Treatment of Cholestasis in Infants and Young Children.

PURPOSE OF REVIEW: Cholestasis is characterized by a conjugated hyperbilirubinemia secondary to impaired bile synthesis, transport, or excretion from the liver. It is always pathologic and can be indicative of an underlying hepatobiliary, genetic, or metabolic disorder, several of which require timely diagnosis to ensure proper management and optimal outcomes. This review provides an overview of the evaluation of cholestasis with a focus on current and emerging treatment strategies. RECENT FINDINGS: Increased accessibility of next generation sequencing (NGS) allows for utilization of genetic testing early in the diagnostic process. This may alter the clinical algorithm for diagnosis of cholestatic disorders. An enhanced understanding of the underlying pathophysiology may help guide future development of targeted therapies, such as ileal bile acid transporter (IBAT) inhibitors. These were recently approved for treatment of cholestatic pruritus in patients with Alagille syndrome and Progressive Familial Intrahepatic Cholestasis. Current management of cholestasis is aimed at the biochemical consequences of impaired bile flow, including malnutrition, pruritus, and progressive fibrosis. NGS has led to an enhanced understanding of biliary pathology and may guide development of future treatment modalities based on specific gene mutations. Rapid discernment of the underlying etiology is essential as new treatment modalities emerge.

Factors Associated With Increasing Length of Stay for Rheumatoid Arthritis Patients Undergoing Total Hip Arthroplasty and Total Knee Arthroplasty.

Background: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are cost-effective procedures that decrease pain and improve health-related quality of life for patients with advanced symptomatic arthritis, including rheumatoid arthritis (RA). Patients with RA have a longer length of stay (LOS) after THA or TKA than patients with osteoarthritis, yet the factors contributing to LOS have not been investigated. Purpose: We sought to identify the factors contributing to LOS for patients with RA undergoing THA and TKA at a single tertiary care orthopedic specialty hospital. Methods: We retrospectively reviewed data from a prospectively collected cohort of 252 RA patients undergoing either THA or TKA. Demographics, RA characteristics, medications, serologies, and disease activity were collected preoperatively. Linear regression was performed to explore the relationship between LOS (log-transformed) and possible predictors. A multivariate model was constructed through backward selection using significant predictors from a univariate analysis. Results: Of the 252 patients with RA, 83% were women; they had a median disease duration of 14 years and moderate disease activity at the time of arthroplasty. We had LOS data on 240 (95%) of the cases. The mean LOS was 3.4 ± 1.5 days. The multivariate analysis revealed a longer LOS for RA patients who underwent TKA versus THA, were women versus men, required a blood transfusion, and took preoperative opioids. Conclusion: Our retrospective study found that increased postoperative LOS in RA patients undergoing THA or TKA was associated with factors both non-modifiable (type of surgery, sex) and modifiable (postoperative blood transfusion, preoperative opioid use). These findings suggest that preoperative optimization of the patient with RA might focus on improving anemia and reducing opioid use in efforts to shorten LOS. More rigorous study is warranted.

Diagnostic and clinical utility of the wireless motility capsule in children: A study in patients with functional gastrointestinal disorders.

BACKGROUND: The wireless motility capsule (WMC) evaluates gastrointestinal motility and transit simultaneously. We evaluated the utility of the WMC in children with functional gastrointestinal symptoms. METHODS: Study in children comparing WMC transit and motility parameters between those with upper (UGI) or lower (LGI) gastrointestinal symptoms, nuclear medicine gastric emptying time (NMGET) and/or a colonic radiopaque marker (CROM) study. KEY RESULTS: We prospectively recruited 57 children (median age 16.45y, range 8.78-17.8y, 44 Female) and 50 completed the study (24 UGI/26 LGI). We found no association between WMC study interpretation, motility and transit parameters and symptoms. WMC and NMGET interpretation agreement observed in 24/34 (70%) (κ = 0.351, p = 0.026) and with CROM in 17/21 (81%) patients (κ = 0.576, p = 0.007). WMC detected abnormal gastric transit in 41% vs. 24% with NMGET (p = 0.04) and abnormal colon transit in 62% vs. 71% of patients by CROM (p = 0.01). We found significant correlation (r = 0.574, p = 0.01) and no difference in median colon transit (p = 0.421) by WMC and CROM. A single WMC motility parameter, mean peak amplitude, was associated with NMGET (p = 0.04), none with CROM. Capsule retention >5 days (n = 9, all passed <2 weeks) was associated with prolonged colon transit, not with symptoms, age and gender. CONCLUSIONS: WMC is well tolerated in children as young as 8 years old. We found no association between WMC and symptoms, fair agreement with NMGET and strong agreement with CROM. WMC increases the yield of finding gastrointestinal transit abnormalities. Capsule retention in children is associated to prolonged colon transit. Larger studies are needed to further validate these findings.

