ATP8B1, ABCB11, and ABCB4 Genes Defects: Novel Mutations Associated with Cholestasis with Different Phenotypes and Outcomes.

OBJECTIVES: To characterize the clinical, laboratory, histologic, molecular features, and outcome of gene-confirmed progressive familial intrahepatic cholestasis (PFIC) 1-3 among Arabs and to evaluate for "genotype-phenotype" correlations. STUDY DESIGN: We retrospectively reviewed charts of 65 children (ATP8B1 defect = 5, ABCB11 = 35, ABCB4 = 25) who presented between 2008 and 2019 with cholestasis. The clinical phenotype of a disease was categorized based on response of cholestasis and itching to ursodeoxycholic acid and ultimate outcome, into mild (complete response), intermediate (partial response, nonprogressive), and severe (progression to end-stage liver disease). RESULTS: Overall, 27 different mutations were identified (ATP8B1, n = 5; ABCB11, n = 11; ABCB4, n = 11), comprising 10 novel ones. Six patients with heterozygous missense mutations (ATP8B1, n = 2; ABCB11, n = 4) had transient cholestasis. Of the remaining 3 patients with PFIC1, 2 developed severe phenotype (splicing and frameshift mutations). Of the remaining 31 patients with PFIC2, 25 developed severe disease (15 due to frameshift and splicing mutations). Of 25 patients with PFIC3, 10 developed a severe phenotype (1 splicing and 3 frameshift mutations; 6 missense). Patients with PFIC2 had significantly shorter survival time and more rapid disease progression than patients with PFIC3 (P < .001). Patients with frameshift mutations in ABCB11 gene (p.Thr127Hisfs∗6) and ABCB4 gene (p.Phe210Serfs∗5) had significantly shorter survival time than missense mutations (P = .011; P = .0039, respectively). CONCLUSIONS: We identified genotype-phenotype correlations among mutations in ABCB11 and ABCB4 genes, which underscore the prognostic value of early genetic diagnosis. The disease course in patients with PFIC3 could be favorably modified by ursodeoxycholic acid therapy.

Impact of Genotype, Serum Bile Acids, and Surgical Biliary Diversion on Native Liver Survival in FIC1 Deficiency.

BACKGROUND AND AIMS: Mutations in ATPase phospholipid transporting 8B1 (ATP8B1) can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1. The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide insights by using the largest genetically defined cohort of patients with FIC1 deficiency to date. APPROACH AND RESULTS: This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication), FIC1-A (n = 67; no PPTMs), FIC1-B (n = 29; one PPTM), or FIC1-C (n = 34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18 years. NLS was comparable among FIC1-A, FIC1-B, and FIC1-C (% NLS at age 10 years: 67%, 41%, and 59%, respectively; P = 0.12), despite FIC1-C undergoing SBD less often (% SBD at age 10 years: 65%, 57%, and 45%, respectively; P = 0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10 years, sBAs < 194 µmol/L: 49% vs. sBAs ≥ 194 µmol/L: 15%; P = 0.03). SBD decreased sBAs (230 [125-282] to 74 [11-177] µmol/L; P = 0.005). SBD (HR 0.55, 95% CI 0.28-1.03, P = 0.06) and post-SBD sBA concentrations < 65 µmol/L (P = 0.05) tended to be associated with improved NLS. CONCLUSIONS: Less than half of patients with FIC1 deficiency reach adulthood with native liver. The number of PPTMs did not associate with the natural history or prognosis of FIC1 deficiency. sBA concentrations at initial presentation and after SBD provide limited prognostic information on long-term NLS.

Long-term survival after intrahepatic cholestasis of pregnancy: A follow-up of 571 mothers.

