Genotype correlates with clinical course and outcome of children with tight junction protein 2 (TJP2) deficiency-related cholestasis.

BACKGROUND AND AIMS: The study aimed to describe the clinical course and outcomes, and analyze the genotype-phenotype correlation in patients with tight junction protein 2 (TJP2) deficiency. APPROACH AND RESULTS: Data from all children with chronic cholestasis and either homozygous or compound heterozygous mutations in TJP2 were extracted and analyzed. The patients were categorized into 3 genotypes: TJP2-A (missense mutations on both alleles), TJP2-B (missense mutation on one allele and a predicted protein-truncating mutation [PPTM] on the other), and TJP2-C (PPTMs on both alleles). A total of 278 cases of genetic intrahepatic cholestasis were studied, with TJP2 deficiency accounting for 44 cases (15.8%). Of these, 29 were homozygous and 15 were compound heterozygous variants of TJP2 . TJP2-A genotype was identified in 21 (47.7%), TJP2-B in 7 cases (15.9%), and TJP2-C in 16 cases (36.4%), respectively. Patients with the TJP2-C genotype were more likely to experience early infantile cholestasis (87.5% vs. 53.5%, p =0.033), less likely to clear jaundice (12.5% vs. 52.2%, p =0.037), more likely to develop ascites, and had higher serum bile acids. Patients with the TJP2-C genotype were more likely to die or require liver transplantation (native liver survival: 12.5% vs. 78.6%, p <0.001), with a median age at death/liver transplantation of 2.5 years. Cox regression analysis revealed that TJP2-C mutations ( p =0.003) and failure to resolve jaundice ( p =0.049) were independent predictors of poor outcomes. CONCLUSIONS: Patients with the TJP2-C genotype carrying PPTMs in both alleles had a rapidly progressive course, leading to early decompensation and death if they did not receive timely liver transplantation.

Association of HLA DRB1 Allele Profile with Pediatric Autoimmune Liver Disease in India.

Objectives: The aim of this study is to study the association of human leukocyte antigen (HLA) DRB1 alleles with treatment response in Indian children with autoimmune liver disease (AILD). Methods: HLA DRB1 alleles of 71 Indian children with pediatric AILD (pAILD) were analyzed along with 25 genetically confirmed patients with Wilson disease as controls. After 1 year of therapy, all those who failed to normalize aspartate & alanine transferase (AST/ ALT) (below 1.5 times of upper limit of normal) and/or failed to normalize IgG levels, or who had >2 relapses (AST/ALT levels >1.5 times of upper limit of normal) while on treatment, were labeled as difficult to treat (DTT). Results: HLA DRB1∗3 was found to be significantly associated with AIH type 1 (46.2% vs. 4% in controls; P corrected = 0.011). Majority of the patients [55 (77.5%)] had chronic liver disease at presentation, with 42 (59.2%) having portal hypertension and 17 (23.9%) having ascites. Out of the 71 with pAILD, 19 (26.8%) were DTT. HLA DRB1∗14 was found to be independently associated with DTT cases (36.8% vs. 9.6%, OR 5.87, 95% CI 1.07-32.09, P = 0.041). Other factors independently associated with DTT were presence of autoimmune sclerosing cholangitis (OR 8.57, P = 0.008) and high-risk varices (OR 7.55, P = 0.016), improving the correctness of classification of the model from 73.2% to 84.5%. Conclusion: HLA DRB1∗14 is independently associated with treatment response in pAILD and HLA DRB1∗3 is associated with AIH type 1. HLA DRB1 alleles may thus provide supportive information for diagnosis and prognosis of AILD.

Rotational thromboelastometry-guided blood component use in cirrhotic children undergoing invasive procedures: Randomized controlled trial.

BACKGROUND & AIMS: This randomized controlled trial (RCT) was conducted with the aim to evaluate the efficacy and safety of using ROTEM-based transfusion strategy in cirrhotic children undergoing invasive procedures. METHODS: This was an open-label, RCT which included (i) children under 18 years of age with liver cirrhosis; (ii) INR between 1.5 and 2.5; and/or (iii) platelet count between 20 × 109 /L and 50 × 109 /L (for procedures other than liver biopsy) and between 40 × 109 /L and 60 × 109 /L (for liver biopsy); and (iv) listed for invasive procedures. Stratified randomization was done for children undergoing liver biopsies. Patients randomized to the ROTEM and conventional groups received blood component transfusion using predefined criteria. RESULTS: A total of 423 invasive procedures were screened for inclusion of which 60 were randomized (30 in each group with comparable baseline parameters). The volume of total blood components, fresh frozen plasma (FFP) and platelets transfused was significantly lower in ROTEM as compared to conventional group. Only 46.7% of children in ROTEM group received a blood component compared to 100% in conventional group (p < .001). The requirement of FFP (ROTEM: 43.3%, Conventional: 83.3%, p = .001) was significantly lower in the patients receiving ROTEM-guided transfusions. There was no difference in procedure-related bleed and transfusion-related complications between the two groups. ROTEM was cost-effective (p = .002) despite the additional cost of the test. CONCLUSION: ROTEM-based transfusion strategies result in lower blood component transfusion in cirrhotic children undergoing invasive procedures without an increase in risk of procedure-related bleed. ROTEM-guided transfusion strategy is cost-effective.