Primary biliary cirrhosis and autoimmune liver disease

台北榮民總醫院 內科部胃腸科

蘇建維 / 黃惠君

Case presentationA 66-year-old gentleman suffered from intermittent pruritus for 8 years. But no yellowish discoloration of skin nor tea-colored urine was complained in that period.

He denied any history of blood transfusion, acupuncture, tattoo, herbal medicine, smoking or alcohol drinking.

He took a physical check up in September 2005.

Serum biochemistry tests showed ALT level 86 U/L (normal, 0-40 U/L), AST level 92 U/L (normal, 5-45 U/L), Alk-P level 229 U/L (normal, 10-100 U/L), total bilirubin 0.9 mg/dL (normal, 0.2-1.6 mg/dL), GGT 630 U/L (normal, 8-61 U/L), albumin 4.5 gm/dL (normal, 3.7-5.3 gm/dL), IgG 2270 mg/dL (normal, 1188-1800 mg/dL), IgA 309 mg/dL (normal, 158-358 mg/dL) and IgM 138 mg/dL (normal, 72-216 mg/dL).

2

Case presentation

The serologic tests for HBsAg, anti-HBs, and anti-HCV were all negative. But antibody against hepatitis B core antigen (anti-HBc) was positive, indicating a previous or occult HBV infection. Serum HBV DNA was negative by polymerase chain reaction (PCR) method.

Serum autoantibodies including anti-nuclear antibody and anti-smooth muscle antibody were negative, but anti-mitochondrial antibody (Fluoro-kit; Incstar, Stillwater, MN) was positive.

3

Liver Biopsy

H&E stain, x 800 Masson, x 1600

focal destruction of bile duct epithelium with lymphocytes infiltration, focal absence of bile duct combined with periportal fibrosis and necrosis

Primary Biliary Cirrhosis

66

Epidemiology

Incidence: 0.7 to 49 per million per year

Point prevalence: 6.7 to 402 per million

Highest in Northern European countries & Northern US

Increase incidence and prevalence of PBC worldwide

exposure to environmental factors↑, elderly population↑, survival↑, earlier diagnosis, improved care, earlier awareness…

Selmi C, Bowlus CL, Gershwin MR, Coppel RL. Lancet 2011;377:1600-9

Risk factors

Smoking, 1.67X Family history, 7.56X

UTI, 2.02XThyroid disease, 3.08X

Liang Y, et al. Hepatology Research 2011;41:572-8

Etiologies• familial clustering• prevalence: 100x in

first-degree relatives

• familial clustering• prevalence: 100x in

first-degree relatives

MHC class IIMHC class II

Innate immunityInnate immunity

adaptative immunityadaptative immunity

adaptative immunityadaptative immunity

disturbances of host resistance to infection and the inflammatory process

disturbances of host resistance to infection and the inflammatory process

xenobioticsxenobiotics

E.coli, Novosphingobiumaromaticivorans

E.coli, Novosphingobiumaromaticivorans

Generate a transient or chronic immune response that is cross-reactive with self PDC: Molecular mimicry

Generate a transient or chronic immune response that is cross-reactive with self PDC: Molecular mimicry

• M:F=1:10 • defects in the X

chromosome↑

• M:F=1:10 • defects in the X

chromosome↑

Selmi C, Bowlus CL, Gershwin MR, Coppel RL. Lancet 2011;377:1600-9

Pathophysiology

9 Kaplan MM, Gershwin ME. N Engl J Med 2005;353:1261-73

Cirrhosis with decrease of small bile ductsIncrease in connective tissue (bridging fibrosis)

Bile duct proliferation, inflammatory infiltrate the periportal field (portal inflammation)

Primary biliary cirrhosis (PBC)

Histology(H.E., 100x)

Stage I Stage II

Stage IVStage III

Bile duct destruction, inflammation (periportal fibrosis)

Prof. Dr. U. Leuschner

Interdisziplinäres Facharztzentrum, Frankfurt/Main (Germany)

Natural HistoryNatural History

PBC progresses through three irreversible states: (a) cirrhosis; (b) a terminal phase defined when serum bilirubin reaches 6 mg/dL with or without GI bleeding, ascites, or encephalopathy; and (c) death

Pre-UDCA eraSerum bilirubin increase preceding death

UDCA eraUDCA therapy delay rate of histological progression to cirrhosis

13–15 mg/kg UDCA daily

Start to treat in early stage good prognosis

Long-term survival rates are comparable between PBC patients and general population

Floreani A, et al. Liver Int 2011;31:361-8

Symptoms and Signs50% patients: asymptomatic at diagnosis

Early phase: fatigue (78%), pruritus (20-70%), osteopenia (33%), and osteoporosis (11%)

Hypercholesterolemia: typically caused by a rise in HDL, not increases cardiovascular risk.

