Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the two most common and well-characterized primary cholestatic disorders. In contrast to pathologic processes derived primarily from hepatocellular dysfunction, such as viral hepatitis and autoimmune hepatitis, the primary insult in cholestatic diseases centers on the bile duct epithelium. As with other diffuse liver diseases, PBC and PSC may progress to liver fibrosis, portal hypertension, cirrhosis, and/or malignancy.
Etiology and Pathogenesis
Primary Biliary Cirrhosis
PBC is a chronic, progressive cholestatic disease of autoimmune origin affecting the small to medium intrahepatic bile ducts. Pathogenically, this is manifested as immune-mediated destruction of bile ducts (“ductopenia”), as well as portal inflammation. As a result, biliary secretion is impaired, toxins accumulate within the liver, and inflammation is exacerbated. Ultimately, the process progresses to fibrosis and cirrhosis.
The cause of PBC is multifactorial. Geographic variations in disease prevalence suggest that environmental factors play a role in the pathogenesis. It is thought that an environmental trigger, such as an infection or toxin, either directly causes bile duct injury or initiates the process of autoimmunity. Infectious organisms, including Helicobacter pylori, Escherichia coli, Chlamydia pneumoniae, and retroviruses, as well as toxins containing halogenated hydrocarbons (found in pesticides and cosmetics), have been implicated.
Pathogenically, cellular and humoral immune mechanisms are involved. CD4+ and CD8+ T lymphocytes aggregate in regions of periportal inflammation and trigger cytokine-mediated cytotoxic reactions. The antimitochondrial antibody (AMA), present in 90% to 95% of patients, is an autoantibody targeted to the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2), which is associated with an immunologic cascade resulting in bile duct cell apoptosis.
Primary Sclerosing Cholangitis
PSC is a chronic, cholestatic disorder associated with inflammatory bowel disease (IBD) and involves the medium to large intrahepatic and extrahepatic bile ducts. Pathogenically, the disease manifests as progressive biliary necroinflammation, fibrosis, multifocal stricturing, and obstruction. Prolonged retention of bile and associated toxins, along with inflammation resulting from recurrent or chronic cholangitis, may ultimately lead to hepatic fibrosis and cirrhosis.
The cause of PSC is thought to be multifactorial. Proposed mechanisms include humoral and cell-mediated immunologic insults to the bile duct epithelium, ischemic ductal injury, and ductal damage induced by chronic cholangitis and recurrent portal phlebitis in IBD patients with increased bacterial permeability across the inflamed colonic wall. As evidenced by familial pedigree studies, genetic factors may make certain patients particularly susceptible to PSC pathogenesis.
The immunologic underpinnings of PSC are supported by the presence of various autoantibodies and immunoglobulins. Autoantibodies, such as antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), and peripheral antineutrophil cytoplasmic antibody (P-ANCA), suggest a loss of self-tolerance to autoantigens, whereas hypergammaglobulinemia and increased levels of serum immunoglobulin M (IgM) imply a heightened immunologic response. Later stages of the immunologic response are mediated by CD4+ and CD8+ T lymphocytes, which are heavily represented in the periportal inflammatory infiltration of PSC.
Prevalence and Epidemiology
Primary Biliary Cirrhosis
The prevalence of PBC varies geographically but is generally thought to be greatest among northern Europeans. Published PBC prevalence rates range from 1.91 to 40.2 per 100,000 persons; incidence rates range from 0.33 to 5.8 per 100,000 persons/year. Women account for 90% of cases. Disease onset is in adulthood, with a median age at diagnosis of 50 years. In familial pedigree studies, 6% of affected individuals have at least one family member with PBC. The concordance frequency of PBC in monozygotic twins is 63%. Risk factors for PBC pathogenesis include smoking, prior abdominal surgeries, and other comorbid autoimmune diseases.
