Post on 21-Sep-2020
Seminario Medicina di Genere
Colestasi e autoimmunitàAnnarosa Floreani
Studioso Senior Università di Padova, Consulente
Scientifico IRCCS Negrar (VR)
14 maggio 2020
• Why autoimmunity is peculiar of women?
• Focus on PBC, PSC
• IgG4-related sclerosing cholangitis
• LPAC
Outline
Factors underlying sexual dimorphism in
autoimmune disease
Ngo St et al, Front Neuroendocrinol 2015
Sex-specific factors that lead to sex bias in
autoimmunity
Rubtsova K et al, JCI 2015
Lee T et al, Autoimmunity Rev 2012
Genetics
and
Epigenetic
changes
Susceptibility
genes
Environmental
factors
Initiating factors
Modulating factors
Sex Hormones
Neuroendocrine
factors
Immune
Response
Outcomes
Exogenous or
Endogenous
Antigen
Tolerance
Protection
from
Infection
Autoimmunity
Adapted from Whitacre, Nature Immunol 2001;2:777
Interactions of the endocrine and
immune systems
The role of hormones in the sexual
dimorphism in autoimmunity
Ngo St et al, Front Neuroendocrinol 2015
A considerable number of sex- and immune-
related genes are located within the X
chromosome
Major disorders of X chromosome, such as X-
linked immunodeficiencies, Turner’s syndrome,
as well as premature ovarian failure, may be
accompanied by autoimmune features and
cholestasis
Sex chromosome and autoimmunity
Microchimerism and autoimmunity
Ngo St et al, Front Neuroendocrinol 2015
• AIH is an non-resolving chronic
liver disease that occurs in both
sexes but affects mainly women
• The incidence of AIH is
increasing
Epidemiology: prevalence
*Statement number: 1
1. Grønbæk L, et al. J Hepatol 2014;60:612–7;
EASL CPG AIH. J Hepatol 2015;63:971–1004
Danish nationwide patient registry1
Guideline statement*,2
Prevalence of AIH ranges from 15 to 25 cases per 100,000 inhabitants in
Europe and is increasing in both women and menII-2
Grade of recommendation
• AIH occurs in all ethnic groups
and in all age groups1,2
• Bimodal distribution usually with
peaks around puberty and
between 4th and 6th decade1,2
• A significant proportion of
patients are above 65 years
of age2
Epidemiology: demographics
*Statement number: 1
1. Grønbæk L, et al. J Hepatol 2014;60:612–7;
EASL CPG AIH. J Hepatol 2015;63:971–1004
Danish nationwide patient registry1
Guideline statement*,2
AIH can affect all populations and all age groups II-2
Grade of recommendation
A. Epatica
Biliary diseases
ICP
PFIC/BRIC
HBV/HCV
Drugs
Hormones
Alcoholic hepatitis
PBC
PSC
Cholangiocarcinoma
Hilary lymphadenopathy
Extrahepatic tumours
Biliary atresia
PBCPrevalence 0.6-40/100,000
Gender F>M, 10:1
Bile ducts: interlobular
PSCPrevalence 0.2-14/100,000
Gender F<M 1:2
Intra/extrahepatic bile ducts
PBC
Autoimmunity
PSCIBD
Autoimmunity
Cancer
Gender differences in PBC & PSC
PBCPrevalence 0.6-40/100,000
Gender F>M, 10:1
Bile ducts: interlobular
PSCPrevalence 0.2-14/100,000
Gender F<M 1:2
Intra/extrahepatic bile ducts
Shared hepatic features
Cholestatic liver disease
Pruritus
Fatigue
Features of AIH (~10%)
Gender differences in PBC & PSC
Hallmarks of PBC/PSC: unspecific
exact target of autoimmunity:
hepatocytes, suggesting AIH, bile
duct cells, suggesting a
cholangitis, or by both
hepatocytes and biliary cells,
suggesting an overlap syndrome.
