Colangitis Esclerosante Secundaria 2013

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Secondary Sclerosing CholangitisPathogenesis, Diagnosis, and Management

Mohamad H. Imam, MBBSa, Jayant A. Talwalkar, MD, MPHa,Keith D. Lindor, MDb,*

INTRODUCTION

Secondary sclerosing cholangitis (SSC) is a chronic disease with phenotypical, clin-

ical, and cholangiographic resemblance to idiopathic primary sclerosing cholangitis

(PSC). Conversely, a known pathologic process underlies SSC, leading to inflamma-

tion, obliterative fibrosis of the bile ducts, stricture formation, and progressive destruc-

tion of the biliary tree that ultimately leads to biliary cirrhosis. Without timelyintervention, the natural history of SSC is less favorable than that of PSC.

The most common disease processes and causes underlying SSC include stones in

the biliary ducts, surgery, chemotherapy, blunt trauma, and recurrent or autoimmune

pancreatitis.1 A new form of SSC, sclerosing cholangitis in critically ill patients (SC-

CIP), is associated with rapid progression to liver cirrhosis. Patients with this form

of sclerosing cholangitis generally do not have a history of preceding biliary or liver

a

Cholestatic Liver Diseases Study Group, Division of Gastroenterology and Hepatology, MayoClinic, 200 First Street SW, Rochester, MN 55905, USA; b College of Health Solutions, ArizonaState University, 500 North 3rd Street, Phoenix, AZ 85004-0698, USA* Corresponding author.E-mail address: [email protected]

KEYWORDS

Liver transplantation Clinical management Cholangiopathy Complications Outcomes

KEY POINTS

Secondary sclerosing cholangitis (SSC) is a rare disease entity with complex

pathogenesis.

Common causes for SSC include obstruction, infection, ischemia, and critical illness.

Although initially asymptomatic, patients with SSC may present later with pruritus,

abdominal pain, and jaundice.

The cholangiographic finding of isolated peripheral ductal abnormalities suggests SSC

over primary sclerosing cholangitis.

Management should address the underlying cause of SSC, and liver transplantation is anoption for advanced disease.

Clin Liver Dis 17 (2013) 269–277http://dx.doi.org/10.1016/j.cld.2012.11.004 liver.theclinics.com1089-3261/13/$ – see front matter Published by Elsevier Inc.

mailto:[email protected]://dx.doi.org/10.1016/j.cld.2012.11.004http://liver.theclinics.com/http://liver.theclinics.com/http://dx.doi.org/10.1016/j.cld.2012.11.004mailto:[email protected]


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disease and do not show evidence of obstructive injury to the bile duct. Therapeutic

options for SSC remain limited, and patients with SSC who do not receive liver trans-

plantation have significantly reduced survival compared with those with PSC.

This article describes the epidemiology, pathogenesis, common causes, diagnostic

modalities, management, and outcomes in patients with SSC.

Epidemiology

Because of a common perception that SSC is a rare disease, relevant epidemiologic

data confirming the prevalence of SSC are lacking. From the authors’ experience at

the Mayo Clinic in Rochester, MN, USA, only 31 cases were described through

a decade of diligent patient follow-up. In this population, the major causes of SCC

were postcholecystectomy trauma, chronic pancreatitis, and intraductal stones.

Patients with SSC who did not undergo transplantation had a shorter period of survival

(72 months) than those with PSC (89 months).2

Pathogenesis

Primary hepatocellular bile has an intricately modulated content comprising a set alka-

linity and fluidity that is adjusted by the intrahepatic bile duct epithelium, which in turn

affects the reabsorption of bile acids, amino acids, and glucose and the secretion of

electrolytes and water.

Orchestration of hepatocytes and cholangiocytes (epithelial cells of bile duct) is

essential for bile formation. Bile is first secreted by hepatocytes as primary bile, which

is modified later by cholangiocytes through secretion of electrolytes and fluids.3,4

Anatomically, the liver consists of a convoluted network of intrahepatic ducts that

are required for bile secretion. In these ducts an increase in alkalinity and fluidityoccurs; this is in contrast to the acidification and concentration that occurs in the gall-

bladder. Specific sections of intrahepatic bile ducts are often targeted by biliary abnor-

malities, and hence different functional properties of these segments can be affected

accordingly.5,6

The intrahepatic bile duct epithelium transport function is synchronized by several

factors, including neurotransmitters, neuropeptides, and hormones. This intrahepatic

biliary epithelium is the primary target of cholestatic insults, which may include auto-

immune diseases, toxic agents, ischemia, infections, and even genetic diseases.

