autoimmune liver diseases · 2018-06-10 · brief overview epidemiology and ... causes the signs...

EXTRAHEPATIC AUTOIMMUNE (EHA)

DISEASES ASSOCIATED WITH PRIMARY

BILIARY CHOLANGITIS (PBC)

Kidist K. Yimam, MD

Medical Director, Autoimmune Liver Disease Program

Division of Hepatology and Liver Transplantation

California Pacific Medical Center (CPMC)

San Francisco, CA U.S.A.

PBCers 2018 Conference

OUTLINE

Brief overview

Epidemiology and natural history of PBC associated extrahepatic

autoimmune (EHA) diseases

In patients with PBC

PBC compared with matched controls

Autoimmune diseases in relatives of patients with PBC

Impact of EHA conditions on PBC patients’ survival

Impact of response to ursodeoxycholic acid (UDCA) on EHA

diseases

AIH-PBC overlap syndrome and EHA disease

Take home points

PRIMARY BILIARY

CHOLANGITIS (PBC)

PBC is characterized by a T-

lymphocyte-mediated attack on small

intrahepatic bile ducts

Leads to gradual destruction and

eventual disappearance of the small

bile ducts (ductopenia)

Causes the signs and symptoms of

cholestasis (such as itching) and

overtime, leads to cirrhosis and liver

failure

Kaplan MM. Primary biliary cirrhosis. N Engl J Med. 1996;335(21):1570.

florid bile duct lesion of PBC

DIAGNOSTIC APPROACH

PBC should be suspected in patients with persistent

cholestatic abnormalities in serum liver tests or symptoms

including pruritus or fatigue

An abnormal serum level of alkaline phosphatase (ALP) is

typical in patients with PBC, mainly affecting women

(female>male,10:1)

Careful personal, social, travel and family history taking

may provide critical clues for the diagnosis of a cholestatic

liver disease of unknown origin, particularly presence of

other autoimmune diseases

Kaplan MM. Primary biliary cirrhosis. N Engl J Med. 1996;335(21):1570.

CLINICAL FEATURES

T. H. Karlsen; M. Vesterhus; K. M. Boberg. Controversies in the

Management of Primary Biliary Cirrhosis and Primary

Sclerosing Cholangitis. Aliment Pharmacol Ther.

2014;39(3):282-30

PBC vs.

Primary Sclerosing

Cholangitis (PSC)

Autoimmunity

AUTOIMMUNITY IN PBC

Several autoimmune diseases have often been found in association with

PBC or AIH

The ‘mosaic of autoimmunity’ has been proposed By Dr. Gershwin and

colleagues

“Autoimmunity mosaic is composed of numerous pieces, all coexisting and

maintaining a certain balance. Reassembling or adding more components

may shatter this steady state and direct the autoimmune process to other

clinical expressions.”

The integration of genetic, environmental, and hormonal factors plays role

in this balance of autoimmunity

In PBC, association with hepatic disease, AIH-PBC overlap syndrome

(OS) has been well characterized

Association with EHA diseases however is not fully described, except its

association with rheumatologic disorders

Floreani A, Franceschet I, Cazzagon N, Spinazzè A, Buja A, Furlan P, Baldo V, Gershwin ME. Extrahepatic autoimmune conditions associated with primary biliary cirrhosis. Clin Rev Allergy Immunol. 2015 Jun;48(2-3):192-7

Amital H, Eric Gershwin M, Shoenfeld Y. Reshaping the mosaic of autoimmunity. Semin Arthritis Rheum 2006; 35:341–343.

PBC ASSOCIATED EHA DISEASES

Using a single-center database, Dr. Gershwin and colleagues evaluated

361 patients with PBC

339 females, 22 males; mean age 53.1 ± 12.4 years

From 1975-2012, with mean follow-up was 8.0±6.9 years

At the time of PBC diagnosis:

221 patients (61.2 %) had at least one EHA condition

123 had only one disease (34.1%)

70 (19.4 %) had two

23 (6.4 %) had three, and

5 (1.4 %) had four or five


PBC ASSOCIATED EHA DISEASES


The proportion of PBC patients with associated EHA conditions remained

unchanged over the years

(comparing representative intervals, i.e., 1973–1980, 1981–1990, 1991–2000, 2001–2010, 2011–2012)

FEMALE GENDER WAS ASSOCIATED WITH EHA

CONDITION IN PBC


ASSOCIATED EHA CONDITIONS WERE NOT RELATED

WITH COMPLICATIONS OF END- STAGE LIVER

DISEASE, HEPATOCELLULAR CARCINOMA (HCC), OR

EXTRAHEPATIC CANCERS, AND THEY DID NOT

AFFECT PATIENT SURVIVAL.


Floreani A, Franceschet I, Cazzagon N, Spinazzè A, Buja A, Furlan P, Baldo V, Gershwin ME.

Extrahepatic autoimmune conditions associated with primary biliary cirrhosis. Clin Rev Allergy

Immunol. 2015 Jun;48(2-3):192-7

Kaplan-Meier survival curves

for PBC patients with and

without EHA conditions

WHAT IS THE RISK OF EHA CONDITIONS IN PBC

PATIENTS WHEN COMPARED WITH CONTROLS?

Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM; USA PBC Epidemiology Group. Hepatology. 2005 Nov;42(5):1194-

202.

Patients with PBC (n = 1032) from 23 tertiary referral centers for liver diseases in

the United States, between November 1999 and June 2004

Controls (n = 1041) matched for sex, age, race, and geographical location

Largest case-control risk factors study in PBC

2-3x

FRENCH PBC CASE-CONTROL STUDY

Corpechot C, Chrétien Y, Chazouillères O, Poupon R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010 Jul;53(1):162-9.

WHAT IS THE PREVALENCE OF AUTOIMMUNE

DISEASES IN FIRST-DEGREE RELATIVES OF PBC

PATIENTS?

CUMULATIVE PREVALENCE OF AUTOIMMUNE DISEASES

IN FIRST-DEGREE RELATIVES OF PBC PATIENTS AND

CONTROLS

Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM; USA PBC Epidemiology Group. Hepatology. 2005 Nov;42(5):1194-202.

US Study

PERCENTAGE OF PBC PATIENTS REPORTING FIRST-

DEGREE FAMILY MEMBERS WITH AUTOIMMUNE DISEASES

Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM; USA PBC Epidemiology Group. Hepatology. 2005 Nov;42(5):1194-202

Familial PBC was reported most frequently by cases in

sisters (4.3%) and mothers (1.7%) (P < .001)

HISTORY OF AUTOIMMUNE DISEASES IN FIRST-DEGREE

RELATIVES REPORTED BY PBC CASES AND CONTROLS

Corpechot C, Chrétien Y, Chazouillères O, Poupon R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010 Jul;53(1):162-9.

French Study

FAMILY HISTORY OF PBC: SIGNIFICANT

INDEPENDENT RISK FOR PBC AFTER ADJUSTING

FOR OTHER FACTORS

Gershwin ME, Selmi C, Worman HJ, Gold EB, Watnik M, Utts J, Lindor KD, Kaplan MM, Vierling JM; USA PBC Epidemiology Group. Hepatology. 2005

Nov;42(5):1194-202.

AUTOIMMUNITY IN FAMILIES WITH PBC

Autoimmunity in the families of PBC patients was common, with ~14%

first-degree relatives suffering from autoimmune disease other than

PBC in another study, further supporting the autoimmune hypothesis

(genetic predisposition)

Individual autoimmune conditions were, however, generally seen at a

markedly lower frequency in first degree relatives than in PBC patients

themselves

Any autoimmune conditions (at least one)

Relative of controls ~20%

Relatives of PBC patients ~30%

PBC patients ~40-60%

Watt FE, James OF, Jones DE. Patterns of autoimmunity in primary biliary cirrhosis patients and their families: a population-based cohort study. QJM. 2004 Jul;97(7):397-406.

Feizi T, Naccarato R, Sherlock S, Doniach D. Mitochondrial and other antibodies in relatives of patients with primary biliary cirrhosis. Clin Exp Immunol 1972; 10:609–22.

AMA POSITIVITY IN FIRST-DEGREE RELATIVES

(FDRS) OF PBC PATIENTS

In 2007, the Mayo group has reported detectable AMAs in 13.1% of

FDRs of PBC probands, most of whom had no biochemical evidence of

cholestasis

Between 2003 and 2009, 476 FDRs were recruited into the Mayo Clinic

PBC Genetic Epidemiology (MCPGE) Registry and Biorepository study

At recruitment, 11% (n = 51) of FDRs were AMA+ and 89% (n = 425)

were AMA−

Among these, 22% (n = 11) of the AMA+ FDRs and 0.5% (n = 2) of the

AMA− FDRs had already been diagnosed with PBC prior to study

enrolment (P < 0.01).

Lazaridis KN, Juran BD, Boe GM, et al. Increased prevalence of antimitochondrial antibodies in first‐degree relatives of patients with primary biliary cirrhosis. Hepatology 2007; 46: 785–

92.

For interval PBC development, they monitored 40 undiagnosed AMA+

FDRs and 423 undiagnosed AMA− FDRs who were followed for a

median of ~ 8 years

During the follow‐up period, only 1 AMA+ FDR (4%) and 1 AMA− FDR

(0.4%) were diagnosed with PBC (P = 0.17).

None of the AMA+ FDRs with a normal AP at recruitment were

diagnosed with PBC after a median 8.9 years of follow‐up.

Lazaridis KN, Juran BD, Boe GM, et al. Increased prevalence of antimitochondrial antibodies in first‐degree relatives of patients with primary biliary cirrhosis. Hepatology 2007; 46:

785–92.

AMA POSITIVITY IN FIRST-DEGREE RELATIVES

(FDRS) OF PBC PATIENTS

In summary, FDRs of patients with PBC are at risk of developing the

disease and, thus, should likely be screened for detectable AMA and

subsequently followed with liver biochemical tests at some regular

interval.

