REVIEW

The Cholangiopathies
Konstantinos N. Lazaridis, MD, and Nicholas F. LaRusso, MD
Abstract
Cholangiocytes (ie, the epithelial cells that line the bile ducts) are an important subset of liver cells. They
are actively involved in the modication of bile volume and composition, are activated by interactions
with endogenous and exogenous stimuli (eg, microorganisms, drugs), and participate in liver injury and
repair. The term cholangiopathies refers to a category of chronic liver diseases that share a central target:
the cholangiocyte. The cholangiopathies account for substantial morbidity and mortality given their
progressive nature, the challenges associated with clinical management, and the lack of effective medical
therapies. Thus, cholangiopathies usually result in end-stage liver disease requiring liver transplant to
extend survival. Approximately 16% of all liver transplants performed in the United States between
1988 and 2014 were for cholangiopathies. For all these reasons, cholangiopathies are an economic
burden on patients, their families, and society. This review offers a concise summary of the biology of
cholangiocytes and describes a conceptual framework for development of the cholangiopathies. We also
present the recent progress made in understanding the pathogenesis of and how this knowledge
has inuenced therapies for the 6 common cholangiopathiesdprimary biliary cirrhosis, primary
sclerosing cholangitis, cystic brosis involving the liver, biliary atresia, polycystic liver disease, and
cholangiocarcinomadbecause the latest scientic progress in the eld concerns these conditions. We
performed a search of the literature in PubMed for published papers using the following terms:
cholangiocytes, biliary epithelia, cholestasis, cholangiopathy, and biliary disease. Studies had to be published
in the past 5 years (from June 1, 2009, through May 31, 2014), and non-English studies were excluded.
2015 Mayo Foundation for Medical Education and Research

he cholangiopathies are progressive

disorders that lead to end-stage liver
disease owing to a lack of effective
medical therapies.1 Approximately 16% of
all liver transplants performed in the United
States between 1988 and 2014 were for cholangiopathies, representing approximately
two thirds of all liver transplants performed
for chronic hepatitis C during the same
period.2 Thus, the cholangiopathies account
for substantial morbidity, mortality, and economic burden; indeed, the annual expenditure for transplant for these conditions was
approximately $400 million in 2011.2,3
This review discusses the biology, describes
a conceptual framework, and summarizes recent
progress in understanding the pathogenesis
of and therapies for the 6 common cholangiopathiesdprimary biliary cirrhosis, primary
sclerosing cholangitis (PSC), cystic brosis
involving the liver, biliary atresia, polycystic liver
disease, and cholangiocarcinomadbecause the
latest scientic progress in the eld concerns
these conditions. For this review, we performed
a search of the literature in PubMed for published

Mayo Clin Proc. 2015;90(6):791-800

papers using the following terms: cholangiocytes,

biliary epithelia, cholestasis, cholangiopathy, and
biliary disease. Studies in the non-English scientic literature were excluded. Studies had to be
published in the past 5 years (from June 1,
2009, through May 31, 2014) and describe an
advancement in the eld.

From the Division of

Gastroenterology and
Hepatology, Mayo Clinic
College of Medicine,
Rochester, MN.

CHOLANGIOCYTES AND THE

CHOLANGIOPATHIES
Cholangiocytes line the biliary tree, a complex
3-dimensional network of conduits inside and
outside the liver,4 and participate in the formation of bile via an array of transmembrane channels, transporters, and exchangers (Figure 1).5
These molecules are expressed on the apical
or basolateral domain of cholangiocytes and
facilitate movement of water, electrolytes
and solutes, modifying bile volume and
composition.4,5 Cholangiocytes are also activated by interactions with endogenous and
exogenous stimuli (eg, microorganisms, xenobiotics, and drugs) and participate in liver injury
and repair (Figure 1).6 To accomplish these tasks,
cholangiocytes exhibit morphologic and

