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Titre: Urinary tract infection as a risk factor for autoimmune liver disease: From bench to bedside
Auteur: Daniel S. Smyk

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Clinics and Research in Hepatology and Gastroenterology (2011) xxx, xxx—xxx

MINI REVIEW

Urinary tract infection as a risk factor for
autoimmune liver disease: From bench to bedside
Daniel S. Smyk a, Dimitrios P. Bogdanos a,1,∗, Stephen Kriese a,
Charalambos Billinis b, Andrew K. Burroughs c, Eirini I. Rigopoulou d
a

Liver Immunopathology, Institute of Liver Studies and Liver Unit, King’s College London School of Medicine at King’s College
Hospital, Denmark Hill Campus, London SE5 9RS, UK
b
Faculty of Veterinary Medicine, University of Thessaly, 43100 Karditsa, Greece
c
The Sheila Sherlock Liver Centre, and University Department of Surgery, Royal Free Hospital, London, UK
d
Department of Medicine, University Hospital of Larissa, University of Thessaly Medical School, 4110 Larissa, Thessaly, Greece

Summary Autoimmune liver diseases include autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis. A variety of environmental and genetic risk
factors have been associated with these conditions. Recurrent urinary tract infections (rUTI)
have been strongly associated with PBC, and to a lesser extent with AIH. These observations were initially based on the observation of significant bacteriuria in female patients with
PBC. Larger epidemiological studies demonstrated that there was indeed a strong correlation
between recurrent UTI and PBC. AIH has not been linked to recurrent UTI in epidemiological
studies; however treatment of UTI with nitrofurantoin can induce AIH. As Escherichia coli is
the most prevalent organism isolated in women with UTI, it has been suggested that molecular
mimicry between microbial and human PDC-E2 (the main autoantigenic target in PBC) epitopes
may explain the link between UTI and PBC. Multiple studies have demonstrated molecular
mimicry and immunological cross-reactivity involving microbial and self-antigen mimics. This
review will examine the literature surrounding UTI and autoimmune liver disease. This will
include case reports and epidemiological studies, as well as experimental data.
© 2011 Published by Elsevier Masson SAS.

Introduction



Corresponding author. Tel.: +44 0 20 32 99 33 97;
fax: +44 0 20 32 99 33 97.
E-mail address: dimitrios.bogdanos@kcl.ac.uk (D.P. Bogdanos).
1 http://www.bogdanoslab.com.

Autoimmune liver diseases associated with recurrent urinary tract infections (UTI) have been almost exclusively
linked to primary biliary cirrhosis (PBC), and to a lesser
extent, autoimmune hepatitis (AIH). PBC is characterised
by the autoimmune destruction of small intrahepatic bile
ducts, with fibrosis progressing to cirrhosis and eventual

2210-7401/$ – see front matter © 2011 Published by Elsevier Masson SAS.
doi:10.1016/j.clinre.2011.07.013

Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
From bench to bedside. Clin Res Hepatol Gastroenterol (2011), doi:10.1016/j.clinre.2011.07.013

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D.S. Smyk et al.

Figure 1 Schematic illustration of cellular structures/organelles targeted by primary biliary cirrhosis (PBC) specific autoantibodies. Disease-specific autoantibodies in PBC give three main patterns by indirect immunofluorescence: anti-mitochondrial antibodies
give a cytoplasmic pattern better seen in kidney tissue sections while PBC-specific anti-nuclear antibodies are better seen using
HEp-2 cells as substrate and give a multiple nuclear dot or a rim-like membranous pattern.

liver failure [1—6]. Patient presentations may vary, with
some being asymptomatic with liver function tests indicating cholestasis [2,7—10]. Symptomatic patients typically
present with pruritus, fatigue and arthralgias [2,10,11],
with more severe symptoms being related to portal

hypertension, including ascites, jaundice, or variceal bleeding [2,10,11]. The diagnosis of PBC is based on biochemical
markers of cholestasis, histological features of PBC, and
the presence of anti-mitochondrial antibodies (AMA) and/or
disease-specific anti-nuclear antibodies (ANA) (Fig. 1)

Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
From bench to bedside. Clin Res Hepatol Gastroenterol (2011), doi:10.1016/j.clinre.2011.07.013

