Serum Proteomics Uncovers Biomarkers of Clinical Portal Hypertension in Children With Biliary Atresia.

Children with biliary atresia (BA) often develop portal hypertension (PHT) and its complications, which are associated with high morbidity and mortality. The goal of this study was to identify serum biomarkers of PHT by using large-scale proteomics. We applied the slow off-rate modified aptamer scan (SOMAscan) to measure 1,305 proteins in serum samples of children with BA with and without clinical evidence of PHT in validation and discovery cohorts enrolled in the Biliary Atresia Study of Infants and Children. Serum proteomics data was analyzed using logistic regression to identify protein(s) with an area under the receiver operating characteristic curve (AUROC) ≥ 0.90. Immunostaining was used to characterize the cellular localization of the new biomarker proteins in liver tissues. We identified nine proteins in the discovery cohort (n = 40 subjects) and five proteins in the validation cohort (n = 80 subjects) that individually or in combination predicted clinical PHT with AUROCs ≥ 0.90. Merging the two cohorts, we found that semaphorin 6B (SEMA6B) alone and three other protein combinations (SEMA6B+secreted frizzle protein 3 [SFRP3], SEMA6B+COMM domain containing 7 [COMMD7], and vascular cell adhesion molecule 1 [VCAM1]+BMX nonreceptor tyrosine kinase [BMX]) had AUROCs ≥ 0.90 in both cohorts, with high positive- and negative-predictive values. Immunostaining of the new protein biomarkers showed increased expression in hepatic endothelial cells, cholangiocytes, and immune cells within portal triads in BA livers with clinical PHT compared to healthy livers. Conclusion: Large-scale proteomics identified SEMA6B, SFRP3, COMMD7, BMX, and VCAM1 as biomarkers highly associated with clinical PHT in BA. The expression of the biomarkers in hepatic epithelial, endothelial, and immune cells support their potential role in the pathophysiology of PHT.

A Comparison of Elevation, Perforation Rate, and Time Spent for the Crestal Sinus Elevation Intervened by Piezosurgery, CAS-Kit, and Osteotome in a Novel Goat Model.

Purpose: This study aimed to compare the differences among Piezosurgery, CAS-kit, and Osteotome regarding safe elevation, perforation rate, and time spent and to observe and analyze different sinus lifting efficacy of the three methods. Materials and Methods: Twenty-one fresh goat heads (42 sinuses) were investigated. CBCT images confirmed the feasibility of the goat model. The maxillary sinus was successively lifted to 5, 7, and 9 mm by Piezosurgery, CAS-kit, and Osteotome until the sinus membrane was perforated or lifted to 9 mm. In the end, final elevation, sinus perforation, and time spent were recorded. Results: Piezosurgery and CAS-kit lifted sinuses to relatively higher heights than did Osteotome (P = 0.000). Perforation rates (14.29, 21.43%) of the Piezosurgery and CAS-kit were far lower than that of the Osteotome (85.71%). In the Osteotome group, the time of lifting to 9 mm was significantly shorter than that of Piezosurgery and CAS-kit (P = 0.000). There was no statistical difference in time spent between the latter two (P = 0.115). Conclusions: The lifting height of the Osteotome was limited, but it took the shortest time for sinus lifting. Piezosurgery and CAS-kit had higher lifting heights and lower perforation rates compared with Osteotome.

Effect of a Practice-wide Anti-TNF Proactive Therapeutic Drug Monitoring Program on Outcomes in Pediatric Patients with Inflammatory Bowel Disease.

