Publications by authors named "Parvathi Mohan"

32 Publications

Granulocyte-colony stimulating factor GCSF mobilizes hematopoietic stem cells in Kasai patients with biliary atresia in a phase 1 study and improves short term outcome.

J Pediatr Surg 2021 Apr 9. Epub 2021 Apr 9.

Vietnam National Children Hospital, Hanoi, Vietnam.

Aims: In RCT of adults with decompensated cirrhosis, GCSF mobilizes hematopoietic stem cells HSC and improves short-term outcome. An FDA-IND for sequential Kasai-GCSF treatment in biliary atresia BA was approved. This phase 1 study examines GCSF safety in Kasai subjects. Preliminary short-term outcome was evaluated.

Methods: GCSF (Neupogen) at 5 or 10 μg/kg (n = 3/group) was given in 3 daily doses starting on day 3 of Kasai surgery (NCT03395028). Serum CD34+ HSC cell counts, and 1-month of GCSF-related adverse events were monitored. The 6-months Phase 1 clinical outcome was compared against 10 subsequent post Phase 1 Kasai patients who did not receive GCSF.

Results: With GCSF, WBC and platelet count transiently increased, LFT and serum creatinine remained stable. Reversible splenic enlargement (by 8.5-20%) occurred in 5/6 subjects. HSC count increased 12-fold and 17.5-fold for the 5 μg/kg and10 ug/kg dose respectively; with respective median total bilirubin levels for GCSF vs no-GCSF groups of 55 vs 91 μM at 1 month, p = 0.05; 15 vs 37 μM at 3 months, p = 0.24); and the 6-months cholangitis frequency of 40% vs 90%, p = 0.077.

Conclusions: GCSF safely mobilizes HSC in Kasai infants and may improve short-term biliary drainage and cholangitis. Phase 2 efficacy outcome of GCSF adjunct therapy for sequential Kasai and GCSF is pending.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.03.038DOI Listing
April 2021

Twelve-year outcomes of intestinal failure-associated liver disease in children with short-bowel syndrome: 97% transplant-free survival and 81% enteral autonomy.

JPEN J Parenter Enteral Nutr 2021 Apr 1. Epub 2021 Apr 1.

Intestinal Rehabilitation Program, Division of Gastroenterology, Hepatology, and Nutrition, Children's National Hospital, Washington, DC, USA.

Our aim was to analyze the outcomes in children with short-bowel syndrome (SBS), parenteral nutrition dependence (PND), and intestinal failure-associated liver disease (IFALD) treated in our Intestinal Rehabilitation Program (IRP) during 2007-2018. We retrospectively reviewed charts of 135 patients with SBS-PND at the time of enrollment in IRP; of these, 89 (66%) had IFALD, defined as conjugated bilirubin (CB) of ≥2 mg/dl at enrollment and/or abnormal liver biopsy showing stage 2-4 fibrosis. Outcomes included resolution of CB, enteral autonomy, laboratory parameters (platelets, aspartate aminotransferase to platelet ratio index), growth trends, transplant rates, and mortality. Of the 89 patients, 74 had elevated CB at enrollment; the other 15 had normalized CB but had fibrosis on liver biopsy. Thirty-eight patients had liver biopsies: 36 (95%) had fibrosis, including 21/36 with bridging fibrosis/cirrhosis. The median proportion of residual small bowel was 23% (interquartile range, 13%-38%) of the expected length for age and median, daily energy requirement by PN was 100%. Two received a transplant, three died (one posttransplant), and the remaining 85 survived; 69 (81%) achieved enteral autonomy. Seventy-three (99%) of the 74 patients with hyperbilirubinemia normalized their CB with medical treatment. In a subset of eight of 89 patients with initial platelet count of <100,000/μl(median 50,500/μl) and median CB of 21 mg/dl, seven achieved CB normalization and had improved platelet count. Overall survival was 97% (censored 96.3%). We demonstrate high transplant-free survival and enteral autonomy rates among children with SBS-IFALD relying on low-dose soybean lipid emulsion.
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http://dx.doi.org/10.1002/jpen.2112DOI Listing
April 2021

Hepatitis C in 2020: A North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper.

J Pediatr Gastroenterol Nutr 2020 09;71(3):407-417

Children's Hospital of Colorado, Digestive Health Institute, University of Colorado School of Medicine, Aurora, CO.

In 1989, a collaboration between the Centers for Disease Control (CDC) and a California biotechnology company identified the hepatitis C virus (HCV, formerly known as non-A, non-B hepatitis virus) as the causative agent in the epidemic of silent posttransfusion hepatitis resulting in cirrhosis. We now know that, the HCV genome is a 9.6 kb positive, single-stranded RNA. A single open reading frame encodes a 3011 amino acid residue polyprotein that undergoes proteolysis to yield 10 individual gene products, consisting of 3 structural proteins (core and envelope glycoproteins E1 and E2) and 7 nonstructural (NS) proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B), which participate in posttranslational proteolytic processing and replication of HCV genetic material. Less than 25 years later, a new class of medications, known as direct-acting antivirals (DAAs) which target these proteins, were introduced to treat HCV infection. These highly effective antiviral agents are now approved for use in children as young as 3 years of age and have demonstrated sustained virologic responses exceeding 90% in most genotypes. Although tremendous scientific progress has been made, the incidence of acute HCV infections has increased by 4-fold since 2005, compounded in the last decade by a surge in opioid and intravenous drug use. Unfortunately, awareness of this deadly hepatotropic virus among members of the lay public remains limited. Patient education, advocacy, and counseling must, therefore, complement the availability of curative treatments against HCV infection if this virus is to be eradicated.
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http://dx.doi.org/10.1097/MPG.0000000000002814DOI Listing
September 2020

A patient with atypical presentation of chronic hepatosteatosis harboring a novel variant in the CPT1A gene.

Eur J Med Genet 2021 Jan 8;64(1):104034. Epub 2020 Aug 8.

