Lee M. Bass

Clinical staging for sleep-disordered breathing

OBJECTIVE: The purpose of this study was to identify prognostic indicators that would lead to stratification of patients likely to have successful surgery for sleep-disordered breathing (SDB) versus those destined to fail. STUDY DESIGN: We retrospectively reviewed 134 patients to correlate palate position and tonsil size to the success of the UPPP as based on postoperative polysomnography results. Similar to our previously published data on the Friedman Score as a predictor of the presence and severity of SDB, the palate position was determined on physical examination of the oral cavity and was graded for each patient. This grade combined with tonsil size was used to stage the patients. Stage I was defined as having palate position 1 or 2 combined with tonsil size 3 or 4. Stage II was defined as having palate position 3 or 4 and tonsil size 3 or 4. Stage III patients had palate position 3 or 4 and tonsil size 0, 1, or 2. Any patient with body mass index of greater than 40 was placed in the stage III group. The results of uvulopalatopharyngoplasty (UPPP) were then graded as success or failure and success rates were compared by stage. SETTING: Academically affiliated tertiary care referral center. RESULTS: Stage I patients who underwent UPPP had a success rate of 80.6%, stage II patients had a success rate of 37.9%, and stage III patients had a success rate of 8.1%. CONCLUSION: A clinical staging system for SDB based on palate position, tonsil size, and body mass index is presented. It appears to be a valuable predictor of the success of UPPP. Additional studies and wider use of the staging system will ultimately define its role in the treatment of SDB.

Hedgehog Activity, Epithelial-Mesenchymal Transitions, and Biliary Dysmorphogenesis in Biliary Atresia

Biliary atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that coexpress mesenchymal markers and may be profibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype. Livers and remnant extrahepatic ducts from BA patients were evaluated by quantitative reverse‐transcription polymerase chain reaction (QRT‐PCR) and immunostaining for Hh ligands, target genes, and markers of mesenchymal cells or ductular progenitors. Findings were compared to children with genetic cholestatic disease, age‐matched deceased donor controls, and adult controls. Ductular cells isolated from adult rats with and without bile duct ligation were incubated with Hh ligand‐enriched medium ± Hh‐neutralizing antibody to determine direct effects of Hh ligands on epithelial to mesenchymal transition (EMT) marker expression. Livers from pediatric controls showed greater innate Hh activation than adult controls. In children with BA, both intra‐ and extrahepatic ductular cells demonstrated striking up‐regulation of Hh ligand production and increased expression of Hh target genes. Excessive accumulation of Hh‐producing cells and Hh‐responsive cells also occurred in other infantile cholestatic diseases. Further analysis of the BA samples demonstrated that immature ductular cells with a mesenchymal phenotype were Hh‐responsive. Treating immature ductular cells with Hh ligand‐enriched medium induced mesenchymal genes; neutralizing Hh ligands inhibited this. Conclusion: BA is characterized by excessive Hh pathway activity, which stimulates biliary EMT and may contribute to biliary dysmorphogenesis. Other cholestatic diseases show similar activation, suggesting that this is a common response to cholestatic injury in infancy. (HEPATOLOGY 2011;)

