1. 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

2. Case presentation
A 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

3. 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

4. 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

5. Primary Biliary Cirrhosis

6. 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

7. 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

8. Etiologies
• familial clustering
• prevalence: 100x in
first-degree relatives
MHC class II
Innate immunity
adaptative immunity
adaptative immunity
disturbances of host
resistance to infection
and the inflammatory
process
xenobiotics
E.coli, Novosphingobium
aromaticivorans
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↑
Selmi C, Bowlus CL, Gershwin MR, Coppel RL. Lancet 2011;377:1600-9

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

10. 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)

11. Natural 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 era
Serum bilirubin increase preceding death
UDCA era
UDCA therapy  delay rate of histological progression to
cirrhosis
13–15 mg/kg UDCA daily
Start to treat in early stage good prognosis

12. Long-term survival rates are comparable between
PBC patients and general population
Floreani A, et al. Liver Int 2011;31:361-8

13. Symptoms and Signs
50% 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

14. 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

15. 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

16. 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

17. Treatment
All PBC patients with abnormal liver biochemistry
should be considered for specific therapy
UDCA
13–15 mg/kg daily
Improves 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

18. Treatment
Adjuvant 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

19. 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

20. 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

21. 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

22. Greatly improved the survival
Decompensated cirrhosis or liver failure: the only
effective Tx
Premature ductopenic variant
Recurrence
20% of patients at 5 years
more frequent in patients w/o a glucocorticoid and
cyclosporine regimen
Liver transplantation for PBC

23. 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

24. Autoimmune hepatitis

25. 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

26. Clinical characteristics
Chronic, unknown cause, in all age
Fluctuating course
Laboratory abnormalities
ALT or AST more striking than ALK-P, T bili
γ-globulins, IgG, 1.2~3.0 X

27. 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;6:803-6
Teufel A, et al. J Clin Gastroenteorlo 2010;44:208-13
Lohse AW, Mieli-Vergani G. J Hepatol 2011;55:171-82

28. Diagnosis scoring system
Czaja et al, Hepatology, 2002;36:479-497

29. 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 AIH
Chronic 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 0
29
Hennes EM, et al. Hepatology 2008;48:169-76
Definite AIH ≧7
Probable AIH ≧6

30. Histology of AIH
Interface hepatitis / zone 3 Plasma cell infiltration
Czaja et al, Hepatology, 2002;36:479-497

31. Management algorithm for patients with definite AIH
Lohse AW, Mieli-Vergani G. Autoimmune hepatitis J Hepatol 2011;55:171-82

32. Management for relapse of AIH
29.9% 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

33. 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

34. Poor prognostic factors of AIH
Cirrhosis 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 relapses Feld JJ, et al. Hepatology 2005;42:53-62
Verma S, et al. Hepatology 2007;46:1828-35
Montano-Loza AJ, et al. Am J Gastroenterol 2007;102:1005-12
Al-Chalabi T, et al. Clin Gastroenterol Hepatol 2008;6:1389-95

35. 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

36. AIH in Japan
Migita K, et al. Liver Int 2012;32:837-44
Mean age at presentation: 56.6 years
Cirrhosis at presentation: 10.9%
Mean prednisolone dose: 28.71 mg/day
Mean follow-up: 8.0 years
Cirrhosis: 7.8%; HCC: 3.6%

37. Clinical features of AIH patients in Taiwan
Number %
Clinical onset
Acute/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%

38. 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.

39. AIH in children
Robert EA. Liver Int 2011;31:1424-31

40. 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%

41. Take Home Message
PBC 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.

42. 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