Update on primary sclerosing cholangitis

Watch a video presentation of this article

Watch the interview with the author

Abbreviations

ALP

alkaline phosphatase

ALT

alkaline transaminase

ANCA

anti‐neutrophil cytoplasmic antibody

ANA

antinuclear antibody

atRA

all‐trans retinoic acid

BA

bile acid

BE

biliary epithelium

CFTR

cystic fibrosis transmembrane conductance

ERCP

endoscopic retrograde cholangiopancreatography

GGT

gamma‐glutamyl transpeptidase

HLA

human leukocyte antigen

IBD

inflammatory bowel disease

IgG

immunoglobulin G

MDR3

multidrug resistance 3 gene

MRCP

magnetic resonance cholangiopancreatography

PAMP

pathogen‐associated molecular patterns

PL

phospholipid

PSC

primary sclerosing cholangitis

SMA

smooth muscle antibody

TGR5

G protein‐coupled receptor

TLR

Toll‐like receptors

UC

ulcerative colitis

UDCA

ursodeoxycholic acid

ULN

upper limit of normal

Primary sclerosing cholangitis (PSC) is a rare, progressive, cholestatic liver disease characterized by inflammation, stricturing, and concentric, obliterative fibrosis of the biliary system, ultimately leading to biliary cirrhosis, portal hypertension, and eventually hepatic failure in the majority of patients.1 PSC is a premalignant disease with a high prevalence of hepatobiliary and colonic malignancy.2 Mortality rates are as high as 30% at 6 years, with the majority of deaths (40%‐50%) due to cancer and around 30% to 40% due to liver failure.1, 2

PSC has become increasingly recognized as one of the major causes of autoimmune liver disease. Although it has been called “the last black box remaining in hepatology,” there have been a number of advances in all aspects of the disease over the last decade. The diagnosis is established by cholangiography (usually magnetic resonance cholangiopancreatography [MRCP]) often in patients with inflammatory bowel disease (IBD) presenting with abnormal, cholestatic liver function tests. It is important to exclude immunoglobulin G4 (IgG4)‐related sclerosing cholangitis (Table 1).

Table 1.

Investigations to Perform at Diagnosis of PSC

Liver enzymes: GGT, ALP, ALT

Bilirubin

Complete blood count

IgG and IgM levels

ANCA

ANA

SMA

IgG1 and IgG4 levels

Ultrasound

MRCP (± ERCP)

Liver biopsya

^aLiver biopsy only indicated when MRCP/endoscopic retrograde cholangiopancreatography (ERCP) was normal and/or suspicion of overlap syndrome or occasionally in IgG4‐RD.

Abbreviations: ALT, alkaline transaminase; ANA, antinuclear antibody; ANCA, anti‐neutrophil cytoplasmic antibody; GGT, gamma‐glutamyl transpeptidase; RD, related disorder; SMA, smooth muscle antibody.

Epidemiology

PSC is a male‐predominant disease, with a male/female ratio of around 2:1. Although the disease can present at any age, the mean age of presentation is 40 years. Prevalence rates are of the order of 0.22 per 100,000 population, with an increasing prevalence in Northern Europe to as high as 16.2 per 100,000 population.3

Pathogenesis

The etiopathogenesis of PSC is unknown, although it is strongly associated with IBD. However, genetic factors appear to play an important role.4 IBD has a strong association with risk loci on chromosome 6, which pertain to the major histocompatibility complex, especially human leukocyte antigen (HLA)‐B8 and HLA‐DR3.4 A further 15 or so non‐HLA risk loci have been identified, including FUT‐2 involved in regulating bacteria in the intestine and interleukin‐2 loci and other genes commonly found in other autoimmune diseases.5 This indicates the importance of the immune response and its interaction with the biome.5 Recent studies have shown a distinctive and specific gut microbial profile in patients with PSC compared with patients with ulcerative colitis (UC) without PSC and normal control subjects.

Other factors are believed to play a role in the etiology, such as a toxic effect of bile on damaged biliary epithelium; the so‐called leaky gut theory, where pre‐existing IBD predisposes to increased bowel wall permeability, and therefore increased exposure of the bile ducts to bacteria and other pathogens and toxins; and also an increase in homing T cells and other cytokines from the bowel to the liver. Current evidence suggests that PSC is a complex, polygenic, immune‐mediated disease related to a specific microbiome (Fig. 1).

Figure 1.

Factors involved in the pathogenesis of PSC.

Although there is a strong genetic predisposition to the disease, environmental factors play a role. PSC is predominantly a disease of nonsmokers, irrespective of the presence of underlying IBD. Coffee drinking appears to be protective.

