR3 defect with high γGT levels, permanent cholestasis, severe pruri-tus and the disease starting between the 1st to5th year of life. Mutations on ABCB4 in less critical regions (Fig. 21 and Fig. 22) can lead toless serious phenotypes, for example to intrahe-patic cholestasis of pregnancy or to gallstones, P.L.M. Jansen explained. In animal studies MDR3mutations are associated with an increased HCCand CCC risk. This correlation was not found inhumans. Furthermore, there is evidence that anMDR3 defect might be the cause of the vanish-ing bile duct syndrome.

Liver Diseases (Part 2)Chair:D.W. Cox, EdmontonG.A. Kullak-Ublick, Zürich

P.L.M. Jansen

Session 3

Fig. 21

I Progressive familial intrahepatic cholestasis (PFIC) type 3 (P.L.M. Jansen, Amsterdam)

MDR3/ABCB4

-/- : del/insertion/nonsense

-/- : missense

+/- : missense

Genetic cause of ARC syndrome explainedARC syndrome, with the obligatory symptoms ofarthrogryptosis, renal dysfunction and cholestasis,is one of the extremely rare hereditary cholestaticdiseases. Once the clinical picture has first beendescribed, the underlying genetic change – atleast in the majority of cases – is now known:

namely mutations on VPS33B, R.J. Thompson,London, explained. In terms of phenotype, theliver disease tends to be slightly pronounced.γGT-staining is slightly positive, (Fig. 23), whileCEA (carcinoembryonic antigen) staining (Fig. 24)produces a dramatically positive result, accordingto R.J. Thompson.

36

Session 3

Fig. 22

I Gallstones – Intrahepatic cholestasis of pregnancy (P.L.M. Jansen, Amsterdam)

MDR3/ABCB4

–/–: homozygous mutation

+/–: heterozygous mutation


37

156

Fig. 23

I γGT staining in ARC (R.J. Thompson, London)

γGT staining in ARC

Control kidney

Fig. 24

I CEA staining in ARC (R.J. Thompson, London)

CEA staining in ARC

Control liver

38

Session 3

Life-saving: screening for MCAD deficiencyP.T. Clayton, London, stressed the necessity forscreening methods for hereditary liver diseases.Selective screening techniques are the method ofchoice for children with liver diseases and childrenof relatives with liver diseases. As populationscreening, he proposed testing for MCAD (medi-um-chain acyl-CoA dehydrogenase) deficiency.The mean age at manifestation is 14 monthsand mortality is 20–25%. A third of the childrendevelop neurological complications. The treat-ment is simple: Merely ensuring the child has an adequate carbohydrate intake.

Crigler-Najjar syndrome type 1:Gene defect reparableRecent findings on the genetic basis of liver dis-eases have made it possible to develop thera-peutic strategies at the gene therapy level. Thus,gene replacement therapy or gene repair lendthemselves, for example, to hereditary mono-genetic diseases such as α1-antitrypsin deficien-cy, cystic fibrosis or Crigler-Najjar syndrome. H.E. Blum, Freiburg, explained that the gene defect can be repaired with chimeric oligonu-cleotides in the animal model of Crigler-Najjarsyndrome type 1. “The serum bilirubin level de-creases in the treated animals”, according toH.E. Blum. This is a very elegant and feasiblemethod in vivo. For acquired, monogenetic dis-eases, such as hepatitis B and C, blockade of the viral gene expression should be possible, for instance by means of siRNA (small interferingRNA).

P.T. Clayton H.E. Blum


39

156

Gene therapy: The principle worksThere are various strategies to consider for genetherapy of carcinomas (Fig. 25). J. Prieto, Pamplona, outlined methods of genetic immunetherapy. Gene therapy is possible in principle,but adequate efficacy is not yet being achievedwith the vectors and genes used. In a pilot studyin patients with hepatocellular carcinoma (HCC),for instance, HSV-tk (thymidine kinase) was administered via an adenoviral vector into thetumor. A high infection rate of the HCC nodeswas achieved. However, the transgene expres-sion was too short and repeated infection with

the same vector was impossible because of theformation of neutralizing antibodies. A key aim,according to J. Prieto, is therefore to increase theperiod of transgene expression. S. Gupta, Bronx,drew attention to the potential of stem cells inreconstituting different types of liver cells. Embry-onic, fetal but also adult stem cells are of inter-est. According to S. Gupta, however, generatingmature liver cells from pluripotent human em-bryonic stem cells (hESC) is particularly attractive,but research on this is only in the early stages.

J. Prieto S. Gupta

Fig. 25

I Gene therapy of cancer (J. Prieto, Pamplona)

Reversing the malig-nant phenotype

Molecularchemotherapy

Interfering with tumor biology:– Antiangiogenic intervention

– Blocking survival signals

Genetic immuno-therapy

Tumor cell

40

Session 1

NAFLD: “Distinguishing winnersfrom losers”Non-alcoholic fatty liver disease (NAFLD) is pres-ent in about a third of the adult population inthe USA. According to A.M. Diehl, Durham, the“winners” can have NAFLD without consequencesin the long term. The “losers”, on the otherhand, develop cirrhosis and, in the worst case,the disease proves fatal for them. “This is why itis important to differentiate the winners fromthe losers. It is difficult, but we have to do it”,A.M. Diehl emphasized. In her opinion, this re-quires a better understanding of the underlyingpathogenesis. The metabolization of free fattyacids in the liver plays a central role in this. It isnot critical if these are stored as triglycerides.However, if increased fatty acid oxidation occurs,particularly via non-mitochondrial metabolicpathways such as microsomes or peroxisomes,toxic substances are formed which can damagethe liver. This then opens the floodgates forNAFLD to progress into NASH (non-alcoholicsteatohepatitis). An excessive accumulation isalso seen as problematic. According to A.M. Diehl,

increased oxidation of free fatty acids and theirexcessive accumulation might therefore be possi-ble markers for the “losers” among NAFLD pa-tients.

ASH: CYP2E1 as a therapeutic target10–35% of alcoholic patients develop ASH,8–20% alcoholic cirrhosis and 1–2% hepatocel-lular carcinoma. The progression is influenced by genetic and dietary factors. Women have ahigher risk than men, even with markedly loweralcohol consumption. The oxidation of free fattyacids to ROS, which is induced by CYP2E1, iscrucial to the development of inflammation. Viaactivation of NFκB, there is then an increase inTNF-α. CYP2E1 induction differs in intensity fromindividual to individual. H.K. Seitz, Heidelberg,recognizes CYP2E1 as a possible target in thetreatment of alcohol-induced liver damage. Theinhibition of CYP2E1 with chlormethiazole sig-nificantly reduces alcohol-induced liver damagein the animal model (Fig. 26).