Portal hypertension in children and young adults with biliary atresia

Objective: Biliary atresia (BA) frequently results in portal hypertension (PHT), complications of which lead to significant morbidity and mortality. The Childhood Liver Disease Research and Education Network was used to perform a cross-sectional multicentered analysis of PHT in children with BA. Methods: Subjects with BA receiving medical management at a Childhood Liver Disease Research and Education Network site were enrolled. A priori, clinically evident PHT was defined as “definite” when there was either history of a complication of PHT or clinical findings consistent with PHT (both splenomegaly and thrombocytopenia). PHT was denoted as “possible” if one of the findings was present in the absence of a complication, whereas PHT was “absent” if none of the criteria were met. Results: A total of 163 subjects were enrolled between May 2006 and December 2009. At baseline, definite PHT was present in 49%, possible in 17%, and absent in 34% of subjects. Demographics, growth, and anthropometrics were similar amongst the 3 PHT categories. Alanine aminotransferase, &ggr;-glutamyl transpeptidase, and sodium levels were similar, whereas there were significant differences in aspartate aminotransferase (AST), AST/alanine aminotransferase, albumin, total bilirubin, prothrombin time, white blood cell count, platelet count, and AST/platelet count between definite and absent PHT. Thirty-four percent of those with definite PHT had either prothrombin time >15 seconds or albumin <3 g/dL. Conclusions: Clinically definable PHT is present in two-thirds of North American long-term BA survivors with their native livers. The presence of PHT is associated with measures of hepatic injury and dysfunction, although in this selected cohort, the degree of hepatic dysfunction is relatively mild and growth is preserved.

Seasonal variation in the presentation of abdominal pain.

Background: Anxiety and depression, conditions frequently associated with childhood chronic abdominal pain (AP), are characterized by seasonal exacerbations. A seasonal pattern characterized by a higher frequency of consultations for AP during winter has been suspected but has never, to our knowledge, been demonstrated. We hypothesize the presence of a seasonal variation in AP consultations with a winter predominance. Aims: To determine the seasonal distribution of AP consultations among centers across time and geographic latitude. Patients and Methods: This was a retrospective cohort study. The number of outpatient consultations from primary care clinics and every pediatric specialty clinic that resulted in a diagnosis of AP and the total number of outpatient consultations (2001–2004) from 6 tertiary care institutions (Chicago, Pittsburgh, Wilmington, Pensacola, Orlando, Jacksonville) was determined. Rates of consultations were compared across time and between cities. Four time periods of interest, with 2- and 3-month definitions, were arbitrarily selected. Seasonal rates across time were compared separately for each of the 2-month (January–February vs June–July) and 3-month periods (January–March vs June–August). Logistic regression models for each city were used to determine variations in the rate of outpatient AP cases by season or by year. Results: A total of 3,929,522 outpatient consultations and 73,591 AP consultations were analyzed. The rates of AP consultations were consistently higher in the winter months at all of the sites. The results differed between sites at northern and southern latitudes. Conclusions: There seems to be a seasonal variation in consultation patterns for AP at the tertiary care level. A possible role of daylight hours, climate, latitude, and stress is proposed.

Accuracy of pain recall in children.

Background and Aim: Chronic abdominal pain (AP) is common in children. Recall of symptoms is used clinically to determine management, to assess treatment progress, and in drug studies to assess outcomes. Limited data exist on accuracy of AP recall in children. The aim of the present study was to assess ability to accurately recall AP in children. Methods: The study was a secondary analysis of data obtained from a double-blind, randomized, placebo-controlled trial, evaluating amitriptyline in children with functional gastrointestinal disorders. Children ages 8 to 17 years with AP predominant functional gastrointestinal disorders based on Rome II criteria were recruited from 6 centers. Those with evidence of organic disease were excluded. Patients maintained AP diary daily for 1 month (presence, frequency, and intensity). At the end of the study, patients reported the number of days of AP during previous month. Agreement between daily pain reports and recalled pain was assessed. Univariate analysis was conducted with Spearman rank correlations. Results: We recruited 63 children (45 girls, mean age 12.8 years). Sixteen percent children had perfect agreement on number of days of AP. Fifty-four percent of children recalled fewer episodes of pain. The average number of days with AP by recall was 17.7/month, whereas by diary it was 23.5/month (P = 0.001). Correlation between patient recall of the last week of symptoms (r = 0.47) was no better than correlation between recall of the last 30 days of symptoms (r = 0.48). On comparing AP recall versus various pain intensities, reported AP did not reflect only AP of greater severity. Higher correlation of recall of symptoms was seen in children 11 years or younger (r = 0.59) as compared with children older than 11 years (r = 0.26). Conclusions: Few children can accurately recall the episodes of AP. Children commonly recall a lower frequency of AP than that assessed by prospective diary reports. Reported recall does not reflect a shorter recollection period. Recall is not related to intensity of pain. Adolescents have worse recall of symptoms.