Division of Genetics and Metabolism, Children's National Hospital, Rare Disease Institute, Washington, DC, 20010, USA. Electronic address:

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a rare disorder of hepatic long-chain fatty acid oxidation. Most patients with CPT1A deficiency present with hypoketotic hypoglycemia and hepatic encephalopathy. We describe an atypical case of an 8-year-old male with CPT1A deficiency presenting with chronic liver steatosis and cirrhosis. He also had a history of developmental delay, autism spectrum disorder, and mild dysmorphic features of unknown cause. His newborn screening test suggested CPT1A deficiency, but confirmatory biochemical testing was not conclusive. The patient never experienced a metabolic crisis. At age six, hepatomegaly was detected. Further investigations showed transaminitis, hepatosteatosis and cirrhosis. Repeat acylcarnitine profile and total/free carnitine were consistent with CPT1A deficiency. The CPTI enzyme activity was 18% of normal on fibroblast enzyme assay. A novel homozygous variant in the CPT1A gene, c.1394G > A (p.Gly465Glu) was identified from whole-exome sequencing. To our knowledge, the patient is the first reported individual with CPT1A deficiency and chronic liver steatosis and fibrosis. Developmental delay and autistic spectrum disorder are not typical features of CPT1A deficiency, given that the patient never experienced any metabolic decompensation.
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http://dx.doi.org/10.1016/j.ejmg.2020.104034DOI Listing
January 2021

The Sclerosing Cholangitis Outcomes in Pediatrics (SCOPE) Index: A Prognostic Tool for Children.

Hepatology 2021 Mar 19;73(3):1074-1087. Epub 2020 Dec 19.

Boston Children's Hospital and Harvard Medical School, Boston, MA.

Background And Aims: Disease progression in children with primary sclerosing cholangitis (PSC) is variable. Prognostic and risk-stratification tools exist for adult-onset PSC, but not for children. We aimed to create a tool that accounts for the biochemical and phenotypic features and early disease stage of pediatric PSC.

Approach And Results: We used retrospective data from the Pediatric PSC Consortium. The training cohort contained 1,012 patients from 40 centers. We generated a multivariate risk index (Sclerosing Cholangitis Outcomes in Pediatrics [SCOPE] index) that contained total bilirubin, albumin, platelet count, gamma glutamyltransferase, and cholangiography to predict a primary outcome of liver transplantation or death (TD) and a broader secondary outcome that included portal hypertensive, biliary, and cancer complications termed hepatobiliary complications (HBCs). The model stratified patients as low, medium, or high risk based on progression to TD at rates of <1%, 3%, and 9% annually and to HBCs at rates of 2%, 6%, and 13% annually, respectively (P < 0.001). C-statistics to discriminate outcomes at 1 and 5 years were 0.95 and 0.82 for TD and 0.80 and 0.76 for HBCs, respectively. Baseline hepatic fibrosis stage was worse with increasing risk score, with extensive fibrosis in 8% of the lowest versus 100% with the highest risk index (P < 0.001). The model was validated in 240 children from 11 additional centers and performed well.

Conclusions: The SCOPE index is a pediatric-specific prognostic tool for PSC. It uses routinely obtained, objective data to predict a complicated clinical course. It correlates strongly with biopsy-proven liver fibrosis. SCOPE can be used with families for shared decision making on clinical care based on a patient's individual risk, and to account for variable disease progression when designing future clinical trials.
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http://dx.doi.org/10.1002/hep.31393DOI Listing
March 2021

Assessing the Validity of Adult-derived Prognostic Models for Primary Sclerosing Cholangitis Outcomes in Children.

J Pediatr Gastroenterol Nutr 2020 01;70(1):e12-e17

University of Rochester Medical Center, Rochester, NY.

Background: Natural history models for primary sclerosing cholangitis (PSC) are derived from adult patient data, but have never been validated in children. It is unclear how accurate such models are for children with PSC.

Methods: We utilized the pediatric PSC consortium database to assess the Revised Mayo Clinic, Amsterdam-Oxford, and Boberg models. We calculated the risk stratum and predicted survival for each patient within each model using patient data at PSC diagnosis, and compared it with observed survival. We evaluated model fit using the c-statistic.

Results: Model fit was good at 1 year (c-statistics 0.93, 0.87, 0.82) and fair at 10 years (0.78, 0.75, 0.69) in the Mayo, Boberg, and Amsterdam-Oxford models, respectively. The Mayo model correctly classified most children as low risk, whereas the Amsterdam-Oxford model incorrectly classified most as high risk. All of the models underestimated survival of patients classified as high risk. Albumin, bilirubin, AST, and platelets were most associated with outcomes. Autoimmune hepatitis was more prevalent in higher risk groups, and over-weighting of AST in these patients accounted for the observed versus predicted survival discrepancy.

Conclusions: All 3 models offered good short-term discrimination of outcomes but only fair long-term discrimination. None of the models account for the high prevalence of features of autoimmune hepatitis overlap in children and the associated elevated aminotransferases. A pediatric-specific model is needed. AST, bilirubin, albumin, and platelets will be important predictors, but must be weighted to account for the unique features of PSC in children.
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http://dx.doi.org/10.1097/MPG.0000000000002522DOI Listing
January 2020

Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course.

J Pediatr 2019 06 14;209:92-96.e1. Epub 2019 Mar 14.

Department of Pediatrics, University of Utah, Salt Lake City, UT.

Objective: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis.

Study Design: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level <50 IU/L without experiencing portal hypertensive or dominant stricture events, liver transplantation, or death during the first year.

Results: We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not.

Conclusions: Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.
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http://dx.doi.org/10.1016/j.jpeds.2019.01.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535363PMC
June 2019

Gamma Glutamyltransferase Reduction Is Associated With Favorable Outcomes in Pediatric Primary Sclerosing Cholangitis.

Hepatol Commun 2018 Nov 25;2(11):1369-1378. Epub 2018 Sep 25.

