Primary sclerosing cholangitis
|Primary sclerosing cholangitis|
Cholangiogram of primary sclerosing cholangitis.
|Classification and external resources|
|Patient UK||Primary sclerosing cholangitis|
Primary sclerosing cholangitis (PSC) is a disease of the bile ducts that causes inflammation and obliterative fibrosis of bile ducts inside and/or outside of the liver. This pathological process impedes the flow of bile to the intestines and can ultimately lead to cirrhosis of the liver, liver failure, and other complications, including but not limited to bile duct and liver cancer. The underlying cause of the inflammation remains unknown, but elements of autoimmunity and microbial dysbiosis have been described and are suggested by the fact that approximately 75% of those with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. The most definitive treatment for PSC is liver transplantation.
Signs and symptoms
|This section does not cite any references or sources. (October 2014)|
Many patients with PSC are asymptomatic, but a substantial proportion will have debilitating signs and symptoms of the disease. These may include:
- Intense pruritus (itching)
- Severe fatigue (a non-specific symptom often present in liver disease)
- Episodes of acute cholangitis (infection within the bile ducts)
- Dark urine due to excess conjugated bilirubin, which is water-soluble, being excreted by the kidneys (i.e. choluria)
- Malabsorption (especially of fat) and steatorrhea (fatty stool) due to biliary obstruction, leading to decreased levels of the fat-soluble vitamins, A, D, E and K.
- Hepatomegaly (enlarged liver) and right upper quadrant abdominal pain
- Portal hypertension, including esophageal and parastomal varices
- Hepatic encephalopathy (mental status alteration/disturbance caused by liver dysfunction and shunting of blood away from the scarred liver)
The cause of PSC is unknown, and thus it is referred to as an "idiopathic" condition. While previously thought to be an autoimmune disease, it does not demonstrate a clear response to immunosuppressants, and thus many experts believe it to be a complex, multifactorial (including immune-mediated) disorder, and perhaps one that encompasses several different hepatobiliary diseases.
Recent data have provided novel insights suggesting: 1) an important association between the intestinal microbiome and PSC  and 2) a process referred to as cellular senescence and the senescence-associated secretory phenotype (SASP) in the pathogenesis of PSC. In addition, there are longstanding, well-recognized associations between PSC and Human leukocyte antigen [HLA] alleles (e.g. A1, B8, and DR3).
Inflammation leads to sclerosis or damage of bile ducts both inside and outside of the liver. The resulting scarring of the bile ducts blocks the flow of bile, causing cholestasis. Bile stasis and back-pressure induces proliferation of epithelial cells and focal destruction of the liver parenchyma, forming bile lakes. Chronic biliary obstruction causes portal tract fibrosis and ultimately biliary cirrhosis and liver failure.
Bile assists in the intestinal breakdown and absorption of fat; the relative deficiency of bile in the intestinal tract leads to fat malabsorption and deficiencies of fat-soluble vitamins (A, D, E, K).
PSC is generally diagnosed on the basis of having at least two of three clinical: serum alkaline phosphatase (ALP) > 1.5x the upper limit of normal, cholangiography demonstrating biliary strictures or irregularity consistent with PSC, and liver histology (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 non-invasive 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.
Most people with PSC have evidence of autoantibodies and abnormal immunoglobulin levels. For example, approximately 80% of people with PSC have perinuclear anti-neutrophil cytoplasmic antibodies; 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 auotimmune hepatitis (i.e. PSC-AIH overlap syndrome).
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. Fecal fat measurement is occasionally ordered when symptoms of malabsorption (e.g. gross steatorrhea) are prominent.
The differential diagnosis can include primary biliary cirrhosis, drug induced cholestasis, cholangiocarcinoma, IgG4-associated disease, post-liver transplantation non-anastomotic biliary strictures, and HIV-associated cholangiopathy.
There is no FDA-approved pharmacologic treatment 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 proven effective in other cholestatic liver diseases. However, UDCA has yet to be shown to clear lead to improved liver histology and adverse event-free survival.
Treatment for patients with PSC also includes therapies to relieve itching (antipruritics) (e.g. the bile acid sequestrant (cholestyramine), antibiotics to treat episodes of acute cholangitis, and vitamin supplements, as people with PSC are often deficient in fat-soluble vitamins (vitamin A, vitamin D, vitamin E, and vitamin K).
Liver transplantation is the only proven long-term treatment of PSC. Indications for transplantation include recurrent bacterial cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. In one series, 1-, 2-, and 5- year survival following liver transplantation for PSC was 90%, 86% and 85% respectively, which is considered very favorable. Unfortunately, not all patients are candidates for liver transplantation, and some will experience disease recurrence afterward.
PSC carries an estimated median liver transplant-free survival time (from diagnosis) of approximately 15 years. Various models have been developed to help predict survival, but their use is generally best suited for research and not clinical purposes. Recently, normalization of serum alkaline phosphatase has been shown to be an accurate and non-invasive predictor of favorable long-term outcomes.
Primary sclerosing cholangitis is associated with cholangiocarcinoma, a cancer of the biliary tree, and the lifetime risk for PSC sufferers is 10-15%. This represents a 160-fold greater risk of developing cholangiocarcinoma compared to the general population. Surveillance for cholangiocarcinoma in patients with PSC is encouraged, with some experts recommending annual surveillance, but there is no official consensus on the modality and interval of choice. Colon cancer is also associated with PSC.
PSC has a significant association with ulcerative colitis, an inflammatory bowel disease primarily affecting the large intestine. As many as 5% of patients with inflammatory bowel disease (IBD), especially ulcerative colitis (UC), may be co-diagnosed with PSC and approximately 70% of people with primary sclerosing cholangitis have ulcerative colitis. Those with PSC and IBD are at approximately 30-fold increased risk of developing colorectal cancer; therefore, regular surveillance is recommended.
Other diseases with which PSC is associated include osteoporosis (hepatic osteodystrophy) and hypothyroidism.
There is a 2-3:1 male-to-female predilection in primary sclerosing cholangitis. The disease can be diagnosed at virtually any age, though most often in the 30s and 40s. 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. There is relatively little data on the prevalence and incidence of primary sclerosing cholangitis, 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, it is likely that the risk is higher in populations where UC is more common. In the United States, an estimated 25,000 individuals have PSC.
- Chris Klug - professional snowboarder with PSC who had liver transplant
- 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 - died of complications of PSC.
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- PSC Partners: Patient organization with additional information
- PSC Support: Charity with additional information, discussion forum and support tools for those affected by PSC
- Additional Literature about PSC
- Information from The Morgan Foundation for the Study of PSC
- SAVE JON: Patient-Led Research Organization with additional information