Primary sclerosing cholangitis is a condition that affects the bile ducts. These ducts carry bile (a fluid that helps to digest fats) from the liver, where bile is produced, to the gallbladder, where it is stored, and to the small intestine, where it aids in digestion. Primary sclerosing cholangitis occurs because of inflammation in the bile ducts (cholangitis) that leads to scarring (sclerosis) and narrowing of the ducts. As a result, bile cannot be released to the gallbladder and small intestine, and it builds up in the liver.
Primary sclerosing cholangitis is usually diagnosed around age 40, and for unknown reasons, it affects men twice as often as women. Many people have no signs or symptoms of the condition when they are diagnosed, but routine blood tests reveal liver problems. When apparent, the earliest signs and symptoms of primary sclerosing cholangitis include extreme tiredness (fatigue), discomfort in the abdomen, and severe itchiness (pruritus). As the condition worsens, affected individuals may develop yellowing of the skin and whites of the eyes (jaundice) and an enlarged spleen (splenomegaly). Eventually, the buildup of bile damages the liver cells, causing chronic liver disease (cirrhosis) and liver failure. Without bile available to digest them, fats pass through the body. As a result, weight loss and shortages of vitamins that are absorbed with and stored in fats (fat-soluble vitamins) can occur. A fat-soluble vitamin called vitamin D helps absorb calcium and helps bones harden, and lack of this vitamin can cause thinning of the bones (osteoporosis) in people with primary sclerosing cholangitis.
Primary sclerosing cholangitis is often associated with another condition called inflammatory bowel disease, which is characterized by inflammation of the intestines that causes open sores (ulcers) in the intestines and abdominal pain. However, the reason for this link is unclear. Approximately 70 percent of people with primary sclerosing cholangitis have inflammatory bowel disease, most commonly a form of the condition known as ulcerative colitis. In addition, people with primary sclerosing cholangitis are more likely to have an autoimmune disorder, such as type 1 diabetes, celiac disease, or thyroid disease, than people without the condition. Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs. People with primary sclerosing cholangitis also have an increased risk of developing cancer, particularly cancer of the bile ducts (cholangiocarcinoma).
Many patients with PSC are asymptomatic, but a substantial proportion will have debilitating signs and symptoms of the disease. These may include:
- Exterme tiredness,
- Abdominal pain
- Enlarged spleen
- 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.
- Liver cirrhosis and failure
- 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
Other complications may include weight loss, vitamin deficiency, and osteoporosis. Many people with PSC develop other autoimmune conditions such asinflammatory bowel disease, type 1 diabetes, celiac disease, or thyroid disease. PSC is also a risk factor for cancer of the bile ducts (cholangiocarcinoma).
Primary sclerosing cholangitis is thought to arise from a combination of genetic and environmental factors. Researchers believe that genetic changes play a role in this condition because it often occurs in several members of a family and because immediate family members of someone with primary sclerosing cholangitis have an increased risk of developing the condition. It is likely that specific genetic variations increase a person's risk of developing primary sclerosing cholangitis, and then exposure to certain environmental factors triggers the disorder. However, the genetic changes that increase susceptibility and the environmental triggers remain unclear.
While thought to be an 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.
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).
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.
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, for which the lifetime risk among patients with PSC 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. The presence of colitis is associated with a greater risk of liver disease progression and bile duct cancer (cholangiocarcinoma). Close monitoring of PSC patients is vital.
Other diseases with which PSC is associated include osteoporosis (hepatic osteodystrophy) and hypothyroidism.
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).
In some cases, ERCP with balloon dilation, with or without stenting, may be necessary in order to open major blockages (dominant strictures) in the biliary tree.
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. Unfortunately, not all patients are candidates for liver transplantation, and some will experience disease recurrence afterward.
Despite there being no curative treatment at present, it is important to note that there are several clinical trials underway that aim to slow progression of this liver disease.
- Genetic Home Reference