Primary sclerosing cholangitis (PSC) is a chronic and progressive cholestatic liver disorder of unknown etiology. Inflammation, fibrosis, and stricturing of intrahepatic and/or extrahepatic biliary ducts characterize PSC. PSC is usually a progressive disorder that leads to complications of cholestasis and liver failure. Median survival from time of diagnosis to death without liver transplantation is around 10 years.
Established subtypes of PSC are:
Healthcare professionals do not fully understand the etiology of PSC; however, they attribute genetic and environmental factors to its development. Inflammatory bowel disease (IBD) is considered to be a significant risk factor for the development of PSC. About 60% to 80% of patients with PSC have IBD (predominantly Ulcerative colitis in about 80% and Crohn disease in 20%), and about 5% to 10% of patients with ulcerative colitis have coexisting PSC.
The incidence rates for PSC range from 0 to 1.3 per 100,000 inhabitants/year and prevalence rates are 0 to 16.2 per 100,000 inhabitants. Incidence and prevalence of PSC are high in North America and Northern Europe when compared to Asia. Patients are diagnosed between the ages of 30 and 40 years. The median age at the diagnosis of PSC was 41 years. PSC is more common in men (65% to 70%), and males have a 2-fold increased risk of developing PSC when compared to females. The relative risk of PSC among siblings with the disease is 9 to 39 times higher when compared as the risk in the general population.
PSC is characterized by inflammation, fibrosis, and cholestasis. Hereditary and environmental factors play a role in the pathogenesis of primary sclerosing cholangitis. Healthcare researchers hypothesize that after exposure to an unidentified environmental source, persistent injury of the cells lining the bile ducts (cholangiocytes) occurs via several genetically predisposed pathways. A large cohort genome-wide association study showed a strong association with human leukocyte antigen (HLA). PSC is strongly associated with HLA class I, II, and III regions (i.e., HLA-B*08, HLA-DRB1 alleles, and a locus near NOTCH4, respectively). Inflammation and fibrosis lead to cholestasis and parenchymal injury. Biliary obstruction might facilitate cholangitis. Biliary scarring leads to portal hypertension which causes venous compression in the portal triads.
PSC is a premalignant disease as 10% to 20% of patients with PSC develop cholangiocarcinoma. PSC induced cholangiocarcinoma is thought to be inflammation-induced cancer contributed by the toxic environment of bile which acts as a cofactor in accelerating the carcinogenesis. Genetic and immune factors may play an important role.
Progressive fibrosis around intrahepatic bile ducts leads to concentric and circumferential laminations called as "onion skin" fibrosis. This leads to the displacement of the pre-biliary capillary plexi and creates a barrier to oxygenation and maintenance of cholehepatic countercurrent circulation between the artery and the bile duct. Arterial or capillary ischemia is involved in the pathogenesis of stricturing and circumferential pre-biliary fibrosis. Secretion of chemokines and cytokines by innate immune cells and inflammatory and fibrotic response to toxic bile leaking between inured cholangiocytes leads to periductal fibrosis.
About 50% of the patients with PSC are asymptomatic on presentation, and they are diagnosed after abnormal liver function tests are found when tested for other reasons. Most patients complain of right upper quadrant abdominal pain (in 20%), pruritus (in 10%) (which might be episodic), fatigue and jaundice (in 6%). Pruritus can be extremely disabling, leading to severe excoriations, and a decreased quality of life. Weight loss may also be reported at presentation. Late symptoms or symptoms of advanced liver disease include jaundice, gastrointestinal (GI) bleeding, ascites, and confusion.
Physical examination may reveal hepatomegaly (in 44% of patients), splenomegaly (in 39%), jaundice, and excoriations from pruritus.
Development of fever, chills and right upper quadrant pain with or without jaundice indicates the development of bacterial cholangitis, which may occur sporadically.
Liver biochemical tests usually demonstrate a cholestatic pattern, with an elevation of the serum alkaline phosphatase being characteristic finding. Elevation of transaminases (aspartate transaminase and alanine transaminase) is modest (2 to 3 times the upper limit of normal). Bilirubin and albumin levels may be normal at the time of diagnosis but become increasingly abnormal as the disease progresses. Elevated serum bilirubin levels suggest the possibility of more advanced disease, dominant biliary strictures or cirrhosis.
