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