Natural history of liver disease in a large international cohort of children with Alagille syndrome: Results from the GALA study.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) is a multisystem disorder, characterized by cholestasis. Existing outcome data are largely derived from tertiary centers, and real-world data are lacking. This study aimed to elucidate the natural history of liver disease in a contemporary, international cohort of children with ALGS. APPROACH AND RESULTS: This was a multicenter retrospective study of children with a clinically and/or genetically confirmed ALGS diagnosis, born between January 1997 and August 2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox models were constructed to identify early biochemical predictors of clinically evident portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%. By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced ≥1 adverse liver-related event (CEPH, transplant, or death). Children (>6 and ≤12 months) with median total bilirubin (TB) levels between ≥5.0 and <10.0 mg/dl had a 4.1-fold (95% confidence interval [CI], 1.6-10.8), and those ≥10.0 mg/dl had an 8.0-fold (95% CI, 3.4-18.4) increased risk of developing CEPH compared with those <5.0 mg/dl. Median TB levels between ≥5.0 and <10.0 mg/dl and >10.0 mg/dl were associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with higher NLS rates relative to ≥5.0 mg/dl, with 79% reaching adulthood with native liver ( p < 0.001). CONCLUSIONS: In this large international cohort of ALGS, only 40.3% of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and 12 months of age is associated with better hepatic outcomes. These thresholds provide clinicians with an objective tool to assist with clinical decision-making and in the evaluation of therapies.

Postoperative hypoalbuminemia and outcomes of pediatric liver transplantation.

BACKGROUND: Hypoalbuminemia after liver transplantation (LT) is associated with acute kidney injury (AKI) and poor outcomes in adult LT recipients. This study was performed to examine the association between the postoperative serum albumin level and early postoperative outcomes of LT in children. METHODS: This single-center retrospective review involved pediatric LT recipients (0-18 years old) treated from January 2013 to June 2020. All patients were admitted to PICU and received standard post-LT care protocol. We divided patients into low (< 30 g/L) and normal (> 30 g/L) groups based on postoperative albumin day 1 to 3. RESULTS: Among 108 LT recipients, most had biliary atresia. The median age at the time of LT was 1.8 years [interquartile range (IQR), 1.5-5.7]. There were 18 patients in low albumin group [median albumin level, 27.9 g/L (IQR, 25.8-29.6) and 90 patients in normal albumin group [median albumin level, 34.5 g/L (IQR, 32.4-36.9). The low albumin group had significantly higher incidence of AKI, occurring in 20% of patients with a median onset of 2.5 days following LT (IQR, 1-5). Postoperative hypoalbuminemia (OR, 4.94; 95% CI, 1.32-18.47; p = 0.01) and a longer operative time (OR, 1.37; 95% CI, 1.01-1.47; p = 0.02) were independent risk factors for AKI by multivariable analysis. No significant differences between the two groups were found in other early postoperative outcomes. CONCLUSION: Postoperative hypoalbuminemia was associated with early postoperative AKI following LT in children but not with other worsening outcomes.

Risk factors of cytomegalovirus infection after pediatric liver transplantation and effectiveness of preemptive therapy.

BACKGROUND: Cytomegalovirus (CMV) infection is the most common infection following pediatric liver transplantation (LT). Preemptive therapy (PET) is an approach to initiate antiviral treatment for asymptomatic early CMV viremia detected by surveillance testing. However, data on CMV infection after PET are scarce, and the optimal cut-off remains controversial. This study aimed to evaluate the incidence, risk factors, and consequences of CMV infection in pediatric LT using 2 different viral load (VL) cut-offs. METHODS: We retrospectively reviewed patients aged 0-18 years who underwent LT at Ramathibodi Hospital between March 2001 and August 2020. Demographic data, CMV infection, CMV treatment, and consequences of CMV infection were collected. CMV viremia was monitored by a quantitative nucleic acid amplification test. Clinical outcomes were compared after starting antiviral therapy at a low (>400 but <2000 IU/mL) and a high VL cut-off (≥2000 IU/mL). RESULTS: A total of 126 patients were included. CMV infection was 71% (90/126), with an incidence rate of 5.5 per 1000 patient-day. Higher tacrolimus and prednisolone dosages were associated with CMV infection with an adjusted hazard ratio of 1.2 (95%CI 1.0-1.4, p = .02) and 2.4 (95%CI 1.9-3.4, p < .001), respectively. The consequences of CMV infection did not differ significantly for the low and high CMV VL cut-off groups. CONCLUSION: CMV infection in LT recipients is common and is associated with higher tacrolimus and corticosteroid dosage. Additionally, using the CMV VL cut-off at 2000 IU/mL to initiate antiviral therapy is practical and effective in preventing CMV disease.

