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CBP . Lancet 2011 .pdf



Nom original: CBP . Lancet 2011.pdf
Titre: Primary biliary cirrhosis
Auteur: Prof Carlo Selmi MD

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Seminar

Primary biliary cirrhosis
Carlo Selmi, Christopher L Bowlus, M Eric Gershwin, Ross L Coppel
Lancet 2011; 377: 1600–09
Published Online
April 28, 2011
DOI:10.1016/S01406736(10)61965-4
Department of Translational
Medicine, IRCCS-Istituto Clinico
Humanitas, University
of Milan, Milan, Italy
(Prof C Selmi MD); Divisions
of Gastroenterology and
Hepatology (C L Bowlus MD)
and Rheumatology, Allergy,
and Clinical Immunology
(Prof M E Gershwin MD),
University of California at
Davis, Davis, CA, USA; and
Department of Microbiology,
Monash University, Clayton,
Vic, Australia
(Prof R L Coppel PhD)
Correspondence to:
Prof Ross L Coppel, Monash
University, Clayton, VIC 3800,
Australia
ross.coppel@monash.edu

Primary biliary cirrhosis is a chronic liver disease characterised by intrahepatic bile-duct destruction, cholestasis, and,
in some cases, cirrhosis. Evidence supporting the autoimmune nature of this disorder includes the appearance of
highly specific antimitochondrial antibodies (AMAs) and autoreactive T cells. Concordance rates in monozygotic
twins, familial prevalence, and genetic associations underscore the importance of genetic factors, whereas findings of
epidemiological studies and murine models suggest a possible role for exogenous chemicals and infectious agents
through molecular mimicry. The incidence of primary biliary cirrhosis has increased over recent decades, possibly
attributable to augmented testing of liver biochemistry rather than a rise in disease incidence. AMAs remain the
hallmark of diagnosis in most cases and allow detection of asymptomatic patients. Symptomatic individuals usually
present with either pruritus or fatigue and, more rarely, with either jaundice or complications of cirrhosis. The
prognosis of primary biliary cirrhosis has improved because of early diagnosis and use of ursodeoxycholic acid, the
only established medical treatment for this disorder. Although not a cure, treatment can slow disease progression and
delay the need for liver transplantation. However, some patients do not respond adequately to ursodeoxycholic acid
and might need alternative therapeutic approaches.

Introduction
Primary biliary cirrhosis is an autoimmune liver disease
characterised by the presence in serum of highly specific
antimitochondrial antibodies (AMAs) and progressive
destruction of intrahepatic bile ducts, resulting in chronic
cholestasis, portal inflammation, and fibrosis that can lead
to cirrhosis and, ultimately, liver failure. The disease
predominantly affects women, who are diagnosed typically
in their fifth and sixth decade, although younger patients
have been described, including children, albeit rarely.1 Loss
of bile ducts leads to intrahepatic retention of detergent
bile acids, resulting in liver damage through interaction
with cell membranes and organelles. Disruption of
enterohepatic bile acid circulation is probably the cause of
other pathophysiological changes, which contribute to
extrahepatic manifestations of this disease.
In 1761, the Italian pathologist Giovanni Battista
Morgagni described biliary cirrhosis, and the earliest report
of non-obstructive biliary cirrhosis was made by Addison
and Gull in 1851.2 The term primary biliary cirrhosis was
coined more than 50 years later.3 Presence of AMAs in
serum samples of patients with primary biliary cirrhosis
was recognised in 1965 by Walker and colleagues,4 and
in 1987, antigens to these antibodies were cloned and

Search strategy and selection criteria
We searched Medline with the terms “primary biliary cirrhosis” and “autoimmune
cholangitis” for original research published in peer-reviewed journals between 1970
and 2010. We focused on publications from the past 5 years, but we did not exclude
commonly cited and highly regarded older publications. We also searched the reference
lists of reports identified by this search strategy and selected articles we judged relevant.
Reviews obtained by the same Medline search were included when they provided a
comprehensive overview of issues beyond the scope of this Seminar. Abstracts presented
at international scientific meetings were cited when the content seemed of seminal
importance. We only included clinical trials published after peer-review, randomised
controlled trials, or both, in which survival, biochemical response, symptom
improvement, or changes in histology were reported.

1600

identified as subunits of the pyruvate dehydrogenase
complex, located on the inner mitochondrial membrane.5,6
Clinical features and natural history of primary biliary
cirrhosis vary greatly between affected individuals,
ranging from either asymptomatic and stable or only
slowly progressive to symptomatic and rapidly progressive.
The typical clinical presentation has changed over the
past few decades because the natural history has been
modified by early recognition of more indolent cases and
use of ursodeoxycholic acid.

