Primary biliary cirrhosis in Brunei Daru (1)
Original Article / Biliary
Primary biliary cirrhosis in Brunei Darussalam
Vui Heng Chong, Pemasiri Upali Telisinghe and Anand Jalihal
Bandar Seri Begawan, Brunei Darussalam
BACKGROUND: Primary biliary cirrhosis (PBC) is an uncom- KEY WORDS: primary biliary cirrhosis;
cholestasis;
mon autoimmune cholestatic disease that predominantly
chronic liver disease;
affects women. Certain human leukocyte antigens (HLAs)
human leukocyte antigen;
have been reported to be associated with susceptibility for
Southeast Asian
PBC. We describe the profiles of PBC in Brunei Darussalam.
METHODS: All patients with PBC (n=10) were identified from
our prospective databases. The HLA profiles (n=9, PBC) were
compared to controls (n=65) and patients with autoimmune
hepatitis (n=13, AIH).
RESULTS: All patients were women with a median age of 51
years (27-83) at diagnosis. The prevalence rate of the disease
was 25.6/million-population and the estimated incidence rate
varied from 0 to 10.3/million-population per year. Chinese
(41.15/million) and the indigenous (42.74/million) groups
had higher prevalence rates compared to Malays (22.62/
million). The prevalence among female population was 54.6/
million-population. All patients were referred for abnormal
liver profiles. Five patients had symptoms at presentations:
jaundice (20%), fatigue (20%), arthralgia (30%) and pruritus
(20%). Serum anti-mitochondrial antibody was positive in
80% of the patients. Overlap with AIH was seen in 30%. Liver
biopsies (n=8) showed stage I (n=2), II (n=4) and III (n=2)
fibrosis. There were no significant differences in the HLA
profiles between PBC and AIH. Compared to the controls, PBC
patients had significantly more HLA class I alleles specifically
B7 (P=0.003), Cw7 (P=0.002) and Cw12 (P=0.007) but not the
class II alleles. At a median follow-up of 23.5 months (2 to 108),
all patients were alive without evidence of disease progression.
CONCLUSIONS: PBC is also a predominant female disorder in
our local setting and most had mild disease. The HLA profiles
of our patients were different to what have been reported.
(Hepatobiliary Pancreat Dis Int 2010; 9: 622-628)
Author Affiliations: Gastroenterology and Hepatology Unit, Department
of Medicine (Chong VH and Jalihal A) and Department of Pathology
(Telisinghe PU), Raja Isteri Pengiran Anak Saleha (RIPAS) Hospital, Bandar
Seri Begawan BA 1710, Brunei Darussalam
Corresponding Author: Vui Heng Chong, MRCP, FAMS, FRCP, Gastroenterology and Hepatology Unit, Department of Medicine, Raja Isteri
Pengiran Anak Saleha (RIPAS) Hospital, Bandar Seri Begawan BA 1710,
Brunei Darussalam (Tel: +673 8778218; Fax: +673 2242690; Email:
chongvuih@yahoo.co.uk)
© 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.
Introduction
P
rimary biliary cirrhosis (PBC) is a chronic
cholestatic autoimmune disease of the liver of
unknown etiologies that affects predominantly
middle aged females usually presenting between the fifth
and seventh decade.[1] It is characterized by the presence
of serum anti-mitochondrial antibody (AMA) against the
pyruvate dehydrogenase complex, an enzyme complex
that is found in the mitochondria and the slow progressive
destruction of the small bile ducts within the liver.[1] In the
early stages of the disease, most patients are asymptomatic
and may only have mild cholestatic liver profiles.
Like many other conditions, both genetic and
environmental factors have important roles in the
development of PBC.[2, 3] The human leukocytes antigens
(HLAs) DRB1*08 and DRB1*12 have been reported to
predispose to the development of PBC whereas DRB1*11
and DRB1*13 are protective according to studies in the
Western populations.[4] However, other studies have
not found such associations. Therefore some genetic
associations may be population or ethnic specific.[5] Data
on PBC in the Southeast Asia region are still limited.[6-10]
We present the clinical and HLA profiles of our patients
with PBC in Brunei Darussalam, a Malay predominant
developing nation.
Methods
All the patients diagnosed and followed up for PBC
were identified from three prospective databases: i)
the hepatology clinics register; ii) the Department of
Pathology register; and ii) the central pharmacy database.
They were identified to those who were prescribed
ursodeoxycholic acid (UDCA). We also contacted
hepatologists at the other district hospitals who were
involved in looking after patients with hepatic disorders
622 • Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com
Primary biliary cirrhosis in Brunei Darussalam
to ensure no patients who might have been missed from
the registries reviews. In our local setting, all patients
with hepatic abnormalities are usually referred to two
main referral centers for evaluations (RIPAS Hospital
and Suri Seri Begawan Hospital). Only those who do not
have any significant abnormalities are referred back to
the outpatient clinics for further management.
Diagnosis of PBC was based on the established
criteria: the presence of consistent clinical symptoms
and abnormal liver profiles, positivity for serum AMA
(≥1∶40) and histological changes consistent with PBC.[11]
Patients were categorized into definite diagnosis for PBC
if all three criteria were present or probable diagnosis if
only two of three criteria were present. Other causes of
cholestatic abnormal liver profiles such as medications,
ingested supplements, stones diseases and other causes
were excluded. Ultrasound scans of the abdomen were
done to exclude other causes such as gallstones diseases or
any space occupying lesions. Serum viral markers (HBsAg
and HCV IgG) and serum auto-antibodies (anti-nuclear
[ANA] and anti-smooth muscle [SMA) antibodies] were
routinely done. Patients were treated with ursodeoxycholic
acid (dose ranging from 10-15 mg/kg daily) with or
without other immuno-suppressants (prednisolone or
azathioprine), depending on whether there is overlap with
autoimmune disease.
Clinical information on the patients was assessed
in detail using pre-designed proforma for data
collections. Data on demography (age, gender and
race), presentations, treatments and outcomes were
retrieved from detailed case notes review. Laboratory
investigations (viral serology, liver function test, clotting
profiles, full blood counts and autoimmune markers)
were retrieved from the hospital computerized laboratory
system. For the purpose of this study, histology of all
the liver biopsies (n=8) were retrieved and reassessed by
a single pathologist. The histology was graded with the
established Scheuer scoring system.[12]
The HLA class I alleles and class II specific alleles
were tested prospectively. These tests were carried out
in collaboration with an established laboratory (Centre
for Transfusion Medicine [Clinical Laboratory], Health
Sciences Authority, Singapore). Class I antigens (HLA A,
B and C) were tested using the complement dependent
cytotoxic (CDC) method whereas the class II antigens
(HLA DR/DQ) were tested using the polymerase chain
reaction-sequence-specific oligonucleaotide technique
(PCR-SSO). Consents were obtained from patients prior
to testing. We collected data from the patients who were
potential donors or who had HLA assessment for various
medical conditions as controls for comparisons (n=65).