Characteristic findings in cholangiopathy include cholangiocyte apoptosis, prolifera-

tion, inflammation, and fibrosis. The pathogenic cascade involving the developmentof SSC targets cholangiocytes. Through production of various proinflammatory medi-

ators, cholangiocyte proliferation and death may contribute to the process of inflam-

mation, resulting in chronic liver destruction. These afflictions of cholangiocytes are

often produced by toxins, ischemia, trauma, or apoptosis. SSC is characterized by

damage to the peribiliary circulation, proliferation of cholangiocytes, alterations in

cholangiolar secretions and transport processes, and, finally, activation of fibrosis.

Specific molecular pathways that lead to fibrosis are still under investigation.7

COMMON CAUSES

Unlike PSC, the origin of which is still under investigation, common causes for SSC are

evident and can be treated accordingly. Common causes include obstruction,

ischemic insult, infections, and immunologic disease. Imaging and diagnostic modal-

ities can help differentiate secondary causes, and can hence aid in implementing the

appropriate treatment in a timely and effective manner. Table 1 provides a summary of

common causes and their related pathogenesis.

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Obstruction

Obstruction of the biliary tree has numerous causes, which may include cholecystitis,

biliary stones, polyps, tumors, arterial aneurysms, pancreatic disease, and strictures

inflicted through surgery or trauma. Obstructive cholangiopathy is characterized bybile stasis, which eventually leads to inflammation and fibrosis. The timing at which

this sequence occurs often depends on the extent and duration of the obstruction.

Along with stasis, the external pressure effect and the possibility of superimposed

infection may also lead to aggravated injury. Eventually, the patient develops a vicious

cycle of biliary stasis and suppurative cholangitis.

Gallbladder and bile duct abnormalities can be associated with portal hypertension

in some patients, which leads to extrinsic obstruction of the common bile duct. More-

over, this may be the pathogenesis that underlies bile duct obstruction in cirrhosis and

liver fibrosis.8 Patients with this disease, termed portal biliopathy , are often symptom-

atic at diagnosis, and liver histology shows minimal or no abnormalities. Cholangiog-raphy is the preferred modality for diagnosing patients with portal biliopathy, in whom

abnormalities in the common bile duct are often prominent.9 Recommendations for

treatment include biliary balloon dilatation, and possibly surgery if persistent obstruc-

tion is present.10,11

Infectious and Inflammatory

Recurrent pyogenic cholangitis is caused by the development of strictures or pig-

mented stones that lead to obstruction of the biliary tract and, subsequently, recurrent

episodes of bacterial cholangitis. This disease entity is also referred to as Oriental cholangiohepatitis.12 Ultrasonography may be used initially to diagnose ductal stones

or dilatation; this can then be followed by a contrast computed tomography to identify

central ductal dilation and peripheral ductal tapering.13,14 Conversely, endoscopic

retrograde cholangiopancreatography (ERCP) and magnetic retrograde cholangio-

pancreatography are not recommended because of the increased risk of sepsis.

This can be managed through conservative measures and antibiotic therapy, with

Table 1

Causes and related pathogenesis of SSC

Causes Related Pathogenesis

Cytomegalovirus/parasites

(mainly in AIDS or organ transplantrecipients)

Infection leading to chronic inflammation

Autoimmune pancreatitis, hypereosinophilicsyndrome

Immunologic modulation

Cholecystitis, biliary stones, polyps, tumors,arterial aneurysms, pancreatic disease,and strictures

Obstruction leading to a cycle of biliary stasisand suppurative cholangitis

Echinococcosis Hydatid cyst rupture leading to necrosis andfibrosis of biliary epithelium

Allograft rejection, vasculitis, thrombotic

obstruction, advanced AIDS, livertransplantation, hypoxia, massivetransfusions, hereditary telangiectasias,radiotherapy, and chemotherapy

