Durability of sustained response shown in paediatric patients with chronic hepatitis C who were treated with interferon alfa-2b plus ribavirin.

Long-term studies in adults indicate that sustained virologic response (SVR) after combination treatment for chronic hepatitis C (CHC) predicts long-term clearance. Although peginterferon plus ribavirin is now standard care for children with CHC, long-term follow-up studies are not yet available. This study evaluated durability of virologic response over 5 years in children previously treated with interferon alfa-2b plus ribavirin (IFN/R). Ninety-seven of 147 children with CHC, who were treated with IFN/R and completed the 6-month follow-up in two previous clinical trials, participated in this long-term follow-up study. All were assessed annually for up to 5 years; patients with SVR were assessed for durability of virologic response. Children with SVR (n = 56) and those with detectable hepatitis C virus (HCV) RNA 24-week post-treatment (n = 41) were followed for a median of 284 weeks. Overall, 70% (68/97) of patients completed the 5-year follow-up. One patient with genotype 1a CHC had SVR and relapsed at year 1 of follow-up with the same genotype. Kaplan-Meier estimate for sustained response at 5 years was 98% (95% CI: 95%, 100%). Six patients with low-positive HCV RNA levels (n = 4) or missing HCV RNA at the 24-week follow-up visit (n = 2) in the initial treatment studies had virologic response during this long-term follow-up study. Linear growth rate was impaired during treatment with rapid increases in the immediate 6 months post-treatment. Mean height percentile at the end of the 5-year follow-up was slightly less than the mean pretreatment height percentile. Five patients experienced serious adverse events; none related to study drug exposure. SVR after IFN/R predicts long-term clearance of HCV in paediatric patients; growth normalized in the majority of children during the long-term follow-up. Similar long-term results could be expected after peginterferon alfa-2b plus ribavirin treatment.

Risk factors for rejection and infection in pediatric liver transplantation.

Rejection and infection are important adverse events after pediatric liver transplantation, not previously subject to concurrent risk analysis. Of 2291 children (<18 years), rejection occurred at least once in 46%, serious bacterial/fungal or viral infections in 52%. Infection caused more deaths than rejection (5.5% vs. 0.6% of patients, p < 0.001). Early rejection (<6 month) did not contribute to mortality or graft failure. Recurrent/chronic rejection was a risk in graft failure, but led to retransplant in only 1.6% of first grafts. Multivariate predictors of bacterial/fungal infection included recipient age (highest in infants), race, donor organ variants, bilirubin, anhepatic time, cyclosporin (vs. tacrolimus) and era of transplant (before 2002 vs. after 2002); serious viral infection predictors included donor organ variants, rejection, Epstein-Barr Virus (EBV) naivety and era; for rejection, predictors included age (lowest in infants), primary diagnosis, donor-recipient blood type mismatch, the use of cyclosporin (vs. tacrolimus), no induction and era. In pediatric liver transplantation, infection risk far exceeds that of rejection, which causes limited harm to the patient or graft, particularly in infants. Aggressive infection control, attention to modifiable factors such as pretransplant nutrition and donor organ options and rigorous age-specific review of the risk/benefit of choice and intensity of immunosuppressive regimes is warranted.

Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence.

We report a 17-month-old female patient with a rare cause of cardiomyopathy secondary to accumulation of amylopectin-like material (fibrillar glycogen) isolated to the heart. Evidence of amylopectinosis isolated to cardiac myocytes in this patient was demonstrated by histology and electron microscopy. Glycogen content, glycogen branching enzyme (GBE) activity, as well as phosphofructokinase enzyme activities measured in liver, skeletal muscle, fibroblasts and ex-transplanted heart tissue were all in the normal to lower normal ranges. Normal skeletal muscle and liver tissue histology and GBE activity, normal GBE activity in skin fibroblasts, plus normal GBE gene sequence in this patient exclude the classical branching enzyme deficiency (type IV GSD). We believe that this is an as yet uncharacterized and novel phenotype of GSD associated with cardiomyopathy, in which there is an imbalance in the regulation of glycogen metabolism limited to the heart.