A case of an Infant with SARS-CoV-2 hepatitis early after liver transplantation.

We present a case of a pediatric liver transplant recipient diagnosed with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection four days after receiving a living donor liver allograft from her mother. The recipient was a 6-month-old with end-stage liver disease due to biliary atresia and failed Kasai. The infant had an uncomplicated implantation, excellent graft function and down-trending liver enzymes until developing fevers, diarrhea, and moderate respiratory distress requiring non-invasive respiratory support. SARS-CoV-2 testing (nasal swab Polymerase Chain Reaction) was positive on post-operative day (POD) 4. Liver enzymes peaked ~1000 U/L (5-fold higher than the previous day) on POD 6. Histology demonstrated a mixed picture of moderate acute hepatitis and classical elements of mild to moderate acute cellular rejection. Her hepatitis and respiratory symptoms improved coincident with completing treatment with hydroxychloroquine, reduced immunosuppression, and intravenous gamma globulin (IVIG).

Tranexamic Acid Does Not Reduce the Risk of Transfusion in Rheumatoid Arthritis Patients Undergoing Total Joint Arthroplasty.

BACKGROUND: Patients with rheumatoid arthritis (RA) receive transfusions more often than patients with osteoarthritis following lower extremity total joint arthroplasty (TJA), but mitigating factors are not described. Tranexamic acid (TXA) is widely used to reduce blood loss in patients undergoing TJA, but its effect on transfusion rates in patients with RA has not been studied. METHODS: We retrospectively reviewed data from a prospectively collected cohort of patients with RA undergoing TJA. Disease activity measured by Clinical Disease Activity Index, patient-reported outcome measures, and serologies was obtained. Baseline characteristics were summarized and compared. Transfusion requirements and TXA usage were obtained from chart review. Logistic regression was used to determine factors associated with transfusion in RA patients undergoing TJA. RESULTS: The cohort included 252 patients, mostly women with longstanding RA and end-stage arthritis requiring TJA. In multivariate analysis, 1 g/dL decrease in baseline hemoglobin (odds ratio [OR] = 0.394, 95% confidence interval [CI] [0.232, 0.669], P = .001), 1-minute increase in surgical duration (OR = 1.022, 95% CI [1.008, 1.037], P = .003), and 1-point increase in Clinical Disease Activity Index (OR = 1.079, 95% CI [1.001, 1.162]) were associated with increased risk of transfusion. TXA use was not associated with decreased risk of postoperative transfusion. CONCLUSIONS: Preoperative health optimization should include assessment and treatment of anemia in RA patients before TJA, as preoperative hemoglobin level is the main risk factor for postoperative transfusion. Increased disease activity and increased surgical time were independent risk factors for postoperative transfusion but are less modifiable. While TXA did not decrease transfusion risk in this population, a prospective trial is needed to confirm this. LEVEL OF EVIDENCE: IV.

Utility of Colon Manometry in Guiding Therapy and Predicting Need for Surgery in Children With Defecation Disorders.