Epidemiology
Data about incidence and prevalence of primary biliary
cirrhosis have generally been obtained passively and might
not indicate true rates in the general population; regional
differences could vary on the basis of medical awareness
and expertise. Indeed, a population-based approach to case
detection has little feasibility for primary biliary cirrhosis
because of its rarity. As a result, reported prevalence ranges
between 19 and 402 cases per million.7,8 By contrast,
findings of serological studies with indirect immunofluorescence in large groups of unselected serum samples
show that prevalence of AMAs in the general population
can be as high as 0·5%, with lower frequencies when blood
donors are investigated.9 Differences in estimates of
incidence and prevalence of primary biliary cirrhosis are
probably secondary to variable diagnostic criteria, casefinding methods, doctors’ awareness, and quality levels of
health-care systems. On the basis of data from case-finding
studies, however, a latitudinal geoepidemiological pattern
of occurrence of primary biliary cirrhosis has been
proposed,10 with the disease being most frequent in
northern Europe and North America. Indeed, the highest
prevalence and incidence rates have been reported in
Scandinavia, Great Britain, and the northern midwest
region of the USA. Exceptions to this pattern are the high
rates noted in the Spanish area of Sabadell.11 Some
researchers suggest that incidence of primary biliary
cirrhosis is also growing. Indeed, rates rose from 5·8 to
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Seminar

20·5 cases per million population of Sheffield, UK, per
year between 1980 and 1999,12,13 and from 11 to 32 cases per
million population per year in Newcastle-upon-Tyne, UK,
between 1976 and 1994.14,15 This increase was paralleled by
prevalence reaching more than 200 cases per million in
the middle to late 1990s. Whether these changes are due to
rising disease incidence or are secondary to augmented
detection of mild asymptomatic cases or slowly progressing
disease remains to be established. However, age at
diagnosis of mid-to-late 50s has remained consistent across
different periods of study.
Most autoimmune diseases are predominant in female
patients, and in primary biliary cirrhosis, this preponderance is especially striking—the ratio of affected
females to males is as high as 10:1.16 The observation that,
in the general population, detection of AMAs in serum is
not skewed to females16 suggests either that the diagnosis
of primary biliary cirrhosis might be suspected more
frequently in women than men or that progression from
loss of tolerance to the autoantigen to clinical liver disease
is more common in female patients.
Risk factors associated with an uncommon disease such
as primary biliary cirrhosis are difficult to ascertain because
of obstacles in undertaking studies of sufficient size;
however, some associations have been found frequently
enough to suggest validity of associations. Cumulatively,
risk of development of primary biliary cirrhosis is raised
with a positive family history of the disease, a history of
urinary or vaginal infections,17 comorbidity with other
autoimmune diseases, past or present smoking, and
previous pregnancies. Frequent use of nail polish or hair
dye has a weak association with disease risk.18,19

Cause and pathogenesis
Three important observations must be taken into account
for us to understand the pathogenic basis of primary
biliary cirrhosis (figure 1). First, appearance of AMAs
before liver disease suggests that loss of tolerance to the
mitochondrial autoantigen is an early event and could be
independent of the development of liver disease. Second,
although the autoantigen is present ubiquitously in all
nucleated cells, the immune response is restricted to
epithelial cells of intrahepatic bile ducts and, to a lesser
degree, to cells of salivary and lacrimal glands. Finally,
recurrence of primary biliary cirrhosis after liver
transplantation supports the idea that the bile duct
epithelial cell is a generic target and is not unique to the
patient with primary biliary cirrhosis.20 Similar to other
complex diseases, the combination of a susceptible
genetic background and exposure to environmental
triggers is needed to initiate and promote the disorder.
Observations that 1–6% of individuals with primary
biliary cirrhosis have at least one family member
manifesting disease,18 and a 63% concordance rate in
monozygotic twins (vs null concordance in dizygotic
sets),21 show the substantial genetic effect on disease
susceptibility, one of the strongest for any autoimmune
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Host susceptibility

Environmental
exposures

Loss of immune
tolerance to PDC-E2

Bile duct damage

eg, female sex, risk
alleles in MHC, IL12A,
and IL12RB2 loci, innate
immunity (IgM
hyper-responsiveness)

eg, bacterial mimics
(eg, Novosphingobium
aromaticvorans),
xenobiotic chemicals

eg, defective
regulatory T cells,
production of AMAs,
autoreactive
CD4/CD8 T cells to
PDC-E2

eg, immune response,
entailing bile duct
apoptotic blebs and
AMAs, primary biliary
cirrhosis macrophages

Figure 1: Factors possibly entailed in onset and perpetuation of bile-duct injury in primary biliary cirrhosis
PDC-E2=E2 component of the pyruvate dehydrogenase complex. AMAs=antimitochondrial antibodies.