We also compared the HLA profiles of PBC patients with
those of our patients with autoimmune hepatitis (n=13).
We calculated the point prevalence by using the
population estimate data (2007) obtained from the
Population Census (Economic and Planning Unit,
Ministry of Finance). This consisted of 390 000 overall
with a breakdown of 206 900 for males and 183 100 for
females. The ethnic breakdown consisted of the Malays
68%, Chinese 12%, Indigenous 6% and others 14%.
Data were coded and entered in the Statistical Package
for Social Sciences (SPSS, Version 10.0, Chicago, Ill, USA)
for analysis. Continuous variables were expressed as
median and range and categorical variables expressed
as absolute number and percentage. We compared the
HLA profiles of the PBC patients with those controls and
patients with autoimmune hepatitis (AIH). The MannWhitney U test, Fisher's exact or the Chi-squared test
were used where appropriate. A P0.05, Mann-Whitney U test).
Table 3. Comparison of HLA class II alleles
HLA
AIH (n=13)
n (%)
Controls (n=65) PBC (n=9)
P for trend
n (%)
n (%)
DRB1*03 3 (23.1)
6 (9.2)
1 (11)
0.360
18 (27.7)
1 (11.1)
0.190
DRB1*04 6 (46.2)
DRB1*07 0 (0)
5 (7.7)
2 (22.2)
0.166
DRB1*08 1 (7.7)
6 (9.2)
0 (0)
0.633
DRB1*09 2 (15.4)
9 (9.2)
1 (11.1)
0.799
DRB1*10 1 (7.7)
0 (0)
0 (0)
0.056
DRB1*11 0 (0)
6 (9.2)
0 (0)
0.336
DRB1*12 2 (15.4)
25 (38.5)
2 (22.2)
0.207
DRB1*14
0 (0)
5 (7.7)
2 (22.2)
0.166
DRB1*15 6 (46.2)
32 (49.2)
6 (66.7)
0.582
DRB1*16 1 (7.7)
1 (1.5)
1 (11.1)
0.223
DRB3
5 (38.5)
39 (60.0)
5 (55.6)
0.360
DRB4
9 (69.2)
30 (46.2)
3 (33.3)
0.201
DRB5
8 (61.5)
31 (47.7)
7 (77.8)
0.189
DQB1*02 3 (23.1)
11 (16.9)
2 (22.2)
0.830
DQB1*03 7 (53.8)
43 (66.2)
4 (44.4)
0.227
DQB1*04 3 (23.1)
4 (6.2)
0 (0)
0.079
DQB1*05 8 (61.5)
37 (56.9)
7 (77.8)
0.484
DQB1*06 4 (30.8)
17 (26.2)
0 (0)
0.190
Statistical analysis using the Chi-square test and Fisher's exact test.
30% and persistence in 70%. On examination, 5 (50%)
patients showed symptoms such as jaundice (20%),
fatigue (20%), arthralgia (30%) and pruritus (20%).
None of our patients had decompensated liver disease.
Serum AMA was positive in 80% of the patients
(median 1∶320; range 1∶80 to 1∶640) and positive at
some points in 70%. Liver biopsies done in 8 patients
showed stage I (n=2), II (n=4) and III (n=2) fibrosis.
Based on histology and serum antibodies profiles,
overlap with AIH was present in 30% of the patients.
All patients were treated with UDCA and showed
Table 4. Comparisons of the HLA class I antigens between AIH
patients and controls
HLA
AIH (n=13)
(n, %)
Controls (n=65)
(n, %)
PBC (n=9)
(n, %)
A1
A2
A3
A11
A24
A33
A34
A74
B7
B13
B18
B27
B35
B38
B39
B44
B46
B51
B55
B56
B58
B60
B61
B62
B75
Cw1
Cw2
Cw3
Cw4
Cw5
Cw6
Cw7
0 (0)
3 (23.1)
0 (0)
6 (46.2)
6 (46.2)
2 (15.4)
4 (30.8)
0 (0)
3 (23.1)
0 (0)
4 (30.8)
0 (0)
2 (15.4)
3 (23.1)
0 (0)
0 (0)
0 (0)
0 (0)
1 (7.7)
0 (0)
3 (23.1)
3 (23.1)
0 (0)
1 (7.7)
4 (30.8)
0 (0)
0 (0)
3 (23.1)
6 (46.2)
0 (0)
0 (0)
9 (69.2)
2 (3.1)
12 (18.5)
4 (6.2)
28 (43.1)
40 (61.5)
11 (16.9)
12 (18.5)
2 (3.1)
1 (1.5)
3 (4.6)
6 (9.2)
6 (9.2)
7 (10.8)
12 (18.5)
3 (4.6)
3 (4.6)
2 (3.1)
12 (18.5)
0 (0)
4 (6.2)
6 (9.2)
14 (21.5)
8 (12.3)
8 (12.3)
15 (23.1)
7 (10.8)
4 (6.2)
13 (20.0)
19 (29.2)
2 (3.1)
4 (6.2)
23 (35.4)
Cw8
Cw12
1 (7.7)
0 (0)
16 (24.6)
0 (0)
0 (0)
2 (22.2)
1 (11.1)
5 (55.6)
5 (55.6)
2 (22.2)
2 (22.2)
0 (0)
2 (22.2)*
0 (0)
2 (22.2)
0 (0)
2 (22.2)
3 (33.3)
1 (11.1)
1 (11.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (22.2)
1 (11.1)
1 (11.1)
1 (11.1)
0 (0)
0 (0)
1 (11.1)
3 (33.3)
0 (0)
0 (0)
8 (88.9)*
2 (22.2)
1 (11.1)*
P for trend
0.707
0.908
0.525
0.775
0.578
0.908
0.602
0.707
0.003
0.591
0.090
0.336
0.594
0.572
0.473
0.473
0.707
0.095
0.056
0.492
0.183
0.992
0.412
0.892
0.559
0.276
0.492
0.771
0.490
0.707
0.492
0.002
0.403
0.012
Statistical analysis using the Chi-square test and Fisher's exact test. *:
P 0.05).
There were 8, 17 and 9 alleles detected for HLA A, B
and C class I alleles respectively. In the class II alleles,
13 and 5 HLA DRB1 and DQB1 alleles were detected
respectively. The most prevalent class I alelles in patients
with PBC were A11, A24 and Cw7, whereas DRB1*15,
DQB1*05 were the most prevalent class II antigens
(Tables 3 and 4). Compared with patients with AIH,
PBC patients demonstrated no significant differences
except slightly less DRB1*04 (P=0.083) and DQB1*06
(P=0.066) and more DRB1*07 (P=0.075) and DRB1*14
(P=0.075). Compared with the controls, PBC patients
had more HLA B7 (P=0.003), Cw7 (P=0.002), Cw12
(P=0.007), DRB1*16 (P=0.097), DRB5 (P=0.091) but
less DBQ1*06 (P=0.080).