A.M. Diehl H.K. Seitz

Falk Symposium 157Chronic Hepatitis:Metabolic, Cholestatic, Viral and AutoimmuneFreiburg, October 10–11, 2006

Metabolic and Toxic HepatitisChair:H.J.F. Hodgson, London


41

157

Fig. 26

I Role of CYP2E1 in alcoholic liver disease (H.K. Seitz, Heidelberg)

EthanolAcetone Free fatty acids

CYP2E1

Ethanol

ROS

Acetaldehyde

Fibrogenesis

LipidsPolyunsat-

urated fatty acids(Fish oil)

CYP2E1 ABChlormethiazole

Cell injury

Lipid peroxidation

LPP (4-Hydroxynonenal)

Carcinogenesis

42

Session 1

Stress kinase inhibitor (JNK)against hepatotoxic paracetamolThe most common cause of acute liver failure isdrug-induced hepatitis. The time taken to makethe correct diagnosis is crucial to the risk of mor-tality. “Ask about a time association with takingthe medication,” N. Kaplowitz, Los Angeles,stressed, “and stop the medication.” However, it

is also important to definitely exclude othercauses. According to N. Kaplowitz, paracetamolis the most thoroughly tested hepatotoxin. Outof 610 cases with acute liver failure, 43% weredue to paracetamol and this was at a therapeu-tic dosage in a sixth of cases. Studies on healthysubjects show an increase in liver enzymes onparacetamol. In the mouse model, the change in the liver enzymes can be completely inhibitedand death can be prevented with the stress kinase inhibitor JNK (Fig. 27). Response to para-cetamol also has to do with the inherited immunesystem. For instance, tolerability is worse in IL-10- and IL-6-ko mice and better in IFNγ-ko mice.

N. Kaplowitz

Fig. 27

I Effect of stress kinase inhibitors on APAP hepatotoxicity in vivo in C57/BL6 mice(N. Kaplowitz, Los Angeles)

Hours

0 12 24 36 48

100%

80%

60%

40%

20%

0% APAP = acetaminophen(paracetamol)

APAP + JNK-Inh.n = 6

APAP1000 mg/kgn = 6

Surv

ival


43

UDCA beneficial in intrahepaticcholestasis of pregnancyWith an incidence of between 0.2% and 4%,cholestasis of pregnancy is the most commonliver disease during pregnancy. It can have seri-ous consequences: 1–2% of children are still-born and the rate of preterm birth is between19% and 60%. The incidence of fetal complica-tions correlates directly with the bile acid serumconcentration (Fig. 28a, b). In terms of treat-ment, according to J. Kondrackiene, Kaunas, thedata clearly favor the use of ursodeoxycholic acid

(UDCA). In direct comparison with cholestyra-mine in 84 pregnant women, there was a signifi-cant reduction of pruritus on UDCA (8–10 mg/kgBW/day) (Fig. 29) and the liver enzymes as wellas the serum concentration of bile acids. The ef-fect on pregnancy was also correspondingly positive. Pregnancy lasted longer on UDCA (38.7 weeks versus 37.4 weeks), the birth weightof the infants was higher (3302 g versus 3078 g)and the APGAR after 5 minutes was better (9.4 versus 8.7).

Cholestatic HepatitisChair:A.M. Diehl, DurhamG. Gerken, Essen

J. Kondrackiene

Session 2

Figs. 28a

I Serum bile acids before and after therapy (UDCA vs. cholestyramine) (J. Kondrackiene, Kaunas)CA = cholic acid, CDCA = chenodeoxycholic acid, DCA = deoxycholic acid,UDCA = ursodeoxycholic acid, LCA = lithocholic acid

0

10

20

30

40

50

60

70

80

90

100

*

*

*

*

BaselineFinal examination

Total bile acid(except UDCA)

[µmol/l)

CA[µmol/l)

CDCA[µmol/l)

DCA[µmol/l)

UDCA[µmol/l)

LCA[µmol/l)

Patients treated with UDCA

44

Session 2

Fig. 29

I Efficacy and safety of UDCA vs. cholestyramine in ICP (J. Kondrackiene, Kaunas)

Intensity of pruritusPatients with values at baseline and at least one post-baseline value, n = 77

Days

1 2 3 4 5 6 7 8 9 10 11 12 13 14

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0Ari

thm

. mea

n +

/– 9

5%co

nfi

den

ce in

terv

al

UDCA, n = 38

Cholestyramine,n = 39

Fig. 28b

0

10

20

30

40

50

60

70

80

90

BaselineFinal examination

Total bile acid(except UDCA)

[µmol/l)

CA[µmol/l)

CDCA[µmol/l)

DCA[µmol/l)

UDCA[µmol/l)

LCA[µmol/l)

Patients treated with cholestyramine


45

157

Autoimmune disease PBC: triggeredby environmental factorsPrimary biliary cirrhosis (PBC) is a key example ofan autoimmune disease that is caused by envi-ronmental factors on the basis of a genetic dispo-sition. This was the conclusion of M.E. Gershwin,Davis, based on results of a current geo-epidemio-logical study on PBC. This study compared 1032 PBC patients (955 women) with 1041 con-trols. It revealed that the risk increases by about10-fold when there is a positive family history ofPBC and by 5.8 times in patients with a positivefamily history of Sjögren syndrome. Significanttriggers of the process are environmental factors,all urinary tract infections in the past, smokingand hormone replacement therapy. M.E. Gershwinsuggested that chemicals contained in cosmeticscould also be possible triggers. They could causeloss of tolerance and pave the way for the devel-opment of an autoimmune process.

Interface hepatitis in PBC“Interface hepatitis” may occur in the context ofPBC, probably as a consequence of cholestasis.R. Poupon, Paris, distinguished between the “bili-ary” and the “lymphocytic” form. Treatment basically involves getting a grip on the complexinflammatory process, blocking the autoimmuneprocess and effectively treating the cholestasis.UDCA is regarded as standard therapy, althoughthe combination with budesonide is superior toUDCA monotherapy. Future strategies encompassthe induction of ductal choleresis, for instancewith glibenclamide or sulindac, and the modula-tion of nuclear receptors to stimulate bile acidtransporter proteins. It has been shown thatUDCA activates the bile acid transporters BSEP,MDR3 and MRP4.

R. PouponM.E. Gershwin

46

Hepatitis C viruses escape NK cell-mediated immune responseNK cells (natural killer cells) play a key role in re-sisting viral infections, according to U. Spengler,Bonn. However, hepatitis C viruses, which lead toa chronic disease in 50–80% of those infected,are able to develop mechanisms to escape theNK cell-mediated immune response. U. Spenglerpresented the results of studies which investigat-ed the expression of the inhibiting NK cell recep-tor NKG2A on NK cells of healthy subjects andHCV RNA-positive patients as well as the expres-

sion of the NKG2A receptor HLA-E, an importantregulator of NK cell function. It was found thatNK cell activity becomes unbalanced in those in-fected with hepatitis C. NKG2A expression onthe NK cells is markedly increased in comparisonwith healthy subjects. The same applies to intra-hepatic HLA-E expression (Fig. 30). Moreover, thelatest studies show that dysfunction of the den-dritic cells also occurs in HCV-infected subjects.Thus HCVE2 has an influence on their matura-tion and differentiation.

