Progressive Familial Intrahepatic Cholestasis Type Research Articles

Challenges faced in establishing a pediatric liver transplant program in a lower-middle-income country with free healthcare service.

Liver transplant is the cure for children with liver failure. Sri Lanka is a lower-middle-income country with a predominant free, state health system. Pediatric liver transplant program in Sri Lanka is still in the budding state where the initial experience of the program is yet to be documented. A retrospective review was performed including the clinical characteristics of all pediatric liver transplant recipients of Colombo North Centre for Liver Diseases since the inception of the program from June 2020 to May 2023. There were 14 PLT performed in 3 years. The median recipient age and weight were 8 years (6 months-15 years) and 23.3 kg (6.4-49.2), respectively. The majority were boys (64%). All were from low-income backgrounds. Indications for LT were acute liver failure (5/14), decompensated chronic liver disease (5/14), and acute on chronic liver failure (4/14). Underlying liver diseases were Wilson disease (6/14), autoimmune liver disease (3/14), biliary atresia (2/14) and progressive familial intrahepatic cholestasis type 3 (1/14), and unknown etiology (2/14). The majority were living donor liver transplants (86%). Of the living donors, 42% (5/12) were Buddhist priests. There were three immediate deaths and two late deaths. The 3-month survival was 78%, and overall survival was 64%. Living donor transplants carried a higher success rate (92%) compared to diseased donor transplants (0%; 2/2). Initial experience of pediatric liver transplant program of Sri Lanka is promising despite being established in a free healthcare system amidst the crisis circumstances.

Successful Use of Bortezomib for Recurrent Progressive Familial Intrahepatic Cholestasis Type II After Liver Transplantation: A Pediatric Case with a 9-Year Follow-Up.

Recurrence of progressive familial intrahepatic cholestasis (PFIC) type II poses challenges during postoperative liver transplant care. Posttransplant patients with PFIC type II risk developing recurrent cholestasis with normal gamma-glutamyl transferase activity, which mimics the original bile salt export pump (BSEP) protein deficiency and is related to a form of immunoglobulin G antibody (anti-BSEP)-mediated rejection. Bortezomib effectively induces apoptosis of actively antibody-producing plasma cells that may have a role in antibody-mediated rejection. In this case, we used bortezomib to treat PFIC type II recurrence after liver transplantation in a child.

Severe Neonatal Presentation of Progressive Familial Intrahepatic Cholestasis Type 4 in an Omani Infant

Progressive familial intrahepatic cholestasis type 4 (PFIC4) is a relatively newly described autosomal recessive disorder caused by biallelic mutations in the gene encoding tight junction protein 2 (TJP2) which is located in chromosome 9q21. PFIC4 is characterised by cholestasis with or without other extrahepatic manifestations. Bleeding tendency due to vitamin k deficiency is a well-known complication of cholestasis. We present a neonate who presented to the Emergency Department at a tertiary care hospital in 2021 with cholestasis and multiple intracranial bleeds. He was found to have severe coagulopathy and his genetic work up revealed a homozygous variant mutation in TJP2 gene causing PFIC4. He had persistent cholestasis that necessitated an internal biliary diversion with some clinical improvement. Keywords: Jaundice; Intracranial haemorrhage; Progressive Familial Intrahepatic Cholestasis type 4; Case Report; Oman.

Management and outcomes after liver transplantation for progressive familial intrahepatic cholestasis: A systematic review and meta-analysis.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous rare congenital cholestatic liver disease. Disease progression might necessitate liver transplantation (LT). The aim of this study was to describe the outcome of PFIC1-4 patients after LT. Electronic databases were searched to identify studies on PFIC and LT. Patients were categorized according to PFIC type, genotype, graft type, age at LT, time of follow-up, and complications and treatment during follow-up. Seventy-nine studies with 507 patients met inclusion criteria; most patients were classified as PFIC1-3. The median age at LT was 50 months. The overall 5-year patient survival was 98.5%. PFIC1 patients with diarrhea after LT were at significant risk of developing graft steatosis ( p < 0.0001). Meta-analysis showed an efficacy of 100% [95% CI: 73.9%-100%] for surgical biliary diversion to ameliorate steatosis and 94.9% [95% CI: 53.7%-100%] to improve diarrhea (n = 8). PFIC2 patients with bile salt export pump (BSEP)2 or BSEP3-genotype were at significant risk of developing antibody-induced BSEP deficiency (AIBD) ( p < 0.0001), which was reported in 16.2% of patients at a median of 36.5 months after LT. Meta-analysis showed an efficacy of 81.1% [95% CI: 47.5%-100%] for rituximab-based treatment regimens to improve AIBD (n = 18). HCC was detected in 3.6% of PFIC2 and 13.8% of PFIC4 patients at LT. Fifty percent of PFIC1 patients develop diarrhea and steatosis after LT. Biliary diversion can protect the graft from injury. PFIC2 patients with BSEP2 and BSEP3 genotypes are at significant risk of developing AIBD, and rituximab-based treatment regimens effectively improve AIBD. PFIC3 patients have no PFIC-specific complications following LT.

