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Cirrosis Biliar Primaria
Cirrosis Biliar Primaria
Lancet 2011; 377: 1600–09 Primary biliary cirrhosis is a chronic liver disease characterised by intrahepatic bile-duct destruction, cholestasis, and,
Published Online in some cases, cirrhosis. Evidence supporting the autoimmune nature of this disorder includes the appearance of
April 28, 2011 highly specific antimitochondrial antibodies (AMAs) and autoreactive T cells. Concordance rates in monozygotic
DOI:10.1016/S0140-
twins, familial prevalence, and genetic associations underscore the importance of genetic factors, whereas findings of
6736(10)61965-4
epidemiological studies and murine models suggest a possible role for exogenous chemicals and infectious agents
Department of Translational
Medicine, IRCCS-Istituto Clinico through molecular mimicry. The incidence of primary biliary cirrhosis has increased over recent decades, possibly
Humanitas, University attributable to augmented testing of liver biochemistry rather than a rise in disease incidence. AMAs remain the
of Milan, Milan, Italy hallmark of diagnosis in most cases and allow detection of asymptomatic patients. Symptomatic individuals usually
(Prof C Selmi MD); Divisions
present with either pruritus or fatigue and, more rarely, with either jaundice or complications of cirrhosis. The
of Gastroenterology and
Hepatology (C L Bowlus MD) prognosis of primary biliary cirrhosis has improved because of early diagnosis and use of ursodeoxycholic acid, the
and Rheumatology, Allergy, only established medical treatment for this disorder. Although not a cure, treatment can slow disease progression and
and Clinical Immunology delay the need for liver transplantation. However, some patients do not respond adequately to ursodeoxycholic acid
(Prof M E Gershwin MD),
and might need alternative therapeutic approaches.
University of California at
Davis, Davis, CA, USA; and
Department of Microbiology, Introduction identified as subunits of the pyruvate dehydrogenase
Monash University, Clayton, Primary biliary cirrhosis is an autoimmune liver disease complex, located on the inner mitochondrial membrane.5,6
Vic, Australia
characterised by the presence in serum of highly specific Clinical features and natural history of primary biliary
(Prof R L Coppel PhD)
antimitochondrial antibodies (AMAs) and progressive cirrhosis vary greatly between affected individuals,
Correspondence to:
Prof Ross L Coppel, Monash destruction of intrahepatic bile ducts, resulting in chronic ranging from either asymptomatic and stable or only
University, Clayton, VIC 3800, cholestasis, portal inflammation, and fibrosis that can lead slowly progressive to symptomatic and rapidly progressive.
Australia to cirrhosis and, ultimately, liver failure. The disease The typical clinical presentation has changed over the
ross.coppel@monash.edu
predominantly affects women, who are diagnosed typically past few decades because the natural history has been
in their fifth and sixth decade, although younger patients modified by early recognition of more indolent cases and
have been described, including children, albeit rarely.1 Loss use of ursodeoxycholic acid.
of bile ducts leads to intrahepatic retention of detergent
bile acids, resulting in liver damage through interaction Epidemiology
with cell membranes and organelles. Disruption of Data about incidence and prevalence of primary biliary
enterohepatic bile acid circulation is probably the cause of cirrhosis have generally been obtained passively and might
other pathophysiological changes, which contribute to not indicate true rates in the general population; regional
extrahepatic manifestations of this disease. differences could vary on the basis of medical awareness
In 1761, the Italian pathologist Giovanni Battista and expertise. Indeed, a population-based approach to case
Morgagni described biliary cirrhosis, and the earliest report detection has little feasibility for primary biliary cirrhosis
of non-obstructive biliary cirrhosis was made by Addison because of its rarity. As a result, reported prevalence ranges
and Gull in 1851.2 The term primary biliary cirrhosis was between 19 and 402 cases per million.7,8 By contrast,
coined more than 50 years later.3 Presence of AMAs in findings of serological studies with indirect immuno-
serum samples of patients with primary biliary cirrhosis fluorescence in large groups of unselected serum samples
was recognised in 1965 by Walker and colleagues,4 and show that prevalence of AMAs in the general population
in 1987, antigens to these antibodies were cloned and 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
Search strategy and selection criteria probably secondary to variable diagnostic criteria, case-
We searched Medline with the terms “primary biliary cirrhosis” and “autoimmune finding methods, doctors’ awareness, and quality levels of
cholangitis” for original research published in peer-reviewed journals between 1970 health-care systems. On the basis of data from case-finding
and 2010. We focused on publications from the past 5 years, but we did not exclude studies, however, a latitudinal geoepidemiological pattern
