History of the first description of childhood liver disease in AATD.

This supplement celebrates the 50th anniversary of Alpha-1 antitrypsin deficiency (AATD). Initially AATD was associated with an inherited form of emphysema. This historical article describes the predisposition of AATD to liver disease. The morphologic findings contributed to a better understanding of low serum levels of A1 AT by the finding of AAT accumulating and stuck in the lumen of the rough endoplasmic reticulum of the hepatocyte. Thus, only low levels of PiZ were secreted for the rest of the human body and the only clinical correction was by liver transplantation.

Status of bacterial colonization, Toll-like receptor expression and nuclear factor-kappa B activation in normal and diseased human livers.

Epidemiological data on bacterial translocation (BT), colonization and inflammation in normal human livers is lacking. In this study we investigated the status of bacterial colonization and inflammation in the normal, cirrhotic primary biliary cirrhosis (PBC), and nonalcoholic steatohepatitis (NASH) human liver tissues. Comparatively normal livers showed increased bacterial colonization than PBC and NASH. We analyzed mRNA levels of Toll-like receptors (TLR) 2 and TLR4, and protein levels of TLR4. Phosphorylated IKKα (pIKKα) protein estimation served as a marker for nuclear factor-kappa B (NF-κB) activation. In spite of the increased bacterial colonization in normal liver tissues, lower levels of TLR2/4 mRNA and TLR4 and pIKKα proteins were found compared to PBC and NASH indicating the maintenance of suppressed inflammation and immune tolerance in normal livers. To our knowledge, this is the first clinical evidence showing suppressed inflammation despite bacterial colonization in normal human livers thus maintaining liver immune homeostasis.

Long-term outcome in 42 pediatric liver transplant patients with alpha 1-antitrypsin deficiency: a single-center experience.

INTRODUCTION: We examined the long-term outcome of transplantation for alpha 1-antitrypsin deficiency (A1ATD). METHOD: Data were reviewed on 42 transplants in 35 children with A1ATD over 42 yr and compared with 129 transplants in 116 children with biliary atresia (BA). RESULTS: Over 50% of patients were followed up for >10 yr. A1ATD were older than BA at transplantation, median age, 6.0 vs. 1.0 yr (p < 0.0001), and transplanted earlier in the course of liver failure (total bilirubin, 2.7 mg/dL [1.4-6.9] vs. 9.7 mg/dL [2.9-15.4], p = 0.005). Patient survival was greater in A1ATD than BA: one-yr post-transplant, 82.7% vs. 67.9%; five yr, 76.5% vs. 60.2%; and 10 yr, 76.5% vs. 55.9% (p = 0.03). Death-censored graft survival was similar: one-yr post-transplant, 68.4% vs. 66.2%; five yr, 68.4% vs. 55.8%; and 10 yr, 68.4% vs. 52.5% (p = 0.2). Deaths were from infection, hemorrhage, and graft failure <6 months post-transplant. Patient survival improved at five yr from 33.3% pre-cyclosporine (CSA) (1969-1984) (n = 6) to 76.5% in the CSA era (1985-1994) (n = 17) and 100% with tacrolimus (1995-2006) (n = 12) (p = 0.007). CONCLUSIONS: The age at transplantation and the degree of liver dysfunction were related to the differences in graft and patient survival between A1AT and BA.

Isoniazid-related hepatic failure in children: a survey of liver transplantation centers.