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Infection and autoimmunity
[1—3,7—10,12—22]. AMA are so prevalent in PBC that the
presence of the disease is questioned in their absence,
and it is commonly the case that AMA is predictive
of future disease development in asymptomatic individuals [1—3,7—10,12—23]. These autoantibodies are more
prevalent in family members of patients with PBC, and
AMA-positive individuals are at risk of developing PBC as
their affected relatives [24]. AMA specific to PBC are
directed against components of the 2-oxo-acid dehydrogenase complexes (also known as M2 antigens previously),
primarily the E2 subunit of the pyruvate dehydrogenase
complex (PDC) [2,8,9,13,25—27]. Medical treatment of PBC
includes urseodeoxycholic acid, which frequently leads to
a good biochemical response and decreased indices of
cholestasis in those diagnosed in the early stages of the
disease, or liver transplantation in more severe cases
[1—3,5,10,28—32].
AIH, formerly known as chronic active hepatitis, is
an inflammatory liver disease characterised by elevated
transaminase levels, the presence of specific autoantibodies, raised IgG, and interface hepatitis on histology
[33—38]. AIH can be divided into AIH type 1 and AIH type
2, based largely on autoantibody profiles [8,33—39]. AIH
type 1 primarily affects adults, and is characterised by
ANA and smooth muscle antibody [8,33—39]. AIH type 2
is more prevalent in the paediatric and adolescent population, and is characterised by antibodies to liver kidney
microsomal antigen type 1 and anti-liver cytosol type 1
antibodies [8,33—39]. Other autoantibodies include antisoluble liver antigen/liver pancreas antibody, perinuclear
anti-neutrophil cytoplasmic antibody, and perinuclear antineutrophil antibody [8,33—39]. As with PBC, patients may
be asymptomatic, or present with splenomegaly, haemorrhage from oesophageal varices, chronic diarrhoea and
weight loss [33—38]. Acute presentation occurs in 40% of
cases, and resembles an acute viral hepatitis, with symptoms of malaise, nausea and vomiting, jaundice, pale stool
and dark urine [33—38]. Chronic disease is characterized
by relapsing jaundice, fatigue and weight loss over months
to years [33—38]. The medical treatment of AIH includes
immunosuppression with prednisolone, supplemented with
azathioprine in some cases [34,37,40]. Untreated AIH progresses to cirrhosis, and requires liver transplantation
[34,37,40].
The aetiology of both PBC and AIH is unclear, but it
appears that a variety of factors including genetics, dysfunction of the regulatory aspects of the immune system,
as well as xenobiotic exposure and infectious agents may
account for the development of the disease in a state
of T cell dysregulation [5,41—47]. PBC appears to be
especially linked with recurrent UTI [48—51], by mechanisms such as molecular mimicry and cross-reactivity
with Escherichia coli (E. coli) [4,7,9,12,52—66]. AIH appears
to be linked with the treatment of recurrent UTI, with
several cases reporting AIH development after treatment
with nitrofurantoin [67,68]. This review will examine the
epidemiological evidence demonstrating an association of
recurrent UTI with PBC (Table 1), as well as case reports
linking nitrofurantoin treatment of recurrent UTI with
AIH. Evidence surrounding molecular mimicry and crossreactivity with E. coli in the induction of PBC will also be
addressed.

3

Bacteriuria and autoimmune liver disease: the
first clues
The first indication of an association between recurrent UTI
and PBC was noted in a British study reporting that 19%
of 87 women with PBC had bacteriuria, compared to 7%
of 89 women with other chronic liver diseases [63]. Further follow-up of 144 women over 12 months showed that
50 (35%) developed bacteriuria, and a recurrence of 34%
indicated a potential susceptibility of women with PBC to
developing recurrent UTI [63]. In that study, bacteriuria was
not associated with disease severity [63]. A Spanish study
also indicated a high rate of bacteriuria in 30 PBC patients,
and it appeared that the frequency increased with age [69].
Again, there was no relationship noted between UTI frequency and histological stage of PBC [69].
A prospective study by Brahm and Chesta [70] compared
the incidence of UTI in PBC and AIH patients. Bacteriological cultures were obtained from mid-stream urine samples
of 20 PBC and 23 AIH patients, collected in three-month
intervals, or when patients became symptomatic for UTI
[70]. A total of 60 samples were obtained from PBC patients,
and 73 from AIH patients over a nine-month period. Significant bacteriuria was found in 35% of PBC samples, compared
to 9% of samples from AIH patients [70]. Further followup showed that 50% of the original PBC cohort reported
UTI, compared to 26% from the AIH cohort [70]. Additionally, some case reports indicate the development of PBC or
AMA positivity after an incidence of bacteriuria. One such
report is of a 28-year-old female who developed AMA positivity with abnormal liver biochemistry following a UTI from
E. coli [71]. Another case reports a 54-year-old female who
developed AMA positivity with deranged liver biochemistry
after an incidence of cystitis [72]. Although PBC was initially
suspected, a liver biopsy was more suggestive of AIH, and
her condition improved after treatment with prednisolone
[72]. The authors of that report indicate the female had
HLA-DR4 which confers risk for AIH, and HLA-DR8 which is
over-presented in PBC patients and suggested that this may
have contributed to the development of AIH [72]. The above
studies demonstrated an association between PBC, AIH and
recurrent UTI, however the cohort sizes were relatively
small. Nevertheless, similar findings have been reported in
larger epidemiological studies of PBC.

