Primary Biliary Cirrhosis and

Primary Biliary Cirrhosis and

Primary Biliary Hepatitis

Primary Biliary Hepatitis

(PBC)

(PBC)

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

Epidemiology PBC

Epidemiology PBC

•

Rare disease

Rare disease

–

0.6 - 2 % deaths from cirrhosis worldwide

0.6 - 2 % deaths from cirrhosis worldwide

–

Annual European incidence 7 - 75 per million Europe

Annual European incidence 7 - 75 per million Europe

•

Disease of civilization

Disease of civilization

–

Middle class women in industrialized countries

Middle class women in industrialized countries

–

Urban > Rural areas

Urban > Rural areas

•

Clustering of disease

Clustering of disease

–

Sweden

Sweden

Selenium deficiency

Selenium deficiency

–

England

England

Water supply

Water supply

–

“

“

Transmission” from patient to nurse

Transmission” from patient to nurse

–

Familial

Familial

Public Health Impact of

PBC in the US

•

Epidemiology of PBC in US

Epidemiology of PBC in US

*

*

–

Prevalence (1995): 400 per million (> 47,000 in US)

Prevalence (1995): 400 per million (> 47,000 in US)

–

Incidence: 27 per million (unchanged >2 decades)

Incidence: 27 per million (unchanged >2 decades)

•

Treatment options for PBC

Treatment options for PBC

–

Liver transplantation (OLT):

Liver transplantation (OLT):





survival

survival





and QOL

and QOL

**

**

–

Ursodeoxycholic acid:

Ursodeoxycholic acid:





time to death or OLT

time to death or OLT





•

The impact of these interventions on mortality and

The impact of these interventions on mortality and

health service utilization on a national scale is

health service utilization on a national scale is

unknown.

unknown.

*

*

Kim (Gastro, 2000

Kim (Gastro, 2000

in press

in press

)

)





Markus (NEJM, 1989)

Markus (NEJM, 1989)

**

**

Gross (Hepatology, 1999)

Gross (Hepatology, 1999)





Poupon (Gasto, 1997)

Poupon (Gasto, 1997)

Overall Mortality from PBC

and PSC

0

0.2

0.4

0.6

0.8

1

1980

1985

1990

1995

C

ru

d

e

d

ea

th

r

at

e

(/

10

0,

00

0)

PSC
PBC

NIH

NIH

consensus

consensus

conference

conference

on OLT

on OLT

Poupon’s

Poupon’s

NEJM paper

NEJM paper

on UDCA

on UDCA

PBC Presentation

PBC Presentation

•

40 - 60 year old middle class woman

40 - 60 year old middle class woman

–

95% AMA positive

95% AMA positive

•

Symptomatic

Symptomatic

–

Fatigue 70% or pruritus 70%

Fatigue 70% or pruritus 70%

–

Mild xerostomia or xero-ophthalmia 30 - 40 %

Mild xerostomia or xero-ophthalmia 30 - 40 %

( 72 - 100 % patients undergoing specific

( 72 - 100 % patients undergoing specific

testing )

testing )