Lymphocitic cholangitis
Periductal concentric fibrosis
PBCHeritability: ls ~10-54
Environmental factors:
smoking ( )
cosmetics ?
infectious trigger ?
PSCHeritability: ls ~9-39
Environmental factors:
smoking (protects)
infectious trigger?
Genetic factors Genetic factors
Gender differences in PBC & PSC
Shared and unique genetic risk
PBCPSC
Influence of Gender and Age in Biochemical
Response to UDCA in PBC
Carbone et al, Gastroenterology 2013; 144: 560-569
Pa
tie
nts
wit
h R
es
po
nse
to
UD
CA
at
2 Y
ea
rs (
%)
80
P<.05
72
<50%
Response
Rate
<30 Years at Diagnosis
90%
Response
Rate
>70 Years at Diagnosis
Author Year Country N. of patients F:M Methodology
Prince3 2001 UK 770 8:1 Case finding
Sood4 2004 Australia 249 9:1 Case finding
Sakauchi5 2005 Japan 9,761 9:1 Case finding
Myers6 2009 Canada 137 5:1 Administrative data
Floreani7 2011 Italy 327 17:1 Prospective cohort
LLeo8 2011 Italy
(Lombardy)
2,970 2.3:1 Administrative data
Lleo8 2011 Denmark 722 4.2:1 Administrative data
Kanth7 2017 USA 71 19:1 Case finding
Lu8 2018 USA 3,408 3.9:1 Data records
Marschall9 2019 Sweden 5,350 4:1 Administrative data
Marzioni11 2019 Italy 412 4.5:1 Data records
SURVIVAL0
.25
.5.7
5
1
0 12 24 36 48 60 72 84 96 108 120months
138 90 72 56 43 29 21 15 10 2 0Maschi584 485 401 340 278 230 177 120 78 40 3Femmine
Number at risk
95% CI 95% CI
Female Male
Survival from diagnosis
0
.25
.5.7
5
1
0 12 24 36 48 60 72 84 96 108 120months
897 627 516 442 382 324 273 230 173 120 64Maschi2073 1746 1561 1409 1252 1066 912 753 608 432 233Femmine
Number at risk
95% CI 95% CI
Female Male
Survival from diagnosis
DENMARK LOMBARDIA
2016
Male sex (N=123/4565)
PSC modeled as a chronic liver disease
•Dominant stricture
•Cholangitis
•Cirrhosis
•Portal hypertension
•ESLD
•Cholangiocarcinoma
•IBD
•Colon cancer
Pre-symptomatic
Symptomatic
Irreversible damage
Birth Death
Variables significantly correlated with survival
Symptomatic vs asymptomatic pts
Dominant strictures
Small duct variant
AIH/PSC overlap variant
IgG4 variant
Variability disease course
Broomè 1996
Asymptomatic better prognosis
Tishendorf 2007
In PSC with dominant stenosis, IBD is associated with an
increase in carcinomas
N=171 pts with a prospective follow-up of 20 years
Rudolph G et al. J Hepatol 2010
Dominant stricture = stenosis with a diameter <1.5 mm in the common bile duct
or <1 mm in the hepatic duct
Small-duct PSC
Bjornsson et al, Gut 2002
N=33 vs n=260 with large
duct PSC [Oxford and Oslo]
Median follow-up: 106 vs
105 months
Bjornsson et al, Gastroenterology 2008
N=83 vs n=166 with large
duct PSC [Europe and USA]
Median follow-up: 11 yrs
AIH/PSC (# 10) Classical PSC (# 69) p
Mean age 23.4 ± 8.5 33 ± 13.8 <0.05
Male:female ratio 5:5 37:32 n.s.
AST (U/L) 177.3 ± 52.8 77 ± 37.3 <0.0001
ALT (U/L) 299.5 ± 25.2 111 ± 145.5 <0.01
ALP (U/L) 270.2 ± 179.6 216 ± 204.9 0.976 n.s.
GGT (U/L) 285.9 ± 374.2 216 ± 204.9 0.371 n.s.
