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2.  Congenital Hepatic Fibrosis and Autosomal Recessive Polycystic Kidney Disease 
The published natural history of congenital hepatic fibrosis (CHF) was examined to inform clinical decision making in autosomal recessive polycystic kidney disease (ARPKD).
A systematic literature search of the data on CHF, ARPKD, Caroli disease, Caroli syndrome, and type V choledochal cyst was performed to extract data related to portal hypertension, infection, malignancy, mortality, and transplantation.
Information related to 1230 patients with CHF was extracted from 155 articles. Median and mean age at diagnosis were 2 and 11.2 years, respectively. Median and mean time followed after diagnosis were 5.0 and 7.5 years, respectively (range 0–38 years). Sequelae of portal hypertension (n = 409), cholangitis (n = 152), and malignancy (n = 21) were noted. The nature of the portal hypertension was similar to that in other pediatric conditions (164 with varices, 74 bleeding varices, 81 underwent portosystemic shunting). Documented cholangitis was fatal in 3 of 23 children who were infected after renal transplantation. Twenty-one patients developed hepatobiliary cancer, with the majority having cholangiocarcinoma (n = 19). Cholangiocarcinoma (CCA) was predominant in individuals older than 40 years with either Caroli syndrome or isolated CHF, not ARPKD (median and mean age at CCA diagnosis were 70.3 and 60.1 years, respectively; range 33–75 years). There was a relative paucity of data on combined liver-kidney transplantation.
Clinical decision making in ARPKD should reflect an understanding of the potential issues emanating from CHF. Accepted pediatric specific approaches to portal hypertension are warranted but must take into consideration the stage of renal insufficiency and potential plans for renal transplantation. Cholangitis is a major issue and necessitates anticipatory guidance and awareness. CCA, although a dreaded complication, does not appear to be a major issue during childhood. The indications for liver and combined liver-kidney transplantation are controversial and warrant further analysis.
PMCID: PMC4369775  PMID: 22197937
cholangiocarcinoma; cholangitis; portal hypertension; transplantation; varices
3.  Use of Corticosteroids After Hepatoportoenterostomy for Bile Drainage in Infants With Biliary Atresia 
JAMA  2014;311(17):1750-1759.
Biliary atresia is the most common cause of end-stage liver disease in children. Controversy exists as to whether use of steroids after hepatoportoenterostomy improves clinical outcome.
To determine whether the addition of high-dose corticosteroids after hepatoportoenterostomy is superior to surgery alone in improving biliary drainage and survival with the native liver.
The multicenter, double-blind Steroids in Biliary Atresia Randomized Trial (START) was conducted in 140 infants (mean age, 2.3 months) between September 2005 and February 2011 in the United States; follow-up ended in January 2013.
Participants were randomized to receive intravenous methylprednisolone (4 mg/kg/d for 2 weeks) and oral prednisolone (2 mg/kg/d for 2 weeks) followed by a tapering protocol for 9 weeks (n = 70) or placebo (n = 70) initiated within 72 hours of hepatoportoenterostomy.
The primary end point (powered to detect a 25% absolute treatment difference) was the percentage of participants with a serum total bilirubin level of less than 1.5 mg/dL with his/her native liver at 6 months posthepatoportoenterostomy. Secondary outcomes included survival with native liver at 24 months of age and serious adverse events.
The proportion of participants with improved bile drainage was not statistically significantly improved by steroids at 6 months posthepatoportoenterostomy (58.6% [41/70] of steroids group vs 48.6% [34/70] of placebo group; adjusted relative risk, 1.14 [95% CI, 0.83 to 1.57]; P = .43). The adjusted absolute risk difference was 8.7% (95% CI, −10.4% to 27.7%). Transplant-free survival was 58.7% in the steroids group vs 59.4% in the placebo group (adjusted hazard ratio, 1.0 [95% CI, 0.6 to 1.8]; P = .99) at 24 months of age. The percentage of participants with serious adverse events was 81.4% [57/70] of the steroids group and 80.0% [56/70] of the placebo group (P > .99); however, participants receiving steroids had an earlier time of onset of their first serious adverse event by 30 days posthepatoportoenterostomy (37.2% [95% CI, 26.9% to 50.0%] of steroids group vs 19.0% [95% CI, 11.5% to 30.4%] of placebo group; P= .008).
