Primary Sclerosing

Primary Sclerosing

Cholangitis (PSC)

Cholangitis (PSC)

Robert G. Gish, M.D

Robert G. Gish, M.D

Medical Director Liver Transplant Program

Medical Director Liver Transplant Program

California Pacific Medical Center

California Pacific Medical Center

San Francisco, California, USA

San Francisco, California, USA

Frequencies of the Variant

Frequencies of the Variant

Syndromes in Autoimmune

Syndromes in Autoimmune

Chronic Liver Disease

Chronic Liver Disease

Variant

Variant

types

types

clinical diagnoses

clinical diagnoses

AIH

AIH

(n = 162)

(n = 162)

PBC

PBC

(n = 37)

(n = 37)

PSC

PSC

(n = 26)

(n = 26)

Total patients

Total patients

(N = 225)

(N = 225)

AIH + PBC

AIH + PBC

AIH + PSC

AIH + PSC

autoimmune

autoimmune

cholangitis

cholangitis

total variants

total variants

8 (5)

8 (5)

0 (0)

0 (0)

11 (7)

11 (7)

19 (12)*

19 (12)*

7 (19)

7 (19)

0 (0)

0 (0)

0 (0)

0 (0)

7 (19)†

7 (19)†

0 (0)

0 (0)

14 (54)

14 (54)

0 (0)

0 (0)

14 (54)*†

14 (54)*†

15 (7)

15 (7)

14 (6)

14 (6)

11 (5) 40

11 (5) 40

(18)

(18)

Note: numbers in parentheses are percentages

Note: numbers in parentheses are percentages

* p = .000004

* p = .000004

† p = .006

† p = .006

Czaja, Hepatology 1998; 28:362

Czaja, Hepatology 1998; 28:362

Aggregate Scores in 114 PSC Patients

Aggregate Scores in 114 PSC Patients

According to a Scoring Table for the

According to a Scoring Table for the

Diagnosis of AIH

Diagnosis of AIH

classification

classification

definite AIH

definite AIH

probable AIH

probable AIH

not AIH

not AIH

>15

>15

15

15

14

14

13

13

12

12

11

11

10

10

5-9

5-9

<5

<5

2 (2)

2 (2)

0 (0)

0 (0)

2 (2)

2 (2)

7 (6)

7 (6)

7 (6)

7 (6)

10 (9)

10 (9)

12 (11)

12 (11)

55 (48)

55 (48)

19 (17)

19 (17)

score

score

no of patients (%)

no of patients (%)

