Spectrum and trend of pediatric inflammatory bowel disease: A two-decade experience from northern India.

BACKGROUND: Pediatric inflammatory bowel disease (IBD) has been known to be a disease predominant in the west. There is scarcity of data on pediatric IBD (P-IBD) from northern India. The objective of our study was to analyze the clinical spectrum of P-IBD in northern India. METHODS: A retrospective analysis of 126 children (<18-year old) diagnosed with IBD from January 1999 to December 2019 was done on a pre-designed proforma. It was systematically entered in a MS Excel spreadsheet and analyzed using Statistical Package for the Social Sciences (SPSS) version 21.0. The descriptive phenotypes of Ulcerative colitis (UC) and Crohn's disease (CD) were revised according to the Paris classification. RESULTS: Of 126 children, UC was diagnosed in 76 (60.3%), CD in 44 (34.9%) and IBD-unclassified (IBD-U) in six (4.76%) patients. The mean age at diagnosis was 11.3 years; 38.8% were < 10 years with the male: female ratio of 1.6:1. Sixteen children (12.7%) had very early onset IBD (VEOBD). Overall, the median time to diagnosis in IBD was 12 months (interquartile range [IQR]: 3.25-24), which was as high as 52.5 months (IQR: 11-98) in CD. Pancolitis with bleeding per rectum and ileocolonic involvement with pain in abdomen were the commonest presentations in UC and CD, respectively. Stricturing disease was seen in 27% of CD cases. Relapses were seen in 46% (35/76) of U.C and 23% (10/44) of CD kids. Step-up treatment protocol was employed in them with the use of biologicals in 12% of cases. There was a 2.75-fold rise in the IBD cases in the last 10 years (2010-20). There was reduction in time to diagnosis (21 months vs. 90 months; p - 0.012) and empirical anti-tubercular therapy use (90% vs. 5.8%) in CD over two decades. CONCLUSION: From our experience in a tertiary care centre in northern India, P-IBD is on the rise. UC is more common than CD. Pancolitis and ileocolonic disease are the commonest disease sites in UC and CD, respectively There is a significant delay in the time to diagnosis in CD. Stricturing disease was seen in a quarter of children with CD.

Restructuring Living-Donor Liver Transplantation at a High-Volume Center During the COVID-19 Pandemic.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has led to deferral of elective transplants and proactive pretransplant testing of the donor/recipient. The impact of these on living-donor liver transplantation (LDLT) activity and outcome is not known. We performed LDLT only for sick patients or patients with advanced hepatocellular carcinoma in this period, with special COVID protocols. METHODS: Patients undergoing LDLT counseling, evaluation, and transplant in the period March to June 2020 (group A) under COVID-19 restrictions and special protocols were included. LDLT activity and outcomes among these patients were compared with those in the same period in 2019 (group B). RESULTS: In the period March 15-June 10, we performed 39 and 23 (59%) LDLTs in 2019 and 2020, respectively. The adult patients with cirrhosis in group A (n = 20) had a significantly higher MELD score, 19.8 ± 7.0 versus 16.1 ± 5.6 in group B (n = 36), p = 0.034. Early recipient mortality was similar in 2019 (2/39) and 2020 (2/23). One of 23 post-transplant recipients, 3/71 recipients and donors during evaluation, and 8/125 healthcare workers (HCWs) developed COVID-19, all of whom recovered uneventfully. CONCLUSION: LDLT activity substantially reduced during the COVID era. The incidence and outcome of COVID-19 among the waiting or transplanted patients and HCWs were similar to those of the general population. The outcome after LDLT in the COVID era was similar to that in non-COVID times. These data suggest that LDLT may be extended to more stable patients with strict protocols.

Indian National Association for the Study of Liver Consensus Statement on Acute Liver Failure (Part-2): Management of Acute Liver Failure.

