Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MdR3

Frider, Bernardo; Castillo, Alejandra Del; Gordo-Gilart, Raquel; Bruno, Andrés; Amante, Marcelo; Álvarez, Luis; Mathet, Verónica Lidia

doi:10.1016/s1665-2681(19)30771-9

Cited by 21 publications

(11 citation statements)

References 18 publications

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“…52 In 20% of patients with no disease-causing mutation, combinations of the common ABCB4 variant c.711A > T with two other common polymorphisms (c.175C > T ¼ rs2302387, c.504C > T ¼ rs1202283) were identified. 50 Patients with PFIC3 can be treated with intermediate to high doses of UDCA (up to 20 mg/kg body weight/day), 53 and bile acid treatment should be initiated in all patients, but response to treatment, in particular in children, is often only intermediate (i.e., without reaching normal liver enzyme activities or with ongoing symptoms) and disease progresses, and liver transplantation is needed in 60% of patients with PFIC3. 43 Overlapping features between PFIC3 and LPAC have been described, and in these cases severe homozygous variants cause PFIC3, whereas heterozygous variants are more likely to confer susceptibility to LPAC.…”

Section: Progressive Familial Intrahepatic Cholestasis Typementioning

confidence: 99%

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Reichert

2018

Semin Liver Dis

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ATP-binding cassette subfamily B member 4 (ABCB4) is a phospholipid translocator at the canalicular membrane of the hepatocyte, which “flops” phosphatidylcholine into bile. Dysfunction of this transporter due to ABCB4 gene variants can cause liver diseases and has been called ABCB4 deficiency. Several diseases including progressive familial intrahepatic cholestasis type 3 (PFIC3), low phospholipid-associated cholelithiasis (LPAC), a subgroup of patients developing intrahepatic cholestasis of pregnancy (ICP), drug-induced liver injury and chronic cholangiopathy with biliary fibrosis and cirrhosis were attributed to ABCB4 deficiency and characterized in the past decade. LPAC and ICP are usually caused by monoallelic variants, whereas patients affected by PFIC3 are homozygous or compound heterozygous carriers of ABCB4 variants. Treatment with ursodeoxycholic acid is often effective, but as the more severe forms of ABCB4 deficiency progress, nevertheless, new diagnostic and therapeutic approaches are warranted. Current functional classifications for ABCB4 deficiency–associated mutations can guide the development of novel genotype–based targeted pharmacotherapies for these conditions. Recently, increasing evidence from genome-wide association studies is emerging on associations of ABCB4 variants with hepatobiliary malignancies.

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Section: Progressive Familial Intrahepatic Cholestasis Typementioning

confidence: 99%

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Reichert

2018

Semin Liver Dis

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“…Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) represent distinct but rare inherited cholestatic disorders that display wide variability in degrees of liver fibrosis, progression of disease, and time to transplant. ( 1‐8 ) Although genetic analysis is emphasized for either diagnosis, percutaneous liver biopsy has historically been an essential tool for histologic staging and monitoring progression of disease. ( 9,10 ) Risks of liver biopsies are relatively low; however, there is still potential for bleeding, patient discomfort, infection, and side effects of anesthesia.…”

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confidence: 99%

Biopsy Validated Study of Biomarkers for Liver Fibrosis and Transplant Prediction in Inherited Cholestasis

Shiau

Guffey²,

Loomes

et al. 2020

Hepatol. Commun.

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Alagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) are inherited cholestatic disorders with risk of developing end-stage liver disease requiring liver transplantation (LT). We investigated aspartate aminotransferase-to-platelet ratio index (APRI), Fibrosis-4 score (FIB-4), and conjugated bilirubin as biomarkers to assess fibrosis severity and risk for LT among children with ALGS and PFIC. This multicenter, cross-sectional study included 64 children with ALGS or PFIC (per genetics or strict clinical criteria) with APRI, FIB-4, and conjugated bilirubin levels collected within ±90 days of their most recent liver biopsy. A single, blinded pathologist staged all biopsies (metavir; F0-F2: nonsevere, F3-F4: severe). Logistic regression and area under the receiver operating characteristic curve analysis (AUC) were used to assess biomarker associations with fibrosis severity and risk for LT. In ALGS, only APRI distinguished F3-F4 (AUC 0.72, P = 0.012), with a cutoff greater than 2.97 demonstrating a sensitivity of 61.5% (95% confidence interval 0.32, 0.86) and specificity of 81.5% (0.62, 0.94). In ALGS, a 50% increase of APRI increased the odds of F3-F4 by 1.31-fold (1.04, 1.65; P = 0.023). In ALGS, APRI (AUC 0.87; P < 0.001) and FIB-4 (AUC 0.84; P < 0.001) were able to predict risk for LT. In PFIC, only APRI distinguished F3-4 (AUC 0.74, P = 0.039), with a cutoff greater than 0.99 demonstrating a sensitivity of 80% (0.44, 0.98) and specificity of 64.3% (0.35, 0.87). In PFIC, only FIB-4 was able predict risk for LT (AUC 0.80; P = 0.002). In ALGS or PFIC, conjugated bilirubin could not distinguish F3-F4 or predict risk for LT. Conclusion: This liver biopsy-validated study suggests that APRI is able to distinguish F3-F4 from F0-F2 in ALGS and PFIC. APRI and FIB-4 may also serve as predictors of risk for LT in ALGS (APRI and FIB-4) and PFIC (FIB-4). (Hepatology Communications 2020;4:1516-1526). A lagille syndrome (ALGS) and progressive familial intrahepatic cholestasis (PFIC) represent distinct but rare inherited cholestatic disorders that display wide variability in degrees of liver fibrosis, progression of disease, and time to transplant. (1-8) Although genetic analysis is emphasized for either diagnosis, percutaneous liver biopsy has historically been an essential tool for histologic staging and monitoring progression of disease. (9,10) Risks of liver biopsies are relatively low; however, there is still potential for bleeding, patient discomfort, infection, and side effects of anesthesia. (10,11) An autosomal dominant disorder, ALGS is characterized by bile duct paucity and often presents with extrahepatic clinical features such as vertebral abnormalities, renal or cardiac disease, posterior embryotoxon,

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“…It may turn out that achieving a therapeutic effect via gene therapy could be feasible in only a subset of the patient population, although we believe most if not all patients in need of treatment could stand to benefit. Along the same lines, 50% of PFIC3 patients do not respond to the current standard of care with UDCA, with those that maintain a certain level of MDR3 activity being the ones that most benefit from this therapy 30,31 . If AAV-mediated gene restoration can increase MDR3 activity even only slightly in patients that do not currently benefit from UDCA, it may be sufficient to make them UDCA-therapy responders.…”

Section: Discussionmentioning

confidence: 98%

Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model

Weber¹,

Odriozola

Martínez-García

et al. 2019

Nat Commun

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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4−/− mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.

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Reversal of advanced fibrosis after long-term ursodeoxycholic acid therapy in a patient with residual expression of MdR3

Cited by 21 publications

References 18 publications

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

ABCB4 Gene Aberrations in Human Liver Disease: An Evolving Spectrum

Biopsy Validated Study of Biomarkers for Liver Fibrosis and Transplant Prediction in Inherited Cholestasis

Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model

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