Primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a long-term progressive disease of the liver and gallbladder characterized by inflammation and scarring of the bile ducts, which normally allow bile to drain from the gallbladder. Affected individuals may have no symptoms or may experience signs and symptoms of liver disease, such as jaundice, itching, and abdominal pain.

The bile duct scarring that occurs in PSC narrows the ducts of the biliary tree and impedes the flow of bile to the duodenum. Eventually, it can lead to cirrhosis of the liver and liver failure. PSC increases the risk of various cancers, including liver cancer, gallbladder carcinoma, colorectal cancer, and cholangiocarcinoma.<ref name="Lazaridis2016">Template:Cite journal</ref><ref name="Folseraas2016">Template:Cite journal</ref> The underlying cause of PSC is unknown. Genetic susceptibility, immune system dysfunction, and abnormal composition of the gut flora may play a role.<ref name="Kummen2013" /><ref name="Charatchar">Template:Cite journal</ref> This is further suggested by the observation that around 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis.<ref>Template:Cite book</ref>

No effective medical treatment for primary sclerosing cholangitis is known. Its most definitive treatment is a liver transplant,<ref name="Lazaridis2016" /> but disease recurrence can occur in 25–30% of cases.<ref name="Melb2022">Template:Cite journal</ref> For patients unable or unwilling to receive a transplant, therapy primarily focuses on relieving symptoms, rather than stopping disease progression. If the sclerosing cholangitis is a secondary effect of a different disease, treatment is directed towards the underlying cause.<ref name=":2">Template:Cite journal</ref>

PSC is a rare disease and most commonly affects people with IBD.<ref name="Folseraas2016"/> About 3.0 to 7.5% of people with ulcerative colitis have PSC, and 80% of people with PSC have some form of IBD.<ref name="Kummen2013">Template:Cite journal</ref> Diagnosis usually occurs in people in their 30s or 40s.<ref name="Kummen2013"/> Individuals of Northern European ancestry are affected more often than people of Southern European or Asian descent.<ref name="Folseraas2016"/> Men are affected more often than women.<ref name="Williamson2015">Template:Cite journal</ref> The disease was initially described in the mid-1800s, but was not fully characterized until the 1970s with the advent of improved medical-imaging techniques such as endoscopic retrograde cholangiopancreatography.<ref name="Williamson2015"/>

Signs and symptoms

Nearly half of people with PSC do not have symptoms, and are often incidentally discovered to have PSC due to abnormal liver function tests;<ref name="Lazaridis2016"/> however, a substantial proportion have debilitating signs and symptoms of the disease.<ref name="ReferenceA">Template:Cite journal</ref> Signs and symptoms of PSC may include severe itching and nonspecific fatigue. Jaundice may also be seen. Enlargement of the liver and spleen are seen in roughly 40% of affected individuals. Abdominal pain affects about 20% of people with PSC.Template:Cn

Multiple episodes of life-threatening acute cholangitis (infection within the bile ducts) can be seen due to impaired drainage of the bile ducts, which increases the risk of infection.<ref>Template:Cite journal Epub 2015 Sep 21.</ref>

• Dark urine due to excess conjugated bilirubin, which is water-soluble and excreted by the kidneys (i.e. choluria)
• Malabsorption, especially of fat, and steatorrhea (fatty stool), due to an inadequate amount of bile reaching the small intestine, leading to decreased levels of the fat-soluble vitamins, A, D, E, and K.
• Portal hypertension, a complication of cirrhosis, which can manifest with esophageal and parastomal varices<ref>Template:Cite journal</ref> as well as hepatic encephalopathy (mental status alteration/disturbance caused by liver dysfunction and shunting of blood away from the scarred liver; such that ammonia detoxification is reduced with concomitant encephalopathy) or ascites.

