Primary%20biliary%20cholangitis Diagnosis
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