Deborah K. Freese

Studies of Pediatric Liver Transplantation (SPLIT) : Year 2000 outcomes

Background. Initiated in 1995, the Studies of Pediatric Liver Transplantation (SPLIT) registry database is a cooperative research network of pediatric transplantation centers in the United States and Canada. The primary objectives are to characterize and follow trends in transplant indications, transplantation techniques, and outcomes (e.g., patient/graft survival, rejection, growth parameters, and immunosuppressive therapy.) Methods. As of June 15, 2000, 29 centers registered 1144 patients, 640 of whom received their first liver-only transplant while registered in SPLIT. Patients are followed every 6 months for 2 years and yearly thereafter. Data are submitted to a central coordinating center. Results. One/two-year patient survival and graft loss estimates are 0.85/0.82 and 0.77/0.72, respectively. Risk factors for death include: in ICU at transplant (relative risk (RR)=2.63, P <0.05) and height/weight deficits of two or more standard deviations (RR=1.67, P <0.05). Risk factors for graft loss include: in ICU at transplant (RR=1.77, P <0.05) and receiving a cadaveric split organ compared with a whole organ (RR=2.3, P <0.05). The percentage of patients diagnosed with hepatic a. and portal v. thrombosis were 9.7% and 7%, respectively; 15% had biliary complications within 30 days. At least one re-operation was required in 45%. One/two-year rejection probability estimates are 0.60/0.66. Tacrolimus, as primary therapy posttransplant, reduces first rejection risk (RR=0.70, P <0.05). Eighty-nine percent of school-aged children are in school full-time, 18 months posttransplant. Conclusions. This report provides one of the first descriptions of characteristics and clinical courses of a multicenter pediatric transplant population. Observations are subject to patient selection biases but are useful for generating hypothesis for future studies.

A population-based study of the frequency of corticosteroid resistance and dependence in pediatric patients with Crohn's disease and ulcerative colitis

Background The goal of this study was to examine the 1‐year outcome after the first course of systemic corticosteroids in an inception cohort of pediatric patients with inflammatory bowel disease. Methods All Olmsted County (Minnesota) residents diagnosed with Crohns disease (n = 50) or ulcerative colitis (n = 36) before 19 years of age from 1940 to 2001 were identified. Outcomes at 30 days and 1 year after the initial course of corticosteroids were recorded. Results Twenty‐six patients with Crohns disease (65%) and 14 with ulcerative colitis (44%) were treated with corticosteroids before age 19. Thirty‐day outcomes for corticosteroid‐treated Crohns disease were complete remission in 16 (62%), partial remission in 7 (27%), and no response in 3 (12%), with 2 of these patients requiring surgery. Thirty‐day outcomes for treated ulcerative colitis were complete remission in 7 (50%), partial remission in 4 (29%), and no response in 3 (21%). One‐year outcomes for Crohns disease were prolonged response in 11 (42%) and corticosteroid dependence in 8 (31%), whereas 7 (27%) were postsurgical. One‐year outcomes for ulcerative colitis were prolonged response in 8 (57%) and corticosteroid dependence in 2 (14%), whereas 4 (29%) were postsurgical. Conclusions Most pediatric patients with inflammatory bowel disease initially responded to corticosteroids. However, after 1 year, 58% of pediatric patients with Crohns disease and 43% of pediatric patients with ulcerative colitis either were steroid dependent or required surgery. This finding emphasizes the need for early steroid‐sparing medications in pediatric inflammatory bowel disease.

Congenital heart disease and the liver.

There are approximately 1 million adult patients with congenital heart disease (CHD) in the United States, and the number is increasing. Hepatic complications are common and may occur secondary to persistent chronic passive venous congestion or decreased cardiac output resulting from the underlying cardiac disease or as a result of palliative cardiac surgery; transfusion or drug‐related hepatitis may also occur. The unique physiology of Fontan circulation is particularly prone to the development of hepatic complications and is, in part, related to the duration of the Fontan procedure. Liver biochemical test abnormalities may be related to cardiac failure, resulting from intrinsic liver disease, secondary to palliative interventions, or drug related. Complications of portal hypertension and, rarely, hepatocellular carcinoma (HCC) may also occur. Abnormalities such as hypervascular nodules are often observed; in the presence of cirrhosis, surveillance for HCC is necessary. Judicious perioperative support is required when cardiac surgery is performed in patients with advanced hepatic disease. Traditional models for liver disease staging may not fully capture the severity of disease in patients with CHD. The effectiveness or safety of isolated liver transplantation in patients with significant CHD is limited in adults; combined heart‐liver transplantation may be required in those with decompensated liver disease or HCC, but experience is limited in the presence of significant CHD. The long‐term sequelae of many reparative cardiac surgical procedures are not yet fully realized; understanding the unique and diverse hepatic associations and the role for early cardiac transplantation in this population is critical. Because this population continues to grow and age, consideration should be given to developing consensus guidelines for a multidisciplinary approach to optimize management of this vulnerable population. (HEPATOLOGY 2012;56:1160–1169)