However, this findings suggest that in AMA− FDRs, and AMA+ FDRs

with normal AP levels at initial testing, the risk of developing clinically

recognized PBC in the subsequent 8 years is low

While these data do not support a recommendation for a standardized

approach to follow‐up of FDRs of patients with PBC, this information

may be useful for counseling and reassuring relatives of their overall

favorable prognosis

Lazaridis KN, Juran BD, Boe GM, et al. Increased prevalence of antimitochondrial antibodies in first‐degree relatives of patients with primary biliary cirrhosis. Hepatology 2007; 46: 785–

92.

DO EHA CONDITIONS IN PBC RESPOND

TO URSODEOXYCHOLIC ACID (UDCA)

UDCA APPEAR NOT TO INFLUENCE EITHER THE

DEVELOPMENT OR RESOLUTION OF EHA

CONDITIONS

Zukowski TH, Jorgensen RA, Dickson ER, Lindor KD. Autoimmune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy. Am J

Gastroenterol. 1998 Jun;93(6):958-61.

• 180 patients with PBC, enrolled in a

prospective randomized controlled

trial of UDCA (13–15mg/ kg/day),

were studied

• After 2 yrs., there was no difference

between the treatment groups with

regard to resolution or

spontaneous onset of these

autoimmune features

EHA CONDITIONS VS. SEVERITY OF LIVER

DISEASE

There was no relationship between change in severity of liver

disease, as assessed by the Mayo Risk Score, and the resolution or

development of sicca syndrome, the most common of the

associated autoimmune conditions in the study patient population

Zukowski TH, Jorgensen RA, Dickson ER, Lindor KD. Autoimmune conditions associated with primary biliary cirrhosis: response to ursodeoxycholic acid therapy. Am J

Gastroenterol. 1998 Jun;93(6):958-61.

IS THERE INCREASE RISK OF CANCERS IN PBC

PATIENTS GIVEN INCREASED EHA CONDITIONS?

NO HISTORY OF SEX-RELATED OR NON-SEX- RELATED

CANCER WAS FOUND TO BE MORE FREQUENTLY REPORTED

IN PBC PATIENTS THAN IN CONTROLS

Corpechot C, Chrétien Y, Chazouillères O, Poupon R. Demographic, lifestyle, medical and familial factors associated with primary biliary cirrhosis. J Hepatol. 2010

Jul;53(1):162-9.

PBC WITH EHA CONDITIONS VS. PBC ALONE—

NO INCREASE RISK OF CANCERS


HOW ABOUT EHA CONDITIONS IN PATIENTS WITH

AIH-PBC OVERLAP SYNDROME (OS)?

71 well-characterized AIH/PBC OS patients were evaluated in a

multicenter European study for concurrent autoimmune diseases.

Efe C, Wahlin S, Ozaslan E, Berlot AH, Purnak T, Muratori L, Quarneti C, Yüksel O, Thiéfin G, Muratori P. Autoimmune hepatitis/primary biliary cirrhosis overlap syndrome and

associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol. 2012 May;24(5):531-4.

Efe C, Wahlin S, Ozaslan E, Berlot AH, Purnak T, Muratori L, Quarneti C, Yüksel O, Thiéfin G, Muratori P. Autoimmune hepatitis/primary biliary cirrhosis

overlap syndrome and associated extrahepatic autoimmune diseases. Eur J Gastroenterol Hepatol. 2012 May;24(5):531-4.

Presence of EHA conditions has no impact on progression of liver

disease or response to therapy

IN SUMMARY

~ 40-60% of patients with PBC/ PBC-AIH overlap syndrome

have at least one extra-hepatic autoimmune condition, mostly

in females

The most common include

Symptoms of Sjögren's syndrome

Raynaud phenomenon

Autoimmune thyroids disease (particularly Hashimoto thyroiditis)

Cutaneous scleroderma or CREST syndrome

Rheumatoid arthritis

Systemic Lupus Erythematous

A thorough history taking is important to identify affected

patients and also identify undiagnosed PBC in patients presenting with

other symptoms

CONT’

EHA conditions don’t affect liver related outcomes, overall

survival and don’t increase risk of gender and non-gender specific

malignancies (liver and non-liver)

Treatment with UDCA has no impact on EHA diseases in PBC

Symptomatic care for these troubling associated autoimmune

conditions as well as appropriate referral to a center with

multidisciplinary specialty care should be offered to help improve

our patients’ quality of lives

Rheumatologist, endocrinologist, dermatologist, hematologist

and others

CONT’

1st degree relative of PBC patients, particularly, females, have increased

risk of other autoimmune conditions, including PBC.

Screened for detectable AMA and subsequently followed with liver

biochemical tests at some regular interval may be appropriate

Particularly FDRs with other autoimmune conditions may be

appropriate

We need to counsel patients and FDRs that AMA− FDRs, and AMA+

FDRs with normal AP levels at initial testing, the risk of developing

clinically recognized PBC in the subsequent 8 years is low however

THANK YOU!

Questions?

CPMC AILD PATIENT SUPPORT GROUP

2ND CONFERENCE

PATIENTS AND

CAREGIVERS

COMING

NOVEMBER 2018

SAN FRANCISCO

autoimmune liver diseases · 2018-06-10 · brief overview epidemiology and ... causes the signs...

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