Urinary tract infections and the epidemiology
of primary biliary cirrhosis
Very little epidemiological evidence in regards to AIH exists,
however several large, comprehensive studies have been
conducted on PBC. These studies have also found an association between PBC and recurrent UTI. Parikh-Patel et al.
examined a cohort of 241 PBC patients in the United States
[50]. These patients were identified from an electronic
mailing list for an Internet support group for PBC. The
epidemiological data was collected in the form of a questionnaire, which surveyed demographics, general medical
history, reproductive history, lifestyle factors, as well as
personal and familial history of PBC and autoimmune disease [50]. Questionnaires sent to patients included a section

Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
From bench to bedside. Clin Res Hepatol Gastroenterol (2011), doi:10.1016/j.clinre.2011.07.013

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D.S. Smyk et al.
Table 1 Numerous epidemiological studies have been conducted analysing risk factors for PBC development. All studies have
indicated an increased prevalence of urinary tract infections (UTI) or bacteriuria among primary biliary cirrhosis (PBC) patients.
Study

Burroughs
et al. (1984)
[63]

Parikh-Patel
et al. (2001)
[50]

Gershwin et al.
(2005) [49]

Prince et al.
(2010) [51]

Corpechot
et al. (2010)
[63]

Varyani et al., in
press [105]

Number of PBC
patients

87a

241

1032

222

800

Number of
controls

89 with chronic
liver diseasea

261 siblings,
225 friends of
PBC patients

1041

318 (from a
geographical
study); 2258
from a PBC
support group
2438

509

7991 general
population; 12,137
chronic liver disease

Identification
of PBC
patients

Verified PBC
patients in a
tertiary care
centrea

Identified
through a
mailing list of a
patient support
group

PBC patients
receiving
treatment in
tertiary care
centres

Hospital
database of
patients
receiving
treatment for
PBC

General Practice
Research Database

Identification
of controls

Patients with
chronic liver
disease in a
tertiary care
centre

Random digit
dialling (age
and sex
matched)

Method of
analysis

Culture of
urine samples

PBC patients
instructed to
provide contact
details of age
and sex match
friends and
siblings
Questionnaire

Two cohorts:
one from a
geographical
study, the
other from a
PBC support
group
Electoral role
(age and sex
matched)

Questionnaire
administered
over telephone

Questionnaire

Questionnaire

Data entries of
diagnosis within the
database

Proportion of
PBC cases
with UTI

19%a
(bacteriuria)

70.1%

59%

48%

29% (within > 1 year
at diagnosis), 19%
(within >5 years)

Proportion of
controls with
UTI

7%a
(bacteriuria)

55.2% female
siblings; 48.1%
female friends

52%

No number or
percentage,
but 2.06 odds
ratio
No number or
percentage but
fewer than in
PBC groups

31%

Matched controls:
22% matched
controls (over time
period >1 years),
14% (over time
period > 5 years)
Chronic liver
disease controls:
17% (within > 1 year
at diagnosis), 11%
(within >5 years at
diagnosis)

General Practice
General
population with Research Database
screening via
telephone
interview

PBC: Primary biliary cirrhosis; UTI: urinary tract infection.
a A follow-up study over 12 months included 144 PBC patients, 35% of which developed bacteriuria, with a recurrence of 34%. It should
be noted that except for Burroughs et al., all other studies did not confirm UTI diagnosis by bacteriological culture, and therefore few
studies have indicated a causative organism.

to provide the names and addresses of siblings and three
friends of the same sex who were within a five-year age
range of the patient [50]. The siblings and friends were used
as controls, and they were sent the same questionnaire as
the patients, although the friends’ questionnaires did not
include questions regarding diet [50]. A total of 241 PBC
patients, 261 siblings, and 225 friends participated [50]. The

PBC group was 90.5% female and 97% Caucasian [50]. UTI
was reported in 70.1% of PBC patients compared to 55.2%
of female siblings, and 48.1% of friends [50]. Vaginal infection was noted in 68.9% of patients compared to 64.2% of
siblings and 35.2% of friends [50]. One of the limitations
of such kind of studies is that UTI cannot be confirmed, as
no microbiological samples or reports were available, and

Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
From bench to bedside. Clin Res Hepatol Gastroenterol (2011), doi:10.1016/j.clinre.2011.07.013

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that the question regarding UTI is based on the individuals
recollection of being told they have UTI by a physician [50].
One of the largest, most comprehensive epidemiological
studies on PBC risk factors was conducted by Gershwin et al.
[49]. Between November 1999 and June 2004, 1090 PBC
patients in 23 tertiary USA clinical centres received letters
from the investigating group, which described the purpose
and methods of the study [49]. A total of 1032 patients indicated an interest in participating, and were administered a
questionnaire via a telephone interview [49]. Controls from
randomised digit dialling of registered post codes were contacted, and matched for sex and age (within 5 years) of
the PBC group [49]. A total of 1041 appropriately identified controls were administered the same questionnaire via
telephone interview [49]. Recurrent UTI was reported in 59%
of female PBC patients, compared to 52% of controls [49].
As well, vaginal infection was noted in 63% of PBC patients
and 56% of controls [49]. Individual history of UTI was associated with PBC in multivariable modelling, as was vaginal
infection [49].
The large epidemiological studies noted above have been
included in a recent meta-analysis by Liang et al., to provide more concise evidence associating smoking, family
history, and UTI with PBC [73]. Those investigators conducted a multisource literature search for papers indicating
risk factors for PBC [73]. Inclusion criteria consisted of
observational studies including relative risk or odds ratio
with 95% confidence interval, case control and cohort studies, and independent studies without repeat reports of the
same population [73]. Five papers were identified, including
the four epidemiological studies noted above [48—51,74],
and gave a total PBC population of 1913 patients, and 4697
controls [73]. The papers covered a 10-year period, with
populations in the United States and Europe [73]. Metaanalysis indicated that smoking, family history, and UTI may
be risk factors for PBC, with a pooled odds ratio of 2.02
for UTI [73]. Significant heterogeneity was found for UTI,
and no evidence for publication bias was indicated for UTI,
smoking, or family history [73].
Recent studies have also demonstrated a positive correlation between UTI and PBC. Prince et al. [51] examined
PBC patients in two groups: one consisted of patients from
and epidemiological study of PBC in the North East of England, and the other from a PBC support group [51]. All cases
of PBC were confirmed by gastroenterologists and hepatologists, and the PBC group was administered a questionnaire
[51]. Controls were obtained from an electoral role dataset,
and administered the same questionnaire [51]. Associations
were noted between PBC and UTI in PBC patients from the
epidemiological study group as well as patients from the support group [51]. A large European study by Corpechot et al.
[48] demonstrated that UTI was the most strongly associated
non-cancerous, non-autoimmune condition associated with
PBC, being present in 48% of PBC cases compared to 31%
of controls [48]. Recurrent UTI was also increased in PBC,
with 18% of PBC patients reporting more than five incidents
of UTI in their lifetime, compared to 7% of controls [48].
Multivariate logistic regression analysis demonstrated recurrent UTI as being independently associated with enhanced
susceptibility of developing PBC [48]. These epidemiological studies demonstrate a clear association between PBC
and recurrent UTI. Interestingly, a number of these studies

5
have indicated that there was also an increased incidence of
vaginal infection among PBC patients [32,33]. These findings
are of interest as Lactobacillus delbrueckii (L. delbrueckii),
an organism found in normal vaginal flora, has also been
linked to PBC, and that alterations in L. delbrueckii have
been linked to vaginal infections which increase susceptibility to recurrent UTI [75]. Rarely, L. delbrueckii has also been
identified as the causative organism of UTI, mainly in older
women [76,77]. Interestingly, one case report indicates the
development of PBC in a 39-year-old female, who developed
the disease following a course of Lactobacilli vaccinations
for recurrent vaginitis [78]. It was demonstrated that molecular mimicry may have been the causative factor in that case
(see below) [78]. It is therefore possible that a synergistic
effect between differing infections may play a role in PBC
development, in that infection with one bacterial species
may create an environment which is prone to infection with
another, possibly pathogenic, bacterial species [79—81].
Significant bacteriuria in PBC patients has been shown to
have an altered course compared to UTI in other groups,
as well as affecting the prognosis [65,82]. An early study
by the Royal Free Hospital group in London [65] evaluated the course of bacteriuria in PBC patients. This cohort
consisted of 21 asymptomatic (for UTI) patients, and 13
symptomatic patients [65]. All symptomatic and 11 asymptomatic patients received antimicrobial treatment, but
often became re-infected after a 3—4-week interval of sterile urine [65]. Apart from symptom relief in symptomatic
patients, there was very little difference in the course of
bacteriuria in all groups [65]. The pattern of bacteriuria in
PBC patients was characterised by a high rate of spontaneous remission and re-infection in untreated asymptomatic
patients, and a low rate of asymptomatic patients becoming
symptomatic on re-infection [65]. There was also very little benefit noted from anti-microbial treatment, apart from
symptom relief in symptomatic patients [65]. Finally, Morreale et al. [82] have evaluated the affect of recurrent UTI
on PBC prognosis. That study prospectively screened 187
women over a 5-year period for bacteriuria, 17% of which
had significant bacteriuria on first sample [82]. Among the
patients screened, 48% died due to the underlying liver disease and its complication within the study period, and 8%
received liver transplantation [82]. It was found that having an index bacteriuric urine sample increased the relative
hazard for death, with a 65% increased risk of death compared to non-bacteriuric patients, and there was also an
association between a positive index sample and a history
of recurrent UTI [82]. It therefore appears that recurrent
UTI may indicate a poor prognosis in a sub-group of PBC
patients, although it is unclear whether this is a causal or
casual effect [82].