Acute liver failure (ALF) is not an uncommon complication of a common disease such as acute hepatitis. Viral hepatitis followed by antituberculosis drug-induced hepatotoxicity are the commonest causes of ALF in India. Clinically, such patients present with appearance of jaundice, encephalopathy, and coagulopathy. Hepatic encephalopathy (HE) and cerebral edema are central and most important clinical event in the course of ALF, followed by superadded infections, and determine the outcome in these patients. The pathogenesis of encephalopathy and cerebral edema in ALF is unique and multifactorial. Ammonia plays a crucial role in the pathogenesis, and several therapies aim to correct this abnormality. The role of newer ammonia-lowering agents is still evolving. These patients are best managed at a tertiary care hospital with facility for liver transplantation (LT). Aggressive intensive medical management has been documented to salvage a substantial proportion of patients. In those with poor prognostic factors, LT is the only effective therapy that has been shown to improve survival. However, recognizing suitable patients with poor prognosis has remained a challenge. Close monitoring, early identification and treatment of complications, and couseling for transplant form the first-line approach to manage such patients. Recent research shows that use of dynamic prognostic models is better for selecting patients undergoing liver transplantation and timely transplant can save life of patients with ALF with poor prognostic factors.

Indian National Association for the Study of the Liver Consensus Statement on Acute Liver Failure (Part 1): Epidemiology, Pathogenesis, Presentation and Prognosis.

Acute liver failure (ALF) is an infrequent, unpredictable, potentially fatal complication of acute liver injury (ALI) consequent to varied etiologies. Etiologies of ALF as reported in the literature have regional differences, which affects the clinical presentation and natural course. In this part of the consensus article designed to reflect the clinical practices in India, disease burden, epidemiology, clinical presentation, monitoring, and prognostication have been discussed. In India, viral hepatitis is the most frequent cause of ALF, with drug-induced hepatitis due to antituberculosis drugs being the second most frequent cause. The clinical presentation of ALF is characterized by jaundice, coagulopathy, and encephalopathy. It is important to differentiate ALF from other causes of liver failure, including acute on chronic liver failure, subacute liver failure, as well as certain tropical infections which can mimic this presentation. The disease often has a fulminant clinical course with high short-term mortality. Death is usually attributable to cerebral complications, infections, and resultant multiorgan failure. Timely liver transplantation (LT) can change the outcome, and hence, it is vital to provide intensive care to patients until LT can be arranged. It is equally important to assess prognosis to select patients who are suitable for LT. Several prognostic scores have been proposed, and their comparisons show that indigenously developed dynamic scores have an edge over scores described from the Western world. Management of ALF will be described in part 2 of this document.

Intussusception in children aged under two years in India: Retrospective surveillance at nineteen tertiary care hospitals.

OBJECTIVE: Intussusception has been linked with rotavirus vaccine (RVV) as a rare adverse reaction. In view of limited background data on intussusception in India and in preparation for RVV introduction, a surveillance network was established to document the epidemiology of intussusception cases in Indian children. METHODS: Intussusception in children 2-23 months were documented at 19 nationally representative sentinel hospitals through a retrospective surveillance for 69 months (July 2010 to March 2016). For each case clinical, hospital course, treatment and outcome data were collected. RESULTS: Among the 1588 intussusception cases, 54.5% were from South India and 66.3% were boys. The median age was 8 months (IQR 6, 12) with 34.6% aged 2-6 months. Seasonal variation with higher cases were documented during March-June period. The most common symptoms and signs were vomiting (63.4%), bloody stool (49.1%), abdominal pain (46.9%) and excessive crying (42.8%). The classical triad (vomiting, abdominal pain, and blood in stools) was observed in 25.6% cases. 96.4% cases were diagnosed by ultrasound with ileocolic location as the commonest (85.3%). Management was done by reduction (50.8%) and surgery (41.1%) and only 1% of the patients' died. 91.1% cases met Brighton criteria level 1 and 3.3% Level 2. Between 2010 and 2015, the case load and case ratio increased across all regions. CONCLUSION: Intussusception cases have occurred in children across all parts of the country, with low case fatality in the settings studied. The progressive rise cases could indicate an increasing awareness and availability of diagnostic facilities.

Wilson's Disease: Clinical Practice Guidelines of the Indian National Association for Study of the Liver, the Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition, and the Movement Disorders Society of India.

