Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Biallelic Mutations in Tetratricopeptide Repeat Domain 26 (Intraflagellar Transport 56) Cause Severe Biliary Ciliopathy in Humans.

BACKGROUND AND AIMS: The clinical consequences of defective primary cilium (ciliopathies) are characterized by marked phenotypic and genetic heterogeneity. Although fibrocystic liver disease is an established ciliopathy phenotype, severe neonatal cholestasis is rarely recognized as such. APPROACH AND RESULTS: We describe seven individuals from seven families with syndromic ciliopathy clinical features, including severe neonatal cholestasis (lethal in one and necessitating liver transplant in two). Positional mapping revealed a single critical locus on chromosome 7. Whole-exome sequencing revealed three different homozygous variants in Tetratricopeptide Repeat Domain 26 (TTC26) that fully segregated with the phenotype. TTC26 (intraflagellar transport [IFT] 56/DYF13) is an atypical component of IFT-B complex, and deficiency of its highly conserved orthologs has been consistently shown to cause defective ciliary function in several model organisms. We show that cilia in TTC26-mutated patient cells display variable length and impaired function, as indicated by dysregulated sonic hedgehog signaling, abnormal staining for IFT-B components, and transcriptomic clustering with cells derived from individuals with closely related ciliopathies. We also demonstrate a strong expression of Ttc26 in the embryonic mouse liver in a pattern consistent with its proposed role in the normal development of the intrahepatic biliary system. CONCLUSIONS: In addition to establishing a TTC26-related ciliopathy phenotype in humans, our results highlight the importance of considering ciliopathies in the differential diagnosis of severe neonatal cholestasis even in the absence of more typical features.

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.

Genotype correlates with the natural history of severe bile salt export pump deficiency.

BACKGROUND & AIMS: Mutations in ABCB11 can cause deficiency of the bile salt export pump (BSEP), leading to cholestasis and end-stage liver disease. Owing to the rarity of the disease, the associations between genotype and natural history, or outcomes following surgical biliary diversion (SBD), remain elusive. We aimed to determine these associations by assembling the largest genetically defined cohort of patients with severe BSEP deficiency to date. METHODS: This multicentre, retrospective cohort study included 264 patients with homozygous or compound heterozygous pathological ABCB11 mutations. Patients were categorized according to genotypic severity (BSEP1, BSEP2, BSEP3). The predicted residual BSEP transport function decreased with each category. RESULTS: Genotype severity was strongly associated with native liver survival (NLS, BSEP1 median 20.4 years; BSEP2, 7.0 years; BSEP3, 3.5 years; p <0.001). At 15 years of age, the proportion of patients with hepatocellular carcinoma was 4% in BSEP1, 7% in BSEP2 and 34% in BSEP3 (p = 0.001). SBD was associated with significantly increased NLS (hazard ratio 0.50; 95% CI 0.27-0.94: p = 0.03) in BSEP1 and BSEP2. A serum bile acid concentration below 102 µmol/L or a decrease of at least 75%, each shortly after SBD, reliably predicted NLS of ≥15 years following SBD (each p <0.001). CONCLUSIONS: The genotype of severe BSEP deficiency strongly predicts long-term NLS, the risk of developing hepatocellular carcinoma, and the chance that SBD will increase NLS. Serum bile acid parameters shortly after SBD can predict long-term NLS. LAY SUMMARY: This study presents data from the largest genetically defined cohort of patients with severe bile salt export pump deficiency to date. The genotype of patients with severe bile salt export pump deficiency is associated with clinical outcomes and the success of therapeutic interventions. Therefore, genotypic data should be used to guide personalized clinical care throughout childhood and adulthood in patients with this disease.

The morbid genome of ciliopathies: an update.

PURPOSE: Ciliopathies are highly heterogeneous clinical disorders of the primary cilium. We aim to characterize a large cohort of ciliopathies phenotypically and molecularly. METHODS: Detailed phenotypic and genomic analysis of patients with ciliopathies, and functional characterization of novel candidate genes. RESULTS: In this study, we describe 125 families with ciliopathies and show that deleterious variants in previously reported genes, including cryptic splicing variants, account for 87% of cases. Additionally, we further support a number of previously reported candidate genes (BBIP1, MAPKBP1, PDE6D, and WDPCP), and propose nine novel candidate genes (CCDC67, CCDC96, CCDC172, CEP295, FAM166B, LRRC34, TMEM17, TTC6, and TTC23), three of which (LRRC34, TTC6, and TTC23) are supported by functional assays that we performed on available patient-derived fibroblasts. From a phenotypic perspective, we expand the phenomenon of allelism that characterizes ciliopathies by describing novel associations including WDR19-related Stargardt disease and SCLT1- and CEP164-related Bardet-Biedl syndrome. CONCLUSION: In this cohort of phenotypically and molecularly characterized ciliopathies, we draw important lessons that inform the clinical management and the diagnostics of this class of disorders as well as their basic biology.