Primary Sclerosing Cholangitis
Worldwide, published prevalence rates of PSC range from 0 to 16.2 per 100,000 persons; incidence rates range from 0 to 1.3 per 100,000 persons per year. As with PBC, rates vary geographically. Approximately 75% of patients with PSC are males, and the average age at diagnosis is 40 years. Family history appears to play an important role; the risk for PSC in first-degree relatives of afflicted patients is roughly 100-fold greater than in the general population.
The most important risk factor for PSC is IBD. Approximately 75% of patients with PSC have IBD, with ulcerative colitis (UC) accounting for 90% of the IBD cases. Conversely, in patients with UC, the risk for developing PSC approaches 4%, with the highest risk in male patients with pancolitis.
Prevalence and Epidemiology
Primary Biliary Cirrhosis
The prevalence of PBC varies geographically but is generally thought to be greatest among northern Europeans. Published PBC prevalence rates range from 1.91 to 40.2 per 100,000 persons; incidence rates range from 0.33 to 5.8 per 100,000 persons/year. Women account for 90% of cases. Disease onset is in adulthood, with a median age at diagnosis of 50 years. In familial pedigree studies, 6% of affected individuals have at least one family member with PBC. The concordance frequency of PBC in monozygotic twins is 63%. Risk factors for PBC pathogenesis include smoking, prior abdominal surgeries, and other comorbid autoimmune diseases.
Primary Sclerosing Cholangitis
Worldwide, published prevalence rates of PSC range from 0 to 16.2 per 100,000 persons; incidence rates range from 0 to 1.3 per 100,000 persons per year. As with PBC, rates vary geographically. Approximately 75% of patients with PSC are males, and the average age at diagnosis is 40 years. Family history appears to play an important role; the risk for PSC in first-degree relatives of afflicted patients is roughly 100-fold greater than in the general population.
The most important risk factor for PSC is IBD. Approximately 75% of patients with PSC have IBD, with ulcerative colitis (UC) accounting for 90% of the IBD cases. Conversely, in patients with UC, the risk for developing PSC approaches 4%, with the highest risk in male patients with pancolitis.
Clinical Presentation
Primary Biliary Cirrhosis
PBC is a progressive disease. Approximately 40% of patients are symptomatic at diagnosis, and an additional 25% develop symptoms within a few years, with rapid progression to cirrhosis over a decade.
The most common symptoms are fatigue and pruritus, occurring in 60% and 50% of patients, respectively. Malabsorption secondary to bile salt deficiency may occur in advanced disease and manifest as steatorrhea and fat-soluble vitamin deficiencies. Bone pain and fractures resulting from osteopenia and osteoporosis related to vitamin D deficiency are common. The clinical manifestations of cirrhosis and portal hypertension in PBC are similar to other causes of chronic liver disease, except that variceal hemorrhage may occur earlier in the disease course, before the development of true cirrhosis. In patients who have progressed to cirrhosis, hepatocellular carcinoma (HCC) occurs with an average yearly incidence of approximately 7%, which is slightly higher than the published incidence for most other causes of cirrhosis.
The serologic hallmark of PBC is AMA positivity. These antibodies have a sensitivity and specificity for PBC of 90% and 95%, respectively. Characteristically, these patients have striking elevations in the serum alkaline phosphatase level (three to four times the upper limit of normal), as well as elevations in gamma-glutamyltransferase (GGT) and abnormalities in immunoglobulins, particularly IgM. Imaging is obtained to exclude biliary obstruction. A liver biopsy is almost always performed for staging and prognostication and as a baseline for evaluating the response to treatment. A definitive diagnosis of PBC requires the presence of AMAs, elevated alkaline phosphatase for 6 months, and characteristic histologic findings; a probable diagnosis requires two of these three criteria.
Primary Sclerosing Cholangitis
Like PBC, PSC is a progressive disease. The most important prognostic factor for predicting the rate of progression is the presence or absence of symptoms at the time of diagnosis. Most patients with PSC are asymptomatic at the time of diagnosis; transplant-free survival in these patients is on average 10 to 12 years, whereas survival is halved in those symptomatic at diagnosis.
