∆4-3-oxo-5ß-reductase deficiency: favorable outcome in 16 patients treated with cholic acid.

BACKGROUND: Oral cholic acid therapy is an effective therapy in children with primary bile acid synthesis deficiencies. Most reported patients with this treatment have 3ß-hydroxy-Δ5-C27-steroid oxidoreductase deficiency. The aim of the study was the evaluation of cholic acid therapy in a cohort of patients with the rarer Δ4-3-oxosteroid 5ß-reductase (Δ4-3-oxo-R) deficiency. METHODS: Sixteen patients with Δ4-3-oxo-R deficiency confirmed by AKR1D1 gene sequencing who received oral cholic acid were retrospectively analyzed. RESULTS: First symptoms were reported early in life (median 2 months of age), with 14 and 3 patients having cholestatic jaundice and severe bleeding respectively. Fifteen patients received ursodeoxycholic acid before diagnosis, with partial improvement in 8 patients. Four patients had liver failure at the time of cholic acid initiation. All 16 patients received cholic acid from a median age of 8.1 months (range 3.1-159) and serum liver tests normalized in all within 6-12 months of treatment. After a median cholic acid therapy of 4.5 years (range 1.1-24), all patients were alive with their native liver. Median daily cholic acid dose at last follow-up was 8.3 mg/kg of body weight. All patients, but one, had normal physical examination and all had normal serum liver tests. Fibrosis, evaluated using liver biopsy (n = 4) or liver elastography (n = 9), had stabilized or improved. Cholic acid therapy enabled a 12-fold decrease of 3-oxo-∆4 derivatives in urine. Patients had normal growth and quality of life. The treatment was well tolerated without serious adverse events and signs of hepatotoxicity. CONCLUSIONS: Oral cholic acid therapy is a safe and effective treatment for patients with Δ4-3-oxo-R deficiency.

Prevalence, management and efficacy of treatment in portal vein obstruction after paediatric liver transplantation: protocol of the retrospective international multicentre PORTAL registry.

INTRODUCTION: Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO. METHODS AND ANALYSIS: The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged <18 years) with a diagnosed PVO between 1 January 2001 and 1 January 2021 after liver transplantation will be eligible for inclusion. The primary endpoints are the prevalence of PVO, primary and secondary patency after PVO intervention and current management practices. Secondary endpoints are patient and graft survival, severe complications of PVO and technical success of revascularisation techniques. ETHICS AND DISSEMINATION: Medical Ethics Review Board of the University Medical Center Groningen has approved the study (METc 2021/072). The results of this study will be disseminated via peer-reviewed publications and scientific presentations at national and international conferences. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL9261).

A retrospective case-control study of gastrostomy use in children undergoing hematopoietic cell transplantation.

BACKGROUND: Maintaining a good nutritional status during the hematopoietic cell transplantation (HCT) procedure is challenging in the pediatric population. METHODS: In a multicentric retrospective study, we compared the outcome of nutritional status and HCT-related parameters in 227 pediatric patients during and after HCT between 2005 and 2015. 112 patients received a gastrostomy before the start of HCT (GS group), and 115 did not receive a gastrostomy (NGS). Data collection was performed at HCT, 3, 6, and 12 months post-HCT. RESULTS: At time point of HCT the Standard Deviation Score (SDS) of weight was 0.17 in the NGS group, and 0.71 in the GS group (p = .01) Patients in the NGS group lost more weight during the first 3 months after HCT than patients in the GS group. At 12 months, patients in the NGS remained at a lower weight, while patients in the GS group slightly increased their weight. There were no differences between the groups in the incidence of acute graft-versus-host-disease (GvHD), overall survival, and non-relapse mortality. However, the number of febrile episodes requiring intravenous treatment with antibiotics, was higher in the GS group as compared to the NGS group, during the first 3 months post-HCT (p < .001). CONCLUSIONS: Our results indicate that gastrostomy can be utilized in children undergoing HCT without any negative effects on mortality. Therefore, the use of a gastrostomy appears to be a safe option to maintain a good nutritional status during the HCT procedure.

Systematic Review and Meta-analysis of Histological Gastric Biopsy Aspects According to the Updated Sydney System in Children.

