primary%20biliary%20cirrhosis
PRIMARY BILIARY CIRRHOSIS

Primary biliary cirrhosis is 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.
At present, the diagnosis is most often made in an asymptomatic patient who presents with abnormal lab results on a routine checkup or as part of workup for an associated illness.


 

Diagnosis

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

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 w/ 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

  • 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 & electromyograph changes secondary to vitamin E (Vit E) malabsorption
  • Rarely, night blindness & osteomalacia are present in primary biliary cirrhosis (PBC) patients

Other Possible Findings in Patients w/ Primary Biliary Cirrhosis (PBC)

  • Xanthomata
    • Cholesterol deposits in the skin, they often occur around the eyes but may also be found on the palms, buttocks & heels
    • May be associated w/ hypercholesterolemia & hyperlipidemia that occurs w/ primary biliary cirrhosis (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 & cell mitochondria is postulated to be the cause

Signs of Metabolic Bone Disease

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

Laboratory Tests

Serum Chemistry

  • High alkaline phosphatase (ALP) of hepatic origin signifying intrahepatic cholestasis is the most common biochemical abnormality in primary biliary cirrhosis (PBC)
    • >1.5 times the upper limit of normal for >24 weeks

Gamma-Glutamyl Transpeptidase

  • Levels are determined to confirm hepatic origin of high alkaline phosphatase (ALP) levels

Bilirubin

  • Elevated bilirubin levels occur late in the course of disease
  • High bilirubin levels signify disease progression & 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 primary biliary cirrhosis (PBC) patients do not have a higher risk for atherosclerosis

Imaging

Hepatobiliary Ultrasound (US)

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

Screening

Antimitochondrial Antibodies (AMA)

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

Liver Biopsy

  • Findings on liver biopsy for primary biliary cirrhosis (PBC) are very specific, esp in non-cirrhotic patients: Nonsuppurative destructive cholangitis & interlobular destruction of the bile ducts
  • A liver biopsy is essential in the following patients to confirm or rule out primary biliary cirrhosis (PBC):
    • Low-titer (<1:40) or negative antimitochondrial antibodies (AMA)
    • Transaminases [alanine aminotransferase (ALT) & aspartate aminotransferase (AST)] are prominently increased
    • Patient w/ a history of taking potentially hepatotoxic drugs
  • In contrast, a patient positive for antimitochondrial antibodies (AMA) w/ a titer ≥1:40 plus typical symptoms & biochemical derangements may not require a liver biopsy to make the diagnosis of primary biliary cirrhosis (PBC)
    • However, the liver biopsy may provide additional information about the stage of the illness & 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 of portal tracts

Disorders Associated with Primary Biliary Cirrhosis (PBC)

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

Further Workup for AMA-Negative Patients w/ clinical suspicion of Primary Biliary Cirrhosis (PBC)

Further Workup for Antimitochondrial Antibody (AMA)-Negative Patients w/ High Alkaline Phosphatase (ALP) & Normal Biliary Ultrasound (US)

  • Certain patients may have clinical, biochemical & histologic evidence of primary biliary cirrhosis (PBC) but consistently test negative for antimitochondrial antibody (AMA)
  • These patients most likely do have primary biliary cirrhosis (PBC) but have an antibody profile more consistent w/ autoimmune hepatitis, a variant known as primary biliary cirrhosis (PBC)-autoimmune hepatitis overlap
  • Patients w/ the above characteristics should undergo further tests

Antinuclear antibodies (ANA) &/or smooth muscle antibodies (SMA)

  • Antimitochondrial antibody (AMA)-negative patients clinically suspicious for primary biliary cirrhosis (PBC) should be tested for antinuclear antibodies (ANA) & smooth muscle antibodies (SMA)
    • One-third of primary biliary cirrhosis (PBC) patients may be positive for antinuclear antibodies (ANA) & smooth muscle antibodies (SMA)
  • High titers of antinuclear antibodies (ANA) &/or smooth muscle antibodies (SMA) are more common in autoimmune hepatitis, but may be present in antimitochondrial antibody (AMA)-negative patients w/ a high clinical suspicion of primary biliary cirrhosis (PBC)
    • In these patients, a thorough review of liver biochemistry & biopsy findings is imperative in making a correct diagnosis; patients w/ autoimmune hepatitis have a serum alanine aminotransferase level of >5x upper limit of normal

Immunoglobulins

  • Testing for the immunoglobulin pattern is probably only needed in unconvincing cases
  • A high level of immunoglobulin M (IgM) is usual in primary biliary cirrhosis (PBC)
  • Immunoglobulin A (IgA) levels are usually normal but primary biliary cirrhosis (PBC) has been found in patients who are IgA deficient
  • In antimitochondrial antibody (AMA)-negative primary biliary cirrhosis (PBC), however, the immunoglobulin G (IgG) fraction is more likely to be elevated than the IgM fraction
    • Autoimmune hepatitis has serum IgG levels >2x upper limit of normal

Liver Biopsy

  • Should be performed if not yet done
    • Moderate or severe periseptal or periportal, lymphocytic, piecemeal necrosis is seen in patients w/ autoimmune hepatitis
Digital Edition
Asia's trusted medical magazine for healthcare professionals. Get your MIMS Gastroenterology - Malaysia digital copy today!
DOWNLOAD
Editor's Recommendations
Most Read Articles
01 May 2014

New drug applications approved by US FDA as of 15-30 May which includes New Molecular Entities (NMEs) and new biologics. It does not include Tentative Approvals. Supplemental approvals may have occurred since the original approval date.

28 Apr 2017
Silymarin does not appear to be significantly better than placebo in reducing disease activity by 30 percent or more in patients with nonalcoholic steatohepatitis (NASH), according to the results of a trial.
28 Aug 2017
Relamorelin appears to be effective in reducing core symptoms of gastroparesis, as well as improving overall composite symptom severity score and accelerated gastric emptying, in diabetic patients with moderate to severe gastroparesis, according to the results of a phase IIB trial.
Chistopher S Pokorny, 01 Dec 2013

Angela, a 28-year-old woman who is 14 weeks pregnant, presents to her GP with a 2-month history of intermittent rectal bleeding. Over this period, she has been passing bright blood on to her toilet paper, and at times into the toilet bowl. In addition, her stools are looser than in the past, and she reports occasional urgency. There has been no abdominal pain or weight loss. Her general health is good, and she is not taking any regular medications. There is no relevant family history.