Among infants with biliary atresia who have undergone hepatoportoenterostomy, high-dose steroid therapy following surgery did not result in statistically significant treatment differences in bile drainage at 6 months, although a small clinical benefit could not be excluded. Steroid treatment was associated with earlier onset of serious adverse events in children with biliary atresia.
PMCID: PMC4303045  PMID: 24794368
4.  Extra-hepatic anomalies in infants with biliary atresia: results of a large prospective North American multi-center study 
Hepatology (Baltimore, Md.)  2013;58(5):1724-1731.
Background and aims
The etiology of biliary atresia (BA) is unknown. Given that patterns of anomalies might provide etiopathogenetic clues, we utilized data from the North American Childhood Liver Disease Research and Education Network to analyze patterns of anomalies in infants with BA.
Two hundred eighty-nine infants who were enrolled into the prospective database prior to surgery at any of 15 centers participating were evaluated.
Group 1 was non-syndromic, isolated BA (without major malformations) (n = 242, 84 %), Group 2 was BA and at least one malformation considered major as defined by the National Birth Defects Prevention Study but without laterality defects (n = 17, 6%). Group 3 was syndromic, with laterality defects (n = 30, 10%). In the population as a whole, anomalies (either major or minor) were most prevalent in the cardiovascular (16%) and gastrointestinal (14%) systems. Group 3 patients accounted for the majority of subjects with cardiac, gastrointestinal and splenic anomalies. Group 2 subjects also frequently displayed cardiovascular (71%) and gastrointestinal (24 %) anomalies; interestingly this group had genitourinary anomalies more frequently (47%) compared to Group 3 subjects (10%).
This study identified a group of BA (Group 2) that differed from the classical syndromic and non-syndromic groups and that was defined by multiple malformations without laterality defects. Careful phenotyping of the patterns of anomalies may be critical to the interpretation of both genetic and environmental risk factors associated with BA, allowing new insight into pathogenesis and/or outcome.
PMCID: PMC3844083  PMID: 23703680
birth defects; laterality defects; cholangiopathy; embryonic; nonsyndromic
5.  Novel Model of Antigen-Specific Induction of Bile Duct Injury 
Gastroenterology  2006;131(6):1899-1906.
Background & Aims
Biliary-directed inflammation is an important cause of acute and chronic liver disease. We developed and characterized a transgenic mouse model of immunemediated hepatobiliary injury.
Ovalbumin (OVA)-BIL mice were developed using 3.0 kilobase of the rat apical sodium-dependent bile acid transporter promoter to drive aberrant expression of a membrane form of ovalbumin (OVA) on biliary epithelium. Liver inflammation resulted from adoptive transfer of OVA-specific T cells. Liver immune cells were characterized to determine the mechanism of the response by assessing activation, proliferation, and intracellular cytokine expression.
OVA-BIL transgenic mice were tolerant to OVA, without evidence of liver disease. Adoptive transfer of OVA-specific CD4+ and CD8+ T cells into naïve OVA-BIL mice led to biliary-centered necroinflammatory damage in a dose-dependent manner. This inflammation absolutely required CD8+ T cells and was augmented by CD4+ T cells. Adoptively transferred OVA CD8+ cells homed to and proliferated in the liver but not the spleen. These activated, adoptively transferred cytotoxic T lymphocytes produced elevated levels of tumor necrosis factor α and interferon γ.
T-cell recognition of antigen aberrantly expressed on bile duct epithelium induced an acute necroinflammatory response specific to the liver, with activation, proliferation, and cytokine production predominantly by the OVA-specific cytotoxic T cells. Thus, OVA BIL represents an antigen-specific animal model of inflammatory bile duct injury.
PMCID: PMC4113411  PMID: 17087941
6.  Intravenous N-acetylcysteine in Pediatric Patients with Non-Acetaminophen Acute Liver Failure: A Placebo-Controlled Clinical Trial 
Hepatology (Baltimore, Md.)  2013;57(4):1542-1549.