OBJECTIVE: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder during pregnancy. ICP has been associated with morbidity but little is known about women's long-term survival. Our aim was to determine whether ICP is associated with mothers' long-term survival. STUDY DESIGN: The study population comprised 571 women with ICP in at least one pregnancy seen at Tampere University Hospital in Finland between 1969‒1988. The reference group comprised 1333 women: the previous and the following participant in the maternity ward diary. The data were obtained from Statistics Finland in March 2017 containing deaths among the study participants between 1971‒2015. The follow-up time of the cohort was 27-46 years. The Kaplan-Meier method was used. RESULTS: Totally, 39 of the mothers with ICP (6.8%) and 111 of the reference group (8.3%) had died by the end of 2015 (p = 0.267). The mean survival time of ICP women was 77.4 years and of the reference group 79.2 years (p = 0.288). The mean survival time from labour in the ICP group was 45.0 years and in the reference group 44.8 years (p = 0.259). CONCLUSIONS: Based on this study ICP does not seem to be associated with women's survival. There is no need to follow-up ICP mothers' health because of the nonexistent risk of premature death.

Ursodeoxycholic acid versus placebo in the treatment of women with intrahepatic cholestasis of pregnancy (ICP) to improve perinatal outcomes: protocol for a randomised controlled trial (PITCHES).

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder specific to pregnancy and presents with maternal pruritus, raised concentrations of serum bile acids and abnormal liver function tests. ICP is associated with increased rates of spontaneous and iatrogenic preterm labour, fetal hypoxia, meconium-stained amniotic fluid and intrauterine death. Some clinicians treat ICP with ursodeoxycholic acid (UDCA) to improve maternal pruritus and biochemical abnormalities. However, there are currently no data to support the use of UDCA to improve pregnancy outcome as none of the trials performed to date have been powered to address this question. METHODS: The PITCHES trial is a triple-masked, placebo-controlled randomised trial, to evaluate UDCA versus placebo in women with ICP between 20 + 0 to 40 + 6 weeks' gestation. The primary objective of the trial is to determine if UDCA treatment of women with ICP between 20 + 0 and 40 + 6 weeks' gestation reduces the primary perinatal outcome: a composite of perinatal death (as defined by in utero fetal death after randomisation or known neonatal death up to 7 days) or preterm delivery (less than 37 weeks' gestation) or neonatal unit admission for at least 4 h (from infant delivery until hospital discharge). The secondary objectives of the trial are (1) to investigate the effect of UDCA on other short-term outcomes for both mother and infant and (2) to assess the impact of UDCA on health care resource use, in terms of the total number of nights for mother and infant, together with level of care. DISCUSSION: Current practice in the UK at the time of trial commencement for the treatment of ICP is inconsistent, with some units routinely prescribing UDCA, others prescribing very little and the remainder offering it variably. Our previous pilot trial of UDCA in women with ICP demonstrated that the trial would be feasible, and the research question remains active and unanswered. Results are highly likely to influence clinical practice, through direct management and impact on national and international guidelines. TRIAL REGISTRATION: ISRCTN registry, ID: ISRCTN91918806 . Prospectively registered on 27 August 2015.

Cholangitis Lenta: A Clinicopathologic Study of 28 Cases.

Cholangitis lenta, also known as ductular cholestasis, cholangiolar cholestasis, or subacute nonsuppurative cholangitis, is an uncommon type of cholangitis characterized by ductular reaction with inspissated bile in dilated ductules. The literature on this unique entity has been limited to only a few studies based on a very limited number of cases, which importantly suggest an association with sepsis and/or intra-abdominal infection. The clinical, laboratory, and histologic features of 28 cases of cholangitis lenta are herein investigated. Twenty-five (89.3%) patients were liver transplant recipients. Most notably, the majority of patients showed clinical signs and symptoms of sepsis, and positive microbiology cultures were demonstrated in 24 (85.7%) patients. Significantly, 15 (53.6%) patients died during their hospitalization, ranging from 2 days to 5 months after the initial liver biopsy that showed histologic features of cholangitis lenta. Among the 13 discharged patients, including 2 who received retransplantation, 4 (14.3%) subsequently died of pneumonia, graft dysfunction, or fungal infection within 7 months to 9.3 years. Only 9 (32.1%) patients were alive at the last follow-up, with the follow-up time ranging from 3.8 to 10.4 years. Our data show that the finding of cholangitis lenta on liver biopsy is thus frequently associated with sepsis and with a high mortality rate. Therefore, accurate diagnosis of this condition on liver biopsy is imperative as it is an indication that the patient may have a potentially life threatening condition that requires immediate medical attention and management.