Large-volume paracentesis in the management of ascites in children.

BACKGROUND: Large-volume paracentesis has been evaluated for both therapeutic and diagnostic purposes in the management of ascites in cirrhotic adults. There are no published data relating to the safety, efficacy, or methods of this procedure in children. The objective of this study was to characterize the authors' initial experience with large-volume paracentesis (> 50 ml/kg of ascites) for removal of tense abdominal ascites in the pediatric population. METHODS: Retrospective chart review was performed of 21 large-volume paracentesis sessions in seven children (ages 6 months-18 years) with tense ascites that did not respond to other measures. RESULTS: Mean volume removed was 3,129 +/- 2,966 ml (mean +/- standard deviation) or 118 +/- 56 ml/kg over 2.9 +/- 3.7 hours by a 16-gauge intravascular catheter in 6 sessions, by an 18-gauge intravascular catheter in three sessions, and by a 15-gauge fenestrated, stainless-steel paracentesis needle in 12 sessions. Large-volume paracenteses performed with the paracentesis needle had significantly shorter duration of drainage and faster flow rates than those performed with the intravascular catheter. The only complication encountered was decreased urine output in one session. CONCLUSIONS: Large-volume paracentesis is a safe and effective therapeutic method for managing tense abdominal ascites in children. The use of the paracentesis needle significantly improved the speed and efficiency of large-volume paracentesis compared with the intravascular catheter.

Survival after first esophageal variceal hemorrhage in patients with biliary atresia.

OBJECTIVE: To determine the influence of the new onset of esophageal variceal hemorrhage (EVH) on transplant-free survival in children with biliary atresia and to examine variables that predicted survival after the onset of EVH. METHODS: Retrospective chart review of 134 patients with biliary atresia who underwent portoenterostomy between 1973 and 1992 at a single institution; 29% had EVH. RESULTS: The risk of death or need for liver transplantation was 50% at 6 years after the initial episode of EVH. Patients with a serum bilirubin concentration < or =4 mg/dL at the first episode of EVH had transplant-free survival of >80% for 4 years after this episode, those with bilirubin levels >4 to 10 mg/dL had 50% survival at 1 year, and those with bilirubin levels >10 mg/dL had 50% survival at 4 months. The risk of death or transplant for a child with EVH and total serum bilirubin levels >10 mg/dL was 12.0 (95% CI: 6.0, 24.1), 4 to 10 mg/dL was 7.2 (3.1, 16.7), and < or =4 mg/dL was 0.6 (0.1, 3.1) times the risk of a same-aged child who did not have EVH. CONCLUSIONS: Children with biliary atresia and first EVH episode have a variable prognosis related to total serum bilirubin concentration at the time of the episode.

Ontogeny of hepatic enzymes involved in serine- and folate-dependent one-carbon metabolism in rabbits.

Serine occupies a central position in folate-dependent, one-carbon metabolism through 5,10-methylenetetrahydrofolate (MTHF) and 5-formyltetrahydrofolate (FTHF). We characterized the ontogeny of the specific activity of key enzymes involved in serine, 5,10-MTHF, and 5-FTHF metabolism: methenyltetrahydrofolate synthetase (MTHFS), MTHF reductase (MTHFR), the glycine cleavage system (GCS), methionine synthase (MS), and serine hydroxymethyltransferase (SHMT) in rabbit liver, placenta, brain, and kidney. In liver, MTHFS activity is low in the fetus (0.36 +/- 0.07 nmol. min(-1). mg protein(-1)), peaks at 3 wk (1.48 +/- 0.50 nmol. min(-1). mg protein(-1)), and then decreases to adult levels (1.13 +/- 0.32 nmol. min(-1). mg protein(-1)). MTHFR activity is highest early in gestation (24.9 +/- 2.4 nmol. h(-1). mg protein(-1)) and declines rapidly by birth (4.7 +/- 1.3 nmol. h(-1). mg protein(-1)). MS is highest during fetal life and declines after birth. Cytosolic SHMT activity does not vary during development, but mitochondrial SHMT peaks at 23 days. GCS activity is high in the fetus and the neonate, declining after weaning. In placenta and brain, all activities are low throughout gestation. Cytosolic and mitochondrial SHMT activities are low in kidney and rise after weaning, whereas MTHFS is low throughout development. These data suggest that the liver is the primary site of activity for these enzymes. Throughout development, there are multiple potential sources for production of 5,10-MTHF, but early in gestation high MTHFR activity and low MTHFS activity could reduce 5,10-MTHF availability.