OBJECTIVES: Colon manometry (CM) has emerged as a tool to evaluate children with defecation problems. Our aim was to evaluate the utility of CM in guiding therapy and predicting surgery in pediatric constipation. METHODS: Retrospective review of children undergoing CM for 4 indications: constipation, fecal incontinence, postsurgical evaluation and chronic intestinal pseudo-obstruction. Variables included age, sex, follow-up, and CM parameters: gastrocolonic response (GC) and quality/quantity of high-amplitude propagating contractions (HAPCs). INTERVENTIONS: medical, surgical or no intervention. OUTCOMES: response to change of therapy guided by CM, response to first intervention guided by CM (CMI) and CM predicting surgery (CMS). Response to therapy was classified according to study indication. RESULTS: Five hundred fifty-five studies (448 patients, 54.4% female; median age 8.9 years) were included, 24% of studies were normal. Change of therapy guided by CM was associated with a high response rate (P = 0.003). Overall response to stimulant laxatives was 48% and was not associated with CM findings. Surgical interventions had a higher response rate than medical or other interventions (P < 0.001). We found no association between the CM interpretation and CMI, but an abnormal CM was predictive of surgery (P < 0.01). GC and presence/number of HAPCs were not associated with CMI or CMS. We also found no association between HAPC quality and CMI but partially propagated HAPCs were predictive of surgery (P < 0.001). Logistic regression analysis showed no factors associated with CMI; however, longer follow up and partially propagated HAPCs were predictive of surgery. CONCLUSIONS: CM is useful in pediatric defecation disorders, although not predictive of successful medical intervention, an abnormal CM is predictive of surgery. CM should be performed only after medical interventions have failed and surgery is contemplated.

Causes of Revision in Young Patients Undergoing Total Hip Arthroplasty.

BACKGROUND: The purpose of this study was to identify reasons for revision of total hip arthroplasty (THA) in patients who underwent primary THA at or before the age of 35 years. We hypothesized that the reasons for revision in younger patients would be different from the general older population of patients undergoing THA because of the differences in diagnoses, complexity of deformities, and differences in activity level. METHODS: Data for 108 hips in 82 patients who underwent primary THA at our institution before the age of 35 years from 1982-2007 and subsequently underwent revision THA were reviewed. Operative reports and clinic notes were reviewed to determine baseline characteristics, reason for revision, timing of revision, and components revised. RESULTS: The mean age at index surgery was 25.4 years, and mean time from index to revision surgery was 10.1 years. The most common preoperative diagnoses included avascular necrosis, juvenile idiopathic arthritis, developmental dysplasia of the hip, and posttraumatic arthritis. The most common reasons for revision were acetabular loosening (30.1%), femoral loosening (23.7%), and polyethylene wear (24.7%). 8.3% of patients underwent primary THA with highly cross-linked polyethylene, while the remainder of the patients underwent THA when conventional polyethylene was used. There was no statistically significant association between which component(s) were revised and initial fixation (ie cemented or uncemented prosthesis) (P = .26). CONCLUSION: Causes of revision in this population appear to differ from the general THA population. In young patients, acetabular loosening, femur loosening, and polyethylene wear were the most common causes of revision. Instability and infection were less common compared with literature reports of causes of revision in older patients. Findings in this study may be useful in counseling young patients undergoing THA, though results were likely influenced by the use of conventional rather than highly cross-linked polyethylene in this cohort.

Same day versus next day antroduodenal manometry results in children with upper gastrointestinal symptoms: A prospective study.

BACKGROUND: We evaluated the changes in antroduodenal manometry (ADM) parameters and interpretation when the test is performed the day of catheter placement and the following day. METHODS: Catheter was placed endoscopically under anesthesia and recorded on day 1 and repeated on day 2. Study parameters including antrum and small bowel motility index (MI) during fasting, meal, postprandial, erythromycin (EES), and octreotide (OCT) challenge phases, the presence of the phase III of the migrating motor complex (MMC), visual postprandial response, and study interpretation were compared between both days. KEY RESULTS: Twenty patients were studied. Antrum and small bowel MI during fasting, postprandial, and EES challenge phases were significantly higher on day 2 than on day 1 (P < 0.05). The proportion of patients having a phase III of the MMC was significantly higher on day 2 compared to day 1 (65% vs 15%; P = 0.006). Study interpretation changed from day 1 to day 2. On day 1, 70% of the patients had a normal study and 30% had an abnormal study. On day 2, 67% of the patients with an abnormal study on day 1 changed to normal and 33% remained abnormal. All patients with a normal study on day 1 remained normal on day 2. CONCLUSIONS AND INFERENCES: ADM parameters are affected the day of catheter placement. The MI and presence of the phase III of the MMC were significantly higher on day 2 compared to day 1. Overall, ADM study interpretation changed from day 1 to day 2 in 20% of the patients.

Microstructural White Matter Abnormalities in the Dorsal Cingulum of Adolescents with IBS.