The landscape of genetic diseases in Saudi Arabia based on the first 1000 diagnostic panels and exomes.

In this study, we report the experience of the only reference clinical next-generation sequencing lab in Saudi Arabia with the first 1000 families who span a wide-range of suspected Mendelian phenotypes. A total of 1019 tests were performed in the period of March 2016-December 2016 comprising 972 solo (index only), 14 duo (parents or affected siblings only), and 33 trio (index and parents). Multigene panels accounted for 672 tests, while whole exome sequencing (WES) represented the remaining 347 tests. Pathogenic or likely pathogenic variants that explain the clinical indications were identified in 34% (27% in panels and 43% in exomes), spanning 279 genes and including 165 novel variants. While recessive mutations dominated the landscape of solved cases (71% of mutations, and 97% of which are homozygous), a substantial minority (27%) were solved on the basis of dominant mutations. The highly consanguineous nature of the study population also facilitated homozygosity for many private mutations (only 32.5% of the recessive mutations are founder), as well as the first instances of recessive inheritance of previously assumed strictly dominant disorders (involving ITPR1, VAMP1, MCTP2, and TBP). Surprisingly, however, dual molecular diagnosis was only observed in 1.5% of cases. Finally, we have encountered candidate variants in 75 genes (ABHD6, ACY3, ADGRB2, ADGRG7, AGTPBP1, AHNAK2, AKAP6, ASB3, ATXN1L, C17orf62, CABP1, CCDC186, CCP110, CLSTN2, CNTN3, CNTN5, CTNNA2, CWC22, DMAP1, DMKN, DMXL1, DSCAM, DVL2, ECI1, EP400, EPB41L5, FBXL22, GAP43, GEMIN7, GIT1, GRIK4, GRSF1, GTRP1, HID1, IFNL1, KCNC4, LRRC52, MAP7D3, MCTP2, MED26, MPP7, MRPS35, MTDH, MTMR9, NECAP2, NPAT, NRAP, PAX7, PCNX, PLCH2, PLEKHF1, PTPN12, QKI, RILPL2, RIMKLA, RIMS2, RNF213, ROBO1, SEC16A, SIAH1, SIRT2, SLAIN2, SLC22A20, SMDT1, SRRT, SSTR1, ST20, SYT9, TSPAN6, UBR4, VAMP4, VPS36, WDR59, WDYHV1, and WHSC1) not previously linked to human phenotypes and these are presented to accelerate post-publication matchmaking. Two of these genes were independently mutated in more than one family with similar phenotypes, which substantiates their link to human disease (AKAP6 in intellectual disability and UBR4 in early dementia). If the novel candidate disease genes in this cohort are independently confirmed, the yield of WES will have increased to 83%, which suggests that most "negative" clinical exome tests are unsolved due to interpretation rather than technical limitations.

Cell-based BSEP trans-inhibition: A novel, non-invasive test for diagnosis of antibody-induced BSEP deficiency.