Cause

The exact cause of primary sclerosing cholangitis is unknown, and its pathogenesis is improperly understood.<ref name="Lazaridis2016"/> Although PSC is thought to be caused by autoimmune disease, it does not demonstrate a clear response to immunosuppressants. Thus, many experts believe it to be a complex, multifactorial (including immune-mediated) disorder and perhaps one that encompasses several different hepatobiliary diseases.<ref name="ReferenceB">Template:Cite journal</ref><ref>Template:Cite journal</ref> Alternatively, some experts have suggested that the reason immunosuppressant medications are ineffective is because PSC almost always remains undiagnosed until a very advanced stage, at which point damage may be irreversible or require more aggressive treatment than other autoimmune diseases.<ref name=":2" />

Data have provided novel insights suggesting:

1. an important association between the intestinal microbiota and PSC<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and
2. a process referred to as cellular senescence and the senescence-associated secretory phenotype in the pathogenesis of PSC.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

In addition, longstanding, well-recognized associations are seen between PSC and human leukocyte antigen alleles (A1, B8, and DR3).<ref name=Charatchar/>

Pathophysiology

PSC is characterized by inflammation of the bile ducts (cholangitis) with consequent stricturing (i.e., narrowing) and hardening (sclerosis) of these ducts due to scar formation, be it inside and/or outside the liver.<ref name=":0">Template:Cite journal</ref> The resulting scarring of the bile ducts obstructs the flow of bile, which further perpetuates bile duct and liver injury. Chronic impairment of bile flow due to blockage and dysfunctional bile transport (cholestasis) causes progressive biliary fibrosis and ultimately biliary cirrhosis and liver failure.<ref name=Robbins>Template:Cite book</ref>

The primary physiological function of bile is to assist in the breakdown and absorption of fat in the intestinal tract; a relative deficiency of bile can lead to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K).<ref>Template:Cite journal</ref>

Liver enlargement is seen due to portal hypertension caused by compression of portal veins by the proximate sclerosed intrahepatic bile ducts, and leads to right upper quadrant abdominal pain.Template:Cn

Diagnosis

File:CT of primary sclerosing cholangitis.jpg

CT scan findings in a case of primary sclerosing cholangitis

File:Sclerosing cholangitis 0001.jpg

Ultrasound of sclerosing cholangitis in the common bile duct

PSC is generally diagnosed on the basis of having at least two of three clinical criteria after secondary causes of sclerosing cholangitis have been ruled out:Template:Cn

• serum alkaline phosphatase (ALP) > 1.5x the upper limit of normal for longer than 6 months
• cholangiography demonstrating biliary strictures or irregularity consistent with PSC
• liver biopsy consistent with PSC (if available)

Historically, a cholangiogram would be obtained via endoscopic retrograde cholangiopancreatography (ERCP), which typically reveals "beading" (alternating strictures and dilation) of the bile ducts inside and/or outside the liver. Currently, the preferred option for diagnostic cholangiography, given its noninvasive yet highly accurate nature, is magnetic resonance cholangiopancreatography (MRCP), a magnetic resonance imaging technique. MRCP has unique strengths, including high spatial resolution, and can even be used to visualize the biliary tract of small animal models of PSC.<ref>Template:Cite journal</ref>

Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels.<ref>Template:Cite journal</ref> For example, approximately 80% of people with PSC have perinuclear antineutrophil cytoplasmic antibodies (P-ANCA); however, this and other immunoglobulin findings are not specific to those with PSC and are of unclear clinical significance/consequence. Antinuclear antibodies and anti-smooth muscle antibody are found in 20–50% of PSC patients, and likewise are not specific for the disease, but may identify a subgroup of PSC patients who also have autoimmune hepatitis (i.e. PSC-AIH overlap syndrome).<ref name=Charatchar/>

The differential diagnosis can include primary biliary cholangitis (formerly referred to as primary biliary cirrhosis), drug-induced cholestasis, cholangiocarcinoma, IgG4-related disease, post-liver transplantation nonanastomotic biliary strictures,<ref>Template:Cite journal</ref> and HIV-associated cholangiopathy.<ref>Template:Cite journal</ref> Primary sclerosing cholangitis and primary biliary cholangitis are distinct entities and exhibit important differences, including the site of tissue damage within the liver, associations with IBD, which includes ulcerative colitis and Crohn's disease, response to treatment, and risks of disease progression.<ref>Template:Cite journal</ref>

Classification

Primary sclerosing cholangitis is typically classified into three subgroups based on whether the small and/or large bile ducts are affected. The subgroups of PSC include:<ref name="Lazaridis2016" />