Characteristic symptoms of PSC are fatigue and pruritus, which typically do not occur until the disease progresses to more advanced stages. Frequent but nonspecific symptoms include right upper quadrant abdominal pain, nausea, anorexia, weight loss, and jaundice. Malabsorption secondary to bile salt deficiency, in the form of steatorrhea and fat-soluble vitamin deficiencies, and osteoporosis-related bone disease manifest in the latest stages of disease.
Twenty percent of patients develop a dominant stricture, manifesting as mechanical obstruction and acute cholangitis. A dominant stricture has been defined as a stenosis with a diameter of 1.5 mm in the common bile duct or 1 mm in the hepatic duct. Although stenotic lesions are far more often benign than malignant, this finding should always raise the suspicion of the presence of a cholangiocarcinoma. Patients with PSC are at risk for developing cholangiocarcinoma (10-year cumulative incidence of 7% to 9%), typically as patients reach their 40s, roughly 20 years before onset in patients without PSC. The prognosis is grim, with median survival of 6 months after diagnosis. In patients in whom cirrhosis develops, HCC occurs at similar rates as in other causes of chronic liver disease.
As stated earlier, there is a strong association between PSC and UC. Although the symptoms of UC may predate or follow the diagnosis of PSC, the majority of patients (~75%) have established UC at the time of their PSC diagnosis. Proctocolectomy for UC has no impact on the course of PSC, and PSC may be detected years after proctocolectomy. UC patients with PSC have a five times greater risk for developing colorectal cancer than UC patients without PSC.
Serologic immunologic markers are abundant in patients with PSC: 30% have hypergammaglobulinemia, 50% demonstrate elevated serum IgM titers, and approximately 65% exhibit P-ANCAs. In contrast to PBC, PSC patients lack AMA positivity. In addition to these immunologic measures, PSC is particularly suspected in patients with IBD with markedly elevated serum alkaline phosphatase levels and GGT. The serum aminotransferases are typically elevated to a lesser degree. The serum bilirubin value is normal early in the disease course but rises in advanced cases. Imaging plays a vital role in the diagnosis of PSC by elucidating ductal abnormalities, and for the detection of cholangiocarcinoma and HCC. Liver biopsy is obtained for prognostication and staging but may not help with diagnosis because the usual findings of ductopenia and portal inflammation and fibrosis are nonspecific and may be missed, owing to their patchy distribution and sampling error inherent to biopsy.
Pathology
Primary Biliary Cirrhosis
In the early stages of PBC, the liver is slightly enlarged and is variably bile stained. In later stages, the liver is cirrhotic and has a green hue, reflecting the extensive cholestasis. The microscopic hallmark of PBC is destructive, nonsuppurative cholangitis affecting the interlobular and septal bile ducts, resulting in duct loss and subsequent biliary cirrhosis.
With disease progression, there is patchy necrosis of the periportal hepatocytes and delicate periportal fibrosis, often with ductular proliferation. Florid duct lesions become less common as the disease advances into the later stages. Fibrous septa appear and extend in a portal-portal distribution, later evolving into biliary cirrhosis. This type of cirrhosis results in regenerative nodules (RNs) with serpentine or garland-like borders, as opposed to the roughly spherical RNs seen in the usual forms of cirrhosis. The RNs in biliary cirrhosis have some resemblance to the pieces of a jigsaw puzzle.
Primary Sclerosing Cholangitis
Similar to the gross findings of PBC, the liver in early PSC is slightly enlarged and variably bile stained, progressing to biliary cirrhosis in the later stages. One characteristic gross finding in PSC is the presence in the hilum of cholangiectases, cystic collections of bilious, dark green material measuring up to several centimeters in size and representing cystically dilated intrahepatic ducts.
The pathognomonic microscopic finding of PSC is the concentric fibrous replacement of bile ducts in an “onionskin” pattern. This fibrous cholangitis is characterized by a mixed inflammatory infiltrate that, over time, results in loss of the bile duct in a process called fibrous obliterative cholangitis. As the disease progresses, fibrous septa form between portal tracts and ductopenia becomes more common; inflammation in this stage typically subsides. End-stage PSC is indistinguishable from other causes of biliary cirrhosis, with large irregularly shaped, bile-stained RNs characteristically arranged in a jigsaw puzzle pattern.