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MAYO CLINIC PROCEEDINGS

ARTICLE HIGHLIGHTS
n

The cholangiopathies are a group of chronic liver diseases that

share a central target: the cholangiocyte (ie, the epithelial cell
that lines the bile ducts).
Each cholangiopathy probably has a heterogeneous pathogenesis and a variable natural history.
Ursodeoxycholic acid, a naturally existing bile acid, is the only
Food and Drug Administrationeapproved medical treatment
for primary biliary cirrhosis, but it has no proven therapeutic
effect in any other cholangiopathy.
Liver transplant is the mainstay therapy for cholangiopathies,
including selected cases of cholangiocarcinoma, and it is proved
to extend survival.
Elucidation of the individual genetic and epigenetic architecture
of the cholangiopathies and understanding the inuence of the
gut microbiome and liver metabolome on cholangiopathies will
ultimately yield novel insights into their pathogenesis, leading to
personalized therapies for these disorders.

functional heterogeneity.7 Cholangiocytes lining

the small bile ducts possess proliferative capabilities and display functional plasticity in disease,
and cholangiocytes lining the large bile ducts
participate in hormone-regulated bile secretion.
Moreover, there is evidence that stem cells reside
in the vicinity of peribiliary glands, can differentiate into cholangiocytes, may be involved in
biliary remodeling, and may contribute to the
pathogenesis of cholangiopathies.8,9 Progress in
understanding the normal biology of cholangiocytes has led to hypotheses about cholangiocyte
dysfunction leading to the cholangiopathies
(Figure 2).
The cholangiopathies can be subclassied
into genetic, idiopathic, malignant, and other
categories (Table). Each cholangiopathy has
a unique presentation and course, yet all
share cholangiocyte-associated processes that
contribute to their pathogenesis. Commonalities
involve proinammatory signaling, innate immune responses, and cholangiocyte proliferation
and differentiation, as well as tissue repair processes. Thus, cholangiocytes become targets but
also contribute to disease development or
recovery after injury. For example, various insults cause cholangiocytes to become reactive,
a process characterized by increased expression
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of proinammatory cytokines and chemokines

(eg, interleukin-6, interleukin-8, tumor necrosis
factor a, and various growth factors) as well as
activation of signaling cascades, such as Notch
and Hedgehog.10 The molecules released then
act in autocrine and paracrine manner to inuence cholangiocyte proliferation, apoptosis,
and senescence and may lead to local angiogenesis, brosis, and recruitment of innate and
adaptive immune cells, mesenchymal cells,
and endothelial cells. Such events contribute
to a ductular reaction in which the number of
ductules increases, accompanied by inltration
of leukocytes and lymphocytes, activation of liver
progenitor cells, and an increase in matrix protein
levels. Unless reversed, these events lead to
periportal brosis, ductopenia, and, eventually, biliary cirrhosis.11 However, the same processes may also protect against further biliary
insult or help repair injury to the biliary tree.
In addition to local cholangiocyte-associated
events, genetic variants (Supplemental Table 1,
available online at http://www.mayoclinic
proceedings.org), epigenetic mechanisms, and
posttranscriptional phenomena (including the
inuence of microRNAs on protein expression)12
may also inuence whether reactive cholangiocytes progress to a cholangiopathy or regress to
a normal phenotype (Figure 2).
Current understanding is limited by the fact
that the involved genetic factors seem complex
and the environmental contributors are largely
unknown. Furthermore, each cholangiopathy
likely has a heterogeneous pathogenesis, a variable natural history, and a different response to
therapy. Moreover, there is a lack of longitudinal registries of affected patients and an absence
of well-characterized animal models. Elucidation of the individual genetic and epigenetic
architecture of the cholangiopathies and the
inuence of the gut microbiome and liver
metabolome on the cholangiopathies may ultimately yield novel insights into pathogenesis
and lead to potential therapeutic targets.13
PRIMARY BILIARY CIRRHOSIS
Primary biliary cirrhosis is characterized by
nonsuppurative inammation and destruction
of the interlobular bile ducts; this condition
progresses variably to biliary cirrhosis. The
prevalence of primary biliary cirrhosis ranges
broadly up to approximately 40 per 100,000