Biliary atresia: an update on our understanding of the disorder.

Biliary atresia is the leading cause of cholestasis in infants younger than 3 months. It is also the leading indication for liver transplantation in children. This review focuses on recent advances in the etiology, diagnosis, and management of biliary atresia.

Serine and glycine transport in fetal ovine hepatocytes.

The role of hepatic serine and glycine transport in the regulation of the biosynthesis of serine by the fetal liver has not been studied. The goal of this study was to characterize serine and glycine transport and utilization at physiologic concentrations in primary cultures of fetal ovine hepatocytes. Primary culture of hepatocytes from mid gestation ( approximately 90 days) and term ( approximately 135 days) fetal sheep were studied after overnight serum free culture. At both gestational ages, the initial rate for sodium dependent 300 microM serine transport (1697+/-131 pmoles/min/mg protein at mid, 1765+/-544 at term) was fourfold greater than sodium dependent 300 microM glycine transport (309+/-54 at mid, 579+/-252 at term). At physiologic concentrations (300 microM), 69+/-7% of serine and 49+/-8% of glycine transport was sodium dependent. At term, sodium dependent serine transport has a V(max) of 1751+/-348 pmoles/min/mg protein and a K(m) of 159+/-111 microM. Sodium independent serine transport has a V(max) of 904+/-185 and a K(m) of 416+/-188 microM. Sodium dependent glycine transport has a V(max) of 410+/-69 and a K(m) of 2290+/-895 microM while sodium independent glycine transport exhibits non-saturable kinetics. Glycine (300 microM) sodium dependent transport was not inhibited by methyl-AIB while sodium dependent 300 microM serine transport was inhibited (31%). n-Ethylmaleimide inhibited sodium dependent serine and glycine transport by 36+/-9% and 37+/-2% respectively in term hepatocytes. Cysteine inhibited sodium dependent serine transport by 37%. Sodium independent glycine transport at 300 microM was higher in low glucose (1.1 mM) medium (881+/-76 pmoles/min/mg protein) compared to high glucose (5.5 mM) medium (510+/-60 P=0.004). There were no significant differences in serine or glycine incorporation into RNA, DNA, glycogen or lipid and protein. The predominance of serine transport over glycine at physiologic concentrations suggests that inward cellular amino acid transport of serine and glycine is not likely to be a regulatory mechanism that would favor serine biosynthesis in fetal ovine hepatocytes.

Ontogeny of serine hydroxymethyltransferase isoenzymes in fetal sheep liver, kidney, and placenta.

