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.

Relapse following withdrawal of D-penicillamine from combination (D-penicillamine + zinc) therapy in hepatic Wilson disease.

OBJECTIVES: Long-term D-penicillamine (D-pen) therapy in Wilson disease (WD) has numerous adverse effects which advocates its withdrawal, but with an inherent risk of relapse. This prospective observational study was conducted with the objective of evaluating incidence of relapse following withdrawal of D-pen from combination (D-pen + zinc) therapy in maintenance phase of previously symptomatic hepatic WD. METHODS: Hepatic WD patients <18 years of age and on combination therapy for >2 years with 6 months of biochemical remission were included. Biochemical remission was defined as achievement of (i) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤1.5 times upper limit of normal (ULN), (ii) serum albumin >3.5 g/dL, international normalized ratio (INR) <1.5 and (iii) 24-h urinary copper excretion (UCE) <500 mcg/day, nonceruloplasmin-bound-copper (NCC) <15 mcg/dL. After D-pen withdrawal, monthly liver function test (LFT) and INR and 3 monthly UCE and NCC were done till 1 year or relapse (elevation of AST/ALT/both >2 times ULN or total bilirubin >2 mg/dL), whichever occurred earlier. RESULTS: Forty-five patients enrolled with median combination therapy duration of 36 months. Sixty percent of them had their index presentation as decompensated cirrhosis. Fourteen patients (31.8%) relapsed (cumulative incidence: 4 at 3 months, 11 at 6 months, and 14 at 12 months after D-pen discontinuation). All relapsers had index presentation as decompensated cirrhosis. On Cox-regression, ALT at D-pen withdrawal was an independent predictor of relapse (hazard ratio [HR]: 1.077, 95% confidence interval [CI]: 1.014-1.145, p = 0.017) with area under the receiver operating characteristic (AUROC) of 0.860. ALT ≥40 U/L predicted risk of relapse with 85.7% sensitivity, 70.9% specificity. CONCLUSION: Incidence of relapse after withdrawal of D-pen from combination therapy is 31.8% in hepatic WD. ALT ≥40 U/L, at the time of D-pen stoppage, predicts future relapse.

Midodrine reduces new-onset acute kidney injury and hyponatremia in children with cirrhosis and ascites awaiting liver transplantation: Results from an open-label RCT.

OBJECTIVES: Midodrine, an oral α-1-adrenergic receptor agonist, counters arterial hypovolemia and reduces complications in adult patients with cirrhosis. This randomized controlled trial (RCT) aimed to assess the efficacy and safety of midodrine in preventing complications and improving survival in children with cirrhosis and ascites who are awaiting liver transplantation (LT). METHODS: This open-label RCT conducted from January 2022 to May 2023 included children under 18 years with cirrhosis and ascites. Patients were randomized to receive either midodrine plus standard medical therapies (SMTs) or SMT alone. The primary outcome measure was the incidence of cirrhosis-related complications within 6 months. RESULTS: Thirty-five subjects were enrolled and randomized. Patients in the midodrine arm had a lower incidence of new-onset acute kidney injury (AKI) compared with the SMT arm (11.1% vs. 41.2%). Patients in the midodrine arm showed a decline in serum creatinine and improvement in glomerular filtration rate, whereas no changes were observed in the SMT arm. There was a lower incidence of new-onset hyponatremia in the midodrine arm (20% vs. 56%). Midodrine led to reduction in plasma rennin activity (PRA) and improvement in systemic hemodynamics. There was no difference in the rate of resolution of ascites, recurrence of ascites, requirement of therapeutic paracentesis, cumulative albumin infusion requirement, episodes of spontaneous bacterial peritonitis, and hepatic encephalopathy between the two arms. CONCLUSION: Midodrine, when added to SMT, was effective in reducing the incidence of new-onset AKI and hyponatremia in pediatric cirrhotics awaiting LT. It also improved systemic hemodynamics and showed a trend towards reducing PRA.

Liver histology and hepatic progenitor cell activity in pediatric acute liver failure: Implications for clinical outcome.