Viral Hepatitis (Part 1)Chair:P. Ferenci, ViennaH.C. Thomas, London

U. Spengler,

Session 3

Fig. 30

I Intrahepatic HLA-E expression in hepatitis C (U. Spengler, Bonn)

HCV (+)

x 400

HCV (+)

X 400

HCV (+)

x 200

HCV (+)

x 200

HCV (+)HCV (-)

HCV (+)HCV (-)

HCV(+) HCV(-)

0

1

2

3

4 p= 0.05

HCV(+) HCV(

0

1

2

3

4

HLA

-E(+

) ce

lls/v

isu

al f

ield


47

157

HBx induces DNA mutations viaROS inductionChronically HBV-infected patients have 100–200times higher risk of hepatocellular carcinoma thanhealthy people. The hepatitis B x protein (HBx) isclosely involved in the carcinogenesis but it doesnot directly interact with the DNA. K. Koike,Tokyo, showed in studies with recombinant HBxthat the protein induces the generation of ROSvia direct contact with mitochondria. In addition,he showed in cell cultures that rHBx quadruplesthe frequency of mutations in comparison withcontrols. Radical scavengers lowered the mutationrate. K. Koike’s conclusion: “HBx causes DNAmutations via the induction of ROS and inducescell transformation (Fig. 31).”

K. Koike

Fig. 31

I Association of rHBx protein with mito-chondria causes ROS-dependent cell deathand/or transformation (K. Koike, Tokyo)

xx

x

Cell death Cell transformation

ROSgeneration

∆ψm

Decreased cellular ATP level

DNA damage

48

Session 3

Hepatitis B: advocating pegylatedinterferonsThere are two treatment options available forhepatitis B: pegylated interferons which can, inprinciple, achieve a lasting response with a limit-ed duration of treatment; and nucleos(t)ide ana-logues, with which long-term antiviral therapypossibly lasting years is carried out, as G.K.K. Lau,Hong Kong, explained. He clearly advocated theuse of pegylated interferons as the treatment ofchoice because a long-lasting response is possi-ble. He regards nucleos(t)ide analogues mainlyas an option for patients with contraindications.He referred to studies with HBeAg-positive pa-tients, in whom pegylated interferon was superi-or to lamivudine in terms of the seroconversionrates. Combination therapy was not better thanthe peginterferon therapy alone.

Treatment of hepatitis C increasingly individualizedThe treatment of chronic hepatitis C with pegy-lated interferons plus ribavirin is being tailoredmore and more closely to the individual patient.Treatment has hitherto been geared to the HCVgenotype. Now the duration of treatment is alsodependent on the initial viral load and the pa-tient’s response. Thus, the standard therapy inthe HCV-1 genotype is 48 weeks. However, ifthe viral load at the start of treatment is below600,000 IU/ml and the patient responds rapidlyto the treatment – with a decrease in viral loadafter 4 weeks < 50 IU/ml – a treatment period of24 weeks seems to be adequate, according to S. Zeuzem, Homburg. Here response rates of 90%are achieved. By contrast, HCV-1 patients whostill test positive after 4 weeks (50–6000 IU/ml)benefit from a treatment period of 72 weeks.

S. ZeuzemG.K.K. Lau


49

Future prospects: toll-like receptoragonists and NS3 protease in-hibitorsDespite enormous advances in the treatment ofhepatitis C, it is not impossible to treat all pa-tients satisfactorily. The treatment fails in about50% of genotype 1 patients and still in about20% of genotype 2/3. New strategies are neces-sary J.-M. Pawlotsky, Créteil, described as partic-ularly promising toll-like receptor agonists, whichstimulate the congenital immune system. Theseoral “IFN inducers” include the TLR7 agonist

isatoribine and the TLR9 agonist Cpg 10101. In a phase IIa trial, the combination of CPG 10101plus peg-IFN proved as effective as peg-IFN plusribavirin in relapsing genotype 1 responders. Themost effective was the three-way combination.However the most “exciting” for J.-M. Pawlotskyis the NS3 protease inhibitor VX950, in responseto which HCV RNA is highly effectively reduced(Fig. 32). The triple combination of peg-IFN plusribavirin plus VX950 showed virtually completeHCV RNA loss within 4 weeks in all patients.

Viral Hepatitis (Part 2)Chair:P.D. Berk, New YorkG. Paumgartner, Munich

J.-M. Pawlotsky

Session 4

Fig. 32

I Peg-IFN-VX950 combination (J.-M. Pawlotsky, Créteil)

-6

-5

-4

-3

-2

-1

0

1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Baseline

peg-IFN + placebo

VX950

Study time [days]

HC

V R

NA

ch

ang

e fr

om

bas

elin

e(l

og

10IU

/ml)

VX950 + peg-IFN

50

Session 4

“Non-responders are not alwaysnon-responders”Hepatitis C patients who do not respond to an-tiviral treatment have twice as a high a risk ofHCC as responders. However, repeated therapymay be worthwhile, according to S.W. Schalm,Rotterdam, “especially if the doses for peg-IFNand ribavirin are optimized.” Up to 30% of non-responders can then achieve a lasting response.“Non-responders are not always non-responders“,stated S.W. Schalm. As a precondition for higherdoses, he stressed optimum management of theside-effects with regular monitoring and earlyadministration of SSRIs at the onset of depres-sion. If peg-IFN therapy is out of the question, he advocated using regimens which at leastlower the liver enzymes. Initial positive resultshave emerged for the plant ingredient glycyrrhizin,among others. M. Nishioka, Kagawa, particularlyaddressed the treatment of HCV in non-respon-ders in Asia.

S.W. Schalm M. Nishioka


51

Highly motivated to search for autoimmune hepatitisIt is a challenge to diagnose autoimmune hepati-tis (AIH) without any doubt. This is because it isan exclusion diagnosis in which a large numberof other diseases have to be included in the cal-culation, according to C.P. Strassburg, Hanover.Nevertheless, in his view the motivation must behigh because AIH responds extremely well to

steroid treatment. Monotherapy with low-dosesteroid or combination therapy with azathioprineshould be considered to maintain remission. Asan alternative for induction and maintenancetherapy, C.P. Strassburg suggests budesonide,which has virtually no systemic activity becauseof its first-pass effect of over 90%. To date,however, it has only been studied in small num-bers of patients. In monotherapy of 12 treat-

Autoimmune HepatitisChair:S. Matern, AachenL.W. Powell, Brisbane

C.P. Strassburg

Session 5

Fig. 33

I Budesonide: monotherapy in naive patients (C.P. Strassburg, Hannover)

Week 0

upper limit of normal

Week 12

12 patients, 9 mg budesonide daily (3 x 3 mg) monotherapy7/12 complete remission (58%), 3/12 partial response (25%)Side effects: diabetes 1/12, flu-like symptoms 1/12, heartburn 1/12

Weeks of treatment

Weeks of treatment

IgG

(g

/l)A

LT (

U/l)

Bili

rub

in (

µm

ol(

l)

Alb

um

in (

g/l)

52

Session 5

ment-naive AIH patients, 7 achieved completeremission on budesonide and 3 partial remission,with markedly improved ALT, IgG and bilirubin(Fig. 33). A large-scale study should now clarifythe value of budesonide.

“Overlap syndromes are old concepts”Overlap syndromes, according to U. Leuschner,Frankfurt, are the co-existence of two autoim-mune diseases of the liver which occur at thesame time or sequentially. These include the fa-miliar overlap syndromes AIH/PBC and AIH/PSCas well as AMA-negative PBC, which is regardedas a variant of PBC. The assessment of the simul-taneous occurrence of AIH and hepatitis C re-mains open. This raises the question of whetherit is an overlap syndrome or a comorbidity. U. Leuschner formulated clear treatment recom-mendations. Treatment is with UDCA for AMA-negative PBC, with UDCA plus steroids forAIH/PBC and with high-dose UDCA possibly plus steroids for AIH/PSC. In AIH-hepatitis C thetreatment is determined by the dominant clinicalpicture. U. Leuschner made it clear, however:“Overlap syndromes are old concepts. We needmore research in this field!”