Serine is an amino acid that is not transported from the placenta to the ovine fetus. Thus, fetal plasma serine levels may be controlled by flux through their relevant biosynthetic pathways. This study was designed to determine, in fetal sheep tissues, the ontogeny of the three key enzymes in the biosynthetic pathway for serine, the cytosolic (c) and mitochondrial (m) isoforms of serine hydroxymethyltransferase (SHMT), phosphoglycerate dehydrogenase (PGD), and phosphoserine aminotransferase (PSAT). PGD and PSAT activity did not vary during gestation in either liver (PSAT, 9.4 +/- 1.3 nmol/min/mg cytosolic protein; and PGD, 76 +/- 10 mU/mg protein) or placenta (PGD, 8.0 +/- 3.6 mU/mg protein). In the liver, cSHMT activity was low early in gestation (0.6 +/- 0.5 nmol/min/mg protein at 45 days), rose in the last one-third of gestation, and peaked in the newborn period (25 +/- 3 nmol/min/mg protein at 1 week of age). Hepatic cSHMT RNA levels parallel the activity pattern. Mitochondrial SHMT was stable throughout gestation and with low constant mSHMT RNA levels. In contrast, the kidney and placenta had high mSHMT and steady low cSHMT activity throughout gestation. These data support the possible role of SHMT in the fetal control of plasma serine levels. While cSHMT may contribute to fetal hepatic serine production, its activity pattern does not support a primary role in the control of fetal hepatic serine biosynthesis. In the placenta, mSHMT may be important for glycine production from serine.

Esophageal varices: current management in children.

The treatment of esophageal variceal hemorrhage is still the subject of some controversy. The main causes of portal hypertension in children are portal vein thrombosis or cirrhosis, most commonly caused by biliary atresia. Many treatment options are available including endoscopic, radiographic, and surgical strategies. In general, children with presinusoidal obstructions have preserved hepatic synthetic function, and, therefore, treatment options include endoscopic strategies or portosystemic shunts, each with advocates. For children with advanced liver disease, liver transplantation offers the only chance for cure, so primary treatment of variceal bleeding should be by endoscopic means or transjugular intrahepatic portosystemic shunt (TIPS). Each modality has specific advantages and disadvantages, and treatment recommendations must therefore be tailored to the individual on a case-by-case basis, largely dependent on the expertise and experience of the health care team.

Use of rifampin for severe pruritus in children with chronic cholestasis.

BACKGROUND: Rifampin has been proposed to reduce pruritus in children and adults with chronic cholestasis; however, there is a paucity of published data regarding the use of rifampin in children. METHODS: In an open trial, 24 children were evaluated during a 6-year period. Diagnoses included 13 patients with extrahepatic biliary atresia (54%), six with Alagille's syndrome, three with Byler's disease, and one each with primary sclerosing cholangitis and alpha1-antitrypsin deficiency. All patients had severe pruritus that had not responded adequately to at least 2 months of therapy with ursodeoxycholic acid, diphenhydramine, or phenobarbital and local skin care measures. Treatment was initiated with rifampin, 10 mg/kg per day in two divided doses for 18+/-20 months, and the effect on the severity of pruritus was assessed by a clinical scoring system. RESULTS: Ten patients showed a complete response, 12 a partial response, and 2 no response. Complete response was more common in extrahepatic cholestasis (64% vs. 10%), whereas partial response was more common in intrahepatic cholestasis (80% vs. 29%). Treatment was associated with reduction of gamma-glutamyl transpeptidase. No clinical or biochemical toxicity of rifampin was observed. CONCLUSIONS: We conclude that for more than 90% of children with chronic cholestasis and severe pruritus unresponsive to other treatments, rifampin appears to be a safe and effective therapy.

Correction of hypozincemia following liver transplantation in children is associated with reduced urinary zinc loss.

