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.
Haemophagocytic syndrome (HPS) following orthotopic liver transplantation is a rare event which is often fatal. We report here a case of HPS in association with cytomegalovirus (CMV) reactivation. The patient was treated with a combination of antiviral agents, immunomodulatory and supportive therapy which resulted in suppression of CMV infection and resolution of the haemophagocytosis.Key words: cytomegalovirus infection; haemophagocytic syndrome; immunoglobulin; liver transplantation. and serum immunoglobulins were within the normal range. A liver ultrasound showed a diffuse increase in parenchymal and periportal echogenicity.By day 14, the patient's clinical state deteriorated with increasing irritability, worsening jaundice (bilirubin 379 µmol/L) and synthetic dysfunction (INR 8.3). A full blood examination showed: haemoglobin 113 g/L, platelets 28 × 10 9 /L, white cell count 3.5 × 10 9 /L with neutrophils 2.9 × 10 9 /L and lymphocytes 0.3 × 10 9 /L. Liver biopsy revealed a non-specific acute hepatitis with subacute hepatic necrosis. Electron microscopy did not show viral inclusions.Orthotopic liver transplantation was performed at day 16. A standard immunosuppressive regimen of tacrolimus (0.1 mg/kg/day), azathioprine (1.5 mg/kg/day) and prednisolone (10 mg/kg/day) was commenced.In the 2 weeks after transplantation, the patient developed a severe pancytopenia. Haemoglobin fell persistently (nadir 73 g/L), platelets declined at a rate of 16 × 10 9 /L per day on average, lymphocytes remained low (<1 × 10 9 /L) and neutropenia was evident 14 days following transplantation (0.4 × 10 9 /L). Azathioprine and Ganciclovir (per protocol) were stopped on day 4 without improvement. A bone marrow aspirate and trephine at 15 days following transplantation showed haemophagocytosis with a marked increase in macrophages and histiocytes and active phagocytosis of myeloid and erythroid cells. Megakaryocytes were markedly reduced (Fig. 1a). CMV reactivation was detected on day 12 following transplantation, with a positive urine culture and positive CMV pp65 antigen on day 23. The patient was treated with supportive therapy including multiple packed cell and platelet transfusions together with granulocyte colony-stimulating factor (G-CSF) (IV 10 µg/kg/day). Specific antiviral therapy in the form of Ganciclovir (5 mg/kg/day) was restarted and after 2 weeks' therapy, CMV antigen became negative and virus was no longer detected in urine. Treatment with Ganciclovir was continued for 1 week, after which he was changed to oral acyclovir 15 mg/kg/dose for 3 months.A 26-month-old male presented with 2 weeks of anorexia, lethargy, a transient fever and 2 days of jaundice. He had not travelled overseas or been exposed to drugs or environmental toxins. His parents were unrelated and well. On admission, he had mild hepatomegaly but no splenomegaly or lymphadenopathy. (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Serology for hepatitis A, B, C and E, Epstein-Barr virus (EBV), parvovirus, and adenovirus were all negative, as w...
BackgroundThe epidemiology and outcomes of biliary atresia (BA) have been well-documented in national cohorts from two main ethnicities, namely, the Asian Orientals and Caucasians, with incidence ranging from 1 in 5,000 to 1 in 9,000 live births in East Asia and 1 in 15,000 to 19,000 live births in Europe and North America.ObjectiveWe report the first nationwide BA study outside North America, Europe, and East Asia to describe the epidemiology and outcomes of BA in Saudi Arabia.MethodsA national database of BA cases diagnosed between 2000 and 2018 was analyzed. We assessed clearance of jaundice (bilirubin <20 μmol/L) in all cases that underwent Kasai portoenterostomy (KPE). We then estimated survival using the Kaplan–Meier method with endpoints of liver transplantation (LT), death, or survival with native liver (SNL).ResultsBA was diagnosed in 204 infants (106 females; 10% pre-term). The incidence of BA was 1 in 44,365, or 2.254 in 100,000 live births (range, 0.5–4 in 100,000). Polysplenia was diagnosed in 22 cases (11%). The median age at referral was 65 days. A total of 146 children (71.5%) underwent KPE at a median age of 70 days. Clearance of jaundice was achieved in 66 of the 146 (45%) infants. The 10-year SNL after KPE was 25.5%, and the overall 10-year estimated survival was 72.5%. The Kaplan–Meier survival curves for patients undergoing KPE at the age of <60, 61–90, and >90 days showed a SNL rate at 51.6, 33, and 12.5%, respectively, at 5 years (P < 0.001). The 2-, 5-, and 10-year post-LT survival rates were 92.5, 90.6, and 90%, respectively. Undergoing an initial KPE did not impact negatively on the overall LT survival rate when compared to BA cases that underwent primary LT (P = 0.88).ConclusionThe incidence rate of BA in Saudi Arabia is lower than the incidence reported elsewhere. Late referral of BA cases remains a problem in Saudi Arabia; as a result, the SNL rate was lower than reported by other national registries. Hence, national policies devoted to timely referral and earlier age at KPE are needed.
Background: Outcomes in biliary atresia (BA) have been well-documented in large national cohorts from Europe, North America, and East Asia. Understanding the challenges that preclude success of the Kasai portoenterostomy (KPE) is the key to improve the overall outcomes of BA and implementing intervention strategies. Here, we analyzed the data from the Saudi national BA study (204 BA cases diagnosed between 2000 and 2018) to identify the prognostic factors of BA outcomes. Methods: One hundred and forty-three cases underwent KPE. Several prognostic factors (center case load, congenital anomalies, serum gamma-glutamyl transferase, use of steroids, ascending cholangitis post-operatively, and degree of portal fibrosis at time of KPE) were investigated and correlated with the primary outcomes of interest: 1) success of KPE (clearance of jaundice and total serum bilirubin <20 mmol/l after KPE), 2) survival with native liver (SNL), and 3) overall survival. Results: Use of steroids after KPE was associated with clearance of jaundice, 68% vs. 36.8% in the BA cases that did not receive steroids (P = 0.013; odds ratio 2.5) and a significantly better SNL rate at 2 - and 10-year of 62.22% and 57.77% vs. 39.47% and 31.57%, respectively (P = 0.01). A better 10-year SNL was observed in centers with caseload <1/year (group 1) as compared to centers that performed ≥1/year (group 2) [45.34% vs. 26.66%, respectively; P = 0.047]. On comparison of the 2 groups, cases in group 1 had KPE at significantly earlier age (median 59.5 vs. 75 days, P = 0.006) and received steroids after KPE more frequently than group 2 (69% vs. 31%, P < 0.001). None of the remaining prognostic variables were identified as being significantly related to BA outcome. Conclusion: Steroids use post-KPE predicted clearance of jaundice and better short- and long-term SNL. There is a need to establish a national BA registry in Saudi Arabia aiming to standardize the pre- and post-operative clinical practices and facilitate clinical and basic research to evaluate factors that influence BA outcome.
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