Many people living with primary biliary cholangitis (PBC) do not completely respond to ursodeoxycholic acid (UDCA) therapy. According to new research recently published in Human Pathology, many of these individuals have advanced liver damage that traditional staging systems miss, but can be detected with a new staging system.
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In this analysis, the authors compared liver biopsies from 33 people who did not respond to UDCA therapy with those of 152 people who had not yet started UDCA therapy. These individuals were further classified by severity using traditional liver disease staging systems and a new staging system the authors had previously designed, which they called the Nakanuma system.
With the Nakanuma system, researchers score PBC severity based on the extent of liver scarring, bile duct loss and the presence of copper-binding protein granules, an indicator of impaired bile flow (cholestasis). An overall score is assigned from zero (no disease) to four (advanced disease).
In comparison, traditional staging systems such as the Scheuer and Ludwig classifications score individuals mainly based on inflammation and scarring patterns. These systems overlook bile duct loss and cholestasis, which impact liver function even before cirrhosis appears.
By focusing solely on fibrosis, these staging methods may miss key risks. The authors noted that when people with PBC were assessed using these traditional systems, they received lower PBC severity scores compared to when the Nakanuma system took bile duct loss and cholestasis into account.
“The Scheuer and Ludwig classifications could not reflect these features, but the Nakanuma classification accurately and precisely illuminated the pathological condition of PBC,” the study’s authors wrote.
Significant differences between the groups stood out. Researchers found that 82% of biopsies from individuals who did not respond to UDCA therapy met Nakanuma criteria for stage four PBC, indicating advanced liver injury. In contrast, older systems such as Scheuer and Ludwig often classified the same biopsies as milder stages.
Compared with people who had never taken UDCA, the UDCA-nonresponders group showed more bile duct loss, greater copper-binding protein deposits and higher levels of inflammation. About half had no detectable bile ducts in the samples — a pattern called ductopenia, which can drive ongoing liver damage even without cirrhosis.
These findings may help clarify why some second-line treatment trials show mixed results when participants already have extensive bile duct loss. By revealing patterns of cholestatic injury that older systems overlook, the Nakanuma classification could help doctors better gauge disease activity and researchers refine patient selection in future trials. Recognizing these features earlier may help guide new therapies for people whose PBC does not fully respond to UDCA and bring care one step closer to preventing irreversible liver injury.
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