Determination of Optimal Vitamin D Dosage in Children with Cholestasis.

BACKGROUND: Vitamin D deficiency in patients with cholestasis is due to impaired intestinal vitamin D absorption, which results from decreased intestinal bile acid concentration. Patients with cholestasis usually do not achieve optimal vitamin D status when a treatment regimen for children without cholestasis is used. However, data on high-dose vitamin D treatment in patients with cholestasis are limited. METHODS: This study is a prospective study that included pediatric patients with cholestasis (serum direct bilirubin > 1 mg/dL) who had vitamin D deficiency (serum 25-hydroxyvitamin D, 25-OHD, < 20 ng/mL). In Phase 1, single-day oral loading of 300,000 IU (or 600,000 IU if weight ≥ 20 kg) of vitamin D2 was administered, followed by an additional loading if serum 25-OHD < 30 ng/mL, and 4-week continuation of treatment using a vitamin D2 dose calculated based on the increment of 25-OHD after first loading. In Phase 2, oral vitamin D2 (200,000 IU/day) was administered for 12 days, followed by 400,000 IU/day of vitamin D2 orally for another 8 weeks if serum 25-OHD < 30 ng/mL. RESULTS: Phase 1: Seven patients were enrolled. Three out of seven patients had a moderate increase in serum 25-OHD after loading (up to 20.3-27.2 ng/mL). These patients had conditions with partially preserved bile flow. The remaining four patients, who had biliary atresia with failed or no Kasai operation, had low increments of serum 25-OHD. Phase 2: Eleven patients were enrolled. Eight out of 11 patients had a moderate increase in serum 25-OHD after 200,000 IU/day of vitamin D2 for 12 days. Serum 25-OHD continued increasing after administering 400,000 IU/day of vitamin D2 for another 8 weeks, with maximal serum 25-OHD of 15.7-22.8 ng/mL. CONCLUSION: Very high doses of vitamin D2 (200,000 and 400,000 IU/day) partly overcame poor intestinal vitamin D absorption and resulted in moderate increases in serum 25-OHD in pediatric patients with cholestasis, particularly when cholestasis was caused by uncorrectable bile duct obstruction.

Cost-effectiveness analysis of liver transplantation in biliary atresia according to the severity of end-stage liver disease.

BACKGROUND: Timing for liver transplantation (LT) in biliary atresia (BA) children with end-stage liver disease (ESLD) is associated with all-cause mortality. The cut-off value of pediatric end-stage liver disease (PELD) score for LT consideration varies across institutions. We aimed to determine the cost-effectiveness of LT to prevent death among BA children registered on the waiting list with different severities of ESLD. METHODS: Subjects were BA children aged < 12 years at a transplant center between 2010 and 2021. A decision tree was developed for cost-effectiveness analysis from a hospital perspective to compare all-cause death between patients initially registered with a low PELD score (< 15) and a high PELD score (≥ 15). Each patient's direct medical cost was retrieved from the beginning of registration until 5 years after LT, adjusted with an inflation rate to 2022 Thai Baht (THB). RESULTS: Among 176 children, 138 (78.4%) were initially registered with the high PELD score. The cost and mortality rate of the low PELD score group (THB1,413,424 or USD41,904 per patient and 31.6% mortality) were less than the high PELD score group (THB1,781,180 or USD52,807 per patient and 47.9% mortality), demonstrating the incremental cost-effectiveness ratio (ICER) of THB2,259,717 or USD66,994 per death prevented. The cost of early post-operative admission had the highest effect on the ICER. Considering the break-even analysis, cost among children initially registered at the low PELD score was also less expensive over time. CONCLUSIONS: Registration for LT at PELD score < 15 was more cost-effective to prevent death among BA children with ESLD.

