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1.  Growth Failure and Outcomes in Infants with Biliary Atresia: A Report from the Biliary Atresia Research Consortium 
Hepatology (Baltimore, Md.)  2007;46(5):10.1002/hep.21923.
Malnutrition is a significant clinical problem in infants with biliary atresia. The natural history of poor growth and its potential association with early transplantation or death in children with biliary atresia was determined. Serial weight- and length-for-age z-scores were computed as part of a retrospective study of 100 infants who underwent hepatoportoenterostomy (HPE) for biliary atresia at 9 U.S. pediatric centers between 1997 and 2000. Poor outcome was defined as transplantation or death by 24 months of age (n = 46) and good outcome was defined as survival with native liver at 24 months of age with total serum bilirubin less than 6 mg/dL (n = 54). Growth velocity was significantly slower in the poor outcome group compared to the good outcome group (P < 0.001 for both weight and length). Mean weight z-scores were significantly lower by 6 months after HPE in the poor outcome group (−2.1 ± 1.4) compared to the good outcome group (−1.2 ± 1.4) (P < 0.001). In a subgroup with total bilirubin between 2 and 6 mg/dL at 3 months after HPE (n = 28), the weight z-scores at 3 months after HPE were significantly lower in the poor outcome group (−2.0 ± 1.2) compared to the good outcome group (−1.0 ± 1.2) (P = 0.04) despite similar bilirubin concentrations.
Conclusion
Growth failure after HPE was associated with transplantation or death by 24 months of age. The combination of intermediate bilirubin concentrations and poor mean weight z-scores 3 months after HPE was also associated with poor clinical outcome.
doi:10.1002/hep.21923
PMCID: PMC3881187  PMID: 17929308
2.  Efficacy of Fat-Soluble Vitamin Supplementation in Infants With Biliary Atresia 
Pediatrics  2012;130(3):e607-e614.
OBJECTIVE:
Cholestasis predisposes to fat-soluble vitamin (FSV) deficiencies. A liquid multiple FSV preparation made with tocopheryl polyethylene glycol-1000 succinate (TPGS) is frequently used in infants with biliary atresia (BA) because of ease of administration and presumed efficacy. In this prospective multicenter study, we assessed the prevalence of FSV deficiency in infants with BA who received this FSV/TPGS preparation.
METHODS:
Infants received FSV/TPGS coadministered with additional vitamin K as routine clinical care in a randomized double-blinded, placebo-controlled trial of corticosteroid therapy after hepatoportoenterostomy (HPE) for BA (identifier NCT 00294684). Levels of FSV, retinol binding protein, total serum lipids, and total bilirubin (TB) were measured 1, 3, and 6 months after HPE.
RESULTS:
Ninety-two infants with BA were enrolled in this study. Biochemical evidence of FSV insufficiency was common at all time points for vitamin A (29%–36% of patients), vitamin D (21%–37%), vitamin K (10%–22%), and vitamin E (16%–18%). Vitamin levels were inversely correlated with serum TB levels. Biochemical FSV insufficiency was much more common (15%–100% for the different vitamins) in infants whose TB was ≥2 mg/dL. At 3 and 6 months post HPE, only 3 of 24 and 0 of 23 infants, respectively, with TB >2 mg/dL were sufficient in all FSV.
CONCLUSIONS:
Biochemical FSV insufficiency is commonly observed in infants with BA and persistent cholestasis despite administration of a TPGS containing liquid multiple FSV preparation. Individual vitamin supplementation and careful monitoring are warranted in infants with BA, especially those with TB >2 mg/dL.
doi:10.1542/peds.2011-1423
PMCID: PMC3428752  PMID: 22891232
cholestasis; nutrition; liver; vitamin deficiency
3.  Hedgehog Activity, Epithelial-Mesenchymal Transitions, and Biliary Dysmorphogenesis in Biliary Atresia 
Hepatology (Baltimore, Md.)  2011;53(4):1246-1258.
