Anti-neutrophil cytoplasmic antibody 50%-80% Anti-nuclear antibody 7%-77% Anti-smooth muscle antibody 13%-20% Anti-endothelial cell antibody 35% Anti-cardiolipin antibody 4%-66% Thyroperoxidase 7%-16% Thyroglobulin 4% Rheumatoid factor 15%

Objectives-To determine short-term outcome for children with acute liver failure (ALF) as it relates to etiology, clinical status, patient demographics and to determine prognostic factors.Study design-A prospective, multi-center case study collecting demographic, clinical, laboratory and short-term outcome data on children from birth to 18 years with ALF. Patients without encephalopathy were included if the prothrombin time and INR remained ≥ 20 seconds and/or >2, respectively, despite vitamin K. Primary outcome measures three weeks after study entry were death, death after transplant, alive with native liver, alive with transplanted organ.Results-The etiology of ALF in 348 children included acute acetaminophen toxicity (14%), metabolic disease (10%), autoimmune liver disease (6%), non-APAP drug-related hepatotoxicity (5%), infections (6%), other diagnosed conditions (10%); 49% were indeterminate. Outcome varied between patient sub-groups; 20% with non-acetaminophen ALF died or underwent liver transplantation and never developed clinical encephalopathy.Conclusions-Etiologies of ALF in children differ from adults. Clinical encephalopathy may not be present in children. The high percentage of indeterminate cases provides an opportunity for investigation.Corresponding Address: Robert H. Squires, Jr., M.D., Professor of Pediatrics, University of Pittsburgh, Children's Hospital of Pittsburgh, 3705 Fifth Avenue, Pittsburgh, PA 15213, Phone: 412-692-8181, Fax: 412-692-7355, Email: Robert.squires@chp.edu. edited by WFB Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. (11), development of a reliable prognostic score will be useful in allocating organs to the most needy patients. NIH Public AccessThe Pediatric Acute Liver Failure (PALF) study group was formed in 1999 to develop a database that would facilitate an improved understanding of the etiopathogenesis, treatment and outcome of ALF in children. These data will also serve to identify factors that will help to predict the likelihood of death or need for liver transplant. Methods OrganizationThe PALF study group began as an adjunct to the Data CollectionFollowing informed consent from a parent or legal guardian, demographic, clinical and laboratory information were recorded daily for seven days. In most patients, an additional aliquot of serum or plasma was collected on each of the seven study days, frozen at −70° C and then shipped to the Data Coordinating Center (DCC) located at the University of Texas Southwestern Medical Center in Dallas, Texas. Diagnostic evaluation and medical management were consistent with the...

BACKGROUND & AIMS:Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely phenotypic severity were correlated with data on BSEP immunohistochemistry and clinical outcome. RESULTS: Eighty-two different mutations (52 novel) were identified in 109 families (9 nonsense mutations, 10 small insertions and deletions, 15 splice-site changes, 3 whole-gene deletions, 45 missense changes). In 7 families, only a single heterozygous mutation was identified despite complete sequence analysis. Thirty-two percent of mutations occurred in >1 family, with E297G and/or D482G present in 58% of European families (52/89). On immunohistochemical analysis (88 patients), 93% had abnormal or absent BSEP staining. Expression varied most for E297G and D482G, with some BSEP detected in 45% of patients (19/42) with these mutations. Hepatocellular carcinoma or cholangiocarcinoma developed in 15% of patients (19/128). Two protein-truncating mutations conferred particular risk; 38% (8/21) of such patients developed malignancy versus 10% (11/107) with potentially less severe genotypes (relative risk, 3.7 [confidence limits, 1.7-8.1; P = .003]). CONCLUSIONS: With this study, >100 ABCB11 mutations are now identified. Immunohistochemically detectable BSEP is typically absent, or much reduced, in severe disease. BSEP deficiency confers risk of hepatobiliary malignancy. Close surveillance of BSEP-deficient patients retaining their native liver, particularly those carrying 2 null mutations, is essential. Abbreviations:ABC, ATP-binding cassette; AFP, α-fetoprotein; BSEP, bile salt export pump; CpG, cytosine-guanine; CC, cholangiocarcinoma; FIC1, familial intrahepatic cholestasis 1; γ-GT, γ-glutamyl transferase; HCC, hepatocellular carcinoma; IC, intracellular loop; MDR1, multidrug resistance protein 1; MDR3, multidrug resistance protein 3; MRP2, multidrug resistance-associated protein 2; NBF, nucleotide-binding fold; OLT, orthotopic liver transplantation; PEBD, partial external biliary diversion; PFIC, progressive familial intrahepatic cholestasis; PCR, polymerase chain reaction; RE, restriction endonuclease; SSCP, single-strand conformation polymorphism; TM, transmembrane domain; UDCA, ursodeoxycholic acid Acknowledgements We thank the families and the Children's Liver Disease Foundation for support and encouragement, and those who referred families for analysis, including Drs U Baumann, W Berquist, M de Vree, K Emerick, G Ferry, M Finegold, W Hardikar, S Horslen, R Houwen, R Jaffe, L Klomp, F Lacaille, K Mann, P McKiernan, H Sharp, R Sokol, E Sturm, L Szönyi, J Taminou, and J Watkins. We also thank Dr R Garcia-Kennedy for access...

