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.

Understanding the living-related pediatric liver transplantation donor's decision process: A questionnaire-based retrospective study.

OBJECTIVES: To analyse the donor characteristics and understand the sociocultural and familial aspects of the decision to donate for living donor liver transplant. METHODS: This is a retrospective study done in the Department of Pediatric Gastroenterology and Hepatology of a liver transplant centre. We enrolled the consenting donors of pediatric liver transplantation between January 2020 and January 2022. The study was conducted through an anonymized questionnaire which was drafted in a multiple-choice format. The questionnaire had three domains having questions pertaining to demographic details, donor characteristics and sociofamilial aspects of the decision-making process. RESULTS: The study cohort consisted of 50 donors, 23 males (46%) and 27 females (54%), with the mean age being 31.8 ± 5.6 years. Parent-to-child was the most frequent relationship (n = 39, 78%). More than half of our donors had annual income <2.5 lakh/annum or <3500 USD (n = 27, 54%). Twenty-six (52%) responders had >4 members in their family; 62% were residing in urban areas and 52% of the donors were graduates. The main source of information regarding the feasibility of living donor liver transplantation was primary physicians in 46%. Financial management was the main hurdle in 72%. Majority (74%) denied any effect on their marital relationship and 6% of donors thought that the degree of information provided to them before the transplantation regarding donation was insufficient. CONCLUSION: Our study serves as an essential tool for health professionals to provide sufficient support to the donor. Clinical outcomes and cost must be part of the discussion between caregivers, health professionals and fund contributors.

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.

Acute Liver Failure in Dengue: A Common but Overlooked Entity in Pediatric Patients in Tropical Countries.

OBJECTIVE: The objective of the study is to estimate the incidence of acute liver failure (ALF) in dengue infection, understand the demographic and biochemical profiles, and identify prognostic factors associated with mortality. METHODOLOGY: This is a retrospective observational study. We evaluated the data of all pediatric dengue patients admitted over the last 5 years in our hospital to identify patients who fulfilled the criteria for pediatric ALF. Demographic profile, and biochemical and radiological parameters were assessed. Their outcomes and mortality data were analyzed to identify prognostic factors. RESULTS: Thirty children with dengue infection were identified to have developed a during the ALF study period which was 29.1% (30 of 103) of all our ALF admissions. A total of 189 children with dengue infection needed admission during the same period and 15.8% (30 of 189) of them developed ALF. The mean duration of onset of ALF was 5.4 days after fever onset. Twenty-two patients (73%) survived, and 8 patients expired. High creatinine, low albumin level, and multisystemic involvement were identified as poor prognostic markers in those patients who did not survive. CONCLUSION: ALF is common in admitted severe dengue patients. A significant proportion of acute liver patients in endemic countries can be attributed to dengue infection. Low serum albumin, high creatinine, and multi-organ dysfunction during acute illness can be used as prognostic markers in these children. Multicentric prospective studies are needed to validate these results.

Intraoperative portal vein stenting through umbilical vein approach: An innovative salvage procedure for portal vein thrombosis in pediatric liver transplant.

BACKGROUND: IPVS is considered a last resort or a salvage procedure in the event of recurrent PV thrombosis despite multiple attempts at redo PV anastomosis. We employed the opened umbilical vein approach to place the stent in the PV and deliver anticoagulation through a catheter. MATERIALS AND METHODS: From Jan 2017 to Feb 2022, 150 patients underwent pediatric transplantation at department of liver transplant and hepatobiliary surgery unit, Indraprastha Apollo hospitals, New Delhi. Age, weight, PELD Score, diagnosis, portal vein diameter on preoperative CT, Portal flow after stenting, decrease in spleen size after stenting in follow-up CT were collected from a prospectively maintained data base and reviewed. RESULTS: Eight patients underwent IPVS following LDLT (mean age-10.6 ± 2.2 months, mean weight 8.1 ± 1.6, mean PELD score 32.7 ± 7.3). The mean PV diameter on preoperative CT scan was 3.6 mm (range 2.7-5.6 mm). The mean portal flow following stenting was 718.75 cc/min. Percentage reduction in size of the spleen was 26.35% beyond 2nd post-operative week. No patient had recurrent PV thrombosis following IPVS and all maintained an adequate portal flow throughout the immediate postoperative period. Two patients had in-hospital mortality secondary to septic complications. CONCLUSION: Umbilical vein approach is technically feasible, easy to manipulate the stent and catheter placement after stenting helps to deliver anticoagulants locally.