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CHRONIC BILIARY DISEASES

Interactions

Cell-cycle phenomena

Normal
function

Bile formation

Cross-talk to
resident and
nonresidents cells

Tissue homeostasis
maintenance

Channels,
transporters,
exchangersa

Inflammatory,
fibrotic mediatorsb

Apoptosis,
senescence,
proliferation,
modulatorsc

Disease
state

Transport

Molecules

Biology of cholangiocytes

Ductopenia
Dysplasia
Malignancy

Inflammation
Fibrosis

Cholestasis

Water channels: aquaporin

Cl/HCO3 exchanger: AE2 (SLC4A2)
Na+-glucose transporter: SGLT1 (SLC5A1)

necrosis factor
Interleukin-6

b Tumor

kinase B (AkT1)
Transforming protein N-RAS
Platelet-derived growth factor

c Protein

FIGURE 1. Cholangiocytes serve several functions in health and disease with the contribution of several
important molecules. For example, bile formation is achieved with the participation of transmembrane
molecules expressed on cholangiocytes like channels (ie, water channels [aquaporins]), transporters (ie,
SGLT1: Na-glucose transporter), and exchangers (ie, SLC4A2: Cle/HCO3e exchanger). Dysfunction of
these molecules could lead to cholestasis. Moreover, cholangiocytes interact with resident and nonresident cells of the bile ducts via inammatory and brotic mediators, such as tumor necrosis factor a and
interleukin-6, which in disease states results in biliary inammation and brosis. Finally, cholangiocytes
contribute to cell-cycle phenomena that are key to maintaining tissue homeostasis in the bile ducts. These
functions are achieved through modulators of apoptosis (ie, AkT1: protein kinase B a) senescence (ie,
N-RAS transforming protein), and proliferation (ie, platelet-derived growth factor), whereas their
malfunction leads to ductopenia, dysplasia, and malignant transformation of the bile ducts.

people.14 Reported prevalence rates have

increased over time; however, whether this increase reects heightened awareness or new
environmental exposures is unclear.14 Established environmental triggers include smoking,
urinary tract infection, microorganisms such as
the ubiquitous bacteria Novosphingobium aromaticivorans, and xenobiotics such as 2-octynoic
acid, commonly used in articial avoring.15
More than 90% of patients with primary biliary
cirrhosis are women, and the mean age at diagnosis is 55 years. Diagnostic criteria are persistent
(>6 months) biochemical evidence of cholestasis
(ie, increased serum alkaline phosphatase levels
more than twice the upper limit of normal),
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positive serum antimitochondrial antibodies

(the disease hallmark), and a diagnostic liver
biopsy.16,17 The typical histologic ndings
include a orid bile duct lesion with
segmental degeneration of ducts and formation of poorly dened noncaseating epithelioid granulomas. Although primary biliary
cirrhosis is considered an autoimmune disease, it does not respond to conventional
immunosuppressive drug therapies.18
Genetic Predisposition and Pathogenesis
Primary biliary cirrhosis has a strong genetic
predisposition.19 To better dene genetic
risk, 4 validated, genome-wide association

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biliary bicarbonate secretion, a process important in preventing bile salt toxicity to cholangiocytes; malfunction of this mechanism
likely contributes to the pathogenesis of the
disease.26 However, existing genome-wide association studies did not identify SLC4A2 as a
susceptibility locus, which suggests that its
pathogenetic involvement may occur at a
posttranscriptional level. 27

Environment

Proposed Pathogenetic Model for Cholangiopathies

Microorganisms
Xenobiotics

Unknown
environmental risks

Exotoxins
Endotoxins

Insult to cholangiocyte

Cholangiopathy

Host factors

Reactive cholangiocyte
Local proinflammatory milieu
Repair/
resolution

Persistence/
progression
Genetic predisposition
Epigenetics
Posttranscriptional regulation

