Pathogenesis of Primary Sclerosing Cholangitis and Advances in Diagnosis and Management

doi:10.1053/j.gastro.2013.06.052

Gastroenterology

Volume 145, Issue 3, September 2013, Pages 521-536

https://doi.org/10.1053/j.gastro.2013.06.052 Get rights and content

Primary sclerosing cholangitis (PSC), first described in the mid-1850s, is a complex liver disease that is heterogeneous in its presentation. PSC is characterized by chronic cholestasis associated with chronic inflammation of the biliary epithelium, resulting in multifocal bile duct strictures that can affect the entire biliary tree. Chronic inflammation leads to fibrosis involving the hepatic parenchyma and biliary tree, which can lead to cirrhosis and malignancy. The etiology of PSC is not fully understood, which in part explains the lack of effective medical therapy for this condition. However, we have begun to better understand the molecular pathogenesis of PSC. The recognition of specific clinical subtypes and their pattern of progression could improve phenotypic and genotypic classification of the disease. We review our current understanding of this enigmatic disorder and discuss important topics for future studies.

Section snippets

Serum Markers

An increased serum level of alkaline phosphatase is the most common biochemical abnormality detected in patients with PSC. In some cases, it is the only biochemical alteration observed, such as in patients with intrahepatic involvement with PSC.¹² However, the level of alkaline phosphatase can vary throughout the disease course and may be normal.¹⁸ Although serum aminotransferase levels are frequently normal, in some patients they can be 2-to 3-fold above the upper limit of normal.¹² Higher

Small Duct PSC

Among cases with suspected PSC and normal cholangiography, liver biopsy analysis is recommended to rule out small duct PSC.¹² Nearly 6% of patients with chronic cholestasis, a normal cholangiogram, and IBD have concurrent small-duct PSC.⁴⁹ Patients with small duct PSC have symptoms and laboratory results similar to those of subjects with classic PSC.⁴⁹ However, patients with small duct PSC survive longer and have a lower cumulative risk of cholangiocarcinoma than patients with large duct

Ursodeoxycholic Acid

All randomized controlled trials of agents designed to prevent the progression of PSC have produced negative results, despite promising results from open-label precursor studies. The most commonly studied agent is ursodeoxycholic acid (UDCA), which significantly slows progression of other chronic biliary diseases such as primary biliary cirrhosis (Table 2).99, 100, 101, 102, 103 A European study did not show increased survival times of patients with PSC treated with 17–23 mg · kg⁻¹ · day⁻¹ UDCA

Endoscopic Therapy

New or worsening symptoms in patients with PSC typically warrant investigation to exclude a dominant extrahepatic biliary stricture. A dominant stricture is defined as a stenosis ≤1.5 mm in the common bile duct or ≤1 mm in the hepatic duct.¹² When present, it should raise concern for cholangiocarcinoma. Although the prevalence of dominant strictures in patients with PSC is unknown, it has been approximated at 50%.¹¹¹ Symptomatic dominant strictures are less common, forming in approximately 10%

Liver Transplantation

PSC is a leading indication for liver transplantation in some Scandinavian countries, and it is the fifth most frequent indication for liver transplantation in the United States.¹¹⁵ With 1- and 5-year rates of survival exceeding 90% and 80%, respectively, patients with PSC have among the most successful outcomes after liver transplantation.¹¹⁶ Typically, a Roux-en-Y choledochojejunostomy is the method of choice for biliary reconstruction during liver transplant.¹¹⁷

Indications for transplants

Cholangiocarcinoma

Cholangiocarcinoma occurs in 1% to 2% of patients annually after a diagnosis of PSC, with a lifetime risk of 5% to 10%.¹²⁴ Cholangiocarcinoma is frequently detected within the first 1 to 3 years after the initial diagnosis of PSC.¹²⁵ The presence of advanced fibrosis is not required for development of cholangiocarcinoma, unlike hepatocellular carcinoma, which is typically found in conjunction with cirrhosis. Increased levels of bilirubin, duration of IBD, and history of IBD-associated CRN have

Novel Pharmacological Therapies

Thus far, antibodies against TNF have been ineffective in patients with PSC.108, 150 The role of biologic agents such as ustekinumab and vedolizumab in the treatment of IBD is being investigated, and their role in treatment of PSC-IBD remains to be seen.151, 152 Given the possible role of lymphocyte trafficking in the pathogenesis of PSC, monoclonal antibodies that alter this process could have a potential therapeutic benefit.

Janus kinase (JAK) is a tyrosine kinase component of signaling

Conclusions

PSC is a rare but important cholestatic liver disease that reduces patient survival and quality of life. Management of patients involves early recognition of the disorder, implementation of routine screening protocols to identify complications (Figure 4), and treating comorbid conditions. In the absence of effective medical therapy for the disease itself, treatment centers on endoscopic management and referral for liver transplantation when necessary.

Although our understanding of PSC and its

References (169)

K. Bambha et al.
Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community
Gastroenterology
(2003)
A. Escorsell et al.
Epidemiology of primary sclerosing cholangitis in Spain. Spanish Association for the Study of the Liver
J Hepatol
(1994)
M.K. Porayko et al.
Patients with asymptomatic primary sclerosing cholangitis frequently have progressive disease
Gastroenterology
(1990)
R. Olsson et al.
Prevalence of primary sclerosing cholangitis in patients with ulcerative colitis
Gastroenterology
(1991)
A. Bergquist et al.
Increased prevalence of primary sclerosing cholangitis among first-degree relatives
J Hepatol
(2005)
W.R. Kim et al.
A revised natural history model for primary sclerosing cholangitis
Mayo Clin Proc
(2000)
Y.M. Lee et al.
Management of primary sclerosing cholangitis
Am J Gastroenterol
(2002)
P.P. Stanich et al.
Alkaline phosphatase normalization is associated with better prognosis in primary sclerosing cholangitis
Dig Liver Dis
(2011)
P. Angulo et al.
Serum autoantibodies in patients with primary sclerosing cholangitis
J Hepatol
(2000)
P.J. Scheuer
Ludwig Symposium on biliary disorders—part II. Pathologic features and evolution of primary biliary cirrhosis and primary sclerosing cholangitis
Mayo Clinic Proc
(1998)

K.W. Burak et al.

Is there a role for liver biopsy in primary sclerosing cholangitis?

Am J Gastroenterol

(2003)

A. Ghazale et al.

Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy

Gastroenterology

(2008)

R.C. Verdonk et al.

Inflammatory bowel disease after liver transplantation: risk factors for recurrence and de novo disease

Am J Transplant

(2006)

R.M. Soetikno et al.

Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis

Gastrointest Endosc

(2002)

R.H. Wiesner et al.

Peristomal varices after proctocolectomy in patients with primary sclerosing cholangitis

Gastroenterology

(1986)

U. Navaneethan et al.

Progressive primary sclerosing cholangitis requiring liver transplantation is associated with reduced need for colectomy in patients with ulcerative colitis

Clin Gastroenterol Hepatol

(2012)

P. Angulo et al.

Small-duct primary sclerosing cholangitis: a long-term follow-up study

Hepatology

(2002)

E. Bjornsson et al.

The natural history of small-duct primary sclerosing cholangitis

Gastroenterology

(2008)

M. Kaya et al.

Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system

J Hepatol

(2000)

K.M. Boberg et al.

Overlap syndromes: the International Autoimmune Hepatitis Group (IAIHG) position statement on a controversial issue

J Hepatol

(2011)

M.J. Pollheimer et al.