commonly cited and highly regarded older publications. We also searched the reference of occurrence of primary biliary cirrhosis has been
lists of reports identified by this search strategy and selected articles we judged relevant. proposed,10 with the disease being most frequent in
Reviews obtained by the same Medline search were included when they provided a northern Europe and North America. Indeed, the highest
comprehensive overview of issues beyond the scope of this Seminar. Abstracts presented prevalence and incidence rates have been reported in
at international scientific meetings were cited when the content seemed of seminal Scandinavia, Great Britain, and the northern midwest
importance. We only included clinical trials published after peer-review, randomised region of the USA. Exceptions to this pattern are the high
controlled trials, or both, in which survival, biochemical response, symptom rates noted in the Spanish area of Sabadell.11 Some
improvement, or changes in histology were reported. researchers suggest that incidence of primary biliary
cirrhosis is also growing. Indeed, rates rose from 5·8 to
primary biliary cirrhosis is supported by serum reactivity self-mitochondrial proteins.39 Panel 1 summarises
against specific organic compounds with structures Witebsky’s criteria both for and against the autoimmune
similar to lipoic acid;34 furthermore, two of these basis of primary biliary cirrhosis.40 Although most
compounds (6-bromohexanoate and 2-octynoic acid) can evidence argues that primary biliary cirrhosis is a
induce AMAs and liver lesions similar to those of primary disease of autoimmunity directed against antimito-
biliary cirrhosis in guinea pigs35 and mouse models.36,37 chondrial antigens on biliary epithelial cells, proof of a
Primary biliary cirrhosis has been regarded as an direct pathogenic role for serum autoantibodies is
autoimmune disease from the time of the first seminal scarce: seronegative patients manifest similar disease
reports38 because of the predominance of female features to those of their AMA-positive counterparts;48
patients, frequent autoimmune comorbidities, and, changes in AMA titres do not correlate with severity of
most importantly, by loss of immune tolerance to primary biliary cirrhosis, disease stage, or both; and
immunosuppressive treatment has been fairly ineffective
in patients with primary biliary cirrhosis.
Panel 1: Features of primary biliary cirrhosis for and against autoimmune AMAs in serum are highly sensitive and specific for
pathogenesis primary biliary cirrhosis: they are detected in nearly
In support of autoimmunity 95% of patients, with specificity close to 100% when
• Specific serum autoantibodies41,42 tested with recombinant antigens.41 Indirect immuno-
• Autoreactive T cells43 fluorescence remains the test used for screening, but it
• Adaptive transfer of cholangitis using CD8+ T cells (in murine models)44 can be associated with a substantial number of false-
• Functional T regulatory defects45 positive results.49 Follow-up data from AMA-positive
• Female predominance16 individuals without signs of liver disease suggest that
• Autoimmune comorbidity46,47 autoantibodies arise several years before onset of primary
• MHC association22 biliary cirrhosis and have a high predictive value.50
Epitopes recognised by AMAs include lipoylated domains
Against autoimmunity (via the Asx-Lys-Ala motif) within subunits of the
• Absence of disease after autoantibody transfer (in mice) 2-oxoacid dehydrogenase family of enzymes of the
• Absence of correlation between titre of antimitochondrial antibodies and mitochondrial respiratory chain,6 in particular, E2 subunit
disease severity48 and E3 binding-protein components of the pyruvate
• Failure to respond to immunosuppressive agents (based on limited data)46,47 dehydrogenase complex and E2 components of the
Features shown according to Witebsky’s criteria, as modified by Rosa and Bona.40
2-oxoglutarate dehydrogenase and branched-chain 2-oxo
acid dehydrogenase complexes (table).51,52
In addition to AMAs, autoreactive CD8+ and CD4+
Indirect ELISA Immunoblotting T cells to the E2 component of the pyruvate dehydrogenase
immunofluorescence complex have been identified both in peripheral blood
AMAs and within the liver of patients with primary biliary
General53,54 70–90% .. .. cirrhosis, and the immunodominant epitope of these
PDC-E254 .. 79·6% 81·7% T cells maps in close proximity to the epitope recognised
OGDC-E254 .. NA 27·4% by AMAs in serum. Autoreactive CD4+ cell clones
BCOADC-E255 .. 56·7% 59·1% specific for the E2 enzyme have been isolated in
pMIT342,54 .. 94% 92% intrahepatic and peripheral lymphocytes, not only in
ANAs AMA-positive individuals but also in patients without
Rim-like pattern56,57 10–52% .. .. antibodies, thus corroborating the notion that primary
Gp21056,58 .. 16–32% 10–42% biliary cirrhosis either positive or negative for AMAs is
Nup6259,60 .. NA 22–32% one nosological entity.43
Multiple nuclear dots61 13–25% .. .. CD4+ CD25high regulatory T cells act to prevent
Sp10062 .. 21–39% NA autoreactivity, as shown in several autoimmune diseases,
PML .. NA NA
including autoimmune hepatitis.65 Patients with primary
Centromere
biliary cirrhosis are characterised by substantially lower
General63 9–20% .. ..