Liver Transplantation for Hepatocellular Carcinoma in Patients with Inherited Metabolic Liver Diseases: A Single-Center Analysis.

Liver transplantation is an acceptable treatment for some selected hepatocellular carcinoma. We report our experience of 6 patients with liver transplantation for hepatocellular carcinoma with background inherited metabolic disease. This is a single-center retrospective, descriptive study. Consecutive patients who underwent liver transplantation for hepatocellular carcinoma with background inherited metabolic disease were included in the study. The record of the patients was accessed, and the following data were extracted: sociodemographic variables, type of metabolic disease, date of liver transplantation, tumor characteristics, laboratory parameters, Model for End-Stage Liver Disease score, immediate- and long-term outcome after transplantation, disease-free survival, and overall survival. Data were analyzed using Statistical Package for the Social Sciences version 25.0. Six patients received liver transplantation for hepatocellular carcinoma with background inherited metabolic liver disease. The median age was 4.5 years. The median Model for End-Stage Liver Disease score was 29.30. The median maximum tumor diameter was 2.15 cm. Three patients had multiple tumor nodules. Half of the patients had microvascular invasion. Four of the patients had a moderately differentiated tumor. Progressive familial intrahepatic cholestasis type II is the commonest inherited metabolic disease seen in 3 patients. Median follow-up is 46.1 months. Half of the patients are currently more than 5 years post liver transplantation with no features of recurrence. The estimated survival rates at 1, 3, and 5 years are 100%, 83.3%, and 83.3%, respectively. Liver transplant for these categories of patients is associated with good disease-free and overall survival, even in the presence of some seemingly poor prognostic features.

Outcomes of 38 patients with PFIC3: Impact of genotype and of response to ursodeoxycholic acid therapy

Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare liver disease caused by biallelic variations in ABCB4. Data reporting on the impact of genotype and of response to ursodeoxycholic acid (UDCA) therapy on long-term outcomes are scarce. We retrospectively describe a cohort of 38 patients with PFIC3 with a median age at last follow-up of 19.5 years (range 3.8-53.8). Twenty patients presented with symptoms before 1 year of age. Thirty-one patients received ursodeoxycholic acid (UDCA) therapy resulting in serum liver test improvement in 20. Twenty-seven patients had cirrhosis at a median age of 8.1 years of whom 18 received a liver transplant at a median age of 8.5 years. Patients carrying at least one missense variation were more likely to present with positive (normal or decreased) canalicular MDR3 expression in the native liver and had prolonged native liver survival (NLS; median 12.4 years [range 3.8-53.8]). In contrast, in patients with severe genotypes (no missense variation), there was no detectable canalicular MDR3 expression, symptom onset and cirrhosis occurred earlier, and all underwent liver transplantation (at a median age of 6.7 years [range 2.3-10.3]). The latter group was refractory to UDCA treatment, whereas 87% of patients with at least one missense variation displayed an improvement in liver biochemistry in response to UDCA. Biliary phospholipid levels over 6.9% of total biliary lipid levels predicted response to UDCA. Response to UDCA predicted NLS. Patients carrying at least one missense variation, with positive canalicular expression of MDR3 and a biliary phospholipid level over 6.9% of total biliary lipid levels were more likely to respond to UDCA and to exhibit prolonged NLS. In this study, data show that genotype and response to ursodeoxycholic acid therapy predicted native liver survival in patients with PFIC3 (progressive familial intrahepatic cholestasis type 3). Patients carrying at least one missense variation, with positive (decreased or normal) immuno-staining for canalicular MDR3, and a biliary phospholipid level over 6.9% of total biliary lipids were more likely to respond to ursodeoxycholic acid therapy and to exhibit prolonged native liver survival.