Tot bilirubin (mg/dL) 1.5 ± 1.1 2 ± 6 0.811 n.s.
Albumin (g/dL) 4.1 ± 0.3 4.1 ± 0.4 0.791 n.s.
PT (%) 88.9 ± 8.2 91 ± 16.5 0.4745 n.s.
IgG (g/L) 24.7 ± 4.1 16 ± 3 <0.0001
IgA (g/L) 2 ± 1 1.2 ± 0.9 <0.05
IgM (g/L) 3.4 ± 1.4 2 ± 1.1 0.176 n.s.
HCV + 0 (0%) 4 (5%) n.s.
IBD 2 (20%) 32 (46.4%) <0.01
Clinical features at presentation
Antoniazzi S et al, Monotematica AISF 2010
300250200150100500
1,0
0,8
0,6
0,4
0,2
0,0
CU
MU
LA
TIV
E S
UR
VIV
AL
FOLLOW-UP (months)
• Global median survival 272.7 (CI 95%: 219.9-325.4)• Cumulative probability of survival at 240 months: PSC 73.6%
AIH/PSC 87.5%
AIH/PSCPSC
Kaplan-Meier survival curves
Antoniazzi S et al, Monotematica AISF 2010
Endoscopic surveillance of PSC-associated IBD
ESGE/EASL CPG Endoscopy in PSC. J Hepatol 2017;66:1265–81
• Risk of CRC in PSC-associated IBD makes it crucial to perform
a full ileocolonoscopy at the time of PSC diagnosis in all patients
– Follow-up based on findings
• Endoscopic surveillance of PSC-associated colitis is presumed to increase the chance of
early detection of dysplasia or malignancy
Recommendations
Screening ileocolonoscopy at PSC diagnosis is
recommendedStrong High
If IBD is documented endoscopically or histologically, annual
surveillance colonoscopies are warrantedStrong Low
If no IBD is documented, consider next ileocolonoscopy at 5 years
or whenever bowel complaints suggestive of IBD occurWeak Low
Ileocolonoscopy with four-quadrant biopsies from all colonic
segments and the terminal ileum is recommendedStrong Low
Ileocolonoscopy with dye-based chromoendoscopy with
targeted biopsies is recommended for dysplasia surveillance
of
PSC-associated IBD
Strong Low
Strength of recommendation Quality of evidence
Shah SC et al, Clin Gastroenterol Hepatol 2018
• Longitudinal study in Netherland and UD in patients who underwent more that 2 surveillancecolonoscopy
• Investigation on factors associated with advenced colo-rectal cancer
The rate of colo-rectal neoplasia following the diagnosisof low grade dysplasia was significantly higher in patients with PSC-IBD than patients with IBD alone
PRIMARY SCLEROSING CHOLANGITIS FROM A GLOBAL PERSPECTIVE
A MULTICENTER, RETROSPECTIVE, OBSERVATIONAL STUDY OF THE
INTERNATIONAL PSC STUDY GROUP
T.J. Weismüller1,2, J.A. Talwalkar3, C.Y. Ponsioen4, D.N. Gotthardt5, H.-U. Marschall6, S. Naess7, K. Holm7, R.K. Weersma8, K.N. Lazaridis3,
J. Fevery9, P.J. Trivedi10, C. Schramm11, O. Chazouilleres12, T. Müller13, M. Farkkila14, S. Almer15,16, S. Pereira17, A.L. Mason18, A. Floreani19,
P. Milkiewicz20, C. Levy32, H. Harley21, A. Pares22, L. de Vries4, C.N. Manser23, D. Huynh21, E. Rauws4, G. Dalekos24, N. Gatselis24, C.
Berg25, H. Lenzen2, M. Benito de Valle6, M. Imam3, G. Kirchner26, P. de Leuw27, V. Zimmer28, L. Fabris19, F. Braun29, P.L. Jansen4, G.M.