frequencies of CD4+ CD25high regulatory T cells as
proportions of total T-cell receptor-αβ+/CD4+ cells, and
CENP A, B, C64 .. 26% 21%
this factor could be important in the breakdown of
AMAs=antimitochondrial antibodies. E2=E2 component. PDC=pyruvate dehydrogenase complex. tolerance.45 Moreover, raised amounts of polyclonal IgM
OGDC=2-oxo-glutarate dehydrogenase. BCOADC=branched-chain 2-oxo acid dehydrogenase. ANAs=antinuclear
and hyper-responsiveness to CpG (cytosine-phosphate-
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 guanine dinucleotide motif),66 and enhanced natural
shown, and references are for the largest studies. killer cell67,68 and monocyte responses,69 which are all
features found in primary biliary cirrhosis, also lend
Table: Sensitivity of serum autoantibodies in primary biliary cirrhosis
support to a role for innate immunity.
Once tolerance to AMAs is lost, additional mechanisms resins—ie, colestyramine—to ameliorate pruritus.87 Sec-
entailed in the immune response to a ubiquitous ond, on the basis of both augmented opioidergic activity
autoantigen begin to be unravelled. These lead to specific reported in individuals with cholestasis and experimental
injury of biliary epithelial cells and seem to be linked to neuroendocrinology data obtained in cultured cholangio-
unique processes of apoptosis.70–73 Unlike other cell types, cytes,88 a central origin of pruritus has been suggested.89
the E2 component of the pyruvate dehydrogenase complex Accordingly, opioid antagonists are currently used to
remains intact in bile-duct cells after apoptosis, thus treat this symptom, although these agents are sometimes
probably retaining its immunogenicity.74 Furthermore, tolerated poorly by patients.90 An important association
this enzyme is found within apoptotic blebs and is has been reported between severity of pruritus and
accessible to AMAs75 and local antigen-presenting cells. circulating concentrations of the extracellular lysophos-
Moreover, findings of in-vitro experiments have shown an pholipase autotaxin, a protein already implicated in
intense and specific immune response when macrophages neoplasia and immunity regulation.91
of patients with primary biliary cirrhosis are combined A reduction in bone density is common in patients
with apoptotic blebs of biliary epithelial cells and AMAs.76 with primary biliary cirrhosis, with features of osteopenia
However, recurrence of primary biliary cirrhosis after (33%) and, less frequently, osteoporosis (11%).92 By
liver transplantation suggests that this occurrence is not contrast with previous reports,93 researchers have
an intrinsic defect of bile-duct cells of affected individuals suggested that primary biliary cirrhosis might not
but is a feature of biliary epithelia in general, not seen in represent an additional risk factor for bone
other epithelial cells. demineralisation in women with compensated disease
supplemented with calcium and vitamin D.94 Therefore,
Clinical features in clinical practice, such supplementation—along with
The clinical features and natural history of primary biliary monitoring of bone density and vitamin D concentrations
cirrhosis vary greatly between patients, ranging from in serum—is highly recommended, even in individuals
asymptomatic and slowly progressive to symptomatic and with early disease.46,95 With more advanced disease,
rapidly evolving. The frequency of asymptomatic disease deficiencies of other fat-soluble vitamins and steatorrhoea
seems to be increasing, probably because of raised are common and must be monitored and supplemented.
