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Aim: To compare the histologic features of the liver in intrahepatic neonatal cholestasis (IHNC) with infectious, genetic-endocrine-metabolic, and idiopathic etiologies., Methods: Liver biopsies from 86 infants with IHNC were evaluated. The inclusion criteria consisted of jaundice beginning at 3 mo of age and a hepatic biopsy during the 1st year of life. The following histologic features were evaluated: cholestasis, eosinophilia, giant cells, erythropoiesis, siderosis, portal fibrosis, and the presence of a septum., Results: Based on the diagnosis, patients were classified into three groups: group 1 (infectious; n=18), group 2 (genetic-endocrine-metabolic; n=18), and group 3 (idiopathic; n=50). There were no significant differences with respect to the following variables: cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and presence of a septum. A significant difference was observed with respect to erythropoiesis, which was more severe in group 1 (Fisher's exact test, P=0.016)., Conclusion: A significant difference was observed in IHNC of infectious etiology, in which erythropoiesis was more severe than that in genetic-endocrine-metabolic and idiopathic etiologies, whereas there were no significant differences among cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and the presence of a septum.

In this article was evaluated correlation between violations of copper exchange and the severity cholestasis at 162 of the patients with chronic liver diseases. There was high correlation between the level of AF and copper content in the blood. Also it was shown that patients with cholestasis significantly more frequently have observed hypercopperemy.

Background: The major beneficial effect of statins- reducing the risk for coronary events-has primarily been ascribed to reductions in low-density lipoprotein cholesterol (LDL-C) but may in part be related to a direct antiinflammatory action (ie, decreased high-sensitivity C-reactive protein [hs-CRP] concentration)., Objectives: The objectives of this CAP (Comparative Atorvastatin Pleiotropic Effects) study were to compare the effects of low- versus high-dose atorvastatin on hs-CRP concentrations and to determine the relationship between changes in LDL-C and hs-CRP concentrations in patients with coronary artery disease (CAD), low-grade inflammation, and normal lipoprotein concentrations., Methods: This multicenter, prospective, randomized, double-blind, double-dummy study was conducted at 65 centers across Canada and Europe. Patients with documented CAD, low-grade inflammation (hs-CRP concentration, 1.5-15.0 mg/L), and a normal-range lipid profile (LDL-C concentration, 1.29-3.87 mmol/L [50-150 mg/dL]; triglyceride [TG] concentration, <4.56 mmol/L [<400 mg/dL]) were randomly assigned to receive 26-week double-blind treatment with atorvastatin 10 or 80 mg QD. Investigators were to aim for the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C target of <2.59 mmol/L (<100 mg/dL). The primary end point was the percentage change from baseline in hs-CRP, as measured at baseline and weeks 5, 13, and 26 using high-sensitivity, latex microparticle-enhanced immunoturbidimetric assay. Changes from baseline in LDL-C, as measured directly in serum at the same time points, were also calculated. The secondary efficacy variables included the percentage changes from baseline in lipid parameters (LDL-C, high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], TG, apolipoprotein B, non-HDL-C, and TC:HDL-C ratio) at 5, 13, and 26 weeks of treatment. Tolerability was assessed using physical examination, including vital sign measurement, and laboratory analyses., Results: A total of 339 patients were enrolled (283 men, 56 women; mean age, 62.5 years; weight, 81.3 kg; 10-mg/d group, 170 patients; 80-mg/d group, 169). No significant differences in baseline demographic or clinical data were found between the 2 treatment arms. In the 10-mg group, hs-CRP was decreased by 25.0% at 5 weeks and remained stable thereafter (%Delta at week 26, -24.3%; P < 0.01). In the 80-mg group, hs-CRP was decreased by 36.4% at 5 weeks and continued to be decreased over the study period (%Delta, -57.1% at week 26; P < 0.001 vs baseline). At 5 weeks, LDL-C was decreased by 35.9% in the 10-mg group and by 52.7% in the 80-mg group (P < 0.001 between groups) and remained stable thereafter (%Delta at week 26, -34.8% and -51.3%, respectively; P < 0.001 between groups). The NCEP ATP III LDL-C target of <2.59 mmol/L (<100 mg/dL) was reached in 77.1% of patients treated with atorvastatin 10 mg and 92.3% of those treated with 80 mg (P < 0.001). Dual targets of hs-CRP <2 mg/L and LDL-C <1.81 mmol/L (<70 mg/dL) were reached in a significantly greater proportion of patients in the 80-mg group compared with the 10-mg group (55.6% vs 13.5%; P < 0.001). The decrease in hs-CRP was largely independent of baseline LDL-C and change in LDL-C. Two serious adverse events were reported by the investigator as treatment related: acute hepatitis in the 10-mg group and intrahepatic cholestasis in the 80-mg group, in 2 patients with multiple comorbidities. Two deaths occurred during the study, both in the atorvastatin 80-mg group (1, myocardial infarction; 1, sudden death), neither of which was deemed treatment related by the investigator., Conclusions: In these patients with documented CAD, evidence of low-grade inflammation, and normal range lipid profiles, the effects of atorvastatin on changes in hs-CRP were dose dependent, with the high dose (80 mg) being associated with significantly greater reductions in hs-CRP concentrations. Both doses were associated with a significant and progressive decline in hs-CRP largely independent of changes in LDL-C, HDL-C, and TG. Clinical Trials Identification Number: NCT00163202.