Retrospective analysis of maternal, fetal, and neonatal outcomesof intrahepatic cholestasis of pregnancy at Gazi University.

BACKGROUND/AIM: Maternal, fetal, and neonatal outcomes in parturients with intrahepatic cholestasis of pregnancy (ICP) have been retrospectively documented. We aimed to present pregnancy outcomes of parturients with ICP who underwent delivery. The study was conducted during a 1-year period. MATERIALS AND METHODS: After ethics committee approval, data from 1 January to 31 December 2015 were collected to identify parturients with ICP. RESULTS: Ten out of 37 patients underwent normal spontaneous vaginal delivery (NSVD), and the remaining 27 parturients underwent cesarean section (CS). Five of 27 parturients underwent nonelective cesarean section, while 22 had elective cesarean delivery. As for NSVD deliveries, only one parturient received combined spinal and epidural anesthesia (CSE) for labor. Neuraxial (n = 22 for spinal and n = 1 for CSE) and general anesthesia (n = 4) rates for CSs were 85% and 15%, respectively. Approximately 96% of neuraxial anesthesia choices were spinal anesthesia. Nearly 18.5% of CSs were not elective. Adverse outcomes included 2 preterm births, 2 preterm labors, 2 newborns with hepatitis, and one perinatal fetal death. CONCLUSION: Parturients with ICP who had normal coagulation parameters despite increased liver enzymes preoperatively underwent cesarean delivery under spinal anesthesia without complication. Although maternal outcomes were generally positive, adverse fetal and neonatal outcomes are more likely to occur, particularly in cases with severe ICP.

Hepatic dysfunction: A common occurrence in severely injured patients.

BACKGROUND: Hepatic dysfunction (HD) is a common finding in critically ill patients. The underlying pathophysiological process is one of either cholestasis or hypoxic liver injury (HLI). Using serum bilirubin, our study aimed to determine the incidence of HD in a critically ill trauma population, identify risk factors and analyse the impact on outcomes. METHODS: A retrospective observational study was performed on all patients admitted to the Level 1 Trauma Unit ICU at Inkosi Albert Luthuli Central Hospital in Durban, South Africa (IALCH) from 01/01/2012 until 31/12/2012. HD was defined as a total bilirubin greater than 34.2µmol/l (2mg/dL). Additional demographic, physiological, biochemical, and pharmaceutical risk factors for hepatic dysfunction were identified and recorded. RESULTS: Two hundred and twenty five patients were included in the study of whom 48 (21.3%) developed HD. An increased duration of ventilation (median 15days [inter-quartile range 6-19] vs 6days [IQR 3-11] p<0.001), prolonged length of stay (median 19days [IQR 8.5-31] vs 7days [IQR 3-13] p<0.001), and higher mortality rate (31.3% vs. 14.7% p=0.01) were all significantly associated with HD. Shock on admission was twice as common in patients developing HD (p<0.001). The only drugs associated with HD were piperacillin-tazobactam (p<0.001) and enalapril (p=0.04). On multivariable analysis however, HD was not associated with mortality. CONCLUSION: HD was common in our study population, and was associated with other organ dysfunction, increased mortality and length of stay.

Intraductal Radiofrequency Ablation Followed by Locoregional Tumor Treatments for Treating Occluded Biliary Stents in Non-Resectable Malignant Biliary Obstruction: A Single-Institution Experience.

OBJECTIVES: To determine the safety and feasibility of intraductal radiofrequency ablation (RFA) followed by locoregional tumor treatments in patients with non-resectable malignant biliary obstruction and stent re-occlusion. METHODS: Fourteen patients with malignant biliary obstruction and blocked metal stents were studied retrospectively. All had intraductal RFA followed by locoregional tumor treatments and were monitored clinically and radiologically. The practicality, safety, postoperative complications, jaundice remission, stent patency and survival time were analyzed. RESULTS: Combination treatment was successful for all patients. There were no severe complications during RFA or local treatments. All patients had stent patency restored, with a decline in serum bilirubin. Three patients had recurrent jaundice by 195, 237 and 357 days; two patients underwent repeat intraductal RFA; and one required an internal-external biliary drain. The average stent patency time was 234 days (range 187-544 days). With a median follow-up of 384 days (range 187-544 days), six patients were alive, while eight had died. There was no mortality at 30 days. The 3, 6, 12 and 18 month survival rates were 100%, 100%, 64.3% and 42.9%, respectively. CONCLUSION: Intraductal RFA followed by locoregional tumor treatments for occluded metal stents is safe and practically feasible and potential increase stent patency and survival times.