Atypical perinuclear antineutrophil cytoplasmic antibodies are positive in about 26% to 94% of patients with PSC, although they are not specific for the disease. Elevated concentrations of total immunoglobulins (IgM in 50%) may be seen. Positive antinuclear antibodies, smooth muscle antibodies should alert clinicians to the possibility of autoimmune hepatitis related PSC or overlap syndromes. Immunoglobulin subsets elevation (IgG4 in 10%) may also be seen. Serum IgG4 elevations are not specific to IgG4-related disease. Serum IgG4 levels of more than four times the upper limit of normal and/or IgG4:IgG1 ratio of more than 0·24 strongly suggests IgG4-associated PSC.
Imaging, usually with ultrasound or computed tomography, may be performed in the patient with persistent cholestatic liver tests to exclude biliary obstruction. The diagnosis of PSC is typically made with the demonstration of characteristic multiple and focal areas of stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography. A cholangiogram may be obtained using magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), or percutaneous transhepatic cholangiography (PTC). MRCP is usually the first test of choice. Because ERCP is an invasive procedure and the diagnostic accuracy of MRCP is comparable to ERCP, MRCP is preferred over ERCP. PTC is reserved for patients who are not able to undergo MRCP, for example, those with implanted metal devices) or ERCP.
A liver biopsy is usually not needed for diagnosis unless overlap with autoimmune hepatitis or a small-duct PSC is suspected. Noninvasive diagnostic tools that assess fibrosis, like magnetic resonance elastography and transient elastography of the liver are promising, but their specific role in evaluating the degree of liver fibrosis in patients with PSC is unclear.
Diagnostic criteria for the diagnosis of PSC include:
Treatment of PSC is challenging and complex. There is no established treatment of PSC yet. Ursodeoxycholic acid (UDCA) has been widely studied as a therapy for PSC patients. Treatment guidelines for PSC are conflicting. American College of Gastroenterology and the American Association for the Study of Liver Diseases do not support the use of ursodeoxycholic acid. Use of moderate doses of ursodeoxycholic acid has been approved by the European Association for the Study of the Liver. Nonetheless, at moderate doses of 15 to 20 mg/kg daily, remains widely used.
Other treatments which have been tested and are not proven to be beneficial are prednisolone, budesonide, colchicine, penicillamine, azathioprine, tacrolimus, methotrexate, mycophenolate mofetil, and antitumor necrosis factor antibodies.
In PSC patients with dominant stricture (defined as stenoses measuring less than 1.5 mm in the common bile duct or less than 1.0 mm in the hepatic ducts) and pruritus, and/or cholangitis, ERCP with balloon dilatation is recommended to relieve symptoms.
Surgical options for PSC include biliary reconstructive procedures like choledochoduodenostomy in with the surgeon attaches the common bile duct to the duodenum, choledochojejunostomy in which the surgeon attaches the common bile duct to the jejunum, and liver transplantation. Liver transplantation is the definitive treatment for patients with decompensated cirrhosis. Patients whose model for end-stage liver disease (MELD) score exceeds 14 should be referred for liver transplantation. Orthotopic liver transplantation has 5-year survival rates of up to 80% in patients with PSC.
The common history of PSC is highly variable and unpredictable. A persistently low serum alkaline phosphatase levels less than 1.5 times the upper limit of normal confers a good prognosis. Patients with small duct PSC have a good prognosis, with no reports of bile duct malignancy in this group, and progression to advanced liver disease is uncommon. The Mayo risk score which includes age, serum bilirubin, serum albumin, serum AST, and a history of variceal bleeding is helpful in predicting survival in PSC patients.
There is no definite cure for PSC at the time of this writing. There have been significant advances in the early diagnosis of PSC. Diagnosing PSC early is essential as treatment can be started early before the development of liver failure.
In patients with PSC and moderate pruritus, bile acid sequestrants such as cholestyramine should be taken to reduce symptoms. Rifampin and naltrexone are second-line treatment agents which can be considered if cholestyramine is ineffective or poorly tolerated.
Patients with PSC should undergo bone mineral density testing at the time of diagnosis and then every 2 to 4 years.
Fat-soluble vitamin deficiencies are common in patients with advanced liver disease, and clinicians should screen for and monitor patients for these.
The treatment of PSC requires an interprofessional approach. Gastroenterology consultation is useful. Surgery consult and referral to a tertiary center is needed in patients undergoing liver transplantation. Patients with osteoporosis might need to be referred to an endocrinologist. Besides the physicians, nurses, dieticians, psychiatric counselors, pharmacists, and physical therapists play a critical role in the management of these patients. Pharmacists should encourage patients to take appropriate medications and educate patients about their side effects. Patients will need to be evaluated by a dietician for appropriate diet recommendations. Physical therapy is encouraged except in patients with advanced osteoporosis. Some patients might benefit from psychiatric counseling.
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