Note: scores represent values before evaluation of response to

Note: scores represent values before evaluation of response to

therapy

therapy

Boberg et al., Hepatology 1996;23:1372

Boberg et al., Hepatology 1996;23:1372

Anti-Neutrophil Cytoplasmic

Anti-Neutrophil Cytoplasmic

Antibodies

Antibodies

Lysosomes

Lysosomes

Vasculitis

Vasculitis

Wegeners granulomatosis

Wegeners granulomatosis

Polyarteritis nodosa

Polyarteritis nodosa

Churg Straus

Churg Straus

•

Cytoplasmic ANCA

Cytoplasmic ANCA

proteinase 3

proteinase 3

Crescentic

Crescentic

Glomerulonephritis

Glomerulonephritis

•

Perinuclear ANCA

Perinuclear ANCA

myeloperoxidase

myeloperoxidase

Inflammatory disorders

Inflammatory disorders

Sclerosing cholangitis

Sclerosing cholangitis

Ulcerative colitis

Ulcerative colitis

•

Atypical ANCA

Atypical ANCA

? Cathepsin G

? Cathepsin G

? b-glucoronidase

? b-glucoronidase

? lactoferin

? lactoferin

AIH PBC

AIH PBC

Rheumatoid Arthritis

Rheumatoid Arthritis

Infections

Infections

Mycobacteria HIV

Mycobacteria HIV

Bacterial endocarditis

Bacterial endocarditis

Neoplastic disease

Neoplastic disease

Colon cancer Small cell bronchial cancer

Colon cancer Small cell bronchial cancer

Atrial myxoma Hypernephroma Myelodysplasia

Atrial myxoma Hypernephroma Myelodysplasia

Diagnosis PBC vs PSC

Diagnosis PBC vs PSC

PBC

PSC

Young males

Young males

vs

vs

Middle aged females

Middle aged females

Young males

Young males

vs

vs

Middle aged females

Middle aged females

CholagioCa

CholagioCa

vs

vs

HCC

HCC

IBD

IBD

vs

vs

Sjogren’s

Sjogren’s

Bile duct strictures

Bile duct strictures

Florid duct lesion

Florid duct lesion

ANCA vs

ANCA vs

AMA

AMA

IgM

IgM

Pigmentation

Pigmentation

Fever

Fever

HLA Association with

HLA Association with

Autoimmune Liver Disease

Autoimmune Liver Disease

Class I Class II Class III Haplotype Amino Acids

Class I Class II Class III Haplotype Amino Acids

AIH

AIH

A1 B8 DR3 & DR4 C4A del. A1 B8 DR3 leucine aa 71

A1 B8 DR3 & DR4 C4A del. A1 B8 DR3 leucine aa 71

RR X 3 RR X 3 DR

RR X 3 RR X 3 DR





95% UK

95% UK

PSC

PSC

A1 B8 DR3 & DR4 A1 B8 DR3

A1 B8 DR3 & DR4 A1 B8 DR3

DR52A

DR52A

RR X 3

RR X 3

PBC

PBC

NR DR8 DPB1 C4B DR8 C4A Q0 leucine aa 35

NR DR8 DPB1 C4B DR8 C4A Q0 leucine aa 35

DR2 DR3 DR4 C4A Q0 RR X 184 DR

DR2 DR3 DR4 C4A Q0 RR X 184 DR





95% Japan

95% Japan

Sclerosing Cholangitis

Sclerosing Cholangitis

Industrializ

Industrializ

ed

ed

countries

countries

sex

sex

IBD

IBD

PSC

PSC

DR52, DR2

DR52, DR2

Congenital

Congenital

Immunodeficiency

Immunodeficiency

syndromes

syndromes

Intra-arterial

Intra-arterial

floxuridine

floxuridine

CMV HIV

CMV HIV

cryptosporidia

cryptosporidia

cryptococcus

cryptococcus

Primary Sclerosing

Primary Sclerosing

Cholangitis

Cholangitis

•

Diffuse inflammation

Diffuse inflammation

and fibrosis of extra-

and fibrosis of extra-

hepatic bile ducts

hepatic bile ducts

with and without

with and without

intra-hepatic biliary

intra-hepatic biliary

disease

disease

•

ANCA: nonspecific

ANCA: nonspecific

•

Absence of

Absence of

–

biliary cholelithiasis

biliary cholelithiasis

–

biliary tract surgery

biliary tract surgery

–

cholangiocarcinoma

cholangiocarcinoma

Overlap Syndromes

Overlap Syndromes

AMA neg PBC with

AMA neg PBC with

normal cholangiogram

normal cholangiogram

AMA neg PBC with

AMA neg PBC with

normal cholangiogram

normal cholangiogram

Autoantibody negative

Autoantibody negative

idiopathic hepatitis

idiopathic hepatitis

Autoantibody negative

Autoantibody negative

idiopathic hepatitis

idiopathic hepatitis

AIH

AIH

HCV

HCV

PSC

PSC

PBC

PBC

Cryptogenic

Cryptogenic

hepatitis

hepatitis

Autoimmune

Autoimmune

cholangitis

cholangitis

2-8%

2-8%

6-25%

6-25%

10-20%

10-20%

11%

11%

10%

10%

Overlap/Variant

Overlap/Variant

Syndromes

Syndromes

Classic

Classic

AIH

AIH

HCV

HCV

PSC

PSC

Cryptogenic

Cryptogenic

hepatitis

hepatitis

Autoimmune

Autoimmune

cholangitis

cholangitis

2-8%

2-8%

6-25%

6-25%

1-2%

1-2%

11%

11%

10%

10%

Granulomatous

Hepatitis

PBC

PBC

Vanishing Bile

Duct Syndrome

Giant Cell Hepatitis

Mild

idiopathic

ductopenia

of adulthood

AMA neg

AMA neg

PBC

PBC

with

with

normal ERCP

normal ERCP

Autoantibody

Autoantibody

negative

negative

idiopathic

idiopathic

hepatitis

hepatitis

Fatty Liver

with

autoantibodies

Central Venulitis

Eosinophilic Hepatitis

Overlap/Variant

Overlap/Variant

Syndromes Simplified

Syndromes Simplified

AIH

AIH

HCV infection

HCV infection

extrahepatic

extrahepatic

syndromes

syndromes

ALKM ANA ASMA

ALKM ANA ASMA

cryptogenic

cryptogenic

hepatitis

hepatitis

=

=

PBC

PBC

phenotype

phenotype

-

-

hepatitis

hepatitis

predominant

predominant

AMA neg

AMA neg

PBC

PBC

AIC

AIC

AIH

AIH

PSC

PSC

phenotype

phenotype

-

-

hepatitis

hepatitis

predominant

predominant





 