Treating fibrosing cholestatic hepatitis C with sofosbuvir and ribavirin: a matched analysis.

BACKGROUND: Fibrosing cholestatic hepatitis (FCH) is an uncommon but potentially fatal complication of recurrent hepatitis C (HCV) in liver transplant recipients. METHODS: We matched the treatment outcomes of 10 liver transplant recipients who developed FCH with those of 10 recipients with recurrent HCV without FCH treated with sofosbuvir and ribavirin. RESULTS: Baseline mean alanine transaminase, aspartate transaminase, alkaline phosphatase, and total bilirubin were 186 U/L, 197 U/L, 243 U/L, and 6.7 mg/dL, respectively, in the FCH recipients and 82 U/L, 60 U/L, 110 U/L, and 0.99 mg/dL, respectively, in non-FCH recipients. The sustained viral response in FCH and non-FCH recipients was 40% and 80%, respectively. One-yr patient and graft survival rates were 90% and 80%, respectively, in FCH recipients, and 100% in non-FCH recipients. Seven FCH and six non-FCH recipients were treated for anemia with blood transfusion and/or erythropoietin growth factors. CONCLUSION: Our results suggest that the use of sofosbuvir and ribavirin is effective and tolerable in liver transplant recipients treated for recurrent FCH. There is a trend of lower sustained viral response, patient survival, and graft survival in the FCH recipients.

Ledipasvir and Sofosbuvir Plus Ribavirin for Treatment of HCV Infection in Patients With Advanced Liver Disease.

BACKGROUND & AIMS: There are no effective and safe treatments for chronic hepatitis C virus (HCV) infection of patients who have advanced liver disease. METHODS: In this phase 2, open-label study, we assessed treatment with the NS5A inhibitor ledipasvir, the nucleotide polymerase inhibitor sofosbuvir, and ribavirin in patients infected with HCV genotypes 1 or 4. Cohort A enrolled patients with cirrhosis and moderate or severe hepatic impairment who had not undergone liver transplantation. Cohort B enrolled patients who had undergone liver transplantation: those without cirrhosis; those with cirrhosis and mild, moderate, or severe hepatic impairment; and those with fibrosing cholestatic hepatitis. Patients were assigned randomly (1:1) to receive 12 or 24 weeks of a fixed-dose combination tablet containing ledipasvir and sofosbuvir, once daily, plus ribavirin. The primary end point was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: We enrolled 337 patients, 332 (99%) with HCV genotype 1 infection and 5 (1%) with HCV genotype 4 infection. In cohort A (nontransplant), SVR12 was achieved by 86%-89% of patients. In cohort B (transplant recipients), SVR12 was achieved by 96%-98% of patients without cirrhosis or with compensated cirrhosis, by 85%-88% of patients with moderate hepatic impairment, by 60%-75% of patients with severe hepatic impairment, and by all 6 patients with fibrosing cholestatic hepatitis. Response rates in the 12- and 24-week groups were similar. Thirteen patients (4%) discontinued the ledipasvir and sofosbuvir combination prematurely because of adverse events; 10 patients died, mainly from complications related to hepatic decompensation. CONCLUSION: The combination of ledipasvir, sofosbuvir, and ribavirin for 12 weeks produced high rates of SVR12 in patients with advanced liver disease, including those with decompensated cirrhosis before and after liver transplantation. ClinTrials.gov: NCT01938430.

Genotype-phenotype correlation of contiguous gene deletions of SLC6A8, BCAP31 and ABCD1.