Optimal liver transplant procedure in progressive familial intrahepatic cholestasis type 1 treated with biliary diversion or intestinal transplantation: Lessons learned from three cases treated with different approaches.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an autosomal recessive cholestatic liver disorder caused by ATP8B1 gene mutations. Although liver transplantation (LT) is indicated for progressive liver disease, postoperative complications, including severe diarrhea and graft steatohepatitis leading to graft loss, have been reported. The first patient had jaundice, pruritus, diarrhea, and growth retardation (weight z-score: -2.5; height z-score: -3.7). She underwent LT with total internal biliary diversion (TIBD) to the colon at 2 years of age. Graft biopsy at the 7-year follow-up examination revealed microvesicular steatosis (60%). Her diarrhea improved, and her growth failure was recovering (weight z-score: -1.0; height z-score: -1.7). The second patient underwent sequential intestine-liver transplantation at 8 years of age due to end-stage liver disease (ESLD) and short bowel syndrome caused by massive bowel resection for internal hernia after partial external biliary diversion (PEBD) at 21 months of age. She developed severe pancreatitis induced by steroid-bolus therapy for rejection after transplantation. She died 1.7 years after intestinal transplantation due to an uncontrollable pancreatic abscess and acute respiratory distress syndrome. The third patient underwent PEBD at 15 months of age and received LT with TEBD at 15 years of age due to ESLD with hepatic encephalopathy. Throughout the perioperative period, she showed no abdominal symptoms, including diarrhea and pancreatitis. Graft biopsy at the 2-year follow-up examination revealed macrovesicular steatosis (60%) with inflammation. The patients showed different outcomes. Effective therapeutic options to mitigate post-LT complications in patients with PFIC1 must be considered individually.

Progressive familial intrahepatic cholestasis type 2 on the example of one family. Liver transplantation as an effective treatment method. Case report

The article presents the structure of diseases that led to the need for liver sector transplantation in children living in the Novosibirsk region. The paper provides a detailed description of progressive familial intrahepatic cholestasis, principles of modern diagnosis and treatment. A description of the medical history of family members and, in particular, a clinical case in a young child with type 2 PFIC (Byler's syndrome) is given.

THU-270 - Clinical characteristics and pathogenic mechanism of five new ABCB4 missense mutations in progressive familial intrahepatic cholestasis type 3

THU-270 - Clinical characteristics and pathogenic mechanism of five new ABCB4 missense mutations in progressive familial intrahepatic cholestasis type 3

Surgical versus Medical Management of Progressive Familial Intrahepatic Cholestasis-Case Compilation and Review of the Literature.

(1) Background: Progressive familial intrahepatic cholestasis (PFIC) is a rare cause of liver failure. Surgical biliary diversion (SBD) and ileal bile salt inhibitors (IBAT) can delay or prevent liver transplantation (LTX). A comparison of the two methodologies in the literature is lacking. The combination has not been investigated. (2) Methods: We performed a literature survey on medical and surgical treatments for PFIC and reviewed the charts of our patients with PFIC of a tertiary hospital. The end points of our analysis were a decrease in serum bile acid (sBA) levels, reduction of pruritus and delay or avoidance of (LTX). (3) Results: We included 17 case series on SBD with more than 5 patients and a total of 536 patients. External or internal SBD, either conventional or minimally invasive, can reduce pruritus and sBA, but not all PFIC types are suitable for SBD. Six publications described the use of two types of IBAT in PFIC with a total of 118 patients. Treatment response was dependent on genetic type and subtype. Patients with PFIC 2 (nt-BSEP) showed the best response to treatment. Four out of eleven PFIC patients underwent SBD at our centre, with two currently receiving IBAT. (4) Conclusions: Limited data on IBAT in selected patients with PFIC show safety and effectiveness, although surgical methods should still be considered as a successful bridging procedure. Further studies to evaluate a possible combination of IBAT and SBD in PFIC are warranted and treatment decision should be discussed in an interdisciplinary board.