Maturity-onset diabetes of the young type 3 (MODY3) is caused by haploinsufficiency of hepatocyte nuclear factor-1alpha (encoded by TCF1). Tcf1-/- mice have type 2 diabetes, dwarfism, renal Fanconi syndrome, hepatic dysfunction and hypercholestrolemia. Here we explore the molecular basis for the hypercholesterolemia using oligonucleotide microchip expression analysis. We demonstrate that Tcf1-/- mice have a defect in bile acid transport, increased bile acid and liver cholesterol synthesis, and impaired HDL metabolism. Tcf1-/- liver has decreased expression of the basolateral membrane bile acid transporters Slc10a1, Slc21a3 and Slc21a5, leading to impaired portal bile acid uptake and elevated plasma bile acid concentrations. In intestine and kidneys, Tcf1-/- mice lack expression of the ileal bile acid transporter (Slc10a2), resulting in increased fecal and urinary bile acid excretion. The Tcf1 protein (also known as HNF-1alpha) also regulates transcription of the gene (Nr1h4) encoding the farnesoid X receptor-1 (Fxr-1), thereby leading to reduced expression of small heterodimer partner-1 (Shp-1) and repression of Cyp7a1, the rate-limiting enzyme in the classic bile acid biosynthesis pathway. In addition, hepatocyte bile acid storage protein is absent from Tcf1-/- mice. Increased plasma cholesterol of Tcf1-/- mice resides predominantly in large, buoyant, high-density lipoprotein (HDL) particles. This is most likely due to reduced activity of the HDL-catabolic enzyme hepatic lipase (Lipc) and increased expression of HDL-cholesterol esterifying enzyme lecithin:cholesterol acyl transferase (Lcat). Our studies demonstrate that Tcf1, in addition to being an important regulator of insulin secretion, is an essential transcriptional regulator of bile acid and HDL-cholesterol metabolism.

Our results indicate that clinical impression is not sufficient to determine whether children and adolescents are taking their medications after they have had a liver transplant. An objective assessment method should be used. Interventions targeting adherence should address the child's increasing role beginning in early adolescence. A clinical protocol incorporating objective assessments of adherence could potentially be implemented in other settings. It could form the basis for the evaluation of efficacy of interventions seeking to improve adherence to medications.

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Non-adherence to medications is associated with poor medical outcomes in adolescent transplant recipients. It is unclear whether non-adherence is further compromised when transplant recipients transition to the adult health care system. The purpose of the present study was to examine whether adherence changes during transition. We reviewed the medical records of 14 recently transitioned patients and compared their adherence and corresponding medical outcomes before and after transition. These outcomes were also compared with two cohorts of patients receiving care solely in pediatric or adult services. Medication adherence, measured through the use of standard deviations of tacrolimus blood levels, was examined for all patients. We found that adherence to tacrolimus significantly decreased after transition. After transitioning, patients furthermore exhibited poorer adherence than patients in the other two cohorts did over time. This small retrospective study suggests that the period of transition from pediatric to adult transplant clinics is a vulnerable one. Larger, prospective investigations of the transition process are necessary before recommendations are made regarding interventions.

Primary sclerosing cholangitis (PSC) is a rare but important liver disease that leads to cirrhosis and need for liver transplantation in a high proportion of cases. The disease occurs in approximately 1 per 100,000 population per year, usually presents in adulthood, and affects men more often than women. Typical serum biochemical results, autoantibodies and liver biopsy are suggestive but not diagnostic of PSC, the diagnosis requiring cholangiographic demonstration of stricturing and dilatation of the intra-and/or extra-hepatic bile ducts. The natural history of PSC is variable, the average survival being 12 to 17 years. The cause of PSC is still unknown. Although considered an autoimmune disease, PSC has several atypical features and a strong genetic component. The therapy of PSC is unsatisfactory. Standard doses of ursodeoxycholic acid (UDCA) lead to improvements in biochemical abnormalities but not in histology, cholangiographic appearance or survival. Several innovative therapies have been tried in PSC, but with scant evidence of benefit. For patients with high grade strictures, endoscopic dilatation is beneficial. Liver transplantation is successful for end-stage liver disease due to PSC and improves survival. PSC may recur after transplantation but is rarely progressive. The most dreaded complication of PSC is cholangiocarcinoma. Diagnosis of this highly malignant tumor is difficult, and there are no biomarkers for its early detection. Liver transplantation for cholangiocarcinoma has an exceedingly poor outcome, although transplantation with neoadjuvant chemoirradiation holds promise in selected patients. Thus, significant opportunities remain for basic and clinical research into the cause, natural history, and therapy of PSC. 44:746-764.)