Malignant
transformation

Fibrosis

Chronic inflammation
of bile ducts

Bile duct
proliferation

Cholestasis

Ductopenia

FIGURE 2. The putative initial insult to cholangiocytes may be an interaction with

an endogenous or exogenous substance, a microorganism, or an unidentied
environmental exposure. The initial host response is the development of a
reactive cholangiocyte phenotype and a bile duct proinammatory microenvironment. The balance of the host response to this insult, likely dependent on
genetic susceptibility, epigenetics, posttranscriptional regulation, or other yet
unknown mechanisms, may result in repair/resolution of the cholangiocyte injury
or in perpetuation of the initial inammatory response, leading to chronic
inammation of the bile ducts and ultimately to cholestasis, bile duct proliferation,
ductopenia, brosis, and potential malignant transformation of cholangiocytes.

studies have been performed to date and have

led to the identication of 30 susceptibility
loci (Supplemental Table 1).20-23 The ndings
indicate that both HLA and non-HLA antigen
risk alleles contribute to disease development.
The susceptibility loci include genes involved
in different immune processes (ie, B-cell function, antigen presentation and T-cell differentiation, and myeloid cell lineage differentiation
(Supplemental Table 1).20-23 However, the
mechanisms by which these genes lead to disease remain unknown. The consensus is that
the innate and adaptive immune systems
contribute to a breach of immune tolerance to
self-antigens that ultimately leads to disease.24
From the nongenetic perspective, studies
have found that patients with primary biliary
cirrhosis have reduced expression of the bicarbonate- transporter (SLC4A2) on the apical
cholangiocyte domain.25 This defect impairs
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Therapeutic Approach to Primary Biliary

Cirrhosis
Ursodeoxycholic acid (13-15 mg/kg per day) is
Food and Drug Administration approved for
the treatment of primary biliary cirrhosis17; however, its long-term therapeutic effect is not well
established.18,28,29 Patients who respond have
normalization of biochemical markers of cholestasis (ie, alkaline phosphatase), fewer symptoms,
and less need for liver transplant; nevertheless,
improvement in biochemical cholestasis does
not occur in 30% of patients, and nonresponders
generally experience accelerated disease progression.30 Several criteria to predict treatment outcomes at 1 or 2 years have been proposed
using scores based on biochemical markers (ie,
alkaline phosphatase, total bilirubin, and aspartate aminotransferase) or liver histology.31-33
Therapy of nonresponders and potential alternative therapies are fully reviewed elsewhere.18
Supplemental Table 2 (available online at http://
www.mayoclinicproceedings.org) lists selected
ongoing clinical trials in primary biliary cirrhosis.
Of particular note, obeticholic acid and bezabrate, probably by activating nuclear receptors
(ie, farnesoid X receptor and pregnane X receptor, respectively),34-36 have shown promising results for nonresponders to ursodeoxycholic acid
in phase 2 clinical trials. Liver transplant is effective for patients with primary biliary cirrhosis
who have advanced disease, with 1- and 5-year
survival of 85% and 72%, respectively.2 Primary
biliary cirrhosis has been reported to recur after
transplant in 9% to 35% of patients based on histologic evidence of orid bile duct lesions on allograft biopsy samples.37 The reason for recurrence
is unclear, and risk factors such as the age of the
recipient and the immunosuppression regimen
remain controversial.38-41
PRIMARY SCLEROSING CHOLANGITIS
Primary sclerosing cholangitis is characterized
by chronic inammation of the intrahepatic

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CHRONIC BILIARY DISEASES

TABLE. Classication of the Cholangiopathiesa

Genetic
Alagille syndrome
Caroli syndrome
Cystic brosis
Polycystic liver disease
ADPLD
ADPKD
ARPKD
Idiopathic
Autoimmune cholangitis
Biliary atresiab
Idiopathic childhood/adulthood ductopenia
IgG4-associated cholangitis
Primary biliary cirrhosisb
Primary sclerosing cholangitisb
Malignant
Cholangiocarcinoma
Secondary sclerosing cholangitis
ABCB4 deciency
Abdominal trauma (surgical or blunt)
AIDS cholangiopathy
Amyloidosis
Chemical/drugs (ie, 5-uorouracil)
Choledocholithiasis
Eosinophilic or mast cell cholangitis
Graft-vs-host disease involving the liver
Iatrogenic biliary strictures
Portal hypertensive biliopathy
Recurrent pyogenic cholangitis
Sarcoidosis
Sickle cell disease
Vascular/ischemic (ie, hepatic artery stenosis after
liver transplant)
ADPLD autosomal dominant polycystic liver disease;
ADPKD autosomal dominant polycystic kidney disease;
AIDS acquired immunodeciency syndrome; ARPKD
autosomal recessive polycystic kidney disease.
b
For the genetic component of these diseases, see
Supplemental Table 2.
a

