Distinguishing between PFIC3, Wilson’s disease key for optimal outcomes
Systematic review looked at more than a dozen misdiagnosed cases
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Progressive familial intrahepatic cholestasis type 3 (PFIC3) can cause abnormalities in copper metabolism that mimic another condition, Wilson’s disease, and early distinction is key to achieving optimal outcomes, according to a review of more than a dozen misdiagnosed cases.
PFIC3 should be considered in suspected cases of Wilson’s disease that do not respond to chelation, a treatment to remove excess copper, and that do not show certain hallmarks of Wilson’s disease, such as rusty-brown or greenish rings in the eyes or changes in the copper-carrying protein ceruloplasmin.
“Genetic testing for ABCB4 mutations [the cause of PFIC3] should be considered in atypical Wilson’s disease presentations,” researchers wrote. “Further observational studies are warranted to estimate misdiagnosis frequency and guide diagnostic protocols.”
The study, “Diagnostic challenges in progressive familial intrahepatic cholestasis type 3 (PFIC3) misdiagnosed as Wilson’s disease: A systematic review,” was published in Advances in Clinical and Experimental Medicine.
PFIC3 caused by mutations in both copies of key gene
PFIC is a group of rare genetic diseases that interfere with the transport of the digestive fluid bile from the liver into the intestines, leading to stalled bile flow, or cholestasis. As bile builds up, it can damage the liver and leak into the bloodstream, causing itching, jaundice (yellowing of the skin and white parts of the eyes), and other cholestasis symptoms.
Left untreated, the disease can ultimately lead to liver failure, when a liver transplant becomes the only therapeutic option.
PFIC3 is caused by mutations in both copies of the ABCB4 gene, which encodes a protein that helps neutralize bile components to prevent damage to cells in the tubes that transport bile. Because excess copper is mainly removed from the body through bile in the intestines, stalled bile flow inside the liver causes copper to accumulate in the liver and enter the blood to be excreted in urine.
Wilson’s disease is a rare inherited disorder caused by mutations in both copies of the ATP7B gene, which encodes a copper-transporting protein.
“The elevated copper levels in PFIC3 lead to the mimicry of other diseases of impaired copper metabolism, such as Wilson’s disease,” the researchers wrote. “This misdiagnosis results in the administration of chelation therapy, to which PFIC3 patients do not respond, ultimately leading to disease progression and deterioration of liver function over time.”
Chelation therapy binds to copper in the body and helps remove it from the body.
Patients initially treated for Wilson’s disease
In this study, an international team conducted a systematic review of studies published up to May 2025 that reported cases of PFIC3 initially misdiagnosed as Wilson’s disease. A total of 11 case reports and case series, describing 16 patients, were included in the final analysis.
Patients (eight males, five females, and one undisclosed) had a mean age of 19 years (range, 2-35 years). Symptoms first appeared within the first two decades of life, and most commonly included elevated liver enzymes in the blood, an indicator of liver damage, enlarged liver and spleen, and increased copper levels in the liver and urine.
“The presentation of impaired copper metabolism and accumulation often leads to the consideration of WD [Wilson’s disease] as the likely [cause] of the observed liver disease in these patients,” the researchers wrote.
Based on their initial diagnosis, all patients were started on chelation treatment.
“However, evidence suggests that these patients do not benefit from chelation therapy, and liver function continues to deteriorate during the treatment period,” the researchers wrote.
Doctors realized the patients had PFIC3 after genetic tests for Wilson’s disease showed no ATP7B mutations and subsequent, often comprehensive genetic testing detected mutations in the ABCB4 gene.
The presentation of impaired copper metabolism and accumulation often leads to the consideration of WD [Wilson’s disease] as the likely [cause] of the observed liver disease in these patients.
The researchers also noted that, unlike people with Wilson’s disease, those with PFIC3 do not have rusty-brown or greenish rings in the eyes (known as Kayser-Fleischer rings) and typically have normal levels of ceruloplasmin, a copper-carrying protein, in the blood.
Once patients were correctly diagnosed with PFIC3, they were switched to ursodeoxycholic acid (UDCA), a first-line treatment for PFIC marketed as Actigall and Urso in the U.S. and available as generics. Most improved with UDCA treatment, with no signs of liver disease progression. Still, a liver transplant was necessary in a few cases.
Although most studies clearly described diagnosis and treatment, some lacked full medical histories or follow-up details. This limits how strongly results can be generalized, but the overall pattern was consistent: PFIC3 can mimic Wilson’s disease and lead to incorrect treatment.
Recognizing PFIC3 sooner allows timely use of UDCA and prevents unnecessary chelation, which “can also contribute to unnecessary treatment-related adverse effects and delayed liver transplantation,” the team wrote.
“Additional retrospective observational studies are warranted to ascertain the frequency with which PFIC3 is misdiagnosed as WD,” the researchers wrote. “This will facilitate the identification of diagnostic challenges and contribute to the development of diagnostic guidelines and protocols.”
