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.

Prolonged Cholestatic Jaundice Associated with Carnitine Palmitoyltransferase IA Deficiency.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a type of fatty acid oxidation disorder in which long chain fatty acids cannot be transported into mitochondria for further processing and storage in our body. Typically, the patients present with lethargy, hypoglycemia, and raised serum transaminase levels before 2 years of age. Cholestatic jaundice as manifestation of this deficiency has been reported rarely; here, we report an adolescent male with CPT1A deficiency who developed prolonged cholestatic jaundice following a febrile illness.

Prehabilitation: A proactive approach to enhancing outcomes in joint replacement surgery.

Prehabilitation is an emerging proactive and preventive approach to healthcare that focuses on preparing individuals for upcoming medical interventions or procedures. It aims to optimize physical and mental health before the planned medical and surgical interventions. By integrating exercise, psychological support, and lifestyle modifications, prehabilitation empowers individuals to face medical interventions with increased resilience and a higher likelihood of successful outcomes. Prehabilitation helps patients build strength and endurance, which can enhance their ability to withstand the physical stress of surgery and contribute to faster recovery. It plays a crucial role in optimizing outcomes for patients undergoing joint replacement surgery, by enhancing postoperative recovery, reducing complications, and improving the overall quality of life for patients. As the field of orthopaedics continues to evolve, the integration of prehabilitation into standard care protocols has the potential to redefine the landscape of joint replacement surgeries, ultimately improving patient outcomes, and hence more research is required from diverse population groups from developed and developing countries to collate required data and formulate evidence-based clinical guidelines.

Trends of Publications and Country Rankings in Pediatrics, Perinatology, and Child Health from Asia: A Bibliometric Study from 1996 to 2022.

There is a need to analyze the trends of country-wise research output in child heath over the past few decades. A total of 7,87,812 global publications in pediatrics, perinatology and child health were found from 1996 to 2022 in SCOPUS, the largest abstract and citation database of peer-reviewed literature, covering over 35,000 journals from diverse disciplines. About 13.4% of these were published from Asia. There was an average growth of global publications of 3.53 times between 1996 and 2022, with China and India showing higher growth than the global average.

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.

Update on the diagnosis and management of neonatal intrahepatic cholestasis caused by citrin deficiency: Expert review on behalf of the Asian Pan-Pacific Society for Pediatric Gastroenterology, Hepatology, and Nutrition.

Citrin deficiency is an autosomal recessive metabolic liver disease caused by mutations in the SLC25A13 gene. The disease typically presents with cholestasis, elevated liver enzymes, hyperammonemia, hypercitrullinemia, and fatty liver in young infants, resulting in a phenotype known as "neonatal intrahepatic cholestasis caused by citrin deficiency" (NICCD). The diagnosis relies on clinical manifestation, biochemical evidence of hypercitrullinemia, and identifying mutations in the SLC25A13 gene. Several common mutations have been found in patients of East Asian background. The mainstay treatment is nutritional therapy in early infancy utilizing a lactose-free and medium-chain triglyceride formula. This approach leads to the majority of patients recovering liver function by 1 year of age. Some patients may remain asymptomatic or undiagnosed, but a small proportion of cases can progress to cirrhosis and liver failure, necessitating liver transplantation. Recently, advancements in newborn screening methods have improved the age of diagnosis. Early diagnosis and timely management improve patient outcomes. Further studies are needed to elucidate the long-term follow-up of NICCD patients into adolescence and adulthood.

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.

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.

Liver Transplantation Research from India During the Last 25 Years: 1998-2022.

Background and aims: Liver transplant surgery has been performed in India for the last 25 years. We aimed to analyse the trends, characteristics, and key elements in the field of liver transplantation research from India. Methods: On April 23, 2023, we conducted a search of the Scopus database for the literature on liver transplantation research, using a well-defined search strategy. MS Excel and VOS viewer software programs were used to examine the articles for organisation, author, journal, keywords, and high-cited literature. Results: This analysis examined a total of 556 papers, which constituted only a 1.55% share of the global output. These papers involved 442 organizations, 1575 authors, and 147 journals. External funding was received in 4.13% and 23.56% were involved in international collaboration. Three Delhi-NCR organizations, namely the Medanta-The Medicity (n = 63), Institute of Liver & Biliary Sciences (n = 60), and Indraprastha Apollo Hospital (n = 48) led in publication productivity. M. Rela (n = 90) and A.S. Soin (n = 63) were the leading authors in publication productivity, while S. Sudhindran and P. Bhangui were the most impactful authors. Liver Transplantation (n = 96) and Journal of Clinical & Experimental Hepatology (n = 65) published the maximum number of these papers, whereas, Annals of Surgery and Journal of Hepatology led in the citation impact per paper. The most significant keywords were "Liver Transplantation" (n = 484), and "Living Donor" (n = 254). Only 1.80% (n = 10) of the papers were highly cited papers that received 50 to 142 citations and they together registered 69.9 citations per paper. Conclusion: Although the number of publications on liver transplantation from India started growing recently, it forms only 1.55% of the global report. There is an unmet need to increase government-supported research and multicenter collaborative studies at national and international levels for high-quality patient care.

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.

Esophageal Stricture and Dermal Pathology Related to Compound Heterozygous Mutations in the TNXB Gene.

The Ehlers-Danlos' syndrome (EDS) constitutes a group of connective tissue disorders that are clinically and genetically heterogeneous. Mutations in the TNXB gene have been recognized as pathogenic causing classical-like EDS due to tenascin-X deficiency. Here, we have reported a unique case of compound heterozygous mutation in TNXB gene leading to esophageal stricture and scarred skin in a 7-year-old boy who presented to us with impacted foreign body in esophagus. The child was also having tendency to atrophic skin scarring secondary to trivial trauma.

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.

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.

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.

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.