Prediction of refractory gastroesophageal reflux disease in young children.

BACKGROUND: Many children respond to medical treatment for gastroesophageal reflux disease (GERD). However, some may require invasive intervention for refractory disease. Due to the lack of prognostic tools in children, this study aimed to develop a predictive model for refractory GERD. METHODS: A retrospective review was performed in children with symptoms of GERD at a university hospital. Refractory GERD was defined as an unresponsive disease after optimal treatment with medication for >8 weeks. The predictive model was constructed based on clinical features and 24-h multichannel intraluminal impedance-pH (MII-pH) monitoring results. RESULTS: A total of 205 children were included with a median (IQR) age of 0.6 (0.3, 2.0) years. Over half of the patients (59.5%) had motor disabilities. Forty-four children (21.5%) were diagnosed with refractory GERD and subsequently underwent fundoplication. Multivariable analysis suggested that the refractory disease was associated with motor disabilities (OR: 5.35; 95% CI: 2.06-13.91), recurrent aspiration pneumonia (OR: 2.78; 95% CI: 1.24-6.26), prematurity with an onset of GERD at a post-conceptual age <40 weeks (OR: 6.76; 95% CI: 1.96-23.33), and abnormal total reflux episodes according to age (OR: 2.78; 95% CI: 1.24-6.19), but not the acid exposure time or symptom association analysis. The predictive model for refractory GERD based on associated factors revealed an area under the ROC curve of 76.8% (95% CI: 69.2%-84.3%) with a sensitivity of 77.3% and a specificity of 64% when applying a cutoff score of ≥2.5. CONCLUSIONS: The predictive model, using clinical features and MII-pH, may be an additional tool to predict refractory GERD in young children.

Seroprevalence of hepatitis E virus after pediatric liver transplantation.

BACKGROUND: Southeast Asia is the endemic area of hepatitis E virus (HEV) infection. We aimed to determine the seroprevalence of the virus, its association, and the prevalence of chronic infection after pediatric liver transplantation (LT). METHODS: A cross-sectional study was performed in Bangkok, Thailand. Patients aged <18 years who had LT for >2 years underwent serologic and real-time polymerase chain reaction (rt-PCR) tests. Acute HEV infection was defined by the presence of positive anti-HEV immunoglobulin (Ig)M and HEV viremia from the rt-PCR. If the viremia persisted for >6 months, chronic HEV infection was diagnosed. RESULTS: A total of 101 patients had a median age of 8.4 years [interqartile range (IQR): 5.8-11.7]. The seroprevalence of anti-HEV IgG and IgM was 15% and 4%, respectively. Positive IgM and/or IgG were associated with a history of elevated transaminases with an unknown cause after LT (p = 0.04 and p = 0.01, respectively). The presence of HEV IgM was associated with a history of elevated transaminases with an unknown cause within 6 months (p = 0.01). The two patients (2%) diagnosed with chronic HEV infection did not fully respond to the reduction of immunosuppression but responded well to ribavirin treatment. CONCLUSIONS: Seroprevalence of HEV among pediatric LT recipients was not rare in Southeast Asia. Since HEV seropositivity was associated with elevated transaminases of an unknown cause, investigation for the virus should be offered in LT children with hepatitis after excluding other etiologies. Pediatric LT recipients with chronic HEV infection may receive a benefit from a specific antiviral treatment.

Prevalence of functional abdominal pain disorders and functional constipation in adolescents.