Alterations in fractional anisotropy (FA) have been considered to reflect microstructural white matter (WM) changes in disease conditions; however, no study to date has examined WM changes using diffusion tensor imaging (DTI) in adolescents with irritable bowel syndrome (IBS). The objective of the present study was two-fold: (1) to determine whether differences in FA, and other non-FA metrics, were present in adolescents with IBS compared to healthy controls using whole-brain, region of interest (ROI)-restricted tract-based spatial statistics (TBSS) and canonical ROI DTI analyses for the cingulum bundle, and (2) to determine whether these metrics were related to clinical measures of disease duration and pain intensity in the IBS group. A total of 16 adolescents with a Rome III diagnosis of IBS (females = 12; mean age = 16.29, age range: 11.96-18.5 years) and 16 age- and gender-matched healthy controls (females = 12; mean age = 16.24; age range: 11.71-20.32 years) participated in this study. Diffusion-weighted images were acquired using a Siemens 3-T Trio Tim Syngo MRI scanner with a 32-channel head coil. The ROI-restricted TBSS and canonical ROI-based DTI analyses revealed that adolescents with IBS showed decreased FA in the right dorsal cingulum bundle compared to controls. No relationship between FA and disease severity measures was found. Microstructural WM alterations in the right dorsal cingulum bundle in adolescents with IBS may reflect a premorbid brain state or the emergence of a disease-driven process that results from complex changes in pain- and affect-related processing via spinothalamic and corticolimbic pathways.

Abdominal Pain, the Adolescent and Altered Brain Structure and Function.

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder of unknown etiology. Although relatively common in children, how this condition affects brain structure and function in a pediatric population remains unclear. Here, we investigate brain changes in adolescents with IBS and healthy controls. Imaging was performed with a Siemens 3 Tesla Trio Tim MRI scanner equipped with a 32-channel head coil. A high-resolution T1-weighted anatomical scan was acquired followed by a T2-weighted functional scan. We used a surface-based morphometric approach along with a seed-based resting-state functional connectivity (RS-FC) analysis to determine if groups differed in cortical thickness and whether areas showing structural differences also showed abnormal RS-FC patterns. Patients completed the Abdominal Pain Index and the GI Module of the Pediatric Quality of Life Inventory to assess abdominal pain severity and impact of GI symptoms on health-related quality of life (HRQOL). Disease duration and pain intensity were also assessed. Pediatric IBS patients, relative to controls, showed cortical thickening in the posterior cingulate (PCC), whereas cortical thinning in posterior parietal and prefrontal areas were found, including the dorsolateral prefrontal cortex (DLPFC). In patients, abdominal pain severity was related to cortical thickening in the intra-abdominal area of the primary somatosensory cortex (SI), whereas HRQOL was associated with insular cortical thinning. Disease severity measures correlated with cortical thickness in bilateral DLPFC and orbitofrontal cortex. Patients also showed reduced anti-correlations between PCC and DLPFC compared to controls, a finding that may reflect aberrant connectivity between default mode and cognitive control networks. We are the first to demonstrate concomitant structural and functional brain changes associated with abdominal pain severity, HRQOL related to GI-specific symptoms, and disease-specific measures in adolescents with IBS. It is possible such changes will be responsive to therapeutic intervention and may be useful as potential markers of disease progression or reversal.

A multicenter study on childhood constipation and fecal incontinence: effects on quality of life.

OBJECTIVE: To describe the effects of childhood functional constipation compared with functional constipation plus fecal incontinence on quality of life, evaluating effects on physical, psychosocial, and family functioning. STUDY DESIGN: This prospective, multicenter study collected data from 5 regional children's hospitals. Children meeting Rome III criteria for functional constipation were included. Parents completed the following 5 instruments: Pediatric Quality of Life Inventory (PedsQL), PedsQL-Family Impact Module, Functional Disability Inventory-Parent Version, Pediatric Inventory for Parents (PIP), and Pediatric Symptom Checklist-Parent Report. RESULTS: Families of 410 children aged 2-18 years (mean [SD], 7.8 [3.5] years; 52% male) were included. Children with functional constipation+fecal incontinence had worse quality of life than children with functional constipation alone (PedsQL Total Score, P ≤ .03). Older children with functional constipation + fecal incontinence had lower quality of life than their younger counterparts (PedsQL Total Score, P ≤ .047). Children with functional constipation+fecal incontinence had worse family functioning (PedsQL-Family Impact Module Total Score, P ≤ .012), greater parental stress (PIP-F Total Score, P ≤ .016; PIP-D Total Score, P ≤ .013), and poorer psychosocial functioning (Pediatric Symptom Checklist Total Score, P ≤ .003). There were no statistically significant between-group differences in physical functioning based on the functional Disability Inventory. CONCLUSION: Fecal incontinence significantly decreases quality of life compared with functional constipation alone in children. Older children with functional constipation+fecal incontinence may be at particular risk. Strategies for early identification and treatment of constipation along with diagnosis and treatment of related adjustment difficulties may mitigate the negative impact of this highly prevalent condition.