OBJECTIVES: A descriptive and comparative study of gastric histological aspects according to the updated Sydney classification (USC), obtained from Helicobacter pylori-positive versus H pylori-negative children referred for upper gastrointestinal endoscopy. METHODS: The Prisma method was used to perform a systematic review and meta-analysis. Selection criteria were based on following key words USC, H pylori, children, endoscopy, or biopsy. Publication biases were assessed according to the Newcastle-Ottawa Scale, and a meta-regression analysis was done. The study was registered on the PROSPERO platform. RESULTS: Between 1994 and 2017, 1238 references were found; 97 studies were retained for the systematic review with a total number of 25,867 children; 75 studies were selected for the meta-analysis concerning 5990 H pylori-infected and 17,782 uninfected children.H pylori-positive versus H pylori-negative children, according to the USC, showed significantly higher relative risk for gastric antral and corpus chronic inflammation, presence of neutrophils, and of lymphoid follicles, and gastric mucosa atrophy, whereas, intestinal metaplasia showed a significantly higher RR only in antral biopsies. The meta-regression analysis showed that H pylori-positive versus H pylori-negative children had significantly higher risk only for corpus activity according to age, recurrent abdominal pain, and geographical area of low H pylori prevalence. CONCLUSIONS: H pylori infection in children was associated with higher relative risk for gastric antral and corpus chronic inflammation, presence of neutrophils, lymphoid follicles, and rare gastric mucosa atrophy, whereas, rare intestinal metaplasia was only significantly higher in the antral area.

[Microwave ablation of the spleen: An easy and gentle method for treatment of secondary splenomegaly in children. A case report]. / Mikrovågsablation ­ en skonsam metod vid splenomegali hos barn.

Portal hypertension (PHT) in children may be caused by many different liver and vascular diseases and can lead to life threatening complications such as splenomegaly with thrombocytopenia. The treatment of choice for symptomatic splenomegaly is Partial Splenic Embolization (PSE) which is effective but painful, and therefore not offered to children younger than 10 years of age at the Karolinska University Hospital in Stockholm.  Percutaneous microwave ablation (MWA) is a well-established method in adults for the treatment of tumors in the liver and other organs. It has been used for the treatment of secondary splenomegaly in adults, but to the best of our knowledge MWA for treatment of pediatric splenomegaly has not been studied. We present a successful case report of MWA of the spleen in a young boy with splenomegaly and thrombocytopenia due to liver cirrhosis and PHT.

Is primary hepatic angiosarcoma in children an indication for liver transplantation?-A single-centre experience and review of the literature.

PHA in the paediatric population is an extremely rare and aggressive malignant soft tissue neoplasm, with less than 50 cases published worldwide. The prognosis is dismal. If the tumour is unresectable, one treatment option is LT. In this article, the current available literature is reviewed and additionally, three cases of paediatric patients with PHA who underwent LT at Karolinska University Hospital, Sweden, are presented. Based on the literature and our own experience, there is undoubtedly possible good outcome of LT due to PHA. On the contrary, no patients have survived PHA without LT. PHA in paediatric patients should be recommended to LT in selected patients. Effect of modern adjuvant chemo and RT should be evaluated further based on international registry for such rare cases of PHA.

Diagnostic disagreement between clinical standard histopathological- and retrospective assessment of histopathology-based gastrointestinal graft-versus-host disease in children.

BACKGROUND: No previous paediatric study has evaluated the frequency of diagnostic disagreement between clinical standard histopathological assessment (CSHA) and retrospective, independent, histopathological assessment (RIHA) of gastrointestinal Graft-Versus-Host Disease (GI-GVHD) METHODS: In a retrospective cohort study, based on gastrointestinal biopsies collected from allogeneic HSCT-treated children (<18 years) with symptom-based GI-GVHD, we evaluated; disagreement of histopathology-based GI-GVHD diagnosis in CSHA vs RIHA, and potential clinical consequences of differences between the assessments. The CSHA-based diagnoses were retrieved from histopathology reports. The RIHA was performed by one pathologist, blinded to the CSHA outcomes and based on the minimal criteria for histopathology-based GI-GVHD diagnosis by the NIH 2014. RESULTS: Seventy children with 92 endoscopic occasions (including 22 re-endoscopies) were enrolled. GI-GVHD was observed in 73% (67/92) of the endoscopies in the RIHA and in 54% (50/92) in the CSHA (P = .014). The RIHA confirmed 94% (47/50) with GI-GVHD and 52% (22/42) with non-GI-GVHD diagnoses, established in the CSHA. Disagreement, that is endoscopic occasions with GI-GVHD solely detected in RIHA or detection of GI-GVHD in CSHA but not in RIHA, was observed in 20/42 (48%) and 3/50 (6%), respectively (McNemar's test, P = .0008). The risk of a subsequent re-endoscopy was higher in endoscopic occasions with GI-GVHD detected in RIHA but not in CSHA vs if non-GI-GVHD were detected in both readings (P = .005). CONCLUSION: Our results suggest that in children with symptom-based GI-GVHD without histopathological confirmation in CSHA, a second, NIH 2014 based histopathological assessment should be considered before performing a re-endoscopy.

