Background
Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by a progressive course of cholestasis with inflammation and fibrosis of the intrahepatic and extrahepatic bile ducts. [1, 2, 3, 4] The underlying cause of the inflammation is believed to be autoimmune. The condition may lead to cirrhosis of the liver with portal hypertension and end-stage liver disease (ESLD). [1, 5] (See Presentation.)
PSC is strongly associated with inflammatory bowel disease (IBD), [5, 6, 7] mainly ulcerative colitis, and is often complicated by the development of cholangiocarcinoma. [2, 8] A higher risk of colorectal cancer has been described among patients with ulcerative colitis and PSC; therefore, surveillance for colorectal cancer is strongly recommended in these patients. [6, 7, 9]
PSC has been reported more frequently since the advent of endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP). Liver function tests, including levels of serum alkaline phosphatase, gamma glutamyl transpeptidase, and serum aminotransferase, and the presence of hypergammaglobulinemia, are the most valuable in the laboratory workup. (See Workup.)
Therapy is aimed at treating symptoms and managing complications. Immunosuppressants, chelators, and steroids are used in an attempt to control the disease process but have not shown significant benefit. Liver transplantation is the only therapy that can alter the eventual outcome. PSC is the fourth leading indication for liver transplantation in adults. (See Treatment and Medication.)
For more information, see the Medscape Drugs & Diseases articles Pediatric Primary Sclerosing Cholangitis and Primary Sclerosing Cholangitis Imaging.
It is suggested the reader also read Primary Sclerosing Cholangitis: Therapeutic Options and Surveillance Management, an overview of PSC and its management options by Kumar, Wheatley, and Puttanna.
Etiopathophysiology
The etiology of primary sclerosing cholangitis (PSC) remains unknown, but it is thought to be multifactorial, including genetic predisposition, exposure to an environmental antigen, and subsequent aberrant immunologic response to that stimulus. [1, 10, 11] There is also an increased prevalence of HLA alleles A1, B8, and DR3 in PSC. [12, 13]
An autoimmune mechanism is suggested, because approximately 70% of patients with PSC have inflammatory bowel disease (IBD). [14] However, only approximately 4% of patients with IBD have or develop PSC. A marked increase in serum autoantibody levels occurs in patients with PSC as well, with antineutrophil cytoplasmic antibodies (ANCA) in 87%, anticardiolipin (aCL) antibodies in 66%, and antinuclear antibodies (ANA) in 53%. It has been reported that PSC and IBD have overlapping yet distinct genetic architectures. [15]
In the biliary ducts, an inflammatory response to chronic or recurrent bacterial infection in the portal circulation and from exposure to toxic bile acids has been postulated. [16] A genetic predisposition has been suggested because of an increased prevalence of HLA-B8, HLA-DR3, and HLA-Drw52a. Genome-wide association studies (GWAS) performed in PSC have identified about 20 genes that are significantly associated with PSC, most of which localize within the human leukocyte antigen (HLA) complex. [14] Subclassification of PSC patients according to their genetic predisposition may well constitute a valuable tool for future research in the subject. [17]
Ischemic damage to the biliary tree has also been postulated, as surgical trauma to the biliary tract can cause similar damage and because of the high number of patients with PSC who are ANCA–positive as observed in other vasculitides. Therefore, the most plausible concept of the pathogenesis of PSC involves the exposure of genetically predisposed individuals to an environmental antigen that subsequently elicits an aberrant immune response, leading to development of the disease.
Epidemiology
In the United States, the prevalence of primary sclerosing cholangitis (PSC) is not known. Inferences have been drawn on the basis of the strong relationship with inflammatory bowel disease (IBD), which has a prevalence of 60-80% in patients with PSC in western countries. [6]
The prevalence of PSC is estimated to be 6.3 cases per 100,000 population. Western Europe is thought to have approximately the same prevalence as in the United States, although Scandinavian countries report a somewhat higher rate. In many developing countries with limited access to advanced health care, the prevalence of PSC is probably underestimated, as the diagnosis cannot be confirmed without endoscopic retrograde cholangiopancreatography (ERCP). The association of PSC with IBD may vary; for example, in Japan, only 34-37% of patients with PSC have IBD. [18, 19] The disease normally starts at age 20-30 years, although it may begin in childhood. PSC may be active for a long time before it is noticed or diagnosed.
A survey of the literature has not revealed a racial bias for PSC, but studies on this aspect of the disease are rather limited. Based on the epidemiologic data available for IBD, the Jewish population might be expected to have a 2- to 4-fold higher prevalence, followed by, in descending order of frequency, white persons, black individuals, Hispanic people, and Asian populations.