Background
Biliary Atresia (BA) is notable for marked ductular reaction and rapid development of fibrosis. Activation of the Hedgehog (Hh) pathway promotes the expansion of populations of immature epithelial cells that co-express mesenchymal markers and may be pro-fibrogenic. We examined the hypothesis that in BA excessive Hh activation impedes ductular morphogenesis and enhances fibrogenesis by promoting accumulation of immature ductular cells with a mesenchymal phenotype.
Methods
Livers and remnant extrahepatic ducts from BA patients were evaluated by QRT-PCR and immunostaining for Hh ligands, target genes, and markers of mesenchymal cells or ductular progenitors. Findings were compared to children with genetic cholestatic disease, age-matched deceased donor controls, and adult controls. Ductular cells isolated from adult rats with and without bile duct ligation were incubated with Hh ligand-enriched medium ± Hh-neutralizing antibody to determine direct effects of Hh ligands on EMT marker expression.
Results
Livers from pediatric controls showed greater innate Hh activation than adult controls. In children with BA, both intra- and extra-hepatic ductular cells demonstrated striking up-regulation of Hh ligand production, and increased expression of Hh target genes. Excessive accumulation of Hh-producing cells and Hh-responsive cells also occurred in other infantile cholestatic diseases. Further analysis of the BA samples demonstrated that immature ductular cells with a mesenchymal phenotype were Hh-responsive. Treating immature ductular cells with Hh ligand-enriched medium induced mesenchymal genes; neutralizing Hh ligands inhibited this.
Conclusions
BA is characterized by excessive Hh pathway activity, which stimulates biliary EMT and may contribute to biliary dysmorphogenesis. Other cholestatic diseases show similar activation, suggesting this is a common response to cholestatic injury in infancy.
doi:10.1002/hep.24156
PMCID: PMC3074103  PMID: 21480329
Pediatric liver disease; immature epithelial cells; biliary morphogenesis; Hedgehog Pathway; Cell differentiation
4.  Osteopontin is Induced by Hedgehog Pathway Activation and Promotes Fibrosis Progression in Nonalcoholic Steatohepatitis 
Hepatology (Baltimore, Md.)  2010;53(1):106-115.
Background
Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding Osteopontin (OPN), a pro-fibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesized that Hh signaling induces OPN to promote liver fibrosis in NASH.
Methods
Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc+/−) (overly-active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine-choline deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and non-diseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSC) were cultured in medium with different OPN activities to determine effects on HSC phenotype.
Results
When fed MCD diets, Ptc+/− mice expressed more OPN and developed worse liver fibrosis (p<0.05) than WT mice, while OPN-deficient mice exhibited reduced fibrosis (p<0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSC, SAG (a Hh agonist) upregulated, while Cyclopamine (a Hh-antagonist) repressed, OPN expression (p<0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSC (p<0.05); neutralizing OPN with RNA-aptamers attenuated this (p<0.05).
Conclusions
OPN is Hh-regulated and directly promotes pro-fibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis-stage Therefore, OPN inhibition may be beneficial in NASH.
doi:10.1002/hep.23998
PMCID: PMC3025083  PMID: 20967826
hedgehog; non-alcoholic fatty liver disease; osteopontin
5.  Differences in presentation and progression between severe FIC1 and BSEP deficiencies 
Journal of hepatology  2010;53(1):170-178.
Background & Aims
Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these 2 disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.
Methods
A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 “FIC1 patients”) or ABCB11 (84 “BSEP patients”) were evaluated.
Results
At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.
Conclusions
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
doi:10.1016/j.jhep.2010.01.034
PMCID: PMC3042805  PMID: 20447715
cholestasis; genetics; transport protein; pediatrics; P-type ATPase; ATP binding cassette protein; ATP8B1; FIC1; ABCB11; BSEP
6.  Nonalcoholic Steatohepatitis in Children: A Multicenter Clinicopathological Study 
Hepatology (Baltimore, Md.)  2009;50(4):1113-1120.
