Primary Biliary Cirrhosis (cont.)

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What are the criteria for a definitive diagnosis of PBC?

The criteria for a definitive diagnosis of PBC were established for the purpose of conducting clinical research, including therapeutic trials, on the disease. The criteria were designed to identify all patients with classic PBC and exclude any patient with a questionable diagnosis. A definitive diagnosis of PBC is established in a patient who has all three of the following:

  • Cholestatic liver tests (alkaline phosphatase and ggt elevated more than ALT and AST)
  • AMA positive at a titer of greater than or equal to 1:40
  • Diagnostic or compatible liver biopsy

What is the course of natural progression in PBC?

The course of natural progression (the natural history) in PBC can be divided into four clinical phases (preclinical, asymptomatic, symptomatic, and advanced). What's more, based on our knowledge of the clinical findings in patients with PBC, mathematical models have been developed that can predict the outcome (prognosis) for individual patients.

What are the sequential clinical phases of PBC?

The four sequential clinical (symptoms and tests) phases of PBC are:

  • Preclinical
  • Asymptomatic
  • Symptomatic
  • Advanced

It is important to realize that the time required to evolve from one clinical phase to another varies substantially among individuals. Also, be aware that these clinical phases are different from the pathological stages determined by the liver biopsy. Most importantly, since the diagnosis is often first made between the ages of 30 and 60 years and progression of the disease is usually so slow, PBC does not result in a reduced life expectancy in all patients.

The sequential phases in the natural progression of PBC without therapy
Phase Characteristics Duration
Preclinical
  • Absence of symptoms
  • Normal liver tests
  • AMA positive
Poorly defined; estimated as 2 to 10 years
Asymptomatic
  • Absence of symptoms
  • Abnormal liver tests
  • AMA positive
Indefinite in some patients; 2 to 20 years in others
Symptomatic
  • Symptoms
  • Abnormal liver tests
  • AMA positive
3 to 11 years
Advanced
  • Symptoms
  • Complications of cirrhosis
    and liver failure
  • Abnormal liver tests
  • AMA positive
0 to 2 years without liver transplant

Preclinical phase The first phase is characterized by the presence of AMA at a titer of greater than or equal to 1:40 in an adult without any abnormality of liver blood tests or any symptoms of liver disease. This phase is referred to as preclinical because there is usually no reason for people in this phase of the disease to see a physician or have testing. Furthermore, since screening tests for AMA are not routinely performed, only small numbers of such people have been identified. So, people with an AMA without symptoms or abnormal liver blood tests have been identified only as the result of research studies of autoantibodies in apparently healthy people.

However, even with only the isolated positive AMA, these people do appear to have PBC. This conclusion is based on the presence of diagnostic or compatible features on a liver biopsy and subsequent findings or clinical events during long-term observation. Thus, more than 80% of these individuals with only a positive AMA ultimately develop cholestatic liver blood tests followed by the typical symptoms of PBC.

After discovery of an isolated positive AMA test, the time before development of cholestatic liver tests ranged from 11 months to 19 years. The median time (the time at which 50% of the people had developed cholestatic liver tests) was 5.6 years. During 11 to 24 years of observation starting in the preclinical phase of 29 patients, 5 died. However, none of the five died as a result of liver disease and the median age at death was 78.

Asymptomatic phase: This phase is characterized by a positive AMA and cholestatic liver blood tests in a person without symptoms of liver disease. The incidental discovery of an elevated alkaline phosphatase is what most commonly leads to the diagnosis of PBC in this phase. The elevated alkaline phosphatase is usually discovered after testing the blood routinely or for another clinical reason.

The results of three large studies indicate that 40% of these asymptomatic patients will develop symptoms of liver disease within the next 6 years. Over and above that, another 33% of patients will likely develop symptoms between 6 and 12 years. Longer follow up is not available, but this asymptomatic phase may persist indefinitely in a minority of patients with PBC.

Symptomatic phase This phase is defined by a positive AMA, persistently abnormal liver blood tests, and the presence of symptoms of PBC. The duration of this phase among patients is also quite variable, lasting from 3 to 11 years.

Advanced phase In this phase, symptomatic patients develop the complications of cirrhosis and progressive liver failure. The duration of this phase ranges from months to 2 years. These patients are at risk of dying unless they undergo successful liver transplantation.

Medically Reviewed by a Doctor on 1/9/2014

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