PSC and IBD

Up to 80% of patients with PSC have IBD. The characteristic phenotype is a pancolitis, usually worse in the right colon. UC makes up around 75% to 80% of cases of IBD, with 10% to 15% being Crohn's disease (colitis) and 5% to 10% IBD‐unspecified.1

Conversely, around 5% to 10% of patients with IBD will experience development of PSC. Recently, 8% of patients with total UC and persistently normal liver function tests have been shown to have diagnostic changes of PSC on cholangiography.

The clinical course of colitis in PSC/UC is usually indolent and runs an independent course from the PSC. In contrast, PSC and Crohn's disease have a better prognosis from their liver disease, although unlike PSC/UC, the bowel disease runs a similar course to Crohn's disease without PSC.1

Current evidence strongly suggests that PSC/IBD is a separate disease entity from IBD without PSC, with distinct and separate genotypes and phenotypes.5

Prognosis

The natural history of PSC is highly variable and unpredictable. Serum alkaline phosphatase (ALP) levels tend to fluctuate over time, but a persistently low ALP (e.g., less than 1.5 times the upper limit of normal [ULN]) has been shown to confer a good clinical outcome.6 The enhanced liver fibrosis score derived from three serum fibrosis markers has also been shown to predict accurately the prognosis of PSC. It is unclear whether these serum biomarkers will prove to be reliable surrogate endpoints in clinical trials.

Initial studies suggested a median time from diagnosis to death or liver transplantation of 10 to 12 years; however, a recent study from the Netherlands gave a more optimistic view of a median time of 21.3 years from diagnosis to PSC‐related death or liver transplantation.3 This is likely a more accurate estimate because it represents a PSC population as a whole, as opposed to tertiary centers with potential referral bias. Approximately 15% of PSC patients will require liver transplantation.

In contrast, patients with small duct PSC (raised ALP, normal cholangiogram, and features of PSC on liver biopsy) have a good prognosis, with no reports of bile duct malignancy in this group, and progression to advanced liver disease is uncommon.

Medical Management

There is no proven medical treatment that prolongs survival in PSC.7 Many immunosuppressive agents have been assessed, including corticosteroids, with little success.

The bile acid ursodeoxycholic acid (UDCA) has been evaluated in varying doses in multiple double‐blinded, placebo‐controlled, randomized, controlled trials, given its beneficial effect shown in PBC.7 At doses of 13 to 21 mg/kg, it has been shown in PSC to reduce cholestatic liver enzymes, bilirubin, and albumin, but not to reduce death, need for liver transplantation, or liver histology progression. Higher doses at 28 to 30 mg/kg were associated with an increased mortality, compared with placebo.

Current American Association for the Study of Liver Diseases8 and European Association for the Study of the Liver guidelines9 do not support the administration of UDCA, although a trial of moderate‐dose UDCA administration has been advocated (Fig. 2).10

Figure 2.

Algorithm for UDCA use in PSC, as proposed by Tabibian and Lindor.10

New potential therapies, including new bile acids, antibiotics (such as vancomycin), nuclear agonists, and immunotherapies are currently in development (Fig. 3).7 The only treatment shown to prolong survival in PSC is orthotopic liver transplantation with 5‐year survival rates of up to 80%.

Figure 3.

Schematic representation of the various elements contributing to the pathophysiology of PSC (in colored boxes) and the therapeutic agents (listed above) that may be directed against this particular element. Agents in italics are still in development and are not licensed.7 Abbreviations: atRA, all‐trans retinoic acid; BA, bile acid; BE, biliary epithelium; CFTR, cystic fibrosis transmembrane conductance; MDR3, multidrug resistance 3 gene; PAMP, pathogen‐associated molecular patterns; PL, phospholipid; SXR, steroid and xenobioticsensing nuclear receptor; TGR5, G protein‐coupled receptor; TLR, Toll‐like receptors; VAP is vascular adhesion protein.

However, it is probable that effective medical therapy for PSC will become available in the next decade. It is likely that the treatment will consist of combination therapy, using different agents targeting different aspects of the disease process together with manipulation of the microbiome. This may involve fecal transplantation.

Conclusion

There is a major, as yet unmet, need to identify subgroups of patients with PSC who are at particularly high risk for development of cholangiocarcinoma, where heightened surveillance may be helpful in identifying cholangiocarcinoma at an earlier, treatable stage. There is increasing evidence that the presence of extrahepatic bile duct involvement in patients with PSC, particularly with the development of dominant strictures, has a significantly worse prognosis, associated with a higher risk for cholangiocarcinoma.

Improved surveillance techniques involving serum microRNAs, cholangioscopy, and improved magnetic resonance imaging are currently being assessed. These advances offer hope that the diagnosis and treatment of cholangiocarcinoma complicating PSC can be greatly improved in the years to come.