All forms of PBC: IgM↑

Typical: ALK-P & GGT↑↑, ALT/AST↑

PBC with AIH features: ALT/AST↑↑, IgG↑↑

Late phase: thrombocytopenia, polyclonal hyperglobulinemia, and hyperbilirubinemia, hypoalbuminemia

Selmi C, Bowlus CL, Gershwin MR, Coppel RL. Lancet 2011;377:1600-9

Diagnosis Criteria

Diagnosis of PBC: two of the three criteria are met

Abnormal biochemical tests with elevation of ALK-P and

GGT

Presence of AMA with M2 specificity

Evidence of non-suppurative destructive cholangitis

(NSDC) at histology

Special Cases

AMA-negative PBC

Nearly all of the patients: ANA (+) and/or ASMA (+)

Require liver biopsy

No different prognosis to UDCA Tx compared with AMA(+)

group

Comparison of demographic and clinical characteristics at diagnosis between AMA-positive and AMA-negative PBC patients

AMA(+) (85, 84%) AMA(-) (16, 16%) p

Sex (M/F) 19/66 4/12 NS

Age of diagnosis (mean ± SD; year) 51.2 ± 12.3 52.5 ± 14.8 NS

Symptoms at diagnosis (yes/no) 75/10 14/2 NS

ANA (positive/negative) 52/28 13/3 NS

Albumin (mean ± SD; gm/dL) 3.99 ± 0.53 3.99 ± 0.55 NS

ALT (mean ± SD; U/L) 118.1 ± 88.3 165.8 ± 87.8 NS

Bilirubin (mean ± SD; mg/dL) 2.14 ± 2.03 2.79 ± 2.39 NS

ALK-P (mean ± SD; U/L) 404.0 ± 222.2 535.9 ± 286.4 0.042

Cholesterol (mean ± SD; mg/dL) 261.6 ± 128.6 371.1 ± 173.3 0.005

Child-Pugh (A/B/C) 62/19/4 9/6/1 NS

Mayo score 5.58 ± 1.66 5.61 ± 1.86 NS

Stage of liver histology (1/2/3/4) 7/22/4/5 3/5/1/2 NS

Su CW, Hung HH, Huo TI, Wu JC, et al. Liver Int 2008;28:1305-13

Treatment

All PBC patients with abnormal liver biochemistry should be considered for specific therapy

UDCA

13–15 mg/kg dailyImproves parameters of liver biochemistry

Delays the progression of fibrosis and histological stage

The survival rate of UDCA-treated patients in early stages of disease is similar to that in a control population

Adverse effect: gastric discomfort, weight gain, increase pruritis

TreatmentAdjuvant therapies

Patients: features of AIH, severe interface hepatitis, abnormal serum bilirubin level, poor response to UDCA

Glucocorticoids + UDCA

Methotrexate + UDCA: benefit in a small subset of patients

Cyclosporine monotherapy: prolonged the time to death or transplantation; high rate of side effects

Colchicine, chlorambucil, penicillamine, azathioprine, malotilate, and thalidomide ineffective or toxic

Factors associated with poor overall survival in PBC patients in Taiwan

Su CW, Hung HH, Huo TI, Wu JC, et al. Liver Int 2008;28:1305-13

Variable Risk ratio 95% Confidence interval Standard error p

UDCA treatment 0.302 0.125-0.728 0.449 0.008

Albumin≧ 4.0 g/dL 0.321 0.123-0.839 0.491 0.021

Creatinine > 0.8 mg/dL 2.539 1.076-5.994 0.438 0.033

Non-invasive serum markers for predicting hepatic fibrosis in patients with PBC

AUROC 95% CI Standard error P

AAR 0.847 0.727-0.966 0.061 0.001

Mayo PBC risk score 0.722 0.535-0.909 0.095 0.028

MELD score 0.617 0.392-0.842 0.115 0.247

Child score 0.608 0.393-0.823 0.110 0.285

Su CW, Chan CC, Hung HH, Wu JC, et al. J Clin Gastroenterol 2009;43:876-83

The application of AAR for predicting clinical adverse outcomes in patients

with primary biliary cirrhosis

Su CW, Chan CC, Hung HH, Wu JC, et al. J Clin Gastroenterol 2009;43:876-83

Greatly improved the survival

Decompensated cirrhosis or liver failure: the only effective Tx

Premature ductopenic variant

Recurrence20% of patients at 5 years

more frequent in patients w/o a glucocorticoid and cyclosporine regimen

Liver transplantation for PBC

Liver transplantation for PBC in Taiwan

From 1984 to 2008, 539 primary liver transplantations were performed in Chang Gung memorial Hospital-Kaohsiung Medical center, including 19 (3.5%) for PBC.