Clinical practice guidelines for Wilson's disease (WD) have been published by the American Association for the Study of Liver Diseases and European Association for the Study of the Liver in 2008 and 2012, respectively. Their focus was on the hepatic aspects of the disease. Recently, a position paper on pediatric WD was published by the European Society of Pediatric Gastroenterology Hepatology and Nutrition. A need was felt to harmonize guidelines for the hepatic, pediatric, and neurological aspects of the disease and contextualize them to the resource-constrained settings. Therefore, experts from national societies from India representing 3 disciplines, hepatology (Indian National Association for Study of the Liver), pediatric hepatology (Indian Society of Pediatric Gastroenterology, Hepatology and Nutrition), and neurology (Movement Disorders Society of India) got together to evolve fresh guidelines. A literature search on retrospective and prospective studies of WD using MEDLINE (PubMed) was performed. Members voted on each recommendation, using the nominal voting technique. The Grades of Recommendation, Assessment, Development and Evaluation system was used to determine the quality of evidence. Questions related to diagnostic tests, scoring system, and its modification to a version suitable for resource-constrained settings were posed. While ceruloplasmin and 24-h urine copper continue to be important, there is little role of serum copper and penicillamine challenge test in the diagnostic algorithm. A new scoring system - Modified Leipzig score has been suggested with extra points being added for family history and serum ceruloplasmin lower than 5 mg/dl. Liver dry copper estimation and penicillamine challenge test have been removed from the scoring system. Differences in pharmacological approach to neurological and hepatic disease and global monitoring scales have been included. Rising bilirubin and worsening encephalopathy are suggested as indicators predicting need for liver transplant but need to be validated. The clinical practice guidelines provide recommendations for a comprehensive management of WD which will be of value to all specialties.

Outcome of 200 Pediatric Living Donor Liver Transplantations in India.

OBJECTIVE: To describe our experience of pediatric living donor liver transplantation from India over a period of 12 years. MATERIALS AND METHODS: A retrospective analysis of 200 living donor liver transplantation in children (18 years or younger) was done for demographic features, indications, donor and graft profile and outcome. RESULTS: Between September 2004 and July 2016, 200 liver transplants were performed on 197 children. Fifty transplants were done in initial 6 years and 150 in next 6 years. All donors (51% mothers) were discharged with a mean stay of 7 days. The leading indications of liver transplants were cholestatic liver disease (46%) followed by metabolic liver disease (33%) and acute liver failure/acute on chronic liver failure (28.5%). Biliary leakage (8.5%), biliary stricture (9%), hepatic artery thrombosis (4.5%) and portal vein thrombosis (4%) were the most common surgical complications; all could be managed by surgical or interventional radiological measures, except in one child who died. Sepsis, acute rejection and CMV hepatitis in first 6 months were seen in 14.5%, 25% and 17% cases, respectively. Post-transplant lymphoproliferative disease was seen in only 1.5%. Re-transplant rate was 1.5%. The overall 1 year survival rate was 94% and 5 year actuarial survival was 87% with no statistically significant difference between children weight <10 kg vs. >10 kg. Outcome in acute liver failure did not differ significantly between those with acute on chronic liver failure vs. those with chronic liver disease. CONCLUSIONS: Advances in medical and surgical techniques associated with multidisciplinary teams including skilled pediatric liver transplant surgeons, anesthetists, dedicated pediatric hepatologists, pediatric intensivists, interventional radiologists and pathologists resulted in an excellent outcome of living related liver transplants in children. Low age and weight of the baby does not seem to be a contraindication for liver transplantation as outcome were comparable in our experience.

Prompt diagnosis and management of Epstein-Barr virus-associated post-transplant lymphoproliferative disorder and hemophagocytosis: A dreaded complication in a post-liver transplant child.