Background: Benign biliary strictures treated radiologically by percutaneous dilatation treatment are usually evaluated by 'clinical test'. For objective evaluation of treatment success, measurement of the pressure inside the biliary tree has been proposed., Aim: The aim of this article is to report our experience with the measurement of the pressure in the biliary tree after treatment, to present the biliary manometric perfusion test (BMPT) as an alternative method of treatment evaluation and to demonstrate why the perfusion test is a better method of evaluation., Materials and Methods: A 65 year old lady with post operative biliary stricture and symptoms of jaundice was treated in our Department with percutaneous dilatation treatment and long-term drainage. The perfusion test (BMPT) was adopted for evaluating treatment success after the treatment for 9 months. An intrabiliary pressure less than 20 cms of water during perfusion test was considered success threshold., Results: The test was carried out without any complications and the pressure inside the biliary tree was less than 20 cms of water during the test. Eventually the drain was removed. On follow-up at 6 months the patient developed no recurrence of jaundice and the quality of life improved clinically. Periodic liver function tests during follow-up were normal., Conclusion: The perfusion test (BMPT) is promising efficacious alternative method for the evaluation of radiological treatment of benign biliary strictures. It helps us to decide the end points in treatment and also helps in identifying patients who might later develop strictures.

Background/purpose: The major side effect of total parenteral nutrition is liver injury leading to liver failure. This study was designed to assess specific growth factors in modulating the hepatic response in an ANIT-induced liver-injury model., Methods: Sprague-Dawley rats were divided into four groups: control (n = 5), liver-injury control (alpha-naphthylisothiocyanate [ANIT], 100 mg/kg, n = 8), ANIT + epidermal growth factor (EGF, 150 mug/kg per day, n = 10), and ANIT + hepatocyte growth factor (HGF, 250 mug/kg per day, n = 9). Rats were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic mini-pump for 7 days of continuous intravenous saline (liver injury control), EGF, or HGF. Seven and 14 days later, liver biopsies were obtained and evaluated for interleukin (IL)-6 and tumor necrosis factor alpha expression by immunofluorescent staining, and for apoptosis, by the terminal transferase dUTP nick end labeling (TUNEL) technique. All animals were euthanized at 14 days., Results: Epidermal growth factor (P < .025) and HGF (P < .001) groups induced less IL-6 expression at day 14 compared to liver-injury controls. In addition, the interval decrease in IL-6 expression between days 7 and 14 was greater in EGF (P < .001) and HGF (P < .001) groups compared to liver-injury controls. At day 14, HGF also demonstrated decreased tumor necrosis factor alpha expression (P < .005). Apoptotic activity was significantly less for the EGF (P < .011) and HGF (P < .0012) groups., Conclusion: Epidermal growth factor and HGF modulated the hepatic inflammatory response and apoptotic index in this established liver-injury model and may diminish or prevent liver damage in patients with total parenteral nutrition-induced liver injury.