Analysis of surgical interruption of the enterohepatic circulation as a treatment for pediatric cholestasis

To evaluate the efficacy of nontransplant surgery for pediatric cholestasis, 58 clinically diagnosed children, including 20 with Alagille syndrome (ALGS), 16 with familial intrahepatic cholestasis‐1 (FIC1), 18 with bile salt export pump (BSEP) disease, and 4 others with low γ‐glutamyl transpeptidase disease (levels <100 U/L), were identified across 14 Childhood Liver Disease Research Network (ChiLDReN) centers. Data were collected retrospectively from individuals who collectively had 39 partial external biliary diversions (PEBDs), 11 ileal exclusions (IEs), and seven gallbladder‐to‐colon (GBC) diversions. Serum total bilirubin decreased after PEBD in FIC1 (8.1 ± 4.0 vs. 2.9 ± 4.1 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.02), but not in ALGS or BSEP. Total serum cholesterol decreased after PEBD in ALGS patients (695 ± 465 vs. 457 ± 319 mg/dL, preoperatively vs. 12‐24 months postoperatively, respectively; P = 0.0001). Alanine aminotransferase levels increased in ALGS after PEBD (182 ± 70 vs. 260 ± 73 IU/L, preoperatively vs. 24 months; P = 0.03), but not in FIC1 or BSEP. ALGS, FIC1, and BSEP patients experienced less severely scored pruritus after PEBD (ALGS, 100% vs. 9% severe; FIC1, 64% vs. 10%; BSEP, 50% vs. 20%, preoperatively vs. >24 months postoperatively, respectively; P < 0.001). ALGS patients experienced a trend toward greater freedom from xanthomata after PEBD. There was a trend toward decreased pruritus in FIC1 after IE and GBC. Vitamin K supplementation increased in ALGS after PEBD (33% vs. 77%; P = 0.03). Overall, there were 15 major complications after surgery. Twelve patients (3 ALGS, 3 FIC1, and 6 BSEP) subsequently underwent liver transplantation. Conclusion: This was a multicenter analysis of nontransplant surgical approaches to intrahepatic cholestasis. Approaches vary, are well tolerated, and generally, although not uniformly, result in improvement of pruritus and cholestasis. (Hepatology 2017;65:1645‐1654).

Use of a real-time viewer for endoscopic deployment of capsule endoscope in the pediatric population.

Objectives: Wireless capsule endoscopy (WCE) is an increasingly used procedure for visualization of the small intestine. One challenge in pediatric WCE is the placement of the capsule in a population unable to swallow it for a variety of reasons. Here we present a novel use of the real-time (RT) viewer in the endoscopic deployment of the capsule endoscope. Methods: We performed a retrospective chart review on all WCE completed at the Childrens Memorial Hospital from February 2010 to May 2011. Following a diagnostic upper endoscopy, the RT viewer was attached to the capsule recorder and image was noted before insertion. The endoscope and AdvanCE capsule delivery device were slowly advanced into duodenum while maintaining visualization on the RT viewer. Results: A total of 17 patients who underwent a WCE with endoscopic placement were identified. They ranged in ages from 2 to 19 years. Thirteen patients required endoscopic placement because of the inability to swallow the capsule, whereas 4 were placed during a scheduled procedure to take advantage of sedation and airway protection. All of the 17 patients had successful deployment of the capsule into the duodenal lumen. In each case, the endoscopist was able to confirm capsule location in duodenum during scope withdrawal. There was no evidence of iatrogenic trauma or bleeding in any patient. There were 5 incomplete studies, a completion rate consistent with that described in the literature. Conclusions: The use of the RT viewer for endoscopic deployment of WCE is an effective technique to improve visualization of capsule placement in the pediatric population.