U. Leuschner


53

Can fibrosis and cirrhosis be reversed?Chronic liver diseases often result in hepatic fi-brosis. However, fibrogenesis is not a homoge-neous process, according to M. Pinzani, Florence.Instead, there are a “large number of patterns of hepatic fibrosis” (Fig. 34). The discussions re-volve around the question of whether fibrosis or cirrhosis are reversible. Studies in cell culturesand animal models have shown that, in princi-ple, normal histology can be restored once the

liver is no longer being damaged. This reversibili-ty is associated with increased collagenolytic ac-tivity and apoptosis of the hepatic stellate cells.However, there are discrepancies in the results inhumans, M. Pinzani emphasized. For instance,the histology does improve in hepatitis patientswho respond to antiviral therapy. However, studyresults indicate that the reversibility of the fibro-sis in a cirrhotic liver is highly variable and theremay be no complete reversion of the cirrhosis.

Sequelae of Chronic Hepatitis (Part 1)Chair:K.-H. Meyer zum Büschenfelde, BerlinJ. Rodés, Barcelona

M. Pinzani

Session 6

Fig. 34

I Patterns of hepatic fibrosis development (M. Pinzani, Florence)

AA BB

CC DD ASH/NASHASH/NASH

Pericellular“chicken wire“

Biliary typePost-necrotic

Vascular type

54

Session 6

Primary prevention for smallvarices: possible but not essentialIn the primary prevention of variceal bleeding,non-selective beta-blockers are indicated forlarge varices. This is because the bleeding rate ismarkedly lower on propranolol than on placebo(22% versus 35%.) However, T. Sauerbruch,Bonn, stressed the problems: 40% of patientsare hemodynamic non-responders, 25% prema-turely stop the treatment which needs to be life-long and 5% have contraindications. Ligature isavailable as an alternative. T. Sauerbruch referredto a current meta-analysis, according to whichboth methods are equally effective, with a slighttrend in favor of ligature. He recommended ligature for patients who are non-compliant, donot tolerate beta-blockers or have contraindica-tions. There has so far been only one controlledstudy on primary prevention for small varices: Thiscompares nadolol with placebo. Within 5 yearsthe bleeding risk was 22% versus 12%, the NNTwas 10. According to T. Sauerbruch, interventionmay be considered. Pre-preventive treatment isineffective in patients with portal hypertensionwithout varices. Timolol showed no advantageover placebo in terms of the incidence of varices,ascites or deaths.

T. Sauerbruch P. Ginès

Initial therapy for ascites: paracentesis plus albuminIn the treatment of refractory ascites in the con-text of cirrhosis of the liver, paracentesis plus albumin infusion is clearly superior to diuretictreatment, P. Ginès, Barcelona, explained. It alsobetter in comparison with the transjugular intra-hepatic portosystemic shunt (TIPS), as shown infive up-to-date studies in the last nine years. However, ascites seems to be better controlledwith TIPS, and hepatorenal syndromes seem tooccur more rarely. Instead, the risk of hepatic en-cephalopathy increases, the costs are higher andthe patients have no survival advantage. Anothertreatment modality is vasopressin V2 receptorantagonists for cirrhosis patients with ascites andhyponatremia. In a current, double-blind, ran-domized parallel-group trial, P. Ginès studied satavaptan, in addition to spironolactone, andfound a decrease in bodyweight as well as an increase in the serum sodium levels.


55

HRS: treat with drugs before transplantationThe survival times for patients with hepatorenalsyndrome (HRS) are short: an average of 15 daysfor HRS type 1 and 150 days for HRS type 2, according to V. Arroyo-Perez, Barcelona. Livertransplantation is the most convincing treatmentoption. In terms of medication, a combination ofvasoconstrictors such as terlipressin in combina-tion with i.v. albumin is possible. This regimen issuperior to the standard treatment in terms ofthe survival rate, stated V. Arroyo-Perez. In addi-tion, he stressed that severe HRS should be treat-ed before liver transplantation because the sur-vival rate can be improved by this approach (Fig. 35).

HPS increases the risk of mortalityafter transplantationThe prognosis for patients with hepatopulmonarysyndrome (HPS) is also poor. M.J. Krowka,Rochester, stressed that hypoxemia can be foundin 40–50% of patients with chronic liver diseaseand HPS in 5–10%. The algorithm of the MayoClinic recommends arterial blood gas analysis ina sitting position under ambient air conditionsfor diagnosis. If PaO2 is below 70 mmHg, con-trast echography should be performed; if posi-tive, 99mTcMAA pulmonary perfusion scintigraphyshould be carried out as well as arterial bloodgas analysis supine and standing in ambient airconditions and with 100% oxygen administra-tion. Transplant patients with severe HPS have amarkedly higher mortality risk: Between 16%and 29% die within a year.

Sequelae of Chronic Hepatitis(Part 2)Chair:W. Stremmel, HeidelbergR. Williams, London

V. Arroyo-Perez M.J. Krowka

Session 7

Fig. 35

I Hepatorenal syndrome (HRS) – Survival after transplantation (V. Arroyo-Perez, Barcelona)

Pro

bab

ility

HRS treated (n = 9)

No HRS (n = 27)

p = NS

Years0 1 2 3

1.0

0.8

0.6

0.4

0.2

0.0

56

Session 7

“Molecular targeting” in HCCThe risk of HCC is high in cirrhosis of the liver,with an incidence of 15–20% within 5 years,and at the same time it is the number 1 cause ofdeath. Male gender, advanced age, elevated AFPlevels, viral etiology, alcohol consumption andportal hypertension are considered risk factors.

With regard to staging and the resulting treat-ment strategies, J. Bruix, Barcelona, referred tothe algorithm of the Barcelona Clinic Liver Can-cer (BCLC) Group (Fig. 36). In addition, strategiesthat are aimed selectively at tumor-specific targetstructures (molecular targeting) are also being scientifically pursued. The RAF inhibitor/VEGF in-hibitor sorafenib and the EGFR inhibitors erlotiniband gefitinib are already in phase III trials. In viewof the lack of transplant organs, M. Malagó,Essen, regards living donor liver donation forHCC as being justified under the expandedMilan criteria. After 72 months, there was nostatistically significant difference in survival be-tween the patients who did or did not satisfy the Milan or UCSF criteria.