and extrahepatic bile ducts, with resultant strictures (obliterative cholangitis) that ultimately
progress to cirrhosis and end-stage liver disease.42 The prevalence of PSC is 0 to 16.2 per
100,000 people.14 The prevalence is rising14
due to either increased disease awareness or unidentied environmental factors leading to a
true increase. The disease has a male preponderance, with a median age at diagnosis of 30 to 40
years.42 Approximately 70% of patients also
have inammatory bowel disease, usually
chronic ulcerative colitis.43 Diagnostic criteria
include persistent (>6 months) biochemical
cholestasis (ie, increased serum alkaline phosphatase levels more than twice the upper limit
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of normal), cholangiographic evidence of

biliary strictures documented most often on
magnetic resonance cholangiopancreatography, and exclusion of secondary sclerosing
cholangitis (Table).42,43 A liver biopsy is not
needed to establish the diagnosis of classic
PSC. The pathognomonic nding includes the
characteristic onion skinetype periductal
brosis lesion that is rarely seen. The typical
liver biopsy of patients with PSC reveals a
bro-obliterative cholangitis. However, liver biopsy is useful for diagnosing small duct PSC, a
variant of the disease where ndings from the
cholangiographic studies are normal yet on liver
biopsy there is evidence of PSC characterized by
portal inammation with mild edema or
brosis, proliferation of ducts or ductules, and
mild nonsuppurative brous cholangitis.
Genetic and environmental factors seem to
contribute to the pathogenesis of PSC.42,43
Validated genome-wide association studies
have identied 16 susceptibility loci that
likely contribute to the pathogenesis of PSC
(Supplemental Table 1).44-46 The most important genomic region predisposing to disease
lies in the HLA antigen-B locus.45 Based on association studies and despite their inherent
limitations, it is estimated that approximately
50% of these susceptibility loci are related to
autoimmune diseases other than inammatory bowel disease.46 Thus, the genomic data
suggest that after an unidentied environmental insult, several genetically predisposed
innate and adaptive immune pathways
contribute to chronic biliary inammation,
with the initial biliary injury likely enhanced
by the intrinsic toxicity of biliary constituents.
Also, it is conceivable that penetration in the
gut of an infectious agent or a microbial
component (eg, lipopolysaccharide) with ultimate entry into the portal system could
contribute to biliary inammation. For example,
fucosyltransferase 2, a molecule involved in the
nal steps of antigen synthesis of the ABO blood
group, is associated with differences in the biliary
microbial composition in PSC, that is, there is
evidence of diminished Proteobacteria and
increased Firmicutes in the bile.47 Moreover,
given the strong association of PSC and inammatory bowel disease, gut-derived activated T
lymphocytes may home to the liver during the
development of PSC.48 Finally, recent data suggest that in PSC, cholangiocytes undergo the