Clinical relevance of endoscopy with histopathological assessment in children with suspected gastrointestinal graft-versus-host disease.

Endoscopy with histopathological assessment is an established practice to confirm gastrointestinal graft-versus-host disease (GI-GVHD). However, the clinical relevance of this approach in children is incompletely evaluated. In a retrospective cohort study, we investigated the frequency of treatment changes in response to histopathological findings in all children (<18 years) in Sweden who underwent endoscopy for suspected GI-GVHD (2000-2013) after receiving hematopoietic stem cell transplantation. Sixty-eight children with ninety-one endoscopic occasions were enrolled. At the time of endoscopy, anti-GI-GVHD treatment was ongoing in 71% (65/91). In 18% (12/65) with ongoing treatment, no histopathological evidence of GI-GVHD or another cause to justify anti-GI-GVHD treatment was found. In 48% (44/91), endoscopy with histopathological assessment led to changes in the treatment regimen. Re-endoscopy was more frequent among those with treatment changes, versus unchanged treatment, 39% (17/44) and 13% (6/47), respectively (P = .007). Histopathological findings generating treatment changes were as follows: GI-GVHD in 68% (30/44), normal histology in 25% (11/44), and an alternative diagnosis in 7% (3/44). In conclusion, this study supports that endoscopy with histopathological assessment should be considered in all children with suspected GI-GVHD.

European paediatric non-alcoholic fatty liver disease registry (EU-PNAFLD): Design and rationale.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in children and has the potential to progress to advanced fibrosis/cirrhosis, end-stage liver disease and hepatocellular carcinoma. However, the natural history of the condition is poorly understood and there are no approved treatments. The European Paediatric Non-Alcoholic Fatty Liver Disease Registry (EU-PNAFLD) is a multi-centre registry of paediatric NAFLD that will serve as a prospective, observational, natural history study and provide a tractable back-bone to support recruitment into subsequent interventional trials. Collection of samples into a bio-repository will facilitate translational studies, including genome sequencing and metabolomics. EU-PNAFLD will work closely alongside the existing adult European NAFLD Registry to obtain data on clinical outcomes after 20-30 years. Through an international, well-characterised large-scale cohort, EU-PNAFLD will address the key questions in paediatric NAFLD and benefit patients with the condition.

Choice of Endoscopic Procedure in Children With Clinically Suspected Gastrointestinal Graft-versus-host Disease.

OBJECTIVES: Gastrointestinal graft-versus-host disease (GI-GVHD) is a potentially life-threatening complication after hematopoietic stem cell transplantation. Symptoms indicating GI-GVHD motivates endoscopy with biopsy sampling and histopathological confirmation. Optimal extent of endoscopy in children is, however, presently unknown. Therefore, we aimed to evaluate whether biopsies from the rectosigmoid area versus the rest of the colon/ileocolon with or without biopsies from simultaneous upper endoscopy, were equally reliable for detection of GI-GVHD and relevant differential diagnoses. METHODS: Retrospective multicenter study based on histopathological re-evaluation of biopsies and hospital record data, collected from children with suspected GI-GVHD. RESULTS: Forty-four children with 51 endoscopic occasions (81 procedures) were included. Thirty-nine of 51 (76.5%) were diagnosed as GI-GVHD, 14 (27.4%) received a differential diagnosis and 7 (13.7%) had normal histology findings. Comorbidity, that is, simultaneous detection of a differential diagnosis and GI-GVHD, was observed in 9 (23.1%) cases. Cytomegalovirus infection was the most frequent differential diagnosis, 6 of 7 were detected in biopsies from rectosigmoid and esophagogastroduodenal areas. Sensitivity for detection of GI-GVHD in biopsies collected from rectosigmoid-ileocolonic-, rectosigmoid-, or esophagogastroduodenal areas were 97.4%, 84.6%, 83.3%, respectively, and 97.4% when the latter 2 were merged. The difference, nondetected GI-GVHD in the rectosigmoid area versus detected elsewhere in the GI tract, was statistically significant (P = 0.03). CONCLUSIONS: Biopsies collected from the rectosigmoid area solely were not optimal for detection of pediatric GI-GVHD. When biopsy sampling from rectosigmoid and upper GI tract areas was combined, the sensitivity for GI-GVHD was, however, equally high as for ileocolonoscopy or full upper and lower endoscopy.

Sequential Therapy for Helicobacter pylori Infection in Treatment-naïve Children.