Nonalcoholic fatty liver disease (NAFLD) may have distinct histological features in children and adults, but to date limited data are available on the spectrum and significance of histological lesions in pediatric patients. We conducted a multicenter study of children with well-characterized, biopsy-proven NAFLD to (1) assess the presence and significance of a constellation of histological lesions and (2) identify clinical and laboratory predictors of disease severity. One hundred thirty children with NAFLD seen from 1995 to 2007 in five centers in the United States and Canada were studied. Clinical and laboratory data were collected. Slides stained with hematoxylin-eosin and trichrome were evaluated by two liver pathologists. The NAFLD activity score (NAS) and the pattern of liver injury (type 1 or adult versus type 2 or pediatric nonalcoholic steatohepatitis [NASH]) were recorded. Fibrosis was staged using a published 7-point scale. The median age was 12 years (range, 4-18 years); 63% were boys, and 52% were Caucasian. Fibrosis was present in 87% of patients; of these, stage 3 (bridging fibrosis) was present in 20%. No patient had cirrhosis. The median NAS was 4. Overlapping features of both type 1 (adult pattern) and type 2 (pediatric pattern) NASH were found in 82% of patients. Compared with patients with no or mild fibrosis, those with significant fibrosis were more likely to have higher lobular and portal inflammation scores (P < 0.01), perisinusoidal fibrosis (P < 0.001), and NAS ≥5 (P < 0.005). Serum aspartate aminotransferase levels were the only clinical or laboratory data that independently predicted severity of fibrosis (P = 0.003).
Conclusion:
Our results highlight the limitations of published proposals to classify pediatric NAFLD, and identified histological lesions associated with progressive disease.
doi:10.1002/hep.23133
PMCID: PMC2775705  PMID: 19637190
7.  Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis 
BMC Gastroenterology  2010;10:30.
Background
BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer.
Case Presentation
A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat.
Conclusions
Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.
doi:10.1186/1471-230X-10-30
PMCID: PMC2841578  PMID: 20226067
8.  Cytokeratin 18, a marker of cell death, is increased in children with suspected nonalcoholic fatty liver disease 
Objectives
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with obesity that is now the most common liver disease in the United States. Cytokeratin 18 (CK18) is an intracellular protein released into the blood by both necrosis and apoptosis of hepatocytes. Levels of CK18 have not been previously reported in children with NAFLD.
Methods
In a cross sectional analysis of 62 children (28 normal weight, 14 obese and 20 suspected NAFLD) we measured CK18 levels as well as alanine aminotransferase, fasting glucose, fasting insulin and TNFα.
Results
CK18 was significantly elevated in the children with suspected NAFLD compared to obese controls and normal weight controls (median 424 U/L compared to 243 and 214 respectively, p <.001). In multiple logistic regression analysis, CK18 was the best single predictor of suspected NAFLD (prediction accuracy 84.1%).
Conclusions
CK18 is elevated in children with suspected NAFLD and should be investigated as a potential diagnostic marker of NAFLD.
doi:10.1097/MPG.0b013e31817e2bfb
PMCID: PMC2628810  PMID: 18852641
Cytokeratin 18; fatty liver; NAFLD; obesity; children
9.  Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion 
BMC Gastroenterology  2008;8:47.
Background
Partial External Biliary Diversion (PEBD) is a surgical intervention to treat children with Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille syndrome (AGS). PEBD can reduce disease progression, and examining the alterations in biliary lipid composition may be a prognostic factor for outcome.
Methods
Biliary lipid composition and the clinical course of AGS and PFIC patients were examined before and after PEBD.
Results
Pre-PEBD bile from AGS patients had greater chenodeoxycholic/cholic acid (CDCA/CA), bile salt, cholesterol and phospholipid concentrations than PFIC patients. AGS patients, and PFIC patients with familial intrahepatic cholestasis 1 (FIC1) genotype, responded better to PEBD than PFIC patients with bile salt export protein (BSEP) genotype. After successful PEBD, AGS patients have higher biliary lipid concentrations than PFIC patients and PEBD also increases biliary phospholipid concentrations in FIC1 patients.