–

Bili x 2 Alk Phos x 4 AST x 2

Bili x 2 Alk Phos x 4 AST x 2





 cholesterol

 cholesterol

•

Asymptomatic

Asymptomatic

–

Abnormal liver enzyme tests on routine

Abnormal liver enzyme tests on routine

screening predominantly elevated Alk Phos

screening predominantly elevated Alk Phos

–

Referred from Rheumatology or Endocrinology

Referred from Rheumatology or Endocrinology

Laboratory Values PBC

Laboratory Values PBC

Lab test

Normal

SymptomaticAsymptomatic

Alk Phos

87-250 IU/L

1695 IU/L

1395 IU/L

Tot Bili

< 1 mg/dl

4.4 mg/dl

0.9 mg/dl

AST

8-20 IU/L

85 IU/L

78 IU/L

Albumin

3.5-4.7 g/dl

3.5 g/dl

3.8 g/dl

Cholesterol

218-300 mg/dl

377 mg/dl

285 mg/dl

Triglycerides

101-150 mg/dl

133 mg/dl

96 mg/dl

Ig Total

0.8-1.6 g/dl

1.9 g/dl

2.1 g/dl

IgM

0.2-1.4 mg/ml

6.0 mg/ml

7.1 mg/ml

Pro Time

10-12 sec

11.3 sec

11.1 sec

ESR

< 40 mm/hr

65 mm/hr

56 mm/hr

Associated Diseases

Associated Diseases

PBC

PBC

0%

20%

40%

60%

80%

100%

Breast

Breast

cancer

cancer

Celiac

Celiac

disease

disease

UTIs

UTIs

RTA

RTA

Arthropathy

Arthropathy

Sjorgrens

Sjorgrens

Thyroiditis

Thyroiditis

Scleroderm

Scleroderm

a

a

4.4 x increase

4.4 x increase

HLA B8

HLA B8

vs 8 % control

vs 8 % control

urinary

urinary

acidification

acidification

100 %

100 %

by

by

Schrimer’s

Schrimer’s

CREST

CREST

NB Lichen planus

NB Lichen planus

Symptoms PBC

Symptoms PBC

% symptoms at presentation

% symptoms at presentation

0

10

20

30

40

50

60

70

fatigue
pruritis
dark urine

jaundice
light stools
easy bruising
weight loss

anorexia
bone pain

abdominal pain
gi bleeding
encephalopathy

Natural History of PBC

Natural History of PBC

Hepatic

Hepatic

failure

failure

0 - 2 years

0 - 2 years

AMA

IgM GT SymptomsSigns

2 - 10 years 2 - 20 years 3 - 11 years

florid duct ductular fibrosis

florid duct ductular fibrosis

cirrhosis

cirrhosis

lesion

lesion

proliferation

proliferation

Age in years 20 30 40 50 60 70

Age in years 20 30 40 50 60 70

Typical

Typical

symptoms none malaise itching jaundice

symptoms none malaise itching jaundice

Pathology

Pathology

Histologic stage i ii iii iv

Histologic stage i ii iii iv

fibrosis/cirrhosis

fibrosis/cirrhosis

number of bile ducts

number of bile ducts

PBC Histology

PBC Histology

NB nodular hyperplasia

NB nodular hyperplasia

•

Progressive non supporative destructive

Progressive non supporative destructive

cholangitis

cholangitis

0

20

40

60

80

100

120

granulomas
copper
cholestasis
florid lesions
decreased ducts

0

20

40

60

80

100

120

granulomas
copper
cholestasis
florid lesions
decreased ducts

florid duct ductular fibrosis

florid duct ductular fibrosis

cirrhosis

cirrhosis

lesion

lesion

proliferation

proliferation

% histologic features

% histologic features

copper

copper

vanishing ducts

vanishing ducts

cholestasis

cholestasis

florid duct lesion

florid duct lesion

granulomas

granulomas

I II III IV stage

I II III IV stage

Immune Related Disorders

Immune Related Disorders

•

Graft Versus Host Disease

Graft Versus Host Disease

–

Vanishing bile ducts syndrome

Vanishing bile ducts syndrome

–

OGDC peptide isolated as T cell epitope from

OGDC peptide isolated as T cell epitope from

allogeneic APC reactive to 2C lymphocyte

allogeneic APC reactive to 2C lymphocyte

clone

clone

•

Scleroderma

Scleroderma

–

anti-centromere antibodies with cholestatic

anti-centromere antibodies with cholestatic

liver disease

liver disease

–

extrahepatic disease CREST

extrahepatic disease CREST

•

Sarcoidosis

Sarcoidosis

–

AMA positive with cholestatic liver disease

AMA positive with cholestatic liver disease

–

extrahepatic disease

extrahepatic disease

Complications of PBC

Complications of PBC

•

End stage liver disease

End stage liver disease

–

Portal hypertension and GI hemorrhage

Portal hypertension and GI hemorrhage

»

Precirrhotic patients with nodular hyperplasia

Precirrhotic patients with nodular hyperplasia

–

Hepatocellular Cancer

Hepatocellular Cancer

rare???

rare???