Liver function returned to normal one month after transplantation.

The overall 1-,3-, and 5-yr survival rates were 94.7%, 89.2%, and 89.2%, respectively

Variable LDLD (n=14) DDLD (n=5)

Mean age (yr) 51.0 ± 1.5 47.3 ± 3.9

M/F 1/13 1/4

MELD 20.7± 2.4 16.4± 2.4

CTP 11± 0.5 11± 1.1

Sun CK, Chen CL, et al. Clin Transplant 2011;25:47-53

Autoimmune hepatitis

Clinical characteristics

Prevalence : 50-200 case/1 million in Western Europe & North American

Presentation – heterogeneous

Variable – no symptoms/signs to fulminant hepatic failure

Malaise, anorexia, nausea, vomiting, abdominal pain, itching

Arthralgia in small joint, hepatomegaly, splenomegaly

Jaundice

Clinical characteristics

Chronic, unknown cause, in all age

Fluctuating course

Laboratory abnormalitiesALT or AST more striking than ALK-P, T bili

γ-globulins, IgG, 1.2~3.0 X

Extra-hepatic disorders associated with AIH

Thyroiditis (Hashimoto) Vitiligo

Ulcerative colitis Celiac disease

Type 1 diabetes mellitus Systemic lupus erythematosus

Rheumatoid arthritis Mixed connective tissue disease

Panniculitis Hyperthyroidism (Graves’ disease)

Sjogren’s syndrome Mononeuritis

Urticaria pigmentosa Sweet’s syndrome

Idiopathic thromocytopenic purpura

Polyglandular autoimmune syndrome, type 1

Glomerulonephritis Hemolytic anemia

Polymyositis Uveitis

27

Caprai S, et al. Clin Gastroenterol Hepatol 2008;6:803-6Teufel A, et al. J Clin Gastroenteorlo 2010;44:208-13Lohse AW, Mieli-Vergani G. J Hepatol 2011;55:171-82

Diagnosis scoring system

Czaja et al, Hepatology, 2002;36:479-497

Simplified diagnostic criteria (2008) of the international autoimmune hepatitis group

Points

Autoantibodies ANA or SMA or LKM > 1:40 1

ANA or SMA or LKM > 1: 80 SLA/LP positive (> 20 unit)

2

IgG (or gamma-globulin) Upper normal limit 1

> 1.10 times normal limit 2

Liver histology Compatible with AIHChronic hepatitis with lymphocytic infiltration without features considered typical

1

Typical for AIH(1) Interface hepatitis:

lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending in the lobule

(2) Emperipolesis: active penetration by one cell into and through larger cell

(3) Hepatic rosette formation

2

Absence of viral hepatitis Yes 2

No 029

Hennes EM, et al. Hepatology 2008;48:169-76

Definite AIH ≧7Probable AIH 6≧

Histology of AIH

Interface hepatitis / zone 3 Plasma cell infiltration

Czaja et al, Hepatology, 2002;36:479-497

Management algorithm for patients with definite AIH

Lohse AW, Mieli-Vergani G. Autoimmune hepatitis J Hepatol 2011;55:171-82

Management for relapse of AIH29.9% AIH patients suffered from relapses during tapering of corticosteroid therapy

Yokokawa J, et al. Hepatol Res 2011;41:641-6

OR 95% CI P

Age at diagnosis (≧50 yr) 0.29 0.10-0.86 0.03

Bilirubin (≧1.5mg/dL) 4.50 1.23-16.45 0.02

AST (≧250 IU/L) 4.88 1.35-17.65 0.02

ALT (≧250 IU/L) 10.0 2.56-39.11 <0.01

Prothrombin activity (≧80%) 0.21 0.06-0.80 0.02

Gamma-globulin (≧3.4 mg/dL) 7.20 1.52-34.02 0.01

IgG (≧3400 mg/dL) 2.68 0.88-8.13 0.08

IAIHG score (≧17) 5.54 1.56-19.75 <0.01

Management for relapse of AIH

Relapse

(n= 20)

With AZP

(n= 7)

Repeated relapse

(n=0)

Sustained remission

(n=7)

No AZP

(n= 13)

Repeated relapse

(n=8)

Sustained remission

(n=5)