The BCAP31 gene is located between SLC6A8, associated with X-linked creatine transporter deficiency, and ABCD1, associated with X-linked adrenoleukodystrophy. Recently, loss-of-function mutations in BCAP31 were reported in association with severe developmental delay, deafness and dystonia. We characterized the break points in eight patients with deletions of SLC6A8, BCAP31 and/or ABCD1 and studied the genotype-phenotype correlations. The phenotype in patients with contiguous gene deletions involving BCAP31 overlaps with the phenotype of isolated BCAP31 deficiency. Only deletions involving both BCAP31 and ABCD1 were associated with hepatic cholestasis and death before 1 year, which might be explained by a synergistic effect. Remarkably, a patient with an isolated deletion at the 3'-end of SLC6A8 had a similar severe phenotype as seen in BCAP31 deficiency but without deafness. This might be caused by the disturbance of a regulatory element between SLC6A8 and BCAP31.

Internal-external percutaneous transhepatic biliary drainage for patients with malignant obstructive jaundice.

PURPOSE: To evaluate the effect of internal-external percutaneous transhepatic biliary drainage (IEPTBD) for patients with malignant obstructive jaundice. METHODS: During the period of January 2008 and July 2013, internal-external drainage was performed in 42 patients with malignant obstructive jaundice. During the procedure, if the guide wire could pass through the occlusion and into the duodenum, IEPTBD was performed. External drainage biliary catheter was placed if the occlusion was not crossed. Newly onset of infection, degree of bilirubin decrease and the survival time of patients were selected as parameters to evaluate the effect of IEPTBD. RESULTS: Twenty newly onset of infection were recorded after procedure and new infectious rate was 47.6%. Sixteen patients with infection (3 before, 13 after drainage) were uncontrolled after procedure, 12 of them (3 before, 9 after drainage) died within 1 month. The mean TBIL levels declined from 299.53 umol/L before drainage to 257.62 umol/L after drainage, while uninfected group decline from 274.86 umol/L to 132.34 umol/Lp (P < 0.5). The median survival time for uninfected group was 107 days, and for infection group was 43 days (P < 0.05). CONCLUSIONS: The IEPTBD drainage may increase the chance of biliary infection, reduce bile drainage efficiency and decrease the long-term prognosis, and the external drainage is a better choice for patients with malignant obstructive jaundice need to biliary drainage.

Prognostic value of biochemical liver parameters in neonatal sepsis-associated cholestasis.

AIMS: The aim of the study was to evaluate the significance of total bilirubin, aspartate transaminase (AST), alanine transaminase and gamma-glutamyltransferase (GGT) for predicting outcome in sepsis-associated cholestasis. METHODS: A retrospective cohort review of the hospital records was performed in 181 neonates admitted to the Neonatal Care Unit. A comparison was performed between subjects with low and high liver values based on cut-off values from ROC analysis. We defined poor prognosis to be when a subject had prolonged cholestasis of more than 3.5 months, developed severe sepsis, septic shock or had a fatal outcome. RESULTS: The majority of the subjects were male (56%), preterm (56%) and had early onset sepsis (73%). The poor prognosis group had lower initial values of GGT compared with the good prognosis group (P = 0.003). Serum GGT (cut-off value of 85.5 U/L) and AST (cut-off value of 51 U/L) showed significant correlation with the outcome following multivariate analysis. The odds ratio (OR) of low GGT and high AST were OR 4.3 (95% CI:1.6 to 11.8) and OR 2.9 (95% CI:1.1 to 8), respectively, for poor prognosis. In subjects with normal AST values, those with low GGT value had relative risk of 2.52 (95% CI:1.4 to 3.5) for poorer prognosis compared with those with normal or high GGT. CONCLUSION: Serum GGT and AST values can be used to predict the prognosis of patients with sepsis-associated cholestasis.

Caroli disease patients have excellent survival after liver transplant.

