Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background &amp; Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. In contrast to two predicted protein truncating mutations (PPTMs), homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n = 31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n = 30), and with two PPTMs (BSEP3/3; n = 77). We compared clinical presentation, native liver survival (NLS), and the effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (p &lt;0.001). Without siEHC, NLS in the BSEP1/3 group was similar to that in BSEP3/3, but considerably lower than in BSEP1/1 (at age 10 years: 38%, 30%, and 71%, respectively; p = 0.003). After siEHC, BSEP1/3 and BSEP3/3 were associated with similarly low NLS, while NLS was much higher in BSEP1/1 (10 years after siEHC, 27%, 14%, and 92%, respectively; p &lt;0.001). Conclusions: Individuals with BSEP deficiency with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as those with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment. Impact and implications: This manuscript defines the clinical features and prognosis of individuals with BSEP deficiency involving the combination of one relatively mild and one very severe BSEP deficiency mutation. Until now, it had always been assumed that the mild mutation would be enough to ensure a relatively good prognosis. However, our manuscript shows that the prognosis of these patients is just as poor as that of patients with two severe mutations. They do not respond to biliary diversion surgery and will likely not respond to the new IBAT (ileal bile acid transporter) inhibitors, which have recently been approved for use in BSEP deficiency.</p

Genotype-phenotype relationships of truncating mutations, p.E297G and p.D482G in bile salt export pump deficiency

Background & Aims: Bile salt export pump (BSEP) deficiency frequently necessitates liver transplantation in childhood. Homozygous p.D482G or p.E297G mutations are associated with relatively mild phenotypes, responsive to surgical interruption of the enterohepatic circulation (siEHC), in contrast to patients with two predicted protein truncating mutations (PPTM). The phenotype of patients with a compound heterozygous genotype of one p.D482G or p.E297G mutation and one PPTM has remained unclear. We aimed to assess their genotype-phenotype relationship. Methods: From the NAPPED database, we selected patients with homozygous p.D482G or p.E297G mutations (BSEP1/1; n=31), with one p.D482G or p.E297G, and one PPTM (BSEP1/3; n=30), and with two PPTMs (BSEP3/3; n=77). We compared presentation, native liver survival (NLS), and effect of siEHC on NLS. Results: The groups had a similar median age at presentation (0.7-1.3 years). Overall NLS at age 10 years was 21% in BSEP1/3 vs. 75% in BSEP1/1 and 23% in BSEP3/3 (P<0.001). Without siEHC in their follow-up, NLS of BSEP1/3 was similar to BSEP3/3 patients, but considerably lower than BSEP1/1 patients (at age 10 years: 38%, 30%, and 71%, resp; P=0.003). After siEHC, BSEP1/3 and BSEP3/3 patients had similarly low NLS, while this was much higher in BSEP1/1 patients (10 years after siEHC, 27%, 14%, and 92%, resp.; P<0.001). Conclusions: BSEP deficiency patients with one p.E297G or p.D482G mutation and one PPTM have a similarly severe disease course and low responsiveness to siEHC as patients with two PPTMs. This identifies a considerable subgroup of patients who are unlikely to benefit from interruption of the enterohepatic circulation by either surgical or ileal bile acid transporter inhibitor treatment

Safety and Feasibility Report of Robotic-assisted Left Lateral Sectionectomy for Pediatric Living Donor Liver Transplantation: A Comparative Analysis of Learning Curves and Mastery Achieved with the Laparoscopic Approach

Background. There is a growing interest in left lateral sectionectomy for donor hepatectomy. No data are available concerning the safety of the robotic (ROB) approach. Methods. A retrospective comparative study was conducted on 75 consecutive minimally invasive donor hepatectomies. The first 25 ROB procedures performed from November 2018 to July 2019 were compared with our first (LAP1) and last 25 (LAP2) laparoscopic cases performed between May 2013 and October 2018. Short-term donors and recipients' outcomes were analyzed. Results. No conversions were noticed in ROB whereas 2 conversions (8%) were recorded in LAP1 and none in LAP2. Blood loss was significantly less in ROB compared with LAP1 (P ≤ 0.001) but not in LAP2. Warm ischemia time was longer in ROB (P ≤ 0.001) with respect to the other groups. Operative time was similar in the 3 groups (P = 0.080); however, the hospital stay was shorter in ROB (P = 0.048). The trend in operative time in ROB was significantly shorter compared to LAP1 and LAP2: linear R20.478, P≤0.001; R20.012, P = 0.596; R30.004, P = 0.772, respectively. Donor morbidity was nihil in ROB, similar in LAP1 and LAP2 (n=3%-12%; P = 0.196). ROB procedures required less postoperative analgesia (P = 0.002). Recipient complications were similar for all groups (P = 0.274), and no early retransplantations were recorded. Conclusions. Robotic left lateral sectionectomy for donor hepatectomy is a safe procedure with results comparable to the laparoscopy in terms of donor morbidity and overall recipients' outcome when the procedure is performed by experts. Certainly, its use is currently very limited

Large for size in pediatrics liver transplant using left lateral segment grafts: A single center experience

Background: There are still controversies in using the large left lateral segment in pediatrics LT, with the possibility of the problem of LFS grafts, and the use of monosegmental or reduced liver grafts in small infants. This study aimed to evaluate our experience with LFSG in pediatrics LT. Methods: A cohort retrospective analysis was conducted including pediatric recipients who underwent LT between January 2011 and October 2019. We compared recipients with GRWR ≥ 4% (LFS) vs GRWR < 4% as an average for size grafts. Results: There were 331 pediatric LT, 74 patients with GRWR ≥ 4%, and 257 patients with GRWR < 4%. In the group of LFS grafts, temporary abdominal closure by silicon patch was done in 39 patients (52.7%), 2 patients (2.7%) had postoperative HAT, 3 patients (4.1%) early PVT, 1 patient (1.3%) bile leak, and 3 patients (4.1%) had wound infection, with no significant difference in these complications between the 2 groups. In patients with LFS- grafts, the 1-, 3-, 5-, and 7-year patients survival rates were 94.6%, 91.7%, 91.7%, and 91.7%, respectively, while the survival rates in patients of the other group were 96.1%, 92.6%, 91.9%, and 91.9%, respectively, with no significant difference (p =.85). Conclusion: Using LFS graft by left lateral segment in pediatric LT with potential delayed abdominal closure is a safe and feasible option with good outcomes and unnecessary need for graft reduction if performed by an experienced multidisciplinary team