Pediatric “psc-ibd”: A Descriptive Report of Associated Inflammatory Bowel Disease Among Pediatric Patients With Psc

Background Inflammatory bowel disease (IBD) in adults with primary sclerosing cholangitis (PSC) is characterized by pancolonic involvement, a high frequency of rectal sparing, and an increased risk of pouchitis and colorectal neoplasia. The clinical features of IBD in pediatric patients with PSC have not been well described. The aim of this study was to characterize the frequency, clinical features, and natural history of IBD in pediatric patients diagnosed with PSC. Methods A retrospective chart review was performed for all patients 18 years of age or younger diagnosed with PSC seen at the Mayo Clinic between 1975 and 1999. Endoscopic and histologic features and surgical and postsurgical outcomes were recorded. Results Fifty-two children with PSC were identified. Forty-three patients (84%) were also diagnosed with IBD. In 36 of 43 cases, there was a sufficient diagnostic evaluation to allow a detailed review. Thirty-two of 36 patients (89%) had ulcerative colitis and 4 of 36 patients (11%) had Crohn’s disease. In 4 of 36 patients (11%), IBD was asymptomatic. Although the most frequent endoscopic presentation of IBD was universal colitis, endoscopic rectal sparing was frequently noted (27% of colonoscopic studies). Of the four patients diagnosed with Crohn disease, in none did perianal, fistulizing, or stricturing disease develop. Proctocolectomy was performed in six patients (17%); three operations were performed for dysplasia. Pouchitis complicated four of the five ileal pouch–anal anastomoses procedures. Conclusions Among pediatric patients (1) PSC without IBD is uncommon; (2) asymptomatic IBD may be associated with PSC; (3) because the time to dysplasia may be accelerated, once the diagnosis of IBD is made in the setting of PSC, heightened endoscopic surveillance may be indicated; (4) pouchitis occurs frequently in these patients.

Clinical characteristics of eosinophilic esophagitis in children

Objectives: The role of eosinophilic esophagitis (EE) in aerodigestive tract disorders in children is underestimated and overlooked, primarily because of a lack of understanding of this disorder by otolaryngologists. We sought to better characterize the clinical presentation of EE in order to increase awareness among otolaryngologists. Methods: We retrospectively reviewed 71 children with biopsy-proven EE to determine the most common symptoms and laboratory findings that should increase the clinical suspicion of EE. Results: Dysphagia, food impaction, and emesis were the most common symptoms in children with EE. Asthma was the most common airway diagnosis. Rhinosinusitis was the most common otolaryngological diagnosis. Food allergy was present in 60% of the children tested. Eighty-three percent of the children with elevated immunoglobulin E levels had thick linear streaking or patchy white exudate of the esophagus seen on esophagoscopy. Other major medical comorbidities existed in more than half of the children with EE, of which psychiatric disorders and other disorders of the aerodigestive tract were the most common. Conclusions: Eosinophilic esophagitis may contribute to treatment failure in patients with common and complicated aerodigestive tract disorders. To encourage clinicians to avoid overlooking the diagnosis, we present an evaluative algorithm to increase the suspicion of this entity.

Functional dyspepsia, upper gastrointestinal symptoms, and transit in children☆

OBJECTIVEnTo assess the prevalence of abnormal gastric emptying and small bowel transit in children with functional dyspepsia at a tertiary care center, and the relationship between abnormal gastric and small bowel transit and symptoms in pediatric patients with functional gastrointestinal disorders.nnnSTUDY DESIGNnPatients were selected by a cross-sectional chart review based on the following inclusion criteria: (1) completion of scintigraphic study of the gastric emptying of solids at 2 hours (GE2), 4 hours (GE4), and small bowel transit at 6 hours (SBT) using a standardized egg meal labeled with 99mTechnetium sulfur colloid, and (2) gastrointestinal (GI) complaints without mucosal or organic disease. Logistic regression analysis was used to assess the association between the presence of upper GI symptoms, and each parameter of gastric and small bowel transit.nnnRESULTSnChildren with upper GI symptoms (n=96) were identified. Among 57 children with functional dyspepsia, 40% had slow SBT. Fast GE at 4 hours, and slow SBT were independently associated with bloating. Children with fast SBT were less likely to report abdominal pain.nnnCONCLUSIONnIncorporating assessments of gastric and small bowel transit may be useful in the evaluation of pediatric patients with upper GI symptoms and functional dyspepsia.