Urinary tract infections-triggered primary
biliary cirrhosis: the role of cross-reactivity
and molecular mimicry
As mentioned, a positive association has been made between
recurrent UTI and PBC. Investigators from the Royal Free
Hospital in London [62] first suggested that the link
between PBC and recurrent UTI may be due to molecular
mimicry between human and E. coli PDC-E2 epitopes [62].

Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
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Figure 2 Three-dimensional modelling of human pyruvate
dehydrogenase complex E2 subunit. The structure was analyzed with the Cn3D visualization tool. The modelling predicts
that the core epitopic region of human PDC-E2 is located in
a solvent-accessible surface region of the protein, compatible
with antibody recognition.

Microbial/self molecular mimicry has been extensively
studied as a mechanism responsible for the induction of gastrointestinal and liver-related autoantibodies, and a potential trigger of autoimmune diseases
[52—54,57,58,75,78,81,83—87]. The researchers from the
Royal Free Hospital described low to modedrate-titre AMA
in more than 60% of females with recurrent UTI but no liver
disease, and reported that women with PBC were more susceptible to developing recurrent UTI compared to those with
other chronic liver diseases [62]. Butler et al. [64] also found
that 52% of patients without clinical liver disease but with a
history of recurrent UTI had AMA specific to the M2 antigens,
compared to 19% of those with chronic liver disease and 4%
of healthy controls. The same group has proposed that Bor T- cell PDC epitopes from E. coli or other microbes mimic
human PDC or other abnormally expressed HLA-DR antigens
on biliary epithelial cells (BEC) [62], which has also been
supported by others [61]. The fact that the major epitopic
region of human PDC-E2 is exposed on the surface of the
epitope (Fig. 2) has explained its antigenicity.
The mechanism by which E. coli may induce PBC may be
through a cross-reactive immune response between homologous epitopes of E. coli and the PDC-E2 epitopes (Fig. 3)
[81,88—91]. Despite a high degree of homology between
several regions of human and E. coli PDC-E2, antibody
responses to the core epitopic region of human PDC-E2 do
not cross react with the corresponding sequence of E. coli
[53,58,75]. As well, human anti-PDC-E2 antibody reactivity to E. coli PDC-E2 was 100 times lower when compared
to reactivity to mammalian PDC-E2 [92,93]. At the B-cell
epitope level, antibodies for PDC-E2212−226 do not cross
react with the corresponding E. coli PDC-E2 sequences [75].
This lack of reactivity may be due to structural differences between human and E. coli PDC-E2 epitopes, which
has been demonstrated at the 3D level [56]. However,
this core epitopic region has a large degree of overlap
with the CD4 and CD8 T-cell epitope on PDC-E2 [81], and
sera from PBC patients is cross reactive with homologous

Figure 3 Schematic illustration of structural molecular
mimicry between the corresponding epitopic regions of E. coli
and human pyruvate dehydrogenase complex E2 (PDC-E2) which
is the basis for the molecular mimicry link in primary biliary cirrhosis. Three-dimensional modelling of the mimicking
sequences was carried using the Cn3D visualization tool. A linear amino acid similarity or a conformational (i.e. structural)
homology between the micro-organism (E. coli PDC-E2) and self
(human PDC-E2) is considered the initial move for setting in
motion the process of antigenic mimicry and cross-reactive
immunity. According to the theory of molecular mimicry, the
foreign (non-self microbial) and human epitopes should be
homologous enough to provoke cross-reactive responses, but
sufficiently distinct to break immunological tolerance. As illustrated in the figure, the corresponding sequences have a
significant degree of structural homology and could be potential
targets of cross-reactive responses. The link between E. coli and
primary biliary cirrhosis is based on a hypothesis which assumes
that recurrent urinary tract infection will initiate B- and T-cell
responses against the E. coli PDC-E2 epitope and will induce
cross-targeted responses to the human PDC-E2 epitope, in a
‘friendly fire’ scenario. The cross-reactive immunity developed
towards the self-mimicking human PDC-E2 autoantigen may
become persistent, leading to autoreactivity, and ultimately,
autoimmune disease in genetically susceptible individuals.