J. Bruix M. Malagó

Fig. 36

I BCLC-Staging and treatment strategy (J. Bruix, Barcelona)

HCC

Stage A–COkuda 1–2, PST 0–2, Child-Pugh A–B

Stage 0PST 0, Child-Pugh A

Stage DOkuda 3, PST > 2, Child-Pugh C

Very early (0)1 nodule < 2 cm

Carcinoma in situ

Early (A)1–3 nodules< 3 cm, PS 0

Intermediate (B)Multinodular, PS 0

Advanced (C)Portal invasion,N1,M1, PS 1–2

Terminal (D)

1 nodule 3 nodules ≤ 3 cm

Portal pressure/bilirubin

Increased

Normal No Yes

Associated diseases Portal infiltration

No Yes

Resection Liver tansplantation(CL//LDLT) ChemoembolizationPEI/RF New agents

Curative treatments50–70% at 5 years

Randomized controlled trials(40–50% at 3 years vs. 10% at 3 years)

Symptomatictreatment


57

AKT protein kinase B

ASBT apical sodium-dependent bile acid transporter

BSEP bile salt export pump

EGFR epidermal growth factor receptor

ERK extracellular signal-regulated kinase

FGF fibroblast growth factor

FoxO1 transcription factor

FXR farnesoid X receptor

GPCR G protein-coupled receptors

MRP multi-drug-resistant protein

NTCP (Na+-dependent taurocholate cotransporting polypeptide)

OATP organic anion transporting polypeptide

OST organic solute transporter

PKA protein kinase A

PKC protein kinase C

PXR pregnane X receptor

ROS reactive oxygen species

SHP short heterodimer partner

SREBP sterol regulatory element-binding protein

SXR steroid and xenobiotic receptor

Glossary

Glossary

58

The International Hans Popper Prize, award-ed during the Falk Symposium 156 “Genetics inLiver Diseases”, was presented to the Spanish re-searcher Prof. P. Ginès, Barcelona. He was hon-ored for his research into the pathogenetic rela-tionship between cirrhosis of the liver, circulatorydisorders and renal failure. The hepatorenal syn-drome is one of the most feared complicationsfacing patients with cirrhosis of the liver. In somecases, spontaneous bacterial peritonitis occurringin patients with liver cirrhosis may trigger the development of hepatorenal syndrome. The si-multaneous increase in cytokine production,among other factors, leads to an increase in ni-tric oxide (NO) with compromised renal function.Prof. Ginès underscored the prime importance ofpreserving renal function for patients’ survival.

Prof. Ginès is the recipient of the sixth Interna-tional Hans Popper Prize, which includes an hon-

orarium of 25,000 Euros. The Prize was endowedfor the purpose of honoring extraordinary re-search accomplishments in the area of experi-mental hepatology, which deals with basic re-search on the molecular biology, molecular ge-netics, physiology, biochemistry and pathologyof acute and chronic liver diseases and their se-quelae. At the same time, the Prize honors thememory of Hans Popper, the internationallyrenowned pioneer in the field of hepatology.Among his contributions was the foundation ofthe International Society for the Study of theLiver, which provided the impetus for the estab-lishment of numerous European and interna-tional specialized societies.

The XIX International Bile Acid Meeting (FalkSymposium 155: “Bile Acids: Biological Actionsand Clinical Relevance”) was the setting forpresentation of the Adolf Windaus Prize,which was awarded to the French researcher Prof. R. Poupon, Paris.Prof. Poupon has conducted numerous studiesusing the hydrophilic bile acid ursodeoxycholicacid (UDCA; e.g. Ursofalk®) in patients withcholestatic liver diseases, especially in primarybiliary cirrhosis (PBC). Among other advances,Prof. Poupon was able to show that UDCA notonly improves histology and hepatic enzyme levels but also prolongs transplant-free survival in PBC patients.

Falk Foundation Awards International Prizes at the XIII Falk Liver Week

Internationally Renowned Hepatologists HonoredAs part of the XIII Falk Liver Week (October 2006 in Freiburg, Germany) the following highly coveted international prizes were awarded by the Falk Foundation e.V.

Presentation of Prizes

The International Hans Popper Prize was presented to Prof. P. Ginès, Barcelona, by Prof. G. Paumgartner, Munich

Congress Short Report Falk Symposia

59

155–157

The award to Prof. Poupon marks the fourteenthpresentation of the Adolf Windaus Prize. The Prize,which includes an honorarium of 5,000 Euros,honors extraordinary scientific work in the areaof bile acid research. The Prize honors the mem-ory of Adolf Windaus, the discoverer of choles-terol and the founder of bile acid research. Win-daus received the Nobel Prize for Chemistry in1928 in recognition of his research on steroids.

The Canadian scientist Prof. Jenny Heathcote,Toronto, was honored at the Falk Symposium157 “Chronic Hepatitis: Metabolic, Cholestatic,Viral and Autoimmune” with the Dame SheilaSherlock Prize for her extraordinary researchwork in the area of clinical hepatology. In her

lecture, Prof. Heathcote drew attention to thesignificant changes that have occurred in hepa-tology over the past decades, such as deeper understanding of the immunology that pavedthe way for liver transplantation and the recog-nition of the role of genetics in the etiology ofcertain liver disorders. In her opinion, however,the greatest progress is to be found in the con-tinued development of technology, which has resulted in more reliable diagnostics. The identifi-cation of specific liver disease has been facilitat-ed, including that of AMA-negative PBC, a dis-ease entity first described by Prof. Heathcote.Prof. Heathcote, a long-time student of SheilaSherlock, also argued for more effective educa-tion of the population regarding the hepaticrisks of drugs and alcohol as well as regardingeffective screening methods and vaccinations.

The Dame Sheila Sherlock Prize, which includesan honorarium of 25,000 Euros, is awarded forextraordinary research work in the area of clini-cal hepatology. The Prize honors the memory ofSheila Sherlock, one of the leading co-foundersof modern hepatology. This marks the secondtime that the Prize has been presented.

Presentation of the Adolf Windaus Prize with Prof. G. Paumgartnerand Prof. R. Poupon, Paris

Prof. H.E. Blum, Freiburg, presents the Dame Sheila SherlockPrize to Prof. J. Heathcote, Toronto

60

On March 27, 2006, Professor Dr. Wolfgang Gerokturned 80. This event calls for a celebration alsoin this forum because Professor Gerok was in-volved in the organization of the Falk Liver Weeksfrom the very beginning, i.e., from the II Falk LiverWeek in 1970 in Freiburg with the Falk Sympo-sium 5 on “Bile Acids” until today.

In the following I would like to briefly summarizethe major contributions of Professor Gerok to ac-ademic medicine in general and to hepatology inparticular.

Wolf Gerok studied medicine at the universitiesof Freiburg and Tübingen from 1945–1950, fol-lowed by a postdoctoral training in biochemistryand pathology at the University of Tübingen anda 2-year research stay at the University of Zürich.This postdoctoral training was followed by a resi-dency in internal medicine and further specializa-tion in gastroenterology and hepatology.

After his clinical training and a period as chiefresident at the Universities of Marburg and Mainzhe took the chair for internal medicine at the

Eulogy on the Occasion of Professor Dr. Wolfgang Gerok’s 80th Birthday

Eulogy

Professor Dr. Wolfgang Gerok


61

University Hospital in Freiburg in 1968, a posi-tion that he filled until his retirement in 1994.Among the many facets of the contributions ofWolf Gerok I would like to mention only three:

1. his excellence as an academic teacher2. his great personal interest in clinical research3 his continuous support for the organization

and funding of clinical research in Germany

1. Academic teacherThe center of the clinical and scientific activitiesof Wolf Gerok was the individual patient. He wasalways available and had a tremendous talent toquickly gain the confidence of his patients andtheir relatives. For his students and associates, he practiced patient-oriented medicine, limitingdiagnostic procedures and therapeutic interven-tions to the essential aspects, always addressingalso the personal needs and anxieties of his pa-tients.

For his students he was a most revered teacherwith the ability to explain complex issues in asimple manner, taking into account the patho-physiologic and pathobiochemical basis of dis-eases.