UNLABELLED: The goal of first-line Helicobacter pylori therapy is to reach an eradication rate of 90% to avoid further investigations, antibiotic use, and spreading of resistant strains. AIM: To evaluate the eradication rate of high-dose sequential therapy in treatment-naïve children and to assess factors associated with failure. METHODS: Prospective data assessed in a registry from nine European centers between October 2009 and December 2011. Children with biopsy-proven Helicobacter pylori infection were prescribed 5 days of esomeprazole and amoxicillin, followed by 5 days of esomeprazole, clarithromycin, and metronidazole according to bodyweight. Eradication was assessed after 8-12 weeks. Primary endpoint was the eradication rate in children who received at least one dose and had follow-up data. Multivariate analysis evaluated potential factors for treatment success including sex, age, center, migrant status, antibiotic resistance, and adherence to therapy. RESULTS: Follow-up was available in 209 of 232 patients (age range 3.1-17.9 years, 118 females). Primary resistance occurred for clarithromycin in 30 of 209 (14.4%), for metronidazole in 32 (15.3%), for both antibiotics in 7 (3.3%), and culture failed in 6 (2.9%). Eradication was achieved in 168 of 209 children (80.4%, 95% CI 75.02-85.78), in 85.8% with no resistance, 72.6% with single resistance, and 28.6% with double resistance. Independent factors affecting eradication rate included resistance to clarithromycin (adjusted ORs 0.27 (0.09-0.84), p = .024), to metronidazole (0.25 (0.009-0.72), p = .010) or to both (0.04 (0.01-0.35), p = .004), and intake of ≤ 90% of prescribed drugs (0.03 (0.01-0.18), p < .001). CONCLUSION: A high-dose 10-day sequential therapy cannot be recommended in treatment-naïve children.

Helicobacter pylori Infection in European children with gastro-duodenal ulcers and erosions.

BACKGROUND: To analyze risk factors associated with gastro-duodenal ulcers and erosions in children. METHODS: Open, prospective, multicenter, case-control study carried out in 11 European countries in patients with gastric or duodenal ulcers/erosions and 2 age-matched controls each. Possible risk factors were recorded. Logistic regression models were performed with adjustment for centers and age groups. RESULTS: Seven-hundred thirty-two patients (244 cases, 153 with erosions only and 91 with ulcers, and 488 controls) were recruited. Children receiving antimicrobials or acid suppressive drugs before endoscopy were excluded (202 cases/390 controls remained for risk factor analysis). Helicobacter pylori was detected more frequently in cases than controls but only in 32.0% versus 20.1% in controls (P = 0.001). Independent exposure factors for gastric ulcers were male gender (P = 0.001), chronic neurologic disease (P = 0.015), chronic renal disease (P < 0.001) and nonsteroidal anti-inflammatory drug consumption (P = 0.035). Exposure factors for duodenal ulcers were H. pylori infection (P < 0.001) and steroid consumption (P = 0.031). Chronic renal disease was the only independent factor associated with gastric erosions (P = 0.026), those associated with duodenal erosions being H. pylori infection (P = 0.023), active smoking (P = 0.006) and chronic arthritis (P = 0.008). No risk factor was identified in 97/202 (48.0%) cases. CONCLUSIONS: H. pylori remains a risk factor for duodenal, but not for gastric lesions in children in countries with low prevalence of infection. No risk factor could be identified in half of the children with gastro-duodenal ulcers/erosions.

Exclusive enteral nutrition in the treatment of children with Crohn's disease in Sweden: a questionnaire survey.

AIM: The general use of exclusive enteral nutrition (EEN) as therapy for children with Crohn's disease (CD) in Sweden has not previously been studied. Thus, the aim of this study was to investigate how EEN is used as therapy in Sweden for children with CD. METHODS: A questionnaire was sent to all 37 paediatric units in Sweden that treat children with inflammatory bowel disease. RESULTS: The response rate was 78%, which covers nearly 90% of Sweden's paediatric population between 0 and 17 years of age. Ninety-six per cent of the units used EEN as a treatment option for children with CD, and 65% of the units used EEN as their primary therapy in newly diagnosed CD. The standard duration of EEN was 6 weeks, but the questionnaire revealed a span of 4-8 weeks. The use of polymeric formula was just as common as a combination of polymeric and elemental formulas. Fifty-seven per cent used oral nutrition supplements, and 81% allowed some extent of concomitant feeding, the addition of food and fluids, during EEN. All units used enteral nutrition to some extent as maintenance therapy after EEN was discontinued. CONCLUSIONS: In Sweden, EEN is used as therapy for children with Crohn's disease (CD), but the EEN protocols vary as to choice of formula and type of food and fluids allowed during EEN. Standardized EEN protocols would enable multicentre studies in Sweden, with the objective of investigating how EEN treatment can be improved and employed in the most efficient way.