BACKGROUND: Isoniazid (INH) therapy for tuberculosis carries a known risk for hepatoxicity, and leads to hepatic failure in a small subset of patients. This incidence has been described for adults, but is uncertain in children. Our aim was to estimate the incidence of pediatric referrals for INH-related liver failure, and to describe the characteristics and outcomes of these patients. METHODS: The 84 U.S. centers performing pediatric liver transplants between 1987 and 1997 were surveyed regarding patients with INH-induced liver failure. Additional transplant statistics were obtained from the United Network for Organ Sharing. Estimates of the number of children taking preventive INH were derived from a nationwide public health database. RESULTS: Twenty cases of INH-related liver failure were found during a 10-year period. Four patients (20%) recovered spontaneously; 10 (50%) underwent orthotopic liver transplantation (OLT), while six (30%) died awaiting OLT. Mean age at presentation was 9.8 years (range 1.3-17). Mean length of INH therapy was 3.3 months (range 0.5-9). Notably, five patients seen for symptoms of hepatitis were initially told not to stop treatment. INH-associated liver failure accounted for 0.2% (8 of 4679) of all pediatric OLTs, and 14% (8/56) of transplants for drug hepatoxicity. The estimated incidence of liver failure was up to 3.2/100,000 for children on prophylactic INH. CONCLUSIONS: While INH-associated liver failure in children is rare, discontinuation at the onset of symptoms does not assure recovery. This indicates a need for increased awareness of hepatotoxicity risk, expanded biochemical monitoring for children receiving INH, and prompt withdrawal in symptomatic patients.

Diagnostic endoscopy in children after hematopoietic stem cell transplantation.

OBJECTIVE: To determine the diagnostic yield versus complications from endoscopy in children after hematopoietic stem cell transplantation (HSCT). DESIGN: Data from 191 patients were reviewed, then separated into procedures within the first 100 days after HSCT (when the risks for complications and prevalence of acute graft-versus-host disease [GVHD] are highest) and those performed beyond 100 days. RESULTS: Visible endoscopic lesions were found in 63 of 198 (32%) esophagogastroduodenoscopies (EGDs) and 36 of 220 (16%) sigmoidoscopies. Acute GVHD was present in 38 of 121 (31%) biopsy specimens from EGDs within the first 100 days, 15 of 73 (21%) samples from EGDs after 100 days, 52 of 136 (38%) sigmoid biopsy specimens before 100 days, and in 25 of 82 (31%) samples after 100 days. Non-GVHD histologic abnormalities were present in 36 of 124 (29%) biopsy samples from EGDs before 100 days, 32 of 74 (43%) specimens after 100 days, 14 of 136 (10%) sigmoid specimens before 100 days, and 11 of 84 (13%) samples beyond 100 days. COMPLICATIONS: Complications occurred in 13 procedures (3.1%): 8 (4.2%) EGDs, 4 (2.0%) sigmoidoscopies, and 1 (5.5%) colonoscopy. Intestinal bleeding occurred in 12 of the 13 procedures. Thrombocytopenia was a statistically significant association (p < 0.01). One death occurred after splenic flexure perforation. CONCLUSIONS: GI abnormalities other than acute GVHD occurred in children after HSCT. Acute GVHD was diagnosed most commonly on sigmoid biopsy. Postprocedure hemorrhage was related to thrombocytopenia.

Argon plasma coagulation: Clinical experience in pediatric patients.

BACKGROUND: Argon plasma coagulation has potential advantages in pediatric endoscopy. METHODS: Argon plasma coagulation was applied in 13 children (age 0.05-17 years; median 3 years) with significant comorbid conditions including immunosuppression, chemotherapy, acute or chronic organ failure, and coagulopathy. Twelve had bleeding lesions; esophageal granulomatous tissue was coagulated in one. The bleeding lesion was located in the stomach in 9 of 12, the duodenum in 2 of 12 (both with granulomatous tissue), and at an enterocolonic anastomosis in 1 of 12. OBSERVATIONS: In total, 23 procedures were performed, 22 for bleeding (range 1-5 per patient). Hemostasis was achieved in 8 of 12 with one session. Blood loss and transfusion requirement were reduced in 3 of the other 4 patients. Blood loss was not affected in 1. Bleeding recurred in 3 of 12, and additional procedures were performed in 7 of 12. Granulomatous tissue was completely eradicated in 2 of 3; in one, granulomatous tissue associated with surgical staples was only partially removed. Complications occurred in 2 of 13 patients and included submucosal argon gas and scar formation. CONCLUSION: Endoscopic argon plasma coagulation is efficacious for hemostasis and tissue ablation in pediatric patients. Minor complications occurred in 17% (2/13) of cases in this series.

Role of serology and routine laboratory tests in childhood inflammatory bowel disease.