As a clinician and academic teacher Wolf Gerokalways had a charismatic personality with a nat-ural authority that made him for his patients to a caring physician and for his colleagues, associ-ates and students to a role model.

2. ResearchThe research interest of Wolf Gerok was in gen-eral terms the understanding of the physiologi-cal, biochemical and molecular basis of diseases.Given this interest, he focussed on the proteinand amino acid metabolism of the liver in healthyindividuals as well as in patients with liver andkidney diseases. Further, he and his associates

studied the bile acid metabolism and in particu-lar the transport systems for bile acids and thekinetics of bile acid transport.

Many of these projects were part of the DFG-funded Center of Collaborative Research (Son-derforschungsbereich) “Clinical and Experimen-tal Hepatology” that he organized together withProfessor Decker from 1982–1994. In additionto his interest in basic sciences he also supportedthe clinical development of new procedures and therapeutic strategies in hepatology. In par-ticular, he and his associates, especially ProfessorRössle brought the transjugular, intrahepatic portosystemic stent procedure (TIPS) to a nowworldwide established clinical application.

3. Support of research organizationand funding

Apart from his enthusiasm for basic as well as ap-plied clinical research, Wolf Gerok was very muchinvolved in the activities of agencies for researchfunding, such as the Deutsche Forschungsgemein-schaft (DFG). For many years he presided theCommittee on “Internal Medicine” and from1979–1985 he was Vice-President of the DeutscheForschungsgemeinschaft. In addition, he wasmember of numerous scientific advisory boards,incl. the Max-Planck-Gesellschaft, the ThyssenFoundation and many other organizations.

As mentioned already, the major commitment ofWolf Gerok was the establishment of basic re-search in a clinical setting. In this context he veryearly recognized the problems associated withperforming laboratory-based research and at thesame time being involved in clinical activities. In1979 he published a DFG-sponsored memoran-dum entitled “State and improvement of clinicalresearch in the Federal Republic of Germany”.This memorandum had a major impact on theresearch programs of the Deutsche Forschungs-gemeinschaft in the ensuing years.

155–157

62

Through his untiring personal input, tremendousworking discipline and his enthusiasm for patientcare as well as teaching and research, he was arole model for many of his associates and greatlycontributed to their career.

For his eminent clinical and scientific contributionsProfessor Gerok already received many honorsand awards. Among others, he became memberof the German Academy of Natural ScientistsLeopoldina in Halle, member of the Ordre pourle Mérite for Sciences and Arts and received nu-merous medals and prizes from different institu-tions and societies, among others the WatsonPrize of the University if Minnesota and theThannhauser Medal of the German Gastroen-terology Society.

Given all his activities and talents Wolf Gerokcertainly was and is one of the most prominentpersonalities in internal medicine in Germany.For his outstanding personal engagement formedicine, teaching and research as well as hispersonal continuous support of the funding ofclinical research in Germany, he can be certain ofthe unconditional admiration and appreciationof his students, associates and colleagues. Butalso from his many patients and their families forwhom he was a charismatic and trusted advisor.

On behalf of all participants of the XIII Falk LiverWeek, I would like to congratulate you to yourbirthday and to wish you the very best for thefuture: health, happiness and time for many ofyour non-medical hobbies, such as music, hiking,skiing as well as in recent years travelling to faraway places.

Eulogy

Professor Dr. H.E. Blum

63


M.S. Anwer, Ph.D.Professor of PharmacologyTufts UniversitySchool of Veterinary MedicineDept. of Biomedical Sciences200 Westboro RoadNorth Grafton, MA 01536-1828USA

Prof. Dr. V. Arroyo-PerezHospital Clinico y ProvincialUniversidad de BarcelonaUnidad de HepatologiaVillarroel 170E-08036 BarcelonaSpain

Prof. Dr. G.P. van Berge HenegouwenAcademisch Ziekenhuis Utrechtde UithofAfd. GastroenterologieBox 85500NL-3508 GA UtrechtThe Netherlands

P.D. Berk, M.D.Professor of MedicineMount Sinai School of MedicineDivision of Liver DiseasesBox 1039, 11th Floor, Rm 231425 Madison Ave.New York, NY 10029USA

Prof. Dr. U. BeuersUniversiteit van AmsterdamAcademisch Medisch CentrumDepartment of Gastroenterology& Hepatology, B1-244.2Meibergdreef 9NL-1105 AZ AmsterdamThe Netherlands

Prof. Dr. I. BjörkhemKarolinska InstituteHuddinge University HospitalDepartment of Clinical ChemistryS-141 86 HuddingeSweden

Prof. Dr. Dr. h.c. mult. H.E. BlumInnere Medizin IIUniversitätsklinikum FreiburgHugstetter Str. 55D-79106 FreiburgGermany

J.L. Boyer, M.D.Professor of MedicineYale University School of MedicineLiver Research Center, LMP 1080333 Cedar StreetNew Haven, CT 06520USA

Prof. Dr. J. BruixHospital Clinico y ProvincialUniversidad de BarcelonaBCLC GroupLiver UnitVillarroel 170E-08036 BarcelonaSpain

Dr. M.-A. BuendiaInstitut PasteurUnité de Recombinaison et Expression GénétiqueInserm U16328, rue du Dr. RouxF-75724 ParisFrance

Prof. Dr. R.W. ChapmanJohn Radcliffe HospitalNHS TrustDept. of GastroenterologyHeadley Way HeadingtonOxford OX3 9DUGreat Britain

J.Y.L. Chiang, Ph.D.Professor of BiochemistryNortheastern Ohio UniversityCollege of MedicineBiochemistry/Molecular Pathology4209 State Route 44Rootstown, OH 44272-0095USA

Prof. Dr. P.T. ClaytonHospital for Sick ChildrenMetabolic Disease andHepatologyGreat Ormond StreetLondon WC1N 3JHGreat Britain

Prof. Dr. C. ColomboUniversità di MilanoDept. of Pediatrics, CF CenterVia Commenda 9I-20122 MilanoItaly

Chairpersons, Speakers andScientific Organizers

64

Prof. Dr. D.W. CoxUniversity of AlbertaDepartment of Medical Genetics8-39 Medical Sciences BuildingEdmonton, AB T6G 2H7Canada

P.A. Dawson, Ph.D.Associate Professor of MedicineWake Forest UniversityBowman Gray School of MedicineDepartment of MedicineMedical Center BoulevardWinston-Salem, NC 27157USA

A.M. Diehl, M.D.Professor of MedicineDuke University Medical CenterGastroenterology DivisionBox 3256, Snyderman/GSRB-1595 LaSalle StreetDurham, NC 27710USA

Prof. Dr. P. FerenciMedizinische Universität WienGastroenterologie/HepatologieWähringer GürtelA-1090 WienAustria

PD Dr. P. FickertMedizinische Universität GrazInnere Medizin I und IIIAuenbruggerplatz 15A-8036 GrazAustria

Prof. Dr. S. FiorucciUniversity of PerugiaPoliclinico MonteluceGastroenterologia ed EpatologiaVia E. del PozzoI-06111 PerugiaItaly

Prof. Dr. G. GerkenGastroenterologie/HepatologieUniversitätsklinikum EssenHufelandstr. 55D-45147 EssenGermany