Young to middle-aged males are primarily affected. [3] Approximately 70% of patients with PSC are men, with a mean age of diagnosis around 40 years. Patients with PSC but without IBD are more likely to be women and to be older at diagnosis.
PSC is also seen predominantly in nonsmokers.
Prognosis
Primary sclerosing cholangitis (PSC) is generally a progressive disease that eventually culminates in cirrhosis with complications (eg, portal hypertension, end-stage liver disease, hepatic failure). The median length of survival from diagnosis to death is approximately 12 years. Liver transplantation is the only treatment modality that appears to change the prognosis. Survival prospects are more dismal for those who are symptomatic at diagnosis.
The revised Mayo Clinic model for survival probability in patients with PSC [20, 21] includes the following:
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Age
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Variceal bleeding history
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Serum bilirubin, albumin, and aspartate aminotransferase (AST) levels
The Child-Turcotte-Pugh (CTP) scale [22] for calculation of severity of disease includes the following:
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Grade of encephalopathy
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Presence or absence of ascites
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Serum albumin level
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Prothrombin time
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Bilirubin level
A study by Rupp et al indicated that patients with PSC who reduce their alkaline phosphatase levels within the first year of having the condition have longer periods of liver transplantation-free survival, independent of the existence of dominant biliary strictures. The study involved 215 patients with PSC, some of whom were without strictures, some of whom presented with strictures, and some of whom developed strictures during the study. The amount and speed of alkaline phosphatase reduction were monitored, with previously published values for alkaline phosphatase decreases in patients with PSC also taken into account. [23]
Complications
PSC is characterized by recurrent episodes of cholangitis, with progressive biliary scarring and obstruction. Chronic cholestasis leads to steatorrhea, fat-soluble vitamin deficiency (vitamins A, D, E, and K), metabolic bone disease with osteoporosis, and calorie loss with resultant weight loss. [1] Secondary biliary cirrhosis (SBC) due to chronic cholestasis occurs in patients with PSC. Portal hypertension with variceal bleeding, ascites, and liver failure then ensue.
PSC might initiate amyloid A protein deposition in diverse tissues, giving rise to systemic amyloidosis, due to a progressive and unresolved inflammatory process, and its possible association with inflammatory bowel disease (IBD). The proper treatment of PSC complicated by systemic Amyloid A amyloidosis remains to be determined. [24]
Cholangiocarcinoma reportedly occurs in association with PSC in 6-30% of patients; on autopsy, it is found in up to 30-40% of patients with PSC. Indeed, about half of patients with PSC are diagnosed with cholangiocarcinoma within 2 years of the initial diagnosis, with an associated poor prognosis owing to advanced disease at the time of diagnosis. [8] The development of cholangiocarcinoma remains unpredictable in any given patient, and no reliable serologic tumor markers have been identified. Worsening jaundice, pruritus, or weight loss may indicate development of a stricture or cholangiocarcinoma.
Dominant biliary strictures can be identified in about 20% of patients with PSC and must be differentiated from cholangiocarcinoma. Strictures cause cholestasis with jaundice and pruritus and may also result in cholangitis.
The risk of colon cancer is increased for patients with both ulcerative colitis and PSC versus those with ulcerative colitis alone.
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Periductal onion skin fibrosis seen in primary sclerosing cholangitis.
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Endoscopic retrograde cholangiopancreatography performed in a patient with abnormal liver function test results shows multiple intrahepatic bile duct strictures and beading.
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Double-contrast barium enema (same patient as in the previous image) shows filiform polyps and an ahaustral colon resulting from ulcerative colitis.
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Percutaneous transhepatic cholangiogram shows dilatation, stricturing, and beading of the intrahepatic bile ducts. Note the surgical clips from a previous cholecystectomy.
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This T-tube cholangiogram shows an irregularity of the common bile duct, stricturing, beading, and dilatation of the intrahepatic bile ducts. Note a calculus in the termination of the left hepatic duct (arrow).
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Magnetic resonance cholangiopancreatography shows a normal-sized common bile duct, but strictures of both the left and right ducts are noted as well as a dilated proximal left hepatic duct.
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This technetium-99m iminodiacetic acid scan shows retention of the radionuclide proximal to strictures in the distribution of the left hepatic duct. Note the lack of filling of the gallbladder because of a previous cholecystectomy. Isotope has entered the small bowel.