Discussion
PBC is reported to be less common in Asians than
in the Westerners, which but have the same natural
history.[10, 13-15] Earlier studies reported lower rates of
PBC, which have been reported to be increasing in
recent years.[16-19] The increase has been attributed
to increasing awareness, better detection and more
rigorous epidemiological studies. This is also true in our
setting as most of the cases have been diagnosed in the
last few years.
The reported prevalence rates in Western contries
were estimated to be between 6.7/million and 940/
million population with the later figure representing
the prevalence rate for women of more than 40 years
old in the United Kingdom. The estimated annual
incidence is between 0.7/million and 49/million
population per year.[16-21] The highest rates are in the
northern hemispheres in countries like the United
Kingdom,[16] Scandinavia (In Sweden the prevalence
of 151/million and the mean annual incidence of
13.3/million, in Finland: 103/million in 1988 and 180/
million in 1999),[17, 20] Canada (an age adjusted annual
incidence of 30.0/million and a prevalence of 227/
million in 2002)[18] and the United States (Minnesota:
an age adjusted incidence of 27/million and an adjusted
prevalence of 402/million; Alaska: a prevalence of
160/million).[19, 21] Among the Caucasian population,
the lowest rate has been reported from Australia (a
prevalence of 19.1/million and a higher prevalence
in women of 24 years old with 51/million).[22] To date,
there are little or no data available on the rates in the
Asia Pacific region. The prevalence, incidence and rate
of the disease in the female population in the present
study were much lower those reported in the western
countries. Interestingly, these results are comparable to
those reported from Australia. However, this study was
reported more than 15 years ago. Among the different
ethnic groups, both our Chinese (41.15/million) and
Indigenous (42.74/million) populations had rates almost
twice of the Malays (22.62/million), indicating genetic
predispositions. None of the previously reported studies
from the Southeast Asia had reported the prevalence
and incidence rates as most studies were center-based,
not population based.[6-10] Given the similarities in the
population demographic and genetic make up in some
nations of the Southeast Asia, especially Malaysia and
Singapore, it is very likely that their prevalence and
incidence rates will be comparable to what we have
reported.
The profiles of our patients are in agreement with
previous reports from our region and the rest of the
world.[6-10] All our patients were females with a median
age of 51 years at diagnosis of the disease. A recent study
from Singapore showed that 97% of the affected were
females with a mean age of 55 years at diagnosis and
81% were positive for AMA.[10] Other two earlier studies
from Singapore both in small case series also showed
similar characteristics. To date, there are only two
studies that specifically looked at PBC in a predominant
Malay population.[6, 7] The first study based on seven
patients over a 12-year period showed that all of the
affected were female Chinese with age ranging from
30 to 55 years. The later study identified 17 cases in a
period of 8 years with a female to male ratio of 3.25∶1
and mean age of 45.9 years (range 14 to 67 years ) at
presentation. Both studies showed that Chinese were at
higher risk and a majority of them were symptomatic
(jaundice, fatigue and pruritus) at presentation.[6, 7]
Our study also showed ethnic differences. Studies from
other parts of Asia other than Southeast Asia have also
reported similar findings.[13, 14, 23]
The clinical manifestations of PBC have changed
from predominantly symptomatic to asymptomatic at
the time of diagnosis. Fifty percent of our patients were
asymptomatic and interestingly even among those with
symptoms; their symptoms were not the main reason
for referrals. The spectrums of symptoms attributable
to PBC were also comparable to the reported rates.
Interestingly, none of our patients had advanced or
decompensated liver disease at diagnosis. Unlike earlier
studies that showed advanced disease at diagnosis, a
recent study from Singapore reported that 50% of the
patients were asymptomatic at diagnosis.[8-10] This
change has largely been attributed to earlier diagnosis.
Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com • 625
Hepatobiliary & Pancreatic Diseases International
In many regions, however, a large proportion of patients
with PBC is still diagnosed at advanced stage of the
disease depending on the health care coverage, and
patients' health seeking behaviors. Ethnic background
has also associated with differences in the disease
profiles. In the United States, non-Caucasian patients
are more likely to have advanced liver disease at
diagnosis.[24] Similarly, an Indian study showed that
Indian patients have advanced diseases (40%) and are
diagnosed at younger ages.[23]
Most patients will progress with follow-up, more
rapid in those who are symptomatic at diagnosis. After
a median follow-up of approximately 2 years, none
of our patients had evidence of disease progression.
However, the duration of follow-up in our study was
short. In a study from Singapore, disease progressions
were noted in 15.6% and 31% of the patients at 5 and 10
years respectively.[10] Serum bilirubin level, prothrombin
time, albumin, alkaline phosphatase and high density
lipoprotein (HDL) at the time of diagnosis were shown
to be predictive factors of disease progression. Not
surprisingly, in the Mayo natural history model, age,
serum bilirubin and albumin, prothrombin time,
presence or absence of ankle edema and diuretics were
used to predict survival without treatment. Use of
UDCA especially in the early stages has been shown to
cause biochemical improvement and even histological
regression. However, controversies remain as other
studies have not found similar findings.
Genetic factors have been reported to be important.
Familial predisposition for PBC among first degrees
relatives has been estimated to be around 5%.[25]
Genetic predisposition has been reported to be related
to maternally inherited factors and to present in the
second generations being most common in motherdaughter or sister-sister combination.[26, 27] Concordance
has been shown to be higher among monozygotic twins
with similar age of onset of disease but differences in the
natural history and disease severity.[28] This suggests the
importance of environmental factors in the pathogenesis
of PBC.
HLA DRB1*08 and DRB1*12 predispose to the
development of PBC, whereas DRB1*11 and DRB1*13
are protective according to the studies on the Caucasians
populations.[4] Other studies based on different populations have not reported such findings but different
protective and predisposing alleles (Table 5).[2-4, 29-39] To
date, most studies on the HLA association from the
Asia Pacific region come from Japan. In Japan, HLA
DR1*08 association has also been reported but it is
weaker. HLA DQA1*0102 has also been shown to be
protective.[37, 38] A Chinese study revealed that only HLA
Table 5. Reported HLA antigens and association with PBC
Regions associations#
Prevalent HLA
antigens
Europe
United Kingdom[5] DRB1*08
Sweden[2, 3, 30]
Italy[4, 5]
B15, B41, B55, B58
Germany[31]
Denmark[32]
South America
Brazil[36]
Asia
Japan[28, 37]
China[39]
DRB1*13
DRB1*08, DQB1*0402
DRB1*08, DRB1*11,
DRB1*13
DPB1*0301
B8, DR3, DQA1*0501,
DQB1*0201
North America
United States[1, 29, 33]
Canada[34]##
Mexico[35]
Significance
B14, B39, B52,
DRB1*04, DRB1*01
DRB1*0801, DQB1*04,
DQA1*0401 DRB1*1501,
DQA1*0102, DQB1*0602,
DRB1*1302, DQB1*0604
DRB1*0801, DQB1*04
None detected
None detected
DR8, DQA1*0103,
DQB1*0601
DR8(DRB1*0803),
PB1*501 DQA1*0102,
DPB1*0402
A2, A9, A11, A19
DRB1*0701, DRB1*03,
DRB1*12
Southeast Asia
Present study
A11, A24, Cw7
B7, Cw7, Cw12
DRB1*15, DQB1*05
#: In significant association column. 1) Alleles highlighted in bold
italic in are found lower in frequency in PBC patients and have
protective effect; 2) Alleles highlighted in normal font are found higher
in frequency in PBC patients and have predisposing effect. ##: AMA
negative patients may have different genetic susceptibility to AMA
positive patients. DRB1*0801 and DQB1*04 that were significantly
more in AMA positive PBC were not found in AMA negative PBC.[34]
DRB1*0701 was significantly associated with PBC.[39]
To date, there has been no study on the profiles of PBC
among Malay patients. Compared to the control group,
our PBC patients had significantly more HLA B7, Cw7
and Cw12. Among the class II antigens, DRB1*16 and
DRB5 were more common and DQB1*06 was less but
all of these were not significant. Interestingly, a study
on Caucasian patients with PBC showed that the genetic
predisposition between AMA-positive and AMAnegative PBC may be different.[34] HLA-DRB1*08 and
DQB1*04 were found in the AMA-positive PBC patients
but not in AMA-negative patients. The importance of
class I antigens is unknown.