 

children

children

AIH

AIH

PSC

PSC

HCV

HCV

AIH

AIH

HIV

HIV

gag

gag

Reactivity in Liver

Reactivity in Liver

Disease

Disease

0

20

40

60

80

100

%

HIV Western blot studies

HIV Western blot studies

singular HIV p24 reactivity

singular HIV p24 reactivity

Healthy Donors

Healthy Donors

n = 175

n = 175

ALD and A-1 AT

ALD and A-1 AT

n = 24

n = 24

HCV

HCV

n = 13

n = 13

HBV

HBV

n = 15

n = 15

PSC

PSC

n = 19

n = 19

PBC

PBC

n = 77

n = 77

Sjogrens

Sjogrens

n = 47

n = 47

HIAP Western Blots in Liver

HIAP Western Blots in Liver

Disease

Disease

0

20

40

60

80

100

%

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

 

 

2 HIAP bands  1 HIAP band

2 HIAP bands  1 HIAP band

Healthy Donors

Healthy Donors

n = 105

n = 105

ALD and A-1 AT

ALD and A-1 AT

n = 24

n = 24

HCV

HCV

n = 53

n = 53

HBV

HBV

n = 75

n = 75

PSC

PSC

n = 19

n = 19

PBC

PBC

n = 72

n = 72

Sjogrens

Sjogrens

n = 190

n = 190

HIAP Immunoblots in Liver Disease

HIAP Immunoblots in Liver Disease

0

20

40

60

80

100

%

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP Western blot reactivity to  2 HIAP bands

HIAP Western blot reactivity to  2 HIAP bands

Healthy Donors

Healthy Donors

n = 105

n = 105

ALD and A-1 AT

ALD and A-1 AT

n = 24

n = 24

HCV

HCV

n = 53

n = 53

HBV

HBV

n = 75

n = 75

PSC

PSC

n = 19

n = 19

PBC

PBC

n = 72

n = 72

Sjogrens

Sjogrens

n = 190

n = 190

HIAP Western Blots in Liver

HIAP Western Blots in Liver

Disease

Disease

0

20

40

60

80

%

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP Western blot reactivity  1 HIAP band

HIAP Western blot reactivity  1 HIAP band

ALD and A-1 AT

ALD and A-1 AT

n = 24

n = 24

HCV

HCV

n =

n =

53

53

HBV

HBV

n =

n =

75

75

PSC

PSC

n =

n =

19

19

PBC

PBC

n =

n =

72

72

Congentital and Neonatal

Congentital and Neonatal

Vanishing Bile Duct

Vanishing Bile Duct

Syndromes

Syndromes

•

Extrahepatic

Extrahepatic

Biliary Atresia

Biliary Atresia

•

Intrahepatic

Intrahepatic

–

Alagille syndrome

Alagille syndrome

–

Infections

Infections

Reovirus CMV

Reovirus CMV

–

Bylers

Bylers

–





-1-antitrypsin

-1-antitrypsin

–

Mucoviscidosis

Mucoviscidosis

–

Trisomy 21

Trisomy 21

–

Hypopituitarism

Hypopituitarism

–

Trihydroxycoprostanic acidemia

Trihydroxycoprostanic acidemia

•

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis

•

Sarcoidosis

Sarcoidosis

•

Sclerosing Cholangitis

Sclerosing Cholangitis

–

Primary Sclerosing cholangitis

Primary Sclerosing cholangitis

–

Histiocytosis X, IgA deficiency,

Histiocytosis X, IgA deficiency,

hupogammaglobulinemia, immunodeficiency states

hupogammaglobulinemia, immunodeficiency states

–

Autoimmune cholangiopathy

Autoimmune cholangiopathy

autoimmune hepatitis

autoimmune hepatitis

–

HIV Cholangiopathy

HIV Cholangiopathy

CMV and

CMV and

Cryptosporidiosis

Cryptosporidiosis

–

Small bowel bacterial overgrowth and septicemia

Small bowel bacterial overgrowth and septicemia

Acquired Vanishing Bile Duct

Acquired Vanishing Bile Duct

Syndromes

Syndromes

•

Transplantation

Transplantation

–

Graft Verses Host DIsease

Graft Verses Host DIsease

–

Liver Allograft Rejection

Liver Allograft Rejection

•

Oriental Cholagiohepatitis

Oriental Cholagiohepatitis

Clonorchis

Clonorchis

sinensis

sinensis

•

Drug-induced and Toxic Cholangitis

Drug-induced and Toxic Cholangitis

–

Hepatic artery infusion with 5-fluorodeoxyuridine

Hepatic artery infusion with 5-fluorodeoxyuridine

–

Hydatid cyst treatment with formaldehyde

Hydatid cyst treatment with formaldehyde

–

Thiabendazole Amitriptiline Trioleandomycin

Thiabendazole Amitriptiline Trioleandomycin

Chlorpropramide Erythromycin Prochloroperazine

Chlorpropramide Erythromycin Prochloroperazine

Chlorythromycin Tolbutamide

Chlorythromycin Tolbutamide

Acquired Vanishing Bile Duct

Acquired Vanishing Bile Duct

Syndromes

Syndromes