•

Malabsorption

Malabsorption

–

Fat soluble vitamin deficiency

Fat soluble vitamin deficiency

–

Vit A Vit D Vit E

Vit A Vit D Vit E

•

Cholestyramine may reduce fat absorption

Cholestyramine may reduce fat absorption

–

Hepatic osteodystrophy

Hepatic osteodystrophy

»

osteoporosis > osteomalacia

osteoporosis > osteomalacia

•

Eye: scleral degeneration

Eye: scleral degeneration

•

Mouth: dental decay

Mouth: dental decay

Therapy for PBC

Therapy for PBC

•

Management of Complications

Management of Complications

–

Pruritis

Pruritis

Cholestyramine H 1 antagonists

Cholestyramine H 1 antagonists

–

Hyperlipidemia

Hyperlipidemia

Diet Statins

Diet Statins

–

Osteodystrophy

Osteodystrophy

Calcium Vit D

Calcium Vit D

•

Immunosuppressive and other agents

Immunosuppressive and other agents

–

Low efficacy and high toxicity

Low efficacy and high toxicity

»

corticosteroids azathiaprine D - penicillamine

corticosteroids azathiaprine D - penicillamine

chlorambucil colchicine cyclosporine A

chlorambucil colchicine cyclosporine A

•

Ursodeoxycholic Acid

Ursodeoxycholic Acid

–

Improves biochemistry

Improves biochemistry

–

Delays need for transplantation

Delays need for transplantation

•

Orthotopic Liver Transplantation

Orthotopic Liver Transplantation

PBC Physical

PBC Physical

Examination

Examination

•

Abdomen

Abdomen

–

Hepatomegaly 55%

Hepatomegaly 55%

–

Splenomegaly 33%

Splenomegaly 33%

–

Ascites 5%

Ascites 5%

•

Musculoskeletal

Musculoskeletal

–

Clubbing 8%

Clubbing 8%

–

Bone tenderness

Bone tenderness

rare

rare

•

Misc.

Misc.

–

Jaundice 55%

Jaundice 55%

–

Edema 5%

Edema 5%

0

10

20

30

40

50

60

Pigmentation
Spider Naevi
Excoriation
Xantholasmsa
Xanthoma

Skin Lesions

Skin Lesions

0.0

0.5

1.0

1.5

1980

1985

1990

1995

D

ea

th

r

at

e

(/

10

0,

00

0)

Age>65

Age<65

Age- and Gender-specific

Mortality from PBC

0.0

0.5

1.0

1.5

1980

1985

1990

1995

Age>65

Age<65

F

F

M

M

In-hospital Deaths from

PBC

-

100

200

300

400

500

600

700

800

900

89-91

92-94

95-97

N

o

. I

n

-h

o

sp

it

al

D

ea

th

s

>65
<65

Number of

Hospitalizations for PBC

-

1,000

2,000

3,000

4,000

5,000

6,000

7,000

89-91

92-94

95-97

N

o

. H

o

sp

it

al

iz

at

io

n

s

< 65

> 65

Total Days in Hospital for

PBC

-

10,000

20,000

30,000

40,000

50,000

60,000

70,000

80,000

89-91

92-94

95-97

T

o

ta

l d

ay

s

in

H

o

sp

it

al

<65

>65

Hospital Charges

-

100

200

300

400

500

89-91

92-94

95-97

T

o

ta

l C

ha

rg

es

(

$m

ill

io

n)

OLT
No OLT

n=96

n=96

8

8

n=93

n=93

2

2

n=63

n=63

9

9

Follow-Up AMA +ve (IF) Subjects

Follow-Up AMA +ve (IF) Subjects

With Normal Biochemistry

With Normal Biochemistry

no: pts

no: pts

29

29

24

24

no: developed

no: developed

symptoms

symptoms

no: developed

no: developed





ALP / AST

ALP / AST

NB: 4/29 biopsies initial not compatible with PBC

NB: 4/29 biopsies initial not compatible with PBC

5 patients died (non-hepatic)

5 patients died (non-hepatic)

Adapted from Metcalf et al., Lancet 1996;348:1400

Adapted from Metcalf et al., Lancet 1996;348:1400

time to develop

time to develop

symptoms

symptoms





ALT

ALT

24 / 26

24 / 26

1 - 17 yrs

1 - 17 yrs

1 - 19 yrs

1 - 19 yrs

(mean 5.6)

(mean 5.6)