It is clear that there are strong genetic predispositions to PBC. However, it is also clear that there
are differences between different populations. As more
626 • Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com
Primary biliary cirrhosis in Brunei Darussalam
large-scale study. Hepatology 2006;44:667-674.
6 Kananathan R, Suresh RL, Merican I. Primary biliary
cirrhosis at Hospital Kuala Lumpur: a study of 17 cases seen
between 1992 and 1999. Med J Malaysia 2002;57:56-60.
7 Mohammed R, Goh KL, Wong NW. Primary biliary
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Med J Malaysia 1996;51:99-102.
8 Chong RS, Ng HS, Seah CS. Primary biliary cirrhosis: a
description of four cases. Singapore Med J 1988;29:68-71.
9 Yap I, Wee A, Tay HH, Guan R, Kang JY. Primary biliary
cirrhosis--an uncommon disease in Singapore. Singapore
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10 Wong RK, Lim SG, Wee A, Chan YH, Aung MO, Wai
CT. Primary biliary cirrhosis in Singapore: evaluation of
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11 Heathcote EJ. Management of primary biliary cirrhosis. The
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12 Scheuer P. Primary biliary cirrhosis. Proc R Soc Med 1967;60:
1257-1260.
13 Wong GL, Law FM, Wong VW, Hui AY, Chan FK, Sung JJ,
et al. Health-related quality of life in Chinese patients with
primary biliary cirrhosis. J Gastroenterol Hepatol 2008;23:
592-598.
14 Su CW, Hung HH, Huo TI, Huang YH, Li CP, Lin HC, et
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15 Farrell GC. Primary biliary cirrhosis in Asians: less common
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Hepatol 2008;23:508-511.
16 James OF, Bhopal R, Howel D, Gray J, Burt AD, Metcalf JV.
Primary biliary cirrhosis once rare, now common in the
Funding: None.
United Kingdom? Hepatology 1999;30:390-394.
Ethical approval: Not needed.
Contributors: CVH and JA conceived the idea for the study. CVH 17 Rautiainen H, Salomaa V, Niemelå S, Karvonen AL, Nurmi H,
Isoniemi H, et al. Prevalence and incidence of primary biliary
collected, analyzed, interpreted the data and wrote the first draft of
cirrhosis are increasing in Finland. Scand J Gastroenterol
the manuscript. TPU assessed the histology. All authors approved
2007;42:1347-1353.
the final manuscript. CVH is the guarantor.
Competing interest: No benefits in any form have been received 18 Myers RP, Shaheen AA, Fong A, Burak KW, Wan A, Swain
MG, et al. Epidemiology and natural history of primary
or will be received from a commercial party related directly or
biliary cirrhosis in a Canadian health region: a populationindirectly to the subject of this article.
based study. Hepatology 2009;50:1884-1892.
19 Kim WR, Lindor KD, Locke GR 3rd, Therneau TM,
Homburger HA, Batts KP, et al. Epidemiology and natural
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21 Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B,
9:45-51.
Williams JL, Kowdley KV. Prevalence of autoimmune liver
3 Selmi C, Gershwin ME. The role of environmental factors in
disease in Alaska Natives. Am J Gastroenterol 2002;97:2402primary biliary cirrhosis. Trends Immunol 2009;30:415-420.
2407.
4 Invernizzi P, Selmi C, Poli F, Frison S, Floreani A, Alvaro D,
et al. Human leukocyte antigen polymorphisms in Italian 22 Watson RG, Angus PW, Dewar M, Goss B, Sewell RB,
Smallwood RA. Low prevalence of primary biliary cirrhosis
primary biliary cirrhosis: a multicenter study of 664 patients
in Victoria, Australia. Melbourne Liver Group. Gut 1995;36:
and 1992 healthy controls. Hepatology 2008;48:1906-1912.
927-930.
5 Donaldson PT, Baragiotta A, Heneghan MA, Floreani A,
Venturi C, Underhill JA, et al. HLA class II alleles, genotypes, 23 Sarin SK, Monga R, Sandhu BS, Sharma BC, Sakhuja P,
Malhotra V. Primary biliary cirrhosis in India. Hepatobiliary
haplotypes, and amino acids in primary biliary cirrhosis: a
sensitive tests are developed, more associations will be
found with newer and more specific alleles, making
the roles of HLA in PBC more complex. Generally,
some genetic associations may be population or ethnic
specific.[5] Therefore, use of HLA markers in PBC should
be tailored depending on regions as well as ethnicity and
genetic background of patients.
Compared to AIH, another autoimmune disorder,
we did not find any significant differences in the present
study. HLA DR3 (DRB1*0301) and DR4 (DRB1*0401)
are reported to be very common in AIH, in particular
DR3.[40] Therefore, the HLA predisposition to PBC
seems to be completely different to AIH.
The main limitation in our study is the small sample
size. However, we believe that the number is true as
the overall population of our country is small. The
calculated rates that we were found were comparable to
the reported rates. The main strength of our paper is the
ability to capture the data from the whole population. If
several reliable databases were sued, it would not have
missed any cases under follow-up.
In conclusion, the prevalence rates of PBC in our
country are comparable to the reported rates. Most of
the PBC cases are diagnosed at the early stages and are
asymptomatic as diagnosed by evaluation of abnormal
liver profiles. The overall profiles are also comparable
to those reported in the literature. However, the HLA
profiles are different to those of Caucasian patients.
Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com • 627
Hepatobiliary & Pancreatic Diseases International
Pancreat Dis Int 2006;5:105-109.
24 Peters MG, Di Bisceglie AM, Kowdley KV, Flye NL, Luketic
VA, Munoz SJ, et al. Differences between Caucasian, African
American, and Hispanic patients with primary biliary
cirrhosis in the United States. Hepatology 2007;46:769-775.