AIM: Functional abdominal pain disorders (FAPDs) and functional constipation (FC) are the common functional gastrointestinal disorders in adolescents. We aimed to determine the prevalence of FAPDs and FC in adolescents using the Rome IV Questionnaire of Pediatric Gastrointestinal Symptoms and the factors associated with these two functional gastrointestinal disorders. METHODS: A survey for the prevalence of FAPDs and FC in adolescents was carried out at two high schools. A translated and validated Thai version of Rome IV Questionnaire of Pediatric Gastrointestinal Symptoms was used. Potential associated factors were also collected. Psychosocial problems were evaluated by using the Strengths and Difficulties Questionnaire. RESULTS: A total of 1700 adolescents (55.5% females) with a mean age (SD) of 16.1 (0.9) years were enrolled. The prevalence of FAPDs and FC was 5.3% and 8.1%, respectively. The subtypes of FAPDs were functional dyspepsia (4.7%; postprandial distress syndrome 3.9% and epigastric pain syndrome 0.8%), irritable bowel syndrome (0.6%), abdominal migraine (0.4%) and functional abdominal pain not otherwise specified (0.3%). Multiple logistic regression analysis revealed that FAPDs were associated with female gender (odds ratio (OR) 3.3, 95% confidence interval (CI): 1.7-6.4), underlying allergic diseases (OR 3.2, 95% CI: 1.6-6.6) and concomitant emotional problem (OR 2.7, 95% CI: 1.2-5.9). No significant associated factors with FC were found. CONCLUSION: FAPDs and FC are common in adolescents. Postprandial distress syndrome is the most common subtype of FAPD. Associated factors for FAPDs may suggest hormonal, immune-related and psychological involvement in the disease pathogenesis.

Etiology and outcome of acute recurrent pancreatitis and chronic pancreatitis.

BACKGROUND: Owing to the lack of data, we aimed to determine the etiology and outcome of acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) in children in Southeast Asia. METHODS: This retrospective study was conducted at a university hospital in Bangkok, Thailand. We included patients aged <18 years who were diagnosed with pancreatitis from 2000 to 2021. RESULTS: Among 155 patients with pancreatitis, 21 (13.5%) were diagnosed with either ARP (n = 7) or CP (n = 14). Clinical manifestations of CP included chronic abdominal pain (n = 10, 71.4%), steatorrhea (n = 8, 57.1%), and diabetes mellitus (n = 1, 7.1%). Positive radiological findings compatible with CP were detected from an abdominal ultrasound, computed tomography, magnetic resonance cholangiopancreatography in 70%, 90.9%, and 92.9% of patients, respectively. Genetic, metabolic, and pancreaticobiliary causes were the major causes of ARP/CP (23.8% each) and the etiologies were unidentified in one-fifth of the patients. Patients with metabolic diseases who had AP were at-risk of developing ARP (hazards ratio [HR], 4.7, 95% confidence interval [CI]: 1.5-13.9). Children with ARP or CP were younger than those with AP (P = 0.04). Approximately two-thirds of patients with CP had growth faltering and they had more episodes of hospitalization due to acute attacks when compared to patients with ARP ( 4 [interquartile range [IQR], 3-6] vs. 3 [IQR, 2-3]; P = 0.02). CONCLUSION: Genetic, metabolic, and pancreaticobiliary diseases were the common etiologies of ARP and CP among children living in a developing country in Southeast Asia. The burden of CP included malnutrition and frequent hospitalization. The findings emphasize the importance of an early etiological diagnosis and monitoring for pancreatic insufficiency in ARP/CP.

Immunogenicity of varicella zoster vaccine in pediatric liver transplantation.

BACKGROUND: Pediatric liver transplant (LT) candidates often miss complete varicella-zoster virus (VZV) vaccination before LT. We aimed to evaluate the immunogenicity of two doses of VZV vaccines in pediatric LT candidates younger than 2 years and persistence of its immunogenicity after LT. METHODS: Patients aged 9-24 months were enrolled before LT. The first dose of VZV vaccine was given at 9 months, and the second dose was given at between 1 to 3 months later, and at least 4 weeks before LT. Varicella-zoster IgG (VZG) was used to detect immunoglobulin G antibodies to VZV and was reported as a test value (TV). A test value ≥ 0.9 was considered as seropositive. TV was measured at enrollment, 1 month after the first and the second dose of VZV vaccine, before LT, and 3 and 6 months after LT. RESULTS: Fourteen children were enrolled in this prospective cohort study. The median age at the first and the second dose of VZV vaccine was 11.5 months (IQR 9-12) and 13 months (IQR 12-33), respectively. The seroconversion rate was 66.7% (8/12) and 70% (7/10) after the first and second VZV vaccine doses, respectively. Seven of nine patients who underwent LT had two doses of VZV vaccine. Six patients were seropositive before LT, which persisted at 3 to 6 months after LT. Of two patients who received only one dose, TV was not detected after LT. CONCLUSIONS: The two doses of VZV vaccine appeared to be more immunogenic than one dose in pediatric LT candidates aged less than 2 years.