BACKGROUND: Hepatic progenitor cell (HPC) activity and regenerative process that follows pediatric acute liver failure (PALF) is still not well understood. This clinicopathological study was thus conducted with an aim to study the correlation of liver histology and HPC activity with outcomes in PALF. METHODS: All PALF patients with available hepatic histological specimens were included and specimens were analyzed for hepatocyte loss, HPC activity [using cytokeratin (CK) 7, CK19, sex-determining region Y-related high mobility group box(SOX)9 and epithelial cell adhesion molecule (EpCAM)], hepatocyte proliferation (using Ki67), and hepatocyte senescence (using p53 and p21). RESULTS: Ninety-four children were included: 22 (23.4%) survived with native liver (SNL) (i.e., the good outcome group) while rest (i.e., the poor outcome group) either died [33%, 35.1%] or received liver transplant (LT) [39%, 41.5%]. When compared to subjects with poor outcomes, those in the SNL group exhibited significantly less severe hepatocyte loss, fewer HPC/hpf, more proliferating hepatocytes, and less senescent hepatocytes (p < .05). Increasing severity of hepatocyte loss (adjusted OR: 9.95, 95% CI: 4.22-23.45, p < .001) was identified as an independent predictor of poor outcome. Eighty percent children with >50% native hepatocyte loss had poor outcome within 10 days of hospitalization. CONCLUSION: In PALF, more severe hepatocyte loss, higher number of HPC activation, lesser number of proliferating hepatocytes, and greater number of senescent hepatocytes are associated with a poor outcome. Loss of >50% hepatocytes is an independent predictor of poor outcome in PALF.

Wedged hepatic vein portovenography for assessment of Rex vein patency in children with extrahepatic portal venous obstruction.

BACKGROUND: Meso-Rex bypass is the surgical intervention of choice for children with extrahepatic portal vein obstruction (EHPVO). Patency of Rex vein, umbilical recessus of the portal vein, is a prerequisite for this surgery. Conventional diagnostic modalities poorly detect patency, while transjugular wedged hepatic vein portography (WHVP) accurately detects patency in 90%. OBJECTIVES: We aimed to assess Rex vein patency and portal vein branching pattern in children with EHPVO using transjugular WHVP and to identify factors associated with Rex vein patency. METHODS: Transjugular WHVP was performed in 31 children with EHPVO by selective cannulation of left and right hepatic veins. Rex vein patency, type of intrahepatic portal venous anatomy (Types A-E), and factors associated with patency of Rex vein were studied. RESULTS: The patency of Rex recess on transjugular WHVP was 29%. Complete obliteration of intrahepatic portal venous radicles was the commonest pattern (Type E, 38.7%) while Type A, the favorable anatomy for meso-Rex bypass, was seen in only 12.9%. Patency of the Rex vein, but not the anatomical pattern, was associated with younger age at evaluation (patent Rex: 6.6 ± 4.9 years vs. nonpatent Rex: 12.7 ± 3.9 years, p = 0.001). Under-5-year children had a 12 times greater chance of having a patent Rex vein (odds ratio: 12.22, 95% confidence interval: 1.65-90.40, p = 0.004). Patency or pattern was unrelated to local factors like umbilical vein catheterization, systemic thrombophilia, or disease severity. CONCLUSION: Less than one-third of our pediatric EHPVO patients have a patent Rex vein. Younger age at evaluation is significantly associated with Rex vein patency.

Natural course and outcomes of children with ubiquitin-specific protease 53 (USP53)-related genetic chronic cholestasis.

Ubiquitin-specific protease 53 (USP53) is essential for formation of cellular tight junctions and variations in this gene disrupt the tight junctions, resulting in cholestasis. We describe the clinical manifestations and outcomes of patients with USP53 mutations from the Indian progressive familial intrahepatic cholestasis registry. All 29 patients who harbored mutations in the USP53 gene either in the homozygous, compound heterozygous, or heterozygous state and presented with cholestasis were included. USP53 variants related to cholestasis had good outcomes, with native liver survival in 82.7%, whereas 17.3% required liver transplantation. Jaundice developed in 93% and within 3 months of age in 48.8%. Jaundice resolved in 21 (72.4%). Pruritus 76% at a median age of 7 months (severe in 10/22, 45% and refractory to medical therapy in 4, 18.1%). Majority of them (82.7%) had biallelic mutations. Protein-truncating mutations were present in 20 (69%) and missense mutations in 9 (31%). No correlation was found between the genotype and the outcome.

Therapeutic plasma exchange provides native liver survival benefit in children with acute liver failure: A propensity score-matched analysis.