Efficacy of therapeutic plasma exchange in pediatric cases of acute liver failure as an extracorporeal liver support system.

BACKGROUND: Acute liver failure in the pediatric population is often accompanied by deranged metabolism, severe encephalopathy and coagulopathy. A liver transplant is the most viable option for the management of such patients. Therapeutic plasma exchange (TPE) is helpful in improving the liver biochemistry profile, thereby, increasing their likelihood of undergoing a liver transplant METHOD: The study was conducted over a period of 3 years (January 2018 to December 2021). Indications mainly consisted of ALF with hepatic encephalopathy, worsening liver parameters in spite of medical management, and candidacy for undergoing a liver transplant. Plasma exchange was performed daily or alternatively until the patient recovered, succumbed, or was stable enough to undergo a transplant. Biochemical parameters serum bilirubin, ALT, AST serum ammonia serum urea, serum creatinine were recorded before and after TPE sessions. RESULTS: The study group comprised 14 patients of which a total of 28 TPE was performed. There were a total of 5 cases of cryptogenic ALF, 4 of Wilson disease, 2 cases each of infection-related ALF and autoimmune hepatitis, and a single case of drug-induced hepatitis. A total of 5 out of 14 patients underwent a liver transplant and amongst the 9 who did not undergo a transplant, 4 patients expired due to septic shock syndrome; the remaining 5 were discharged in a stable condition following TPE sessions. The disease-free survival was 78.9% and the transplant-free survival was 35.71%. CONCLUSION: TPE plays a crucial role in improving the biochemistry profile of the liver in children with liver failure.

Clinical Profile of Acute Pancreatitis in Children and Adolescents from a Single Center in Northern India.

Introduction: There has been an increase in incidence of pancreatitis in children all over the world; studies in developed countries shown multiple etiological factors such as drugs, infections, trauma, anatomic abnormalities, and/or genetic pancreatitis in children; however, there are sparse data from the developing countries. This study was undertaken to determine the characteristics of Indian children with acute pancreatitis (AP), mainly the clinical features, etiology, complication, association, genetic factors, and outcome and recurrence. Methods: We performed a retrospective study of all patients under the age of 18 years, who had a final diagnosis of pancreatitis admitted at our center between 2017 and 2019. Results: During the 3-year period from 2017 to 2019, 40 patients were admitted at our center with AP. We found a definite etiology in 62.5% cases of patients, which were broadly grouped into seven etiologies: structural, genetic, drug induced, concurrent illness, cholelithiasis related, metabolic, and autoimmune. Recurrence of acute episodes was noted in 13 patients (32.5%). Of these, 11 were found to have a genetic mutation, underlying structural abnormality, or concurrent illness. In our study, we found that 23 patients (57.5%) had mild AP, while 14 patients (35%) had moderately severe pancreatitis; however, 3 patients (7.5%) had severe AP. Discussion: We found that most cases of pancreatitis in children were of mild severity, and the etiology was quite different than adults, and most cases of acute recurrent pancreatitis have a definite etiology of either genetic mutation or structural anomaly.

Differential expression of peroxidase and ABC transporter as the key regulatory components for degradation of azo dyes by Penicillium oxalicum SAR-3.

Fungal species are potential dye decomposers since these secrete spectra of extracellular enzymes involved in catabolism. However, cellular mechanisms underlying azo dye catalysis and detoxification are incompletely understood and obscure. A potential strain designated as Penicillium oxalicum SAR-3 demonstrated broad-spectrum catabolic ability of different azo dyes. A forward suppression subtractive hybridization (SSH) cDNA library of P. oxalicum SAR-3 constructed in presence and absence of azo dye Acid Red 183 resulted in identification of 183 unique expressed sequence tags (ESTs) which were functionally classified into 12 functional categories. A number of novel genes that affect specifically organic azo dye degradation were discovered. Although the ABC transporters and peroxidases emerged as prominent hot spot for azo dye detoxification, we also identified a number of proteins that are more proximally related to stress-responsive gene expression. Majority of the ESTs (29.5%) were grouped as hypothetical/unknown indicating the presence of putatively novel genes. Analysis of few ESTs through quantitative real-time reverse transcription polymerase chain reaction revealed their possible role in AR183 degradation. The ESTs identified in the SSH library provide a novel insight on the transcripts that are expressed in P. oxalicum strain SAR-3 in response to AR183.