Low psoas muscle index as an unfavorable factor in children with end-stage liver disease undergoing liver transplantation.

Sarcopenia is common in cirrhotic adults and associated with waitlist mortality and worse outcome after liver transplantation. Psoas muscle mass has been used to define sarcopenia. Therefore, we aimed to determine the association between psoas muscle mass and waitlist mortality as well as post-transplant outcome in children with end-stage liver disease. Medical records and abdominal imaging of pediatric liver transplant candidates during 2010-2019 were reviewed. A subset of images was measured by two radiologists to determine inter-rater reliability. Psoas muscle surface area was determined at intervertebral lumbar disk 3-4 (L3-4) and 4-5 (L4-5) levels. PMI was calculated by psoas muscle surface area divided by height squared. We included 105 children, most with biliary atresia (84%). Patients with waitlist mortality had lower PMI compared to the ones who survived to transplantation (PMI at L3-4 levels 352.8 ± 162.5 vs. 416.8 ± 136.2 mm2 /m2 and at L4-5 levels 497.3 ± 167.8 vs. 571.4 ± 163.4 mm2 /m2 , both p = .04), but not in the multivariate analyses. For transplanted patients (n = 75), a higher rate of re-operation (39% vs. 15%, p = .03) and longer hospital stay (53 vs. 45 days, p = .02) were found in patients with lower PMI. Lower PMI is associated with higher re-operation rate and longer hospital stay following transplantation, but not waitlist mortality. PMI may be taken into consideration with other biomarkers to predict post-transplant complications.

Late allograft fibrosis in pediatric liver transplant recipients: Assessed by histology and transient elastography.

Late allograft fibrosis in LT recipients can cause graft dysfunction and may result in re-transplantation. TE is a non-invasive tool for the assessment of liver fibrosis. We aimed to evaluate the prevalence of allograft fibrosis in pediatric LT recipients, identify factors associated with allograft fibrosis, and determine the diagnostic value of TE, compared to histology. All children who underwent LT for ≥3 years were included. TE was performed for LSM in all patients. LSM of ≥7.5 kPa was considered as abnormal and suggestive of allograft fibrosis. Percutaneous liver biopsy was performed when patients had abnormal LSM and/or abnormal LFTs. Histological fibrosis was diagnosed when METAVIR score ≥F1 or LAF scores ≥1. TE was performed in 43 patients and 14 (32.5%) had abnormal LSM suggestive of allograft fibrosis. Histological fibrosis was identified in 10 of the 15 patients (66.7%) who underwent percutaneous liver biopsy and associated findings included chronic active HBV infection (n = 3), and late acute rejection (n = 3). Multivariate analysis showed that graft age was significantly associated with allograft fibrosis (OR = 1.22, 95% CI: 1.05-1.41, P = 0.01). In conclusion, late allograft fibrosis is common in children undergoing LT for ≥3 years and associated with graft age. HBV infection and late acute rejection are common associated findings. Abnormal TE and/or LFTs may guide physicians to consider liver biopsy for the detection of late allograft fibrosis in LT children.

Various initial presentations of Epstein-Barr virus infection-associated post-transplant lymphoproliferative disorder in pediatric liver transplantation recipients: Case series and literature review.