University of Rochester Medical Center Rochester NY.

Adverse clinical events in primary sclerosing cholangitis (PSC) happen too slowly to capture during clinical trials. Surrogate endpoints are needed, but no such validated endpoints exist for children with PSC. We evaluated the association between gamma glutamyltransferase (GGT) reduction and long-term outcomes in pediatric PSC patients. We evaluated GGT normalization (< 50 IU/L) at 1 year among a multicenter cohort of children with PSC who did or did not receive treatment with ursodeoxycholic acid (UDCA). We compared rates of event-free survival (no portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or liver-related death) at 5 years. Of the 287 children, mean age of 11.4 years old, UDCA was used in 81% at a mean dose of 17 mg/kg/day. Treated and untreated groups had similar GGT at diagnosis (314 versus 300, = not significant [NS]). The mean GGT was reduced at 1 year in both groups, with lower values seen in treated (versus untreated) patients (99 versus 175, = 0.002), but 5-year event-free survival was similar (74% versus 77%, = NS). In patients with GGT normalization (versus no normalization) by 1 year, regardless of UDCA treatment status, 5-year event-free survival was better (91% versus 67%, < 0.001). Similarly, larger reduction in GGT over 1 year (> 75% versus < 25% reduction) was also associated with improved outcome (5-year event-free survival 88% versus 61%, = 0.005). A GGT < 50 and/or GGT reduction of > 75% by 1 year after PSC diagnosis predicts favorable 5-year outcomes in children. GGT has promise as a potential surrogate endpoint in future clinical trials for pediatric PSC.
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http://dx.doi.org/10.1002/hep4.1251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6211333PMC
November 2018

The natural history of primary sclerosing cholangitis in 781 children: A multicenter, international collaboration.

Hepatology 2017 08 26;66(2):518-527. Epub 2017 Jun 26.

Texas Children's Hospital, Houston, TX, and Phoenix Children's Hospital, Phoenix, AZ.

There are limited data on the natural history of primary sclerosing cholangitis (PSC) in children. We aimed to describe the disease characteristics and long-term outcomes of pediatric PSC. We retrospectively collected all pediatric PSC cases from 36 participating institutions and conducted a survival analysis from the date of PSC diagnosis to dates of diagnosis of portal hypertensive or biliary complications, cholangiocarcinoma, liver transplantation, or death. We analyzed patients grouped by disease phenotype and laboratory studies at diagnosis to identify objective predictors of long-term outcome. We identified 781 patients, median age 12 years, with 4,277 person-years of follow-up; 33% with autoimmune hepatitis, 76% with inflammatory bowel disease, and 13% with small duct PSC. Portal hypertensive and biliary complications developed in 38% and 25%, respectively, after 10 years of disease. Once these complications developed, median survival with native liver was 2.8 and 3.5 years, respectively. Cholangiocarcinoma occurred in 1%. Overall event-free survival was 70% at 5 years and 53% at 10 years. Patient groups with the most elevated total bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis had the worst outcomes. In multivariate analysis PSC-inflammatory bowel disease and small duct phenotypes were associated with favorable prognosis (hazard ratios 0.6, 95% confidence interval 0.5-0.9, and 0.7, 95% confidence interval 0.5-0.96, respectively). Age, gender, and autoimmune hepatitis overlap did not impact long-term outcome.

Conclusion: PSC has a chronic, progressive course in children, and nearly half of patients develop an adverse liver outcome after 10 years of disease; elevations in bilirubin, gamma-glutamyltransferase, and aspartate aminotransferase-to-platelet ratio index at diagnosis can identify patients at highest risk; small duct PSC and PSC-inflammatory bowel disease are more favorable disease phenotypes. (Hepatology 2017;66:518-527).
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http://dx.doi.org/10.1002/hep.29204DOI Listing
August 2017

Integrin β-8, but not β-5 or -6, protein expression is increased in livers of children with biliary atresia.

J Pediatr Gastroenterol Nutr 2014 Dec;59(6):679-83

*Sheikh Zayed Institute for Pediatric Surgical Innovation †Department of Pathology ‡Department of Gastroenterology, Hepatology, and Nutrition, Children's National Medical Center, Washington, DC §Division of Pediatric Gastroenterology and Nutrition ||Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland.

Objectives: Our previous work demonstrated altered messenger RNA expression of integrin β-5 and -8, using an in silico analysis of publically available data from patients with biliary atresia (BA); however, we were unable to demonstrate statistically significant differences in protein expression because of sample size. In the present study, we repeated the analysis of liver fibrosis and protein expression of the integrins in a larger cohort of patients with BA and compared them with patients undergoing liver biopsy for other diagnoses, with the hypothesis that ≥ 1 of the integrins would be differentially expressed.

Methods: Liver specimens were obtained at 2 collaborating institutions. Samples from infants with BA (n = 23) were compared with samples from those who underwent liver biopsy for neonatal hepatitis (n = 9). All of the specimens were analyzed by 2 pathologists (C.R. and R.A.), who were blinded to the diagnoses. Standard Ishak scoring was performed to evaluate fibrosis and inflammation, and immunohistochemical (IHC) positivity was graded from 0 to 4. Comparisons between the IHC positivity and Ishak scoring for the BA and control groups were performed using the Student t test with P < 0.01 considered significant because of the multiple comparisons. Interobserver variability was assessed by intraclass correlation (ICC).

Results: Pooled analysis from specimens from patients with BA showed significantly more fibrosis than controls based on Ishak scores (3.21 ± 1.82 vs 1.17 ± 1.00, P < 0.005). IHC evaluation showed increased integrin ανβ8 protein expression when compared with controls (2.67 ± 0.81 vs 1.72 ± 0.62, P < 0.005); however, there were no significant differences in integrin ανβ5 (1.93 ± 0.84 vs 1.50 ± 0.90, P = 0.23) or integrin ανβ6 (0.85 ± 1.20 vs 0.94 ± 0.85, P = 0.82) expression. These data were confirmed on individual analysis. Interobserver agreement was fair for integrin ανβ5 (ICC 0.52), good for integrin ανβ6 (ICC 0.72), and excellent for integrin ανβ8 (ICC 0.79) and fibrosis (ICC 0.89).

