primary%20biliary%20cholangitis
PRIMARY BILIARY CHOLANGITIS

Primary biliary cholangitis (formerly primary biliary cirrhosis) is a chronic, progressive, autoimmune, cholestatic liver disease more common in middle-aged women. It is characterized by destruction of small to medium bile ducts leading to cholestasis and frequently, end-stage liver disease.
Diagnostic features are chronic biochemical cholestasis, presence of antimitochondrial antibodies and the characteristic liver biopsy findings.


 

Diagnosis

  • At present, the diagnosis is most often made in an asymptomatic patient who presents with abnormal lab results (eg abnormal liver biochemistry profile and/or the presence of AMA) on a routine checkup or as part of workup for an associated illness

Physical Examination

  • In the early stages of disease, findings may be normal
  • Abnormal findings increase as the disease progresses

Portal Hypertension

  • Patients may present initially with variceal hemorrhage secondary to portal hypertension, which may be of a cirrhotic or non-cirrhotic nature
  • Anemia may develop from occult bleeding of varices

Stigmata of Liver Disease

  • The following may be present: Spider nevi, palmar erythema, muscle wasting, peripheral edema, parotid gland enlargement, gynecomastia, testicular atrophy, Dupuytren contracture

Signs of Malabsorption of Fat-Soluble Vitamins

  • Results from insufficient biliary secretion of bile acids
  • Neurological impairment and electromyograph changes secondary to vitamin E malabsorption
  • Rarely, night blindness and osteomalacia are present in PBC patients

Other Possible Findings in Patients with PBC

  • Xanthomata
    • Cholesterol deposits in the skin, they often occur around the eyes but may also be found on the palms, buttocks and heels
    • May be associated with hypercholesterolemia and hyperlipidemia that occur with PBC 
  • Hyperpigmentation, splenomegaly, hematemesis, melena, abdominal fullness
  • Urinary tract infections
    • Usually asymptomatic but recurrent
    • Etiologic agents are usually Gram-negative organisms, ie Enterobacteriaceae
    • Cross reactivity between antigens on the bacterial wall and cell mitochondria is postulated to be the cause

Signs of Metabolic Bone Disease

  • A patient with PBC may present with osteoporosis while remaining asymptomatic from the liver disease
    • An elevated alkaline phosphatase (ALP) level in a patient with osteoporosis should alert a physician of the possibility of PBC 
  • PBC patients may have associated pancreatic insufficiency and celiac disease which may aggravate vitamin D malabsorption, contributing to osteoporosis
  • Decreased osteoblastic activity and increased osteoclastic activity lead to development of osteoporosis in PBC patients

Laboratory Tests

  • At least 2 of the following criteria should be present for the diagnosis of PBC: Biochemical cholestasis with elevated ALP, presence of AMA, and the characteristic liver biopsy findings

Serum Chemistry

Alkaline Phosphatase (ALP)

  • High ALP of hepatic origin signifying intrahepatic cholestasis is the most common biochemical abnormality in PBC 
    • >1.5 times the upper limit of normal (ULN) for >24 weeks
  • Response to therapy may be seen with an ALP level <2x ULN with treatment 

Gamma-Glutamyl Transpeptidase (GGT)

  • Levels are determined to confirm hepatic origin of high ALP levels

Bilirubin

  • Elevated bilirubin levels occur late in the course of disease
  • High bilirubin levels signify disease progression and are used as a predictor of prognosis

Cholesterol

  • Total serum cholesterol levels may go up as a result of chronic cholestasis
  • The high-density lipoprotein (HDL) fraction is increased, which is the reason why PBC patients do not have a higher risk for atherosclerosis

Antimitochondrial Antibodies (AMA)

  • The presence of AMA in the serum, often in high titers (≥1:40), is the hallmark of PBC
  • AMA, which target different mitochondrial enzymes, are found in up to 95% of PBC patients
  • The simplest test for detection of AMA is immunofluorescence, but newer tests eg enzyme-linked immunosorbent assay (ELISA) and immunoblotting are more specific and sensitive
  • Sensitivity and specificity of AMA for PBC is >95%
  • Patients with an elevated ALP and normal hepatobiliary ultrasound should undergo serum testing for AMA

Imaging

Hepatobiliary Ultrasound (US)