BACKGROUND: Reports on the feasibility and effectiveness of translating proactive, antitumor necrosis factor (TNF) therapeutic drug monitoring (TDM) for inflammatory bowel disease into practice-wide quality improvement (QI) are lacking. We aimed to determine whether a TDM QI program improved outcomes at a large academic pediatric gastroenterology practice. METHODS: We instituted local anti-TNF TDM practice guidelines to proactively monitor and optimize drug levels (goal >5 µg/mL). We conducted a retrospective single-center cohort analysis of patient outcomes before (pre-TDM) and after (post-TDM) guideline institution and assessed the independent effect by multivariable regression. Primary outcome was sustained clinical remission (SCR22-52), defined as physician global assessment (PGA) of inactive from 22 to 52 weeks and off corticosteroids at 52 weeks. RESULTS: We identified 108 pre-TDM and 206 post-TDM patients. The SCR22-52 was achieved in 42% of pre-TDM and 59% of post-TDM patients (risk difference, 17.6%; 95% CI, 5.4-29%; P = 0.004). The post-TDM group had an increased adjusted odds of achieving SCR22-52 (odds ratio, 2.03; 95% CI, 1.27-3.26; P = 0.003). The adjusted risk of developing high titer antidrug antibodies (ADAs) was lower in the post-TDM group (hazard ratio, 0.18; 95% CI, 0.09-0.35; P < 0.001). Although the risk of anti-TNF cessation for any reason was not significantly different, there was a lower adjusted risk of cessation related to any detectable ADA in the post-TDM group (hazard ratio, 0.45; 95% CI, 0.26-0.77; P = 0.003). CONCLUSIONS: A practice-wide proactive anti-TNF TDM QI program improved key clinical outcomes at our institution, including sustained clinical remission, incidence of high titer ADA, and anti-TNF cessation related to ADA.

Primary thyroid dysfunction after single intravenous iodinated contrast exposure in young children: a propensity score matched analysis.

BACKGROUND: Data suggest an increased risk of thyroid dysfunction following iodine-based contrast material (IBCM) in children. OBJECTIVE: To estimate the prevalence of thyroid stimulating hormone (TSH) abnormalities following exposure to a single dose of intravenous IBCM during computed tomography (CT) in young children. MATERIALS AND METHODS: Inpatients ≤24 months of age who underwent a single CT with intravenous IBCM (exposed cohort) or abdominal ultrasound (US) (unexposed cohort) examination and had a TSH value obtained within 90 days after imaging between January 2009 to November 2018 were identified. Propensity score matching with 20 variables was performed. Primary thyroid dysfunction was defined by abnormally high or low TSH value. Multivariable logistic regression identified risk factors, including intravenous IBCM, for thyroid dysfunction. RESULTS: From the eligible 4,215 imaging examinations, 114 unique patients were included in the propensity matched population (n=57 per group). Thyroid dysfunction was identified in 14% (8/57) and 7% (4/57) of the IBCM-exposed and IBCM-unexposed cohorts, respectively. No patient in either cohort was started on thyroid hormone supplementation within the 3 months after imaging. Intravenous IBCM exposure was not a significant predictor of thyroid dysfunction on univariable (odds ratio [OR]=2.16, 95% confidence interval [CI]=0.61-7.64, P=0.23) or multivariable (OR=2.61, 95% CI=0.65-10.55, P=0.18) analyses. Significant independent predictors of post-imaging thyroid dysfunction included height (OR=1.25, P=0.0095) and trisomy 21 (OR=4.04, P=0.019). CONCLUSION: Hospitalized children ≤24 months of age who received a single dose of intravenous IBCM for CT examination had a similar prevalence of TSH abnormalities compared to a propensity score matched group who underwent abdominal US. One dose of intravenous IBCM likely does not cause prolonged TSH abnormalities; however, larger studies are needed.

Serum Matrix Metalloproteinase 7 Is a Diagnostic Biomarker of Biliary Injury and Fibrosis in Pediatric Autoimmune Liver Disease.