Conclusion
Both AGS and FIC1 patients can benefit from PEBD, and preserved biliary phospholipid concentrations may be associated with better outcomes post-PEBD.
doi:10.1186/1471-230X-8-47
PMCID: PMC2585081  PMID: 18937870
10.  Biliary Atresia Is Associated with CD4+ Th1 Cell–Mediated Portal Tract Inflammation 
Pediatric research  2004;56(1):79-87.
A proposed mechanism in the pathogenesis of biliary atresia involves an initial virus-induced, progressive T cell–mediated inflammatory obliteration of bile ducts. The aim of this study was to characterize the inflammatory environment present within the liver of infants with biliary atresia to gain insight into the role of a primary immune-mediated process versus a nonspecific secondary response to biliary obstruction. Frozen liver tissue obtained from patients with biliary atresia, neonatal giant cell hepatitis, total parenteral nutrition (TPN)–related cholestasis, choledochal cysts, and normal control subjects was used for fluorescent immunohistochemistry studies of cellular infiltrates, cytokine mRNA expression, and in situ hybridization for localization of cytokine-producing cells. Immunohistochemistry revealed increases in CD8+ and CD4+ T cells and Kupffer cells (CD68+) in the portal tracts of biliary atresia. Reverse transcription–PCR analysis of biliary atresia tissue showed a Th1-type cytokine profile with expression of IL-2, interferon-γ, tumor necrosis factor-α, and IL-12. This profile was not seen in normal, neonatal hepatitis or choledochal cyst livers but was present in TPN-related cholestasis. In situ hybridization revealed that the Th1 cytokine–producing cells were located in the portal tracts in biliary atresia and in the parenchyma of TPN-related cholestasis. A distinctive portal tract inflammatory environment is present in biliary atresia, involving CD4+ Th1 cell–mediated immunity. The absence of similar inflammation in other pediatric cholestatic conditions suggests that the portal tract inflammation in biliary atresia is not a secondary response to cholestasis but rather indicates a specific immune response involved in the pathogenesis of biliary atresia.
doi:10.1203/01.PDR.0000130480.51066.FB
PMCID: PMC1948976  PMID: 15128911
11.  Segmental Liver Transplantation From Living Donors Report of the Technique and Preliminary Results in Dogs  
HPB Surgery  1990;2(3):189-204.
A technique of orthotopic liver transplantation using a segmental graft from living donors was developed in the dog. Male mongrel dogs weighing 25–30 kg were used as donors and 10–15 kg as recipients. The donor operation consists of harvesting the left lobe of the liver (left medial and left lateral segments) with the left branches of the portal vein, hepatic artery and bile duct, and the left hepatic vein. The grafts are perfused in situ through the left portal branch to prevent warm ischemia. The recipient operation consists of two phases: 1total hepatectomy with preservation of the inferior vena cava using total vascular exclusion of the liver and veno-venous bypass, 2implantation of the graft in the orthotopic position with anastomosis of the left hepatic vein to the inferior vena cava and portal, arterial and biliary reconstruction. Preliminary experiments consisted of four autologous left lobe transplants and nine non survival allogenic left lobe transplants. Ten survival experiments were conducted. There were no intraoperative deaths in the donors and none required transfusions. One donor died of sepsis, but all the other donor dogs survived without complication. Among the 10 grafts harvested, one was not used because of insufficient bile duct and artery. Two recipients died intraoperatively of air embolus and cardiac arrest at the time of reperfusion. Three dogs survived, two for 24 hours and one for 48 hours. They were awake and alert a few hours after surgery, but eventually died of pulmonary edema in 2 cases and of an unknown reason in the other. Four dogs died 2–12 hours postoperatively as a result of hemorrhage for the graft's transected surface. An outflow block after reperfusion was deemed to be the cause of hemorrhage in these cases. On histologic examination of the grafts, there were no signs of ischemic necrosis or preservation damage.
This study demonstrates the technical feasibility of living hepatic allograft donation. It shows that it is possible, in the dog, to safely harvest non ischemic segmental grafts with adequate pedicles without altering the vascularization and the biliary drainage of the remaining liver. We propose that this technique is applicable to human anatomy.
doi:10.1155/1990/74721
PMCID: PMC2423581  PMID: 2278916

Results 1-11 (11)