N-acetylcysteine (NAC) was found to improve transplantation-free survival in only those adults with non-acetaminophen (non-APAP) acute liver failure (ALF) and grade 1–2 hepatic encephalopathy (HE). Because non-APAP ALF differs significantly between children and adults, the Pediatric Acute Liver Failure (PALF) Study Group evaluated NAC in non-APAP PALF. Children from birth through age 17 years with non-APAP ALF enrolled in the PALF registry were eligible to enter an adaptively allocated, doubly masked, placebo-controlled trial using a continuous intravenous infusion of NAC (150 mg/kg/day in 5% dextrose in water [D5W]) or placebo (D5W) for up to 7 days. The primary outcome was 1-year survival. Secondary outcomes included liver transplantation-free survival, liver transplantation (LTx), length of ICU and hospital stays, organ system failure and maximum HE score. A total of 184 participants were enrolled in the trial with 92 in each arm. The 1-year survival did not differ significantly (p=0.19) between the NAC (73%) and placebo (82%) treatment groups. The 1-year LTx-free survival was significantly lower (p=0.03) in those who received NAC (35%) than those who received placebo (53%), particularly, but not significantly so, among those less than 2 years old with HE grade 0–1 (NAC 25%; placebo 60%; p=0.0493). There were no significant differences between treatment arms for hospital or ICU length of stay, organ systems failing, or highest recorded grade of HE.
NAC did not improve 1-year survival in non-APAP PALF. 1-year LTx-free survival was significantly lower with NAC, particularly among those < 2 years old. These results do not support broad use of NAC in non-APAP PALF and emphasizes the importance of conducting controlled pediatric drug trials, regardless of results in adults.
PMCID: PMC3509266  PMID: 22886633
Child; hepatic encephalopathy; liver transplantation; multi-organ system failure; treatment
7.  King’s College Hospital criteria for non-acetaminophen induced acute liver failure in an international cohort of children 
The Journal of pediatrics  2012;162(2):319-323.e1.
To validate King’s College Hospital criteria (KCHC) in children with non-acetaminophen (APAP) induced pediatric acute liver failure (PALF) and to determine whether re-optimizing the KCHC would improve predictive accuracy.
Study design
We utilized the PALF study group database. Primary outcomes were survival without liver transplantation (LT) versus death at 21 days following enrollment. Classification and Regression Tree (CART) analysis was used to determine if modification of KCHC parameters would improve classification of death versus survival.
Among 163 patients who met KCHC, 54 patients (33.1%) died within 21 days. Sensitivity of KCHC in this cohort was significantly lower than in the original study (61% vs 91%, p=0.002), and specificity did not differ significantly. The positive predictive value (PPV) and negative predictive value (NPV) of KCHC for this cohort was 33% and 88% respectively. CART analysis yielded the following optimized parameters to predict death: grade 2–4 encephalopathy, international normalized ratio >4.02 and total bilirubin >2.02 mg/dL. These parameters did not improve PPV, but NPV was significantly better (88% vs. 92%, p<0.0001).
KCHC does not reliably predict death in PALF. With a PPV of 33%, twice as many participants who met KCHC recovered spontaneously than died, indicating that using KCHC may cause over utilization of LT. Re-optimized cutpoints for KCHC parameters improved NPV, but not PPV. Parameters beyond the KCHC should be evaluated to create a predictive model for PALF.
PMCID: PMC3504621  PMID: 22906509
coagulopathy; prognosis; hepatic encephalopathy
8.  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.
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.
PMCID: PMC3881187  PMID: 17929308
9.  Cross-sectional Multi-center Analysis of Portal Hypertension in 163 Children and Young Adults with Biliary Atresia 
Biliary atresia (BA) frequently results in portal hypertension (PHT), complications of which lead to significant morbidity and mortality. The Childhood Liver Disease Research and Education Network (ChiLDREN) was utilized to perform a cross-sectional multi-centered analysis of PHT in children with BA.
BA subjects receiving medical management at a ChiLDREN site were enrolled. A priori, clinically evident PHT was defined as “definite” when there was either 1) history of a complication of PHT or 2) clinical findings consistent with PHT (both splenomegaly and thrombocytopenia). PHT was denoted as “possible” if one of the findings was present in the absence of a complication, while PHT was “absent” if none of the criteria were met.
163 subjects were enrolled between May 2006 and December 2009. At baseline, definite PHT was present in 49%, possible in 17% and absent in 34% of subjects. Demographics, growth and anthropometrics were similar amongst the 3 PHT categories. ALT, GGTP, and sodium levels were similar, while there were significant differences in AST, AST/ALT, albumin, total bilirubin, PT, WBC, platelet count and AST/platelet between definite and absent PHT. Thirty-four percent of those with definite PHT had either PT > 15s or albumin < 3 g/L.
Clinically definable PHT is present in two thirds of North American long-term BA survivors with their native livers. The presence of PHT is associated with measures of hepatic injury and dysfunction, although in this selected cohort the degree of hepatic dysfunction is relatively mild and growth is preserved.