25 Jones DE, Watt FE, Metcalf JV, Bassendine MF, James
OF. Familial primary biliary cirrhosis reassessed: a
geographically-based population study. J Hepatol 1999;30:
402-407.
26 Brind AM, Bray GP, Portmann BC, Williams R. Prevalence
and pattern of familial disease in primary biliary cirrhosis.
Gut 1995;36:615-617.
27 Bittencourt PL, Farias AQ, Abrantes-Lemos CP, Goncalves
LL, Goncalves PL, Magalhães EP, et al. Prevalence of immune
disturbances and chronic liver disease in family members
of patients with primary biliary cirrhosis. J Gastroenterol
Hepatol 2004;19:873-878.
28 Selmi C, Mayo MJ, Bach N, Ishibashi H, Invernizzi P, Gish
RG, et al. Primary biliary cirrhosis in monozygotic and
dizygotic twins: genetics, epigenetics, and environment.
Gastroenterology 2004;127:485-492.
29 Mullarkey ME, Stevens AM, McDonnell WM, Loubière LS,
Brackensick JA, Pang JM, et al. Human leukocyte antigen
class II alleles in Caucasian women with primary biliary
cirrhosis. Tissue Antigens 2005;65:199-205.
30 Wassmuth R, Depner F, Danielsson A, Hultcrantz R,
Lööf L, Olson R, et al. HLA class II markers and clinical
heterogeneity in Swedish patients with primary biliary
cirrhosis. Tissue Antigens 2002;59:381-387.
31 Mella JG, Roschmann E, Maier KP, Volk BA. Association of
primary biliary cirrhosis with the allele HLA-DPB1*0301 in a
German population. Hepatology 1995;21:398-402.
32 Morling N, Dalhoff K, Fugger L, Georgsen J, Jakobsen B,
Ranek L, et al. DNA polymorphism of HLA class II genes in
primary biliary cirrhosis. Immunogenetics 1992;35:112-116.
33 Begovich AB, Klitz W, Moonsamy PV, Van de Water J, Peltz
34
35
36
37
38
39
40
G, Gershwin ME. Genes within the HLA class II region
confer both predisposition and resistance to primary biliary
cirrhosis. Tissue Antigens 1994;43:71-77.
Stone J, Wade JA, Cauch-Dudek K, Ng C, Lindor KD,
Heathcote EJ. Human leukocyte antigen Class II associations
in serum antimitochondrial antibodies (AMA)-positive and
AMA-negative primary biliary cirrhosis. J Hepatol 2002;36:
8-13.
Vázquez-Elizondo G, Ponciano-Rodríguez G, Uribe M,
Méndez-Sánchez N. Human leukocyte antigens among
primary biliary cirrhosis patients born in Mexico. Ann
Hepatol 2009;8:32-37.
Bittencourt PL, Palácios SA, Farias AQ, Abrantes-Lemos
CP, Cançado EL, Carrilho FJ, et al. Analysis of major
histocompatibility complex and CTLA-4 alleles in Brazilian
patients with primary biliary cirrhosis. J Gastroenterol
Hepatol 2003;18:1061-1066.
Onishi S, Sakamaki T, Maeda T, Iwamura S, Tomita
A, Saibara T, et al. DNA typing of HLA class II genes;
DRB1*0803 increases the susceptibility of Japanese to
primary biliary cirrhosis. J Hepatol 1994;21:1053-1060.
Seki T, Kiyosawa K, Ota M, Furuta S, Fukushima H, Tanaka
E, et al. Association of primary biliary cirrhosis with
human leukocyte antigen DPB1*0501 in Japanese patients.
Hepatology 1993;18:73-78.
Liu HY, Deng AM, Zhou Y, Yao DK, Xu DX, Zhong RQ.
Analysis of HLA alleles polymorphism in Chinese patients
with primary biliary cirrhosis. Hepatobiliary Pancreat Dis
Int 2006;5:129-132.
Czaja AJ, Freese DK; American Association for the Study
of Liver Disease. Diagnosis and treatment of autoimmune
hepatitis. Hepatology 2002;36:479-497.
Received April 26, 2010
Accepted after revision August 21, 2010
628 • Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com
Primary biliary cirrhosis in Brunei Darussalam
Vui Heng Chong, Pemasiri Upali Telisinghe and Anand Jalihal
Bandar Seri Begawan, Brunei Darussalam
BACKGROUND: Primary biliary cirrhosis (PBC) is an uncom- KEY WORDS: primary biliary cirrhosis;
cholestasis;
mon autoimmune cholestatic disease that predominantly
chronic liver disease;
affects women. Certain human leukocyte antigens (HLAs)
human leukocyte antigen;
have been reported to be associated with susceptibility for
Southeast Asian
PBC. We describe the profiles of PBC in Brunei Darussalam.
METHODS: All patients with PBC (n=10) were identified from
our prospective databases. The HLA profiles (n=9, PBC) were
compared to controls (n=65) and patients with autoimmune
hepatitis (n=13, AIH).
RESULTS: All patients were women with a median age of 51
years (27-83) at diagnosis. The prevalence rate of the disease
was 25.6/million-population and the estimated incidence rate
varied from 0 to 10.3/million-population per year. Chinese
(41.15/million) and the indigenous (42.74/million) groups
had higher prevalence rates compared to Malays (22.62/
million). The prevalence among female population was 54.6/
million-population. All patients were referred for abnormal
liver profiles. Five patients had symptoms at presentations:
jaundice (20%), fatigue (20%), arthralgia (30%) and pruritus
(20%). Serum anti-mitochondrial antibody was positive in
80% of the patients. Overlap with AIH was seen in 30%. Liver
biopsies (n=8) showed stage I (n=2), II (n=4) and III (n=2)
fibrosis. There were no significant differences in the HLA
profiles between PBC and AIH. Compared to the controls, PBC
patients had significantly more HLA class I alleles specifically
B7 (P=0.003), Cw7 (P=0.002) and Cw12 (P=0.007) but not the
class II alleles. At a median follow-up of 23.5 months (2 to 108),
all patients were alive without evidence of disease progression.
CONCLUSIONS: PBC is also a predominant female disorder in
our local setting and most had mild disease. The HLA profiles
of our patients were different to what have been reported.
(Hepatobiliary Pancreat Dis Int 2010; 9: 622-628)
Author Affiliations: Gastroenterology and Hepatology Unit, Department
of Medicine (Chong VH and Jalihal A) and Department of Pathology
(Telisinghe PU), Raja Isteri Pengiran Anak Saleha (RIPAS) Hospital, Bandar
Seri Begawan BA 1710, Brunei Darussalam
Corresponding Author: Vui Heng Chong, MRCP, FAMS, FRCP, Gastroenterology and Hepatology Unit, Department of Medicine, Raja Isteri
Pengiran Anak Saleha (RIPAS) Hospital, Bandar Seri Begawan BA 1710,
Brunei Darussalam (Tel: +673 8778218; Fax: +673 2242690; Email:
chongvuih@yahoo.co.uk)
© 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.
