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.

Circulating bacterial peptides and linked metabolomic signatures are indicative of early mortality in pediatric cirrhosis.

BACKGROUND: Patients with pediatric cirrhosis-sepsis (PC-S) attain early mortality. Plasma bacterial composition, the cognate metabolites, and their contribution to the deterioration of patients with PC-S to early mortality are unknown. We aimed to delineate the plasma metaproteome-metabolome landscape and identify molecular indicators capable of segregating patients with PC-S predisposed to early mortality in plasma, and we further validated the selected metabolite panel in paired 1-drop blood samples using untargeted metaproteomics-metabolomics by UHPLC-HRMS followed by validation using machine-learning algorithms. METHODS: We enrolled 160 patients with liver diseases (cirrhosis-sepsis/nonsepsis [n=110] and noncirrhosis [n=50]) and performed untargeted metaproteomics-metabolomics on a training cohort of 110 patients (Cirrhosis-Sepsis/Nonsepsis, n=70 and noncirrhosis, n=40). The candidate predictors were validated on 2 test cohorts-T1 (plasma test cohort) and T2 (1-drop blood test cohort). Both T1 and T2 had 120 patients each, of which 70 were from the training cohort. RESULTS: Increased levels of tryptophan metabolites and Salmonella enterica and Escherichia coli-associated peptides segregated patients with cirrhosis. Increased levels of deoxyribose-1-phosphate, N5-citryl-d-ornithine, and Herbinix hemicellulolytic and Leifsonia xyli segregated patients with PC-S. MMCN-based integration analysis of WMCNA-WMpCNA identified key microbial-metabolic modules linked to PC-S nonsurvivors. Increased Indican, Staphylobillin, glucose-6-phosphate, 2-octenoylcarnitine, palmitic acid, and guanidoacetic acid along with L. xyli, Mycoplasma genitalium, and Hungateiclostridium thermocellum segregated PC-S nonsurvivors and superseded the liver disease severity indices with high accuracy, sensitivity, and specificity for mortality prediction using random forest machine-learning algorithm. CONCLUSIONS: Our study reveals a novel metabolite signature panel capable of segregating patients with PC-S predisposed to early mortality using as low as 1-drop blood.

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.

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.

Pediatric Acute-on-Chronic Liver Failure.

Acute-on-chronic liver failure (ACLF) is characterized by an acute hepatic insult happening in a patient with underlying cirrhosis with compromised hepatic reserve leading to development of systemic inflammation, sepsis, and organ failure resulting in poor outcome in majority. While Asia Pacific Association for Study of Liver Diseases (APASL) emphasizes on early diagnosis before development of organ failure, European Association for Study of Liver Diseases (EASL) mandates the presence of organ failures to define ACLF. There is a lack of consensus definition of pediatric ACLF although recent APASL guidelines have tried to address the issue. While Wilson disease (WD) and autoimmune hepatitis (AIH) are the most common cause of underlying cirrhosis in children, acute viral hepatitis and flares of WD and AIH are the commonest acute precipitating events. Poor outcomes [death and liver transplantation (LT)] ranging from 19 to 59% have been reported. Prognosis in pediatric ACLF is usually better than that in adults due to greater proportion of treatable etiologies, lesser organ failures, comorbidities and better hepatic reserves. APASL ACLF Research Consortium (AARC) score more than or equal to 11 is predictive of poor 28-90 d mortality. Treatment of pediatric ACLF relies mainly on prompt diagnosis and medical management of a potentially treatable etiology of underlying cirrhosis. Bridging therapies, especially high volume plasma exchange can be initiated early as a bridge to LT or native liver recovery. Those with no improvement in 4-7 d should undergo LT before development of sepsis or multi-organ failure.

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.

Live donor liver transplantation for pediatric acute liver failure: challenges and outcomes.