PTLD is a rare but potentially life-threatening condition, which shows a higher prevalence in children than in adults. From 129 children who underwent LT, we reported 5 cases with biopsy-proven PTLD at a single teaching hospital. Four patients had shared clinical presentations including fever, lymphadenopathy, and splenomegaly. They were noted to be given a prolonged course of IS due to the management of comorbid complications such as acute cellular rejection or severe food allergy or eosinophilic gastrointestinal disease. The other one patient presented with upper gastrointestinal bleeding from gastric mass during an early post-transplantation period. Notably, hypoalbuminemia was noted in all reported patients. Similar to previous studies, both EBV serology mismatch between the donor and recipient with high EBV viral load were noted in all except one case, whose EBV serology was unknown before LT. At least one episode of CMV reactivation was also observed in 3 of 5 patients prior to the PTLD diagnosis. The histopathology revealed 1 of 5 early PTLD, 1 of 5 polymorphic PTLD, and 3 of 5 monomorphic PTLD. The treatment included IS withdrawal, chemotherapy, and/or rituximab. One patient died of multiorgan dysfunction, one remains in complete remission, and three patients are either still on treatment or await response evaluation. Even though most of our reported PTLD cases had shared manifestations with fever, lymphadenopathy, splenomegaly, EBV serology mismatch, and high EBV viral load, various initial presentations such as respiratory symptoms, hypoalbuminemia, and prolonged use of IS from other causes such as significant food allergy were noted.

No association between month of birth and biliary atresia in a country with tropical climate.

AIM: Children with biliary atresia (BA) born in countries with temperate climate showed month-of-birth (MoB) predilection during cooler months. To date, no study on the MoB-BA association has been performed in a tropical country. Our aim was to define MoB variation in children with BA in a tropical country. METHODS: We studied 150 children diagnosed with BA between January 1996 and April 2015 at a teaching hospital. MoB was defined by two categories based on the precipitation: rain and dry, and three categories based on the air temperature: high, average and low. We applied the country's population data on the number of births in each period as the expected proportions of birth. RESULTS: A slightly higher proportion of BA children was born in the rainy months (52.7%); however, the difference was not significant compared to the general population's birth (P = 0.87). For the MoB based on the air temperature, no statistically significant difference was noted. Males with BA seemed to have a greater MoB variation compared to females, but this did not reach statistical significance. CONCLUSION: We could not find an association between MoB and BA in a tropical country. Multinational studies may aid in understanding the MoB-BA association in the tropical countries.

Henoch-Schönlein without Purpura: A Case Report and Review Literature.

Henoch-Schönlein purpura (HSP) is a multi-organ vasculitis involving skin, joints, gastrointestinal tract, and kidneys. The present study reported a 5-year-old boy presenting with intense abdominal pain, bloody diarrhea, and protein-losing enteropathy. Investigations for infectious enteritis were negative. Esophagogastroduodenoscopy showed swelling and erythematous mucosa with hemorrhagic spots at duodenal bulb to the third part of duodenum. Histopathology of endoscopic biopsies revealed non-specific duodenitis. HSP was suspected, based on duodenitis and the presence of inflammatory markers without identifiable causes. Corticosteroid was started resulting in marked improvement of his clinical symptoms. Two weeks later, he developed nephrotic-range proteinuria, thus kidney biopsy was performed. Renal histology was consistent with IgA nephropathy, supporting the diagnosis of HSP This report emphasizes that patients with HSP may not always show visible purpura, and the diagnosis requires a high index of suspicion. GI endoscopy and renal biopsy may be helpful for the diagnosis in selected patients presenting with atypical presentations.

Short- and long-term outcomes of children with cyclic vomiting syndrome.