disorder. Many candidate genes have been investigated
for a role in susceptibility to primary biliary cirrhosis,
disease progression, or both in case-control crosssectional studies. Findings of a genome-wide association
study undertaken in a northern American set of patients
and controls22 indicated a significant association between
primary biliary cirrhosis and polymorphisms of
HLA-DQB1, IL12A, IL12RB2, and to a minor extent,
STAT4, and these associations have been confirmed in an
independent cohort of Italian patients and controls with
a combined analysis.23
Several environmental factors—mainly infectious and
chemical—are also thought to contribute to the onset of
primary biliary cirrhosis, largely through molecular
mimicry or modification of autoantigens. Geographic
clustering of cases near toxic waste sites in New York
City24 and space-time clustering in northeast England25
provide epidemiological evidence for a role of chemicals,
infectious agents, or both. Additional data that lend
support to a role for infections in disease development
include the significantly higher prevalence than usual of
recurrent urinary-tract infections in patients with primary
biliary cirrhosis17,18 and experimental findings of sequence
similarity between the E2 enzyme of the pyruvate
dehydrogenase complex recognised by autoantibodies
and bacterial proteins.26 Several bacterial strains—
including the non-pathogenic gram-negative bacterium
Novosphingobium aromaticivorans—have the highest
known homology to the immunodominant autoepitope
of the E2 enzyme.18,27 Several other infectious agents have
been proposed, including Escherichia coli, Helicobacter
spp,28 organisms of the genus Mycoplasma,29 and a human
β retrovirus,30 although support for the retrovirus has not
been substantiated.31
Other environmental factors proposed to trigger disease
onset are foreign chemicals (ie, xenobiotics) that can
either alter or form a complex with a defined self or
non-self protein, causing a change in the protein’s
molecular structure that induces an immune response.
Lipoic acid is attached to only a few proteins, yet it is a
vital component of the E2 epitope.32 The structure of the
E2 enzyme exposes lipoic acid at the exterior of the
protein complex, making this compound accessible to
chemical modification.33 The role of xenobiotics in
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primary biliary cirrhosis is supported by serum reactivity
against specific organic compounds with structures
similar to lipoic acid;34 furthermore, two of these
compounds (6-bromohexanoate and 2-octynoic acid) can
induce AMAs and liver lesions similar to those of primary
biliary cirrhosis in guinea pigs35 and mouse models.36,37
Primary biliary cirrhosis has been regarded as an
autoimmune disease from the time of the first seminal
reports38 because of the predominance of female
patients, frequent autoimmune comorbidities, and,
most importantly, by loss of immune tolerance to
Panel 1: Features of primary biliary cirrhosis for and against autoimmune
pathogenesis
In support of autoimmunity
• Specific serum autoantibodies41,42
• Autoreactive T cells43
• Adaptive transfer of cholangitis using CD8+ T cells (in murine models)44
• Functional T regulatory defects45
• Female predominance16
• Autoimmune comorbidity46,47
• MHC association22
Against autoimmunity
• Absence of disease after autoantibody transfer (in mice)
• Absence of correlation between titre of antimitochondrial antibodies and
disease severity48
• Failure to respond to immunosuppressive agents (based on limited data)46,47
Features shown according to Witebsky’s criteria, as modified by Rosa and Bona.40

Indirect
immunofluorescence

ELISA

Immunoblotting

AMAs
General53,54

70–90%

..

..

PDC-E254

..

79·6%

81·7%

OGDC-E254

..

NA

27·4%

BCOADC-E255

..

56·7%

59·1%

pMIT342,54

..

94%

92%

ANAs
Rim-like pattern56,57
Gp21056,58
Nup6259,60
Multiple nuclear dots61

10–52%

..

..

..

16–32%

10–42%

..

NA

22–32%

13–25%

..

..

Sp10062

..

21–39%

NA

PML

..

NA

NA

Centromere
General63

9–20%

CENP A, B, C64

..

..

..

26%

21%

AMAs=antimitochondrial antibodies. E2=E2 component. PDC=pyruvate dehydrogenase complex.
OGDC=2-oxo-glutarate dehydrogenase. BCOADC=branched-chain 2-oxo acid dehydrogenase. ANAs=antinuclear
antibodies. Gp210=glycoprotein 210. Nup62=nucleoporin 62. PML=promyelocytic leukaemia. CENP=centromere
protein. NA=data not available. For ELISA and immunoblotting, only data obtained with recombinant antigens are
shown, and references are for the largest studies.

