Excessive copper in PFIC3 may lead to misdiagnosis: Case report
Genetic testing ultimately led to PFIC diagnosis in 12-year-old
Excessive copper levels in the body led to an initial misdiagnosis of Wilson disease, a rare condition marked by copper buildup in the liver and other organs, in a 12-year-old boy who was later found to have progressive familial intrahepatic cholestasis type 3 (PFIC3), according to a case report from India.
When appropriate treatment for Wilson disease did not ease the boy’s symptoms, he underwent comprehensive genetic testing, revealing a PFIC3-causing mutation in the ABCB4 gene.
Prior to the boy’s case, there had been five case reports documenting six patients initially diagnosed with Wilson disease based on biochemical tests and later diagnosed with PFIC3 after genetic testing, the team noted.
“The diagnostic odyssey, therapeutic interventions, and outcome of this case underscore the intricate interplay between clinical suspicion, investigative strategies, and the pivotal role of genetic testing to elucidate rare liver disorders in children,” the researchers wrote.
The study, “Progressive familial intrahepatic cholestasis 3 Camouflaging as Wilson disease in a 12-year-old: a diagnostic Odyssey,” was published in Gastroenterology and Hepatology From Bed to Bench.
‘A diagnostic challenge’
PFIC refers to a group of rare genetic liver diseases that occur when liver cells have problems producing and/or secreting bile, a digestive fluid that flows through a series of bile ducts to the intestines.
As a result, PFIC patients experience intrahepatic cholestasis, a condition in which bile flow is slowed or stalled inside the liver. Bile then builds up, causing liver damage that can ultimately scar the liver and cause organ failure.
Patients experience symptoms, including itching, dark urine, and jaundice, or yellowing of the skin and whites of the eyes, early in life.
PFIC3 is caused by mutations in the ABCB4 gene that result in a deficient production of a working MDR3 protein, which is involved in transporting compounds that neutralize bile components to prevent damage to bile duct cells.
In rare instances, PFIC3 “can mimic [Wilson disease] clinically and biochemically thus posing a diagnostic challenge for clinicians,” the researchers wrote.
Wilson disease is a rare disease caused by mutations in the ATP7B gene that results in excessive copper levels in several organs, mainly the liver, brain, and eyes. The condition can, therefore, result in certain symptoms that are shared with other liver diseases such as PFIC.
Certain cholestatic diseases, including PFIC3, have been shown to cause copper buildup throughout the body and result in abnormal copper test results.
“The suggested cause of the secondary copper overload in cholestatic liver disorders are the disturbances of copper transport via bile caused by duct collapse,” the researchers wrote.
The team described the case of a 12-year-old boy with PFIC3 who was initially misdiagnosed with Wilson disease due to the presence of excessive copper levels.
The boy came to the researchers’ pediatric hepatology unit due to worsening abdominal distension for the previous two months and swelling in the lower limbs for the previous two weeks. His urine had shown yellowish discoloration for three months.
Physical examination showed an enlarged liver and spleen, mild pallor and jaundice, impaired growth, swelling of the feet and ankles, and ascites, or buildup of fluid in the abdomen — all signs of potential liver damage. However, he did not have itching.
Blood work showed high levels of several liver damage markers and mildly elevated markers of cholestasis, like alkaline phosphatase and gamma-glutamyl transferase. Further scans revealed spleen abnormalities and liver stiffness suggestive of cirrhosis, or permanent liver scarring.
While the boy tested negative for markers of autoimmune diseases or viral infections that could cause his liver disease, he had low blood levels of ceruloplasmin, a major copper-carrying protein, and high copper levels in his urine — two signs of Wilson disease.
These two signs were enough for the boy to have a Leipzig score, Wilson’s standard diagnostic measure, of 4, indicating the disease was very likely, and a diagnosis was made.
He was given chelation therapy, a treatment that aims to remove metal molecules from the blood. However, there were no signs of improvement after three months, and the boy’s liver function tests worsened.
Genetic testing found no mutations in the ATP7B gene, leading the researchers to conduct more comprehensive genetic testing that revealed a mutation (c.2906G>A) in both ABCB4 gene copies, confirming a PFIC3 diagnosis.
Chelation therapy was stopped, and he was given ursodeoxycholic acid (UCDA), the mainstay first-line therapy for PFIC and other forms of cholestasis, sold as Urso and Actigall. He also received vitamin supplementation and nutritional support.
His clinical status continued to worsen, “highlighting the progressive nature of PFIC-3,” the team wrote.
The boy was listed for liver transplant and was awaiting a suitable donor.
The researchers wrote that the Leipzig score “has certain caveats which may result in misdiagnosis as highlighted in our patient,” and that “alternative diagnosis and … advanced genetic testing” should be considered in patients “not showing improvement despite adequate chelation [treatment].”
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