Autoantibodies in Liver

Autoantibodies in Liver

Disease

Disease

Anti-Liver Kidney

Anti-Liver Kidney

Microsomal

Microsomal

cytochrome

cytochrome

P450 IID6

P450 IID6

Anti - Nuclear

Anti - Nuclear

Antibodies

Antibodies

RNPs

RNPs

nuclear pore

nuclear pore

lamins histones

lamins histones

Anti-Smooth Muscle

Anti-Smooth Muscle

Antibody

Antibody





- actin

- actin

Anti-Neutrophil Cytoplasmic

Anti-Neutrophil Cytoplasmic

Antibody

Antibody

lysosomal proteins

lysosomal proteins

Anti-Centromere

Anti-Centromere

kinetochore proteins

kinetochore proteins

Anti-Mitochondrial

Anti-Mitochondrial

Antibody

Antibody

pyruvate

pyruvate

dehydrogenase E2

dehydrogenase E2

Soluble Liver Antigen

Soluble Liver Antigen

glutathione s- transferase

glutathione s- transferase

source of

source of

sera

sera

total

total

no.

no.

indirect

indirect

immunofluorescence

immunofluorescence

(no: positive)

(no: positive)

ELISA PDH

ELISA PDH

(no: positive against)

(no: positive against)

PBC

PBC

Rheum Dis

Rheum Dis

CAH

CAH

ALD

ALD

Control

Control

14

14

23

23

30

30

10

10

5

5

13

13

23

23

30

30

0

0

0

0

13

13

0

0

0

0

0

0

0

0

Reactivity of Patient Sera Against

Reactivity of Patient Sera Against

Mitochondrial Dehydrogenase Enzyme

Mitochondrial Dehydrogenase Enzyme

Complexes

Complexes

Immunoblot PDH-E2

Immunoblot PDH-E2

(no: positive against)

(no: positive against)

13

13

0

0

0

0

0

0

0

0

PDH, pyruvate dehydrogenase complex; E2, E2 subunit of PDH; PBC, primary billary

PDH, pyruvate dehydrogenase complex; E2, E2 subunit of PDH; PBC, primary billary

cirrhosis; Rheum Dis, rheumatic disease; CAH, chronic active hepatitis; ALD,

cirrhosis; Rheum Dis, rheumatic disease; CAH, chronic active hepatitis; ALD,

alcoholic liver disease;

alcoholic liver disease;

Yoshida et al., Gastroenterology 1990;99:190

Yoshida et al., Gastroenterology 1990;99:190

Immunoblotting in 20 AMA Negative

Immunoblotting in 20 AMA Negative

and 20 AMA Positive (IF) PBC Patients

and 20 AMA Positive (IF) PBC Patients

method

method

Immunofluorescence

Immunofluorescence

ELISA for E2/X immunoblotting for

ELISA for E2/X immunoblotting for

PDC immunoblotting for OGDC

PDC immunoblotting for OGDC

immunoblotting for BCOADC

immunoblotting for BCOADC

0

0

3

3

2

2

0

0

1

1

20

20

20

20

20

20

2

2

8

8

AMA-IF -ve pts

AMA-IF -ve pts

testing +ve (n+20*)

testing +ve (n+20*)

AMA-IF +ve pts testing

AMA-IF +ve pts testing

+ve (n=20*)

+ve (n=20*)

PDC=pyruvate dehydrogenase complex; OGDC=2-oxo-glutarate

PDC=pyruvate dehydrogenase complex; OGDC=2-oxo-glutarate

dehydrogenase complex; BCOADC=branch chain 2-oxo acid dehydrogenase

dehydrogenase complex; BCOADC=branch chain 2-oxo acid dehydrogenase

complex; * for BCOADC, n=14

complex; * for BCOADC, n=14

Michielletti et al., Gut 1994;35:261

Michielletti et al., Gut 1994;35:261

Molecular Mimicry

Molecular Mimicry

A

A

Shared Microbial and Host Immunodominant Epitopes

Shared Microbial and Host Immunodominant Epitopes

helps to prevent immune

helps to prevent immune

recognition of microbe

recognition of microbe

may promote autoimmune

may promote autoimmune

damage to the host

damage to the host

NB antigenic distance

NB antigenic distance

PBC and Bacterial

PBC and Bacterial

Infections

Infections

•

Increased prevalence of bacterial

Increased prevalence of bacterial

infections

infections

–

Greater incidence of UTI’s

Greater incidence of UTI’s

–

Detection of bacterial R mutants in stool

Detection of bacterial R mutants in stool

–

Demonstration of AMA reactivity with R

Demonstration of AMA reactivity with R

mutants

mutants

»

