Primary Sclerosing Cholangitis

Etiology

The etiology of PSC is not understood; however, genetic and environmental factors contribute to its development.[3] Inflammatory bowel disease (IBD) is considered to be a significant risk factor for the development of PSC.[4] 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.[5] PSC is believed to be an autoimmune disorder. Some patients have elevated levels of antineutrophilic cytoplasmic antibodies, antinuclear antibodies, and anticardiolipin antibodies. In addition, individuals with HLA B8 and HLA DR3 genes are at a higher risk of developing the disorder.

Epidemiology

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.[6] PSC incidence and prevalence are higher in North America and Northern Europe than in 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.[7] The relative risk of PSC among siblings with the disease is 9 to 39 times higher when compared to the risk in the general population. A distinct feature is that PSC is commonly observed in nonsmokers.

Pathophysiology

PSC is characterized by inflammation, fibrosis, and cholestasis. Hereditary and environmental factors play a role in the pathogenesis of PSC. 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.[8] A large cohort genome-wide association study showed a strong association with specific human leukocyte antigens (HLA).[9] PSC is strongly associated with HLA class 1, 2, and 3 regions (ie, HLA-B*08, HLA-DRB1 alleles, and a locus near NOTCH4, respectively).[8] Inflammation and fibrosis lead to cholestasis and parenchymal injury. Biliary obstruction might facilitate cholangitis.[10] 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 carcinogenesis. Genetic and immune factors may play an important role.

Histopathology

Progressive fibrosis around intrahepatic bile ducts leads to concentric and circumferential laminations called "onion skin" fibrosis. This leads to the displacement of the pre-biliary capillary plexus 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 stricturing and circumferential pre-biliary fibrosis pathogenesis. The 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.[11]

History and Physical

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 are males in the third or fourth decade of life. Most patients complain of right upper quadrant abdominal pain (20%) and pruritus (10%), which might be episodic, fatigue, and jaundice (6%). Pruritus can be extremely disabling, leading to severe excoriations and a decreased quality of life. Weight loss may also be reported at the presentation. Late symptoms or symptoms of advanced liver disease include jaundice, gastrointestinal bleeding, ascites, and confusion. Physical examination may reveal hepatomegaly (44% of patients), splenomegaly (39%), jaundice, and excoriations from pruritus. The development of fever, chills, and right upper quadrant pain with or without jaundice indicates the development of bacterial cholangitis, which may occur sporadically.

Evaluation

Liver biochemical tests usually demonstrate a cholestatic pattern, with an elevation of the serum alkaline phosphatase being a characteristic finding. The elevation of transaminases (aspartate transaminase and alanine transaminase) is modest at 2 to 3 times the upper limit of normal. Bilirubin and albumin levels may be normal at 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 to the disease. Elevated concentrations of total immunoglobulins (IgM in 50%) may be seen. Positive antinuclear antibodies and 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 diseases. Serum IgG4 levels of more than 4 times the upper limit of normal or IgG4:IgG1 ratio of more than 0.24 strongly suggest IgG4-associated PSC.[10]

Imaging, usually with ultrasound or computed tomography, may be performed in patients 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 or extrahepatic bile ducts on cholangiography. A cholangiogram may be obtained using magnetic resonance cholangiopancreatography (MRCP), 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 it overlaps 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. Still, their specific role in evaluating the degree of liver fibrosis in patients with PSC is unclear.[8] Diagnostic criteria for the diagnosis of PSC include:

1. An increased serum alkaline phosphatase level that persists for more than 6 months
2. Cholangiographic findings of bile-duct strictures detected using either MRCP or ERCP
3. Exclusion of causes of secondary sclerosing cholangitis

The key feature in histology is periductal or onion skin fibrosis.

Treatment / Management

The treatment of PSC is challenging and complex. There is no established treatment for 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 using ursodeoxycholic acid. The European Association has approved using moderate doses of ursodeoxycholic acid for the Study of the Liver. Nonetheless, it remains widely used at moderate doses of 15 to 20 mg/kg daily.[10][12] A few studies do show that UDCA can improve symptoms and survival.

Other treatments that 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 patients with PSC 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 or cholangitis, ERCP with balloon dilatation is recommended to relieve symptoms.

Surgical options for PSC include biliary reconstructive procedures like choledochoduodenostomy, in which the surgeon attaches the common bile duct to the duodenum, and 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 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.[12]

General Measures

Bile acid sequestrants such as cholestyramine should be taken to reduce symptoms in patients with PSC and moderate pruritus. 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; clinicians should screen for and monitor patients for these.

Differential Diagnosis

The differential diagnosis for primary sclerosing cholangitis includes:

• Secondary sclerosing cholangitis: Secondary causes of PSC include chronic bacterial cholangitis, cholangiocarcinoma, choledocholithiasis, recurrent pancreatitis, and surgical biliary trauma.
• IgG4-associated cholangitis
• PSC-autoimmune hepatitis overlap syndrome is typically seen in children and young adults
• Histiocytosis X
• HIV syndrome
• Bile duct strictures
• Primary biliary cirrhosis
• Papillary tumors

Prognosis

The common history of PSC is highly variable and unpredictable. A persistently low serum alkaline phosphatase level of less than 1.5 times the upper limit of normal confers a good prognosis.[13] 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 history of variceal bleeding, helps predict survival in patients with PSC.[14]

Complications

The following are some significant complications of PSC:

1. Fat-soluble A, D, E, and K vitamin deficiencies
2. Metabolic bone disease (osteoporosis)
3. Cholangiocarcinoma
4. Gallbladder cancer 
5. Dominant biliary strictures
6. Cholangitis
7. Hepatocellular carcinoma in patients with cirrhosis.[15] Hepatic fibrosis progressively develops in these patients, leading to cirrhosis and hepatocellular carcinoma.
8. Colon cancer in patients with concomitant ulcerative colitis. Surveillance with colonoscopy should be performed annually in these patients who have concomitant PSC and IBD.[16]
9. Cholelithiasis
10. Portal hypertension