Objective: To investigate the role of CD(4)(+)CD(25)(+) regulatory T cells and CD(4)(+)CD(25)(high) regulatory T cells in peripheral blood and decidua in the pathogenesis of intrahepatic cholestasis of pregnancy (ICP)., Methods: Peripheral blood and decidua CD(4)(+)CD(25)(+) regulatory T cells and CD(4)(+)CD(25)(high) regulatory T cells in 30 ICP patients (15 mild ICP and 15 severe ICP) and 28 normal pregnant women were analyzed by flow cytometry., Results: The percentage of CD(4)(+)CD(25)(+) regulatory T cells and CD(4)(+)CD(25)(high) regulatory T cells in the CD(4)(+) T cells population in both peripheral blood and decidua in ICP patients were significantly lower than those in control women [(7.96 +/- 1.32)% vs (17.05 +/- 2.86)%, (17.18 +/- 2.27)% vs (32.01 +/- 3.88)%; (0.78 +/- 0.22)% vs (1.71 +/- 0.69)%, (2.25 +/- 0.89)% vs (8.30 +/- 1.13)%; P < 0.01]. Meanwhile, a significantly higher percentage of CD(4)(+)CD(25)(+) regulatory T cells and CD(4)(+)CD(25)(high) regulatory T cells in the CD(4)(+) T cells population was observed in all decidua samples compared to peripheral blood both in ICP patients (P < 0.01) and in control women (P < 0.01). In addition, the percentages of CD(4)(+)CD(25)(+) regulatory T cells and CD(4)(+)CD(25)(high) regulatory T cells in the CD(4)(+) T cell population in both decidua and peripheral blood in severe ICP [(15.94 +/- 1.95)%, (7.17 +/- 1.17)%, (1.87 +/- 0.90)%, (0.68 +/- 0.19)%] were lower than those in mild ICP [(18.43 +/- 1.90)%, (8.74 +/- 0.96)%, (2.62 +/- 0.72)%, (0.89 +/- 0.20)%] and normal pregnancy (all P < 0.05)., Conclusions: CD(4)(+)CD(25)(high) regulatory T cell may play an important role in the pathogenesis of ICP and control of disease progression.

Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICP.

Background: Cystinosis is a metabolic disease characterized by accumulation of cystine in different organs and tissues, leading to potentially life-threatening organ dysfunction. Infantile cystinosis typically leads to end-stage renal disease, necessitating renal replacement therapy. Liver disease in cystinosis is rare and is mostly reported as nodular regenerative hyperplasia leading to portal hypertension., Methods: Two patients with infantile cystinosis developed cholestatic liver disease (increasing alkaline phosphatases, gamma-glutamyltransferase and mild increase in transaminases). Severe accumulation of cystine was demonstrated on liver biopsy, predominantly localized in Kupffer cells, together with morphological signs of sclerosing cholangitis on liver biopsy. One patient showed changes compatible with sclerosing cholangitis on magnetic resonance imaging. Therapy with ursodeoxycholic acid led to biochemical improvement in one and stabilization in the other patient., Conclusion: Long-term infantile nephropathic cystinosis can be associated with a form of sclerosing cholangitis, which can respond to therapy with ursodeoxycholic acid.