Hirschfield10, M. Marzioni30, P. Invernizzi31, B.D. Juran3, C.P. Strassburg1,2, U. Beuers4, M.P. Manns2, E. Schrumpf7, T.H. Karlsen7, A.
Bergquist16, K.M. Boberg7
International PSC Study Group
1Department of Internal Medicine 1, University of Bonn, Bonn, Germany 2Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School,
Hannover, Germany, 3Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States, 4Department of Gastroenterology and Hepatology,
Academic Medical Center, Amsterdam, Netherlands, 5Department of Internal Medicine, University Hospital of Heidelberg, Heidelberg, Germany, 6Department
of Molecular and Clinical Medicine, Sahlgrenska Academy,University of Gothenburg, Gothenburg, Sweden, 7Norwegian PSC Research Center, Oslo University Hospital
Rikshospitalet, Oslo, Norway, 8Department of Gastroenterology and Hepatology, University Medical Center Groningen and University of Groningen, Groningen,
Netherlands, 9Department of Hepatology, University Hospital Gasthuisberg, Leuven, Belgium, 10NIHR Biomedical Research Unit and Centre for Liver Research,
University of Birmingham, Birmingham, United Kingdom, 111st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 12Service
d'Hépatologie, Hôpital Saint Antoine, Assistance Publique-Hôpitaux de Paris,Faculté de Médecine Pierre et Marie Curie, Paris, France, 13Department of Internal
Medicine, Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Berlin, Germany, 14Division of Gastroenterology, Department of Medicine, Helsinki
University Central Hospital, Helsinki, Finland, 15Gastroenterology & Hepatology, Linköping University, Linköping, 16Division of Gastroenterology and Hepatology,
Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden, 17UCL Institute for Liver and Digestive Health, London, United Kingdom, 18Division
of Gastroenterology and Hepatology, University of Alberta, Edmonton, AB, Canada, 19Department of Surgical, Oncological and Gastroenterological Sciences,
University of Padova, Padova, Italy, 20Liver Unit and Liver Research Laboratories, Pomeranian Medical University, Szczecin, Poland, 21Department of
Gastroenterology and Hepatology, Royal Adelaide Hospital, Adelaide, SA, Australia, 22Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Spain, 23Division
for Gastroenterology and Hepatology, University Hospital Zurich (USZ), Zürich, Switzerland, 24Department of Medicine and Research Laboratory of Internal Medicine,
University Hospital of Larissa, University of Thessaly, Larissa, Greece, 25Department of Gastroenterology, Hepatology, and Infectiology, Medical Clinic, University of
Tübingen, Tübingen, 26Department of Internal Medicine I, University Hospital of Regensburg, Regensburg, 27Department of Internal Medicine 1, Johann Wolfgang
Goethe-University Hospital, Frankfurt, 28Saarland University Medical Center, Homburg, 29UKSH, Campus Kiel, Kiel, Germany, 30Department of Gastroenterology,
Università Politecnica delle Marche, Ancona, Italy, 31 Center for Aotoimmune Liver Diseases, Humaitis Clinical and Research Center, Rozzano (MI), Italy, 32Center for
Liver Diseases University of Miami, Miami, Florida, United States
North America
Edmonton
Miami
Rochester
Western Europe
Amsterdam
Birmingham
Groningen
Leuven
London
Paris
Southern Europe
Ancona
Barcelona
Larissa
Milano
Padua
Australia
Adelaide
Northern Europe
Gothenburg
Helsinki
Linköping
Oslo
Stockholm
Central Europe
Berlin
Bonn
Frankfurt
Hamburg
Hannover
Heidelberg
Homburg
Kiel
Regensburg