Conclusions: Our data show that integrin ανβ8, but not integrin ανβ5 or integrin ανβ6, protein expression is increased in liver specimens of patients with BA. These data support the mounting evidence that transforming growth factor-β (TGF-β) activation is responsible for the fibrosis found in BA. Anti-integrin ανβ8 or more global integrin blocking strategies may be therapeutic options in BA, but further work is clearly needed.
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http://dx.doi.org/10.1097/MPG.0000000000000518DOI Listing
December 2014

Evaluating progression of liver disease from repeat liver biopsies in children with chronic hepatitis C: a retrospective study.

Hepatology 2013 Nov 30;58(5):1580-6. Epub 2013 Sep 30.

Children's National Medical Center, The George Washington School of Medicine, Washington, DC.

Unlabelled: Clinical and histologic progression of liver disease in untreated children with chronic hepatitis C virus (HCV) infection is poorly documented. The aim of this retrospective study was to characterize changes in liver histology over time in a cohort of HCV-infected children who had more than one liver biopsy separated by over 1 year. Forty-four untreated children without concurrent liver diseases, who had repeat liver biopsies at eight U.S.-based medical centers, were included. Biopsies were scored by a single pathologist for inflammation, fibrosis, and steatosis and were correlated with demographic data including age at biopsy, time from infection to biopsies, and laboratory values such as serum alanine aminotransferase (ALT). Mode of transmission was vertical in 25 (57%) and from transfusions in 17 children (39%). Genotype 1 was present in 30/35 (84%) children. The mean age at first and final biopsy was 8.6 and 14.5 years, respectively, and the mean interval between biopsies was 5.8 ± 3.5 years. Duration of infection to biopsy was 7.7 and 13.5 years, respectively. Laboratory values did not change significantly between the biopsies. Inflammation was minimal in about 50% at both timepoints. Fibrosis was absent in 16% in both biopsies, limited to portal/periportal in 73% in the first biopsy, and 64% in the final biopsy. Between the two biopsies, the proportion of patients with bridging fibrosis/cirrhosis increased from 11% to 20% (P = 0.005).

Conclusion: Although in aggregate this cohort did not show significant histologic progression of liver disease over 5 years, 29.5% (n = 13) of children showed an increase in severity of fibrosis. These findings may have long-term implications for the timing of follow-up biopsies and treatment decisions.
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http://dx.doi.org/10.1002/hep.26519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493995PMC
November 2013

Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center.

Pediatr Radiol 2013 Oct 11;43(10):1365-75. Epub 2013 May 11.

Division of Diagnostic Imaging and Radiology, Children's National Medical Center, The George Washington University Medical Center, 111 Michigan Ave. NW, Washington, DC, 20010, USA.

Background: Hepatobiliary scintigraphy is highly sensitive for diagnosing biliary atresia; however, its specificity has varied in the literature from 35% to 97%.

Objective: The purpose of this study was to re-evaluate the accuracy of phenobarbital-enhanced hepatobiliary scintigraphy in differentiating biliary atresia from other causes of neonatal cholestasis.

Materials And Methods: We retrospectively reviewed all hepatobiliary scans of infants with cholestasis at our institution from December 1990 to May 2011. Per our routine protocol the scans were obtained after pretreatment with phenobarbital (5 mg/kg/day for 5 days) to achieve a serum level of ≥15 mcg/ml. Normal hepatic uptake with no biliary excretion by 24 h was considered consistent with biliary atresia.

Results: One hundred eighty-six infants with 210 hepatobiliary scans composed the study group. Forty-three (23%) infants had the final diagnosis of biliary atresia. Hepatobiliary scintigraphy was 100% sensitive, 93% specific and 94.6% accurate in diagnosing biliary atresia. Of the 186, 39/111 (35.1%) term and 2/68 (2.9%) preterm infants had biliary atresia; two of seven children with unknown gestational age also had biliary atresia. Other diagnoses included neonatal hepatitis, total parenteral nutrition cholestasis, Alagille syndrome, cystic fibrosis, choledochal cyst, hypothyroidism, alpha-1 antitrypsin deficiency and persistent cholestasis of unknown etiology.

Conclusion: Phenobarbital-enhanced hepatobiliary scintigraphy is highly accurate in differentiating biliary atresia from other causes of neonatal cholestasis. Biliary atresia is rare in premature infants.
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http://dx.doi.org/10.1007/s00247-013-2704-3DOI Listing
October 2013

Autoantibodies and autoimmune disease during treatment of children with chronic hepatitis C.

J Pediatr Gastroenterol Nutr 2013 Mar;56(3):304-10

Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Indiana University School of Medicine, Indianapolis, IN, USA.

Objectives: Autoantibodies were studied in a well-characterized cohort of children with chronic hepatitis C during treatment with pegylated interferon and ribavirin to assess the relation with treatment and development of autoimmune disease.

Methods: : A total of 114 children (5-17 years), screened for the presence of high-titer autoantibodies, were randomized to pegylated interferon with or without ribavirin. Anti-nuclear, anti-liver-kidney-microsomal, anti-thyroglobulin, anti-thyroid peroxidase, insulin, anti-glutamic acid decarboxylase (GAD) antibodies were measured after trial completion using frozen sera.