Hepatoblastoma in a cirrhotic child with Alagille syndrome.

Alagille syndrome (AGS) is a genetic disorder due to mutations in the JAGGED 1 or NOTCH 2 genes leading to multisystemic manifestations. Though these patients are at risk of developing various liver tumours, no cases of hepatoblastoma among young children with cirrhosis in AGS have been reported. We report a male toddler, with cirrhosis due to AGS who developed a hepatoblastoma. He underwent a liver transplant for decompensated chronic liver disease with marked pruritus, very high alpha-fetoprotein levels and malignant liver lesions on positron emission tomography CT. His explant histology revealed a paucity of bile ducts and liver lesions turned out to be hepatoblastoma for which he received postoperative chemotherapy. The genetic testing sent before transplantation confirmed the clinical diagnosis of AGS. Hepatoblastoma should be suspected in any child with AGS presenting with a right upper quadrant mass even in the setting of chronic liver disease.

Diagnosis and management of pediatric acute liver failure: consensus recommendations of the Indian Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ISPGHAN).

Timely diagnosis and management of pediatric acute liver failure (PALF) is of paramount importance to improve survival. The Indian Society of Pediatric Gastroenterology, Hepatology, and Nutrition invited national and international experts to identify and review important management and research questions. These covered the definition, age appropriate stepwise workup for the etiology, non-invasive diagnosis and management of cerebral edema, prognostic scores, criteria for listing for liver transplantation (LT) and bridging therapies in PALF. Statements and recommendations based on evidences assessed using the modified Grading of Recommendations Assessment, Development and Evaluation (GRADE) system were developed, deliberated and critically reappraised by circulation. The final consensus recommendations along with relevant published background information are presented here. We expect that these recommendations would be followed by the pediatric and adult medical fraternity to improve the outcomes of PALF patients.

Novel mutation in the HSD3B7 gene causes bile acid synthetic disorder and presents as recurrent liver failure in early childhood.

Bile acid synthetic disorders are rare inborn errors of metabolism, and presentations include neonatal cholestasis, neurological disease or deficiency of fat-soluble vitamins. Affected patients fail to produce standard bile acids but accumulate unusual bile acids and intermediates, resulting in liver failure and complications. Most of them improve with bile acid supplementation, but delaying initiating treatment is detrimental to the outcome.A young child presented to us with recurrent episodes of acute liver failure. In the first episode, both coagulopathy and encephalopathy improved on supportive treatment, but the aetiological evaluation was inconclusive. During the second presentation, whole-exome sequencing was sent, identifying a compound heterozygous novel mutation in the 3-ß-hydroxysteroid dehydrogenase type 7 gene leading to bile acid synthetic defect.

Enteric fever masquerading as Crohn's disease in a child with abdominal tuberculosis.

In tropical countries, like India, various types of infectious diseases like tuberculosis, enteric fever, malaria and dengue are prevalent. Disease trend over time has been gradually shifting from infective to inflammatory frame because of increasing awareness regarding hygiene and increasing immunisation coverage. This case report describes an adolescent boy having a long history of abdominal pain, bleeding per rectum and documented weight loss, presented with an acute episode of fever. But the coexisting infections and/or inflammatory conditions presented challenges to the treating physician in diagnosis and management despite of good clinical experience. In this case, a chronic gastrointestinal infection caused by Mycobacterium tuberculosis with a superadded Salmonella typhi infection was masquerading as inflammatory bowel disease (Crohn's disease). Utmost caution should be exercised to reach the correct diagnosis and take the necessary steps to manage this type of situation in tropical countries like India.

Functional constipation: A common and often overlooked cause for abdominal pain in children.

