Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune liver disorder characterized by chronic, progressive cholestatic disease. If untreated, PBC leads to cirrhosis, or scarring of the entire liver, which can result in liver failure. The prevalence of PBC is estimated at 19-402 per million individuals. PBC is more common in women than in men, and usually arises at 40-50 years of age. Symptoms of PBC may include chronic pruritus (itching), fatigue, sicca symptoms, abdominal pain, jaundice, and arthralgia. PBC is thought to develop through a combination of genetic and environmental factors, including urinary tract infections, reproductive hormone replacement, nail polish use, and cigarette smoking. Additional risk factors include the presence of another autoimmune disorder (particularly celiac disease, systemic sclerosis, thyroid disease, and Sjögren syndrome ) and family history of PBC. Laboratory tests in the workup of PBC include liver biochemistry tests (such as alkaline phosphatase [ALP] and aminotransferase tests) and tests for autoantibodies (including antimitochondrial M2 antibodies [AMAs] and antinuclear antibodies [ANAs] such as anti-sp100 and antiglycoprotein 210 [anti-gp210] antibodies). Liver biochemistry tests can be used for prognosis and for monitoring treatment response.
Quick Answers for Clinicians
Antimitochondrial M2 antibodies (AMAs) are present in the serum of >90% of patients with primary biliary cholangitis (PBC), and antinuclear antibodies (ANAs) are often present. Serum antibodies are detected via enzyme-linked immunosorbent assays (ELISAs) or other immunoassays. The diagnostic performance characteristics of these assays and results may not be commutable. Positive results for ANAs using solid-phase immunoassays (eg, ELISAs) are generally meaningless, as PBC-relevant ANA patterns (including nuclear dot, nuclear rim, centromere, and cytoplasmic patterns) can only be observed via immunofluorescence (IF) antibody assays. Immunoassays for detecting specific ANAs (eg, anti-sp100 and antiglycoprotein 210 [anti-gp210]) are important for confirmation.
Although liver biopsy is no longer recommended for the majority of patients with primary biliary cholangitis (PBC), specificity issues may arise with antimitochondrial M2 antibodies (AMAs) and antinuclear antibodies (ANAs). Thus, histology may be needed if liver biochemistry tests, autoantibody tests, and imaging fail to establish a diagnosis of PBC or are equivocal. Histology is also useful to establish diagnosis in overlap syndromes, such as PBC/autoimmune hepatitis (PBC/AIH).
Although earlier detection and intervention have reduced the need for liver transplantation in patients with primary biliary cholangitis (PBC), the British Society of Gastroenterology (BSG) recommends consideration of liver transplantation in all patients with bilirubin >50 µmol/L or with pruritus that is refractory to all medical therapy.
Indications for Testing
Laboratory testing for PBC is used to
- Diagnose PBC in patients who present with symptoms (chronic pruritus, fatigue, sicca symptoms, and abdominal pain) or with evidence of cholestatic liver disease or jaundice without evidence of other causes
- Establish prognosis in patients diagnosed with PBC
- Monitor therapeutic response, disease progression, and development of comorbidities in patients diagnosed with PBC
Criteria for Diagnosis
Suspicion of PBC is increased in the setting of chronic cholestasis after exclusion of other liver disease. Guidelines recommend consideration of PBC in patients with otherwise unexplained elevated ALP and/or pruritus or fatigue.
PBC may occur with autoimmune hepatitis (AIH). PBC/AIH overlap syndrome usually refers to AIH in a patient with a diagnosis of PBC. Diagnosis of PBC or PBC/AIH overlap syndrome is based on cholestatic liver biochemistry, the presence of PBC-specific autoantibodies, and if needed, imaging, liver biopsy, or genetic testing.
|AASLD, 2018||BSG, 2018||EASL, 2017|
|Criteria for Diagnosis of PBC|
|At least 2 of the following:
||1 of the following:
||1 of the following, in the appropriate clinical context:
|Criteria for Diagnosis of PBC/AIH Overlap Syndrome|
|Confirmed PBC and at least 2 of the following:
||Histopathologic evidence on liver biopsy||At least 2 of the following:
And at least 2 of the following:
|AASLD, American Association for the Study of Liver Diseases; ALT, alanine transaminase; BSG, British Society of Gastroenterology; EASL, European Association for the Study of the Liver; EUS, endoscopic ultrasound (abdominal); GGT, gamma-glutamyl transferase; IgG, immunoglobulin G; MRCP, magnetic resonance cholangiopancreatography; SMA, smooth muscle antibody; ULN, upper limit of normal|
Liver Biochemistry Tests
The majority of patients with PBC exhibit elevated ALP, and may exhibit elevated serum transaminase (specifically ALT or aspartate aminotransferase [AST]) activity. Sustained elevation of ALP for >6 months is characteristic of PBC. Elevation of ALP correlates with the severity of ductopenia and inflammation, while increases in aminotransferase activity correlate with periportal and lobular necrosis and inflammation. Although ALP is not specific to the liver, the hepatic origin of elevated serum ALP may be supported by simultaneous elevation of serum GGT and/or conjugated bilirubin. In pediatric patients, GGT is a better marker of cholestasis than ALP, given that there are several possible etiologies of elevated ALP in children. In addition to ALP and aminotransferases, an increase in international normalized ratio (INR) may serve as a marker for progression to cirrhosis. Serum bile acid levels may also be increased in PBC.