Table: Sensitivity of serum autoantibodies in primary biliary cirrhosis

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self-mitochondrial proteins.39 Panel 1 summarises
Witebsky’s criteria both for and against the autoimmune
basis of primary biliary cirrhosis.40 Although most
evidence argues that primary biliary cirrhosis is a
disease of autoimmunity directed against antimitochondrial antigens on biliary epithelial cells, proof of a
direct pathogenic role for serum autoantibodies is
scarce: seronegative patients manifest similar disease
features to those of their AMA-positive counterparts;48
changes in AMA titres do not correlate with severity of
primary biliary cirrhosis, disease stage, or both; and
immunosuppressive treatment has been fairly ineffective
in patients with primary biliary cirrhosis.
AMAs in serum are highly sensitive and specific for
primary biliary cirrhosis: they are detected in nearly
95% of patients, with specificity close to 100% when
tested with recombinant antigens.41 Indirect immunofluorescence remains the test used for screening, but it
can be associated with a substantial number of falsepositive results.49 Follow-up data from AMA-positive
individuals without signs of liver disease suggest that
autoantibodies arise several years before onset of primary
biliary cirrhosis and have a high predictive value.50
Epitopes recognised by AMAs include lipoylated domains
(via the Asx-Lys-Ala motif) within subunits of the
2-oxoacid dehydrogenase family of enzymes of the
mitochondrial respiratory chain,6 in particular, E2 subunit
and E3 binding-protein components of the pyruvate
dehydrogenase complex and E2 components of the
2-oxoglutarate dehydrogenase and branched-chain 2-oxo
acid dehydrogenase complexes (table).51,52
In addition to AMAs, autoreactive CD8+ and CD4+
T cells to the E2 component of the pyruvate dehydrogenase
complex have been identified both in peripheral blood
and within the liver of patients with primary biliary
cirrhosis, and the immunodominant epitope of these
T cells maps in close proximity to the epitope recognised
by AMAs in serum. Autoreactive CD4+ cell clones
specific for the E2 enzyme have been isolated in
intrahepatic and peripheral lymphocytes, not only in
AMA-positive individuals but also in patients without
antibodies, thus corroborating the notion that primary
biliary cirrhosis either positive or negative for AMAs is
one nosological entity.43
CD4+ CD25high regulatory T cells act to prevent
autoreactivity, as shown in several autoimmune diseases,
including autoimmune hepatitis.65 Patients with primary
biliary cirrhosis are characterised by substantially lower
frequencies of CD4+ CD25high regulatory T cells as
proportions of total T-cell receptor-αβ+/CD4+ cells, and
this factor could be important in the breakdown of
tolerance.45 Moreover, raised amounts of polyclonal IgM
and hyper-responsiveness to CpG (cytosine-phosphateguanine dinucleotide motif),66 and enhanced natural
killer cell67,68 and monocyte responses,69 which are all
features found in primary biliary cirrhosis, also lend
support to a role for innate immunity.
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Once tolerance to AMAs is lost, additional mechanisms
entailed in the immune response to a ubiquitous
autoantigen begin to be unravelled. These lead to specific
injury of biliary epithelial cells and seem to be linked to
unique processes of apoptosis.70–73 Unlike other cell types,
the E2 component of the pyruvate dehydrogenase complex
remains intact in bile-duct cells after apoptosis, thus
probably retaining its immunogenicity.74 Furthermore,
this enzyme is found within apoptotic blebs and is
accessible to AMAs75 and local antigen-presenting cells.
Moreover, findings of in-vitro experiments have shown an
intense and specific immune response when macrophages
of patients with primary biliary cirrhosis are combined
with apoptotic blebs of biliary epithelial cells and AMAs.76
However, recurrence of primary biliary cirrhosis after
liver transplantation suggests that this occurrence is not
an intrinsic defect of bile-duct cells of affected individuals
but is a feature of biliary epithelia in general, not seen in
other epithelial cells.