E. coli epitopes of the PDC-E2 complex at the B and T cell
levels [7,9,53—55,59,89—91,94]. In fact, affinity of antihuman PDC-E2 to E. coli PDC-E2 was 100-times higher in
PBC patients when compared to controls [95]. Several studies have found cross-reactivity between the human PDC-E2
autoepitope (GDLLAEIETDKATI), and that of E. coli (EQSLITVEGDKASM) at the CD4 T cell level (Fig. 3) [89—91]. As
well, a motif shared by human and E. coli PDC-E2 (ExDK)
was found to be critical for T cell epitope recognition
[7,9,53—55,59,89—91,94]. T cells specific for human PDCE2 have also been shown to be activated by a motif sharing
peptide of E. coli OGDC-E2 [89—91]. The opposite of this has
been demonstrated by Tanimoto et al., where it was investigated whether human PDC-E2 epitopes could activate T

Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
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cells specific to E. coli epitopes [96]. In that study, 16 T cell
clones specific for E. coli OGDC-E2 were tested for proliferation when stimulated by human OADC-E2 autoepitopes
from PDC-E2, OGDC-E2 and BCOADC-E2 [96]. Activation in
response to human OADC-E2 was seen in 13/16 of the clones
[96]. These studies have demonstrated that cross-reactivity
between the highly conserved human and E. coli PDC-E2 epitopes, may be a factor leading to the loss of tolerance to
PDC-E2 seen in PBC patients with rUTI.
Apart from PDC-E2, homology between six other epitopes
of E. coli, and the major human PDC-E2 autoepitope has
been demonstrated at the linear epitope and 3D levels [61].
A linear analysis of these sequences shows a variable degree
of homology between the E. coli peptides and PDC-E2, ranging from 53% sequence similarity in regards to Nitrate
reductase 2, to 93% sequence similarity with ClpX [53,81].
Further evidence of cross-reactivity between human PDCE2 and the mimicking E. coli peptide ClpX (280-294) at the
T cell level has also been reported [56,97]. In addition to
ClpX, E. coli sequences of the ATP-dependent helicase hrpA,
and the periplasmic binding sequences are also of interest, as a large proportion of the PBC patients with UTI
reacted with these epitopes [53]. When used as competitors,
ATP-dependent helicase hrpA, and the periplasmic binding
sequences from E. coli were able to absorb antibody reactivity to PDC-E2212−226 autoepitopes, suggesting cross-reactivity
[53].
In addition to AMA, ANA has also been indicated as a
potential target of cross-reactive immune responses [52].
A study has found that 80% of AMA positive patients without liver disease also reacted to sp100, a PBC-specific
nuclear body autoantigen, compared to none of the AMA
negative patients [52]. As well, 74% of PBC patients with
recurrent UTI reacted with Sp100, compared to 4.8% of
PBC patients with no history of recurrent UTI, and none
of the recurrent UTI patients without liver disease, suggesting that E. coli infection may be a specific trigger of
anti-mitochondrial and anti-nuclear antibody responses in
susceptible individuals who develop PBC [52]. These findings
suggest that an addition to a loss of tolerance to mitochondrial antigens, E. coli infection may also lead to a loss
of tolerance to nuclear antigens in susceptible individuals.
The cross-reactivity between ANA and E. coli epitopes may
also occur at the B or T cell level, as is observed with
AMA.
Rough form E. coli, so called due to its fragile cell wall
as a result of defective polysaccharide synthesis, are of particular interest to investigators. Hopf et al. [98] found the
rough form of E. coli was the predominant form of intestinal
E. coli in a cohort of 21 PBC patients, compared to controls.
Rough E. coli has been associated with recurrent UTI, as it
was found to be prevalent in 41% of patients with recurrent UTI but no PBC, as well as in 39% of PBC patients
with recurrent UTI [66]. Interestingly, Butler et al. note
several regions of cross-reactivity between the cell wall of
E. coli and antibodies directed against mitochondrial antigens [66]. In addition to this, animal studies have found
that uropathogenic E. coli forms reservoirs in the bladder
of mice, acting as a source for continued infection [99].
Mice infected with uropathogenic E. coli developed AMA positivity, as well as histological features consistent with PBC
[99].