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MAYO CLINIC PROCEEDINGS

phenomenon of cellular senescence, a phenotype

associated with exuberant secretion of various
cytokines49 that could participate in the pathogenesis of PSC.50
No effective medical therapy exists for PSC.
Although well-designed clinical trials of ursodeoxycholic acid therapy have reported improvement in serum liver biochemistries and
liver histology,28 no study has found increased
patient survival.51 Furthermore, a study of
high-dose ursodeoxycholic acid therapy in PSC
revealed a 2.3-fold risk of reaching a primary
end point dened as development of cirrhosis,
varices, cholangiocarcinoma, need for liver transplant, and death in the treatment group
compared with the placebo group (P<.01).52
Guidelines from the American Association
for the Study of Liver Diseases do not endorse
the use of ursodeoxycholic acid in PSC.43 In
contrast, guidelines from the European Association for the Study of the Liver suggest that
moderate doses of ursodeoxycholic acid may
improve the results of liver tests and surrogate
markers of prognosis in patients yet not improve
survival.28 This controversy surrounding ursodeoxycholic acid use stems from lack of benet
on set clinical end points in fairly underpowered
studies of relatively short duration. Larger studies
with longer follow-up and better-dened clinical
end points are needed to settle this issue. Beyond
ursodeoxycholic acid, alternative therapies are
being evaluated in ongoing clinical trials
(Supplemental Table 2).
Liver transplant remains the main therapy for
patients with advanced PSC, with 1- and 5-year
survival of 85% and 72%, respectively.2 However, the disease may reappear in approximately
25% of patients after transplant.53 Diagnosis of
recurrence is made when there is no evidence
of long-term rejection or vascular insults in the
liver. Colectomy before or during the rst liver
transplant in patients with associated inammatory bowel disease may reduce the rate of posttransplant recurrence.54
CYSTIC FIBROSIS
Cystic brosis (CF) is a systemic disease caused by
mutations in the CF transmembrane conductance
regulator (CFTR) gene. It is the most common
autosomal recessive genetic disease in white people, affecting 1 in 3000 births in the United
States.55 Cystic brosis involves several organs,
including the lungs, reproductive tracts, pancreas,
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Mayo Clin Proc.

intestine, and liver. CFTR is a transmembrane

protein expressed on epithelia that acts as an
anion channel. Mutations of CFTR result in alterations of Cle and Na transport across epithelia
that, in turn, cause water efux abnormalities
responsible for increasing the density of secretions
in different tissues. Cholangiocytes are the only
cells in the liver that express CFTR. Indeed, the
CFTR protein is expressed on the apical domain
of cholangiocytes and regulates the water secretion and alkalinity of bile. A dysfunctional CFTR
protein reduces the water secretion in bile (ie,
cholestasis) and makes bile less alkaline. Yet, the
exact pathogenesis of liver disease in patients
with CF remains unknown. Of interest, only
approximately 30% of patients with CF have clinically signicant liver disease.56 In a longitudinal
study of patients with CF, it was found that liver
disease was more prevalent in the pediatric population (41% at 12 years of age) and decreased later
in life.57 In the same study, only 7.8% of patients
with CF developed liver cirrhosis, and less than
2% required liver transplant.57
The clinical manifestations of liver disease in
patients with CF vary. These encompass a wide
range presentations, from neonatal cholestasis
to asymptomatic elevation of liver transaminases,
liver steatosis, focal biliary cirrhosis, and liver
cirrhosis with or without portal hypertension.
The most common presentation of liver disease
in patients with CF is hepatomegaly, often unassociated with liver test abnormalities. Up to 50%
of patients with CF and liver disease have
elevated liver transaminase or g-glutamyl transferase levels. The diagnosis of liver disease in
patients with CF is made based on clinical,
biochemical, liver biopsy, and imaging criteria.
Presence of hepatomegaly (ie, palpable liver >2
cm below the right costal margin conrmed by
abdominal ultrasound) and persistent elevation
of liver transaminase or g-glutamyl transferase
levels (more than twice the upper limit of normal)
along with history of CF can make the diagnosis.58 Liver biopsy could be performed to
conrm the disease and usually reveals focal or
multifocal biliary cirrhosis. To date, there is no
direct correlation between specic CFTR mutations and development of liver disease.
There is no specic therapy for patients with
CF who develop liver disease. Ursodeoxycholic
acid therapy is recommended for these patients,
although there is no evidence that it prevents disease progression. The suggested dose of