absence of cell wall with

absence of cell wall with





 PDH E2 reactivity

 PDH E2 reactivity

•

Organisms implicated in disease

Organisms implicated in disease

–

Mycobacteria Gordonae

Mycobacteria Gordonae

•

Mouse model

Mouse model

–

Mycoplasma and biliary disease

Mycoplasma and biliary disease

Bacterial Endosymbiosis

Bacterial Endosymbiosis

in Eukaryotic Cell

in Eukaryotic Cell

Evolution

Evolution

Coccoid cyanobacteria

Coccoid cyanobacteria

Chloroxybacteria

Chloroxybacteria

photosynthesis

photosynthesis

Spiroplasmas

Spiroplasmas

Spirochetes

Spirochetes

motility

motility

Thermoplasmas

Thermoplasmas

heat and acid

heat and acid

resistance

resistance

Bdellvibrio

Bdellvibrio

Paracocci

Paracocci

respiration

respiration

Plant

Plant

Animal

Animal

Fungus

Fungus

Is PBC an Infectious

Is PBC an Infectious

Disorder?

Disorder?

•

Clustering of disease

Clustering of disease

–

Sweden

Sweden

Selenium deficiency

Selenium deficiency

–

England

England

Water supply

Water supply

–

Transmission

Transmission

Patient to nurse

Patient to nurse

–

Familial

Familial

•

False positive HIV ELISA in 15% patients

False positive HIV ELISA in 15% patients

•

Recurrent disease after OLT

Recurrent disease after OLT

–

Vanishing bile duct syndrome with

Vanishing bile duct syndrome with





AMA

AMA

–

PDC-E2 reactivity on biliary epithelium

PDC-E2 reactivity on biliary epithelium

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

Representational Difference

Representational Difference

Analysis

Analysis

5.0 kb
2.2 kb
1.3 kb
1.0 kb

500 bp

Extract DNA from PBC Liver and skin to make representations

Extract DNA from PBC Liver and skin to make representations

Subtract representations from liver and skin then PCR amplify the difference

Subtract representations from liver and skin then PCR amplify the difference

PBC

PBC

skin

skin

--

-

-
--

-

-

--

-

-
--

-

-

* Representations PCR fragments < 1kb

Representations PCR fragments < 1kb

complexity BamHI < BglII < HindIII

complexity BamHI < BglII < HindIII

55 13 8

55 13 8

Restriction digest

Restriction digest

GATC

Ligate

Ligate

GATC

adaptors

adaptors

to

to

Add

Add

primer

primer

and amplify

and amplify

Ligate

Ligate

GATC

adaptors

adaptors

tester

tester

then mix melt Restriction digest

then mix melt Restriction digest

GATC

PCR representations

PCR representations

anneal & fill in ends

anneal & fill in ends

MB nuclease digest ssDNA

MB nuclease digest ssDNA

Tester

Tester

Driver

Driver

--

-

-
--

-

-

--

-

-
--

-

-

--

-

-
--

-

-

--

-

-
--

-

-

--

--

-

--

--

-

--

--

--

--

--

--

--

--

--

--

--

--

--

--

--

--

--

Amplification

Amplification

exponential

exponential

linear

linear

no

no

--

--

--

--

--

--

--

--

--

--

--

--

--

--

--

--

--

in excess

in excess

1

2

3

Representational Difference

Representational Difference

Analysis

Analysis

hybrid

hybrid

DNA

DNA

ssDNA

ssDNA

Repeat step

Repeat step

2 with new

with new

GATC

adaptors

adaptors

+

+

primers

primers

2

PBC Serum Reactivity to HIV

PBC Serum Reactivity to HIV

Proteins

Proteins

•

PBC patients assessed for liver

PBC patients assessed for liver

transplantation

transplantation

•

HIV ELISA

HIV ELISA

–

15% patients positive

15% patients positive

n=46

n=46

–

ELISA titres corelated with AMA levels

ELISA titres corelated with AMA levels

•

HIV Western blot

HIV Western blot

–

1 patient with p41 and p24 reactivity

1 patient with p41 and p24 reactivity

•

Risk factors for HIV

Risk factors for HIV

–

1 patient ( WB -ve ) received multiple blood

1 patient ( WB -ve ) received multiple blood

transfusions prior to tests for HIV

transfusions prior to tests for HIV

Complexity of

Complexity of

Autoimmune Liver Disease

Autoimmune Liver Disease

Infection

Infection

Geograp

Geograp

hy

hy

Female Sex

Female Sex

Environment

Environment

al

al

Factors

Factors

Immunogenetic

Immunogenetic

Genetic

Genetic

Autoimmunity

Autoimmunity

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

Summary of the Comfirmed HLA

Summary of the Comfirmed HLA

Associations in Primary Biliary Cirrhosis

Associations in Primary Biliary Cirrhosis

(First Studies Only

(First Studies Only

)

