Specialty Gastroenterology ICD-9-CM 576.1 DiseasesDB 10643 | ICD-10 K83.0 OMIM 613806 MedlinePlus 000285 | |
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 lead to cirrhosis of the liver, liver failure, and other complications, including 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 observation that approximately 75% of individuals with PSC also have inflammatory bowel disease (IBD), most often ulcerative colitis. The most definitive treatment for PSC is liver transplantation, though only a fraction of individuals with PSC will ultimately require it.
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Signs and symptoms
Many patients with PSC are asymptomatic, but a substantial proportion will have debilitating signs and symptoms of the disease. These may include:
Cause
Primary sclerosing cholangitis is idiopathic (i.e., having, as at present, no known cause). 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.
Data have provided novel insights suggesting:
- an important association between the intestinal microbiota and PSC and
- 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).
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 of the liver. 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.
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).
Diagnosis
PSC is generally diagnosed on the basis of having at least two of three clinical:
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 autoimmune 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 cholangitis (formerly referred to as primary biliary cirrhosis), drug induced cholestasis, cholangiocarcinoma, IgG4-related disease, post-liver transplantation non-anastomotic biliary strictures, and HIV-associated cholangiopathy. 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 inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohn's disease response to treatment, and risks of disease progression.
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 adverse event-free survival.
Treatment for symptoms of PSC include 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. ERCP and specialized techniques may also be needed to help distinguish between a benign PSC stricture and a bile duct cancer (cholangiocarcinoma)
Liver transplantation is the only proven long-term treatment of PSC, although only a fraction of individuals with PSC will need it. Indications for transplantation include recurrent bacterial cholangitis, decompensated cirrhosis, hepatocellular carcinoma, hilar cholangiocarcinoma, and complications of portal hypertension. Not all patients are candidates for liver transplantation, and some will experience disease recurrence afterward.
Although there is no curative treatment, several clinical trials are underway that aim to slow progression of this liver disease.
Prognosis
Estimated median survival from diagnosis until liver transplant or PSC-related death is 21.3 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.
Related diseases
Primary sclerosing cholangitis is one of the major known risk factors for 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 with a specialized imaging study and serum markers, although consensus regarding the modality and interval has yet to be established.
PSC is strongly associated with inflammatory bowel disease (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 and approximately 70% of people with PSC have IBD. Those with both PSC and IBD are at approximately 30-fold increased risk of developing colon cancer; therefore, regular surveillance with high-resolution colonoscopy is recommended. 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. Close monitoring of PSC patients is vital.
Other diseases with which PSC is associated include osteoporosis (hepatic osteodystrophy) and hypothyroidism.
Epidemiology
There is a 2-3:1 male-to-female predilection in primary sclerosing cholangitis. 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 inflammatory bowel disease (IBD). 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.