BACKGROUND: Caroli disease (CD) is characterized by dilation of the intrahepatic biliary tree, which may result in malignancy. Treatments include management of symptoms and hepatic resection to decrease disease burden. In patients with CD not amenable to these treatments, orthotopic liver transplantation (OLT) has been used. This study examines if OLT is a reasonable treatment for patients with CD. MATERIALS AND METHODS: The United Network of Organ Sharing/Organ Procurement and Transplantation Network database between September 30, 1987 and March 31, 2011 was queried. Cases without patient or allograft survival time or without a diagnosis were excluded from analysis. Patients with CD were compared to patients with primary biliary cirrhosis (PBC), secondary biliary cirrhosis (BC), primary sclerosing cholangitis (PSC), and all indications for OLT. Survival analysis was performed by log-rank test and Kaplan-Meier. RESULTS: One hundred forty patients with CD were compared to 4797 patients with PBC, 489 patients with secondary BC, 6033 patients with PSC, and 92,210 patients post-OLT. Patient and allograft survivals of CD patients at 1, 3, 5, and 10 y are, respectively, 88.5%, 83.4%, 80.9%, and 77.8%; and 81.2%, 74.8%, 70.6%, and 67.9%. CD patients have significantly improved patient and allograft survivals after OLT compared to patients with secondary BC (P = 0.003, P = 0.015) and all other patients undergoing OLT (P = 0.003, P = 0.026). There is a trend towards long-term improved patient and allograft survival in transplanted patients with CD compared to patients with PBC and PSC. CONCLUSIONS: These results suggest that OLT should be considered an effective treatment modality for patients with CD resulting in excellent long-term outcomes.

Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis.

BACKGROUND: Alcoholic steatohepatitis (ASH) is a serious complication of alcoholic liver disease. The diagnosis of ASH requires the association of steatosis, evidence of hepatocellular injury with ballooning degeneration, and polynuclear neutrophil infiltration on liver biopsy. Whether these lesions, in addition to other histological features observed in liver tissue specimens, have prognostic significance is unclear. METHODS: We studied 163 patients (age 55 yrs [35-78], male/female 102/61) with recent, heavy (> 80 gr/day) alcohol intake, histologically-proven ASH (97% with underlying cirrhosis, Maddrey's score 39 [13-200], no sepsis), who had a liver biopsy performed 3 days [0-10] after hospital admission for clinical decompensation. A semi-quantitative evaluation of steatosis, hepatocellular damage, neutrophilic infiltration, periportal ductular reaction, intraparenchymal cholestasis, and iron deposits was performed by two pathologists. All patients with a Maddrey's score ≥ 32 received steroids. The outcome at 3 months was determined. Statistical analysis was performed using the Wilcoxon and Fisher's exact tests, Kaplan-Meier method, and the Cox proportional hazard model. RESULTS: 43 patients died after 31 days [5-85] following biopsy. The 3-month survival rate was 74%. Mean kappa value for histological assessment by the two pathologists was excellent (0.92). Univariate analysis identified age, the Maddrey's score, the Pugh's score, the MELD score and parenchymal cholestasis, but not other histological features, as factors associated with 3-month mortality. At multivariate analysis, age (p = 0.029, OR 2.83 [1.11-7.2], intraparenchymal cholestasis (p = 0.001, OR 3.9 [1.96-7.8], and the Maddrey's score (p = 0.027, OR 3.93 [1.17-13.23] were independent predictors of outcome. Intraparenchymal cholestasis was more frequent in non survivors compared to survivors (70% versus 25%, p < 0.001). Serum bilirubin was higher in patients with severe compared to those with no or mild intraparenchymal cholestasis (238 [27-636] versus 69 [22-640] umol/l, p < 0.001). CONCLUSIONS: In this large cohort of patients with histologically documented ASH early after admission and no sepsis, liver biopsy identified marked intraparenchymal cholestasis as an independent predictor of poor short term outcome together with age and the Maddrey's score. It may be hypothesized that incorporation of this particular variable into existing disease severity scores for ASH would improve their performance.

Incidence and risk factors for the development of prolonged severe intrahepatic cholestasis after pediatric living-donor liver transplantation.