)

C4B2

C4B2

DR8/DR11

DR8/DR11

C4AQ0

C4AQ0

DQB1*0402

DQB1*0402

DPB1*0301

DPB1*0301

DR8

DR8

DPB1*0501

DPB1*0501

DRB10803

DRB10803

Brigg et al 1987

Brigg et al 1987

Gores et al 1987

Gores et al 1987

Manns et al 1991

Manns et al 1991

Underhill et al 1992

Underhill et al 1992

Mella et al. 1995

Mella et al. 1995

Maeda et al 1992

Maeda et al 1992

Seki et al 1993

Seki et al 1993

Ogura et al 1994

Ogura et al 1994

S

S

S/R

S/R

S

S

S

S

S

S

S

S

S

S

S

S

N. Europe

N. Europe

USA

USA

N. EUROPE

N. EUROPE

N. EUROPE

N. EUROPE

N. EUROPE

N. EUROPE

Japan

Japan

Japan

Japan

Japan

Japan

Allele

Allele

Author

Author

S/R

S/R

Group

Group

Summary of Non-MHC Genes in

Summary of Non-MHC Genes in

Autoimmune Liver Diseases

Autoimmune Liver Diseases

IL-1B

IL-1B

1L-1RN

1L-1RN

CTLA-4

CTLA-4

IL-10

IL-10

TCR C

TCR C

lg allotype

lg allotype

2q13-q21

2q13-q21

2q13-q21

2q13-q21

2q33

2q33

1q31-32

1q31-32

7p14-15

7p14-15

14q32-33

14q32-33

AIH

AIH

No

No

No

No

Unkown

Unkown

No

No

Yes

Yes

Yes

Yes

PSC

PSC

No

No

No

No

Yes

Yes

No

No

Unkown

Unkown

Unknown

Unknown

Gene

Gene

Location

Location

Association

Association

PBC

PBC

No

No

No

No

Yes

Yes

No

No

Unkow

Unkow

n

n

Unkno

Unkno

wn

wn

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis

Northern

Northern

Latitudes

Latitudes

Female

Female

9:1

9:1

MDR2

MDR2

AMA ANA

AMA ANA

DR8 C4AQ0

DR8 C4AQ0

Se deficiency

Se deficiency

water supply

water supply

Mycobacteria

Mycobacteria

R mutants

R mutants

HIV reactivity

HIV reactivity

Primary Biliary Cirrhosis

Primary Biliary Cirrhosis

•

Granulomatous destruction of

Granulomatous destruction of

interlobular bile ducts

interlobular bile ducts

•

Anti-mitochondrial antibodies

Anti-mitochondrial antibodies

–

PDH-E2

PDH-E2

95%

95%

–

OGDH-E2

OGDH-E2

40-85%

40-85%

–

BCODH-E2

BCODH-E2

55%

55%

•

AMA immunohistochemistry

AMA immunohistochemistry





 

 