OBJECTIVES: This study aimed to evaluate the safety and efficacy of therapeutic plasma exchange (TPE) in pediatric acute liver failure (PALF). METHODS: All children aged 2-18 years with PALF were included. The intervention cohort included a subset of PALF patients undergoing complete three sessions of TPE, whereas the matching controls were derived by propensity score matching from the patient cohort who did not receive any TPE. Propensity matching was performed based on the international normalized ratio (INR), grade of hepatic encephalopathy (HE), age, bilirubin, and ammonia levels. The primary outcome measure was native liver survival (NLS) in the two arms on day 28. RESULTS: Of the total cohort of 403 patients with PALF, 65 patients who received TPE and 65 propensity-matched controls were included in analysis. The 2 groups were well balanced with comparable baseline parameters. On day 4, patients in the TPE group had significantly lower INR (P = 0.001), lower bilirubin (P = 0.008), and higher mean arterial pressure (MAP) (P = 0.033) than controls. The NLS was 46.15% in the TPE arm and 26.15% in the control arm. The overall survival (OS) was 50.8% in the TPE arm and 35.4% in the control arm. Kaplan-Meier survival analysis showed a significantly higher NLS in patients receiving TPE than controls (P = 0.001). On subgroup analysis, NLS benefit was predominantly seen in hepatitis A-related and indeterminate PALF. CONCLUSION: TPE improved NLS and OS in a propensity-matched cohort of patients with PALF. Patients receiving TPE had lower INR and bilirubin levels and higher MAP on day 4.

Splenic Stiffness Is the Best Predictor of Clinically Significant Varices in Children With Portal Hypertension.

BACKGROUND AND AIMS: We studied splenic stiffness measurement (SSM) by transient elastography (TE) and portal hemodynamics parameters (PHDp) on Doppler as predictors of clinically significant varices (CSV) in children. METHODS: All children of 6 months to 18 years of age with portal hypertension (PHT) (chronic liver disease, CLD and non-cirrhotic portal hypertension, NCPH) were enrolled. TE for spleen (SSM) and liver (liver stiffness measurement, LSM) and PHDp by Doppler ultrasonography were measured. Noninvasive indices for PHT were calculated. CSV were defined as esophageal varices ≥grade 2 and/or gastric varix. Binary logistic regression analysis (LRA) and receiver operating characteristic statistics were applied. RESULTS: A total of 150 (120 CLD and 30 NCPH) children formed the study cohort. Prevalence of CSV was higher in NCPH than CLD [73.3% vs 53.3%, Odd's ratio (OR) 2.369, P = 0.04]. On LRA, SSM was found to be the only independent predictor of CSV in children with CLD [OR 1.19 (95% Confidence Interval (CI) 1.018-1.16), P = 0.000] as well as in NCPH [OR 1.088 (95% CI 1.018-1.16), P = 0.013]. This model improved prediction of CSV in CLD from 52.5% to 83.9% and in NCPH from 73.3% to 86.7%. In children with CLD, SSM at a cut-off ≥27.6 kPa and in NCPH, SSM at a cut-off ≥29.5 kPa predicted CSV. In children with CLD, SSM correlated with LSM ( R = 0.610, P <0.001) and with noninvasive PHT indices except aspartate aminotransferase-to-platelet ratio index. CONCLUSION: SSM is the best noninvasive predictor of CSV in childhood CLD and NCPH and can be used as screening test for endoscopy in children with PHT.

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.

Subjective global nutritional assessment as a nutritional tool in childhood chronic liver disease.

Objective of the study was to assess subjective global nutritional assessment (SGNA) in children with chronic liver diseases (CLD). Children aged 3 months to 18 years with CLD were prospectively enrolled (January 2016 to October 2018). SGNA was performed as per validated pro forma for children. Nutritional categories were categorised into three groups: A (well-nourished), B (moderately malnourished) and C (severely malnourished). Agreement between SGNA and anthropometric measures, prediction of morbidity and death or liver transplantation (LT) at 1-year post-enrolment by SGNA and inter-observer reliability of SGNA were assessed. Ninety-two subjects were enrolled, median age 23·5 (3-216) months. SGNA classified 47 patients (51·1 %) in group A, 26 (28·3 %) in group B and 19 (20·6 %) in group C. Kendall coefficients disclosed significant association of SGNA with all anthropometric measurements, greatest with weight for age (r = -0·637), height for age (r = -0·581) and mid-arm fat area (r = -0·449). At 12 months follow-up, twenty children died and four received LT. A significantly higher number of children with malnutrition (groups B and C) had poor outcome (OR 6·74 (95 % CI 2·21, 20·55), P = 0·001), increased risk of hospital readmission (OR 12·2 (95 % CI 4·60, 35·88), P = 0·001), higher rate of infectious complications (OR 22·68 (95 % CI 7·29, 70·53), P < 0·0001) and lower median survival with native liver (Log Rank < 0·001) as compared with group A. Inter-observer agreement in assessment of SGNA was good (90·2 %). SGNA, in contrast to anthropometric measures, is a better nutritional assessment tool. It is reliable, comprehensive and predicts poor outcome in childhood CLD.

