Verena Keitel

Hereditary cholestasis comprises a broad spectrum of clinical phenotypes of varying severity. Severe forms such as progressive familial intrahepatic cholestasis (PFIC) mostly affect children with disease onset within their first years. Nevertheless, late-onset PFIC forms are increasingly diagnosed. Most adults present with less severe forms of hereditary cholestasis, often suffering from pruritus, gallstone disease, jaundice, or elevated liver enzymes. To identify the underlying genetic background and to rule out potential differential diagnoses, a broad genetic analysis like whole exome sequencing (WES) is recommended. Knowledge of the affected gene may have an impact not only on patient surveillance due to risk for disease progression or tumor development but also on potential therapeutic strategies. This case of the adult patient illustrates the importance of broad genetic analysis, which brought up the potentially relevant rare multidrug resistance protein 3 (MDR3) missense variant p.(Asn489Tyr) underlying the patient’s clinical phenotype of low phospholipid-associated cholelithiasis (LPAC). Patients with MDR3 disease may have an increased risk for cholangiocarcinoma (CCA) development and therefore need an individualized surveillance strategy. Most MDR3-affected patients benefit from life-long therapy with ursodeoxycholic acid (UDCA), which is well tolerated. Bezafibrate treatment can reduce pruritus, one of the main symptoms affecting the quality of life. Whether the administration of ileal bile acid transporter (IBAT) inhibitors is beneficial in adult patients with MDR3 disease is so far unknown.