7
Finally, L. delbrueckii has also been identified as a
potential organism involved in PBC, and it has been demonstrated that this may be due to molecular mimicry [75,78].
The mechanism of molecular mimicry is based on amino
acid similarities between microbial sequences and autoepitopic regions [81,84,86,87,100,101]. These homologies may
be responsible for the initiation of immunological crossreactivity during infection [59,102]. In 2008, a case of a
39-year-old female who developed PBC following a course
of vaccinations for recurrent vaginitis has been reported
[78]. Serum AMA from this patient reacted against PDC-E2
(212-226), and was cross reactive with beta-galactosidase of
L. delbrueckii (LACDE BGAL 266-280) [78]. As well, the antibody reactivity to the bacterial mimic was higher than to
PDC-E2 (212-226), indicating that the antibodies may have
been initially formed against the microbial sequence [78].

Urinary tract infections in primary biliary
cirrhosis: past or present?
Although the data above is convincing for a link between
PBC and organisms involved in recurrent UTI, the critical
question of when UTI occurred is lacking. All of the larger
epidemiological studies do not indicate whether the high
incidence of UTI occurred before or after PBC diagnosis. It
may be argued that the incidence of UTI may be related to
an increased susceptibility to infection which may be sequelae of autoimmune disease. As many women with PBC also
suffer from Sicca syndrome, it is possible that alterations of
mucosal immunity in the vagina lead to alterations in the
normal genital flora, and therefore an increased incidence
of UTI [103,104]. For a causal link to be likely, it must be
demonstrated that UTI was present before the diagnosis of
PBC, and ideally, before the onset of biochemical, immunological, and histological evidence of PBC. A recent study by
Varyani et al. have provided evidence that UTI occurs long
before the diagnosis of PBC [105]. That study obtained data
on PBC patients and controls through the General Practice
Research Database, which provided data on diagnosis as well
as the dates of when the diagnosis was made. UTI occurring
at least 1 year before PBC diagnosis was found in 29% of PBC
patients, compared to 22% in the general population, and
17% in chronic liver disease controls. UTI occurring at least
5 years before diagnosis was found in 19% of PBC cases, 14%
in the general population, and 11% chronic liver disease controls [105]. As well, 1.75% of PBC patients had an episode
of pyelonephritis compared to 0.99% of general population
controls, and 0.70% of chronic liver disease controls. In relation to age, 31% of PBC patients diagnosed under the age of
55 years had a UTI at least 1 year prior to diagnosis [105].
The results of this study provide strong evidence that UTI in
female PBC patients does occur before PBC diagnosis, and
this relationship was especially strong in younger patients. It
is likely that the study by Varyani et al. will instigate further
studies examining the chronology of recurrent UTI and PBC,
incorporating liver biochemistry, autoantibody profiles, and
possibly histopathological data.
Several mechanisms may be involved in the initiation of
PBC by infectious agents causing recurrent UTI. It therefore could be argued that if recurrent UTI participates in
the initiation of the pathogenic processes leading to the

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D.S. Smyk et al.

induction of PBC, treatment with antibiotics would prevent
PBC, and improve disease-related cholestatic biochemical
indices as well as symptoms. Large-scale data addressing
this are currently lacking. Of interest, a case study by Ohno
et al. [71] reports a 28-year-old female who presented with
an increased CRP and white cell count, who complained
of pyrexia, fever and headache. E. coli was grown in both
blood and urine samples, and a diagnosis of pyelonephritis and sepsis was made [71]. Interestingly, this patient had
a cholestatic picture of liver biochemistry, as well as AMA
positivity [71]. Antimicrobial treatment improved her clinical condition, her liver enzymes normalised, and AMA levels
decreased [71]. With that said, it also remains a possibility that in several cases, the antibiotic therapy itself may
induce destruction of intrahepatic cholangiocytes in PBC.
Data investigating this possibility are also currently lacking.
However, antibiotics in the treatment of recurrent UTI have
been linked to AIH.
Recent genome wide association studies (GWAS) have
provided a great deal of information in regards to the role
of genetics in PBC, and the findings from these studies may
also provide some clues in relation to infectious agents
involved in PBC. Non-HLA genes found to be associated with
PBC include IRF5, STAT4, IL12A, IL12RB, MMEL1, CXCR5,
and NKFB1 [106—112]. The presence of certain susceptibility genes appears to be affected by ethnicity/geographical
location [112]. HLA positive associations include HLA-DR8,
DQB1, DRB1, DQA2 and DQA1, and the importance of HLA
genes in PBC development are now becoming more apparent, in contrast to previous views that associated HLA
genes were limited to related individuals and small groups
[43,113]. Of interest, HLA-DRB1*11 and DRB1*13 were found
to be protective for PBC in Italian patients, and these genes
have also been found to be protective against a number
of infectious agents such as viral hepatitis, human papilloma viruses, human immunodeficiency virus, and malaria
[113,114]. As protective HLA alleles, such as HLA-DRB1*11
and DRB1*13, are associated to resistance with several infections, it has been proposed that the lack of such alleles may
account for their negative association with PBC [114].