awareness of the disease together with broad use of Hypercholesterolaemia, typically caused by a rise in
routine testing of liver biochemistry. Many asymptomatic HDL cholesterol, is common in patients with primary
patients will, however, develop symptomatic liver disease biliary cirrhosis but does not increase cardiovascular
within 5 years of diagnosis, although a third could remain risk96 or cause early signs of atherosclerosis.97 Use of
symptom-free for many years.77 statins is, therefore, not usually necessary, but these
Although non-specific, fatigue is the most common drugs are tolerated safely in people with other
symptom of primary biliary cirrhosis; it is present in cardiovascular risk factors.98
nearly 80% of patients and more than 40% report Several autoimmune diseases could coexist with
moderate-to-severe symptoms.78,79 The mechanism of primary biliary cirrhosis. In our experience, as many as
fatigue associated with this disease remains unknown a third of patients are diagnosed with another
despite many proposals, including autonomic dys- autoimmune disease,18 most frequently Sjögren’s
function,80 muscle impairment,81 excessive daytime syndrome and autoimmune thyroid disease. Whether
somnolence,82 changes in cortical excitability,83 and coexisting autoimmune diseases indicate a common
altered manganese homoeostasis within the CNS.84 genetic background or represent similar pathogenetic
Fatigue in patients with primary biliary cirrhosis is mechanisms is unclear.99 Autoimmune comorbidities
typically characterised as excessive daytime somnolence do not modify the natural history or clinical presentation
and can impair quality of life. Despite sparse correlation of primary biliary cirrhosis, with the exception of a
between fatigue and severity of liver disease, fatigue can reported slower progression of liver fibrosis in patients
be associated with decreased overall survival.85,86 with scleroderma.100
Of symptoms related to longstanding cholestasis, Once primary biliary cirrhosis has progressed to frank
pruritus seems to be the most typical complaint and is cirrhosis, liver complications do not differ much from
reported by 20–70% of patients in studies, usually those seen in cases of cirrhosis due to other causes, with
preceding jaundice. Widespread use of ursodeoxycholic the exception of oesophageal varices, which can arise
acid has led to a substantial reduction in the frequency early in the disease course, sometimes before other signs
of this distressing symptom despite the absence of a of cirrhosis. This outcome is probably attributable to the
direct effect. Many factors contribute to pruritus onset presence of presinusoidal inflammation and consequent
and intensity. First, cholestasis itself impairs biliary fibrosis induced by granulomas. Other complications of
excretion of several compounds leading to an increased portal hypertension (ie, ascites and hepatic encephal-
systemic concentration of putative so-called pruritogenic opathy) happen typically in end-stage primary biliary
compounds. Of these substances, bile acids could be cirrhosis. The occurrence of hepatocellular carcinoma in
important, as suggested by the ability of bile-acid binding individuals with primary biliary cirrhosis is similar to
other forms of cirrhosis and warrants surveillance in with predominantly lymphoplasmacytoid infiltrates and
patients at advanced disease stages.101 septal and interlobular bile-duct loss (stage I) to frank
cirrhosis (stage IV). Eosinophils and granulomas are also
Diagnosis and liver histology characteristic but not diagnostic of primary biliary
The diagnosis of primary biliary cirrhosis should be cirrhosis. When two or more stages manifest within the
suspected in anyone with findings of chronic cholestasis same liver sample, the patient is classified as belonging
after liver tests, particularly with raised concentrations of to the more severe stage. However, because of the
alkaline phosphatase. Furthermore, patients with primary heterogeneous nature of biliary involvement, liver biopsy
biliary cirrhosis generally have increased amounts of findings could include sampling error on the basis of
aminotransferases and immunoglobulins (mainly IgM). histological variability in different areas,106 but this factor
Diagnosis can be established if two of three objective does not warrant taking of several biopsy specimens.