In autoimmune liver disease (AILD), including autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and overlap syndrome of AIH and PSC (ASC), the presence of biliary injury portends a worse prognosis. We studied serum matrix metalloproteinase 7 (sMMP7) as a biomarker for pediatric sclerosing cholangitis (SC). We prospectively enrolled 54 children (median age, 16 years) with AILD (AIH, n = 26; ASC, n = 16; and PSC, n = 12) at our center. The sMMP7 concentrations were higher in patients with SC compared to those without cholangiopathy (P < 0.001). An sMMP7 concentration >23.7 ng/mL had a sensitivity and specificity of 79% and 96%, respectively, and outperformed alkaline phosphatase (ALP) and gamma-glutamyltransferase (GGT) in segregating patients with SC. Serum concentrations correlated with liver gene expression levels for MMP7 (r = 0.70; P < 0.001). Using immunofluorescence, MMP7 was localized primarily to the cholangiocytes of patients with SC. In 46 subjects with liver biopsy available for blinded review, elevation in sMMP7 concentrations segregated with the presence of lymphocytic and neutrophilic cholangitis and periductal fibrosis and correlated with Ishak, Ludwig, and Nakanuma scoring systems. Liver stiffness measured by magnetic resonance elastography also correlated with sMMP7 concentrations (r = 0.56; P < 0.01). Using magnetic resonance cholangiopancreatography plus (MRCP+), sMMP7 in 34 patients correlated with the number of biliary dilatations (r = 0.54; P < 0.01) and strictures (r = 0.56; P < 0.01). MMP7 as a marker of biliary injury was validated in an independent cohort of children with ulcerative colitis. Higher sMMP7 concentrations also correlated with a history of SC-related complication. Conclusion: MMP7 is a promising biomarker for pediatric SC that diagnostically outperforms ALP and GGT. sMMP7 may directly reflect biliary injury and fibrosis, the main drivers of disease progression in SC.

Risk of Acute Kidney Injury Following Contrast-enhanced CT in Hospitalized Pediatric Patients: A Propensity Score Analysis.

Background Acute kidney injury (AKI) remains a concern in hospitalized children undergoing CT with intravenous iodinated contrast material (ICM). Adult studies have shown frequencies of AKI after CT with intravenous ICM to be similar to propensity score-matched ICM-unexposed patient groups; similar data in pediatric patients are lacking. Purpose To evaluate the association between intravenous ICM exposure and AKI in hospitalized pediatric patients with stable kidney function undergoing contrast material-enhanced CT by comparing with a propensity score-matched ICM-unexposed patient sample undergoing abdominal US. Materials and Methods In this retrospective observational study, hospitalized patients aged 18 years or younger with stable kidney function and available serum creatinine (SCr) measurement before and after imaging who underwent CT with intravenous ICM or abdominal US (control group) between January 2009 and November 2018 were identified. The 1:1 propensity score matching was performed by using 23 covariates, stratified by estimated glomerular filtration rate (eGFR) before imaging (≥60 mL/min/1.73 m2 or <60 mL/min/1.73 m2). AKI was defined by using Acute Kidney Injury Network SCr-related criteria. Multivariable logistic regression was performed to identify risk factors for AKI after imaging, including the effects of eGFR and intravenous ICM exposure before imaging. Results A total of 1850 unique patients were included in the propensity score-matched sample (925 exposed to ICM [mean age ± standard deviation, 8 years ± 6; 484 female patients]; 925 unexposed to ICM [mean age, 7 years ± 6; 484 female patients]). Frequency of AKI with eGFR greater than or equal to 60 mL/min/1.73 m2 was 2.2% (20 of 889) for CT and US (odds ratio [OR]: 0.98; 95% confidence interval [CI]: 0.52, 1.86; adjusted P = .95) and with eGFR less than 60 mL/min/1.73 m2 was 5.6% (two of 36) and 11.1% (four of 36) for CT and US, respectively (OR: 0.75; 95% CI: 0.11, 5.00; adjusted P = .76). Significant multivariable predictors of AKI included eGFR before imaging (OR: 0.99; 95% CI: 0.98, 0.995; P = .001), body mass index (OR: 1.06; 95% CI: 1.02, 1.10; P = .003), acquired kidney disease (OR: 1.95; 95% CI: 1.004, 3.78; P = .049), and nephrotoxic antibiotic exposure (OR: 2.86; 95% CI: 1.55, 5.25; P < .001). Intravenous ICM exposure was not predictive (OR: 0.91; 95% CI: 0.51, 1.64; P > .05). Conclusion Hospitalized children with stable kidney function who underwent CT with intravenous iodinated contrast material (ICM) had a similar frequency of acute kidney injury (AKI) compared with a propensity score-matched ICM-unexposed patient group. In pediatric inpatients with estimated glomerular filtration rate greater than or equal to 60 mL/min/1.73 m2, ICM was not independently associated with AKI. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Paltiel in this issue.