EBV-associated PTLD is increasingly recognized as an important cause of morbidity and mortality in both solid organ and hematopoietic stem cell transplant recipients. Mortality rates due to PTLD and virus-induced HLH are reported to be quite high. We report a case of EBV-associated PTLD and HLH in a child after liver transplantation who was successfully managed due to timely intervention. This case highlights that measurement of EBV load by quantitative polymerase chain reaction assays is an important aid in the surveillance and diagnosis of PTLD and early detection of EBV-induced PTLD, and aggressive treatment with rituximab is a key to survival in patients who have undergone liver transplantation.

Molecular Diagnosis of Hereditary Fructose Intolerance: Founder Mutation in a Community from India.

Hereditary fructose intolerance (HFI) is a difficult-to-confirm diagnosis, requiring either invasive liver biopsy-enzyme assay or potentially hazardous fructose challenge test or expensive molecular genetic analysis. Therefore, worldwide there has been a trend towards finding "common mutations" in distinct ethnic groups to simplify the process of diagnosis. The nonspecific presentation of the disease often leads to diagnostic confusion with other metabolic liver disorders such as glycogenoses, galactosemia, and tyrosinemia. This leads to much delay in diagnosis with consequent harm to the patient.We report mutations in the ALDOB gene, from eleven Indian patients, seven of whom belong to the Agarwal community. Six patients from the Agarwal community and two non-Agarwal patients harbored one novel mutation, c.324+1G>A (five homozygous and one heterozygous), in the ALDOB gene. Haplotyping performed in families confirmed a founder effect. The community has been known to harbor founder mutations in other genes such as the MLC1, PANK2, and CAPN3 genes, thus providing another evidence for a founder effect in the community in case of HFI. This may pave the path for a simpler and quicker test at least for this community in India. In addition to the founder mutation, we report four other novel mutations, c.112+1delG, c.380-1G>A, c.677G>A, and c.689delA, and a previously reported mutation, c.1013C>T, in the cohort from India.

A questionnaire survey of pediatric inflammatory bowel disease in India.

BACKGROUND: Inflammatory bowel disease (IBD) is not uncommon in children and is an important cause of morbidity. Since information on IBD in Indian children is sparse, the study aimed at highlighting the salient features in them. MATERIALS AND METHODS: A questionnaire survey was done among 221 children and adolescents with IBD [ulcerative colitis (UC) 93 (42.1 %); Crohn's disease (CD) 122 (55.2 %); unclassified (IBD-U) 6 (2.7 %)] across seven centers in India. The cut-off age was 18 years and below. RESULTS: The mean age of presentation for UC and CD was 10.2 ± 4.4 and 11.0 ± 4.5 years, respectively, with no gender difference. Diarrhea (69.9 %, p = 0.001) and blood in the stools (90.3 %, p = 0.0001) were common in UC, whereas abdominal pain (73.8 %, p = 0.01), fever (39.3 %, p = 0.0001), anemia (64.7 %, p = 0.001), and growth failure (76.2 %, p = 0.0001) were common in CD. Extraintestinal manifestations (EIM) were a feature in 23.6 % and 36.1 % of UC and CD, respectively. Pancolitis (E3) was predominant in UC (70.9 %) and 88 % required steroids. Ileocolonic CD (L3) was common in 72.9 %; 76.2 % required azathioprine for maintenance. Of the children with UC, 11.8 % had complications like massive hemorrhage and toxic megacolon, while 27 % of CD had fistulae, perianal abscess, stricture, and perforation. Biologicals were used in 0.8 % of severe UC and in 12.2 % of CD. In UC, 4.3 % required surgical intervention. CONCLUSION: Pediatric inflammatory bowel disease (P-IBD) in India shares similarities with adult-onset IBD. Distinctive features were growth failure and more severe forms of the disease necessitating immunomodulators.

Gastrointestinal mucormycosis--four cases with different risk factors, involving different anatomical sites.

Mucormycosis of the gastrointestinal tract is a rare infection that usually occurs in patients who are immunocompromised and carries a high mortality. We report four cases of gastrointestinal mucormycosis seen over a one year period with different presentations, risk factors and different anatomical sites of involvement. A preoperative diagnosis was made only in one patient. All underwent surgery, three survived and one died postoperatively from multiorgan failure.