Prof. Dr. Dr. h.c. W. GerokInnere MedizinUniversitätsklinikum FreiburgHugstetter Str. 55D-79106 FreiburgGermany

M.E. Gershwin, M.D.Professor of MedicineUniversity of CaliforniaSchool of MedicineRheumatology and AllergyOne Shields Ave., Tupper HallDavis, CA 95616USA

Prof. Dr. P. GinèsHospital Clinico y ProvincialUniversidad de BarcelonaUnidad de HepatologiaVillarroel 170E-08036 BarcelonaSpain

S. Gupta, M.D.Prof. of Medicine & PathologyAlbert EinsteinCollege of MedicineDept. of Medicine & Pathology1300 Morris Park Ave.Bronx, NY 10461USA

Prof. Dr. D. HäussingerGastroenterologie/HepatologieUniversitätsklinikum DüsseldorfMoorenstr. 5D-40225 DüsseldorfGermany

Prof. Dr. J.L. HeathcoteUniversity of TorontoToronto Western HospitalFell Pavilion 6-170399 Bathurst StreetToronto, ON M5T 2S8Canada

Prof. Dr. H.J.F. HodgsonRoyal Free HospitalSchool of MedicineMedicine/HepatologyRowland Hill StreetLondon NW3 2PFGreat Britain

A.F. Hofmann, M.D., Ph.D.Professor of Medicine (Emeritus)Univ. of California, San DiegoDepartment of Medicine (0813)Division of Gastroenterology9500 Gilman DriveLa Jolla, CA 92093USA

P.B. Hylemon, Ph.D.Professor of Microbiology & MedicineMedical College of VirginiaBox 980678Richmond, VA 23298USA

Prof. Dr. P.L.M. JansenUniversiteit van AmsterdamAcademisch Medisch CentrumDepartment of Gastroenterologyand HepatologyMeibergdreef 9NL-1105 AZ AmsterdamThe Netherlands

N. Kaplowitz, M.D.Professor of MedicineUniv. of Southern CaliforniaKeck School of MedicineGastrointestinal and Liver DiseaseBldg. HMR 101, Mail Code 9091Los Angeles, CA 90089USA

Dr. T.H. KarlsenUniversity of OsloRikshospitaletInstitute of ImmunologyOsloNorway

Index

65


Dr. S.J. KeelyBeaumont HospitalRCSI Education & Research CenterSmurfit BuildingBeaumont RoadDublinIreland

Dr. V. KeitelExperimentelle HepatologieUniversität DüsseldorfGebäude 23.12Universitätsstr. 1D-40225 DüsseldorfGermany

Prof. Dr. D. KepplerTumorbiochemieDeutsches KrebsforschungszentrumIm Neuenheimer Feld 280D-69120 HeidelbergGermany

S. Kliewer, M.D.Professor of Molecular BiologyUniversity of TexasSouthwestern Medical CenterDepartment of Molecular Biology5323 Harry Hines Blvd.Dallas, TX 75390-9046USA

Prof. Dr. K. KoikeThe Cancer InstituteDepartment of Gene Research1-37-501, KamiikebukuroToshima-ku, Tokyo 170-0012Japan

Dr. J. KondrackieneKaunas Medical University ClinicDepartment of GastroenterologyEiveniu Str. 2LT-50009 KaunasLithuania

Prof. Dr. Dr. W. KramerD.G. StoffwechselAventis Pharma DeutschlandD-65926 FrankfurtGermany

M.J. Krowka, M.D.Professor of MedicineMayo ClinicE-18200 First Street SWRochester, MN 55905USA

PD Dr. R. KubitzGastroenterologie/HepatologieUniversitätsklinikum DüsseldorfMoorenstr. 5D-40225 DüsseldorfGermany

Prof. Dr. G.A. Kullak-UblickUniversitätsspital ZürichDept. für Innere MedizinKlinische Pharmakologie/ToxikologieRämistr. 100CH-8091 ZürichSwitzerland

Prof. Dr. F. LammertMedizinische Klinik IUniversitätsklinikum BonnSigmund-Freud-Str. 25D-53127 BonnGermany

Dr. G.K.K. LauQueen Mary HospitalThe University of Hong Kong1102 Pokfulam RoadHong KongHong Kong

G.D. LeSage, M.D.Professor of MedicineUniversity of Texas Medical SchoolGastroenterology & Hepatology6431 Fannin StreetHouston, TX 77030-1501USA

Prof. Dr. U. LeuschnerZentrum der Inneren MedizinKlinikum der UniversitätTheodor-Stern-Kai 7D-60590 FrankfurtGermany

K.D. Lindor, M.D.Professor of MedicineMayo ClinicGastroenterology Unit, Box 0001200 First Street SWRochester, MN 55905USA

Dr. K. MaedaUniversity of TokyoSchool of Pharmaceutical SciencesDepartment of Biopharmaceutics7-3-1 HongoBunkyo-ku, Tokyo 113-0033Japan

Dr. M. MalagóChirurgische KlinikUniversitätsklinikum EssenHufelandstr. 55D-45147 EssenGermany

D.J. Mangelsdorf, Ph.D.Professor of PharmacologyUniversity of TexasSouthwestern Medical CenterDepartment of Pharmacology5323 Harry Hines Blvd.Dallas, TX 75390-9046USA

Prof. Dr. M.P. MannsGastroenterologie/HepatologieMedizinische Hochschule HannoverCarl-Neuberg-Str. 1D-30625 HannoverGermany

Prof. Dr. Dr. H.-U. MarschallKarolinska InstituteHuddinge University HospitalDivision of Gastroenterologyand HepatologyS-141 86 HuddingeSweden

Prof. Dr. S. MaternHöfchensweg 113D-52066 AachenGermany

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66

Prof. Dr. P.J. Meier-AbtUniversität BaselVizerektor ForschungPetersgraben 35CH-4003 BaselSwitzerland

Prof. Dr. U.A. MeyerUniversität BaselBiozentrumPharmakologieKlingelbergstr. 70CH-4056 BaselSwitzerland

Prof. Dr. Dr. Dr. K.-H. Meyer zumBüschenfeldeTrabener Str. 8D-14193 BerlinGermany

Prof. Dr. H. MoshageAcademisch Ziekenhuis GroningenDepartment of Pathology & Laboratory MedicineP.O. Box 30.001NL-9700 RB GroningenThe Netherlands

Prof. Dr. M. NishiokaYashimanishimachi 1119-20Takamatsu, Kagawa 760-0018Japan

Prof. Dr. H. OmranKinder- und JugendmedizinUniversitätsklinikum FreiburgMathildenstr. 1D-79106 FreiburgGermany

Prof. Dr. G. PaumgartnerInnere Medizin IIKlinikum der UniversitätMünchen-GroßhadernMarchioninistr. 15D-81377 MünchenGermany

Prof. Dr. J.-M. PawlotskyHôpital Henri MondorUnité Virologie51, av. Mal. de Lattre de TassignyF-94010 CréteilFrance

Prof. Dr. A. PietrangeloPoliclinico di ModenaClinica Medica IIIDivisione di Medicina InternaVia del Pozzo, 71I-41100 ModenaItaly

Prof. Dr. M. PinzaniUniversità di FirenzeOspedale CareggiFisiopatologia EpaticaClinica Medica IIViale G.B. Morgagni 85I-50134 FirenzeItaly