Accuracy of digital mRNA profiling of oesophageal biopsies as a novel diagnostic approach to eosinophilic oesophagitis.

BACKGROUND: Quantification of tissue eosinophils remains the golden standard in diagnosing eosinophilic oesophagitis (EoE), but this approach suffers from poor specificity. It has been recognized that histopathological changes that occur in patients with EoE are associated with a disease-specific tissue transcriptome. OBJECTIVE: We hypothesized that digital mRNA profiling targeted at a set of EoE-specific and Th2 inflammatory genes in oesophageal biopsies could help differentiate patients with EoE from those with reflux oesophagitis (RE) or normal tissue histology (NH). METHODS: The mRNA expression levels of 79 target genes were defined in both proximal and distal biopsies of 196 patients with nCounter® (Nanostring) technology. According to clinicopathological diagnosis, these patients were grouped in a training set (35 EoE, 30 RE, 30 NH) for building of a three-class prediction model using the random forest method, and a blinded predictive set (n = 47) for model validation. RESULTS: A diagnostic model built on ten differentially expressed genes was able to differentiate with 100% sensitivity and specificity between conditions in the training set. In a blinded predictive set, this model was able to correctly predict EoE in 14 of 18 patients in distal (sensitivity 78%, 95% CI 52-93%) and 16 of 18 patients in proximal biopsies (sensitivity 89%, 95% CI 64-98%), without false-positive diagnosis of EoE in RE or NH patients (specificity 100%, 95% CI 85-100%). Sensitivity was increased to 94% (95% CI 71-100%) when either the best predictive distal or proximal biopsy was used. CONCLUSION AND CLINICAL RELEVANCE: We conclude that mRNA profiling of oesophageal tissue is an accurate diagnostic strategy in detecting EoE.

PedsQL gastrointestinal symptoms module: feasibility, reliability, and validity.

OBJECTIVE: The objective of this study was to report on the measurement properties of the Pediatric Quality of Life Inventory (PedsQL) Gastrointestinal Symptoms Module for patients with functional gastrointestinal (GI) disorders (FGIDs) and organic GI diseases, hereafter referred to as "GI disorders," for patient self-report ages between 5 and 18 and parent proxy-report for ages between 2 and 18 years. METHODS: The 74-item PedsQL GI Module and 23-item PedsQL Generic Core Scales were completed in a 9-site study by 584 patients and 682 parents. Patients had physician-diagnosed GI disorders (such as chronic constipation, functional abdominal pain, irritable bowel syndrome, functional dyspepsia, Crohn disease, ulcerative colitis, gastroesophageal reflux disease). RESULTS: Fourteen unidimensional scales were derived measuring stomach pain, stomach discomfort when eating, food and drink limits, trouble swallowing, heartburn and reflux, nausea and vomiting, gas and bloating, constipation, blood, diarrhea, worry, medicines, and communication. The PedsQL GI Module Scales evidenced excellent feasibility, excellent reliability for the Total Scale Scores (patient self-report α = 0.97, parent proxy-report α = 0.97), and good-to-excellent reliability for the 14 individual scales (patient self-report α = 0.67-0.94, parent proxy-report α = 0.77-0.95). Intercorrelations with the Generic Core Scales supported construct validity. Individual Symptoms Scales known-groups validity across 7 GI disorders was generally supported. Factor analysis supported the unidimensionality of the individual scales. CONCLUSIONS: The PedsQL GI Module Scales demonstrated acceptable-to-excellent measurement properties and may be used as common metrics to compare GI-specific symptoms in clinical research and practice both within and across patient groups for FGIDs and organic GI diseases.