Prevalence and clinical significance of human herpesviruses 6 and 7 active infection in pediatric liver transplant patients

Abstract:u2002 Recent studies in adult liver transplant patients have suggested that both human herpesvirus (HHV)‐6 and HHV‐7 infection are important causes of morbidity following liver transplantation. However, the impact of HHV‐6 and ‐7 infection in pediatric liver transplant patients remains largely unknown. The aims were to determine the prevalence of HHV‐6 and ‐7 infection in pediatric liver transplant patients and to determine whether there is an association between HHV‐6 and ‐7 infection with episodes of graft rejection and cytomegalovirus (CMV) infection. A total of 46 pediatric liver transplant patients transplanted at Mayo Clinic between January 1994 and January 2000 were evaluated. Quantitative polymerase chain reaction (PCR) assays for CMV, HHV‐6 and HHV‐7 were performed on stored sera obtained prior to transplant, weekly for 8 wk and at 4 months and 1 yr post‐transplant. Pretransplant sera were tested for HHV‐6 antibodies by indirect immunofluorescence assay. A total of 215 blood samples were tested (mean 6.5 ± 3.1, range 3–18). CMV infection occurred in 11 of 33 (33.3%) patients, while CMV disease occurred in 4 of 33 (12%) patients. Infection with HHV‐6 (variant B) was detected in three of 33 (9.1%) patients. HHV‐7 infection was not detected. Case 1 and 2 were infants (10‐ and 11‐month old, respectively). Both were seronegative for HHV‐6 pretransplant. In both cases, HHV‐6 infection was associated with concurrent episodes of moderate to severe acute graft rejection. Case 3 was a 16‐yr‐old girl who was seropositive for HHV‐6 pretransplant. No clinical events were recorded and a liver biopsy performed per protocol showed no evidence of rejection. None of the three patients had concomitant CMV infection or disease. In this study, HHV‐6 infection occurred in 9% of pediatric liver transplant patients while HHV‐7 was not detected. A potential association between primary HHV‐6 infection and allograft rejection warrants further investigation.

The role of pelvic floor dysfunction and slow colonic transit in adolescents with refractory constipation.

OBJECTIVE:Although pelvic floor dysfunction (PFD) is recognized as a cause of refractory constipation in adults, this diagnosis is not frequently considered in children and adolescents with refractory constipation. The purpose of this study was to examine the symptoms and colonic transit in adolescents with constipation evaluated for a disorder in pelvic floor function.METHODS:Adolescents with refractory constipation who had undergone anorectal manometry (ARM) and balloon expulsion test (BET) were identified by retrospective review of records. Initial symptoms and the clinicians assessment were used to categorize patients by pediatric Rome II criteria, that is, functional constipation (FC), constipation-predominant irritable bowel syndrome (C-IBS) or functional fecal retention (FFR). Results of scintigraphic colonic transit studies were evaluated. A χ2 test was used to assess the association between individual clinical symptoms and Rome II criteria.RESULTS:Sixty-seven adolescents underwent evaluation of pelvic floor function by tests for PFD: BET was abnormal in 42%. There was no underlying disease or alternative diagnosis to account for the constipation in these patients. Among the 41 patients who also underwent scintigraphic colonic transit, 30% had slow transit constipation and 12% had both slow colonic transit and abnormal BET. Patients classified as C-IBS were more likely to report weight loss (p =0.03), bloating (p = 0.04), and incomplete rectal evacuation (p = 0.03).CONCLUSION:Abnormal pelvic floor function and delayed colonic transit are demonstrable as single or combined problems in adolescents with refractory constipation.