PMCID: PMC3483444  PMID: 22903006
varices; pediatric; ascites; hepatopulmonary syndrome; hypersplenism
10.  Efficacy of Fat-Soluble Vitamin Supplementation in Infants With Biliary Atresia 
Pediatrics  2012;130(3):e607-e614.
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.
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.
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.
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.
PMCID: PMC3428752  PMID: 22891232
cholestasis; nutrition; liver; vitamin deficiency
11.  Primary Prophylaxis of Variceal Hemorrhage in Children With Portal Hypertension: A Framework for Future Research 
Nonselective β-blocker therapy and endoscopic variceal ligation reduce the incidence of variceal hemorrhage in cirrhotic adults, but their use in children is controversial. There are no evidence-based recommendations for the prophylactic management of children at risk of variceal hemorrhage due to the lack of appropriate randomized controlled trials. In a recent gathering of experts at the American Association for the Study of Liver Diseases annual meeting, significant challenges were identified in attempting to design and implement a clinical trial of primary prophylaxis in children using either of these therapies. These challenges render such a trial unfeasible, primarily due to the large sample size required, inadequate knowledge of appropriate dosing of β-blockers, and difficulty in recruiting to a trial of endoscopic variceal ligation. Pediatric research should focus on addressing questions of natural history and diagnosis of varices, prediction of variceal bleeding, optimal approaches to β-blocker and ligation therapy, and alternative study designs to explore therapeutic efficacy in children.
PMCID: PMC3728696  PMID: 21336158
endoscopic variceal ligation; esophageal varices; nonselective β-blockers; portal hypertension; primary prophylaxis; variceal bleeding
12.  Liver Transplantation for Classical Maple Syrup Urine Disease: Long-Term Follow-Up in 37 Patients and Comparative United Network for Organ Sharing Experience 
The Journal of pediatrics  2011;160(1):116-21.e1.
To assess clinical and neurocognitive function in children who have undergone liver transplantation for classical maple syrup urine disease (MSUD).
Study design
A total of 35 patients with classical MSUD (age 9.9 ± 7.9 years) underwent liver transplantation between 2004 and 2009. Six patients donated their liver to recipients without MSUD (“domino” transplant). We analyzed clinical outcomes for our cohort and 17 additional cases from the national United Network for Organ Sharing registry; 33 patients completed IQ and adaptive testing before transplantation, and 14 completed testing 1 year later.
Patient and graft survival were 100% at 4.5 ± 2.2 years of follow-up. Liver function was normal in all patients. Branched-chain amino acid levels were corrected within hours after surgery and remained stable, with leucine tolerance increasing more than 10-fold. All domino transplant recipients were alive and well with normal branched-chain amino acid homeostasis at the time of this report. Patient and graft survival for all 54 patients with MSUD undergoing liver transplantation in the United States during this period were 98%and 96%, respectively. One-third of our patients were mentally impaired (IQ ≤ 70) before transplantation, with no statistically significant change 1 year later.
Liver transplantation is an effective long-term treatment for classical MSUD and may arrest brain damage, but will not reverse it.
PMCID: PMC3671923  PMID: 21839471
13.  Hu Antigen R and Tristetraprolin – Counter-Regulators of Rat Apical Sodium Dependent Bile Acid Transporter via Effects on mRNA Stability 
Hepatology (Baltimore, Md.)  2011;54(4):1371-1378.
The apical sodium dependent bile acid transporter (ASBT –SLC10A2) mediates intestinal, renal and cholangiocyte bile acid reclamation. Transcriptional regulation of ASBT is well-described, while information on post-transcriptional regulation is limited. Prior studies suggested that ontogeny of ASBT is controlled in part by changes in mRNA stability. We studied the role that HuR and TTP play in regulating the expression of mRNA that contains the 3’UTR of rat ASBT. The 3’ UTR was incorporated into an SV-40 driven luciferase reporter (rASBT3-luciferase) for rapid screening of regulatory effects. Silencing HuR reduced luciferase reporter activity, while silencing TTP enhanced luciferase activity. Conversely, overexpression of HuR enhanced rASBT3-luciferase reporter activity. The same 3’UTR fragments of rat ASBT were incorporated into a beta-globin coding mRNA construct for analysis of mRNA stability (rASBT3-ßglobin). mRNA half-life was progressively shortened by the incorporation of increasing sized fragments of the 3’UTR. Silencing HuR shortened the half-life of rASBT3-ßglobin containing 0.3 kb of the rat ASBT 3’UTR. Gel shift assays revealed binding of HuR and TTP to rat ASBT 3’UTR. Endogenously expressed human ASBT mRNA half-lives and steady-state protein levels in Caco-2 cells were repressed when HuR was silenced but was enhanced when TTP was silenced. Developmental changes in HuR and TTP protein abundance correlated with previously characterized ontogenic changes in rat ileal and renal ASBT expression.