  • US of the liver and biliary tract should be done to differentiate intrahepatic versus extrahepatic cholestasis
  • Bile ducts appear normal in patients with PBC
  • A dilated biliary system characterizes biliary obstruction and is not consistent with PBC 
  • PBC patients may have nonspecific findings on US, eg increased echogenicity of liver parenchyma and portal lymphadenopathy
  • Portal hypertension may be present, as evidenced by a nodular liver appearance, ascites and intra-abdominal varices

Transient Elastography

  • Accurate in diagnosing advanced fibrosis in PBC patients 
  • May be used in assessing prognosis and response to therapy 
    • Also used to risk-stratify patients: Liver stiffness progression is a predictor of poor outcome

Liver Biopsy

  • Findings on liver biopsy for PBC are very specific, especially in non-cirrhotic patients: Nonsuppurative destructive cholangitis and interlobular destruction of the bile ducts  
  • A liver biopsy is essential in the following patients to confirm or rule out PBC:
    • Low-titer (<1:40) or negative AMA  
    • Transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase (AST)] are prominently increased 
    • Patient with a history of taking potentially hepatotoxic drugs
  • In contrast, a patient positive for AMA with a titer ≥1:40 plus typical symptoms and biochemical derangements may not require a liver biopsy to make the diagnosis of PBC
    • However, the liver biopsy may provide additional information about the stage of the illness and the patient’s prognosis 
  • For biopsy findings to provide a precise evaluation of bile duct damage, it is very important that the specimen has an adequate number (at least 10-15) of portal tracts 
  • Not to be used to monitor patient’s response to therapy

Disorders Associated with PBC

  • Sicca syndrome
    • Symptoms include xerophthalmia, xerostomia, dental caries, dysphagia, dyspareunia and tracheobronchitis
    • Investigate symptoms by direct questioning
    • Sicca symptoms are present in about ¾ of PBC patients
  • Thyroid dysfunction
    • Thyroid disease is also of autoimmune origin
    • Symptoms usually precede diagnosis of PBC  
  • CREST (C-calcinosis cutis, R-Raynaud’s phenomena, E-esophageal dysmotility, S-sclerodactyly, T-telangiectasia) syndrome
    • Complete form is rarely seen in PBC patients
    • Raynaud’s syndrome by itself is seen more often and is more problematic for patients who live in cold climates
  • Rheumatoid factor is detected in 25% of PBC patients
    • Symptomatic arthritis is less common
  • Celiac disease and inflammatory bowel disease (IBD) occur rarely

Further Workup for AMA-Negative Patients with Clinical Suspicion of PBC

  • Certain patients may have clinical, biochemical and histologic evidence of PBC but consistently test negative for AMA 
    • Further workup should be considered in patients negative for AMA but with high ALP and normal biliary US
  • These patients most likely do have PBC but have an antibody profile more consistent with autoimmune hepatitis (AIH), a variant known as PBC/AIH overlap
    • In patients with PBC/AIH overlap, the predominant histological pattern of injury should be targeted for treatment 
  • Patients with the above characteristics should undergo further tests

Antinuclear Antibodies (ANA) and/or Smooth Muscle Antibodies (SMA)

  • AMA-negative patients clinically suspicious for PBC should be tested for ANA and SMA
    • Nearly half of PBC patients may be positive for ANA and SMA
  • High titers of ANA and/or SMA are more common in AIH, but may be present in AMA-negative patients with a high clinical suspicion of PBC 
    • In these patients, a thorough review of liver biochemistry and biopsy findings is imperative in making a correct diagnosis; patients with AIH have a serum ALT level of >5x ULN

Immunoglobulins (Ig)

  • Testing for the immunoglobulin pattern is probably only needed in unconvincing cases
  • A high level of IgM is usual in PBC
  • IgA levels are usually normal but PBC has been found in patients who are IgA deficient
  • In AMA-negative PBC, however, the IgG fraction is more likely to be elevated than the IgM fraction
    • AIH has serum IgG levels >2x ULN

Imaging

  • Magnetic resonance cholangiopancreatography (MRCP) can be performed in patients with unexplained cholestasis  
  • Endoscopic US, an alternative to MRCP, can be used in evaluating distal biliary disease

Liver Biopsy

  • May be done in patients with unexplained intrahepatic cholestasis after serologic screening and additional imaging     
  • Considered in ruling out concomitant AIH in PBC patients with highly elevated ALT and/or IgG 
  • Not required in diagnosing AMA-negative PBC if other criteria, eg cholestatic liver tests and PBC-specific autoantibodies (sp100 or gp210), are met
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