Primary Biliary Cholangitis - PBC

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

How are primary biliary cholangitis antibody serology results interpreted?

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.

When is it appropriate to perform a liver biopsy for suspected primary biliary cholangitis?

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). 

What are indications for liver transplantation in patients with primary biliary cholangitis?

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. 

Should nutritional status be assessed in patients with primary biliary cholangitis?

In patients with advanced primary biliary cholangitis (PBC), fat and fat-soluble vitamins (A, D, E, and K) may not be well absorbed. Laboratory testing for vitamin deficiency and supplementation should be considered. 

Which testing algorithms are related to this topic?

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.

Society-Recommended Diagnostic Criteria for PBC and PBC/AIH Overlap Syndrome
AASLD, 2018 BSG, 2018 EASL, 2017
Criteria for Diagnosis of PBC
At least 2 of the following:
  • Biochemical evidence of cholestasis with elevation of ALP activity
  • Presence of AMAs or other PBC-specific antibodies (anti-sp100, anti-gp210, antikelchlike 12, and/or antihexokinase 1)
  • Histopathologic evidence of nonsuppurative cholangitis and destruction of small or medium bile ducts on liver biopsy
1 of the following:
  • Presence of AMAs (titer >1:40) or PBC-specific ANAs in the context of otherwise unexplained cholestatic liver biochemistry (increased ALP or GGT)
  • Histopathologic evidence on liver biopsy
1 of the following, in the appropriate clinical context:
  • Elevated ALP and GGT and/or conjugated bilirubin, in conjunction with history, physical examination, and abdominal findings of focal lesions and dilated bile ducts
  • AMA or PBC-specific ANA positivity in the context of clinical presentation
  • Bile duct abnormalities on MRCP with or without EUS
  • Abnormal findings (parenchymal damage or biliary lesions) on liver biopsy
  • Positive genetic test results
Criteria for Diagnosis of PBC/AIH Overlap Syndrome
Confirmed PBC and at least 2 of the following:
  • ALT activity >5 x ULN
  • IgG ≥2 x ULN and/or SMA positivity
  • Liver biopsy with moderate or severe interface hepatitis
Histopathologic evidence on liver biopsy At least 2 of the following:
  • ALP  >2 x ULN or GGT >5 x ULN
  • AMA titer >1:40
  • Florid bile duct lesions on liver biopsy

And at least 2 of the following:

  • ALT >5 x ULN
  • IgG >2 x ULN or SMA positivity
  • Liver biopsy with moderate or severe interface hepatitis
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

Sources: AASLD, 2018 ; BSG, 2018 ; EASL, 2017 

Laboratory Testing

Diagnosis

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. 

Autoantibody Tests

PBC is characterized by specific autoantibodies for mitochondrial, nuclear, and centromere antigens.    A titer of >1:40 is considered positive for any antibody. 

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.

Immunoglobulin Tests

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. 

Genetic Tests

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. 

Other Tests

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. 

Prognosis

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.

Recent Prognostic Models in PBC
  GLOBE UK-PBC
Laboratory tests Serum bilirubin

Albumin

ALP

Platelet count (after 1 yr of therapy)

ALP

Aminotransferases

Serum bilirubin (after 1 yr of therapy)

Albumin (baseline)

Platelets (baseline)

Other factors Age at start of therapy None
Predictions Transplantation-free survival Risk of liver transplantation or liver-related death within 5, 10, or 15 yrs
Source: AASLD, 2018 

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). 

The presence of ANAs may be predictive of poor prognosis.  Hyaluronic acid is also associated with outcomes. 

Monitoring

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. 

Recommended Laboratory Tests for Monitoring in PBC
Testa Patient Population Recommended Frequency
Liver tests All patients with PBC Every 3-6 mos ; annually 
Thyroid stimulating hormone All patients with PBC Annually 
Vitamins A, D, E, and prothrombin time Patients with bilirubin >2.0 mg/dL Annually 
Repeated risk assessment All patients with PBC Every 3 yrs 
aBone mineral densitometry, upper endoscopy for varices, and abdominal ultrasound are also recommended 

Sources: AASLD, 2018 ; BSG, 2018 

ARUP Lab Tests

Liver Biochemistry Tests

Initial screening for hepatobiliary inflammation

Components: albumin, ALP, AST, ALT, and bilirubin, protein

Evaluate liver function (characteristically elevated in PBC)

Determine amount of ALP contributed by bone and liver isoenzymes

Evaluate liver function (may be elevated in PBC)

Determine hepatic origin of elevated ALP

Evaluate biliary involvement in liver dysfunction

Evaluate liver function

Autoantibody Tests

Recommended first-line panel for the evaluation of autoimmune liver disease (ALD)

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

Recommended autoantibody panel for the evaluation of individuals with suspected PBC

Components: AMA, IgG; ANA, IgG; anti-gp210 antibody, IgG; anti-sp100 antibody, IgG

Confirm diagnosis of PBC

Initial screen for autoimmune connective tissue diseases

For additional test information and limitations, refer to the Antinuclear Antibody (ANA) with HEp-2 Substrate Test Fact Sheet

May be elevated in PBC

Recommended for the evaluation of individuals with suspected PBC who test negative for AMA

Immunoglobulin Tests

May be elevated in PBC; may indicate the development of cirrhosis and portal hypertension

May be elevated in PBC

Other Serologic Tests

Assess development of cirrhosis and portal hypertension

May be elevated in PBC

Evaluate for ALD

Differential evaluation of ALD of unknown etiology, especially AIH

Evaluate for viral cause of liver damage

Screen for viral cause of liver damage

Confirm viral cause of liver damage

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