Clinical features
The clinical features and natural history of primary biliary
cirrhosis vary greatly between patients, ranging from
asymptomatic and slowly progressive to symptomatic and
rapidly evolving. The frequency of asymptomatic disease
seems to be increasing, probably because of raised
awareness of the disease together with broad use of
routine testing of liver biochemistry. Many asymptomatic
patients will, however, develop symptomatic liver disease
within 5 years of diagnosis, although a third could remain
symptom-free for many years.77
Although non-specific, fatigue is the most common
symptom of primary biliary cirrhosis; it is present in
nearly 80% of patients and more than 40% report
moderate-to-severe symptoms.78,79 The mechanism of
fatigue associated with this disease remains unknown
despite many proposals, including autonomic dysfunction,80 muscle impairment,81 excessive daytime
somnolence,82 changes in cortical excitability,83 and
altered manganese homoeostasis within the CNS.84
Fatigue in patients with primary biliary cirrhosis is
typically characterised as excessive daytime somnolence
and can impair quality of life. Despite sparse correlation
between fatigue and severity of liver disease, fatigue can
be associated with decreased overall survival.85,86
Of symptoms related to longstanding cholestasis,
pruritus seems to be the most typical complaint and is
reported by 20–70% of patients in studies, usually
preceding jaundice. Widespread use of ursodeoxycholic
acid has led to a substantial reduction in the frequency
of this distressing symptom despite the absence of a
direct effect. Many factors contribute to pruritus onset
and intensity. First, cholestasis itself impairs biliary
excretion of several compounds leading to an increased
systemic concentration of putative so-called pruritogenic
compounds. Of these substances, bile acids could be
important, as suggested by the ability of bile-acid binding
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resins—ie, colestyramine—to ameliorate pruritus.87 Second, on the basis of both augmented opioidergic activity
reported in individuals with cholestasis and experimental
neuroendocrinology data obtained in cultured cholangiocytes,88 a central origin of pruritus has been suggested.89
Accordingly, opioid antagonists are currently used to
treat this symptom, although these agents are sometimes
tolerated poorly by patients.90 An important association
has been reported between severity of pruritus and
circulating concentrations of the extracellular lysophospholipase autotaxin, a protein already implicated in
neoplasia and immunity regulation.91
A reduction in bone density is common in patients
with primary biliary cirrhosis, with features of osteopenia
(33%) and, less frequently, osteoporosis (11%).92 By
contrast with previous reports,93 researchers have
suggested that primary biliary cirrhosis might not
represent an additional risk factor for bone
demineralisation in women with compensated disease
supplemented with calcium and vitamin D.94 Therefore,
in clinical practice, such supplementation—along with
monitoring of bone density and vitamin D concentrations
in serum—is highly recommended, even in individuals
with early disease.46,95 With more advanced disease,
deficiencies of other fat-soluble vitamins and steatorrhoea
are common and must be monitored and supplemented.
Hypercholesterolaemia, typically caused by a rise in
HDL cholesterol, is common in patients with primary
biliary cirrhosis but does not increase cardiovascular
risk96 or cause early signs of atherosclerosis.97 Use of
statins is, therefore, not usually necessary, but these
drugs are tolerated safely in people with other
cardiovascular risk factors.98
Several autoimmune diseases could coexist with
primary biliary cirrhosis. In our experience, as many as
a third of patients are diagnosed with another
autoimmune disease,18 most frequently Sjögren’s
syndrome and autoimmune thyroid disease. Whether
coexisting autoimmune diseases indicate a common
genetic background or represent similar pathogenetic
mechanisms is unclear.99 Autoimmune comorbidities
do not modify the natural history or clinical presentation
of primary biliary cirrhosis, with the exception of a
reported slower progression of liver fibrosis in patients
with scleroderma.100
Once primary biliary cirrhosis has progressed to frank
cirrhosis, liver complications do not differ much from
those seen in cases of cirrhosis due to other causes, with
the exception of oesophageal varices, which can arise
early in the disease course, sometimes before other signs
of cirrhosis. This outcome is probably attributable to the
presence of presinusoidal inflammation and consequent
fibrosis induced by granulomas. Other complications of
portal hypertension (ie, ascites and hepatic encephalopathy) happen typically in end-stage primary biliary
cirrhosis. The occurrence of hepatocellular carcinoma in
individuals with primary biliary cirrhosis is similar to
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other forms of cirrhosis and warrants surveillance in
patients at advanced disease stages.101