Background: Endoscopic access to the biliary system can be difficult in patients with surgically altered anatomy, such as a Roux-en-Y reconstruction. Double balloon enteroscopy (DBE) is a relatively new procedure that enables access to the small bowel. DBE has recently been advocated as a method for endoscopic retrograde cholangiopancreaticography (ERCP) in patients with surgical reconstructions, with the potential to perform diagnostic and therapeutic interventions., Methods: In three patients with a hepaticojejunostomy and Roux-en-Y reconstruction, the experiences using DBE to perform ERCP are described. The literature on DB-ERCP in patients with a Roux-en-Y reconstruction was reviewed., Results: In all patients, the Roux limb was entered and a diagnostic cholangiography was carried out. In one patient, endoscopic therapy could be performed, consisting of balloon dilation of a stenotic biliodigestive anastomosis, repeated balloon dilation of biliary strictures and removal of bile casts., Conclusion: This series confirms recent data emerging from the literature that double balloon enteroscopy is a safe and feasible technique to obtain biliary access in patients with surgically altered anatomical configurations, such as those with a Roux-en-Y reconstruction. The diagnostic and therapeutic potential of DB-ERCP is great, and the utility of the procedure could be further improved if customised accessories become more widely available.

Background: Intrahepatic bile duct strictures are a serious complication after non-heart-beating (NHB) liver transplantation. Bile salt toxicity has been identified as an important factor in the pathogenesis of bile duct injury and cholangiopathies. The role of bile salt toxicity in the development of biliary strictures after NHB liver transplantation is unclear., Methods: In a porcine model of NHB liver transplantation, we studied the effect of different periods of warm ischemia in the donor on bile composition and subsequent bile duct injury after transplantation. After induction of cardiac arrest in the donor, liver procurement was delayed for 0 min (group A), 15 min (group B), or more or equal to 30 min (group C). Livers were subsequently transplanted after 4 hr of cold preservation. In the recipients, bile flow was measured, and bile samples were collected daily to determine the bile salt-to-phospholipid ratio. Severity of bile duct injury was semiquantified by using a histologic grading scale., Results: Posttransplantation survival was directly related to the duration of warm ischemia in the donor. The bile salt-to-phospholipid ratio in bile produced early after transplantation was significantly higher in group C, compared with group A and B. Histopathologic condition showed the highest degree of bile duct injury in group C., Conclusion: Prolonged warm ischemia in NHB donors is associated with the formation of toxic bile after transplantation, with a high biliary bile salt-to-phospholipid ratio. These data suggest that bile salt toxicity contributes to the pathogenesis of bile duct injury after NHB liver transplantation.

Objective: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD, OMIM #605814) is a novel autosomal recessive disease caused by mutations in the gene SLC25A13 that encodes for citrin, a liver-type aspartate/glutamate carrier located in the mitochondrial inner membrane. SLC25A13 was cloned in 1999 by Kobayashi et al at Kagoshima University in Japan, and until now, most of the NICCD patients reported in the world were Japanese. Most of the Chinese NICCD patients diagnosed by genetic analysis had the same SLC25A13 mutations as Japanese, however, in some cases, known mutations were not detected. This research aimed to identify novel SLC25A13 mutations in Chinese NICCD patients and to explore the experimental conditions for their genetic diagnosis., Methods: Genomic DNA was extracted from blood samples of 3 NICCD patients from Taiwan (P757), Guangdong (P1194) and Hebei province (P1443) of China, respectively, and all the 18 exons and their flanking sequences of SLC25A13 gene were sequenced. Furthermore, the identified novel mutations were diagnosed by amplification with PCR, digestion with corresponding restriction endonuclease, and agarose gel electrophoresis., Results: Three novel mutations identified in SLC25A13 gene of the 3 NICCD patients were an abnormal splicing IVS7-2A > G (P757), a missense A541D (c.1622C > A, P1194) and a nonsense R319X (c.955C > T, P1443). The PCR-restriction fragment length polymorphism (RFLP) procedures for their genetic diagnosis were also established, with specific fragments on electrophoresis after digestion of the PCR products with three different restriction endonucleases Msp I, Hpy188I and Taq I, respectively., Conclusions: So far as we know, the three novel mutations in SLC25A13 gene of Chinese NICCD patients were first identified, suggesting that SLC25A13 mutation distributed in Chinese population is somewhat different from that in Japanese. Moreover, the PCR-RFLP diagnostic procedures established in this research provide valuable tools not only for the genetic diagnosis of NICCD but also for further molecular epidemiologic investigations in Chinese population.

