To evaluate the utility of molecular genetic diagnostics in distinguishing between Wilson disease and Progressive Familial Intrahepatic Cholestasis type 3 (PFIC3) in patients with overlapping clinical features.

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive hepatic disorder of cholestasis caused by a defect in the ABCB4 on chromosome 7. Wilson disease (WD) is a neurodegenerative disease with neurologic and hepatic manifestations resulting from an autosomal recessive mutation of the ATP7B gene on chromosome 13.

An older female patient, aged 33 years, born to a consanguineous marriage, presented with a prolonged history of fatigue and elevated liver enzymes persisting for 2-3 years. She currently exhibits painless progressive jaundice (Bilirubin- 7.4 (6.6) mg/dl, SGOT/SGPT- 252/196, ALP/GGT- 100/107) and had significant family h/o jaundice with the death of a sibling due to jaundice at a young age. Biochemical testing (raised 24-hour urinary copper: 185 mcg) and a significant family history of jaundice in 2 siblings led to an initial consideration of a diagnosis of Wilson disease (WD), and the patient was started on oral D-Pencillamine. The patient didn’t show improvement in symptoms. So because of prominent cholestatic features on liver biopsy and diagnostic dilemma, a genetic study was planned and whole genome sequencing was sent, which revealed an ABCB4 mutation (suggestive of PFIC 3) and a negative ATP7B mutation. Cholestasis due to PFIC3 can cause elevated hepatic copper and increased urine copper excretion that overlap with current diagnostic criteria for Wilson disease. Molecular diagnostics are very useful for establishing the diagnosis of PFIC3.

This case highlights the critical role of genetic testing in differentiating WD and PFIC3. Elevated urinary copper levels can overlap in both conditions, emphasizing the need for precise molecular diagnostics. Early genetic evaluation in treatment failure of WD is crucial for appropriate management and prognosis.