Zinc deficiency is a relatively common problem in children with chronic liver disease. We have previously shown inappropriate urinary zinc excretion in children with chronic liver disease and hypozincemia. This study was designed to determine if zinc deficiency and inappropriate urinary zinc losses are corrected in children with liver disease by liver transplantation. Thirty-three patients (age 1-19 years) underwent 35 liver transplants for acute and chronic liver disease. At the time of transplant, 17 patients had low plasma zinc (hypozincemic) (plasma zinc, 45.4 +/- 1.8 microg/dL), whereas 18 had normal plasma zinc (75.7 +/- 3.8). Before transplant, patients with zinc deficiency had higher urinary zinc to creatinine ratio compared with those with normal zinc status (6.6 +/- 1.9 vs. 2.2 +/- 0.6; P =.03) and lower serum albumin concentrations (low: 2.8 +/- 0.1 vs. normal: 3.3 +/- 0.2; P =.02). After transplant, there was a significant reduction in urinary zinc losses in the hypozincemic group followed by normalization of plasma zinc levels by 7 days posttransplant. These data suggest that the abnormal renal zinc homeostasis that is present in approximately 50% of pediatric patients undergoing liver transplant is rapidly improved and biochemical zinc deficiency is reversed after liver transplantation.

Partial splenic embolization in five children with hypersplenism: effects of reduced-volume embolization on efficacy and morbidity.

PURPOSE: To evaluate the effects of reducing the volume of spleen infarcted during partial splenic embolization (PSE) for treatment of hypersplenism in children. MATERIALS AND METHODS: Five children with hypersplenism underwent embolization of 30%-40% of the splenic volume. The results were compared with those of a previous study of 70%-80% PSE performed in 17 children. RESULTS: The hospital stay after the procedure was reduced from 16.0 days +/- 8.0 to 6.6 days +/- 5.6. The febrile period decreased from 15.0 days +/- 8.1 to 5.0 days +/- 6.6. The peak white blood cell count was 8,300/mm3 +/- 4,600 (8.3 x 10(9)/L +/- 4.6) versus 19,400/mm3 +/- 7,800 (19.4 x 10(9)/L +/- 7.8) in the earlier study. The peak platelet count was 153,000/mm3 +/- 65,000 (153 x 10(9)/L +/- 65) versus 636,000/mm3 +/- 406,000 (636 x 10(9)/L +/- 406). The platelet count after a mean follow-up of 14 months was 70,000/mm3 +/- 7,000 (70 x 10(9)/L +/- 7) versus 230,000/mm3 +/- 62,000 (230 x 10(9)/L +/- 62) after a mean follow-up of 45 months. The frequency of variceal hemorrhage decreased from 3.5 to 0.5 episodes per year. The frequency of epistaxis decreased from 30 to 15 episodes per month. CONCLUSION: Reduced-volume embolization decreased morbidity. All patients maintained a platelet count above baseline, and no patient required repeat embolization.

Fulminant Epstein-Barr viral hepatitis: orthotopic liver transplantation and review of the literature.

Acute hepatic failure caused by primary Epstein-Barr virus (EBV) infection has been reported in the literature in 16 cases, with an overall mortality of 87%. We report a case of fulminant hepatic failure in an immunocompetent young girl caused by primary EBV infection that was treated by orthotopic liver transplantation. After transplantation she has been treated with low-dose immunosuppression, a pooled gammaglobulin preparation containing anti-EBV antibodies, and anti-viral therapy. The patient is presently doing well 2 years after transplantation without evidence of clinical EBV infection, primary immunodeficiency, or lymphoproliferative disease.

ERCP in the management of pediatric pancreatitis.

BACKGROUND: Although ERCP is commonly performed in children, the effect of findings at ERCP on the subsequent management of pediatric pancreatitis is unknown. METHODS: We retrospectively reviewed charts to determine the impact of ERCP on the management of recurrent acute or chronic pancreatitis in 17 consecutive children (3 boys and 14 girls, 3 to 16 years, mean 11.2 years) with recurrent acute (n = 13) or chronic pancreatitis (n = 4) who underwent ERCP. Radiographs were reviewed in a blinded manner, and the effect of ERCP findings on subsequent management was determined. RESULTS: In 16 of 17 patients (94%), the pancreatic duct was successfully visualized. Of the 16 studies, 9 (56%) had abnormal findings. A change in therapy occurred in all 9 patients as a result of the findings at ERCP. Of the 7 patients with a prior abnormal CT or ultrasound, 5 (71%) had an abnormal ERCP, all resulting in a change in therapy. Three of the 9 patients (33%) without radiographic abnormalities had an abnormal ERCP that, in each case, resulted in a change in therapy. Overall, findings at ERCP altered therapy in 52% of pediatric patients studied with recurrent acute or chronic pancreatitis. A prior abnormal CT had a high predictive value with respect to ERCP resulting in a change in management (83%). CONCLUSIONS: ERCP is useful in the management of pediatric recurrent acute or chronic pancreatitis; abnormalities are found at a rate similar to those found in adults.