The most common causes for chronic pain abdomen in pediatric practice are functional abdominal pain disorders, a subgroup of functional gastrointestinal disorders under the Rome IV classification. Constipation is usually associated with painful defecation, but abdominal pain as a predominant or presenting symptom of functional constipation (FC) is not very well recognized. We conducted this study to ascertain the prevalence of FC in chronic pain abdomen and proportion of FC children presenting with predominant complaints of pain abdomen. Prevalence of FC and functional abdominal pain was ascertained separately over a 1-year in children > 4 years of age in our hospital. The number of children with FC presenting with abdominal pain was noted. Abdominal pain site and duration were noted in the FC group and were compared with those in the functional abdominal pain group to find out any significance. Diagnosis was based on Rome IV criteria, but relevant investigations to rule out organic pathology were done whenever clinically indicated. The prevalence of abdominal pain was 22% in our gastroenterology service and that of FC was 27%. Among the children presenting with chronic abdominal pain, FC was seen in 10% of the patients and functional abdominal pain disorders in 34%. Among children presenting with constipation, 12% had pain as the sole complaint. However, some form of pain or pain as one of the symptoms was seen in 47.5%.  FC is a major cause for abdomen pain in children and is often overlooked. Not attributing pain to constipation may delay the diagnosis, which may have poor prognosis.

Epiploic appendagitis: Not so unusual cause of paediatric abdominal pain.

Paediatric abdominal pain continues to pose a diagnostic challenge in the acute hospital care setting. We describe an eleven-year-old boy who presented to the emergency department with acute-onset, sharp abdominal pain localised to right lower quadrant. Abdominal imaging was diagnostic for epiploic appendagitis (EA), with pathognomonic 'ring sign' and 'central dot' visualised on the axial computed tomography images. He responded well to conservative treatment, including a short course of non-steroidal anti-inflammatory drugs. EA is a lesser-known paediatric entity mimicking surgical conditions. However, steady but sharp and non-migratory characteristic of the pain in either of the lower abdominal quadrants should raise suspicion for EA. Early accurate diagnosis can prevent unnecessary surgical exploration in these patients.

Pediatric liver transplantation for autoimmune liver disease: Ten-year experience from a liver transplant center in India.

Liver transplantation (LT) has emerged as the best therapeutic modality for end-stage liver disease in pediatric autoimmune liver disease (AILD). We aimed to describe our experience of pediatric living donor liver transplantation for AILD from India over a period of 10 years. We did a retrospective analysis of 244 liver transplants at our center over the last 10 years to identify children with AILD (18 years or younger). We aimed to describe the demographic features, clinical profile, graft survival, patient outcome, and predictors of mortality in our cohort. Between July 2010 and May 2020, 13 liver transplants were performed for AILD out of total 244 children transplanted over the last 10 years at our center. Mean (standard deviation [SD]) age at LT was 12 (± 3.84) years. Leading indications for LT were decompensated liver disease (61.5%), acute-on-chronic liver failure (23.1%), acute liver failure (ALF) (7.7%), and recurrent cholangitis and growth failure (7.7%). Mean Pediatric End-stage Liver Disease (PELD) score/model for end-stage liver disease (MELD) score and international normalized ratio (INR) (SD) at presentation were 24 (± 12.81) and 2.48 (± 1.54), respectively. Median discharge duration was 23 days (interquartile range [IQR] 21-36 days). 30.7% (4/13) of the subjects had no postoperative complications. Diarrhea (15.3%), pneumonia (7.7%), jejunostomy site bleed (7.7%), tacrolimus toxicity (7.7%), and vascular complications (7.7%) were seen, which resolved with satisfactory graft function. Three subjects died post-LT; causes of death included sepsis (n=3), renal dysfunction (n=1), and pneumonia (n=1). Others have been well on follow-up with no graft rejection or need for re-transplantation. Overall, 1-year and 5-year patient survival rates were 76.9% and 70%, respectively. Lower platelet count, autoimmune hepatitis (AIH) 2, and PELD/MELD score were found to be significant predictors of mortality on univariate analysis, which were not significant on multivariate modelling. The complications, graft and patient survival rates in our experience were quite encouraging, and are comparable with the best centers worldwide. After instituting appropriate treatment, early referral of such patients to an equipped center should be facilitated.

Rare case of primary carnitine deficiency presenting as acute liver failure.