Safety, Feasibility, Yield, Diagnostic and Prognostic Implications of Transjugular Liver Biopsy in Children and Adolescents.

OBJECTIVES: The objectives of the study were to evaluate the indications, feasibility, complications and clinical implications of transjugular liver biopsy (TJLB) in children. METHODS: Data of all TJLB performed in children <18 years old was retrieved from the computerized hospital information system. TJLB was done using a 19 G quick-core needle biopsy system with 20 mm throw length. Hepatic venous pressure gradient was additionally measured in children with portal hypertension. A single pathologist reviewed all the biopsies again and provided structured information. RESULTS: A total of 102 children, including 5 with acute liver failure underwent TJLB with technical success in 101 (99%). A mean of 2.3 ±â€Š0.9 passes (range: 1-5) was taken for the biopsy. The most common indications for TJLB in our cohort were elevated international normalized ratio >1.5 (66, 64.7%), ascites (46, 45.1%) and thrombocytopenia (platelet count < 60,000/mm3) (42, 41.2%). Mean size of the tissue received was 14.5 ±â€Š5.6 mm with an average of 10.2 ±â€Š4.7 portal tracts. Only one child developed major (category D) complication (hemobilia) and 12 (11.8%) developed minor complications post-procedure. Etiological diagnosis could be made in a total of 64 (63.9%) children undergoing TJLB, the most common diagnosis being autoimmune hepatitis (n = 31), non-cirrhotic portal fibrosis (n = 16) and drug-induced liver injury (n = 4). CONCLUSION: TJLB is well tolerated, feasible and helps make a diagnosis in close to 64% children allowing timely medical and/or surgical intervention. It is especially useful for diagnosis of autoimmune liver diseases, drug-induced liver injury and non-cirrhotic portal fibrosis.

Cystatin C: best biomarker for acute kidney injury and estimation of glomerular filtration rate in childhood cirrhosis.

The objective of the study was to evaluate the diagnostic and prognostic role of serum cystatin C, urinary neutrophil gelatinase-associated lipocalin (NGAL), and renal resistive index (RRI) in AKI among pediatric cirrhotics. The study included cirrhotic children under 18 years of age. AKI was diagnosed as per Kidney Diseases-Improving Global Outcomes (KDIGO) guidelines. All patients underwent measurement of serum cystatin C, urinary NGAL, and RRI at baseline, 3 months, and 6 months. eGFR was calculated using both creatinine- and cystatin-based equations. Of the 247 cirrhotics admitted during the study, 100 gave consent and were included. Forty-one fulfilled the KDIGO definition of AKI of whom 22 showed resolution. Two of these children had a repeat AKI at 2 and 4 months after initial AKI; both resolved with medical management. On logistic regression analysis, serum cystatin C (OR: 544.8, 95% CI: 24.4-12170, p < 0.0005) and urinary NGAL (OR: 1.006, 95% CI: 1001-1.012, p = 0.019) were found to be significantly associated with AKI. Cystatin C alone was the best biomarker for diagnosing AKI in children with decompensation (OR: 486.7, p < 0.0005) or spontaneous bacterial peritonitis (p = 0.02). eGFR calculated by serum cystatin C-based formulas was more reliable than that calculated by creatinine-based equations.Conclusion: Serum cystatin C is the best biomarker for diagnosis of AKI in pediatric cirrhotics, especially with decompensation and SBP. eGFR calculated on serum cystatin C-based equations is more reliable than creatinine-based ones. What is Known: • Acute kidney injury (AKI) is a common complication in cirrhotic adults. • Newer biomarkers have diagnostic and prognostic role in adult cirrhotics. What is New: • Serum cystatin C is a useful biomarker to identify acute kidney injury in cirrhotic children with decompensation. • Glomerular filtration rate calculation is more accurate by cystatin-based equations than creatinine-based equations.