Introduction
P
rimary biliary cirrhosis (PBC) is a chronic
cholestatic autoimmune disease of the liver of
unknown etiologies that affects predominantly
middle aged females usually presenting between the fifth
and seventh decade.[1] It is characterized by the presence
of serum anti-mitochondrial antibody (AMA) against the
pyruvate dehydrogenase complex, an enzyme complex
that is found in the mitochondria and the slow progressive
destruction of the small bile ducts within the liver.[1] In the
early stages of the disease, most patients are asymptomatic
and may only have mild cholestatic liver profiles.
Like many other conditions, both genetic and
environmental factors have important roles in the
development of PBC.[2, 3] The human leukocytes antigens
(HLAs) DRB1*08 and DRB1*12 have been reported to
predispose to the development of PBC whereas DRB1*11
and DRB1*13 are protective according to studies in the
Western populations.[4] However, other studies have
not found such associations. Therefore some genetic
associations may be population or ethnic specific.[5] Data
on PBC in the Southeast Asia region are still limited.[6-10]
We present the clinical and HLA profiles of our patients
with PBC in Brunei Darussalam, a Malay predominant
developing nation.
Methods
All the patients diagnosed and followed up for PBC
were identified from three prospective databases: i)
the hepatology clinics register; ii) the Department of
Pathology register; and ii) the central pharmacy database.
They were identified to those who were prescribed
ursodeoxycholic acid (UDCA). We also contacted
hepatologists at the other district hospitals who were
involved in looking after patients with hepatic disorders
622 • Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com
Primary biliary cirrhosis in Brunei Darussalam
to ensure no patients who might have been missed from
the registries reviews. In our local setting, all patients
with hepatic abnormalities are usually referred to two
main referral centers for evaluations (RIPAS Hospital
and Suri Seri Begawan Hospital). Only those who do not
have any significant abnormalities are referred back to
the outpatient clinics for further management.
Diagnosis of PBC was based on the established
criteria: the presence of consistent clinical symptoms
and abnormal liver profiles, positivity for serum AMA
(≥1∶40) and histological changes consistent with PBC.[11]
Patients were categorized into definite diagnosis for PBC
if all three criteria were present or probable diagnosis if
only two of three criteria were present. Other causes of
cholestatic abnormal liver profiles such as medications,
ingested supplements, stones diseases and other causes
were excluded. Ultrasound scans of the abdomen were
done to exclude other causes such as gallstones diseases or
any space occupying lesions. Serum viral markers (HBsAg
and HCV IgG) and serum auto-antibodies (anti-nuclear
[ANA] and anti-smooth muscle [SMA) antibodies] were
routinely done. Patients were treated with ursodeoxycholic
acid (dose ranging from 10-15 mg/kg daily) with or
without other immuno-suppressants (prednisolone or
azathioprine), depending on whether there is overlap with
autoimmune disease.
Clinical information on the patients was assessed
in detail using pre-designed proforma for data
collections. Data on demography (age, gender and
race), presentations, treatments and outcomes were
retrieved from detailed case notes review. Laboratory
investigations (viral serology, liver function test, clotting
profiles, full blood counts and autoimmune markers)
were retrieved from the hospital computerized laboratory
system. For the purpose of this study, histology of all
the liver biopsies (n=8) were retrieved and reassessed by
a single pathologist. The histology was graded with the
established Scheuer scoring system.[12]
The HLA class I alleles and class II specific alleles
were tested prospectively. These tests were carried out
in collaboration with an established laboratory (Centre
for Transfusion Medicine [Clinical Laboratory], Health
Sciences Authority, Singapore). Class I antigens (HLA A,
B and C) were tested using the complement dependent
cytotoxic (CDC) method whereas the class II antigens
(HLA DR/DQ) were tested using the polymerase chain
reaction-sequence-specific oligonucleaotide technique
(PCR-SSO). Consents were obtained from patients prior
to testing. We collected data from the patients who were
potential donors or who had HLA assessment for various
medical conditions as controls for comparisons (n=65).
We also compared the HLA profiles of PBC patients with
those of our patients with autoimmune hepatitis (n=13).
We calculated the point prevalence by using the
population estimate data (2007) obtained from the
Population Census (Economic and Planning Unit,
Ministry of Finance). This consisted of 390 000 overall
with a breakdown of 206 900 for males and 183 100 for
females. The ethnic breakdown consisted of the Malays
68%, Chinese 12%, Indigenous 6% and others 14%.
Data were coded and entered in the Statistical Package
for Social Sciences (SPSS, Version 10.0, Chicago, Ill, USA)
for analysis. Continuous variables were expressed as
median and range and categorical variables expressed
as absolute number and percentage. We compared the
HLA profiles of the PBC patients with those controls and
patients with autoimmune hepatitis (AIH). The MannWhitney U test, Fisher's exact or the Chi-squared test
were used where appropriate. A P0.05, Mann-Whitney U test).
Table 3. Comparison of HLA class II alleles
HLA
AIH (n=13)
n (%)
Controls (n=65) PBC (n=9)
P for trend
n (%)
n (%)
DRB1*03 3 (23.1)
6 (9.2)
1 (11)
0.360
18 (27.7)
1 (11.1)
0.190
DRB1*04 6 (46.2)
DRB1*07 0 (0)
5 (7.7)
2 (22.2)
0.166
DRB1*08 1 (7.7)
6 (9.2)
0 (0)
0.633
DRB1*09 2 (15.4)
9 (9.2)
1 (11.1)
0.799
DRB1*10 1 (7.7)
0 (0)
0 (0)
0.056
DRB1*11 0 (0)
6 (9.2)
0 (0)
0.336
DRB1*12 2 (15.4)
25 (38.5)
2 (22.2)
0.207
DRB1*14
0 (0)
5 (7.7)
2 (22.2)
0.166
DRB1*15 6 (46.2)
32 (49.2)
6 (66.7)
0.582
DRB1*16 1 (7.7)
1 (1.5)
1 (11.1)
0.223
DRB3
5 (38.5)
39 (60.0)
5 (55.6)
0.360
DRB4
9 (69.2)
30 (46.2)
3 (33.3)
0.201
DRB5
8 (61.5)
31 (47.7)
7 (77.8)
0.189
DQB1*02 3 (23.1)
11 (16.9)
2 (22.2)
0.830
DQB1*03 7 (53.8)
43 (66.2)
4 (44.4)
0.227
DQB1*04 3 (23.1)
4 (6.2)
0 (0)
0.079
DQB1*05 8 (61.5)
37 (56.9)
7 (77.8)
0.484
DQB1*06 4 (30.8)
17 (26.2)
0 (0)
0.190
Statistical analysis using the Chi-square test and Fisher's exact test.
30% and persistence in 70%. On examination, 5 (50%)
patients showed symptoms such as jaundice (20%),
fatigue (20%), arthralgia (30%) and pruritus (20%).