Living donor liver transplantation for giant cavernous hemangioma of liver in a child.

A 10-yr-old girl presented with a seven-month history of upper abdominal discomfort and weight loss. Physical examination revealed an abdominal lump in the right hypochondrium and epigastrium. Ultrasound examination and a computerized tomographic scan showed a large lobulated mass arising from segments I, 1V, and VIII of liver with arteriovenous shunting and multiple small masses in segments VI and VII. An initial diagnosis of hemangioendothelioma with metastasis was made elsewhere following which she received chemotherapy. She had persistent abdominal discomfort because of which she became dependent on narcotics. The patient had fever because of tumor necrosis and also developed peripheral neuropathy. Finally, owing to progressively worsening of symptoms, she underwent left lobe living donor liver transplantation. Histopathological examination showed the mass to be a cavernous hemangioma, and the patient is now well.

Evolution of a reliable biliary reconstructive technique in 400 consecutive living donor liver transplants.

BACKGROUND: Biliary complications (BCs) are a major cause of morbidity and mortality after living donor liver transplantation (LDLT). They occur because the graft hepatic ducts are often small, thin walled, multiple, and may become ischemic during transection. STUDY DESIGN: Of the 460 LDLTs done at our center before November 2009, the first 402 partial liver grafts had at least 3 months of follow-up. In the first 158, conventional hepatic duct isolation was used in the donor (group C). In the last 244 cases, the complete hilar plate and Glissonian sheath approach (HPGS) was used (group H). We compared the incidence and outcomes of BCs in the 2 groups. RESULTS: The rate of BC was significantly lower in group H (5.3%) than in group C (15.8%, p = 0.000). The incidence of early (within 3 months of transplant) BCs was similarly significantly lower in group H (3.3%) than in group C (13.2%, P=0.000). The incidence of late BCs in the 145 patients in group H who had completed at least 12 months of follow-up was 2.8%.The proportion of BCs needing surgical correction was much higher in group C (44%) than in group H (7.7%, p = 0.022). CONCLUSIONS: By providing a graft with a well-vascularized hepatic duct or ducts with a sheath of supporting tissue that holds sutures well, the HPGS approach minimizes the incidence and severity of BCs in LDLT.

Langerhans cell histiocytosis with digestive tract involvement.

Gastrointestinal tract (GIT) involvement in Langerhans cell histiocytosis (LCH) is not commonly described. We present two children presenting with GIT involvement with LCH, one successfully treated on standard protocol and other being treated on a protocol for relapsed disease. A review of literature showed almost 95% children were less than 2 years of age and 62% were females. Vomiting, abdominal pain, constipation, intractable diarrhea, malabsorption, bloody stools, protein-losing enteropathy, and even intestinal perforation are some of the reported symptoms. More than 50% patients died within 18 months from diagnosis.

Management of chronic hepatitis B in children.

Hepatitis B virus (HBV) infection is a worldwide problem and can cause acute liver failure, acute hepatitis, chronic hepatitis, liver cirrhosis, and liver cancer. In areas of high prevalence such as in Asia, Africa, southern Europe, and Latin America, the hepatitis B surface antigen positive rate ranges from 2% to 20%.In endemic areas, HBV infection occurs mainly during infancy and early childhood. Mother-to-infant transmission accounts for approximately half of the chronic HBV infections. In contrast to infection in adults, HBV infection during early childhood results in a much higher rate of persistent infection and long-term serious complications such as liver cirrhosis and HCC.Three phases of chronic hepatitis B have been identified: the immune-tolerant phase, the immune-active phase, and the inactive hepatitis B phase. These phases of infection are characterized by variations in viral replication, hepatic inflammation, spontaneous clearance, and response to antiviral therapy.The optimal goal of antiviral therapy for chronic HBV infection is to eradicate HBV and to prevent its related liver complications. However, due to the limited effect of available therapies in viral eradication, the goal of treatment is to reduce viral replication, to minimize liver injury, and to reduce infectivity. In this review the current recommendations for monitoring and treating chronic HBV infection in children are reviewed.