Autoantibodies in Liver Disease

Primary Sclerosing

Cholangitis (PSC)

Robert G. Gish, M.D

Medical Director Liver Transplant Program

California Pacific Medical Center

San Francisco, California, USA

Frequencies of the Variant

Syndromes in Autoimmune

Chronic Liver Disease

Variant

types

clinical diagnoses

AIH

(n = 162)

PBC

(n = 37)

PSC

(n = 26)

Total patients

(N = 225)

AIH + PBC

AIH + PSC

autoimmune

cholangitis

total variants

8 (5)

0 (0)

11 (7)

19 (12)*

7 (19)

0 (0)

7 (19)†

0 (0)

14 (54)

0 (0)

14 (54)*†

15 (7)

14 (6)

11 (5) 40

(18)

Note: numbers in parentheses are percentages

* p = .000004

† p = .006

Czaja, Hepatology 1998; 28:362

Aggregate Scores in 114 PSC Patients

According to a Scoring Table for the

Diagnosis of AIH

classification

definite AIH

probable AIH

not AIH

>15

5-9

2 (2)

0 (0)

2 (2)

7 (6)

10 (9)

12 (11)

55 (48)

19 (17)

score

no of patients (%)

Note: scores represent values before evaluation of response to

therapy

Boberg et al., Hepatology 1996;23:1372

Anti-Neutrophil Cytoplasmic

Antibodies

Lysosomes

Vasculitis

Wegeners granulomatosis

Polyarteritis nodosa

Churg Straus

•

Cytoplasmic ANCA

proteinase 3

Crescentic

Glomerulonephritis

•

Perinuclear ANCA

myeloperoxidase

Inflammatory disorders

Sclerosing cholangitis

Ulcerative colitis

•

Atypical ANCA

? Cathepsin G

? b-glucoronidase

? lactoferin

AIH PBC

Rheumatoid Arthritis

Infections

Mycobacteria HIV

Bacterial endocarditis

Neoplastic disease

Colon cancer Small cell bronchial cancer

Atrial myxoma Hypernephroma Myelodysplasia

Diagnosis PBC vs PSC

PBC

PSC

Young males

Middle aged females

Young males

Middle aged females

CholagioCa

HCC

IBD

Sjogren’s

Bile duct strictures

Florid duct lesion

ANCA vs

AMA

IgM

Pigmentation

Fever

HLA Association with

Autoimmune Liver Disease

Class I Class II Class III Haplotype Amino Acids

AIH

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

RR X 3 RR X 3 DR



95% UK

PSC

A1 B8 DR3 & DR4 A1 B8 DR3

DR52A

RR X 3

PBC

NR DR8 DPB1 C4B DR8 C4A Q0 leucine aa 35

DR2 DR3 DR4 C4A Q0 RR X 184 DR



95% Japan

Sclerosing Cholangitis

Industrializ

countries

sex

IBD

PSC

DR52, DR2

Congenital

Immunodeficiency

syndromes

Intra-arterial

floxuridine

CMV HIV

cryptosporidia

cryptococcus

Primary Sclerosing

Cholangitis

•

Diffuse inflammation

and fibrosis of extra-

hepatic bile ducts

with and without

intra-hepatic biliary

disease

•

ANCA: nonspecific

•

Absence of

–

biliary cholelithiasis

–

biliary tract surgery

–

cholangiocarcinoma

Overlap Syndromes

AMA neg PBC with

normal cholangiogram

AMA neg PBC with

normal cholangiogram

Autoantibody negative

idiopathic hepatitis

Autoantibody negative

idiopathic hepatitis

AIH

HCV

PSC

PBC

Cryptogenic

hepatitis

Autoimmune

cholangitis

2-8%

6-25%

10-20%

11%

10%

Overlap/Variant

Syndromes

Classic

AIH

HCV

PSC

Cryptogenic

hepatitis

Autoimmune

cholangitis

2-8%

6-25%

1-2%

11%

10%

Granulomatous

Hepatitis

PBC

Vanishing Bile

Duct Syndrome

Giant Cell Hepatitis

Mild

idiopathic

ductopenia

of adulthood

AMA neg

PBC

with

normal ERCP

Autoantibody

negative

idiopathic

hepatitis

Fatty Liver

with

autoantibodies

Central Venulitis

Eosinophilic Hepatitis

Overlap/Variant

Syndromes Simplified

AIH

HCV infection

extrahepatic

syndromes

ALKM ANA ASMA

cryptogenic

hepatitis

PBC

phenotype

hepatitis

predominant

AMA neg

PBC

AIC

AIH

PSC

phenotype

hepatitis

predominant



children

AIH

PSC

HCV

AIH

HIV

gag

Reactivity in Liver

Disease

100

HIV Western blot studies

singular HIV p24 reactivity

Healthy Donors

n = 175

ALD and A-1 AT

n = 24

HCV

n = 13

HBV

n = 15

PSC

n = 19

PBC

n = 77

Sjogrens

n = 47

HIAP Western Blots in Liver

Disease

100

HIAP retrovirus derived from Sjogren’s syndrome pts



2 HIAP bands  1 HIAP band

Healthy Donors

n = 105

ALD and A-1 AT

n = 24

HCV

n = 53

HBV

n = 75

PSC

n = 19

PBC

n = 72

Sjogrens

n = 190

HIAP Immunoblots in Liver Disease

100

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP Western blot reactivity to  2 HIAP bands

Healthy Donors

n = 105

ALD and A-1 AT

n = 24

HCV

n = 53

HBV

n = 75

PSC

n = 19

PBC

n = 72

Sjogrens

n = 190

HIAP Western Blots in Liver

Disease

HIAP retrovirus derived from Sjogren’s syndrome pts

HIAP Western blot reactivity  1 HIAP band

ALD and A-1 AT

n = 24

HCV

n =

HBV

n =

PSC

n =

PBC

n =

Congentital and Neonatal

Vanishing Bile Duct

Syndromes

•

Extrahepatic

Biliary Atresia

•

Intrahepatic

–

Alagille syndrome

–

Infections

Reovirus CMV

–

Bylers

–



-1-antitrypsin

–

Mucoviscidosis

–

Trisomy 21

–

Hypopituitarism

–

Trihydroxycoprostanic acidemia

•

Primary Biliary Cirrhosis

•

Sarcoidosis

•

Sclerosing Cholangitis

–

Primary Sclerosing cholangitis

–

Histiocytosis X, IgA deficiency,

hupogammaglobulinemia, immunodeficiency states

–

Autoimmune cholangiopathy

autoimmune hepatitis

–

HIV Cholangiopathy

CMV and

Cryptosporidiosis

–

Small bowel bacterial overgrowth and septicemia

Acquired Vanishing Bile Duct

Syndromes

•

Transplantation

–

Graft Verses Host DIsease

–

Liver Allograft Rejection

•

Oriental Cholagiohepatitis

Clonorchis

sinensis

•

Drug-induced and Toxic Cholangitis

–

Hepatic artery infusion with 5-fluorodeoxyuridine

–

Hydatid cyst treatment with formaldehyde

–

Thiabendazole Amitriptiline Trioleandomycin

Chlorpropramide Erythromycin Prochloroperazine

Chlorythromycin Tolbutamide

Acquired Vanishing Bile Duct

Syndromes

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