Background & Aims: Antibody-induced bile salt export pump deficiency (AIBD) is an acquired form of intrahepatic cholestasis, which may develop following orthotopic liver transplantation (OLT) for progressive familial intrahepatic cholestasis type 2 (PFIC-2). Approximately 8-33% of patients with PFIC-2 who underwent a transplant develop bile salt export pump (BSEP) antibodies, which trans-inhibit this bile salt transporter from the extracellular, biliary side. AIBD is diagnosed by demonstration of BSEP-reactive and BSEP-inhibitory antibodies in patient serum. We developed a cell-based test directly measuring BSEP trans-inhibition by antibodies in serum samples to confirm AIBD diagnosis. Methods: Sera from healthy controls and cholestatic non-AIBD or AIBD cases were tested (1) for anticanalicular reactivity by immunofluorescence staining of human liver cryosections, (2) for anti-BSEP reactivity by immunofluorescence staining of human embryonic kidney 293 (HEK293) cells expressing BSEP-enhanced yellow fluorescent protein (EYFP) and immunodetection of BSEP-EYFP on Western blot, and (3) for BSEP trans-inhibition using HEK293 cells stably expressing Na+/taurocholate cotransporting polypeptide (NTCP)-mCherry and BSEP-EYFP. The trans-inhibition test uses [3H]-taurocholate as substrate and is divided into an uptake phase dominated by NTCP followed by BSEP-mediated export. For functional analysis, sera were bile salt depleted. Results: We found BSEP trans-inhibition by seven sera containing anti-BSEP antibodies, but not by five cholestatic or nine control sera, all lacking BSEP reactivity. Prospective screening of a patient with PFIC-2 post OLT showed seroconversion to AIBD, and the novel test method allowed monitoring of treatment response. Notably, we identified a patient with PFIC-2 post OLT with anti-BSEP antibodies yet without BSEP trans-inhibition activity, in line with asymptomatic presentation at serum sampling. Conclusions: Our cell-based assay is the first direct functional test for AIBD and allows confirmation of diagnosis as well as monitoring under therapy. We propose an updated workflow for AIBD diagnosis including this functional assay. Impact and Implications: Antibody-induced BSEP deficiency (AIBD) is a potentially serious complication that may affect patients with PFIC-2 after liver transplantation. To improve its early diagnosis and thus immediate treatment, we developed a novel functional assay to confirm AIBD diagnosis using a patient's serum and propose an updated diagnostic algorithm for AIBD.

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. 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 <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 <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.

First Experience in Living Liver Donation From Donors With Sickle Cell Trait.

Living donor liver transplantation is the main source of organs in the Middle East. Therefore, well balanced criteria are needed to avoid unnecessary exclusion of potential donors, while prioritizing donor safety. We face a high incidence of sickle cell trait (SCT; and disease). Therefore, there is vast experience in general and cardiac surgeries in SCT carriers at our center. After studying their management in detail, we considered accepting SCT carriers as living liver donors, on an exceptional basis. This the first single-center case series of living donor liver transplantation with SCT. Methods: Between January 2012 and September 2021, 20 donors with SCT were reviewed for age, gender, relation to the recipient, hemoglobin, hemoglobin S (HbS), surgical approach, intensive care unit stay, donor and recipients' complications, and graft and recipient survival. Results: Average age of donors was 28.4 y. Sixteen donated the left lateral segment, 4 the left lobe. Recipients were related children or adults. HbS ranged from 21.2% to 39.9%, being ≥30% in 14 donors. HbS was reduced by phlebotomy or exchange transfusion. We performed 7 open, one laparoscopic, and 12 robotic donor surgeries. Operating room time, blood loss, and intensive care unit stay were comparable to non-SCT donors. There was no SCT-related complication. All donors are alive and free of thromboembolic events. Graft and recipient survival is 100% until follow-up. Conclusion: Our experience should encourage other countries with high incidence of SCT to report their experience with this donor population.

ABO-incompatible Pediatric Liver Transplantation With Antibody and B-cell Depletion-free Immunosuppressive Protocol in High Consanguinity Communities.

The success of orthotopic liver transplantation as a life-saving treatment has led to new indications and a greater competition for organ grafts. Pediatric patients with acute liver-related crises can benefit from orthotopic liver transplantation, but organ availability in the limited time can be a major obstacle. Crossing ABO blood group barriers could increase the organs available to such patients. Methods: From November 2010 to June 2015, 176 children aged 0.2-to18 y were transplanted in the King Faisal Specialist Hospital and Research Center. Out of those, 19 children were transplanted across blood group barriers (ABO incompatible). The underlying diseases were biliary atresia (n = 6); progressive familial intrahepatic cholestasis type 2 (n = 4); Crigler-Najjar syndrome (n = 3); hepatoblastoma (n = 2); and urea cycle disorder, Caroli disease, cryptogenic cirrhosis, and neonatal sclerosing cholangitis (n = 1 each). Immunosuppression consisted of basiliximab, mycophenolate, tacrolimus, and steroids. Pretransplant prophylactic plasmapheresis, high-dose immunoglobulins, and rituximab were not administered. Results: The grafts were from living donors (n = 17) and deceased donors (n = 2). Living donor morbidity was nil. The recipient median age was 21 mo (5-70 mo). After a median follow-up of 44 mo, 2 recipients (10%) died because of sepsis, 1 because of uncontrolled acute myeloid leukemia. The overall rejection rate was 7%, and no grafts were lost because of antibody-mediated rejection (AMR). HLA matching was 3.8 of 6 (A, B, DR), and there were 2 patients presented with acute cellular rejection, 1 patient with AMR, and 1 patient with biliary strictures. Conclusions: ABO incompatible liver transplantation is a feasible and life-saving option even with antibody and B-cell depletion-free protocol without increasing the risks for AMR. We speculate that this excellent result is most likely because of presence of relatively low titer ABO isoagglutinins and the high HLA match compatibility caused by habit of longstanding interfamilial marriages as typical of Saudi Arabia.