Systemic primary carnitine deficiency (PCD) is an autosomal recessive disorder caused by mutations in the SLC22A5 gene that encodes carnitine transporter, OCTN2. Transporter deficiency leads to defective fatty acid oxidation. Signs and symptoms ranging from liver injury in children to cardiomyopathy and skeletal myopathy in adults, manifest during periods of stress and fasting. Though acute liver failure is infrequently described, young children presenting as acute liver failure should be screened for fatty acid oxidation defects including PCD by testing plasma for amino acids and further confirmed by genetic sequencing. Early identification and treatment using L-carnitine is lifesaving. Our patient presented as acute liver failure and diagnosis of PCD was confirmed by metabolic screening and genetic sequencing. He responded to the treatment.

Novel mutation causing congenital disorder of glycosylation in a child with recurrent anasarca.

Protein-losing enteropathy entails an excessive loss of proteins in intestinal tract due to underlying primary or secondary pathologies. It is suspected in patients with chronic diarrhoea and peripheral oedema. Faecal alpha 1 antitrypsin clearance is the gold standard for diagnosis. Treatment includes a high-protein fat-modified diet, and replacements for micronutrients, electrolytes and vitamin deficiencies. Prognosis is variable depending on the underlying cause.

Transient infantile hypertriglyceridaemia due to homozygous mutation in GPD1 presenting in childhood with hepatic adenoma.

Hypertriglyceridaemia in infancy is usually secondary to underlying metabolic disorder which usually has a genetic basis unlike the adult population. One such recently described entity is transient infantile hypertriglyceridaemia (HTGTI). In this disorder, mutation in glycerol-3-phosphate (G3P) dehydrogenase gene leads to deficiency of G3P dehydrogenase resulting in hypertriglyceridaemia and hepatomegaly. Clinical features tend to improve with age but may develop fibrosis. Our patient presented in infancy with hypoglycaemia, hepatomegaly, high transaminases and hypertriglyceridaemia. Limited genetic test for glycogen storage disorder was negative and was kept under follow-up. On follow-up, he developed hepatic lesion and his hepatomegaly with hypertriglyceridaemia persisted. There are only a few cases reported worldwide and none has reported development of adenoma so far. This could be the first report of development of adenoma in transient HTGTI.

Novel Mutation of Tyrosinemia in a Child With Hypophosphatemic Rickets.

Tyrosinemia is an inherited metabolic disease of fumarylacetoacetate enzyme. A male infant presented to us with clinical features of rickets, floppiness, and a deranged coagulation profile. A novel mutation causing Tyrosinemia was discovered on the basis of genetic sequencing.

Progressive Familial Intrahepatic Cholestasis: A Study in Children From a Liver Transplant Center in India.

Background/Aims: This study aimed to delineate the clinical profile of children diagnosed with progressive familial intrahepatic cholestasis (PFIC). Methods: This study was a retrospective analysis of case records of children in the tertiary care hospital, with the diagnosis of PFIC from January 2017 to January 2020. The diagnosis was made using clinical and laboratory parameters and with genetic testing when available. Medical and surgical management was according to the departmental protocol. Liver transplant was offered to children with end-stage liver disease, intractable pruritus, or severe growth failure. Result: There were 13 identified PFIC cases (familial intrahepatic cholestasis 1 [FIC1] deficiency-4, bile salt export pump (BSEP) deficiency-3, tight junction protein [TJP2] deficiency 3, multidrug-resistant protein 3 [MDR3] deficiency 2 and farnesoid X receptor deficiency-1). PFIC subtypes 1, 2, and 5 presented in infancy, whereas MDR3 presented in childhood. TJP2 deficiency had varied age of presentation from infancy to adolescence. Jaundice with or without pruritus was present in most cases. Genetic testing was carried out in 10 children, of which five had a homozygous mutation, three had a compound heterozygous mutation, and two had a heterozygous mutation. Three children (FIC1-2 and TJP2-1) underwent biliary diversion, of which clinical improvement was seen in two. Six children underwent liver transplantation, which was successful in four. Conclusion: Byler's disease was the most common subtype. A clinicopathologic correlation with molecular diagnosis leads to early diagnosis and management. Liver transplantation provides good outcomes in children with end-stage liver disease.