Identifying Predictors of Response to Vitamin E for the Treatment of Pediatric Nonalcoholic Steatohepatitis.

BACKGROUND: A subset of patients with nonalcoholic steatohepatitis (NASH) respond to treatment with vitamin E. The characteristics of responders are not known. The objective of this study was to investigate the outcomes of vitamin E use in clinical practice and to determine factors associated with response to treatment. METHODS: A pediatric cohort with NASH treated with vitamin E for 6-24 months was studied retrospectively. Vitamin E response was defined as alanine aminotransferase (ALT) normalization or >50% ALT reduction from baseline. Univariate and multivariate logistic regression was used to determine the predictors of response to vitamin E. Available paired liver biopsy data were analyzed to determine histologic response. RESULTS: Of the 151 children prescribed vitamin E, 73 met inclusion/exclusion criteria. Of those, 28 (38%) were vitamin E responders. Higher baseline serum alkaline phosphatase (ALP) levels, steatosis grade, and Nonalcoholic Fatty Liver Disease Activity Score (NAS) were associated with response to vitamin E (ALP: odds ratio [OR], 14.1; 95% CI, 1.7-118.6; steatosis: OR 2.5; 95% CI, 1.2-5.0; NAS: OR 1.6; 95% CI, 1.1-2.4). In a multivariate logistic regression model, ALP and steatosis grade rendered an area under the curve of 0.75 (P < .001) for the prediction of response to treatment. Ballooning, NAS, and portal inflammation improved significantly with vitamin E in the subcohort (n = 15) with paired liver biopsies. CONCLUSIONS: Vitamin E treatment was associated with significant ALT response in 38% of children. Baseline serum ALP levels and steatosis grade were associated with response to treatment.

GER characteristics after fundoplication in children with aerodigestive disorders.

PURPOSE: The purpose of this study was to determine GER characteristics after Nissen fundoplication in children with aerodigestive disorders using pH-impedance technology. METHODS: In this cross-sectional study, the institutional database of Cincinnati Children's Hospital Medical Center was reviewed to identify patients ages below 21 years who had a Nissen fundoplication and underwent esophageal pH-impedance (pH-MII) monitoring over a nine-year period. All reflux-related metrics were modeled as a Poisson random variable as a function of time since fundoplication. RESULTS: A total of 242 patients were included in the study. The range for time since surgery was 1-192 months. Median total reflux events were 8.5 episodes per 24 h, median acidic reflux events were 0, and median proximal reflux event was 2. There was no significant trend towards increasing reflux episodes over time. CONCLUSIONS: Children had a low number of reflux events after a fundoplication, as measured by pH-impedance, and there was no statistically significant increase observed in the number of reflux events over time. Despite most patients having a functional fundoplication with minimal reflux events throughout the entire age range, up to 58% of our cohort was still on a proton pump inhibitor.

Research status of IgG4⁃related sialadenitis / 口腔疾病防治

@#IgG4⁃related sialadenitis (IgG4⁃RS) is a type of autoimmune disease that has been recognized in recent years, and the pathogenesis remains unclear. IgG4⁃RS mainly affects the submandibular gland and parotid gland and is characterized by diffuse painless swelling of the bilateral salivary glands and/or lacrimal glands, usually lasting more than 3 months. Some patients have accompanying hearing loss or hearing impairment, sinusitis, lymphadenopathy and other symptoms; nearly half of patients have different degrees of salivary gland secretion disorders. Most patients have elevated serum IgG4 levels, but they cannot be used as the only marker for diagnosis. Histopathology remains the“gold standard”for diagnosis. Presently, submandibular gland biopsy is often used for diagnosis. Histopathology showed lym⁃phoplasmacytic infiltration, occlusive phlebitis, striated fibrosis; immunohistochemistry showed IgG4 + /IgG + plasma cells >40%, and IgG4 + plasma cell/high⁃power field vision > 10. Glucocorticoids are regarded as first⁃line drugs for the treat⁃ment of this disease. Clinically, glucocorticoids are often combined with immunosuppressive agents such as cyclophos⁃phamide, but no standard drug regimen exists. Most patients have a significant short⁃term treatment effect, and the long⁃term prognosis requires further study. Patients with a recurrence tendency should adjust the hormone dose over time. In the future, further research is needed regarding the pathogenesis and treatment of the disease to improve the clinical di⁃agnosis rate and therapeutic effect.