Szczecin
Tübingen
Zürich
20,0%
24,6%
20,4%
2,3%
32,2%
0,5%
Resultsoverall
N 6205
%male 65.1%
age at dg PSC 40.4
sdPSC 4.2%
PSC+AIH 6.4%
IBD 68.7%
UC 54.6%
CD 11,5%
IC 2.6%
Colorectal carcinoma 4% (8.9%)
Hepatobil malignancy 11.9%
CCA 10.3%
GB-Ca 0.9%
HCC 0.7%
Liver-Transpl 20.9%
Overall-Tx-free-survival 65.6%
» Data on 8212 patients submitted
» after exclusion of patients who did not
meet the inclusion criteria or had
insufficient follow-up information 6205
patients remained
» Mean follow-up time: 21 years
Pancreatic Ca: 0.2%
0 2 4 6 10 15 20 25
Years after 1st diagnosis PSC
CCA Incidence
Long standing UC in PSC patients is a predisposing condition for the
development of colon cancer (Broome U et al, Hepatology 1995; Kornfeld D et
al, Gut 1997, Brentnall TA, et al, Gastroenterology 1996)
Development of colon cancer pre-OLTx
Colo-rectal cancer in PSC
without IBD:
10 years: 2%
20 years: 2%
Colo-rectal cancer in PSC +
IBD:
10 years 14%
20 years: 31%
Claessen M et al, J Hepatol 2009
• Immuno – mediatedfibroinflammatory condition
• Links many disorderspreviously regarded asisolated, single-organ diseaseswithout any known underlyingsystemic condition
Histopathology is the key to diagnosis, 3 central pathology features• lymphoplasmacytic infiltration (A) • storiform fibrosis (B)• obliterative phlebitis (C)
Generally responds to immunosuppressive therapies
IgG4 Sclerosing Cholangitis
Nakazawa T et al, World J Gastroenterol 2013
Clinical profile older (mean age 62 yrs)men (85%) presenting with obstructive
jaundice (77%) associated with AIP (92%) abundant IgG4 infiltrate in
biopsy duct specimens (88%) normalization of liver enzymes
with steroids (61%)
IgG4 –SC cholangiographic classification and differential diagnosis
Nakazawa T et all, World J Gastroenterolog 2013
Nakazawa et al, Semin Liver Dis 2016
IgG4-SC vs PSC
Worldwide prevalence of GS in females
based on US surveys
Stinton LM & Shaffer E, Gut and Liver 2012
FAIR FAT FORTY FEMALE
Those who are most at risk
Prevalence of GD according to AGE
Festi D et al, WJG 2008
Biliary sludge and GS during pregnancy
Ko CW, et al, Hepatology 2005
Benign
Recurrent
Intrahepatic
Cholestasis
normal gGT high gGT
PFIC 1
Byler Disease
• Amish
PFIC 2
Byler Syndrome
• Middle Eastern
PFIC 3
18q21-22 2q24
Intrahepatic
Cholestasis
Pregnancy
7q21
Persistent Familial Intrahepatic Cholestasis
Colestasi genetiche
Phospholipids
MDR3
MultiDrugResistancegene product
Davit-Spraul A et al Sem Liver Dis 2010
Phospholipids
MDR3
MultiDrugResistancegene product
MDR deficiency
Progressive familial
intrahepatic cholestasis
type 3 (PFIC3)
Low phospholipids-
Associated cholestasis
(LPAC)
ICP type 3
BRIC3
Drug-induced liver
injury
Transient neonatal
cholestasis
Davit-Spraul A et al Sem Liver Dis 2010
LPAC syndrome Classical gallstone
diseaseAge at onset of symptoms Before 30 years After 45 years
Associate conditions Conditions linked to
ABCB4 mutations
Metabolic syndrome
Female/male ratio 3:1 1.5:1Family history Symptomatic intrahepatic
lithiasis in first-degree
relatives
Gallstones frequent in
relatives
Imaging Gallstones and
intrahepatic lithiasis
Gallstones
Intrahepatic cholestasis of
pregnancy (female patients)50% of cases Rare
Complications (pancreatitis,
cholangitis, migration of
calculi)
Frequent Rare
Recurrence of pain after
cholecystectomyFrequent Very rare
Clinical characteristics of LPAC syndrome in
comparison with classical gallstone disease
A. Floreani & C. Corpechot in press