criteria are present: a concentration in serum of AMAs at Although many patients with primary biliary cirrhosis
titres of 1:40 or higher; an unexplained rise in the amount will have mildly raised concentrations of amino-
of alkaline phosphatase of at least 1·5 times the upper transferases, and findings of liver biopsy might even show
limit of normal for more than 24 weeks; and compatible some degree of piecemeal necrosis, a poorly characterised
liver histological findings, specifically non-suppurative subgroup exists in which features of so-called hepatitis
cholangitis and interlobular bile duct injury.47 Whether are relevant.107 This finding has led to the designation of
AMA-positive individuals without biochemical abnormal- primary biliary cirrhosis–autoimmune hepatitis overlap,
ities will eventually develop primary biliary cirrhosis is but specific diagnostic criteria for this disorder remain to
still debatable, but expectant follow-up with annual liver be established. In addition to histological findings,
biochemical analysis is reasonable.47 By contrast, primary biliary cirrhosis–autoimmune hepatitis overlap
individuals with AMA-negative primary biliary cirrhosis should be considered when the ratio of alkaline
(currently synonymous with autoimmune cholangitis) phosphatase to aspartate aminotransferase is less
diagnosed on the basis of abnormal concentrations of than 1·5, serum concentration of IgG is increased, and
alkaline phosphatase and liver histological findings antibodies against smooth muscle are present at greater
manifest a similar course to their seropositive than 1:80 titre. A suspected diagnosis of primary biliary
counterparts.48 In these cases, MRI or endoscopic cirrhosis–autoimmune hepatitis overlap could be
retrograde cholangiography are recommended to rule clinically relevant because this disorder seems to have a
out primary sclerosing cholangitis or other disorders that more severe prognosis than primary biliary cirrhosis
might lead to chronic cholestasis. alone, and other treatments could be considered,
In addition to AMAs, antinuclear antibodies (ANAs) are including immunosuppressive agents.108
detected by indirect immunofluorescence in about 50% of
serum samples from patients with primary biliary Treatment and natural history
cirrhosis (table). Two nuclear fluorescence patterns are The natural history and prognosis of primary biliary
found in primary biliary cirrhosis. A rim-like pattern cirrhosis has become notably more benign, with
results from autoantibody reaction with glycoprotein 210 substantial improvements in disease outcome reported
and nucleoporin 62 (within the nuclear pore complex), in studies. Although these observations could be
and a pattern of multiple nuclear dots results from reaction secondary to early diagnosis and a consequent lead-time
with Sp100 and the promyelocytic leukaemia antigen bias,109 falling rates of liver transplantation for primary
(possibly also cross-reacting with small ubiquitin-like biliary cirrhosis in Europe and North America since
modifiers).102 The pathogenic role of ANAs in primary widespread use of ursodeoxycholic acid was introduced
biliary cirrhosis remains to be established, as is the case suggest a true change in natural history.110,111 Figure 2
with AMAs, although cross-sectional and longitudinal presents a schematic and somewhat arbitrary view of the
data suggest an association between ANA positivity natural history of primary biliary cirrhosis. Before the
specific to primary biliary cirrhosis and severe disease.59,103 introduction of ursodeoxycholic acid, time from
The need to undergo liver biopsy in primary biliary diagnosis to symptom-onset was about 2·0–4·2 years,
cirrhosis is controversial, although most clinicians agree and survival was compromised relative to a healthy
that this procedure is valuable for disease staging, population.112,113 Classically, presence of symptoms at
particularly in clinical trials.95 From a diagnostic point of diagnosis was an important determinant of disease
view, liver biopsy specimens are not required when the progression and survival.114 However, in a study from the
other two less invasive diagnostic criteria are fulfilled. UK77 of a large cohort of patients followed up for 24 years,
Thus, routine liver biopsy should be done only when although mortality due to liver disease was greatest in
considering a differential diagnosis from other disorders, symptomatic patients, overall survival was similar in
including small-duct primary sclerosing cholangitis, individuals with and without symptoms at time of
sarcoidosis, or drug-induced cholestasis. Histological presentation. Prediction of patients’ survival in primary
staging is based on Ludwig’s104 and Scheuer’s105 biliary cirrhosis has been attempted, and the Mayo
classifications, ranging from portal-tract inflammation model is the most well regarded,115 which includes five
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