Prof. Dr. R. PouponHôpital Saint-AntoineService d’Hépato-Entérologie184, rue du Faubourg St. AntoineF-75571 ParisFrance

Prof. Dr. L.W. PowellThe University of QueenslandSchool of MedicineRoyal Brisbane HospitalLevel 6 Ned Hanlon BuildingHerston Road, HerstonBrisbane, QLD 4029Australia

Prof. Dr. J. PrietoClinica Universitaria de NavarraDepartamento de Medicina InternaApartado 192E-31080 PamplonaSpain

S. Ren, M.D.Virginia Medical CenterResearch 1511201 Broad Rock Blvd.Richmond, VA 23233USA

Dr. E.A. RobertsUniversity of TorontoThe Hospital for Sick ChildrenDepartment of Gastroenterology555 University AvenueToronto, ON M5G 1X8Canada

Prof. Dr. J. RodésHospital Clinico y ProvincialUniversidad de BarcelonaUnidad de HepatologiaVillarroel 170E-08036 BarcelonaSpain

Dr. M. RudlingKarolinska InstituteHuddinge University HospitalDepartment of MedicineM 63 CMES-141 86 HuddingeSweden

D.W. Russell, Ph.D.Professor of MedicineUniversity of TexasSouthwestern Medical CenterBiophysics & Molecular Genetics5323 Harry Hines Blvd.Dallas, TX 75390-9046USA

Dr. C. RustInnere Medizin IIKlinikum der UniversitätMünchen-GroßhadernMarchioninistr. 15D-81377 MünchenGermany

Prof. Dr. T. SauerbruchMedizinische Klinik IUniversitätsklinikum BonnSigmund-Freud-Str. 25D-53127 BonnGermany

Prof. Dr. S.W. SchalmLiverDoc B.V.Room Ee 1973Dr. Molewaterplein 50NL-3015 GE RotterdamThe Netherlands

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Prof. Dr. H.K. SeitzInnere MedizinKrankenhaus Salem derEvang. Stadtmission HeidelbergZeppelinstr. 11–33D-69121 HeidelbergGermany

K.D.R. Setchell, Ph.D.Professor of PediatricsCincinnati Children's HospitalMedical CenterMass Spectrometry Laboratory3333 Burnet AvenueCincinnati, OH 45229-3039USA

B.L. Shneider, M.D.Professor of PediatricsMount Sinai School of MedicineDivision of Pediatric HepatologyBox 1656One Gustave L. Levy PlaceNew York, NY 10029-6574USA

Prof. Dr. J. SjövallKarolinska InstitutetDepartment of MedicalBiochemistry and BiophysicsS-171 77 StockholmSweden

C.J. Soroka, M.D.Yale UniversitySchool of MedicineDepartment of Internal MedicineSection of Digestive Diseases333 Cedar StreetNew Haven, CT 06520USA

Prof. Dr. U. SpenglerMedizinische Klinik IUniversitätsklinikum BonnSigmund-Freud-Str. 25D-53127 BonnGermany

Prof. Dr. A. StiehlInnere Medizin IVKlinikum der UniversitätIm Neuenheimer Feld 410D-69120 HeidelbergGermany

Prof. Dr. C.P. StrassburgGastroenterologie/HepatologieMedizinische Hochschule HannoverCarl-Neuberg-Str. 1D-30625 HannoverGermany

Prof. Dr. W. StremmelInnere Medizin IVKlinikum der UniversitätIm Neuenheimer Feld 410D-69120 HeidelbergGermany

F.J. Suchy, M.D.Professor of PediatricsMount Sinai School of MedicineDepartment of HepatologyOne Gustave L. Levy PlaceNew York, NY 10029-6574USA

Dr. T. SvegerUniversity HospitalDepartment of PediatricsS-205 02 MalmöSweden

Prof. Dr. R. ThimmeInnere Medizin IIUniversitätsklinikum FreiburgHugstetter Str. 55D-79106 FreiburgGermany

Prof. Dr. H.C. ThomasSt. Mary’s HospitalMedical SchoolDepartment of MedicinePraed StreetLondon W2 1NYGreat Britain

Dr. R.J. ThompsonKing's College HospitalInstitute of Liver StudiesDenmark HillLondon SE5 9RSGreat Britain

S. Thorgeirsson, M.D., Ph.D.National Institutes of HealthNCI, NIHLab. of Experimental Carcinogenesis37 Convent Dr. MSC 4262Bethesda, MD 20892-4262USA

Prof. Dr. M. TraunerMedizinische Universität GrazKlinische Abteilung fürGastroenterologie & HepatologieAuenbruggerplatz 15A-8036 GrazAustria

D.Q.-H. Wang, M.D., Ph.D.Assistant Professor of MedicineBeth Israel DeaconessMedical CenterGastroenterology Division330 Brookline Ave.Boston, MA 02215USA

Prof. Dr. R. WilliamsUniversity College HospitalMedical SchoolInstitute of Hepatology69-75 Chenies MewsLondon WC1E 6HXGreat Britain

Prof. Dr. S. ZeuzemKlinik für Innere Medizin IIUniversitätsklinikum des SaarlandesKirrberger Str.D-66424 HomburgGermany

Dr. Y. ZhangUniversity of TsukubaDivision of Gastroenterology &Hepatology1-1-1 TennoudaiTsukuba City 305-8575Japan

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68

Further Congress Short Reportsof Falk Symposia

FSK136/137e“Cholestatic Liver Diseases: Therapeutic Options andPerspectives”“Liver Diseases: Advances in Treatment and Prevention”Compiled by U. Leuschner and C. Vetter(2004) 56 pages

FSK142e“Autoimmune Liver Diseases”“Pancreatitis: Advances in Pathobiology,Diagnosis and Treatment”“Gastroenterology Yesterday – Today – Tomorrow:A Review and Preview”Compiled by B. Fessler and C. Vetter(2005) 60 pages

FSK148e“Diverticular Disease: Emerging Evidencein a Common Condition”Compiled by C. Vetter(2005) 38 pages

FSK149/150e“Highlights in Gastrointestinal Oncology”“Disease Progression and Disease Prevention inHepatology and Gastroenterology”Compiled by B. Fessler(2006) 52 pages

FSK152/153eIntestinal Disease Meeting Berlin 2006“Endoscopy 2006 – Update and Live Demonstration”“Immunoregulation in Inflammatory Bowel Diseases –Current Understanding and Innovation”Compiled by C. Vetter(2006) 56 pages

These reports are free of charge and can be ordered from Falk Foundation e.V. or the local Falk partner.

Congress Reports:The official congress reports of Falk Symposia 155–157 “Bile Acids: Biological Actions and Clinical Relevance” (E155), “Genetics in Liver Diseases” (E156) and “Chronic Hepatitis: Metabolic, Cholestatic,Viral and Autoimmune” (E157) will be published by Springer, Dordrecht, The Netherlands, in the first half of 2007 and can be ordered at reduced prices (E155 and E157 3 35,– each, E156 3 30,–) from Falk Foundation e.V. or the local Falk partner.

The books can be obtained on CD-ROM at the same prices.

FSK

155–

157e

1-4/

2007

/5.0

00 K

onk

FOUNDATION e.V.

FALK FOUNDATION e.V.Leinenweberstr. 5Postfach 652979041 FreiburgGermany

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