Odevixibat treatment in progressive familial intrahepatic cholestasis: a randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) is a group of inherited paediatric liver diseases resulting from mutations in genes that impact bile secretion. We aimed to evaluate the effects of odevixibat, an ileal bile acid transporter inhibitor, versus placebo in children with PFIC. METHODS: Patients eligible for this 24-week, randomised, double-blind, completed, phase 3 study were paediatric outpatients diagnosed with PFIC1 or PFIC2 who had pruritus and elevated serum bile acids at screening. Patients were randomly assigned (1:1:1) using an interactive web-based system to once a day oral placebo, odevixibat 40 µg/kg, or odevixibat 120 µg/kg. Randomisation was done in a block size of six and stratified by PFIC type and patient age; patients, clinicians, and study staff were blinded to treatment allocation. Patients were enrolled at one of 33 global sites. Two primary endpoints were evaluated: proportion of positive pruritus assessments (PPAs; ie, scratching score of ≤1 or ≥1-point decrease as assessed by caregivers using the Albireo observer-reported outcome [ObsRO] PRUCISION instrument) over 24 weeks, and proportion of patients with serum bile acid response (ie, serum bile acids reduced by ≥70% from baseline or concentrations of ≤70 µmol/L) at week 24. Efficacy and safety were analysed in randomly allocated patients who received one or more doses of study drug. This study is registered with ClinicalTrials.gov, NCT03566238. FINDINGS: Between June 21, 2018, and Feb 10, 2020, 62 patients (median age 3·2 [range 0·5-15·9] years) were randomly allocated to placebo (n=20), odevixibat 40 µg/kg per day (n=23), or odevixibat 120 µg/kg per day (n=19). Model-adjusted (least squares) mean proportion of PPAs was significantly higher with odevixibat versus placebo (55% [SE 8] in the combined odevixibat group [58% in the 40 µg/kg per day group and 52% in the 120 µg/kg per day group] vs 30% [SE 9] in the placebo group; model-adjusted mean difference 25·0% [95% CI 8·5-41·5]; p=0·0038). The percentage of patients with serum bile acid response was also significantly higher with odevixibat versus placebo (14 [33%] of 42 patients in the combined odevixibat group [10 in the 40 µg/kg per day group and four in the 120 µg/kg per day group] vs none of 20 in the placebo group; adjusting for stratification factor [PFIC type], the proportion difference was 30·7% [95% CI 12·6-48·8; p=0·0030]). The most common treatment-emergent adverse events (TEAEs) were diarrhoea or frequent bowel movements (13 [31%] of 42 for odevixibat vs two [10%] of 20 for placebo) and fever (12 [29%] of 42 vs five [25%] of 20); serious TEAEs occurred in three (7%) of 42 odevixibat-treated patients and in five (25%) of 20 placebo-treated patients. INTERPRETATION: In children with PFIC, odevixibat effectively reduced pruritus and serum bile acids versus placebo and was generally well tolerated. Odevixibat, administered as once a day oral capsules, is a non-surgical, pharmacological option to interrupt the enterohepatic circulation in patients with PFIC. FUNDING: Albireo Pharma.

Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.

There is a growing interest in standardizing gene-disease associations for the purpose of facilitating the proper classification of variants in the context of Mendelian diseases. One key line of evidence is the independent observation of pathogenic variants in unrelated individuals with similar phenotypes. Here, we expand on our previous effort to exploit the power of autozygosity to produce homozygous pathogenic variants that are otherwise very difficult to encounter in the homozygous state due to their rarity. The identification of such variants in genes with only tentative associations to Mendelian diseases can add to the existing evidence when observed in the context of compatible phenotypes. In this study, we report 20 homozygous variants in 18 genes (ADAMTS18, ARNT2, ASTN1, C3, DMBX1, DUT, GABRB3, GM2A, KIF12, LOXL3, NUP160, PTRHD1, RAP1GDS1, RHOBTB2, SIGMAR1, SPAST, TENM3, and WASHC5) that satisfy the ACMG classification for pathogenic/likely pathogenic if the involved genes had confirmed rather than tentative links to diseases. These variants were selected because they were truncating, founder with compelling segregation or supported by robust functional assays as with the DUT variant that we present its validation using yeast model. Our findings support the previously reported disease associations for these genes and represent a step toward their confirmation.