Frequency and risk factors of gastric and duodenal ulcers or erosions in children: a prospective 1-month European multicenter study.

UNLABELLED: There are no solid figures of the frequency of ulcer disease during childhood in Europe. We assessed its frequency and analyzed known risk factors. PATIENTS AND METHODS: Ulcers, erosions, indications, and risk factors were recorded in all children undergoing an upper gastrointestinal endoscopy in a prospective study carried out during 1-month simultaneously in 19 centers among 14 European countries. RESULTS: Ulcers and/or erosions were observed in 56 out of 694 children. Children with ulcers/erosions were significantly older than those without lesions (10.3+/-5.5 vs. 8.1+/-5.7 years, P=0.002). Helicobacter pylori infection was present in 15 of 56 children (27%) where NSAIDs were used in eight, steroids in five, immune-suppressive drugs in five, antibiotics in six, antacids in one, H2-blockers in six and proton pump inhibitors in eight children (more than one risk factor was detected in 32 of 56 children). No risk factors were observed in 24 of 56 children (43%). The main indications for endoscopy were epigastric or abdominal pain (24%) and suspicion of gastroesophageal reflux disease (15%). Similarly, epigastric tenderness, hematemesis, melena, and weight stagnation were significantly associated with ulcers/erosions, whereas sex, H. pylori infection, socioeconomic and lifestyle factors were equally distributed. CONCLUSION: Although limited by the short-time duration and the heterogeneity of the patients included throughout the 19 centers, our study shows a frequency of 8.1% of ulcers and/or erosions in children, occurring mainly in the second decade of life. H. pylori infection and gastrotoxic medications were less frequently implicated than expected.

Severe liver damage associated with celiac disease: findings in six toddler-aged girls.

OBJECTIVE: Light-to-moderate liver damage is often seen in children diagnosed with celiac disease, but severe liver damage is rarely observed. METHODS: During a 12-year-long period our center took care of six 13-36-month-old girls who developed severe liver damage 1-24 months after the diagnosis of celiac disease. RESULTS: Four girls had acute liver failure; two of them had to be liver transplanted. The other four girls recovered without transplantation and none of the six patients developed autoimmune disease during the 2-14-year-long follow-up period. Although adenovirus type 2 was found in the urine and stools of one girl, her liver histopathology did not resemble viral hepatitis. Certain autoimmune features could be observed initially in some of the children but finally none of them fulfilled the criteria for autoimmune liver disease and this pattern did not change during the several years of follow-up. Thorough investigation could not find any alternative pathogenetic cause and thus, the association with celiac disease is obvious. Histopathology showed various degrees of intralobular inflammation, necrosis, involvement of the small bile ducts, and in one case interface hepatitis; but in general, histopathology did not reveal a common pathogenetic mechanism. CONCLUSION: Although rare, severe hepatic damage or failure can develop in association with celiac disease. The etiology is varying and multifactorial. Consequently, children with newly onset celiac disease should be routinely checked for liver function and vice versa, children with severe liver damage should be investigated for untreated celiac disease.

Ganciclovir treatment in infants with cytomegalovirus infection and cholestasis.

BACKGROUND: The authors have previously described an association between cytomegalovirus (CMV) infection and intrahepatic and extrahepatic forms of neonatal cholestasis. Pediatric use of the antiviral drug ganciclovir to treat patients with CMV infection has increased. In this study, infants with CMV infection and cholestasis were treated with ganciclovir. METHODS: Six infants with cholestasis (age, 3-16 weeks) and with signs of ongoing CMV infection were treated with intravenous ganciclovir for 3 to 7 weeks and observed for 4 to 31 months after treatment. Two patients had biliary atresia, one had suspected septo-optic dysplasia and three had no obvious cause for intrahepatic cholestasis other than ongoing CMV infection. RESULTS: Four patients, including one with biliary atresia, responded to the treatment, whereas two patients, including the one with septo-optic dysplasia did not. The latter patient had episodes of symptomatic hypoglycemia during the treatment, which was subsequently stopped. Liver function at the end of follow-up was good in four patients, intermediate in one, and poor in one. CONCLUSION: Ganciclovir treatment may be beneficial in infants with CMV-associated intrahepatic cholestasis, but controlled studies are needed. Because of the possible side effect of hypoglycemia, infants with cholestasis who have increased risk for such episodes should not be treated.