These studies not only show that ASBT expression is controlled at the level of mRNA stability via its 3’UTR, but also identify HuR and TTP as two key trans-acting factors that are involved in exerting counterregulatory effects on ASBT mRNA stability.
PMCID: PMC3205920  PMID: 21688286
gene expression; ileum; intestine; ontogeny; RNA binding protein
14.  ABCB4 Disease Presenting with Cirrhosis and Copper Overload-Potential Confusion with Wilson Disease 
A 2-year-old female with cirrhosis was found to have a liver copper of 248 μg/g dry weight. She was eventually diagnosed with ABCB4 disease on the basis of heterozygote A546D and R176W mutations. Her liver disease was partially responsive to ursodeoxycholic acid therapy. Copper overload occurs in cholestatic liver disease and this must be considered to avoid misdiagnosis of Wilson disease.
PMCID: PMC3940549  PMID: 25755323
Bile; cholestasis; pediatric; phospholipid; SIFT, sorting intolerant from tolerant
15.  Valproic Acid-Associated Acute Liver Failure in Children: Case Report and Analysis of Liver Transplantation Outcomes in the United States 
The Journal of pediatrics  2010;158(5):802-807.
To determine if valproic acid (VPA)-associated ALF (VPA-ALF) explains the poor outcomes following liver transplantation (LT) in children.
Study design
Organ Procurement and Transplantation Network data of pediatric patients who underwent LT for VPA-ALF and ALF secondary to other drugs (nonVPA- drug-induced acute liver failure [DIALF]) were analyzed. Pre- and post-transplant variables and post-LT survival were compared between VPA-ALF and nonVPA-DIALF.
Seventeen children were transplanted for VPA-ALF. Of those, 82% died within one year of LT. Pre- and post-transplant parameters of VPA versus nonVPA-DIALF were comparable with two exceptions. Median alanine aminotransferase at transplant was remarkably lower in VPA-ALF compared with nonVPA-DIALF (45 versus 1179 IU/L, P=0.004). One-year survival probability was worse in VPA-ALF than nonVPA-DIALF (20% versus 69%, P<0.0001). Median post-LT survival time for VPA-ALF was 2.8 months.
Children who underwent LT for VPA-ALF had significantly lower survival probability than those with nonVPA-DIALF. Current data suggest that VPA-ALF in children represents an “unmasking” of mitochondrial disease. VPA-ALF should be a contraindication for LT, even in the absence of a documented mitochondrial disease.
PMCID: PMC3075355  PMID: 21167499
Children; valproic acid; mitochondria; seizure; hepatotoxicity; POLG1
16.  Barriers to the successful treatment of liver disease by hepatocyte transplantation 
Journal of hepatology  2010;53(4):769-774.
Management of patients with hepatic failure and liver-based metabolic disorders is complex and expensive. Hepatic failure results in impaired coagulation, altered consciousness and cerebral function, a heightened risk of multiple organ system failure, and sepsis [1]. Such manifold problems are only treatable today and for the foreseeable future by transplantation. In fact, whole or auxiliary partial liver transplantation is often the only available treatment option for severe, even if transient, hepatic failure. Patients with life-threatening liver-based metabolic disorders similarly require organ transplantation even though their metabolic diseases are typically the result of a single enzyme deficiency, and the liver otherwise functions normally. For all of the benefits it may confer, liver transplantation is not an ideal therapy, even for severe hepatic failure. More than 17,000 patients currently await liver transplantation in the United States, a number that seriously underestimates the number of patients that need treatment [2], as it has been estimated that more than a million patients could benefit from transplantation [3]. Unfortunately, use of whole liver transplantation to treat these disorders is limited by a severe shortage of donors and by the risks to the recipient associated with major surgery [4].
PMCID: PMC2930077  PMID: 20667616
17.  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.
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.
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.
Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.