Baseline Analysis of a Young α-1-Antitrypsin Deficiency Liver Disease Cohort Reveals Frequent Portal Hypertension

Objectives: &agr;-1-Antitrypsin (A1AT) deficiency is a common genetic disease with an unpredictable and highly variable course. The Childhood Liver Disease Research and Education Network is a National Institutes of Health, multicenter, longitudinal consortium studying pediatric liver diseases, with the objective of prospectively defining natural history and identifying disease modifiers. Methods: Longitudinal, cohort study of A1AT patients’ birth through 25 years diagnosed as having liver disease, type PIZZ or PISZ. Medical history, physical examination, laboratory, imaging, and standardized survey tool data were collected during the provision of standard of care. Results: In the present report of the cohort at baseline, 269 subjects were enrolled between November 2008 and October 2012 (208 with their native livers and 61 postliver transplant). Subjects with mild disease (native livers and no portal hypertension [PHT]) compared to severe disease (with PHT or postliver transplant) were not different in age at presentation. A total of 57% of subjects with mild disease and 76% with severe disease were jaundiced at presentation (P = 0.0024). A total of 29% of subjects with native livers had PHT, but age at diagnosis and growth were not different between the no-PHT and PHT groups (P > 0.05). Subjects with native livers and PHT were more likely to have elevated bilirubin, ALT, AST, INR, and GGTP than the no-PHT group (P << 0.001), but overlap was large. Chemistries alone could not identify PHT. Conclusions: Many subjects with A1AT presenting with elevated liver tests and jaundice improve spontaneously. Subjects with PHT have few symptoms and normal growth. Longitudinal cohort follow-up will identify genetic and environmental disease modifiers.

Humoral immune mechanism of liver injury in giant cell hepatitis with autoimmune hemolytic anemia.

Background and Aims: Giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA) is presumed to be an autoimmune disease, but the mechanism of liver injury is unknown. We proposed that in CGH-AHA, the humoral limb of autoimmunity is the dominant force driving progressive liver injury. Methods: We studied 6 cases of GCH-AHA and 6 cases of autoimmune hepatitis (AIH) with early childhood onset (3 type 1 and 3 type 2). Liver biopsies were graded for portal and periportal inflammation and for giant cells. Immunohistochemistry characterized cellular inflammation and complement involvement in injury by showing C5b-9 complex in hepatocytes. Results: Clinical and biochemical features at presentation were generally similar; however, the absence of autoantibodies and the presence of Coombs positivity did distinguish GCH-AHA from early-onset AIH. Liver biopsy pathology in CGH-AHA showed giant cells and little inflammation, whereas AIH showed the opposite. C5b-9 staining showed high-grade complement-mediated pan-lobular hepatocyte injury in all of the cases with GCH-AHA, whereas little C5b-9 was seen in hepatocytes in cases with AIH. Inflammation in GCH-AHA comprised mainly lobular macrophages and neutrophils, whereas portal and periportal T-cell and B-cell inflammation characterized cases with AIH. Most cases with AIH responded to therapy with prednisone and azathioprine, whereas most cases with GCH-AHA responded only to rituximab. Conclusions: Widespread complement-mediated hepatocyte injury and typical C3a and C5a complement-driven liver inflammation along with Coombs-positive hemolytic anemia in GCH-AHA provide convincing evidence that systemic B-cell autoimmunity plays a central pathologic mechanism in the disease. Our findings support B-cell–directed immunotherapy as a first-line treatment of GCH-AHA.

Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome

Liver disease in Alagille syndrome is highly variable. Many of the patients presenting with severe cholestasis early in life improve spontaneously; 10–20%, however, have progressive disease. It is currently not possible to predict long‐term hepatic outcomes in Alagille syndrome. This international, multicentre study was aimed at identifying early life predictors of liver disease outcome.