Azathioprine (AZP) 50-100mg/day

Yokokawa J, et al. Hepatol Res 2011;41:641-6

Poor prognostic factors of AIHCirrhosis at diagnosis

Development of cirrhosis during treatment

Nonwhite ethnicity

Female sex

Presence of symptoms

Severe liver dysfunction

Less than 10-fold elevation of ALT levels at presentation

Failure to normalize ALT levels with treatment

Recurrent relapsesFeld JJ, et al. Hepatology 2005;42:53-62Verma S, et al. Hepatology 2007;46:1828-35Montano-Loza AJ, et al. Am J Gastroenterol 2007;102:1005-12Al-Chalabi T, et al. Clin Gastroenterol Hepatol 2008;6:1389-95

Long –term outcomes of patients with AIH

Hoeroldt B, et al. Gastroenterology 2011;140:1980-9

Hazard ratio 95% confidence interval

P

Decompensation at presentation

3.92 2.40-6.38 <0.001

Failure to normalize serum ALT levels within 12 months of treatment

4.27 2.05-8.89 <0.001

No. of relapses per decade 1.12 1.01-1.25 <0.001

Nontreatment with azathioprine

2.71 1.59-4.60 0.001

Age at presentation (y) 1.05 1.03-1.07 <0.001

AIH in Japan

Migita K, et al. Liver Int 2012;32:837-44

Mean age at presentation: 56.6 yearsCirrhosis at presentation: 10.9%

Mean prednisolone dose: 28.71 mg/dayMean follow-up: 8.0 years

Cirrhosis: 7.8%; HCC: 3.6%

Clinical features of AIH patients in TaiwanNumber %

Clinical onsetAcute/insidious/asymptomatic

20/22/6 41.7/45.8/12.5

Cirrhosis at presentation 17 35.4

Fatigue 29 60.4

Jaundice 27 56.3

Anorexia 24 50.0

Abdominal fullness 21 43.8

Splenomegaly 16 33.3

Abdominal pain 16 33.3

Ascites 12 25.0

Arthralgia 10 20.8

Edema 8 16.7

Hepatomegaly 6 12.5

Pruritis 5 10.4

Fever 3 6.3

Hepatic encephalopathy 1 2.1

Koay LK, et al. Dig Dis Sci 2006;51:1978-84

Treatment response to prednisolone: 70.3%5-year overall survival rate: 85.4%

Comparison of pretreatment data between cirrhotic and non-cirrhotic patients with AIH in Taiwan

Parameters Cirrhotic (n=5) Non-cirrhotic (n=17) P

Age (years) 60 ± 22 53 ± 20 0.446

Female/Male 3/2 12/5 1.000

ALT (U/L) 100 ± 102 634 ± 394 0.002

AST (U/L) 154 ± 181 652 ± 479 0.015

ALK-P (U/L) 177 ± 127 230 ± 97 0.256

GGT (U/L) 71 ± 37 335 ± 277 0.002

Bilirubin (mg/dL) 1.7 ± 0.6 6.8 ± 7.4 0.247

Albumin (g/dL) 2.8 ± 0.4 3.7 ± 0.6 0.014

Globulin (g/dL) 4.2 ± 0.4 4.0 ± 1.0 0.636

IgG (mg/dL) 3650 ± 1143 2875 ± 1127 0.545

Platelet (/mm3) 79600 ± 24876 209571 ± 81149 0.002

Huang HC, Huang YS, Wu JC, et al. Chin Med J 2002;65:563-9

More than 30% of AIH patients in Taiwan have cirrhosis at diagnosis.Long-term prognosis are significantly poorer than those without cirrhosis.AIH should be diagnosed and treated before cirrhosis developed.

AIH in children

Robert EA. Liver Int 2011;31:1424-31

AIH in children in Taiwan

Yeh SH, Ni YH, Chang MH, et al. Pediatr Neonatol 2009;50:65-9

Incidence of AIH among children hospitalized with hepatitis: 2.3%

Take Home MessagePBC is a chronic inflammatory autoimmune disease that mainly targets the cholangiocytes of the interlobular bile ducts in the liver.

When administered at doses of 13-15 mg/kg/day of UDCA therapy, a majority of patients with PBC have a normal life expectancy.

AIH is diagnosed based on elevation of IgG, demonstration of characteristics autoantibodies, and histological features of hepatitis in the absence of viral disease.

Adequately dosed steroids are the mainstay of remission induction treatment, while remission maintenance may need azathioprine in some patients.

AIH patients in Taiwan have comparable therapeutic effects to steroid in a lower doses.

致謝台北榮民總醫院

內科部胃腸科黃惠君醫師 謝昀蓁醫師 李重賓副教授 霍德義教授

黃以信教授 林漢傑主任 李發耀主任 教學研究部

吳肇卿教授家庭醫學部

黃信彰主任胸腔部

丁文穎醫師桃園分院

高偉育醫師

振興醫院李壽東院長 洪宏緒醫師

中國醫藥大學附設醫院陳祖裕主任