Clinical and genetic analysis of cases of progressive familial intrahepatic cholestasis type 3

Objective: To conduct clinical and genetic analysis in two cases of cholestatic liver disease to determine the specific etiology of cholestasis. Methods: Clinical data and the medical histories in family members of two cases were collected. The gene variation was detected by whole-exome sequencing technology. Sanger sequencing validation and bioinformatics analysis were performed on patients and their parents with suspected pathogenic mutations. Results: Whole-exome sequencing showed that the ABCB4 gene of case 1 (a male, 16 years old) had compound heterozygous mutations of c.646C > T from the father and c.927T > A from the mother, while the ABCB4 gene of case 2 (a female, 17 years old) had a compound heterozygous mutation of c.2784-1G > A from the father and c.646C > T from the mother. New mutation sites that had not been previously reported were c.646C > T, c.927T > A, and c.2784-1G > A. Conclusion: In this study, both cases had progressive familial intrahepatic cholestasis type 3 (PFIC-3) caused by ABCB4 gene mutations, and it also enriched the ABCB4 pathogenic variant spectrum. Whole-exome sequencing technology provides a reliable diagnostic tool for etiological analysis.

Rescue of infant progressive familial intrahepatic cholestasis type 3 mice by repeated dosing of AAV gene therapy

Background & AimsGene therapy using recombinant adeno-associated virus (rAAV) vector carrying multidrug resistance protein 3 (MDR3) coding sequence (AAV8-MDR3) represents a potential curative treatment for progressive familial intrahepatic cholestasis type 3 (PFIC3), which presents in early childhood. However, patients with the severest form of PFIC3 should receive treatment early after detection to prevent irreversible hepatic fibrosis leading ultimately to liver transplantation or death. This represents a challenge for rAAV-based gene therapy because therapeutic efficacy is expected to wane as rAAV genomes are lost owing to hepatocyte division, and the formation of AAV-specific neutralising antibodies precludes re-administration. Here, we tested a strategy of vector re-administration in infant PFIC3 mice with careful evaluation of its oncogenicity – a particular concern surrounding rAAV treatment. MethodsAAV8-MDR3 was re-administered to infant Abcb4-/- mice 2 weeks after a first dose co-administered with tolerogenic nanoparticles carrying rapamycin (ImmTOR) given at 2 weeks of age. Eight months later, long-term therapeutic efficacy and safety were assessed with special attention paid to the potential oncogenicity of rAAV treatment. ResultsCo-administration with ImmTOR mitigated the formation of rAAV-specific neutralising antibodies and enabled an efficacious second administration of AAV8-MDR3, resulting in stable correction of the disease phenotype, including a restoration of bile phospholipid content and healthy liver function, as well as the prevention of liver fibrosis, hepatosplenomegaly, and gallstones. Furthermore, efficacious repeat rAAV administration prevented the appearance of liver malignancies in an animal model highly prone to developing hepatocellular carcinoma. ConclusionsThese outcomes provide strong evidence for rAAV redosing through co-administration with ImmTOR, as it resulted in a long-term therapeutic effect in a paediatric liver metabolic disorder, including the prevention of oncogenesis. Impact and implicationsRedosing of gene therapy for inborn hepatobiliary disorders may be essential as effect wanes during hepatocyte division and renewal, particularly in paediatric patients, but the approach may carry long-term risks of liver cancer. Viral vectors carrying a therapeutic gene exerted a durable cure of progressive familial intrahepatic cholestasis type 3 in infant mice and reduced the risk of liver cancer only following a second administration.

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

<h2>Abstract</h2><h3>Background&Aims</h3> 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 transplanted PFIC-2 patients 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 -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. <h3>Methods</h3> Sera from healthy controls and cholestatic Non-AIBD or AIBD cases were tested I) for anti-canalicular reactivity by immunofluorescence (IF) staining of human liver cryosections, II) for anti-BSEP reactivity by IF staining of HEK293 cells expressing BSEP-EYFP and immunodetection of BSEP-EYFP on Western blot, and III) for BSEP trans-inhibition using HEK293 cells stably expressing 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. <h3>Results</h3> 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 post-OLT PFIC-2 patient showed seroconversion to AIBD and the novel test method allowed monitoring of treatment response. Notably, we identified a post-OLT PFIC-2 patient with anti-BSEP antibodies yet without BSEP trans-inhibition activity, in line with asymptomatic presentation at serum sampling. <h3>Conclusions</h3> 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. <h3>Lay Summary</h3> Antibody-induced BSEP deficiency (AIBD) is a potentially serious complication that may affect PFIC-2 patients after liver transplantation. To improve its early diagnosis and thus immediate treatment, we developed a novel functional assay to confirm AIBD diagnosis using patient's serum and propose an updated diagnostic algorithm for AIBD.

Successful Treatment of Patient With Ewing Sarcoma in the Setting of Inherited Cholestatic Liver Disease.