OBJECTIVE: To determine the efficacy of prophylactic pharmacotherapy on the short- and long-term outcomes of children with cyclic vomiting syndrome (CVS). MATERIAL AND METHOD: Medical records were reviewed in 32 children who were diagnosed with CVS between 2000 and 2013. Efficacy ofprophylactic medications was classified as good vs. no response after treatment for three to six months. Long-term outcome was evaluated inpatients who had been diagnosedfor > or =2 years and classiied as 1) excellent: no episode, 2) good: one to two episodes, and 3) poor: three episodes or more during the past year. RESULTS: At three to six months after treatment, good response to amitriptyline was significantly higher than propranolol (73% vs. 36%, p = 0.04). Of the 24 CVS patients whohad been diagnosed > or =2 years, data was available in 19 patients (mean age, 11.3 +/- 4.9; and mean duration from diagnosis to follow-up, 6.3+3.3 years). Excellent outcome was achieved in seven, good in seven, and poor in five children. Overall, the favorable long-term outcome (good and excellent) was 74%. Most children (86%) who hadfavorable long-term outcome had good response to the prophylactic medications in the early period of treatment. CONCLUSION: Amitriptyline may be more effective than propranololforprophylaxis of CVS. However, a randomized controlled trial is required to confirm this result. Children with CVS have a relatively favorable long-term outcome, particularly those who initially responded well to the prophylactic medications.

Use of transient elastography to assess hepatic steatosis and fibrosis in patients with juvenile idiopathic arthritis during methotrexate treatment.

OBJECTIVES: This study aimed to assess the prevalence and identify predictors of hepatic steatosis and fibrosis in patients with juvenile idiopathic arthritis (JIA) during methotrexate treatment. METHOD: This cross-sectional study included JIA patients who had received methotrexate for > 1 year. Laboratory data including liver chemistry and lipid profiles were collected. Liver stiffness measurements (LSM) and controlled attenuation parameters (CAP) were determined by transient elastography. Significant hepatic fibrosis was defined as LSM > 7 kilopascal (kPa), and hepatic steatosis was defined as CAP > 225 decibel/meter (dB/m). Logistic regression analysis was performed to identify predictors associated with hepatic steatosis and fibrosis. RESULTS: Of 60 patients, 66.7% were female, and the median age (IQR) was 12.8 (10.6-15.0) years. The median duration of methotrexate usage (IQR) was 45 (22-85) months, and the median cumulative dose of methotrexate (IQR) was 3768 (1806-6466) mg. The median LSM (IQR) and CAP (IQR) were 4.1 (3.4-4.6) kPa and 191.0 (170.3-223.8) dB/m, respectively. No patients had transient elastography-defined hepatic fibrosis, whereas 21.7% had hepatic steatosis. A body mass index Z-score > 1 (OR 5.71 [95%CI 1.31-24.98], p = 0.021) and higher cumulative dose of methotrexate (OR 1.02 [95%CI 1.00-1.04], p = 0.041) were associated with hepatic steatosis, whereas the cumulative dose of steroids was not (OR 1.00 [95%CI 1.00-1.01], p = 0.097). CONCLUSIONS: Hepatic steatosis is common among JIA patients receiving methotrexate, but none had transient elastography-defined hepatic fibrosis. Overweight/obese JIA adolescents and patients with a high cumulative dose of methotrexate are at risk for hepatic steatosis. Key Points •Long-term low-dose methotrexate usage and the concomitant use of other DMARDs did not increase the risk of hepatic fibrosis in JIA patients. •The prevalence of hepatic steatosis in JIA patients receiving methotrexate was higher than in a healthy pediatric population. •Overweight/obesity and a higher cumulative dose of methotrexate were predictors of hepatic steatosis.

Prevalence and Associated Factors of Vertebral Fractures in Children with Chronic Liver Disease with and without Liver Transplantation.

Purpose: To evaluate the prevalence of vertebral fracture (VF) in children with chronic liver disease (CLD) with and without liver transplantation (LT) and to determine the associated factors. Methods: A cross-sectional study was conducted. Patients aged 3-21 years with CLD both before and after LT were enrolled in the study. Lateral thoracolumbar spine radiographs were obtained and assessed for VF using Mäkitie's method. Clinical and biochemical data were collected. Results: We enrolled 147 patients (80 females; median age 8.8 years [interquartile range 6.0-11.8]; 110 [74.8%] in the LT group and 37 [25.2%] in the non-LT group). VF was identified in 21 patients (14.3%): 17/110 (15.5%) in the LT group and 4/37 (10.8%) in the non-LT group (p=0.54). Back pain was noted in only three patients with VF. In the univariate analysis, a height z-score below -2.0 (p=0.010), pre-LT hepatopulmonary syndrome (p=0.014), elevated serum direct and total bilirubin levels (p=0.037 and p=0.049, respectively), and vitamin D deficiency at 1-year post-LT (p=0.048) were associated with VF in the LT group. In multivariate analysis, height z-score below -2.0 was the only significant associated factor (odds ratio, 5.94; 95% confidence interval, 1.49-23.76; p=0.012) for VF. All VFs in the non-LT group were reported in males. Conclusion: In children with CLD, VF is common before and after LT. Most patients with VF are asymptomatic. Screening for VF should be considered in patients with a height z-score below -2.0 after LT.