Diagnosis and liver histology
The diagnosis of primary biliary cirrhosis should be
suspected in anyone with findings of chronic cholestasis
after liver tests, particularly with raised concentrations of
alkaline phosphatase. Furthermore, patients with primary
biliary cirrhosis generally have increased amounts of
aminotransferases and immunoglobulins (mainly IgM).
Diagnosis can be established if two of three objective
criteria are present: a concentration in serum of AMAs at
titres of 1:40 or higher; an unexplained rise in the amount
of alkaline phosphatase of at least 1·5 times the upper
limit of normal for more than 24 weeks; and compatible
liver histological findings, specifically non-suppurative
cholangitis and interlobular bile duct injury.47 Whether
AMA-positive individuals without biochemical abnormalities will eventually develop primary biliary cirrhosis is
still debatable, but expectant follow-up with annual liver
biochemical analysis is reasonable.47 By contrast,
individuals with AMA-negative primary biliary cirrhosis
(currently synonymous with autoimmune cholangitis)
diagnosed on the basis of abnormal concentrations of
alkaline phosphatase and liver histological findings
manifest a similar course to their seropositive
counterparts.48 In these cases, MRI or endoscopic
retrograde cholangiography are recommended to rule
out primary sclerosing cholangitis or other disorders that
might lead to chronic cholestasis.
In addition to AMAs, antinuclear antibodies (ANAs) are
detected by indirect immunofluorescence in about 50% of
serum samples from patients with primary biliary
cirrhosis (table). Two nuclear fluorescence patterns are
found in primary biliary cirrhosis. A rim-like pattern
results from autoantibody reaction with glycoprotein 210
and nucleoporin 62 (within the nuclear pore complex),
and a pattern of multiple nuclear dots results from reaction
with Sp100 and the promyelocytic leukaemia antigen
(possibly also cross-reacting with small ubiquitin-like
modifiers).102 The pathogenic role of ANAs in primary
biliary cirrhosis remains to be established, as is the case
with AMAs, although cross-sectional and longitudinal
data suggest an association between ANA positivity
specific to primary biliary cirrhosis and severe disease.59,103
The need to undergo liver biopsy in primary biliary
cirrhosis is controversial, although most clinicians agree
that this procedure is valuable for disease staging,
particularly in clinical trials.95 From a diagnostic point of
view, liver biopsy specimens are not required when the
other two less invasive diagnostic criteria are fulfilled.
Thus, routine liver biopsy should be done only when
considering a differential diagnosis from other disorders,
including small-duct primary sclerosing cholangitis,
sarcoidosis, or drug-induced cholestasis. Histological
staging is based on Ludwig’s104 and Scheuer’s105
classifications, ranging from portal-tract inflammation
1604

with predominantly lymphoplasmacytoid infiltrates and
septal and interlobular bile-duct loss (stage I) to frank
cirrhosis (stage IV). Eosinophils and granulomas are also
characteristic but not diagnostic of primary biliary
cirrhosis. When two or more stages manifest within the
same liver sample, the patient is classified as belonging
to the more severe stage. However, because of the
heterogeneous nature of biliary involvement, liver biopsy
findings could include sampling error on the basis of
histological variability in different areas,106 but this factor
does not warrant taking of several biopsy specimens.
Although many patients with primary biliary cirrhosis
will have mildly raised concentrations of aminotransferases, and findings of liver biopsy might even show
some degree of piecemeal necrosis, a poorly characterised
subgroup exists in which features of so-called hepatitis
are relevant.107 This finding has led to the designation of
primary biliary cirrhosis–autoimmune hepatitis overlap,
but specific diagnostic criteria for this disorder remain to
be established. In addition to histological findings,
primary biliary cirrhosis–autoimmune hepatitis overlap
should be considered when the ratio of alkaline
phosphatase to aspartate aminotransferase is less
than 1·5, serum concentration of IgG is increased, and
antibodies against smooth muscle are present at greater
than 1:80 titre. A suspected diagnosis of primary biliary
cirrhosis–autoimmune hepatitis overlap could be
clinically relevant because this disorder seems to have a
more severe prognosis than primary biliary cirrhosis
alone, and other treatments could be considered,
including immunosuppressive agents.108

Treatment and natural history
The natural history and prognosis of primary biliary
cirrhosis has become notably more benign, with
substantial improvements in disease outcome reported
in studies. Although these observations could be
secondary to early diagnosis and a consequent lead-time
bias,109 falling rates of liver transplantation for primary
biliary cirrhosis in Europe and North America since
widespread use of ursodeoxycholic acid was introduced
suggest a true change in natural history.110,111 Figure 2
presents a schematic and somewhat arbitrary view of the
natural history of primary biliary cirrhosis. Before the
introduction of ursodeoxycholic acid, time from
diagnosis to symptom-onset was about 2·0–4·2 years,
and survival was compromised relative to a healthy
population.112,113 Classically, presence of symptoms at
diagnosis was an important determinant of disease
progression and survival.114 However, in a study from the
UK77 of a large cohort of patients followed up for 24 years,
although mortality due to liver disease was greatest in
symptomatic patients, overall survival was similar in
individuals with and without symptoms at time of
presentation. Prediction of patients’ survival in primary
biliary cirrhosis has been attempted, and the Mayo
model is the most well regarded,115 which includes five
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100
Normal function (%)