Ischemia caused by direct effect of trauma or

subsequent massive transfusions,medications, or hypotension

Critical illness (SC-CIP) Interference with the biliary blood supply

Secondary Cholangitis 271


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surgery indicated in patients experiencing persistent symptoms or decompensation or

those developing peritonitis.15

In patients with immunodeficiency, susceptibility to parasitic infections may predis-

pose to SSC. For example, patients with advanced AIDS often develop a cholangiop-

athy caused by biliary infection with Cryptosporidium par vum or Microsporidia, which

presents with papillary stenosis and features of SSC.16,17 Moreover, in patients under-

going organ transplantation, cryptosporidiosis has been described to cause SSC and

viral infection, with cytomegalovirus as the second leading cause of SSC in AIDS

cholangiopathy.17–20

Echinococcosis can be complicated by hydatid cyst rupture, which may lead to

necrosis of biliary epithelia and fibrosis through toxin mediated mechanisms.21

Hepatic stellate cells seem to have a role in interacting with parasitic antigens, leading

to liver fibrosis.22 Leakage of fluid from the hydatid cyst through a biliary fistula may

also cause SSC.23

A histologic finding of a heterogeneous population of plasma cells, fibroblasts,

macrophages, and eosinophils may denote the presence of a rare pathologic entity

referred to as hepatic inflammatory pseudotumor . Despite associations with Crohn

disease, its pathophysiology remains obscure.24,25

Ischemia

The biliary system is a highly vascular network, which necessitates the maintenance of

an adequate blood supply to avoid injury. The right and left hepatic arteries form the

major blood supply to the extrahepatic biliary system, except for the gallbladder,

which receives its blood supply from the retroduodenal artery and is less vascular

than the remaining biliary formation.Ischemic cholangitis is an umbrella term that can comprise several causes with

a common pathophysiology, including allograft rejection, vasculitis, thrombotic

obstruction, advanced AIDS, liver transplantation, hypoxia, massive transfusions,

hereditary telangiectasias, radiotherapy, and chemotherapy.1,26 After trauma, a patient

may develop ischemic cholangitis either from the direct effects of the trauma on the

biliary tree or as a result of subsequent massive transfusions, medications, or hypo-

tension. In patients undergoing liver transplantation, ischemic injury may result from

destruction of small arteries and thrombosis of larger arteries; this may occur in up

to 19% of patients undergoing transplant. The risk for biliary ischemia is even higher

in liver transplantation from donation after cardiac death, in which donor age and cold

ischemic time act as major risk factors for the development of ischemic cholangiop-

athy.27 Chemotherapy can affect the bile ducts through ischemia and hence lead to

secondary sclerosing cholangitis; common agents include floxuridine, paclitaxel,

5-fluorouracil, formaldehyde, and yttrium 90.1,26,28

Sclerosing Cholangitis in Critically Ill Patients

Patients with life-threatening illnesses are prone to developing secondary sclerosing

cholangitis, a disease entity coined as SC-CIP. Surprisingly, this pathogenetic process

persists even after recovery from the primary illness, and leads to rapid developmentof cholestasis despite the absence of baseline liver disease. Investigators have sug-

gested that the underlying pathogenesis is centered on interference with the biliary

blood supply.29 Cholangiography may initially show simple filling defects, but later

stages may be confused with PSC, an important differential to consider when assess-

ing patients. Casts are the hallmark of sclerosing cholangitis in critically ill patients and

may be useful in distinguishing it from different disease entities. Once this disease

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develops, the outcomes are truly detrimental, with rapid progression to cirrhosis and

an urgent need for transplantation.30

Immunologic

Several autoimmune disorders may be involved in the pathogenesis of SSC. One

disorder is autoimmune pancreatitis, a distinct primary pancreatic disease with no

gold standard for diagnosis but features of autoimmunity, such as the presence of

hypergammaglobulinemia, elevated serum immunoglobulin G 4 (IgG4) levels, and

elevated liver enzymes.31–33 IgG4 levels are the most important in distinguishing auto-

immune pancreatitis from pancreatic cancer.32 On histology, autoimmune hepatitis

shows diffuse lymphoplasmacytic infiltration with acinar atrophy, obliterative phlebitis,

and marked fibrosis.34 A varying array of symptoms may occur in patients with auto-

immune pancreatitis, often related to strictures or pancreatitis; obstructive jaundice

may be present in a little fewer than half of the patients with autoimmune pancreatitis.

Patients with eosinophilic infiltration from hypereosinophilic syndrome commonly

present with features of sclerosing cholangitis. Infiltration of the liver with eosinophils

may occur in several liver diseases or as an immune response to other pathogenetic

processes. The role of this infiltration in inducing biliary fibrosis remains uncertain.

