AG&M annual report 2018

AG&M Science Impressions 2018
The pathogenesis and treatment of cholestatic liver diseases and itch. Unraveling
Immunoglobulin G4 Associated Cholangitis and the ‘biliary HCO3- umbrella’.
Ulrich Beuers and Jorrit van Niekerk
Prof dr. Ulrich Beuers has been appointed Professor
of Gastroenterology and Hepatology since 2007 at
the Amsterdam University Medical Center and Core
Professor and Head of Hepatology in 2010. After
being raised in Germany, he studied medicine in Gent,
Berlin and Freiburg. He obtained his Dr.med. in 1983
in Freiburg. After a postdoc period in biochemistry in
Göttingen, he was trained in Internal Medicine and
Gastroenterology/Hepatology in Munich. During this
time, he undertook a fellowship for two years at the
Liver Center of the Yale University. He received his
Dr.med.habil. (‘Habilitation’) in 1994 in Munich and
became a Professor of Internal Medicine in 2001. In
2015, he spent a sabbatical again at the Liver Center
of Yale University where meanwhile a considerable
number of AMC students have performed their
‘wetenschappelijke stage’.
For three decades, Beuers’ research focusses on
the pathogenesis and treatment of patients with
cholestatic liver diseases. He has supervised over
20 PhDs and next to experimental laboratory work,
he has initiated or participated in large clinical trials
to evaluate treatment options for primary biliary
cholangitis (PBC), primary sclerosing cholangitis (PSC),
intrahepatic cholestasis of pregnancy (ICP) and IgG4-
relaed cholangitis (IRC) of which the pathogenesis
remains incompletely understood. The prognosis of PBC
and PSC without treatment is dismal, the diseases often
lead to liver cirrhosis and eventually the need for liver
transplantation. Common to all these diseases is the
symptom of pruritus (itch) which may severely affect
quality of life.
In search of a possible pathophysiological explanation,
evidence from experimental, clinical and genetic
studies led Beuers and his group to introduce the
‘biliary bicarbonate umbrella hypothesis’. This
hypothesis, that has been experimentally confirmed,
states that cholangiocytes (and hepatocytes) create
a protective apical alkaline barrier by secreting
bicarbonate (HCO 3
-) into the bile duct lumen. This
(~30-50 nm) alkaline barrier, which is stabilized by the
cholangiocyte glycocalyx, would retain bile salts in their
polar, deprotonated and membrane-impermeant state.
When the apical HCO 3
- secretory apparatus is defective
(as it is in PBC), the alkaline barrier would diminish,
leading to partial protonation of bile salts, rendering
the resulting bile acids apolar and capable of crossing
the cholangiocyte membrane independent of bile salt
transporter activity. These apolar bile acids have been
shown to induce cellular damage and growth arrest.
Jorrit van Niekerk is currently working as a PhD fellow
under supervision of Prof. dr. Ulrich Beuers and dr.
Stan van de Graaf at the Tytgat Institute for Intestinal
& Liver Research on the molecular regulation and
stabilization of the ‘biliary bicarbonate umbrella’ in
human cholangiocytes. By a close interplay between
several ion channels and proteins targeting the apical
membrane in cholangiocytes a pH nanoenvironment in
close proximity of the apical membrane is maintained.
Our group has recently shown that the integrity of this
apical layer of bicarbonate is fine-tuned by intracellular
signaling pathways mediated by bile salt sensitive
receptors in cholangiocytes. This enables a potential
therapeutic window for endogenous and therapeutic
bile salts and bile salt analogues to regulate the apical
membrane expression of key elements of the ‘biliary
bicarbonate umbrella’, responsible for the protection of
cholangiocytes from the detergent properties of biliary
bile salts in human bile.
Another cholestatic liver disease entity of which the
pathogenesis remains partly unknown is immunoglobulin
G4-related cholangitis (IRC). Experimental work by
Lowiek Hubers , PhD fellow under supervision of Prof. dr.
Ulrich Beuers and dr. Stan van de Graaf , had disclosed
Annexin A11 as the first IgG4/IgG1 autoantigen in IRC, and
had shown that specific targeting of Annexin A11 by IgG1
in patients with IRC might be attenuated by IgG4. Work
by his successor, Toni Herta, suggests that the IgG4/IgG1
autoantigen Annexin A11 might be a potential regulator
of the intracellular trafficking of some of the key
elements of the ‘biliary bicarbonate umbrella’ in human
cholangiocytes. Thus, Annexin A11 dysfunction might play
a role in the pathogenesis of IgG4-related cholangitis.
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