• Classic PSC
• Small-duct PSC
• PSC associated with autoimmune hepatitis

Management

No pharmacologic treatment has been approved by the U.S. Food and Drug Administration for PSC. Some experts recommend a trial of ursodeoxycholic acid (UDCA), a bile acid occurring naturally in small quantities in humans, as it has been shown to lower elevated liver enzyme numbers in patients with PSC and has proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clearly lead to improved liver histology and survival.<ref name="ReferenceA" /><ref name="Lindor">Template:Cite journal</ref> Guidelines from the American Association for the Study of Liver Diseases and the American College of Gastroenterology do not support the use of UDCA but guidelines from the European Association for the Study of the Liver do endorse the use of moderate doses (13–15 milligrams per kilogram) of UDCA for PSC.<ref name="Lazaridis2016" /><ref name="Chapman2010">Template:Cite journal</ref><ref name="Lindor2015">Template:Cite journal</ref><ref name="EASL2009">Template:Cite journal</ref>

Supportive treatment for PSC symptoms is the cornerstone of management. These therapies are aimed at relieving symptoms such as itching with antipruritics (e.g. bile acid sequestrants such as cholestyramine); antibiotics to treat episodes of ascending cholangitis; and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (A, D, E, and K).<ref>Template:Cite journal</ref>

ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile-duct cancer (cholangiocarcinoma).<ref>Template:Cite journal</ref>

Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial ascending cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. Not all patients are candidates for liver transplantation, and some experience disease recurrence afterward.<ref name="ReferenceB" /> The reasons why some patients develop recurrent PSC remains largely obscure, but surprisingly, those without recurrence of disease (hence protected from recurrence) are characterized by an increased presence of the potentially pathogenic Shigella species.<ref>Template:Cite journal</ref>

Complications

Cholangiocarcinoma (CCA) represents a major complication and the leading cause of death in patients with primary sclerosing cholangitis (PSC), with a lifetime prevalence ranging from 6-13%. Patients with PSC have a 400-600 fold higher risk of developing CCA compared to the general population, with an annual risk between 0.5-1.5%. Notably, 30-50% of PSC-associated CCAs are diagnosed within the first year after PSC diagnosis, and up to 80% of patients die within one year of CCA detection. Risk factors include advanced age, male sex, concomitant inflammatory bowel disease, and high-grade biliary strictures. The development of CCA follows a multistep carcinogenesis model involving chronic inflammation, which progresses from damaged biliary epithelium to dysplasia and eventually invasive cancer, with molecular mechanisms including inflammatory pathways, oxidative stress, genetic alterations (commonly affecting p53), and epigenetic changes that create an aberrant phenotype in cholangiocytes.<ref name=":3">Template:Cite journal</ref>

Prognosis

There are no reliable prognostic models for PSC, owing to the highly variable disease course. Patients who are asymptomatic at the time of diagnosis are known to have better outcomes than those who have symptoms. However, many asymptomatic patients will develop symptoms later in time. Laboratory tests such as liver function tests are surprisingly unreliable when used as prognostic indicators for PSC.<ref name=":2" />

Estimated median survival from diagnosis until liver transplant or PSC-related death is 21.3 years.<ref>Template:Cite journal</ref> Various models have been developed to help predict survival,<ref>Template:Cite journal</ref> but their use is generally best suited for research and not clinical purposes. A serum alkaline phosphatase less than 1.5 times the upper limit of normal has been associated with better outcomes, but its use in predicting long-term outcomes is unclear.<ref name="Lazaridis2016" /> An IgA isotype autoantibody to the pancreatic GP2 protein (anti-GP2 IgA antibody) is the first verified prognostic biomarker in PSC.<ref name=":1">Template:Cite journal</ref> The role of anti-GP2 IgA in PSC was simultaneously investigated and reported by two research groups,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> and later confirmed by others.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Association was demonstrated between anti-GP2 IgA and progressive liver fibrosis, cholangiocarcinoma development and shorter transplantation free survival in PSC patients.<ref name=":1" />

Other markers which may be measured and monitored are a complete blood count, serum liver enzymes, bilirubin levels (usually grossly elevated), kidney function, and electrolytes. However, none of these tests are reliable indicators of prognosis, as they are either specific to certain disease complications or have a tendency to fluctuate over time, irrespective of the actual disease progression.<ref name=":2" /> Fecal fat measurement is occasionally ordered when symptoms of malabsorption (e.g., gross steatorrhea) are prominent.Template:Cn

Cancer

Cholangiocarcinoma, a major complication of PSC, is associated with a very poor prognosis. Approximately 80% of patients diagnosed with PSC-associated cholangiocarcinoma die within 1 year.<ref name=":3" />