Patients with SSC from hypereosinophilic syndrome show good response to steroids,

reflected by a decrease in sclerosing cholangitis and eosinophilic infiltration.1,35

Fibrotic tissue is mast cell–rich, reflecting the role of mast cells in the produ ction of

fibrogenic factors, such as heparin, tryptase, stem cell factor, and histamine.36–39 In

patients with systemic mastocytosis, this infiltration of mast cells could lead to scle-

rosing cholangitis.35,40

Children with a diagnosis of cystic fibrosis may present with changes concordantwith PSC. This finding can be explained by the increased expression of cystic fibrosis

transmembrane conductance regulator (CFTR) gene.41 Although some older studies

contradict this theory, showing a lack of association between CFTR mutations and

PSC,42 more recent reports convey a link between CFTR dysfunction in the pediatric

population and the development of PSC.43,44

Langerhans cell histiocytosis (LCH), also known as histiocytosis X , has been linked

in several reports to PSC.45,46 Patients with LCH may develop end-stage liver disease

and hence require liver transplantation. Outcomes of patients with LCH after liver

transplantation for advanced liver disease show good outcomes, but further study

is required in a larger cohort of patients.47

CLINICAL SYMPTOMS AND DIAGNOSIS

Most patients at the initial stages of the disease are asymptomatic, with elevated alka-

line phosphatase and gamma glutamyltransferase levels. Several symptoms may

occur as the disease progresses, which may include pruritus, abdominal pain, and

jaundice. In patients with SSC, recurrent episodes of bacterial cholangitis from

ascending infection are common.48–50

After the identification of abnormal liver test results, patients should undergo ultraso-

nography to detect biliary abnormalities relating to obstruction. If the underlying causeis not obstruction and the ultrasound shows no findings, the use of ERCP is recommen-

ded. Findings on ERCP are similar to those for PSC, with ductal dilatation and beading.

RADIOLOGIC DIFFERENTIATION

Cholangiographic findings may be helpful in distinguishing SSC from PSC. Diffuse

ductal narrowing and multifocal strictures suggest PSC, whereas isolated peripheral



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ductal abnormalities suggest SSC. Recurrent pyogenic cholangitis may show sudden

ductal cutoff, intrahepatic bile collections, and ductal stones. Autoimmune pancrea-

titis may show changes to the pancreatic duct, whereas AIDS cholangiopathy is char-

acterized by papillary stenosis and accompanying intrahepatic disease.

MANAGEMENT, COMPLICATIONS, AND OUTCOMES

The management of SSC depends on the underlying cause. Patients with recurrent

pyogenic cholangitis may benefit from prompt supportive care and institution of

empiric antibiotics, followed by monitoring. If decompensation occurs or the disease

is persistent, surgical intervention may be necessary. Surgery focuses on drainage

and exploration of the bile ducts. Endoscopic intervention may also be used when

needed, and long-term drainage may be the only option in a few patients with wide-

spread disease.15,51,52

Conversely, therapeutic options in patients with AIDS cholangiopathy are limited,because none have been shown to be beneficial in improving survival. Patients usually

have advanced immunosuppression from AIDS, which contributes greatly to the poor

prognosis in this subset of patients. Average survival is estimated merely as 12 months

and is not affected by endoscopic interventions.18,53 AIDS cholangiopathy has not

been shown to benefit from antimicrobial therapy, and hence prognosis depends on

the status of the underlying immunosuppression, with decreased viral load and

improved counts being favorable signs.17

In symptomatic patients with portal biliopathy who develop obstructive jaundice

from stones or stricture endoscopic sphincterotomy, balloon dilatation of the stricture

or portosystemic shunting may be instituted.10,11,54–58

Despite the common notion perceived through retrospective study of patients with

SSC that these patients are at no increased risk of developing cholangiocarcinoma,

several case reports have shown an increased occurrence in patients with subtypes

of SSC.2,59,60 The possibility exists that the detection rate of cholangiocarcinoma in

this population remains minimal because of the poor outcomes caused by comorbid-

ities. Advances in diagnostic modalities may lead to increased diagnosis of cholangio-

carcinoma in patients with SSC.

Liver transplantation seems to be an appropriate method of management for

patients with advanced SSC. A French study of 5 patients with SSC requiring liver

transplantation after biliary surgery who were followed up for 39 months posttrans-plant showed excellent outcomes with no recurrence.61

SUMMARY

Because of the reversible nature of secondary sclerosing cholangitis, a high suspicion

for the diagnosis should be maintained, especially in patients with PSC with unclear

diagnostic features.

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