INTRODUCTION: Serology is reported to be helpful in evaluating children for inflammatory bowel disease (IBD), and distinguishing chronic ulcerative colitis (CUC) from Crohn's disease (CD). The markers include perinuclear staining antineutrophil cytoplasmic antibody (pANCA) for CUC and anti-Saccharomyces cerevisiae antibody (ASCA) for CD. In the clinical setting, hemoglobin (Hgb) and erythrocyte sedimentation rate (ESR) are commonly performed for screening symptomatic children for IBD. We examined whether there was an additional benefit of serology in addition to specific symptoms and routine laboratory tests in screening for IBD. METHOD: Medical record data was reviewed on children investigated for IBD from February 1999 to April 2001. Children were included if they had blood analyzed for pANCA and ASCA, Hgb, ESR, and colonoscopy as part of their assessment. RESULTS: Of 177 cases reviewed, 51 were diagnosed with CUC, 39 with CD, and 26 other inflammatory conditions. Visible rectal bleeding was the most discriminating symptom (occurred in 60/90 cases of IBD and 5/61 without IBD). There was a significant difference between the proportion with CUC positive for pANCA (42/51) and those with abnormal Hgb and ESR (30/51) (p < 0.05), but not between children with CD who were ASCA positive (18/39) and those with abnormal Hgb and ESR (26/39) (p = 0.27). The sensitivity and specificity of combined pANCA and ASCA was 68% and 92%, respectively. For the combination of Hgb, ESR, and the presence of rectal bleeding the respective values were 86% and 67%. Serology combined with Hgb and ESR and rectal bleeding as independent factors significantly (p < 0.05) improved sensitivity (89%) but reduced specificity (60%). Screening with the combination of rectal bleeding, Hgb, and ESR identified 86% (77/90) patients with IBD prior to an endoscopic procedure. A further 3 of 90 (3.3%) screened positive with the addition of serology. CONCLUSION: Serology tests have a high degree of specificity for IBD while routine laboratory test have a higher sensitivity. When serology is combined with rectal bleeding, Hgb, and ESR, the sensitivity of screening children for IBD is significantly improved. However the large majority of children with IBD can be identified with a clinical history and routine laboratory tests as needing an endoscopic procedure with little benefit of adding serology.

Morbidity from congenital hepatic fibrosis after renal transplantation for autosomal recessive polycystic kidney disease.

Presentation of autosomal recessive polycystic kidney disease (ARPKD) ranges from severe renal impairment and a high mortality rate in infancy to older children and adolescents with minimal renal disease and complications of congenital hepatic fibrosis (CHF), cholangitis and portal hypertension. Renal transplantation improves prognosis but it is unclear whether CHF in transplanted children follows the same clinical course as in older children with less severe renal disease. The aim of this study was to evaluate morbidity from CHF in ARPKD post renal transplantation. Data were analyzed for six males and eight females, transplanted for ARPKD (mean age 8.3 years, range 1-22.3 years) at the University of Minnesota between 1972 and 1998. Follow-up was for a mean of 14.5 years (range 3.1-33.6 years). One and 5 years patient survival rates were 93% and 86%, respectively. Overall five patients (36%) died; 4/5 deaths were related to CHF. Causes of death were hepatic failure immediately post transplant (n = 1), septicemia related to bile duct dilatation (n = 3) and multiorgan failure (n = 1). One and 5years graft survival rates were 87% and 70%, respectively. One patient had a combined liver-kidney transplant and two were re-transplanted. Initial signs of CHF were splenomegaly (n = 5), hepatosplenomegaly (n = 4) and gastrointestinal bleed (n = 2). Progression of CHF through childhood included hypersplenism (n = 7), esophageal varices with gastrointestinal bleeding (n = 5) and bile duct dilatation (n = 5). Portal hypertension was treated with portosystemic shunt (n = 3), sclerotherapy (n = 2), banding of varices (n = 1) and transjugular intrahepatic portosystemic shunt (n = 1). Of the nine survivors (mean age 12.8 years) 78% have functioning grafts (one liver-kidney transplant), 63% have portal hypertension and 22% have asymptomatic biliary dilatation. Complications of CHF developed in 79% of children who received a renal transplant for ARPKD. Mortality related to CHF occurred in 29% and accounted for 80% (4/5) of the deaths.