OBJECTIVE: This study aimed at studying the challenges and outcomes of live-donor liver transplantation (LDLT) for pediatric acute liver failure (PALF). STUDY DESIGN: A total of 315 patients with PALF were treated over a period of 11 years. 42 underwent LT (41 LDLT and one DDLT), constituting 38% (41/110) of all pediatric transplants during this duration. The outcomes of LDLT for PALF were analyzed. RESULTS: All the 41 children who underwent LT met the Kings College criteria (KCC). The etiology was indeterminate in 46.3% (n = 19) children. 75.6% (n = 31) were on mechanical ventilation for grade 3/4 hepatic encephalopathy. There was presence of cerebral edema on a computed tomography scan of the brain in 50% of the children. One-third of our children required hemodynamic support with vasopressors. Systemic inflammatory response syndrome and sepsis were observed in 46.3% and 41.4% of patients, respectively. Post-LDLT 1- and 5-yr patient and graft survival were 75.6% and 70.9%, respectively. The survival in children satisfying KCC but did not undergo LT was 24% (38/161). Vascular and biliary complication rates were 2.4% and 4.8%, respectively. No graft loss occurred because of acute rejection. In multivariate analysis, pre-LT culture positivity and cerebral edema, persistence of brain edema after transplantation, and resultant pulmonary complications were significantly associated with post-LT death. Thirteen (32%) children who underwent plasmapheresis prior to LT had better post-LT neurological recovery, as evidenced by early extubation. CONCLUSION: LDLT for PALF is lifesaving and provides a unique opportunity to time transplantation. Good long-term survival can be achieved, despite the majority of patients presenting late for transplantation. Early referral and better selection can save more lives through timely transplantation.

Treatment of intractable cholangitis in children with biliary atresia: Impact on outcome.

OBJECTIVES: To evaluate the response and outcome with prolonged intravenous antibiotics including home-based intravenous antibiotics in children with intractable cholangitis (IC) after Kasai portoenterostomy (KPE) for biliary atresia (BA). METHODS: A retrospective review of treatment and outcome of children with IC post KPE (no resolution after four weeks of antibiotics) was done between 2014 and 2020. A protocol-based antibiotic regimen was used based on sensitivity and hospital antibiogram. Children afebrile for more than three days were discharged on home intravenous antibiotics (HIVA). RESULTS: Twenty children with IC were managed with prolonged antibiotic regimen, including HIVA. All patients were initially listed for liver transplantation (LT) with indication being IC (n = 20) with portal hypertension (n = 12). Seven patients had bile lakes of which four underwent percutaneous transhepatic biliary drainage. Bile culture grew Klebsiella in four and Escherichia coli and Pseudomonas one each. There were eight children with IC who had positive blood culture with most of these organisms being gram-negative (Escherichia coli: 5, Klebsiella pneumoniae: 2, Enterococcus: 1). Median duration of antibiotics was 58 days (interquartile range [IQR] 56-84). Median follow-up period post cholangitis was three years (IQR 2-4). Following treatment, 14 patients were successfully delisted from LT waitlist and are presently jaundice-free. Two of the five patients undergoing LT died of sepsis. One patient died awaiting LT. CONCLUSION: Timely and aggressive step-up antibiotic regimen may successfully treat IC and prevent/delay LT. HIVA provides a cost-effective and comfortable environment for a child which might improve compliance with intravenous antibiotics.

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.

Percutaneous Cholecystocholangiography-A Tool to Conclusively Exclude Biliary Atresia.

The objective of this study was to evaluate the feasibility, safety, and diagnostic accuracy of percutaneous cholecystocholangiography (PCC) in cases of conjugated hyperbilirubinemia in which biliary atresia (BA) could not be diagnosed or ruled out based on clinical, radiological, and histopathological findings. This was a retrospective, chart review of all cholestatic infants who underwent PCC within the last 5 y. PCC was performed via the transhepatic route using 23-g needle. The patency of both the proximal and distal biliary trees was assessed. PCC was technically feasible in 12/13 (92.3%) of infants without any procedure-related complications. PCC demonstrated proximal and distal biliary patencyin 7/12 (58.3%) infants, thereby avoiding unnecessary laparotomy in them. PCC failed to demonstrate biliary patency in 5 infants; of which, 4 were confirmed as cases of BA on laparotomy. PCC can correctly differentiate BA from non-BA cases of conjugated hyperbilirubinemia preoperatively, reducing the negative laparotomy rates.

Incidence and Predictors of Relapse After Stopping Antiviral Therapy in Pediatric Chronic Hepatitis B.