Relationship between abdominal fat stores and liver fat, pancreatic fat, and metabolic comorbidities in a pediatric population with non-alcoholic fatty liver disease.

PURPOSE: To define the relationship between compartmental abdominal fat stores, liver and pancreatic fat fractions, and type 2 diabetes mellitus (T2DM) in children with non-alcoholic fatty liver disease (NAFLD). METHODS: This was a retrospective study of patients with NAFLD who underwent abdominal MRI between August 2015 and July 2017. Using an axial multi-echo Dixon-based sequence, liver fat fraction (LFF) and pancreatic fat fraction (PFF) were measured. The fat image was used to quantify abdominal fat depots (thickness, cross-sectional area) at the L2 vertebral level. Multivariable models with stepwise selection were created for prediction of LFF, PFF, and T2DM status based upon variables of clinical interest. RESULTS: 86 patients (70% male, 25% Hispanic, 58% Caucasian, 11% African American) with a mean age of 14.2 ± 3.2 years were included. 19 (22%) patients were pre-diabetic or diabetic. Only ethnicity was a predictor of LFF (P = 0.0023) with Hispanic ethnicity associated with the highest LFF. Depending on the model, either total abdominal fat area (P = 0.0003) or patient weight (P = 0.008) were the only predictors of PFF. No patient variable predicted T2DM status. CONCLUSIONS: In our population, there was an association between ethnicity and LFF, with the highest LFF in Hispanics. The presence or severity of hepatic steatosis could not be predicted based on patient size or the distribution of abdominal fat in our cohort. Neither LFF nor PFF were predictive of T2DM.

Diagnostic Performance of MR Elastography for Liver Fibrosis in Children and Young Adults with a Spectrum of Liver Diseases.

Purpose To assess the diagnostic performance of magnetic resonance (MR) elastography-derived liver stiffness to detect liver fibrosis in a pediatric and young adult population with a spectrum of liver diseases. Materials and Methods This retrospective study included patients younger than 21 years of age who underwent MR elastography and liver biopsy within 3 months of one another between January 2012 and September 2016 for indications other than liver transplantation or Fontan palliation of congenital heart disease. MR elastography examinations were reprocessed by a single observer, blinded to pathologic findings. Pathology specimens were reviewed by a single pathologist who scored steatosis (lipid in ≥ 5% of hepatocytes) and staged fibrosis. Receiver operating characteristic (ROC) curves were used to assess diagnostic performance. Results A total of 86 patients, 49 (57%) male with a median age of 14.2 years (range, 0.3-20.6 years), were included. Fifty-one patients (59.3%) had Ludwig stage 2 or higher fibrosis; 44 patients (51.2%) had hepatic steatosis. The area under the ROC curve for Ludwig stage 0-1 versus stage 2 or higher fibrosis was 0.70 (95% confidence interval [CI]: 0.59, 0.81) for the whole population and was significantly lower for patients with steatosis versus those without (0.53 [95% CI: 0.35, 0.71] vs 0.82 [95% CI: 0.67, 0.96], P = .014). Optimal stiffness cut-offs for the entire population were 2.27 kPa with 68.6% sensitivity (95% CI: 57.2%, 80.1%) and 74.3% specificity (95% CI: 63.5%, 85.1%) or 1.67 kPa with 35.3% sensitivity (95% CI: 23.5%, 47.1%) and 91.4% specificity (95% CI: 84.5%, 98.3%). Conclusion In children and young adults, MR elastography performs significantly better for distinguishing stage 0-1 versus stage 2 or higher fibrosis in patients without steatosis than in those with steatosis. This suggests a confounding effect of steatosis or inflammation in the population with nonalcoholic fatty liver disease. © RSNA, 2018.

Quantitative MRI of fatty liver disease in a large pediatric cohort: correlation between liver fat fraction, stiffness, volume, and patient-specific factors.