Results: At baseline, 19% had autoantibodies: anti-nuclear antibodies (8%), anti-liver-kidney-microsomal antibodies (4%), and glutamic acid decarboxylase antibodies (4%). At 24 and 72 weeks (24 weeks after treatment completion), 23% and 26% had autoantibodies (P=0.50, 0.48 compared with baseline). One child developed diabetes and 2 hypothyroidism during treatment; none developed autoimmune hepatitis. At 24 weeks, the incidence of flu-like symptoms, gastrointestinal symptoms, and headaches was 42%, 8% and 19% in those with autoantibodies versus 52%, 17%, and 26% in those without (P=0.18, 0.36, and 0.20, respectively). In children with negative hepatitis C virus polymerase chain reaction at 24 weeks, there was no difference in the rate of early virologic response/sustained virologic response, respectively, in those with autoantibodies 76%/69% vs 58%/65% in those without (P=0.48).

Conclusions: Despite screening, we found autoantibodies commonly at baseline, during treatment for chronic hepatitis C and after. The presence of antibodies did not correlate with viral response, adverse effects, or autoimmune hepatitis. Neither screening nor archived samples assayed for thyroid and diabetes-related antibodies identified the 3 subjects who developed overt autoimmune disease, diabetes (1), and hypothyroidism (2).
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http://dx.doi.org/10.1097/MPG.0b013e3182774caeDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583208PMC
March 2013

Characteristics of congenital hepatic fibrosis in a large cohort of patients with autosomal recessive polycystic kidney disease.

Gastroenterology 2013 Jan 3;144(1):112-121.e2. Epub 2012 Oct 3.

Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA.

Background & Aims: Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1.

Methods: Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1.

Results: Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient's height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct.

Conclusions: Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224.
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http://dx.doi.org/10.1053/j.gastro.2012.09.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162098PMC
January 2013

Pegylated interferon for chronic hepatitis C in children affects growth and body composition: results from the pediatric study of hepatitis C (PEDS-C) trial.

Hepatology 2012 Aug 6;56(2):523-31. Epub 2012 Jul 6.

Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.

Unlabelled: Weight loss and changes in growth are noted in children treated with interferon alpha (IFN-α). The aim of this study was to prospectively determine changes in weight, height, body mass index (BMI), and body composition during and after treatment of children with hepatitis C virus (HCV). Children treated with pegylated interferon alpha-2a (Peg-IFN-α2a) ± ribavirin in the Pediatric Study of Hepatitis C (PEDS-C) trial underwent anthropometric measurements, dual-energy X-ray absorptiometry scan, as well as dietary and activity assessments during and after treatment. One hundred and fourteen (55% male) children, with a mean age of 11 ± 3 years, were randomized, and 107 received treatment for at least 24 weeks. Subjects were divided into three groups according to duration of treatment: 24 (N = 14), 48 (N = 82), or 72 (N = 11) weeks. Decrements of up to 0.50 z score were observed for weight, height, and BMI while on therapy among all groups (P ≤ 0.01, compared to baseline). In the group treated for 48 weeks, 29 (33%) subjects had greater than 0.5-unit decrement in height-for-age z (HAZ) score. Though weight-for-age and BMI z scores returned to baseline after cessation of therapy, mean HAZ score was slower to rebound, still lower than baseline at 96 weeks post-therapy for the long-treatment duration group (P = 0.03) and lower than baseline in most children treated for 48 weeks. Percent body fat, fat-free mass z scores, and triceps skinfold z scores decreased with therapy. Dietary energy intake and levels of physical activity did not change during treatment.

Conclusions: Peg-IFN-α2a was associated with significant changes in body weight, linear growth, BMI, and body composition in children. These effects were generally reversible with cessation of therapy, although HAZ scores had not returned to baseline after 2 years of observation in many. Longer term growth data are needed among children treated for chronic HCV.
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http://dx.doi.org/10.1002/hep.25690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382022PMC
August 2012

Choline intake in a large cohort of patients with nonalcoholic fatty liver disease.

Am J Clin Nutr 2012 Apr 15;95(4):892-900. Epub 2012 Feb 15.

Division of Pediatric Gastroenterology and Nutrition, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: There is significant histologic and biochemical overlap between nonalcoholic fatty liver disease (NAFLD) and steatohepatitis associated with choline deficiency.

Objective: We sought to determine whether subjects with biopsy-proven NAFLD and evidence of an inadequate intake of choline had more severe histologic features.

Design: We performed a cross-sectional analysis of 664 subjects enrolled in the multicenter, prospective Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) with baseline data on diet composition (from a recall-based food-frequency questionnaire) within 6 mo of a liver biopsy. Food questionnaires were analyzed with proprietary software to estimate daily intakes of choline. Liver biopsies were centrally read, and consensus was scored with the NASH CRN-developed scoring system. Because choline needs vary by age, sex, and menopausal status, participants were segregated into corresponding categories (children 9-13 y old, males ≥14 y old, premenopausal women ≥19 y old, and postmenopausal women) on the basis of the Institute of Medicine's definition of adequate intake (AI) for choline. Deficient intake was defined as <50% AI.

Results: Postmenopausal women with deficient choline intake had worse fibrosis (P = 0.002) once factors associated with NAFLD (age, race-ethnicity, obesity, elevated triglycerides, diabetes, alcohol use, and steroid use) were considered in multiple ordinal logistic regression models. Choline intake was not identified as a contributor to disease severity in children, men, or premenopausal women.

Conclusion: Decreased choline intake is significantly associated with increased fibrosis in postmenopausal women with NAFLD. The Pioglitazone vs Vitamin E vs Placebo for Treatment of Non-Diabetic Patients With Nonalcoholic Steatohepatitis trial was registered at clinicaltrials.gov as NCT00063622, and the Treatment of Nonalcoholic Fatty Liver Disease in Children trial was registered at clinicaltrials.gov as NCT00063635.
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http://dx.doi.org/10.3945/ajcn.111.020156DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302364PMC
April 2012

Congenital hepatic fibrosis and portal hypertension in autosomal dominant polycystic kidney disease.