Significance of Central Perivenulitis in Pediatric Liver Transplantation

Central perivenulitis (CP) encompasses dropout of zone 3 hepatocytes, red blood cell extravasation, and perivenular mononuclear inflammation. In the liver transplant setting, CP can occur in isolation or it can occur in association with portal-based disease such as acute cellular rejection (PB-ACR). Some CP is also thought to be a manifestation of chronic rejection, particularly when accompanied by zone 3 fibrosis. Prior studies of CP in pediatric liver allografts have been hampered by lack of protocol biopsies and low rates of histologic follow-up. We studied 62 consecutive liver allografts from 55 pediatric patients (age: ≤18u2009y) who underwent transplant from the years 1995 to 2007. Forty-nine allografts (79%) had ≥1 year of histologic follow-up, 32 (52%) ≥3 years, and 24 (39%) ≥5 years. We reviewed a total of 445 allograft biopsies (mean: 7.2 per allograft) obtained at 2 days to 11 years; 213 (48%) of these were protocol biopsies. Seven explanted livers that were removed during the course of retransplantation for graft failure in this group were also reviewed. All specimens were scored for the following features: (1) CP (mild, moderate, and severe), (2) portal ACR (mild, moderate, and severe), (3) zone 3 fibrosis (mild=perivenular or severe=bridging), and (4) ductopenia. CP was present in 120 (27%) of 445 biopsies, including 73 with CP+PB-ACR, 16 with CP within 1 month of PB-ACR, 27 with isolated CP, 3 with CP+de-novo autoimmune hepatitis, and 1 with CP+Epstein-Barr virus infection. Overall, CP was observed on at least 1 occasion in 41 (66%) allografts. It was not associated with any specific liver function test abnormality or pattern of liver function test abnormalities, it was not associated with vascular compromise as judged by Doppler ultrasound examinations, and it was not related to type of immunosuppression. CP overall was equally prevalent in the early (≤3u2009mo) and late (>3u2009mo) post-transplant periods, but isolated CP increased in the late period. On follow-up, 6 (15%) of 41 allografts with CP developed ductopenic chronic rejection (4 requiring retransplantation) and 10 (25%) developed zone 3-based fibrosis without ductopenia (2 severe, 8 mild). In contrast, none of the 21 allografts without CP developed chronic rejection (P=0.09) and none had zone 3-based fibrosis on their last biopsy (P<0.001). All patients who developed ductopenia had 1 or more episodes of CP+PB-ACR. In contrast, isolated CP [seen in 17 (27%) allografts on at least 1 occasion] was associated with zone 3-based fibrosis in 50%, but did not lead to ductopenic chronic rejection. These results underscore the high frequency of CP in pediatric liver transplantation, occurring in 27% of all allograft biopsies and 66% of allografts overall. CP is most common in conjunction with portal ACR, where it carries a significant risk for the development of zone 3 fibrosis and a trend toward the development of ductopenic chronic rejection.

A 3-year-old with immunoglobulin G4-associated cholangitis.

JPGN Volume 53, N I mmunoglobulin G4 (IgG4)-associated cholangitis (IAC) is recognized in the adult population as a steroid-responsive biliary disease, often associated with autoimmune pancreatitis (1). IAC has been reported in some instances in the absence of pancreatic involvement (2). IAC is characterized by the elevation of serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts (3). We report on a 3-year-old female patient with features of IgG4associated cholangitis (markedly elevated serum IgG4 and heavy hepatic infiltration with IgG4-positive plasma cells), without evidence of pancreatic involvement. To the best of our knowledge, our patient is the first reported pediatric patient with IAC. A 3-year-old female patient presented in February 2009 to the outpatient pediatric gastroenterology clinic with a 6-month history of dark urine and intermittent episodes of acholic stools. Three months before presentation she was noted to have an enlarged abdomen. She had not been noticeably jaundiced nor did she have scleral icterus until about 3 months before presentation. There were no reported fevers, joint pains, abdominal complaints, and no obvious episode of hepatitis. The patient denied diarrhea, vomiting, hematemesis, hematochezia, or lethargy. Family history is not suggestive of liver or autoimmune diseases. Physical examination revealed a 14.7-kg child (weight at the 63rd percentile), body mass index 17.8 kg/m (at the 93rd percentile), with jaundice and scleral icterus. The liver extended 5 cm below the right costal margin and across the midline to the left midclavicular line. There was no splenomegaly, obvious ascites, or signs of chronic liver disease. The cardiovascular and respiratory examinations were normal. The liver tests at her initial evaluation revealed an alanine aminotransferase (ALT) of 407 U/L (normal 7–45 U/L), an aspartate aminotransferase (AST) of 297 U/L (normal 8–50 U/L), a total protein of 8.6 g/dL, an albumin of 3.4 g/dL, total bilirubin of 4.2 mg/dL with a direct fraction of 2.8 mg/dL, alkaline phosphatase 1990 U/L (normal 169–372 U/L), gamma-glutamyl transpeptidase (GGT) 969 U/L (normal 6–29 U/L), international normalized ratio 1.3, and partial thromboplastin time of 42 seconds. Coagulation factor analysis revealed an isolated decrease in factor V (39% activity) with otherwise normal coagulation factors including a normal factor VII activity of 122%. Total IgG was 3122 mg/dL