independent prognostic variables (age, total concentrations in serum of bilirubin and albumin, prothrombin
time, and severity of ascites), with amount of bilirubin in
serum as the most heavily weighted. Use of an enhanced
liver fibrosis algorithm (based on fibrosis markers in
serum)116 or presence of ANAs in serum specific to
primary biliary cirrhosis59 might predict the occurrence
of major events and survival of patients with primary
biliary cirrhosis, especially in early-stage disease, but
independent verification is awaited.
Many therapeutic agents have been proposed for
primary biliary cirrhosis on the basis of different views
of disease pathogenesis. Rarity of the disorder, its
variable natural history, and slow progression necessitate
large, multicentre, and long-term studies. The only
currently established treatment for primary biliary
cirrhosis is ursodeoxycholic acid 13–15 mg/kg a day,
which can be subdivided into two or three doses.46 The
treatment is well tolerated and, with the exception of
moderate weight gain, does not lead to substantial
adverse effects over time.
Mechanisms of action of ursodeoxycholic acid in
primary biliary cirrhosis remain unclear, yet the
hydrophilic nature of this agent could lead to a reduction
in amounts of primary bile acids, and the substance
might also regulate cellular signalling and protect against
apoptosis.117,118 Several randomised controlled trials have
been undertaken to assess the efficacy of ursodeoxycholic
acid, and in all series, this agent resulted in a substantial
improvement in serum markers of cholestasis. Results
of randomised placebo-controlled studies of ursodeoxycholic acid, which were of sufficient duration to
assess the effects on histology and survival, have been
reviewed.119 Although some consistency was recorded
across studies in terms of biochemical, clinical, and
histological response,120,121 an effect on general survival
was noted in only one study.122 About 20% of patients
treated with ursodeoxycholic acid will have no histological
progression over 4 years, and some will have no
progression over a decade or longer.123 This agent has the
potential to prevent portal hypertension and the
appearance of oesophageal varices and to delay time to
liver transplantation.124 Survival rates of patients with
stage I or II disease treated with ursodeoxycholic acid
are similar to those of age-matched healthy controls.125 A
combined analysis of three studies126 and three metaanalyses127–129 has been done to achieve sufficient statistical
power to investigate the effects of ursodeoxycholic acid
on survival. A significant survival improvement was only
seen in patients with amounts of bilirubin in serum
higher than 24 μmol/L at baseline.126
Despite the effectiveness of ursodeoxycholic acid, a
subgroup of patients with primary biliary cirrhosis will
have an incomplete response to treatment and are at
greatest risk of progression. Criteria have been proposed
to define the group of complete responders, including: a
decrease in the amount of alkaline phosphatase greater

50

Intact bile ducts
Cholestasis
0
Preclinical

Asymptomatic

Manifest

Decompensated

Disease clinical phases
Liver function
Duration
Stage

>10 years
0–I

>5 years
I–IV

<10 years
II–IV

<3 years
III–IV

Figure 2: Schematic representation of the natural history of primary biliary cirrhosis
Duration of clinical phases should be regarded as merely indicative because they could vary significantly between
patients, with some rapidly progressing to end-stage disease and liver transplantation at a young age and others
remaining asymptomatic for decades. In general terms, over time, coexistence of chronic cholestasis and bile-duct
destruction—affected by many synergistic determinants—leads ultimately to impairment of liver function only at
advanced stages, once a critical threshold of liver damage is reached.

than 40% of the baseline or to a normal level;130
concentrations of alkaline phosphatase less than three
times the upper limit of normal, aspartate aminotransferase less than twice the upper limit of normal, and
bilirubin less than 17 μmol/L;125 and normalisation of
abnormal concentrations of bilirubin, albumin, or both.131
In a prospective assessment of these criteria, response—
as defined by the latter two criteria—was associated with
better survival in patients with moderately advanced
disease, compared with the group of patients who did not
have these features.132
For patients who do not have a complete response to
ursodeoxycholic acid, a need for new treatments remains.
Future trials should focus specifically on this subpopulation
with primary biliary cirrhosis, and most data on use of a
farnesoid X receptor agonist have been promising.133 The
benefit of steroids remains to be established in primary
biliary cirrhosis.134 However, in view of the many adverse
effects, short-term steroid use should be considered only
in individuals with primary biliary cirrhosis–autoimmune
hepatitis overlap or with other autoimmune comorbidities.
Use of other immunosuppressive or antifibrotic agents,
alone or in combination with ursodeoxycholic acid, is not
recommended, either because toxic effects outweigh any
potential benefits or owing to absence of effectiveness.
In addition to prevention of liver disease progression,
management of primary biliary cirrhosis includes
treatment of symptoms and comorbidities associated
with the disorder, which constitute a clinical challenge.
Proposed treatments are sometimes unsatisfactory,
particularly for symptoms that substantially reduce quality
of life, such as pruritus. In general terms, the oral anion
exchange resin colestyramine remains the treatment of
choice for pruritus, whereas rifampicin can be used in the
short term for unresponsive cases (panel 2). Of note,
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Panel 2: Current medical treatments for pruritus and bone loss in patients with
primary biliary cirrhosis
Pruritus
• Colestyramine (oral administration; up to 16 g subdivided into four daily doses with
food; separate from ursodeoxycholic acid by 2 h)
• Rifampicin (oral administration; up to 600 mg a day for 6 months)
• Sertraline (oral administration; 75–100 mg a day)
• Opiate antagonists
• Naloxone (intravenous continuous infusion; very short half life;
0·2–0·4 μg kg ¹ min ¹)
• Nalmefene (oral administration; longer half life than naloxone and naltrexone;
2 mg twice a day with a gradual increase until 20 mg twice a day)
• Naltrexone (oral administration; longer half life than naloxone; 50 mg a day in
two divided doses on the first day and subsequently in one daily dose)
• Anecdotal treatments for intractable pruritus
• Dronabinol (one evening dose of 5 mg)
Osteopenia and osteoporosis
• Prevention
• Oral vitamin D3 supplementation (indicated for all patients to prevent
osteomalacic lesions)
• Calcium carbonate supplementation
• Treatment
• Oestrogen (few data but effective; some safety concerns)
• Etidronate (conflicting data; indicated in case of concomitant corticosteroid
administration)
• Alendronate (few data but effective and safe)
• Calcitonin (probably ineffective)