The development of any of the cancers associated with PSC predicts a poor prognosis. Complications from PSC-associated cancers account for 40% of deaths from PSC.<ref name="Folseraas2016" /> Primary sclerosing cholangitis is one of the major known risk factors for cholangiocarcinoma,<ref name="Tsaitas2014">Template:Cite journal</ref> a cancer of the biliary tree, for which the lifetime risk among patients with PSC is 10-15%.<ref name="Kummen2013" /> This represents a 400-fold greater risk of developing cholangiocarcinoma compared to the general population.<ref name="Lazaridis2016" /> Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance with a specialized imaging study and serum markers,<ref>Tabibian JH, Lindor KD. Challenges of Cholangiocarcinoma Detection in Patients with Primary Sclerosing Cholangitis. J Analytical Oncology. 2012;1(1):50–55.</ref> although consensus regarding the modality and interval has yet to be established.Template:Citation needed Similarly, a screening colonoscopy is recommended in people who receive a new diagnosis of primary sclerosing cholangitis since their risk of colorectal cancer is 10 times higher than that of the general population.<ref name="Lazaridis2016" />

Related diseases

PSC is strongly associated with IBD, in particular ulcerative colitis (UC) and to a lesser extent Crohn's disease. As many as 5% of patients with IBD are co-diagnosed with PSC,<ref>Template:Cite journal</ref> and approximately 70% of people with PSC have IBD.<ref name=Robbins/> Of note, the presence of colitis appears to be associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma) development, although this relationship remains poorly understood.<ref>Template:Cite journal</ref> Close monitoring of PSC patients is vital.

Various forms of gallbladder disease such as gallstones and gallbladder polyps are also common in those with PSC.<ref name="Lazaridis2016"/> Approximately 25% of people with PSC have gallstones.<ref name="Lazaridis2016"/> Ultrasound surveillance of the gallbladder every year is recommended for people with PSC.<ref name="Lazaridis2016"/> Any person with PSC who is found to have a mass in the gallbladder should undergo surgical removal of the gallbladder due to the high risk of cholangiocarcinoma.<ref name="Lazaridis2016"/> Osteoporosis (hepatic osteodystrophy) and hypothyroidism are also associated with PSC.Template:Cn

A 2–3:1 male-to-female predilection occurs in primary sclerosing cholangitis.<ref name=Robbins/> PSC can affect men and women at any age, although it is commonly diagnosed in the fourth decade of life, most often in the presence of IBD.<ref name=":0" /> PSC progresses slowly and is often asymptomatic, so it can be present for years before it is diagnosed and before it causes clinically significant consequences. Relatively few data are available on the prevalence and incidence of PSC, with studies in different countries showing annual incidence of 0.068–1.3 per 100,000 people and prevalence 0.22–8.5 per 100,000; given that PSC is closely linked with ulcerative colitis, the risk is likely higher in populations where UC is more common.<ref>Template:Cite journal</ref> In the United States, an estimated 29,000 individuals have PSC.<ref name="Lazaridis2016"/>

Research

Although no curative treatment is known, several clinical trials are underway that aim to slow progression of this liver disease.<ref>Template:Cite journal</ref> Obeticholic acid is being investigated as a possible treatment for PSC due to its antifibrotic effects. Simtuzumab is a monoclonal antibody against the profibrotic enzyme LOXL2 that is being developed as a possible therapy for PSC.<ref name="Lazaridis2016"/>

Notable cases

• Chris Klug – professional snowboarder with PSC who had liver transplant <ref name="SportsRef">Template:Cite Sports-Reference</ref>
• Chris LeDoux – professional rodeo rider and country musician with PSC who died of cholangiocarcinoma
• Elena Baltacha – British professional tennis player, diagnosed with PSC at age 19 and died five months after being diagnosed with PSC-associated liver cancer (specifically cholangiocarcinoma) at the age of 30
• Walter Payton – professional American Football player and humanitarian, died of complications of PSC
• Kieron Dyer – professional footballer
• James Redford – director and son of Robert Redford who underwent two liver transplants due to PSC<ref>Template:Cite news</ref>
• Lars-Göran Petrov – Swedish death metal vocalist best known for his work with Entombed

External links

Patient support organizations:

• www.pscpartners.org—based in the US
• www.pscpartners.ca—based in Canada
• www.pscsupport.org.au—based in Australia
• www.pscsupport.org.uk—based in the UK