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CHRONIC BILIARY DISEASES

ursodeoxycholic acid in these patients is 20 mg/

kg per day divided into 2 to 3 doses. More studies
are needed to better understand the disease modier genes. One- and 5-year patient survival after
liver transplant are 80% and 75%, respectively.2
BILIARY ATRESIA
Biliary atresia is an infantile obstructive cholangiopathy of unknown etiology that accounts for
approximately 50% of pediatric liver transplants.59 Biliary atresia (incidence of 1 per
12,000 births in the United States) is characterized by persistent jaundice and acholic stools
due to bro-obliterative blocklage of the bile
ducts.59 It is postulated that a prenatal or perinatal viral infection may initiate cholangiocyte
apoptosis, which causes the release of antigens
that trigger an immune response involving Thelper cell lymphocytes that amplify the ongoing
bile duct injury, inammation, and obstructive
brosis.60 Humoral immunity and activation of
the innate immune system may also contribute
to this process.61 Recent studies suggest that regulatory T cells and genetic susceptibility factors
may activate destructive autoimmune mechanisms in biliary atresia.62,63
A validated genome-wide association
study of patients with biliary atresia from
China revealed a strong association with a
single nucleotide polymorphism on chromosome 10q24.64 Based on biological plausibility
and bioinformatics assessment, 2 genes in this
genomic region, X-prolyl aminopeptidase P1
(XPNPEP1) and adducin 3 (ADD3), may
contribute to the pathogenesis of biliary
atresia given that they are expressed in cholangiocytes and are known to be involved in
the metabolism of inammatory mediators.64
A subsequent genome-wide association study
from the United States has also implicated ADD3
as a possible predisposing factor in biliary
atresia.65 Genetic defects of XPNPEP1 could result
in dysregulation of the inammatory response in
these patients, and mutation in ADD3 could lead
to excessive deposition of actin and myosin,
contributing to biliary brosis.64
Hepatoportoenterostomy (the Kasai procedure) is the rst-line surgical approach for
biliary atresia; however, it requires that the
disease be diagnosed shortly after birth
because hepatoportoenterostomy prevents
worsening of disease only if performed before
30 to 45 days of life.59 A stool card screening
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method for newborns has shown promise in

identifying patients with biliary atresia during
the rst month of life.66 This card depicts
photographs of normal and abnormal (ie,
acholic) colored stool samples and is incorporated into the child health booklet to educate
the parents and health providers about the
characteristic stool of the disease.67 If hepatoportoenterostomy is not successful, liver
transplant is the next line of therapy. Even
after a successful hepatoportoenterostomy,
more than 70% of affected children eventually develop liver cirrhosis and require liver
transplant by adulthood.60 One- and 5-year
patient survival after liver transplant are
85% and 73%, respectively.2 Ongoing clinical trials for the therapy of biliary atresia
are recorded in Supplemental Table 2.
POLYCYSTIC LIVER DISEASE
The polycystic liver diseases are inherited disorders that occur alone (autosomal dominant
polycystic liver disease) or in association with
polycystic kidney disease (autosomal dominant or autosomal recessive polycystic kidney
disease). Autosomal dominant polycystic liver
disease has a prevalence of approximately 1 per
100,000 people and is due to a mutation of
PRKCSH or Sec63 genes, both of which are
expressed in cholangiocytes.68 Autosomal dominant polycystic kidney disease, most often due to
mutations in polycystin 1 or 2, is the most
common inherited renal cystic disease; it affects the liver in approximately 85% of patients.68 Autosomal recessive polycystic
kidney disease is due to mutations of
PKHD1, which encodes for brocystin/polyductin, and is characterized by bile duct
dysgenesis, intrahepatic bile duct dilatation,
and congenital hepatic brosis.69
The mechanism of hepatic cystogenesis involves benign cholangiocyte hyperproliferation,
abnormal uid transport, and cell-cycle dysregulation. Recent work in cell systems and in animal
models found that increased levels of intracellular cyclic adenosine monophosphate (cAMP)
in cholangiocytes play a key role in hepatic cyst
formation and progression.70
The observation that increased levels of
intracellular cAMP in cholangiocytes are
pivotal in hepatic cyst formation and progression,70 coupled with the knowledge that
cAMP levels are regulated by the binding of