BACKGROUND: There are no definite end-points for stopping therapy in pediatric chronic hepatitis B (CHB). The study objective was to evaluate the incidence of relapse after stopping antiviral therapy and to identify its predictors. METHODS: All hepatitis B surface antigen (HBsAg) positive children presenting to our hospital, who had been on antivirals for at least 2 years with undetectable hepatitis B virus-deoxyribonucleic acid (HBV-DNA) and normal alanine aminotransferase (ALT) on 3 consecutive occasions over last 12 months were included. Antivirals were stopped if liver biopsy showed histological activity index <5 and fibrosis (Ishak) <3. Virological relapse was defined as the elevation of HBV-DNA (>2000 IU/mL) and biochemical relapse as a rise in ALT levels to >2 times the upper limit of normal. Those having biochemical relapse were started on pegylated interferon alpha-2b-based sequential therapy. RESULTS: Of the 114 children with CHB screened, 31 HBsAg-positive children fulfilled inclusion criteria and antivirals were stopped in them. Virological and biochemical relapse was seen in 12 (38.7%) and 5 (16.1%) children within 12 months of stopping antiviral treatment. On Cox regression, hepatitis B e antigen (HBeAg) positive status at the time of stopping antiviral therapy (HR: 6.208, 95% CI: 1.630-23.638) and longer time taken for HBV-DNA to become undetectable while on antivirals (HR: 1.027, 95% CI: 1.000-1.055) were the independent predictors of relapse. CONCLUSION: Discontinuation of antiviral treatment in children with CHB resulted in relapse in one-third of the patients. Relapse was frequent in those who were HBeAg-positive at the time of stopping therapy and in those who required longer therapy for HBV-DNA to become undetectable.

Recent updates on progressive familial intrahepatic cholestasis types 1, 2 and 3: Outcome and therapeutic strategies.

Recent evidence points towards the role of genotype to understand the phenotype, predict the natural course and long term outcome of patients with progressive familial intrahepatic cholestasis (PFIC). Expanded role of the heterozygous transporter defects presenting late needs to be suspected and identified. Treatment of pruritus, nutritional rehabilitation, prevention of fibrosis progression and liver transplantation (LT) in those with end stage liver disease form the crux of the treatment. LT in PFIC has its own unique issues like high rates of intractable diarrhoea, growth failure; steatohepatitis and graft failure in PFIC1 and antibody-mediated bile salt export pump deficiency in PFIC2. Drugs inhibiting apical sodium-dependent bile transporter and adenovirus-associated vector mediated gene therapy hold promise for future.

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.

Dynamic Optic Nerve Sheath Diameter (ONSD) guided management of raised intracranial pressure in pediatric acute liver failure.

BACKGROUND AND AIMS: The objectives were to evaluate the role of optic nerve sheath diameter (ONSD) to detect raised intracranial pressure (ICP) in pediatric acute liver failure (PALF), study the variations in ONSD with ICP-lowering measures and to evaluate its prognostic role. METHODS: PALF with clinical evidence of raised ICP were enrolled as cases, while those without raised ICP were control group A. ONSD was measured at admission and repeated regularly. It was also measured at time of each new episode of raised ICP and 2 h after the management of such episode. RESULTS: 31 PALF with raised ICP were included as cases and 15 without as control group A. ONSD was significantly higher in cases: 5 mm (IQR: 4.7-5.4) as compared to control group A: 3.8 mm (IQR: 3.3-4). ONSD greater than 4.55 mm at baseline diagnosed clinically raised ICP with 87.5% sensitivity and 100% specificity. The mean ONSD was 5.44 ± 0.49 mm during a total of 90 events of acute raised ICP. Clinical responders had a decrease in ONSD by 0.59 ± 0.24 mm by 2 h, whereas non-responders showed a decrease of 0.18 ± 0.23 mm, p < 0.0005. ONSD persisting more than 4.6 mm by 24 h of management predicted poor outcome with sensitivity and specificity of 83.3% and 72.7%. CONCLUSION: ONSD is a simple, bedside, inexpensive, reproducible and repeatable modality to assess ongoing change in ICP in PALF. ONSD more than 4.55 mm suggests raised ICP. The goal should be to bring ONSD down to less than 4.6 mm within 24 h by aggressive anti-ICP therapy to achieve favourable outcome.