Ninety days transplant free survival with high volume plasma exchange in Wilson disease presenting as acute liver failure.

OBJECTIVE: To study the efficacy and safety of high volume plasma exchange (HVPE) in Wilson disease presenting as acute liver failure (WD-ALF). METHODS: An analysis of prospectively collected data of consecutively admitted WD-ALF cases was done and patients were divided into two groups: (i) high volume plasma exchange (HVPE) group- who received HVPE + standard medical therapy (SMT), and (ii) SMT group- received only SMT. Outcome measure was transplant free survival (TFS) at 90 days post enrollment, change in biochemical, hemodynamic parameters & incidence of organ dysfunction in HVPE as compared to SMT group, and HVPE related complications. RESULTS: Out of the total 43 cases of WD-ALF reported in the study period, 37 were enrolled (median age 9 years, 62.2% males). All biochemical parameters and prognostic indices except blood ammonia and serum creatinine improved significantly at 72 to 96 hours after enrollment in the HVPE group. Overall, TFS at 90 days was present in 9/19 (47.3%) in HVPE group vs 3/18 (16.6%) in the SMT group (OR 2.84, 95% CI 0.91-8.8, P = .049). Kaplan Meier survival analysis revealed that HVPE group had significantly higher cumulative survival as per the Log Rank test (P = .027); median days of survival was 38 days (IQR 12-63) in HVPE group vs 14 (IQR 5-22) days in SMT group. CONCLUSIONS: The present study indicates that in children with WD-ALF, HVPE not only acts as a bridging therapy to LT but may also improve proportion of the cases with TFS.

Efficacy and Safety of Sodium Benzoate in The Management of Hyperammonemia in Decompensated Chronic Liver Disease of the Childhood-A Double-blind Randomized Controlled Trial.

OBJECTIVE: The objective was to evaluate the efficacy and safety of sodium benzoate in the management of hyperammonemia and hepatic encephalopathy (HE) in decompensated chronic liver disease. METHODS: It was a prospective, interventional, double-blinded randomized controlled trial conducted from August 2017 to December 2018. Children with decompensated chronic liver disease and hyperammonemia were included in the study. Those with ammonia >400 µg/dL, already receiving sodium benzoate or with grade III ascites were excluded. Group A received sodium benzoate (400 mg/kg loading dose followed by 200 mg ·â€Škg ·â€Šdaymaintenance for 5 days) along with the standard medical therapy. Group B received standard medical therapy with placebo. RESULTS: A total of 108 episodes of hyperammonemia occurred in 86 patients of whom 16 were excluded. The final analysis included 46 episodes in each group. The median decrease in ammonia from baseline to day 5 was 52 µg/dL in group A versus 42 µg/dL in group B (P = 0.321). There was a significant decrease in ammonia on days 1 and 2 in group A as compared to group B, but not on subsequent days. There was no significant difference in the resolution of HE (57.1% vs 50%; P = 1), but there was higher, albeit insignificant increase in ascites in group A (15.9% vs 4.5%). CONCLUSIONS: Addition of sodium benzoate significantly reduced the ammonia levels on the first 2 days of therapy but the effect was not sustained till day 5. The effect of sodium benzoate would probably be more sustained, if higher dosage (400 mg ·â€Škg ·â€Šday) could be used under monitoring of benzoate levels. There was no effect on resolution of HE. Sodium benzoate caused an increasing trend of adverse events with no effect on short-term survival.

Comparison of Two Diagnostic Criteria for Hepatopulmonary Syndrome-High Prevalence in Biliary Atresia.

OBJECTIVES: There is lack of clarity regarding the exact prevalence of hepatopulmonary syndrome (HPS) in pediatric liver diseases owing to lack of standardized diagnostic criteria. Thus, we aimed to do a comparative study of HPS with respect to its prevalence using the available diagnostic criteria. METHODS: All consecutive children with biliary atresia (BA) and other chronic liver diseases (CLDs) were studied. Prevalence of HPS was compared using the 2 available criteria: demonstration of intrapulmonary vascular dilatation along with either alveolar-arterial oxygen difference (P [A-a] O2) on arterial blood gas analysis of more than 15 mmHg (criteria 1), or higher than age-appropriate calculated value for P (A-a) O2 (criteria 2). RESULTS: A total of 42 children in BA group and 62 in the non-BA CLD group were included. Using the criteria 1, the prevalence of HPS was 42.3%: 57.1% in the BA group and 32.2% in the CLD group, whereas using criteria 2, the prevalence was 48.1%: 61.9% in the BA group and 38.7% in the CLD group. Criteria 2 diagnosed 6 additional patients with HPS compared to criteria 1 (P value 0.405). BA subjects had higher risk (2.9-3 folds) of developing HPS compared to other CLDs. CONCLUSION: There is high prevalence of HPS in pediatric liver disease subjects. Age-appropriate formula for HPS diagnosis may be better applicable in pediatric population. BA subjects have a higher risk of developing HPS compared to other CLDs overall, irrespective of the severity of liver disease and/or portal hypertension.