J Pediatr Gastroenterol Nutr 2012 Jan;54(1):83-9

Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Objectives: Autosomal dominant (ADPKD) and recessive (ARPKD) polycystic kidney diseases are the most common hepatorenal fibrocystic diseases (ciliopathies). Characteristics of liver disease of these disorders are quite different. All of the patients with ARPKD have congenital hepatic fibrosis (CHF) often complicated by portal hypertension. In contrast, typical liver involvement in ADPKD is polycystic liver disease, although rare atypical cases with CHF are reported. Our goal was to describe the characteristics of CHF in ADPKD.

Patients And Methods: As a part of an intramural study of the National Institutes of Health on ciliopathies (www.clinicaltrials.gov, trial NCT00068224), we evaluated 8 patients from 3 ADPKD families with CHF. We present their clinical, biochemical, imaging, and PKD1 and PKHD1 sequencing results. In addition, we tabulate the characteristics of 15 previously reported patients with ADPKD-CHF from 11 families.

Results: In all of the 19 patients with ADPKD-CHF (9 boys, 10 girls), portal hypertension was the main manifestation of CHF; hepatocelllular function was preserved and liver enzymes were largely normal. In all of the 14 families, CHF was not inherited vertically, that is the parents of the index cases had PKD but did not have CHF-suggesting modifier gene(s). Our 3 families had pathogenic mutations in PKD1; sequencing of the PKHD1 gene as a potential modifier did not reveal any mutations.

Conclusions: Characteristics of CHF in ADPKD are similar to CHF in ARPKD. ADPKD-CHF is caused by PKD1 mutations, with probable contribution from modifying gene(s). Given that both boys and girls are affected, these modifier(s) are likely located on autosomal chromosome(s) and less likely X-linked.
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http://dx.doi.org/10.1097/MPG.0b013e318228330cDOI Listing
January 2012

Peginterferon with or without ribavirin has minimal effect on quality of life, behavioral/emotional, and cognitive outcomes in children.

Hepatology 2011 May;53(5):1468-75

Beth Israel Deaconess Medical Center, Boston, MA.

Unlabelled: The aim of this study was to prospectively assess the quality of life (QOL), behavioral/emotional functioning, and cognitive status of children undergoing treatment for hepatitis C virus (HCV) infection. In all, 114 children (5 to 18 years old) enrolled in a multisite randomized clinical trial (Peds-C) to evaluate peginterferon alpha 2a (PEG 2a) with ribavirin (RV) or with placebo (PL) completed several standardized measures prior to treatment and at 24 weeks, 48 weeks, 6 months following treatment, and at two annual follow-up visits. After 24 weeks of treatment, mean physical QOL scores declined significantly for both groups from baseline to 24 weeks of treatment (F = 5.8, P = 0.004), although scores remained in the average range. There were no significant time or group effects for behavioral/emotional or cognitive functioning. Three children (5%) in the PEG 2a + RV group and no children in the PEG 2a + PL group had a clinically significant increase in depression symptoms. For those children who received 48 weeks of treatment, there were no significant time or group effects on any of the outcome measures (P > 0.05). A majority of children in both the PEG 2a + RV and PEG 2a + PL groups experienced no clinically significant change in physical QOL, behavioral adjustment, depression, or cognitive functioning during or after treatment.

Conclusion: Overall QOL and psychosocial functioning are not deleteriously impacted by PEG 2a + RV or PL treatment of children with HCV.
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http://dx.doi.org/10.1002/hep.24248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082614PMC
May 2011

The combination of ribavirin and peginterferon is superior to peginterferon and placebo for children and adolescents with chronic hepatitis C.

Gastroenterology 2011 Feb 28;140(2):450-458.e1. Epub 2010 Oct 28.

Department of Pediatrics, Division of Gastroenterology and Nutrition, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Background & Aims: Although randomized trials of adults infected with hepatitis C virus (HCV) have shown that ribavirin increases the efficacy of pegylated interferon (PEG), such trials have not been performed in children. We conducted a randomized controlled trial of PEG and ribavirin, compared with PEG and placebo, in children 5 to 17 years old with chronic hepatitis C.

Methods: HCV RNA-positive children from 11 university medical centers were randomly assigned to receive either PEG alfa-2a (PEG-2a; 180 μg/1.73 m(2) body surface area, subcutaneously each week; n = 55) and ribavirin (15 mg/kg orally in 2 doses daily) or PEG-2a and placebo (n = 59) for 48 weeks. The primary end point was sustained virologic response (SVR; lack of detectable HCV RNA at least 24 weeks after stopping therapy).

Results: SVR was achieved in 53% of children treated with PEG-2a and ribavirin, compared with 21% of children who received PEG-2a and placebo (P < .001). Early virologic response (HCV RNA reduction >2 log(10) IU at 12 weeks) had a negative predictive value of only 0.89 in children with genotype 1, indicating that these children might benefit from 24 weeks of therapy before stopping treatment. Side effects, especially neutropenia, led to dose modification in 40% of children. Eighty-two percent of the PEG/ribavirin and 86% of the PEG/placebo group were in compliance with the year 2 follow-up visit; the durability of virologic response was 100% in both groups.

Conclusions: The combination of PEG and ribavirin is superior to PEG and placebo as therapy for chronic hepatitis C in children and adolescents.
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http://dx.doi.org/10.1053/j.gastro.2010.10.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3042126PMC
February 2011

Hepatocellular carcinoma in 2 young adolescents with chronic hepatitis C.

J Pediatr Gastroenterol Nutr 2009 May;48(5):630-5

Pediatric Hepatology and Liver Transplantation, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Florida College of Medicine, 720 SW 2nd Av, Gainesville, FL 32610-0296, USA.

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http://dx.doi.org/10.1097/MPG.0b013e318170af04DOI Listing
May 2009

Dysmorphic findings in two cases of abeta/hypobetalipoproteinemia.

Clin Dysmorphol 2009 Apr;18(2):90-1

Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

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http://dx.doi.org/10.1097/MCD.0b013e3283279a0fDOI Listing
April 2009

Impact of hepatitis C virus infection on children and their caregivers: quality of life, cognitive, and emotional outcomes.