The aim of this study is to evaluate the incidence, etiology, and risk facrors for prolonged severe intrahepatic cholestasis (PSIC) after 129 pediatric living-donor liver transplantations (LDLT). The incidence of PSIC was 25.6% (n = 33). Twenty-eight (84.8%) versus 5 (15.2%) children experienced early versus late PSIC, respectively. Among these 33 children with PSIC, 8 (24.2%) received a donor liver with mild to moderate fatty change, 4 (12.1%) with low graft-body weight ratios, and 4 (12.1%) with ABO incompatibility. The predominant etiologies were acute rejection (n = 15; 45.5%), chronic rejection (n = 6; 18.2%), virus (n = 3; 9.1%), vascular complications (n = 4; 12.1%), and initial graft dysfunction (n = 10; 30.3%). ABO incompatibility (P = .032; odds ratio [OR] 3.25), chronic rejection (P = .012; OR 4.76), and vascular complications (P = .046; OR 1.82) were significant variables associated with PSIC. Donor selection with ABO compatibility as well as early detection and management of chronic rejection and vascular complications may be important to prevet PSIC in LDLT.

Outcomes of orthotopic liver transplantation for hepatic sarcoidosis: an analysis of the United Network for Organ Sharing/Organ Procurement and Transplantation Network data files for a comparative study with cholestatic liver diseases.

Hepatic sarcoidosis is a rare indication for liver transplantation. Using the United Network for Organ Sharing (UNOS)/Organ Procurement and Transplantation Network (OPTN) database, we evaluated patient and graft survival after orthotopic liver transplantation for sarcoidosis between October 1987 and December 2007. We assessed the potential prognostic value of multiple demographic and clinical variables, and we also compared these patients to a case-matched group of patients with primary sclerosing cholangitis (PSC) or primary biliary cirrhosis (PBC). The 1- and 5-year survival rates for the sarcoidosis group were 78% and 61%, respectively, and these rates were significantly worse than the rates for the PSC/PBC group (P = 0.001). Disease recurrence in the liver is a rare cause of graft loss or patient death. Three deaths occurred in the sarcoidosis group because of recurrent hepatic sarcoidosis, and 1 death was a result of cardiac sarcoidosis. A univariate analysis identified an increasing donor risk index as a significant negative factor for outcomes for the sarcoidosis group [hazard ratio (HR) = 2.06, confidence interval (CI) = 1.04-4.06, P = 0.037], but this finding was not found in a multivariate analysis, in which no independent predictors were found to have a significant impact. A case-matched univariate analysis demonstrated that sarcoidosis and morbid obesity were significant negative factors for outcomes, and in a multivariate analysis, sarcoidosis continued to predict worse outcomes (HR = 2.39, CI = 1.21-4.73, P = 0.012). In conclusion, an analysis of the UNOS/OPTN database indicates that the patient and allograft survival rates for hepatic sarcoidosis are satisfactory, but they are worse in comparison with the rates for other cholestatic liver diseases.

Progressive familial intrahepatic cholestasis: a single-center experience of living-donor liver transplantation during two decades in Japan.

BACKGROUND: Progressive familial intrahepatic cholestasis (PFIC) results in liver cirrhosis. Therefore, some PFIC patients require liver transplantation (LT). Although three types of PFIC have been identified, their etiologies include unknown mechanisms. PATIENTS: A total of 717 recipients who underwent living-donor LT (LDLT) at <20 yr old were enrolled in this study. Among these recipients, 14 PFIC recipients comprising 11 PFIC type 1 (PFIC1) and three PFIC type 2 (PFIC2) were evaluated. RESULTS: Three of 11 PFIC1 recipients died, while all three PFIC2 recipients survived. Eight of 11 PFIC1 recipients showed steatosis after LDLT. Among the eight steatosis-positive PFIC1 recipients, seven showed severe steatosis and seven were complicated with steatohepatitis. Nine of 11 PFIC1 recipients showed fibrosis after LDLT, and eight of the nine fibrosis-positive PFIC1 recipients showed severe fibrosis. In contrast to the PFIC1 recipients, the PFIC2 recipients did not show any steatosis or fibrosis after LDLT. CONCLUSIONS: The clinical courses and outcomes of PFIC1 recipients after LDLT are still not sufficient owing to steatosis/fibrosis, unlike the case for PFIC2 recipients. As PFIC1 patients will require LT during the long-term progression of the disease, further strategy improvements are required for PFIC1 patients.