Detection of reovirus RNA in hepatobiliary tissues from patients with extrahepatic biliary atresia and choledochal cysts.

Extrahepatic biliary atresia (EHBA) and choledochal cysts (CDC) are important causes of obstructive jaundice in pediatric patients. Viruses in general, and reoviruses in particular, have long been considered as possible etiologic agents responsible for inciting the inflammatory process that leads to these infantile obstructive cholangiopathies. In an effort to determine whether reovirus infection is associated with these disorders, we used a sensitive and specific reverse-transcriptase polymerase chain reaction (RT-PCR) technique designed to amplify a portion of the reovirus L1 gene segment from extracts of liver and/or biliary tissues. These tissues were obtained at the time of liver biopsy or surgical procedures from 23 patients with EHBA, 9 patients with CDC, and 33 patients with other hepatobiliary diseases. Hepatic and biliary tissues obtained at autopsy from 17 patients who died without known liver or biliary disease were also analyzed. Reovirus RNA was detected in hepatic and/or biliary tissues from 55% of patients with EHBA and 78% of patients with CDC. Reovirus RNA was found also in extracts of hepatic and/or biliary tissue from 21% of patients with other hepatobiliary diseases and in 12% of autopsy cases. The prevalence of reovirus RNA in tissues from patients with EHBA and CDC was significantly greater than that in patients with other hepatobiliary diseases (chi2 P = .012 EHBA vs. OTHER, P = .001 CDC vs. OTHER), or AUTOPSY cases (chi2 P = .006 EHBA vs. AUTOPSY, P < .001 CDC vs. AUTOPSY).

Effect of ursodeoxycholic acid therapy on hepatic function in children with intrahepatic cholestatic liver disease.

BACKGROUND: Ursodeoxycholic acid (UDCA) has been shown to improve pruritus, alanine aminotransferase (ALT), and cholesterol levels in children with intrahepatic cholestatic liver disease. However, the effect of UDCA on quantitative tests of hepatic function in children is uncertain. METHODS: A 2.5-year, open label, crossover study, was designed to determine the effect of UDCA (15-20 mg/kg per day for 12 months, off for 6 months, and on again for 12 months) on clinical symptoms, biochemical test results, galactose and caffeine elimination half-lives (t1/2), and quantitative hepatic scintigraphy in 13 subjects aged 13.1 +/- 2.1 years (10 of whom completed the entire study), with intrahepatic cholestasis. RESULTS: Pruritus improved with UDCA in the 6 patients with pruritus on entry into the study. At 12 months, there was a significant decline in ALT, gamma-glutamyl transpeptidase, and plasma levels of copper and manganese, with no further decline in these levels at 24 months. There were no changes in bilirubin or cholylglycine levels. After therapy was discontinued at 12 months, UDCA was restarted within 1 month in 9 of 12 patients in response to a doubling of ALT (n = 6) or worsening pruritus (n = 3). Galactose t1/2 increased after 12 months, with no further increases after 24 months of UDCA therapy, whereas caffeine t1/2 did not change. There were no significant changes in hepatic scintigraphy throughout the study. CONCLUSIONS: These data suggest that although UDCA therapy improves pruritus and results in a reduction in ALT and gamma-glutamyl transpeptidase, UDCA therapy did not improve quantitative measures of hepatic function in children with intrahepatic cholestasis.