J Pediatr Gastroenterol Nutr 2009 Mar;48(3):341-7

The Transplant Center, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

Objective: Hepatitis C virus (HCV) infection is associated with decreased quality of life (QOL) and neurocognitive dysfunction in adults, but little is known about its impact on children and their caregivers.

Patients And Methods: We studied the QOL, behavioral, emotional, and cognitive functioning of 114 treatment-naïve children with HCV enrolled in a placebo-controlled, randomized, multisite clinical trial evaluating peginterferon alpha-2a alone or with ribavirin. Baseline assessment included measures of children's QOL, cognitive functioning, behavioral adaptation, and depression. Caregivers' QOL also was assessed.

Results: Relative to published normative data, caregivers were more likely to believe that their children's health was poor and would likely worsen (t = 3.93; P < 0.0001), and reported higher concern about their children's health status (t = 6.63; P < 0.0001) and that this concern limited family activities (t = 2.45; P < 0.01); they also viewed their children as having more internalizing behavioral problems (t = 1.98; P < 0.05). Only 2 (2%) children had a score in the clinically depressed range. Children with HCV had worse cognitive functioning than the normative sample but significantly better functioning than children with attention-deficit/hyperactivity disorder. Caregivers' QOL scores did not differ significantly from the normative sample, but infected mothers had lower QOL than noninfected caregivers. Caregivers were highly distressed about their children's medical circumstances.

Conclusions: Although HCV infection, in its early stages, does not lead to global impairment in QOL, cognitive, behavioral, or emotional functioning in children, it is associated with higher caregiver stress and strain on the family system, and it may be associated with some cognitive changes in children.
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http://dx.doi.org/10.1097/MPG.0b013e318185998fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649743PMC
March 2009

Autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF).

Pediatr Radiol 2009 Feb 17;39(2):100-11. Epub 2008 Dec 17.

Molecular Imaging Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

ARPKD/CHF is an inherited disease characterized by non-obstructive fusiform dilatation of the renal collecting ducts leading to enlarged spongiform kidneys and ductal plate malformation of the liver resulting in congenital hepatic fibrosis. ARPKD/CHF has a broad spectrum of clinical presentations involving the kidney and liver. Imaging plays an important role in the diagnosis and follow-up of ARPKD/CHF. Combined use of conventional and high-resolution US with MR cholangiography in ARPKD/CHF patients allows detailed definition of the extent of kidney and hepatobiliary manifestations without requiring ionizing radiation and contrast agents.
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http://dx.doi.org/10.1007/s00247-008-1064-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918426PMC
February 2009

Pathology of chronic hepatitis C in children: liver biopsy findings in the Peds-C Trial.

Hepatology 2008 Mar;47(3):836-43

Armed Forces Institute of Pathology and Veterans Administration Special Reference Laboratory for Pathology, Washington, DC, USA.

There is relatively little information in the literature on the histopathology of chronic hepatitis C in children. The Peds-C Trial, designed to test the efficacy and safety of peginterferon alfa-2a and ribavirin in children, provided an opportunity to examine liver biopsies from 121 treatment-naïve children, ages 2 to 16 (mean, 9.8 years) infected with the hepatitis C virus (HCV) and with no other identifiable cause for liver disease, signs of hepatic decompensation, or another significant nonhepatic disease. Liver biopsies were scored for inflammation, fibrosis, steatosis, and other histological features. Inflammation in the biopsy was minimal in 42%, mild in 17%, moderate in 38%, and severe in only 3%. Five had bridging fibrosis, and 2 had cirrhosis. Steatosis was absent in 56%, minimal in 34%, and mild in 10%. Inflammation scores correlated with fibrosis scores, serum alanine aminotransferase levels, and duration of infection, but not with age, body mass index z score, or HCV genotype. Fibrosis scores correlated with inflammation but not with age, HCV genotype, body mass index z score, or steatosis parameters. Steatosis correlated with serum alanine aminotransferase levels and body mass index z scores; overweight children had more fibrosis than the non-overweight. In conclusion, in this cohort of HCV-infected children, inflammation, fibrosis, and steatosis were milder than reported for treatment-naïve adults with chronic hepatitis C, but there were several with bridging fibrosis or cirrhosis. The positive correlation of inflammation with duration of infection and fibrosis and of obesity with fibrosis suggest that children with chronic hepatitis C will be at risk for progressive liver disease as they age and possibly acquire other comorbid risk factors.
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http://dx.doi.org/10.1002/hep.22094DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755275PMC
March 2008

The epidemiology of transfusion-associated hepatitis C in a children's hospital.

Transfusion 2007 Apr;47(4):615-20

Division of Laboratory Medicine and Pathology, Children's National Medical Center, Washington, DC 20010, USA.

Background: Children transfused with blood and blood products before 1992 are at risk for chronic hepatitis C virus (HCV) infection. To determine the prevalence of HCV infection and risks associated with acquisition of HCV, a single-institution lookback study was performed.

Study Design And Methods: A total of 5473 infants and children who received transfusions between 1982 and 1992 were identified. A control population of 600 age-, sex-, race- and zip code-matched children who did not receive transfusions with the same exclusions provided background seroprevalence data. Patients were tested for antibodies to HCV, confirmed with second generation recombinant immunoblot assay (RIBA) and when appropriate quantitative and qualitative HCV RNA by reverse transcription polymerase chain reaction (PCR). Viral persistence was assessed by serial PCR determinations for HCV RNA.

Results: Of the 5473 eligible patients, 4726 were locatable and 2758 were tested. Forty-three children (1.6%) were persistently anti-HCV enzyme immunoassay (EIA)-positive, confirmed by RIBA; 39 were positive for the presence of HCV RNA. Four cleared their virus as assessed by two negative HCV PCRs 6 months apart. There was a borderline higher number of children with HCV who received fresh whole blood than those who tested HCV-negative.