Antimitochondrial M2 Antibodies
AMAs are present in >90% of patients with PBC. AMA testing is not useful in the absence of symptoms, as the frequency of AMAs in the general population is reported to be high (up to one per 1,000), but the frequency of PBC is much lower (19-402 per million individuals). Several methods are available to detect AMAs, including immunofluorescence (IF), immunoblotting, enzyme immunoassays, Luminex bead assays, and enzyme inhibition assays ; these methods vary in their performance characteristics. AMA positivity is a defining serologic signature of PBC in the setting of chronic intrahepatic cholestasis.
Antinuclear Antibodies and Centromere Antibodies
ANAs, particularly anti-gp210 and/or anti-sp100, but also antikelchlike 12 and antihexokinase 1, are present in approximately 30% of patients with PBC ; their presence may correlate with prognosis. Centromere antibodies are found in varying percentages in patients with PBC, with significant frequency in PBC/systemic sclerosis (PBC/SSc) overlap syndrome. While ANAs may be detected by enzyme-linked immunosorbent assays (ELISAs) or other immunoassays, the IF method is the most suitable technique, as only specific ANA patterns (nuclear dot, nuclear rim, and cytoplasmic) are relevant to the diagnosis of PBC. Testing for anti-sp100 and anti-gp210 is useful for diagnostic confirmation.
Immunoglobulins are often increased in PBC, particularly IgM and IgG. Serum bilirubin, globulin, and hyaluronic acid elevation in the context of a decreased serum albumin level and platelet count may indicate the development of cirrhosis and portal hypertension.
Other Serologic Tests
Serum cholesterol may be elevated in PBC. SMA is often elevated in AIH. If SMA is positive (>1:80) in conjunction with PBC, consider PBC/AIH overlap syndrome. Liver-kidney microsome-1 antibody testing can also be used in combination with SMA and ANA testing to diagnose AIH. In addition, hepatitis serologies may be useful to assess whether there is a viral cause of liver damage.
In cases in which a diagnosis of PBC cannot be established via serologic testing, imaging, or liver biopsy, but clinical suspicion persists, genetic testing may be performed for inherited cholestatic disorders. Variants occur most commonly in ATP8B1, ABCB11, and ABCB4 genes, although many others are being identified.
Imaging is largely used to exclude diagnoses of other biliary and infiltrative diseases in patients who present with symptoms suggestive of PBC. Liver biopsy is not required for diagnosis in the majority of patients. However, biopsy may be required to diagnose genuinely antibody-negative disease or disease that cannot be detected via imaging, or in patients with suspected concurrent AIH, nonalcoholic steatohepatitis, or other comorbidities.
Several prognostic models exist to assess patients with PBC in terms of treatment response, survival, and the need for transplantation. The most recent models are the GLOBE and UK-PBC scoring systems. EASL recommends the use of transient elastography, in addition to a risk score, to assess a patient’s risk of advanced liver disease.
Serum bilirubin level is the most heavily weighted factor in all PBC prognostic models and is the best predictor of survival. ALP is also an important parameter; in multiple models, elevated serum ALP contributes to a prediction of treatment failure. In conjunction with baseline serum albumin, serum bilirubin measurements can be used to stratify patients into risk groups, depending on whether baseline and follow-up bilirubin measurements are both normal (low risk), both abnormal (high risk), or one is normal and the other abnormal (medium risk).
Various criteria may be used to assess the biochemical response to ursodeoxycholic acid (UDCA) therapy. Noninvasive tests, including bilirubin, ALP, AST, albumin, and platelet count tests, can be used at baseline and for ongoing monitoring. Transient elastography may also be used to assess response to treatment. In patients with cirrhosis complications, persistent markers of severe disease, and/or severe medically resistant pruritus, consider evaluation for liver transplant. Evaluation of biochemical response to UDCA is recommended 12 months after treatment initiation to determine whether second-line therapy (obeticholic acid) should be considered. Guidelines also recommend periodic monitoring of liver biochemistry and monitoring for related complications, per the table below. Lifelong follow-up is recommended.
ARUP Laboratory Tests
Quantitative Heat Inactivation/Enzymatic Assay
Electromagnetic Mechanical Clot Detection
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Components: AMA, IgG; liver-kidney microsome-1 antibody, IgG; F-actin (smooth muscle) antibody, IgG; SMA, IgG titer; soluble liver antigen antibody, IgG; ANA with HEp-2 substrate, IgG
Semi-Quantitative Indirect Fluorescent Antibody/Qualitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Multiplex Bead Assay/Qualitative Immunoblot
Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Semi-Quantitative Indirect Fluorescent Antibody
Qualitative Chemiluminescent Immunoassay
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