antigens resembling

antigens resembling

PDH-E2 on cell surface

PDH-E2 on cell surface

specifically in PBC pts

specifically in PBC pts

PBC

PBC

PBC

PBC

PSC

PSC

PSC

PSC

Rationale for PBC

Rationale for PBC

Therapy

Therapy

Hepatic

Hepatic

failure

failure

0 - 2 years

0 - 2 years

AMA

IgM GT SymptomsSigns

2 - 10 years 2 - 20 years 3 - 11 years

Age in years 20 30 40 50 60 70

Age in years 20 30 40 50 60 70

Typical

Typical

symptoms none malaise itching jaundice

symptoms none malaise itching jaundice

Histologic stage i ii iii iv

Histologic stage i ii iii iv

Therapy related to disease process

Therapy related to disease process

Immunosuppression +++ +

Immunosuppression +++ +

-

-

Anti-fibrosis

Anti-fibrosis

- ++

- ++

+/-

+/-

Bile acid

Bile acid

+++ +++

+++ +++

++

++

Transplantation - +

Transplantation - +

+++

+++

Treatments for PBC - Single Agents

Treatments for PBC - Single Agents

Penicillamine

Penicillamine

Cyclosporine

Cyclosporine

Cholorambucil

Cholorambucil

Tacrolimus

Tacrolimus

Azathioprine

Azathioprine

Cholchicine

Cholchicine

Thalidomide

Thalidomide

Methotrexate

Methotrexate

Urodeoxycholic

Urodeoxycholic

acid

acid

Levamisole

Levamisole

Steroids

Steroids

Malotilate

Malotilate

Ineffective

Ineffective

Equivocol or

Equivocol or

Unknown

Unknown

Effective

Effective

Treatments for PBC( in Combination with

Treatments for PBC( in Combination with

Ursodiol)

Ursodiol)

Cholchicine

Cholchicine

Cholysarcosine

Cholysarcosine

Ineffective

Ineffective

Equivocol or

Equivocol or

Unknown

Unknown

Effective

Effective

Methotrexate

Methotrexate

Corticosteroids

Corticosteroids

Corticosteroids

Corticosteroids

& Azathioprine

& Azathioprine

Better Pacebo

Better Pacebo

Better UDCA

Better UDCA

1/64

1/64

1/16

1/16

1/14

1/14

1

1

4

4

16

16

64

64

1/64

1/64

1/16

1/16

1/14

1/14

1

1

4

4

16

16

64

64

Better Pacebo

Better Pacebo

Better UDCA

Better UDCA

A

A

B

B

16

16

18

18

19

19

20

20

21

21

22

22

23

23

9

9

16

16

18

18

19

19

20

20

21

21

22

22

23

23

9

9

Does Ursodeoxycholic Acid Work?

0

0

month

month

Kisand et al, J Molec Med 1996; 74:271

Kisand et al, J Molec Med 1996; 74:271

0

0

months

months

24

24

months

months

0

0

months

months

24

24

months

months

24

24

months

months

Effect of Therapy on AMA in PBC

Effect of Therapy on AMA in PBC

0

0

0.2

0.2

0.4

0.4

0.6

0.6

0.8

0.8

1

1

1.2

1.2

1.4

1.4

Ursodeoxycolic acid

Ursodeoxycolic acid

Colchicine

Colchicine

Placeb

Placeb

o

o

p<0.1

p<0.1

p>0.5

p>0.5

p>0.5

p>0.5

ELISA

ELISA

Index

Index

PBC - AIH Overlap

PBC - AIH Overlap

Definition of AIH if one or more:

Definition of AIH if one or more:
•

ALT > 5x ULN

ALT > 5x ULN

•

SMA +ve and/or lg G > 2 ULN

SMA +ve and/or lg G > 2 ULN

•

liver biopsy with piecemeal necrosis

liver biopsy with piecemeal necrosis

(moderate/severe)

(moderate/severe)

130 PBC patients assessed,

130 PBC patients assessed,

12 (9.2%) AIH criteria present

12 (9.2%) AIH criteria present

Chazouilleres, Hepatology 1998;28:296

Chazouilleres, Hepatology 1998;28:296

`

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

alkaline phosphatase (ALP)

alkaline phosphatase (ALP)

asparate aminotransferase (AST)

asparate aminotransferase (AST)

Prednisone

Prednisone

UDCA 750 mg/d

UDCA 750 mg/d

20 mg d/l

20 mg d/l

0

0

450

450

400

400

350

350

300

300

250

250

200

200

150

150

100

100

50

50

0

0

-6

-6

-3

-3

0

0

3

3

6

6

9

9

12

12

15

15

18

18

21

21

24

24

27

27

30

30

33

33

36

36

39

39

42

42

biopsey

biopsey

biopsey

biopsey

AMA

AMA

ANA

ANA

1:320

1:320

neg

neg

1:80

1:80

neg

neg

1:40

1:40

neg

neg

neg

neg

>1:1280

>1:1280

neg

neg

>1:1280

>1:1280

neg

neg

>1:1280

>1:1280

neg

neg

>1:1280

>1:1280

U

/L

U

/L

Colombato et al, Gastroenterology 1994; 107:1840

Colombato et al, Gastroenterology 1994; 107:1840

Consecutive PBC

Consecutive PBC

and AIH

and AIH

Time(months)

Time(months)

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

Liver Transplantation for

Liver Transplantation for

PBC

PBC

•

Superior outcome for patients transplanted

Superior outcome for patients transplanted

earlier in course of disease

earlier in course of disease

–

Morbidity Mortality and Cost

Morbidity Mortality and Cost

•

Consider transplantation if....