Progressive familial intrahepatic cholestasis type 1 (PFIC1) is an inherited, progressive cholestatic liver disease. Here, we present an approach to the treatment of Ewing sarcoma in a patient with PFIC1. The diagnosis of PFIC1 presents a unique challenge in the treatment of Ewing sarcoma, as the standard-of-care vincristine, doxorubicin, cyclophosphamide/ifosfamide and etoposide chemotherapy backbone for Ewing sarcoma therapy treatment relies heavily on intact hepatic metabolism. In addition, we report prolonged lymphopenia and severe infectious complications in this patient, both of which may be attributed to more severe immunosuppression in setting of poor hepatic metabolism of chemotherapeutic agents.

Ivacaftor-Mediated Potentiation of ABCB4 Missense Mutations Affecting Critical Motifs of the NBDs: Repositioning Perspectives for Hepatobiliary Diseases.

ABCB4 (ATP-binding cassette subfamily B member 4) is a hepatocanalicular floppase involved in biliary phosphatidylcholine (PC) secretion. Variations in the ABCB4 gene give rise to several biliary diseases, including progressive familial intrahepatic cholestasis type 3 (PFIC3), an autosomal recessive disease that can be lethal in the absence of liver transplantation. In this study, we investigated the effect and potential rescue of ten ABCB4 missense variations in NBD1:NBD2 homologous positions (Y403H/Y1043H, K435M/K1075M, E558K/E1200A, D564G/D1206G and H589Y/H1231Y) all localized at the conserved and functionally critical motifs of ABC transporters, six of which are mutated in patients. By combining structure analysis and in vitro studies, we found that all ten mutants were normally processed and localized at the canalicular membrane of HepG2 cells, but showed dramatically impaired PC transport activity that was significantly rescued by treatment with the clinically approved CFTR potentiator ivacaftor. Our results provide evidence that functional ABCB4 mutations are rescued by ivacaftor, paving the way for the repositioning of this potentiator for the treatment of selected patients with PFIC3 caused by mutations in the ATP-binding sites of ABCB4.

Progressive Familial Intrahepatic Cholestasis: A Descriptive Study in a Tertiary Care Center.

Progressive familial intrahepatic cholestasis (PFIC) is a rare genetic disorder that results from defective mechanisms of bile secretion. We aim to describe different types of PFIC and their clinical features, treatment modalities, and outcomes in Saudi Arabia. Patients and Methods. This is a retrospective study of all patients diagnosed with PFIC at King Faisal Specialist Hospital and Research Center in Riyadh from January 1, 2002, to December 31, 2021. All relevant information was collected from patient charts and transferred into the REDcap® database for statistical analysis. A total of 79 patients were identified with PFIC, and PFIC type 3 was the most common (59.5%), followed by PFIC type 2 (34.2%), PFIC type 1 (5.1%), and PFIC type 4 (1.3%). Males and females were affected in 54.4% and 45.6%, respectively. Mutations in ATP8B1, ABCB11, and ABCB4 genes were observed in PFIC type 1, PFIC type 2, and PFIC type 3, and loss of function in a variant of TJP2 was detected in PFIC type 4, respectively. A total of 51 (64.6%) patients underwent liver transplantation: three patients (3/4) with PFIC type 1 (75%), twenty patients (20/27) with PFIC type 2 (74.1%), twenty-seven patients (27/47) with PFIC type 3 (57.4%), and one patient with PFIC type 4 (100%). The mean duration of disease before transplantation was 53.9 ± 67 months with a median of 30 months. Following liver transplantation, symptomatic control was achieved in 47 patients (92.2%). Recurrence after transplantation occurred in 4 patients (7.8%) within an average of 22.5 months and a median of 17 months. PFIC is considered a rare disorder in Saudi Arabia; however, early recognition of the disease is important for appropriate management and early referral for liver transplantation evaluation. The overall rate of liver transplantation in our cohort was 64.6% with an excellent five-year survival rate.