Early Hepatocellular Carcinoma Associated With Fibrocystic Liver Disease in a 10-Year-Old Child: A Case Report.

BACKGROUND: Fibrocystic liver-kidney disease is caused by a group of rare and genetically diverse disorders that are associated with kidney cysts or dysplasia and ductal plate malformation in the liver. There have been several reports of liver neoplasias arising in hepatobiliary fibrocystic diseases. However, most were cholangiocarcinoma; cases involving hepatocellular carcinoma (HCC) are rare, and all the reported cases are related with adults. CASE REPORT: A 10-year-old girl with a history of repeated gastrointestinal bleeding underwent banding and sclerotherapy multiple times and had a history of a Portosystemic shunt without any significant benefit. She was referred to us as a case of fibrocystic liver disease with decompensated liver disease for liver transplantation. The patient underwent living donor liver transplantation, and the explanted liver histopathology report is documented. The explant liver weighed 838 g and measured 21 × 13 × 8.5 cm with the attached gallbladder measuring 7 × 3 × 0.2 cm (in wall thickness). The external surface was covered with multiple white nodules ranging in size from 0.4 to 1 cm. Serial slicing revealed an ill-defined, yellow, soft lesion (4 × 2.5 × 2.5 cm) localized in the subcapsular area of the left lobe (segment 4). The rest of the cut surface was green and nodular (cirrhotic). Microscopy from largest nodule was consistent with early hepatocellular carcinoma.The rest of the liver was cirrhotic, and the morphology was consistent with fibrocystic disease of liver. CONCLUSION: We report a rare case of HCC associated with fibrocystic liver disease. When diagnosing fibrocystic liver disease without known risk factors, the presence of HCC must be considered, and vice versa. To our knowledge, this is the first reported case of HCC associated with fibrocystic liver disease in a 10-year-old child.

First fully laparoscopic donor hepatectomy for pediatric liver transplantation using the indocyanine green near-infrared fluorescence imaging in the Middle East: a case report.

Living donor liver transplantation (LDLT) is a well-established treatment modality for several pediatric end-stage liver diseases owning excellent long-term results. Left lateral sectionectomy (LLS) through an open approach is a well-standardized procedure. This technique has been modified for a fully laparoscopic approach and gaining more and more interest worldwide. We report herein the first fully laparoscopic LLS for pediatric LDLT in the Middle East with the use of indocyanine green dye and near-infrared fluorescence imaging to identify the biliary ducts intraoperatively. The recipient was a 2-year-old girl affected by glycogen storage disease type IV. The mother, aged 21 years, was her donor. The surgical technique, key-points of this procedure, and outcome are hereby discussed.

Role of wireless capsule endoscopy in reclassifying inflammatory bowel disease in children.

OBJECTIVE: To evaluate the role of wireless capsule endoscopy in identifying small bowel lesions in pediatric patients with newly diagnosed colonic inflammatory bowel disease (IBD) type unclassified (IBDU), and to assess whether capsule endoscopy findings result in altered patient management. METHODS: Ten pediatric patients recently diagnosed with IBDU through standard investigations were recruited from the pediatric gastroenterology clinic at McMaster Children's Hospital to undergo capsule endoscopy using the Pillcam SB(TM) (Given Imaging) capsule. Findings consistent with a diagnosis of Crohn's disease required the identification of at least three ulcerations. RESULTS: Three out of ten patients had newly identified findings on capsule endoscopy that met criteria for Crohn's disease. Three more patients had findings suspicious for Crohn's disease, but failed to meet the diagnostic criteria. Three additional patients had findings most consistent with ulcerative colitis, and one had possible gastritis with a normal intestine. Findings from capsule endoscopy allowed for changes in the medical management of three patients. In all ten cases, capsule endoscopy allowed for a better characterization of the type and extent of disease. No adverse outcomes occurred in the present cohort. CONCLUSION: This prospective study reveals that wireless capsule endoscopy is feasible, valuable, and non-invasive, offering the ability to potentially better characterize newly diagnosed pediatric IBDU cases by identifying lesions in the small bowel and reclassifying these as Crohn's disease.

Progress and outcomes of the first high-volume pediatric liver transplantation program in Saudi Arabia.