Consider transplantation if....

–

Bilirubin > 7.0 mg/dl

Bilirubin > 7.0 mg/dl

–

Major complications with bilirubin < 7.0 mg/dl

Major complications with bilirubin < 7.0 mg/dl

»

Uncontrolled ascities

Uncontrolled ascities

»

Variceal hemorrage

Variceal hemorrage

»

Severe osteodystrophy

Severe osteodystrophy

»

Intolerable pruritis

Intolerable pruritis

»

Invalidating malaise

Invalidating malaise

Improved Prognosis in PBC

Improved Prognosis in PBC

Patients

Patients

with Liver Transplantation

with Liver Transplantation

0

20

40

60

80

100

120

% Survival 161 PBC patients following Transplantation

% Survival 161 PBC patients following Transplantation

Liver Transplantation

Liver Transplantation

group 1 OLT

group 1 OLT

group 2 OLT

group 2 OLT

group 3 OLT

group 3 OLT

Mayo score prediction

Mayo score prediction

group 1 Mayo

group 1 Mayo

group 2 Mayo

group 2 Mayo

group 3 Mayo

group 3 Mayo

Years

Years

•

Mayo Prognostic index for PBC

Mayo Prognostic index for PBC

Bilirubin Albumin Age Prothrombin time Edema

Bilirubin Albumin Age Prothrombin time Edema

Recurrent PBC after

Recurrent PBC after

Transplantation

Transplantation

•

Cholestatic liver function tests

Cholestatic liver function tests

•

Bile duct disease

Bile duct disease

–

Vanishing bile duct syndrome vs. PBC

Vanishing bile duct syndrome vs. PBC

•

Elevated serum AMA

Elevated serum AMA

–

Reappearance of serum antibodies

Reappearance of serum antibodies

•

Bile duct reactivity with AMA

Bile duct reactivity with AMA

–

AMA immunohistochemistry

AMA immunohistochemistry

OLT Utilization for Liver

Failure from PBC

•

Logistic model to assess the likelihood of OLT among

Logistic model to assess the likelihood of OLT among

those with liver failure

those with liver failure

Variable

Variable

Odds ratio

Odds ratio

95% CI

95% CI

p

p

Age > 65

Age > 65

0.04

0.04

(0.03-0.05)

(0.03-0.05)

<.01

<.01

Diabetes

Diabetes

0.63

0.63

(0.46-0.85)

(0.46-0.85)

<.01

<.01

Year 89-91

Year 89-91

1

1

Year 92-94

Year 92-94

1.29

1.29

(1.08-1.54)

(1.08-1.54)

<.01

<.01

Year 95-97

Year 95-97

1.28

1.28

(1.05-1.55)

(1.05-1.55)

.01

.01

•

Decrease in utilization was due to

Decrease in utilization was due to

–

patients’ age and comorbidity

patients’ age and comorbidity

–

reduction in need, not availability

reduction in need, not availability

Conclusions

•

Mortality and hospital service utilization decreased

Mortality and hospital service utilization decreased

in patients with PBC 65 years or younger during the

in patients with PBC 65 years or younger during the

last 10-15 years.

last 10-15 years.

•

While the early reduction in PBC mortality in the

While the early reduction in PBC mortality in the

1980s were likely due to liver transplantation,

1980s were likely due to liver transplantation,

ursodeoxycholic acid may be responsible for more

ursodeoxycholic acid may be responsible for more

recent changes.

recent changes.

–

Reduction in need for liver transplantation (a

Reduction in need for liver transplantation (a

true reduction in the incidence of end-stage PBC)

true reduction in the incidence of end-stage PBC)

–

No changes in mortality from PSC

No changes in mortality from PSC

Primary Biliary Cirrhosis and

Primary Biliary Cirrhosis and

Primary Biliary Hepatitis

Primary Biliary Hepatitis

(PBC)

(PBC)

Robert G. Gish, M.D

Robert G. Gish, M.D

Would like to thank:

Would like to thank:

our kind hosts in China

our kind hosts in China

and

and

The AGA

The AGA