Living Donor Liver Transplantation for Acute Liver Failure: Donor Safety and Recipient Outcome.

In countries where deceased organ donation is sparse, emergency living donor liver transplantation (LDLT) is the only lifesaving option in select patients with acute liver failure (ALF). The aim of the current study is living liver donor safety and recipient outcomes following LDLT for ALF. A total of 410 patients underwent LDLT between March 2011 and February 2018, out of which 61 (14.9%) were for ALF. All satisfied the King's College criteria (KCC). Median admission to transplant time was 48 hours (range, 24-80.5 hours), and median living donor evaluation time was 18 hours (14-20 hours). Median Model for End-Stage Liver Disease score was 37 (32-40) with more than two-thirds having grade 3 or 4 encephalopathy and 70% being on mechanical ventilation. The most common etiology was viral (37%). Median jaundice-to-encephalopathy time was 15 (9-29) days. Preoperative culture was positive in 47.5%. There was no difference in the complication rate among emergency and elective living liver donors (13.1% versus 21.2%; P = 0.19). There was no donor mortality. For patients who met the KCC but did not undergo LT, survival was 22.8% (29/127). The 5-year post-LT actuarial survival was 65.57% with a median follow-up of 35 months. On multivariate analysis, postoperative worsening of cerebral edema (CE; hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.01-6.31), systemic inflammatory response syndrome (SIRS; HR, 16.7; 95% CI, 2.05-136.7), preoperative culture positivity (HR, 6.54; 95% CI, 2.24-19.07), and a longer anhepatic phase duration (HR, 1.01; 95% CI, 1.00-1.02) predicted poor outcomes. In conclusion, emergency LDLT is lifesaving in selected patients with ALF. Outcomes of emergency living liver donation were comparable to that of elective donors. Postoperative worsening of CE, preoperative SIRS, and sepsis predicted outcome after LDLT for ALF.

Profile, risk factors and outcome of acute kidney injury in paediatric acute-on-chronic liver failure.

BACKGROUND & AIMS: There are no studies on acute kidney injury in paediatric acute-on-chronic liver failure. This study was planned with aim to describe the clinical presentation and outcome of acute kidney injury among paediatric acute-on-chronic liver failure patients. METHODS: Data of all children 1-18 years of age presenting with acute chronic liver failure (Asia pacific association for the study of the liver definition) was reviewed. Acute kidney injury was defined as per Kidney Diseases-Improving Global Outcomes guidelines. Poor outcome was defined as death or need for liver transplant within 3 months of development of acute kidney injury. RESULTS: A total of 84 children with acute-on-chronic liver failure were presented to us in the study period. Acute kidney injury developed in 22.6% of patients with acute-on-chronic liver failure. The median duration from acute-on-chronic liver failure to development of acute kidney injury was 4 weeks (Range: 2-10 weeks). The causes of acute kidney injury were hepatorenal syndrome (31.6%), sepsis (31.6%), nephrotoxic drugs (21%), dehydration (10.5%) and bile pigment related acute tubular necrosis in one patient. On univariate analysis, higher baseline bilirubin, higher international normalized ratio, higher paediatric end stage liver disease, presence of systemic inflammatory response syndrome and presence of spontaneous bacterial peritonitis had significant association with presence of acute kidney injury. On logistic regression analysis, presence of systemic inflammatory response syndrome (adjusted OR: 8.659, 95% CI: 2.18-34.37, P = .002) and higher baseline bilirubin (adjusted OR: 1.07, 95% CI: 1.008-1.135, P = .025) were independently associated with presence of acute kidney injury. Of the patients with acute kidney injury, 5(26.3%) survived with native liver, 10(52.6%) died and 4 (21.1%) underwent liver transplantation. CONCLUSION: Acute kidney injury developed in 22.6% of children with acute-on-chronic liver failure. Bilirubin more than 17.7 mg/dL and presence of systemic inflammatory response syndrome were high risk factors for acute kidney injury. Development of acute kidney injury in a child with acute-on-chronic liver failure suggests poor outcome and need for early intervention.