An international multidisciplinary consensus on pediatric metabolic dysfunction-associated fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent in children and adolescents, particularly those with obesity. NAFLD is considered a hepatic manifestation of the metabolic syndrome due to its close associations with abdominal obesity, insulin resistance, and atherogenic dyslipidemia. Experts have proposed an alternative terminology, metabolic dysfunction-associated fatty liver disease (MAFLD), to better reflect its pathophysiology. This study aimed to develop consensus statements and recommendations for pediatric MAFLD through collaboration among international experts. METHODS: A group of 65 experts from 35 countries and six continents, including pediatricians, hepatologists, and endocrinologists, participated in a consensus development process. The process encompassed various aspects of pediatric MAFLD, including epidemiology, mechanisms, screening, and management. FINDINGS: In round 1, we received 65 surveys from 35 countries and analyzed these results, which informed us that 73.3% of respondents agreed with 20 draft statements while 23.8% agreed somewhat. The mean percentage of agreement or somewhat agreement increased to 80.85% and 15.75%, respectively, in round 2. The final statements covered a wide range of topics related to epidemiology, pathophysiology, and strategies for screening and managing pediatric MAFLD. CONCLUSIONS: The consensus statements and recommendations developed by an international expert panel serve to optimize clinical outcomes and improve the quality of life for children and adolescents with MAFLD. These findings emphasize the need for standardized approaches in diagnosing and treating pediatric MAFLD. FUNDING: This work was funded by the National Natural Science Foundation of China (82070588, 82370577), the National Key R&D Program of China (2023YFA1800801), National High Level Hospital Clinical Research Funding (2022-PUMCH-C-014), the Wuxi Taihu Talent Plan (DJTD202106), and the Medical Key Discipline Program of Wuxi Health Commission (ZDXK2021007).

Efficacy of Bacillus clausii in Pediatric Functional Constipation: A Pilot of a Randomized, Double-Blind, Placebo-Controlled Trial.

PURPOSE: To evaluate the efficacy of Bacillus clausii in the treatment of pediatric constipation. METHODS: A randomized, double-blind, placebo-controlled trial was conducted from January, 2021 to January, 2022 in children aged 1-5 years diagnosed with functional constipation according to Rome IV criteria. They were assigned to receive either B. clausii or placebo, once daily for four weeks. The primary out-come was treatment success (defined as ≥3 spontaneous stools per week and stool consistency grade ≥3 on Bristol stool chart). The secondary outcome was a comparison of stool frequency, consistency (defined by Bristol stool grade), and constipation-related symptoms. RESULTS: This trial enrolled 38 children (B. clausii, n=20 and placebo, n=18). At 4 weeks, no significant difference was noted in the treatment success between B. clausii and placebo groups [45% vs 56%; P=0.52). On within-group analyses, the mean (SD) of Bristol stool grade increased in both the B. clausii [1.7 (0.5) to 2.8 (1.2); P=0.003] and placebo [1.8 (0.5) to 2.8 (1.2); P=0.01] groups. Significant increases in the treatment success rate (22% to 56%, P=0.01) and mean stool frequency per week [3 (0.9) to 4.2 (1.7), P=0.01] were pronounced only in the placebo group. The frequency of painful defecation and large fecal mass were also significantly decreased in both the groups. No serious adverse events were observed. CONCLUSIONS: A 4-week course of B. clausii as the sole treatment was not more effective than a placebo for the management of functional constipation in children aged 1-5 years.