Primary sclerosing cholangitis overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Dima Nimri, M.D. [2]
Overview
Primary sclerosing cholangitis is a relatively rare disease with a progressive nature, characterized by the development of fibrosis and strictures within the intrahepatic and extrahepatic bile ducts. The incidence ranges from 0 to 1.3 per 100,000 cases and prevalence from 0 to 16.2 per 100,000 cases. The disease primarily affects young adult males and the mean age at diagnosis is 41 years. The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors. The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population. The HLA locus on chromosome 6p21 and genes of the IL-2 pathway are associated with increased susceptibility to the development of primary sclerosing cholangitis. Environmental factors associated with increased risk of primary sclerosing cholangitis include exposure to farm animals during childhood and other dietary habits, such as less consumption of coffee and fish than controls. Smoking seems to be a protective factor against the development of primary sclerosing cholangitis. The majority of patients with primary sclerosing cholangitis are asymptomatic and are only diagnosed following abnormal liver function tests. However, those who are symptomatic often present with nonspecific symptoms, such as fever, fatigue, abdominal pain and/or diarrhea, as well as yellowish discoloration of the skin and mucous membranes. The workup in these patients consists of LFTs, serum immunoglobulins, as well as a number of autoantibodies. Patients with primary sclerosing cholangitis typically have an elevated level of ALP, amongst other findings. However, laboratory results in many patients may be normal. ERCP was considered the gold standard for diagnosis of primary sclerosing cholangitis, because it allows visualization of the biliary tree. However, MRCP is now preferred because of its non-invasive nature. Findings on these imaging modalities include alternating areas of strictures and dilatations of the intrahepatic and extra hepatic bile ducts. Liver transplantation is the gold standard for treatment of primary sclerosing cholangitis and there is no effective medical treatment. Ursodeoxycholic acid has been studied as a treatment for the disease. However, there is no proof for its benefit and the American College of Gastroenterology does not support its use in patients with primary sclerosing cholangitis. Unfortunately, there is no screening for primary sclerosis cholangitis and the prognosis is somewhat poor, even with liver transplantation.
Historical Perspective
Due to the rarity of the disease, primary sclerosing cholangitis has not been well studied in the past and cases were reported as individual cases. The first case of primary sclerosing cholangitis was documented in 1924.
Classification
Primary sclerosing cholangitis may be classified according to the size of bile ducts involved, as well as its association with autoimmune hepatitis. The 3 main subtypes are the classic subtype, small ducts subtype and primary sclerosing cholangitis associated with autoimmune hepatitis.
Pathophysiology
The pathophysiology of primary sclerosing cholangitis is not fully understood, although it is thought to be the result of a combination of genetic as well as environmental factors. The risk of primary sclerosing cholangitis among siblings is estimated to be 9-39 times higher than the general population. The HLA locus on chromosome 6p21 and genes of the IL-2 pathway are associated with increased susceptibility to the development of primary sclerosing cholangitis. Environmental factors associated with increased risk of primary sclerosing cholangitis include exposure to farm animals during childhood and other dietary habits, such as less consumption of coffee and fish than controls. Smoking seems to be a protective factor against the development of primary sclerosing cholangitis.
Causes
The cause of primary sclerosing cholangitis is unclear and not fully understood. However, genetic and environmental factors are thought to contribute to the development of the disease.
Differentiating primary sclerosing cholangitis from Other Diseases
Primary sclerosing cholangitis must be differentiated from causes of secondary sclerosing cholangitis.
Epidemiology and Demographics
Primary sclerosing cholangitis is a relatively rare disease, with the incidence ranging from 0 to 1.3 per 100,000 cases and prevalence of 0 to 16.2 per 100,000 cases. The disease primarily affects young adult males and the mean age at diagnosis is 41 years.
Risk Factors
The most important risk factors associated with primary sclerosing cholangitis include family history and personal history of IBD.
Screening
There are no screening recommendations for primary sclerosing cholangitis.
Natural History, Complications, and Prognosis
Primary sclerosing cholangitis is a progressive disease that often results in death from complications of liver failure, liver transplantation or associated carcinomas. Even with liver transplantation, there is a substantial risk of recurrence of the disease. Complications of primary sclerosing cholangitis include osteoporosis, cholangiocarcinoma and liver failure.
Diagnosis
History and Symptoms
The majority of patients with primary sclerosing cholangitis are asymptomatic and are only diagnosed following an abnormal liver function tests. However, those who are symptomatic often present with nonspecific symptoms, such as fever, fatigue, abdominal pain and/or diarrhea, as well as yellowish discoloration of the skin and mucous membranes.
Physical Examination
Some of the physical examination findings in primary sclerosing cholangitis include hepatomegaly, splenomegaly, ascites, jaundice and fever.
Laboratory Findings
The workup in patients with primary sclerosing cholangitis consists of LFTs, serum immunoglobulins, as well as a number of autoantibodies. Patients with primary sclerosing cholangitis typically have an elevated level of ALP, amongst other findings. However, laboratory results in many patients may be normal.
Electrocardiogram
There are no ECG findings associated with primary sclerosing cholangitis.
X Ray
There are no x-ray findings associated with primary sclerosing cholangitis.
CT Scan
A CT scan of the abdomen is not routinely done as part of the workup for primary sclerosing cholangitis and findings are non-specific. However, findings include: mass lesions, evidence of portal hypertension, such as ascites, splenomegaly and varices, thickening of the bile ducts and bile duct dilatations and abdominal lymphadenopathy.
MRI
In primary sclerosing cholangitis, MRCP rather than standard MRI is used for diagnosis.
Ultrasound
Ultrasound may be done as part of the workup for primary sclerosing cholangitis. However, findings are nonspecific, non-diagnostic and may even be normal. However, approximately 40% of patients have associated gallbladder abnormalities, which may be identified on an abdominal ultrasound. These include thickening of the gallbladder wall, gallbladder enlargement, gallbladder stones (cholelithiasis) and masses and other findings suggestive of cholecystitis.
Other Imaging Findings
ERCP was considered the gold standard for diagnosis of primary sclerosing cholangitis, because it allows visualization of the biliary tree. However, MRCP is now preferred because of its non-invasive nature. Findings on these imaging modalities include alternating areas of strictures and dilatations of the intrahepatic and extra hepatic bile ducts.
Other Diagnostic Studies
A liver biopsy may be performed in patients with primary sclerosing cholangitis, although it is not necessary for diagnosis. The pathognomonic finding of periductal onion-skin fibrosis is rarely seen. However, a liver biopsy may be useful when the small ducts subtype of the primary sclerosing cholangitis or that associated with autoimmune hepatitis are suspected.
Treatment
Medical Therapy
Liver transplantation is the gold standard for treatment of primary sclerosing cholangitis and there is no effective medical treatment. Ursodeoxycholic acid has been studied as a treatment for the disease. However, there is no proof for its benefit and the American College of Gastroenterology does not support its use in patients with primary sclerosing cholangitis.
Surgery
Primary sclerosing cholangitis is a progressive disease that ultimately leads to end-stage liver disease (ESLD). Endoscopic management can be targeted for dominant strictures or as palliative treatment. However, current gold standard of treatment for primary sclerosing cholangitis is liver transplantation. Despite liver transplantation, disease may still recur in 25% of patients.
Primary Prevention
There are no primary preventive measures for primary sclerosing cholangitis.
Secondary Prevention
Secondary prevention in patients with primary sclerosing cholangitis is aimed at screening for complications and coexisting conditions in these patients. These include screening for complications of liver cirrhosis, screening for colon and gallbladder cancers, as well as metabolic bone disease.