None of our patients had decompensated liver disease.
Serum AMA was positive in 80% of the patients
(median 1∶320; range 1∶80 to 1∶640) and positive at
some points in 70%. Liver biopsies done in 8 patients
showed stage I (n=2), II (n=4) and III (n=2) fibrosis.
Based on histology and serum antibodies profiles,
overlap with AIH was present in 30% of the patients.
All patients were treated with UDCA and showed
Table 4. Comparisons of the HLA class I antigens between AIH
patients and controls
HLA
AIH (n=13)
(n, %)
Controls (n=65)
(n, %)
PBC (n=9)
(n, %)
A1
A2
A3
A11
A24
A33
A34
A74
B7
B13
B18
B27
B35
B38
B39
B44
B46
B51
B55
B56
B58
B60
B61
B62
B75
Cw1
Cw2
Cw3
Cw4
Cw5
Cw6
Cw7
0 (0)
3 (23.1)
0 (0)
6 (46.2)
6 (46.2)
2 (15.4)
4 (30.8)
0 (0)
3 (23.1)
0 (0)
4 (30.8)
0 (0)
2 (15.4)
3 (23.1)
0 (0)
0 (0)
0 (0)
0 (0)
1 (7.7)
0 (0)
3 (23.1)
3 (23.1)
0 (0)
1 (7.7)
4 (30.8)
0 (0)
0 (0)
3 (23.1)
6 (46.2)
0 (0)
0 (0)
9 (69.2)
2 (3.1)
12 (18.5)
4 (6.2)
28 (43.1)
40 (61.5)
11 (16.9)
12 (18.5)
2 (3.1)
1 (1.5)
3 (4.6)
6 (9.2)
6 (9.2)
7 (10.8)
12 (18.5)
3 (4.6)
3 (4.6)
2 (3.1)
12 (18.5)
0 (0)
4 (6.2)
6 (9.2)
14 (21.5)
8 (12.3)
8 (12.3)
15 (23.1)
7 (10.8)
4 (6.2)
13 (20.0)
19 (29.2)
2 (3.1)
4 (6.2)
23 (35.4)
Cw8
Cw12
1 (7.7)
0 (0)
16 (24.6)
0 (0)
0 (0)
2 (22.2)
1 (11.1)
5 (55.6)
5 (55.6)
2 (22.2)
2 (22.2)
0 (0)
2 (22.2)*
0 (0)
2 (22.2)
0 (0)
2 (22.2)
3 (33.3)
1 (11.1)
1 (11.1)
0 (0)
0 (0)
0 (0)
0 (0)
0 (0)
2 (22.2)
1 (11.1)
1 (11.1)
1 (11.1)
0 (0)
0 (0)
1 (11.1)
3 (33.3)
0 (0)
0 (0)
8 (88.9)*
2 (22.2)
1 (11.1)*
P for trend
0.707
0.908
0.525
0.775
0.578
0.908
0.602
0.707
0.003
0.591
0.090
0.336
0.594
0.572
0.473
0.473
0.707
0.095
0.056
0.492
0.183
0.992
0.412
0.892
0.559
0.276
0.492
0.771
0.490
0.707
0.492
0.002
0.403
0.012
Statistical analysis using the Chi-square test and Fisher's exact test. *:
P 0.05).
There were 8, 17 and 9 alleles detected for HLA A, B
and C class I alleles respectively. In the class II alleles,
13 and 5 HLA DRB1 and DQB1 alleles were detected
respectively. The most prevalent class I alelles in patients
with PBC were A11, A24 and Cw7, whereas DRB1*15,
DQB1*05 were the most prevalent class II antigens
(Tables 3 and 4). Compared with patients with AIH,
PBC patients demonstrated no significant differences
except slightly less DRB1*04 (P=0.083) and DQB1*06
(P=0.066) and more DRB1*07 (P=0.075) and DRB1*14
(P=0.075). Compared with the controls, PBC patients
had more HLA B7 (P=0.003), Cw7 (P=0.002), Cw12
(P=0.007), DRB1*16 (P=0.097), DRB5 (P=0.091) but
less DBQ1*06 (P=0.080).
Discussion
PBC is reported to be less common in Asians than
in the Westerners, which but have the same natural
history.[10, 13-15] Earlier studies reported lower rates of
PBC, which have been reported to be increasing in
recent years.[16-19] The increase has been attributed
to increasing awareness, better detection and more
rigorous epidemiological studies. This is also true in our
setting as most of the cases have been diagnosed in the
last few years.
The reported prevalence rates in Western contries
were estimated to be between 6.7/million and 940/
million population with the later figure representing
the prevalence rate for women of more than 40 years
old in the United Kingdom. The estimated annual
incidence is between 0.7/million and 49/million
population per year.[16-21] The highest rates are in the
northern hemispheres in countries like the United
Kingdom,[16] Scandinavia (In Sweden the prevalence
of 151/million and the mean annual incidence of
13.3/million, in Finland: 103/million in 1988 and 180/
million in 1999),[17, 20] Canada (an age adjusted annual
incidence of 30.0/million and a prevalence of 227/
million in 2002)[18] and the United States (Minnesota:
an age adjusted incidence of 27/million and an adjusted
prevalence of 402/million; Alaska: a prevalence of
160/million).[19, 21] Among the Caucasian population,
the lowest rate has been reported from Australia (a
prevalence of 19.1/million and a higher prevalence
in women of 24 years old with 51/million).[22] To date,
there are little or no data available on the rates in the
Asia Pacific region. The prevalence, incidence and rate
of the disease in the female population in the present
study were much lower those reported in the western
countries. Interestingly, these results are comparable to
those reported from Australia. However, this study was
reported more than 15 years ago. Among the different
ethnic groups, both our Chinese (41.15/million) and
Indigenous (42.74/million) populations had rates almost
twice of the Malays (22.62/million), indicating genetic
predispositions. None of the previously reported studies
from the Southeast Asia had reported the prevalence
and incidence rates as most studies were center-based,
not population based.[6-10] Given the similarities in the
population demographic and genetic make up in some
nations of the Southeast Asia, especially Malaysia and
Singapore, it is very likely that their prevalence and
incidence rates will be comparable to what we have
reported.
The profiles of our patients are in agreement with
previous reports from our region and the rest of the
world.[6-10] All our patients were females with a median
age of 51 years at diagnosis of the disease. A recent study
from Singapore showed that 97% of the affected were
females with a mean age of 55 years at diagnosis and
81% were positive for AMA.[10] Other two earlier studies
from Singapore both in small case series also showed
similar characteristics. To date, there are only two
studies that specifically looked at PBC in a predominant
Malay population.[6, 7] The first study based on seven
patients over a 12-year period showed that all of the
affected were female Chinese with age ranging from
30 to 55 years. The later study identified 17 cases in a
period of 8 years with a female to male ratio of 3.25∶1
and mean age of 45.9 years (range 14 to 67 years ) at
presentation. Both studies showed that Chinese were at
higher risk and a majority of them were symptomatic
(jaundice, fatigue and pruritus) at presentation.[6, 7]
Our study also showed ethnic differences. Studies from
other parts of Asia other than Southeast Asia have also
reported similar findings.[13, 14, 23]
The clinical manifestations of PBC have changed
from predominantly symptomatic to asymptomatic at
the time of diagnosis. Fifty percent of our patients were
asymptomatic and interestingly even among those with
symptoms; their symptoms were not the main reason
for referrals. The spectrums of symptoms attributable
to PBC were also comparable to the reported rates.