Urinary tract infections treatment and
autoimmune hepatitis
The association, if any, of UTI with AIH is largely based on
the association of nitrofurantoin-induced features indistinguishable to those seen in patients with AIH. Nitrofurantoin
is an antibiotic used in the treatment of recurrent UTI,
and has been found to induce AIH in a number of cases
[67,68,115—117]. Liver injury induced by nitrofurantoin may
manifest as a limited acute hepatitis, chronic hepatitis
or hepatic failure [115]. Hatoff et al. [68], reports the
case of a 27-year-old female with the HLA-B8 antigen who
developed AIH, after nitrofurantoin exposure for recurrent
UTI [68]. Another study [51] reports three women aged
65, 42 and 74, who developed AIH after receiving nitrofurantoin for long-term prophylaxis for recurrent UTI. In
these cases, AIH improved after nitrofurantoin was withdrawn and immunosuppressive therapy was initiated [51].
The ages of the patients in that study are more consistent
with other studies indicating that nitrofurantoin induced

AIH is more common in the elderly [117]. Interestingly,
Striker et al. [117] notes the presence of autoantibodies
in drug-induced AIH, with ANA being present in 82% of
cases, and smooth muscle autoantibody (SMA) in 73%. ANA
and SMA are detectable in practically all cases with type
1 AIH. Additionally, patients with nitrofurantoin induced
AIH had an increased prevalence of HLA-DR8 and HLADRw3 [117]. It has also been found that drug-induced AIH
does not often require long-term immunosuppressive treatment [118]. These cases demonstrate that drug induced
AIH should be suspected in patients receiving nitrofurantoin treatment, who present with signs of liver injury.
As it becomes clear, there is no true causal relationship
between AIH and UTI and AIH can be a complication of
recurrent UTI treatment with nitrofurantoin. Drug-induced
AIH is not limited to nitrofurantoin and several other
drugs have been implicated in the induction of the disease
[116,119—123].
Unlike AIH, nitrofurantoin has not been implicated in the
induction of PBC. However, other drugs have been implicated in liver injury which gives a PBC-like granulomatous
hepatitis [116]. These drugs include isoniazid, interferon,
phenytoin, and allopurinol [116]. Other xenobiotics and
pollutants have also been implicated in PBC, including compounds found in cosmetics and nail polish which may act in
concert with infectious agents to inflict damage in predisposed women [44,124—129].

Concluding remarks
Recurrent UTI has been indicated as a risk factor for
the development of autoimmune liver disease, especially
PBC. High rates of bacteriuria in PBC patients led to this
hypothesis, with several case reports and smaller studies also finding higher rates of UTI in women with PBC.
Subsequently, large epidemiological studies in Europe and
the United States have confirmed that there is a correlation between PBC and recurrent UTI. Immunological
studies suggest that the link between the two may be
due to molecular mimicry and cross-reactivity between
E. coli and PBC-specific autoantigens. Studies have demonstrated cross-reactivity, and regions of homology between
human PDC-E2 and E. coli PDC-E2, as well as non-PDC-E2
mimic’s. Cross-reactivity has also been noted to occur with
L. delbrueckii mimics, which is of interest as this bacteria has been found to be a cause of recurrent UTI in older
females. It is also possible that a number of bacterial species
may act synergistically in the development of PBC, with
some bacteria (such as L. delbrueckii) creating an environment suitable for infection with pathogenic bacteria, such
as E. coli.
AIH has been associated with treatment of recurrent UTI,
namely with nitrofurantoin. Few epidemiological studies on
the risk factors of AIH exist, and it is not known what the
incidence of recurrent UTI is in AIH, as well as other autoimmune liver diseases. It is therefore difficult to investigate
potential urinary tract sources for bacterial cross-reactivity
in these conditions, despite molecular mimicry and crossreactivity also being indicated as potential inducers of these
conditions.

Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
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9

Disclosure of interest

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Please cite this article in press as: Smyk DS, et al. Urinary tract infection as a risk factor for autoimmune liver disease:
From bench to bedside. Clin Res Hepatol Gastroenterol (2011), doi:10.1016/j.clinre.2011.07.013


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