Comparison of outcomes among secondary covered metallic, uncovered metallic, and plastic biliary stents in treating occluded primary metallic stents in malignant distal biliary obstruction.

BACKGROUND: The self-expandable metallic stent (SEMS) has been widely used for unresectable malignant biliary obstruction but eventually becomes occluded by tumor ingrowth/overgrowth and sludge. Therefore, we aimed to determine the therapeutic effectiveness of secondary stents and to find differences according to various combinations of the first and second stents for the management of occluded SEMSs in patients with malignant distal biliary obstruction. METHODS: Between 1999 and November 2008, 77 patients with malignant biliary obstruction underwent secondary biliary stent placement as "stent-in-stent" at three university hospitals in Korea (40 covered, 26 uncovered, and 11 plastic stents). The membrane of the covered SEMS was regarded as the barrier against tumor ingrowth. We categorized the patients into three groups based on whether the covered SEMS was either the first or the second stent: membrane-SEMS (18 covered-covered; 9 covered-uncovered; 22 uncovered-covered SEMS), bare-SEMS (17 uncovered-uncovered SEMS), and plastic stent (3 covered-plastic; 8 uncovered-plastic). RESULTS: The median patency of second stents was 138, 109, and 88 days (covered, uncovered, and plastic stents). The second covered SEMSs had a significantly longer patency than plastic stents (p=0.047). In a multivariate analysis including membrane-SEMS, bare-SEMS, and plastic stent groups, the bare-SEMS had a worse cumulative stent patency (HR=2.04, CI=1.08-3.86) and survival time (HR=2.37, CI=1.25-4.49) than the membrane-SEMS. Patients with ampulla of Vater cancer had better stent patency (HR=0.27, CI=0.08-0.98) and survival (HR=0.17, CI=0.04-0.77) than those with other pancreatobiliary malignancies. In addition, antitumor treatment prolonged survival time (HR=0.50, CI=0.26-0.99). CONCLUSIONS: The placement of additional biliary stents using the "stent-in-stent" method is an effective treatment for an occluded metallic primary stent. In addition, double biliary SEMS placement using at least one covered SEMS (in the primary and/or secondary procedure) might provide longer cumulative stent patency and survival than using uncovered SEMSs in both procedures.

Newly designed large cell Niti-S stent for malignant hilar biliary obstruction: a pilot study.

BACKGROUND: Whether uni- or bilateral drainage should be performed for malignant hilar biliary obstruction remains a matter of debate. Moreover, endoscopic placement of bilateral metallic stents has been considered difficult and complicated. Although the Y-stent with a central wide-open mesh facilitates bilateral stent placement, it has limitations. This study evaluated the feasibility and efficacy of the Niti-S large cell D-type biliary stent (LCD) with a uniform large cell for both uni- and bilateral drainage of malignant hilar biliary obstruction. METHODS: From April 2008 to March 2009, a total of 12 consecutive patients with unresectable malignant hilar biliary obstruction of Bismuth type 2 or greater underwent placement of LCD. Before LCD placement, all the patients underwent endoscopic unilateral biliary drainage using a plastic stent or a nasobiliary drainage tube. If jaundice improved after the procedure, the plastic stent or nasobiliary drainage tube was replaced with the unilateral LCD. If jaundice did not resolve or contralateral cholangitis occurred, bilateral LCD placement was performed. RESULTS: Seven patients had unilateral and five patients had bilateral LCD placement. Technical success was achieved for all 12 patients. An early complication occurred for one patient (8%), and stent occlusion occurred for six patients (50%) because of tumor ingrowth (n=4) or sludge (n=2). These patients were managed by insertion of plastic stents (n=4) or percutaneous transhepatic biliary drainage (n=2). The median stent patency period was 202 days. CONCLUSIONS: The newly designed endoscopic metallic stent may be feasible and effective for malignant hilar biliary obstruction, and endoscopic reintervention is relatively simple.