colestyramine can inhibit absorption of ursodeoxycholic
acid, requiring a break of 2 h between drugs. Unless
another underlying cause—such as hypothyroidism or
anaemia—can be identified, fatigue is poorly responsive
to treatment. Antidepressants have not been effective,
and in small trials of modafinil, only a few patients have
been able to tolerate the drug.135,136 Sjögren’s syndrome,
which can be seen in up to 75% of patients, should initially
be managed with liberal use of artificial tears and saliva.
Pilocarpine or cevimeline can be used in refractory cases.
Because of the high rate of osteopenia and osteoporosis
in patients with primary biliary cirrhosis, bone density
measurements should be done every 2–3 years. Daily
supplementation of vitamin D (1000 IU) and calcium
(1500 mg) is advisable, with alendronate 70 mg per week
given to individuals with osteopenia (panel 2).
Primary biliary cirrhosis is a common indication for
liver transplantation; this procedure is the only effective
treatment in patients with end-stage disease. Indications
for liver transplantation in individuals with primary
biliary cirrhosis do not differ from those in other liver
diseases, namely decompensated cirrhosis with diureticresistant ascites and spontaneous bacterial peritonitis,
recurrent variceal bleeding, encephalopathy, or hepatocellular carcinoma. Severe pruritus that is refractory to
treatment could be judged an indication in special cases.
Post-transplant survival rates are 92% at 1 year and 85%
1606

at 5 years,137 and the recurrence rate is 30% at 10 years.20
Fortunately, recurrence of primary biliary cirrhosis affects
survival rarely, and retransplantation is uncommon.138
Although ursodeoxycholic acid has not been shown to
enhance post-transplant outcomes, it does lead to
biochemical improvements post transplant and should
be considered in view of its good safety profile. Use of
high-dose steroids immediately after transplantation can
lead to severe bone loss and should be monitored and
treated aggressively.47

Management guidelines
On the basis of guidelines from the American Association
for the Study of Liver Diseases47 and the European
Association for the Study of the Liver46 for management
of primary biliary cirrhosis, we propose a pragmatic
approach to patients with this disorder. Irrespective of
the presence of symptoms or signs of liver cirrhosis,
individuals with primary biliary cirrhosis should be
treated with ursodeoxycholic acid (13–15 mg/kg per
day).139 Monitoring of biochemical response is helpful for
prediction of those at greatest risk of progressive liver
disease. If no response to ursodeoxycholic acid arises, or
if features of autoimmune hepatitis are present, alternative treatment strategies should be considered. In all
patients, the concentration of bilirubin in serum and
platelet count should be measured regularly to detect
early signs of disease progression or portal hypertension.
As with other chronic liver diseases, we recommend that
individuals with primary biliary cirrhosis should undergo
ultrasonography and be measured for amount of
α-fetoprotein every 6 months, to screen for hepatocellular
carcinoma. Liver transplantation is to be considered in
patients with advanced disease, as shown by appropriate
staging methods.139

Future perspectives
Several important steps towards better understanding of
the causes and pathogenesis of primary biliary cirrhosis
have been taken in recent years, yet important knowledge
gaps remain with respect to genetic and immunological
aberrancies that lead to the disorder. Data for epigenetic
changes in primary biliary cirrhosis are sparse, which is
perhaps surprising in view of the regularity with which
such studies are reported for other complex conditions.
Despite improvements in outcomes with ursodeoxycholic
acid, additional treatments are needed for patients who
have an incomplete response or have features of
autoimmune hepatitis. As our understanding of underlying immune effector mechanisms grows, we are
optimistic that new biological agents targeted at specific
immune response mechanisms will prove beneficial for
this subgroup of patients.
Contributors
All authors contributed to the literature search and writing of the Seminar.
Conflicts of interest
We declare that we have no conflicts of interest.

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