Spectrum of Pediatric Autoimmune Liver Disease and Validation of Its Diagnostic Scores in Indian Children.

OBJECTIVES: There is limited literature on the spectrum of pediatric autoimmune liver disease (AILD, encompassing both autoimmune hepatitis/AIH and autoimmune sclerosing cholangitis [ASC]) in Asian populations and its diagnostic scores similarly require further validation. This work thus aimed to study the clinical characteristics, and to validate available diagnostic criteria in the local pediatric AILD cohort. METHODS: A review of all pediatric AILD cases, presenting over a 6-year (2011-2017) period was done, along with comparison of the available diagnostic scores: original (1999), simplified (2008) score, and new proposed (2017) score. RESULTS: A total of 85 subjects (AIH = 70 and ASC = 15) were diagnosed as having AILD. Majority of the cases in both groups presented with advanced hepatic disease (portal hypertension and/or hepatic decompensation). Overall 38 (44.7%) subjects had extrahepatic autoimmune disorders. Good outcome (survival with native liver with medically controllable disease), was seen in 80% AIH subjects, while poor outcome (death/need for liver transplantation or LT) was seen in 13% subjects, with similar results in the ASC cohort. All the 3 available scores had area under receiver operating characteristic (AUROC) curves exceeding 0.9 suggestive of excellent discrimination of AILD (to non-AILD patients), with no statistical difference between them (P >0.05). CONCLUSIONS: In Indian subcontinent, pediatric AILD subjects usually present with advanced hepatic disease, but may have a good outcome if timely therapy can be instituted. Associated autoimmune disorders should be carefully screened. There is no difference in the predictive value of the available diagnostic scores for pediatric AILD.

Weekly regimen of vitamin D supplementation is more efficacious than stoss regimen for treatment of vitamin D deficiency in children with chronic liver diseases.

There are no evidence-based recommendations on the ideal dose and regimen for supplementation of vitamin D in children with chronic liver disease (CLD). This study aimed to compare the safety and efficacy of weekly and stoss regimens for treatment of vitamin D deficiency in these children. Children between the ages of 1 to 18 years with CLD and hypovitaminosis D defined by 25-OH vitamin D (25(OH)D) < 30µg/l were included. They were randomized to receive either stoss regimen (600,000 IU on day 1) or weekly (60,000 IU weekly) regimen of vitamin D. The 25(OH)D levels at 3 and 6 months were compared in the two groups. A total of 210 suspected cases of CLD were assessed for eligibility. Of a total of 67 children satisfying the inclusion criteria, 33 and 34 were randomized to receive stoss and weekly regimen, respectively. Final analysis included 28 children in each group. Clinical rickets was seen in 25.4% of children with hypovitaminosis D. The rise in levels of 25(OH)D at 3 months was higher with weekly regimen (34.3 ± 30.7 µg/l) as compared to stoss regimen (17.2 ± 11.5 µg/l) (p = 0.009). Rise at 6 months as compared to baseline was significantly higher with weekly regimen (30.7 ± 24µg/l) as compared to stoss regimen (11 ± 8.4 µg/l) (p < 0.001). Normal levels of 25(OH)D at 6 months were achieved in 24/28 (85.7%) of those receiving weekly regimen and 9/28 (32.1%) of those receiving stoss regimen (p < 0.001). With stoss therapy, 25(OH)D increased at 3 months as compared to baseline but thereafter dropped significantly at 6 months (p = 0.008). CONCLUSION: Weekly regimen of vitamin D supplementation is more effective than stoss regimen for treatment of hypovitaminosis D in children with CLD. Once normal levels are achieved, child should be shifted to 60,000 IU per month as maintenance dose. What is Known: • Vitamin D deficiency is more common and severe in children with chronic liver diseases. • Currently used doses fail to achieve normal vitamin D levels in these children. What is New? • Weekly regimen of 60,000 IU of vitamin D3 is the most effective regimen for treating vitamin D deficiency in children with CLD. • Children with CLD should further receive maintenance dose of 60,000 IU every month.