Imaging
Radiologic imaging is obtained in the initial evaluation of patients with PBC to assess the differential diagnosis of cholestasis and, importantly, rule out biliary obstruction. Imaging also plays an important role in the surveillance of this chronic condition, particularly with regard to the evolution of portal hypertension and detection of HCC.
Rather than playing an ancillary role as it does in PBC, imaging has a central diagnostic responsibility in PSC and fundamentally affects treatment options. Similar to PBC, however, imaging is useful in excluding secondary causes of biliary obstruction and surveillance of complications of portal hypertension, cholangiocarcinoma, and HCC. The two principal techniques used to highlight the structure of the intrahepatic and extrahepatic ducts are cholangiography and magnetic resonance cholangiopancreatography (MRCP). Cholangiography, in particular, is most commonly accomplished via endoscopic retrograde cholangiopancreatography (ERCP); transhepatic cholangiography is generally pursued only if ERCP is unsuccessful. In all techniques, the characteristic finding of PSC is a “beaded” appearance of the biliary tree consisting of short-segment, multifocal stricturing with intervening areas of normal or dilated intervening intrahepatic and extrahepatic ducts ( Table 43-1 ).
| Modality | Accuracy | Limitations | Pitfalls |
|---|---|---|---|
| PRIMARY BILIARY CIRRHOSIS | |||
| CT | No data on the accuracy of CT in the diagnosis of PBC | ||
| MRI | In one retrospective study, periportal halo sign had 43% sensitivity and 100% specificity for diagnosis of PBC in patients with known cirrhosis | Low sensitivity | |
| MRCP | No data on the accuracy of MRCP in the diagnosis of PBC | ||
| Ultrasound | No data on the accuracy of ultrasound in the diagnosis of PBC | ||
| PRIMARY SCLEROSING CHOLANGITIS | |||
| CT | No data on the accuracy of CT in the diagnosis of PSC | ||
| MRCP | Sensitivity of 85% to 88% Specificity of 92% to 97% Positive predictive value of 85% to 94% Negative predicted value of 93% to 94% Overall diagnostic accuracy is 90%. | May be negative in the early stages of PSC Lower spatial resolution than ERCP Does not permit tissue sampling or treatment of stenoses | Secondary causes of chronic cholangitis may be indistinguishable from PSC. Biliary neoplasia and PSC may be difficult to differentiate. Performed in the physiologic nondistended state, lending more difficulty to visualizing small ducts |
| ERCP | Considered the gold standard for the diagnosis Overall diagnostic accuracy is 97% | Invasive; may cause complications such as sepsis, hemorrhage, pancreatitis, bowel perforation, and cholangitis | Visualization of the peripheral ducts limited because of central obstruction from stones, strictures, and thick bile |
| Ultrasound | No data on the accuracy of ultrasound in the diagnosis of PSC | ||
Computed Tomography, Magnetic Resonance Imaging, Ultrasound, and Cholangiography
Primary Biliary Cirrhosis
Patients with PBC have a spectrum of disease severity ranging from asymptomatic to cirrhosis. In the initial presentation, the liver may be normal or slightly enlarged. Splenomegaly, sometimes severe, is a common finding in early stages. Early disease is also associated with periportal hyperintensity on T2-weighted magnetic resonance (MR) images, a finding that is less common in late PBC.
With disease progression, the liver demonstrates heterogeneous enhancement that may be associated with small, punctuated arterial-portal shunts in the early phase of dynamic contrast injection ( Figure 43-1 ). Hepatic fibrosis presenting as reticular, confluent, or both patterns also may be observed. In some cases, RNs of various sizes can be seen intercalated by coarse fibrous reticulations ( Figure 43-2 ). Additionally, upper abdominal and retroperitoneal lymphadenopathy is a frequent finding, seen in 60% to 80% of patients.