In 2010, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, established a dedicated Organ Transplant Center to overcome the inadequacy in transplantation care in the region. Due to the high need for solid organ transplantation in children, this center focused on pediatric transplantation. Between 2011 and 2013, a total of 112 pediatric liver transplantations have been performed in our center, mostly from living donors (n=103, 92%). Eight percent of transplants were performed from deceased donors (n=9). Of the 112 transplants, 38.4% of children were below one year of age. There was a predominance of genetic-metabolic disorders (48.2%) as indications for transplant. Extra-hepatic biliary atresia was the indication in only 29.5% of transplant cases. End-stage liver disease of unknown origin accounted for 7.1% of cases. The actuarial recipient and graft survival are 93% and 89%, respectively. In-hospital morbidities amounted to 17% for surgical complications (n=19) and 18% for medical complications (n=20). Seven percent of recipients developed biopsy proven rejection during hospital stay. Five patients died late after discharge suddenly at home or at peripheral hospitals for unknown reasons. Overall, this newly established pediatric liver transplantation program could develop into a high-volume pediatric liver transplantation center in a short period of time due to the high need for liver transplantation in the country. In contrast to the experience in western or eastern countries, there is a high rate of indications for metabolic/genetic disorders. The early results of patient and graft survival are convincing. The long-term outcomes were compromised by an insufficient general healthcare system and cultural barriers.

Papel da cápsula endoscópica na reclassificação da doença inflamatória intestinal em crianças / Role of wireless capsule endoscopy in reclassifying inflammatory bowel disease in children

OBJECTIVE: To evaluate the role of wireless capsule endoscopy in identifying small bowel lesions in pediatric patients with newly diagnosed colonic inflammatory bowel disease (IBD) type unclassified (IBDU), and to assess whether capsule endoscopy findings result in altered patient management. METHODS: Ten pediatric patients recently diagnosed with IBDU through standard investigations were recruited from the pediatric gastroenterology clinic at McMaster Children's Hospital to undergo capsule endoscopy using the Pillcam SB TM (Given Imaging) capsule. Findings consistent with a diagnosis of Crohn's disease required the identification of at least three ulcerations. RESULTS: Three out of ten patients had newly identified findings on capsule endoscopy that met criteria for Crohn's disease. Three more patients had findings suspicious for Crohn's disease, but failed to meet the diagnostic criteria. Three additional patients had findings most consistent with ulcerative colitis, and one had possible gastritis with a normal intestine. Findings from capsule endoscopy allowed for changes in the medical management of three patients. In all ten cases, capsule endoscopy allowed for a better characterization of the type and extent of disease. No adverse outcomes occurred in the present cohort. CONCLUSIONS: This prospective study reveals that wireless capsule endoscopy is feasible, valuable, and non-invasive, offering the ability to potentially better characterize newly diagnosed pediatric IBDU cases by identifying lesions in the small bowel and reclassifying these as Crohn's disease. Further investigation is warranted.

OBJETIVO: Avaliar o papel da cápsula endoscópica na identificação de lesões no intestino delgado em pacientes pediátricos com DII inespecífica (DIII) diagnosticada recentemente e avaliar se os achados da cápsula endoscópica resultam em alterações no tratamento dos pacientes. MÉTODOS: Dez pacientes pediátricos recém-diagnosticados com DIII por meio de investigações padrão foram recrutados da clínica de gastroenterologia pediátrica no McMaster Children's Hospital, para serem submetidos a exame com a cápsula endoscópica Pillcam SB TM (Given Imaging). Achados compatíveis com o diagnóstico da doença de Crohn exigiram a identificação de pelo menos três ulcerações. RESULTADOS: De 10 pacientes, três apresentaram achados novos com a cápsula endoscópica que satisfizeram o critério para a doença de Crohn. Outros três apresentaram achados com suspeita de doença de Crohn, porém não atenderam nossos critérios de diagnóstico. Apresentaram achados mais compatíveis com colite ulcerativa outros três pacientes, e um apresentava possível gastrite com intestino normal. Os achados da cápsula endoscópica possibilitaram mudanças no tratamento médico de três pacientes. Em todos os dez casos, a cápsula endoscópica permitiu uma melhor caracterização do tipo e da extensão da doença. Não houve resultado adverso em nossa coorte. CONCLUSÃO: Este estudo prospectivo revela que a cápsula endoscópica é viável, útil e não invasiva, que oferece a possibilidade de melhor caracterização de casos de DIII pediátricos recém-diagnosticados ao identificar lesões no intestino delgado e reclassificá-las como doença de Crohn.