Cholestatic Liver Disease in Late Childhood: A Report of Two Rare Cases

Cholestatic liver disease in late childhood has a comprehensive list of aetiologies, requiring a multidimensional approach. Among these, the genetic aetiology can range from having a self-limiting course to being associated with morbidity and mortality, requiring liver transplantation. Progressive Familial Intrahepatic Cholestasis (PFIC) and Benign Recurrent Intrahepatic Cholestasis (BRIC) are two rare inherited autosomal recessive cholestatic disorders. Both are related to mutations in the bile formation transport system and typically manifest in infancy or early childhood. Among the PFIC types, The PFIC type 3 rapidly progresses to end-stage liver disease, while BRIC follows a benign course with intermittent asymptomatic periods. Here, authors describe two (17-year-old male, 19-year-old male) such unusual inherited autosomal recessive cholestatic disorders in late childhood: PFIC (type 3) and BRIC, which have distinct clinical presentations and liver function derangements.

Clinical and genetic characterization of pediatric patients with progressive familial intrahepatic cholestasis type 3 (PFIC3): identification of 14 novel ABCB4 variants and review of the literatures

BackgroundProgressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disease caused by pathogenic variants of the gene ABCB4. This study aimed to investigate the ABCB4 genotypic and the clinical phenotypic features of PFIC3 patients.MethodsThe clinical and molecular genetic data of 13 new pediatric patients with PFIC3 as well as 82 reported ones in the PubMed and CNKI databases were collected and analyzed.ResultsThe 13 new PFIC3 patients included six females and seven males, and the main presentations were hepatomegaly, splenomegaly, jaundice, and pruritus, as well as increased levels of gamma-glutamyl transpeptidase (GGT). Fourteen new ABCB4 variants were detected, including eight diagnosed to be likely-pathogenic and six, pathogenic. Among all the 95 PFIC3 cases, hepatomegaly was observed in 85.3% (81/95), pruritus in 67.4% (64/95), splenomegaly in 52.6% (50/95), jaundice in 48.4% (46/95), portal hypertension in 34.7% (33/95) and GGT elevation in 100% (88/88) of the patients. Positive responses at varied degrees to oral ursodeoxycholic acid (UDCA) treatment were observed in 66.1% (39/59) of the patients, among whom 38.5% (15/39) fully recovered in terms of the laboratory changes. Although the condition remained stable in 53 patients (58.9%, 53/90), the clinical outcomes were not promising in the rest 37 cases (41.1%, 37/90), including 7 died, 27 having undergone while another 3 waiting for liver transplantation. A total of 96 ABCB4 variants were detected in the 95 patients. PFIC3 patients with biallelic null variants exhibited earlier onset ages [10.5 (2, 18) vs. 19 (8, 60) months, p = 0.007], lower UDCA response rate [18.2% (2/11) vs. 77.1% (37/48), p = 0.001], and more unpromising clinical outcomes [80% (12/15) vs. 33.3% (25/75), p = 0.001], compared with those with non-biallelic null variants.ConclusionsPFIC3 presented with hepatomegaly, pruritus, splenomegaly and jaundice with increased serum GGT level as a biochemistry hallmark. Although varying degrees of improvement in response to UDCA therapy were observed, 41.1% of PFIC3 patients exhibited unfavorable prognosis. ABCB4 genotypes of biallelic null variants were associated with severer PFIC3 phenotypes. Moreover, the 14 novel variants in this study expanded the ABCB4 mutation spectrum, and provided novel molecular biomarkers for diagnosis of PFIC3 patients.

Case series of progressive familial intrahepatic cholestasis type 3: Characterization of variants in ABCB4 in China.

To improve the accuracy of the diagnosis of familial progressive intrahepatic cholestasis type 3 (PFIC3, https://www.omim.org/entry/602347). Between September 2019 and March 2021, we recruited four patients with PFIC3 from two liver centers in East China. Molecular genetic findings of ATP-binding cassette subfamily B member 4 [ATP binding cassette transporter A4 (ABCB4), https://www.omim.org/entry/171060] were prospectively examined, and clinical records, laboratory readouts, and macroscopic and microscopic appearances of the liver were analyzed. Four patients experienced cholestasis, mild jaundice, and elevated levels of serum direct bilirubin, γ-glutamyltransferase, or total bile acids. All patients had moderate-to-severe liver fibrosis or biliary cirrhosis, and their liver biopsy specimens stained positive with rhodamine. Molecular immunohistochemistry revealed reduced or absent MDR3 expression in all liver specimens. A novel mutation of ABCB4 (c.1560 + 2T > A) was identified in patients with PFIC3, which is of high clinical significance and may help understand mutant ABCB4 pathogenesis. MDR3 immunohistochemistry and molecular genetic analyses of ABCB4 are essential for the accurate diagnosis of PFIC3.

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

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. 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. 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.