Interestingly, none of our patients had advanced or
decompensated liver disease at diagnosis. Unlike earlier
studies that showed advanced disease at diagnosis, a
recent study from Singapore reported that 50% of the
patients were asymptomatic at diagnosis.[8-10] This
change has largely been attributed to earlier diagnosis.
Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com • 625
Hepatobiliary & Pancreatic Diseases International
In many regions, however, a large proportion of patients
with PBC is still diagnosed at advanced stage of the
disease depending on the health care coverage, and
patients' health seeking behaviors. Ethnic background
has also associated with differences in the disease
profiles. In the United States, non-Caucasian patients
are more likely to have advanced liver disease at
diagnosis.[24] Similarly, an Indian study showed that
Indian patients have advanced diseases (40%) and are
diagnosed at younger ages.[23]
Most patients will progress with follow-up, more
rapid in those who are symptomatic at diagnosis. After
a median follow-up of approximately 2 years, none
of our patients had evidence of disease progression.
However, the duration of follow-up in our study was
short. In a study from Singapore, disease progressions
were noted in 15.6% and 31% of the patients at 5 and 10
years respectively.[10] Serum bilirubin level, prothrombin
time, albumin, alkaline phosphatase and high density
lipoprotein (HDL) at the time of diagnosis were shown
to be predictive factors of disease progression. Not
surprisingly, in the Mayo natural history model, age,
serum bilirubin and albumin, prothrombin time,
presence or absence of ankle edema and diuretics were
used to predict survival without treatment. Use of
UDCA especially in the early stages has been shown to
cause biochemical improvement and even histological
regression. However, controversies remain as other
studies have not found similar findings.
Genetic factors have been reported to be important.
Familial predisposition for PBC among first degrees
relatives has been estimated to be around 5%.[25]
Genetic predisposition has been reported to be related
to maternally inherited factors and to present in the
second generations being most common in motherdaughter or sister-sister combination.[26, 27] Concordance
has been shown to be higher among monozygotic twins
with similar age of onset of disease but differences in the
natural history and disease severity.[28] This suggests the
importance of environmental factors in the pathogenesis
of PBC.
HLA DRB1*08 and DRB1*12 predispose to the
development of PBC, whereas DRB1*11 and DRB1*13
are protective according to the studies on the Caucasians
populations.[4] Other studies based on different populations have not reported such findings but different
protective and predisposing alleles (Table 5).[2-4, 29-39] To
date, most studies on the HLA association from the
Asia Pacific region come from Japan. In Japan, HLA
DR1*08 association has also been reported but it is
weaker. HLA DQA1*0102 has also been shown to be
protective.[37, 38] A Chinese study revealed that only HLA
Table 5. Reported HLA antigens and association with PBC
Regions associations#
Prevalent HLA
antigens
Europe
United Kingdom[5] DRB1*08
Sweden[2, 3, 30]
Italy[4, 5]
B15, B41, B55, B58
Germany[31]
Denmark[32]
South America
Brazil[36]
Asia
Japan[28, 37]
China[39]
DRB1*13
DRB1*08, DQB1*0402
DRB1*08, DRB1*11,
DRB1*13
DPB1*0301
B8, DR3, DQA1*0501,
DQB1*0201
North America
United States[1, 29, 33]
Canada[34]##
Mexico[35]
Significance
B14, B39, B52,
DRB1*04, DRB1*01
DRB1*0801, DQB1*04,
DQA1*0401 DRB1*1501,
DQA1*0102, DQB1*0602,
DRB1*1302, DQB1*0604
DRB1*0801, DQB1*04
None detected
None detected
DR8, DQA1*0103,
DQB1*0601
DR8(DRB1*0803),
PB1*501 DQA1*0102,
DPB1*0402
A2, A9, A11, A19
DRB1*0701, DRB1*03,
DRB1*12
Southeast Asia
Present study
A11, A24, Cw7
B7, Cw7, Cw12
DRB1*15, DQB1*05
#: In significant association column. 1) Alleles highlighted in bold
italic in are found lower in frequency in PBC patients and have
protective effect; 2) Alleles highlighted in normal font are found higher
in frequency in PBC patients and have predisposing effect. ##: AMA
negative patients may have different genetic susceptibility to AMA
positive patients. DRB1*0801 and DQB1*04 that were significantly
more in AMA positive PBC were not found in AMA negative PBC.[34]
DRB1*0701 was significantly associated with PBC.[39]
To date, there has been no study on the profiles of PBC
among Malay patients. Compared to the control group,
our PBC patients had significantly more HLA B7, Cw7
and Cw12. Among the class II antigens, DRB1*16 and
DRB5 were more common and DQB1*06 was less but
all of these were not significant. Interestingly, a study
on Caucasian patients with PBC showed that the genetic
predisposition between AMA-positive and AMAnegative PBC may be different.[34] HLA-DRB1*08 and
DQB1*04 were found in the AMA-positive PBC patients
but not in AMA-negative patients. The importance of
class I antigens is unknown.
It is clear that there are strong genetic predispositions to PBC. However, it is also clear that there
are differences between different populations. As more
626 • Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com
Primary biliary cirrhosis in Brunei Darussalam
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Primary biliary cirrhosis once rare, now common in the
Funding: None.
United Kingdom? Hepatology 1999;30:390-394.
Ethical approval: Not needed.
Contributors: CVH and JA conceived the idea for the study. CVH 17 Rautiainen H, Salomaa V, Niemelå S, Karvonen AL, Nurmi H,
Isoniemi H, et al. Prevalence and incidence of primary biliary
collected, analyzed, interpreted the data and wrote the first draft of
cirrhosis are increasing in Finland. Scand J Gastroenterol
the manuscript. TPU assessed the histology. All authors approved
2007;42:1347-1353.
the final manuscript. CVH is the guarantor.
Competing interest: No benefits in any form have been received 18 Myers RP, Shaheen AA, Fong A, Burak KW, Wan A, Swain
MG, et al. Epidemiology and natural history of primary
or will be received from a commercial party related directly or
biliary cirrhosis in a Canadian health region: a populationindirectly to the subject of this article.
based study. Hepatology 2009;50:1884-1892.
19 Kim WR, Lindor KD, Locke GR 3rd, Therneau TM,
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Received April 26, 2010
Accepted after revision August 21, 2010
628 • Hepatobiliary Pancreat Dis Int，Vol 9，No 6 • December 15，2010 • www.hbpdint.com