PMCID: PMC3042805  PMID: 20447715
cholestasis; genetics; transport protein; pediatrics; P-type ATPase; ATP binding cassette protein; ATP8B1; FIC1; ABCB11; BSEP
18.  ATPase Class I Type 8B Member 1 and Protein Kinase C-ζ Induce the Expression of the Canalicular Bile Salt Export Pump in Human Hepatocytes 
Pediatric research  2010;67(2):183.
The exact molecular mechanism(s) of the disease that results from defects in the ATPase Class I Type 8B Member 1 gene remains controversial. Prior investigations of human ileum and in intestinal and ovarian cell lines have suggested that Familial Intrahepatic Cholestasis 1 (FIC1) activates the Farnesoid X-Receptor (FXR) via a pathway involving Protein Kinase C ζ (PKCζ). Translational investigations of human liver from individuals with FIC1 disease have been confounded by secondary affects of progressive cholestatic liver disease and limited numbers of samples for analysis. These studies, performed in primarily derived human hepatocytes, circumvent this issue. The canalicular bile salt export pump (BSEP) served as a downstream target of FXR. siRNA mediated silencing of FIC1 in human hepatocytes led to a reduction in both human BSEP promoter activity and BSEP protein expression, which correlated with a reduction in FXR expression and redistribution of its localization from the nucleus to the cytoplasm. These changes in BSEP expression could be reproduced by altering the expression of PKCζ; with a positive correlation of PKCζ activity and BSEP expression. Overall, these findings support the hypothesis that FIC1 enhances FXR signaling via a PKCζ dependent signaling pathway.
PMCID: PMC2819672  PMID: 19809379
The Journal of pediatrics  2006;149(2):159-164.
Researchers and clinicians with expertise in autosomal recessive polycystic kidney disease and congenital hepatic fibrosis (ARPKD/CHF) and related fields met on May 5-6, 2005, on the National Institutes of Health (NIH) campus for a 1.5-day symposium sponsored by the NIH Office of Rare Diseases, the National Human Genome Research Institute (NHGRI), and in part by the ARPKD/CHF Alliance. The meeting addressed the present status and the future of ARPKD/CHF research.
PMCID: PMC2918414  PMID: 16887426
20.  The Membrane Protein, ATP8B1, Signals Through Protein Kinase C-Zeta to Activate the Farnesoid X Receptor 
Hepatology (Baltimore, Md.)  2008;48(6):1896-1905.
Prior loss-of-function analyses revealed that ATP8B1 (FIC1) post-translationally activated the Farnesoid X-Receptor (FXR).
Mechanisms underlying this regulation are elaborated upon by these gain-of-function studies in UPS cells, which lack endogenous FIC1 expression. FXR function was assayed in response to wild type and mutated FIC1 expression constructs using a human bile salt export pump (BSEP) promoter and a variety of cellular localization techniques.
FIC1 overexpression led to enhanced phosphorylation and nuclear localization of FXR that was associated with FXR-dependent activation of the BSEP promoter. The FIC1 effect was lost after mutation of the FXR response element in the BSEP promoter. Despite similar levels of FIC1 protein expression, Byler-disease FIC1 mutants did not activate BSEP, while benign recurrent intrahepatic cholestasis mutants partially activated BSEP. The FIC1 effect was dependent upon the presence of the FXR ligand, chenodeoxycholic acid. The FIC1 effect on FXR phosphorylation and nuclear localization and its effects on BSEP promoter activity could be blocked with protein kinase C (PKC) ζ inhibitors (pseudosubstrate or siRNA silencing). Recombinant PKCζ directly phosphorylated immunoprecipitated FXR. Mutation of threonine 442 of FXR to alanine yielded a dominant negative protein, while the phosphomimetic conversion to glutamate resulted in FXR with enhanced activity and nuclear localization. Inhibition of PKCζ in Caco-2 cells resulted in activation of the human apical sodium dependent bile acid transporter promoter.
These results demonstrate that FIC1 signals to FXR via PKCζ. FIC1-related liver disease is likely related to downstream effects of FXR on bile acid homeostasis. BRIC emanates from a partially functional FIC1 protein. Phosphorylation of FXR is an important mechanism for regulating its activity.
PMCID: PMC2774894  PMID: 18668687
nuclear receptor; cholestasis; liver; ileum; bile acid
21.  Acute Liver Failure in Children: The First 348 Patients in The Pediatric Acute Liver Failure Study Group 
The Journal of pediatrics  2006;148(5):652-658.
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.
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.
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.
PMCID: PMC2662127  PMID: 16737880

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