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2 circulating peptides, secretin (which increases cAMP levels) and somatostatin (which
decreases cAMP levels), to their receptors on
the cholangiocyte membrane, prompted
in vitro and in vivo studies in rodent disease
models that found that somatostatin analogues could decrease the levels of cAMP in
cystic cholangiocytes and reduce cyst expansion.71 These studies ultimately led to clinical
trials, and, thus, in addition to surgical therapy (ie, liver cyst resection), octreotide, a
somatostatin analogue, is now a pharmacologic
treatment option for patients with symptomatic,
progressive cystic liver disease.72 An ongoing
clinical trial for polycystic liver disease is listed
in Supplemental Table 2.
CHOLANGIOCARCINOMA
Cholangiocarcinoma is a biliary malignancy that
originates from oncogenic transformation of
cholangiocytes and is classied as intrahepatic
(10%), perihilar (50%), and distal (40%).73 During the past 3 decades, the overall incidence of
cholangiocarcinoma has increased,74 and survival rates have not improved (5-year survival
for R0-resected patients, ie, microscopically negative surgical margins, of 63% for intrahepatic,
30% for perihilar, and 27% for distal tumors).73,75 Although most patients with cholangiocarcinoma have no identiable risk factors,
PSC is the most important risk factor in developed countries.76
The clinical presentation of cholangiocarcinoma varies depending on the location of disease.
Intrahepatic cholangiocarcinoma presents as a
liver mass generally in a noncirrhotic liver,
and perihilar and distal cholangiocarcinoma
present with jaundice. Cross-sectional imaging
studies, endoscopic retrograde cholangiopancreatography, magnetic resonance cholangiopancreatography, and endoscopic ultrasound
can dene the extent and resectability of cholangiocarcinoma. Diagnosis of perihilar and
distal cholangiocarcinoma is particularly challenging in patients with PSC because differentiation between benign and malignant strictures
is difcult. Conventional cytologic analysis and
uorescence in situ hybridization of biliary
samples obtained during endoscopic retrograde cholangiopancreatography can be helpful.77 Finally, IgG4-associated cholangitis,
characterized by benign biliary strictures and
elevated serum levels of IgG4, should be
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included in the differential diagnosis of perihilar and distal cholangiocarcinoma.43,78

Surgery is the preferred therapy for any type
of cholangiocarcinoma contingent on tumor
resectability. However, curative resection of
intrahepatic cholangiocarcinoma with negative
margins is achieved in only approximately
30% of cases.73 Perihilar and distal tumors are
usually either unresectable at diagnosis or technically difcult to surgically resect because of
the complex anatomy and the requirement of
biliary reconstruction.73 Liver transplant after
neoadjuvant chemotherapy and radiotherapy
has been reported for selected cases of perihilar
cholangiocarcinoma,79 with 5-year recurrencefree survival of 65%, a value similar to outcomes
for other indications for liver transplant.79 For
unresectable cholangiocarcinoma, treatment includes chemotherapy with gemcitabine and
cisplatin.80 Ongoing clinical trials for cholangiocarcinoma are listed in Supplemental Table 2.
CONCLUSION
The cholangiopathies continue to have high
morbidity and mortality, pose substantial challenges for clinical management, and confer
considerable economic burden on patients and
society. Further understanding of the normal
biology of cholangiocytes and elucidation of
the genetic and nongenetic contributors associated with the cholangiopathies may result in
more accurate prognostication and more effective therapies.
SUPPLEMENTAL ONLINE MATERIAL
Supplemental material can be found online at
http://www.mayoclinicproceedings.org.
Abbreviations and Acronyms: ADPLD = autosomal
dominant polycystic liver disease; ADPKD = autosomal
dominant polycystic kidney disease; AIDS = acquired immunodeciency syndrome; ARPKD = autosomal recessive
polycystic kidney disease; cAMP = cyclic adenosine monophosphate; CF = cystic brosis; CFTR = cystic brosis
transmembrane conductance regulator; PSC = primary
sclerosing cholangitis
Correspondence: Address to Nicholas F. LaRusso, MD,
Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (larusso.nicholas@mayo.edu).

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