Basiliximab in pediatric liver transplantation: a pharmacokinetic-derived dosing algorithm.

The pharmacokinetics and immunodynamics of basiliximab were assessed in 37 pediatric de novo liver allograft recipients to rationally design a dose regimen for this age-group. In part one of the study, patients were given 12 mg/m2 basiliximab by bolus intravenous injection after organ perfusion and on day 4 after transplant. An interim pharmacokinetic evaluation supported a fixed-dose approach for part two of the study in which infants and children received two 10-mg doses of basiliximab and adolescents received two 20-mg doses. Blood samples were collected over a 12-week period for screening for anti-idiotype antibodies and analysis of basiliximab and soluble interleukin-2 receptor (IL-2R) concentrations. Basiliximab clearance in infants and children < 9 yr of age (n = 30) was reduced by approximately 50% compared with adults from a previous study and was independent of age to 9 yr, weight to 30 kg, and body surface area to 1.0 m2. Clearance in children and adolescents 9-14 yr of age (n = 7) approached or reached adult values. An average of 15% of the dose was eliminated via drained ascites fluid, and drug clearance via this route averaged 29% of total body clearance. Patients with > 5 L of ascites fluid drainage tended to have lower systemic exposure to basiliximab. CD25-saturating basiliximab concentrations were maintained for 27 +/- 9 days in part one of the study (mg/m2 dosing) with infants exhibiting the lowest durations. CD25 saturation lasted 37 +/- 11 days in part two of the study, based on the fixed-dose regimen (p = 0.004 vs. mg/mg2 dosing), but did not show the age-related bias observed in part one of the study. Anti-idiotype antibodies were detected in four patients, but this did not influence the clearance of basiliximab or duration of CD25 saturation. All 40 enrolled patients were included in the intent-to-treat clinical analysis. Episodes of acute rejection occurred in 22 patients (55%) during the first 12 months post-transplant. Three patients experienced loss of their graft as a result of technical complications, and six patients died during the 12-month study. Basiliximab was well tolerated by intravenous bolus injection, with no cytokine-release syndrome or other infusion-related adverse events. Hence, basiliximab was safe and well tolerated in pediatric patients undergoing orthotopic liver transplantation. To achieve similar basiliximab exposure as is efficacious in adults, pediatric patients < 35 kg in weight should receive two 10-mg doses and those > or = 35 kg should receive two 20-mg doses of basiliximab by intravenous infusion or bolus injection. The first dose should be given within 6 h after organ perfusion and the second on day 4 after transplantation. A supplemental dose may be considered for patients with a large volume of drained ascites fluid relative to body size.

Biliary stricture in living-related donor liver transplantation: management with balloon dilation.

Biliary stricture is a recipient graft complication, occurring late in the post-operative period, which appears to occur with increased frequency in living-related donor liver transplantation (LRD LTx). We reviewed the experience at the University of Minnesota in managing a biliary complication of LRD LTx. Since January 1997, 13 LRD transplants have been performed using the technique of transplantation of the left lateral segments with a small portion of segment IV. All patients had hepaticojejunostomies using a Roux-en-Y loop. Of the 11 surviving patients, eight had evidence of cholangitis (Gram-negative sepsis, two patients; ascending cholangitis, three patients; or unexplained fever with elevated liver enzymes, three patients) 4-8 months after otherwise successful transplantation. Six of the patients underwent percutaneous transhepatic cholangiography (PTC) with demonstration of a stenosis at the site of the biliary anastomosis. Repeated dilation of the anastomosis led to resolution of the stenoses, normalization of liver enzymes, and prevention of further episodes of infection. No patient required revision of the hepaticojejunostomy. Computed axial tomography evidence of ductal stenosis may be subtle in this group of patients, but PTC is diagnostic. We suggest a high index of suspicion of biliary stricture in the LRD LTx population. Biliary dilation reduces the risk of life-threatening sepsis.