Conclusion: Because HCV infection is generally asymptomatic, children are not identified unless they are specifically tested. We identified, enrolled, tested, and confirmed a new diagnosis of HCV infection in 43 patients. As HCV treatments become increasingly effective, it is important to identify silently infected individuals, particularly when the infection was iatrogenically induced.
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http://dx.doi.org/10.1111/j.1537-2995.2007.01162.xDOI Listing
April 2007

Clinical spectrum and histopathologic features of chronic hepatitis C infection in children.

J Pediatr 2007 Feb;150(2):168-74, 174.e1

Department of Gastroenterology and Nutrition, Children's National Medical Center, Washington, DC 20010, USA.

Objective: To define the natural history and outcomes of children infected with hepatitis C virus (HCV) at birth or in early childhood.

Study Design: This retrospective, prospective study identified 60 HCV-infected children through a transfusion look-back program (group 1) and by referrals (group 2). Perinatal/transfusion history, clinical course, and laboratory studies were correlated with findings from 42 liver biopsy specimens.

Results: Mean age at infection was 7.1 months, and duration of infection 13.4 years. The sources of infection were blood transfusion (68%), perinatal transmission (13%), and both (7%). Most patients were asymptomatic; three referral patients had advanced liver disease at presentation. Mean alanine aminotransferase level was normal in 25%, 1 to 3 times normal in 62%, and greater than 3 times normal in 13%. Liver biopsy specimens showed minimal to mild inflammation in 71%, absent or minimal fibrosis in 88%, and bridging fibrosis in 12%. Age at infection and serum gamma-glutamyltranspeptidase correlated with fibrosis; serum alanine aminotransferase correlated with inflammation unless complicated by comorbidity. Repeat biopsies within 1 to 4 years in four patients showed no significant progression in three and cirrhosis in one. Two patients died after liver transplantation.

Conclusions: Children with chronic HCV infection are generally asymptomatic. By 13 years after infection, 12% of patients had significant fibrosis. Patients enrolled by referral had more severe liver disease than those identified through the look-back program, demonstrating the importance of selection bias in assessing the long-term outcome of HCV infection.
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http://dx.doi.org/10.1016/j.jpeds.2006.11.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1934338PMC
February 2007

Modulation of the IL-12/IFN-gamma axis by IFN-alpha therapy for hepatitis C.

J Leukoc Biol 2007 Mar 15;81(3):825-34. Epub 2006 Dec 15.

Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.

Although IFN-alpha forms the foundation of therapy for chronic hepatitis C, only a minority of patients has a sustained response to IFN-alpha alone. The antiviral activities of IFN-alpha formed the rationale for its use in viral hepatitis. However, IFN-alpha and the other Type I IFNs are also pleiotropic immune regulators. Type I IFNs can promote IFN-gamma production by activating STAT4 but can also inhibit production of IL-12, a potent activator of STAT4 and IFN-gamma production. The efficacy of IFN-alpha in the treatment of hepatitis C may therefore depend in part on the balance of IFN-gamma-inducing and IL-12-suppressing effects. We characterized the effects of pegylated IFN-alpha therapy for hepatitis C on the capacity of patients' PBMC to produce IL-12 and IFN-gamma ex vivo. Cells from patients with a sustained virological response to therapy had significantly greater levels of IFN-alpha-driven IFN-gamma production prior to treatment than those from nonresponding patients. No differences in pretreatment IL-12 productive capacity were seen between patient groups. However, therapy with IFN-alpha led to suppression of inducible IL-12 production throughout the course of therapy in both groups of patients.
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http://dx.doi.org/10.1189/jlb.1006622DOI Listing
March 2007

Safety, efficacy and pharmacokinetics of peginterferon alpha2a (40 kd) in children with chronic hepatitis C.

J Pediatr Gastroenterol Nutr 2006 Oct;43(4):499-505

Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.

Chronic hepatitis C virus (HCV) infection in children is a problem affecting thousands of children worldwide. Although standard interferon (INF) has better efficacy in pediatric patients than in adults, results in children with genotype 1 are poor; response rates to combination treatment with standard INF and ribavirin are better but the treatment requires thrice-weekly injections. The improved antiviral efficacy of weekly pegylated interferons relative to standard interferons in adults with chronic HCV infection suggests that pegylated interferons may also improve antiviral efficacy in children. We therefore investigated the pharmacokinetics, efficacy and safety of peginterferon alpha2a (pegINF-alpha2a) (40 kd) in 14 children ages 2 to 8 years with chronic hepatitis C (13 genotype 1, 1 non-1 genotype). Drug dose was calculated from each patient's body surface area (BSA) according to the formula BSA (m2)/(1.73 m2) x 180 microg, and patients were administered once-weekly subcutaneous injections for 48 weeks. Viral load and pharmacokinetic parameters were determined from blood drawn throughout the study and during follow-up. At week 24, the mean trough concentration was about 20% below values obtained from adults treated with pegINF-alpha2a, and the area under the curve from 0 to 168 hours was about 20% above adult values, suggesting that drug doses calculated from BSA achieved therapeutically adequate concentrations. Six of 14 patients (43%), all infected with genotype 1, achieved a sustained virological response. Adverse events were those commonly associated with INF-based treatment, and none was deemed serious. In conclusion, our findings provide a basis for larger studies evaluating the efficacy and safety of pegINF-alpha2a as monotherapy as well as in combination with ribavirin in pediatric patients with chronic hepatitis C.
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http://dx.doi.org/10.1097/01.mpg.0000235974.67496.e6DOI Listing
October 2006

Fatal acute liver failure in a child with metastatic gastric adenocarcinoma.

J Pediatr Gastroenterol Nutr 2006 Jul;43(1):116-8

Department of Gastroenterology and Nutrition, Children's National Medical Center, Washington, DC 20010, USA.

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http://dx.doi.org/10.1097/01.mpg.0000189365.91792.bfDOI Listing
July 2006