PURPOSE: Magnetic resonance imaging (MRI) techniques are increasingly used to quantify and monitor liver tissue characteristics including fat fraction, stiffness, and liver volume. The purpose of this study was to assess the inter-relationships between multiple quantitative liver metrics and patient-specific factors in a large pediatric cohort with known or suspected fatty liver disease. MATERIALS AND METHODS: In this IRB-approved, HIPAA-compliant study, we retrospectively reviewed patient data and quantitative liver MRI results in children with known/suspected fatty liver disease. Relationships between liver MRI tissue characteristics and patient variables [sex, age, body mass index (BMI), diabetic status (no diabetes mellitus, insulin resistance/"prediabetes" diagnosis, or confirmed diabetes mellitus), and serum alanine transaminase (ALT)] were assessed using linear mixed models. RESULTS: 294 quantitative liver MRI examinations were performed in 202 patients [128/202 (63.4%) boys], with a mean age of 13.4 ± 2.9 years. Based on linear mixed models, liver fat fraction was influenced by age (-0.71%/+1 year, p = 0.0002), liver volume (+0.006%/+1 mL, p < 0.0001), liver stiffness (-2.80%/+1 kPa, p = 0.0006), and serum ALT (+0.02%/+1 U/L, p = 0.0019). Liver stiffness was influenced by liver volume (+0.0003 kPa/+1 mL, p = 0.001), fat fraction (-0.02 kPa/+1% fat, p = 0.0006), and ALT (0.002 kPa/+1 U/L, p = 0.0002). Liver volume was influenced by sex (-262.1 mL for girls, p = 0.0003), age (+51.8 mL/+1 year, p = 0.0001), BMI (+49.1 mL/+1 kg/m2, p < 0.0001), fat fraction (+30.5 mL/+1% fat, p < 0.0001), stiffness (+192.6 mL/+1 kPa, p = 0.001), and diabetic status (+518.94 mL for diabetics, p = 0.0009). CONCLUSIONS: Liver volume, fat fraction, and stiffness are inter-related and associated with multiple patient-specific factors. These relationships warrant further study as MRI is increasingly used as a non-invasive biomarker for fatty liver disease diagnosis and monitoring.

Change in liver, spleen and bone marrow magnetic resonance imaging signal intensity over time in children with solid abdominal tumors.

BACKGROUND: Reticuloendothelial system MRI signal hypointensity is common in pediatric oncology patients with solid abdominal tumors. OBJECTIVE: To assess changes in liver, spleen and bone marrow T2-weighted MRI signal intensity over time and their relationship to blood transfusion history in children with solid abdominal tumors. MATERIALS AND METHODS: In this retrospective study we measured liver, spleen and bone marrow signal intensity on axial T2-weighted MR images obtained December 2009 through February 2016 in children with hepatoblastoma, neuroblastoma, ganglioneuroblastoma and Wilms tumor. All signal intensity measurements were normalized to paraspinal muscle signal intensity. We used linear mixed models (including a day*day quadratic term) to determine whether organ signal intensity changed over time and whether change was associated with blood transfusion volume or tumor type. RESULTS: We included 133 children (mean age at diagnosis =2.9 years); 56 had neuroblastoma, 42 hepatoblastoma, 28 Wilms tumor and 7 ganglioneuroblastoma. Seventy-nine (59.4%) children received transfusions (median: 8 transfusions, range: 1-30; mean volume: 1,148.5 mL). Hepatic, splenic and bone marrow signal intensity ratios changed quadratically over time for the study population, initially decreasing and then increasing (P<0.0001). Children receiving less than the mean blood transfusion volume showed no significant change in tissue signal intensity, while those receiving more than the mean volume showed significant changes in signal intensity over time (P<0.0001). Compared to children with Wilms tumor, those with neuroblastoma exhibited significantly lower hepatic (P=0.03) signal intensity ratios. CONCLUSION: Liver, spleen and bone marrow T2-weighted MRI signal intensity ratios change over time in some pediatric patients with solid abdominal tumors, likely from tissue iron deposition related to blood transfusions and perhaps because of tumor type.