Carriers of ABCB4 gene variants show a mild clinical course, but impaired quality of life and limited risk for cholangiocarcinoma

Abstract

Background and Aims Adenosine triphosphate‐binding cassette subfamily B member 4 (ABCB4) deficiency may lead to progressive familial intrahepatic cholestasis type 3 (PFIC3), biliary cirrhosis, low phospholipid‐associated cholelithiasis (LPAC), intrahepatic cholestasis of pregnancy (ICP), oral contraceptive‐induced cholestasis (CIC) or may remain asymptomatic. The long‐term course, quality of life and histology were investigated in ABCB4 deficiency. Methods Adult carriers of ABCB4 gene variants from two regional academic centres were analysed by history taking, electronic patient files, physical examination, blood analysis, abdominal ultrasound (US) and liver elastography. Patients completed a 36‐Item Short Form Health Survey (SF‐36) for quality of life and a Visual Analogue Scale (VAS) for pruritus. Available liver specimens were re‐classified according to the Nakanuma scoring system, so far validated for primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) only. Quality of life data were compared to published data of patients with PBC, PSC and the general population. Results Sixty‐seven patients were identified, 64 (96%) were alive at the time of analysis and 62 (93%) were (at some time) treated with ursodeoxycholic acid (UDCA). Two patients died of cholangiocarcinoma (CCA), and one of decompensated biliary cirrhosis. Three additional deaths of CCA were reported in first‐degree relatives. Transplant‐free survival was 91% (median follow‐up 14 years). Liver stiffness was normal (<6.3 kPa) in 75%, intrahepatic stones were detected at ultrasound (US) in 33% and microcalcifications in 22% of cases. Quality of life (n = 48) was lower than in the general population particularly in energy/fatigue and general health domains and comparable to that in PSC. Staging according to Nakanuma in 15 specimens reflected the clinical course. Conclusions ABCB4 deficiency has a mild clinical course, but impaired quality of life and limited risk of CCA. The Nakanuma scoring system appears feasible for histological evaluation in ABCB4 deficiency.

Cholestatic liver diseases of genetic etiology: Advances and controversies

“…[ 29 ] With increased availability and lower cost of genetic testing, it is likely that ABCB4 variants will be identified in more adults with idiopathic liver disease, optimizing care and counseling for these individuals and their family members, who may also be at risk of cholangiocarcinoma. [ 30 ]…”

Extrahepatic manifestations of progressive familial intrahepatic cholestasis syndromes: Presentation of a case series and literature review

“…42 Quality of life was reduced in ABCB4 variant carriers (n = 48) as compared to the general population on a 36-Item Short Form Health Survey (SF-36), particularly in energy/fatigue and general health domains, comparable to patients with primary sclerosing cholangitis (PSC). 42,43 Impaired bone density has been described in Abcb4 knockout mice. 44 In humans, reduced bone density appears to be a frequent feature of congenital biliary disease, although less so in Alagille syndrome, 45 and regular monitoring by dual-energy x-ray absorptiometry (DEXA) at 1-2 year intervals is recommended to prevent adverse outcomes, such as spine fractures.…”

“…The present article will describe and discuss this aspect in greater detail based on patients treated in our centres. Since larger case series on MDR3 disease have recently been published for both paediatric and adult patients, 33,41,42,54 we did not include an MDR3 case in this series.…”

Bile formation and secretion: An update

“…Mutations in MDR3 result in 4 clinical disorders: PIFC3 in children, low phospholipid-associated cholelithiasis, intrahepatic cholestasis of pregnancy and a progressive cholangiopathy in adults including drug-induced liver injury. 98,99 Deficiencies in MDR3 are often misdiagnosed, particularly in children. 100 Sequencing of cholestasis-related genes often results in genetic variants of unknown clinical significance, creating a need to assess their functional phenotype.…”