Citrin is the liver-type aspartate-glutamate carrier that resides within the inner mitochondrial membrane. Citrin deficiency (due to homozygous or compound heterozygous mutations in the gene SLC25A13) causes both adult-onset type II citrullinaemia (CTLN2) and neonatal intrahepatic cholestasis (NICCD). Clinically, CTLN2 is characterized by hyperammonaemia and citrullinaemia, whereas NICCD has a much more varied and transient presentation that can include multiple aminoacidaemias, hypoproteinaemia, galactosaemia, hypoglycaemia, and jaundice. Personal histories from CTLN2 patients have repeatedly described an aversion to carbohydrate-rich foods, and clinical observations of dietary and therapeutic outcomes have suggested that their unusual food preferences may be directly related to their pathophysiology. In the present study, we monitored the food intake of 18 Japanese citrin-deficient subjects whose ages ranged from 1 to 33 years, comparing them against published values for the general Japanese population. Our survey confirmed a marked decrease in carbohydrate intake, which accounts for a smaller proportion of carbohydrates contributing to the total energy intake (PFC ratio) as well as a shift towards a lower centile distribution for carbohydrate intake relative to age- and sex-matched controls. These results strongly support an avoidance of carbohydrate-rich foods by citrin-deficient patients that may lead to worsening of symptoms.

We describe a case of extreme hypercholesterolemia, mediated by lipoprotein X, in a 12-year-old Caucasian female who underwent an unrelated allogenic bone marrow transplant for relapsed acute myelocytic leukemia (AML). Her post-transplant course was complicated by severe chronic graft-versus-host disease (GVHD) of the liver. Previously normal serum cholesterol and triglycerides rose to 1,122 mg/dl (29.0 mmol/L) and 1,100 mg/dl (12.4 mmol/L), respectively. Serum cholesterol appeared to be dominantly carried by lipoprotein X. Intra-hepatic cholestasis leading to reflux of bile lipoproteins into the blood stream and subsequent formation of lipoprotein X appears to be the mechanism underlying this phenomenon., ((c) 2007 Wiley-Liss, Inc.)

Hypothesis: Primary intrahepatic lithiasis occurs frequently in East Asia but is rare in Western countries. Biliary pain and episodes of cholangitis are the most common presenting symptoms, whereas intrahepatic cholangiocarcinoma represents a long-term unfavorable complication of the disease. When a single liver lobe or segment is involved, partial hepatectomy may be regarded today as an effective method of treatment., Design: Retrospective study., Setting: Hepatobiliary unit in a tertiary care hospital., Patients: The clinical records of 35 patients treated for primary intrahepatic lithiasis between January 1, 1992, and December 31, 2005, were reviewed and clinical data, cholangiograms, operative procedures, and early and late results were examined., Interventions: Thirty-four patients underwent liver resection; left hepatectomy (18 patients) and left lateral segmentectomy (10 patients) were the most frequently performed procedures. A cholangiocarcinoma was found in 3 patients (8.6%): 2 underwent liver resection and 1, who was found unresectable at surgery, underwent only explorative laparotomy., Main Outcome Measures: Survival, quality of life, laboratory data, and need for further treatments., Results: There was no postoperative mortality. Morbidity was 20.0% with a prevalence of infectious complications related to bile leakage. Long-term results, assessed in 26 patients with follow-up longer than 12 months (range, 12-170 months; mean, 63 months), were good or fair in 24 patients (92.3%), including 3 patients who needed subsequent endoscopic removal of biliary stones., Conclusions: Primary intrahepatic lithiasis more commonly involves 1 single liver segment or lobe. Partial hepatectomy is a safe and effective procedure, allowing definitive treatment of the disease and prevention of cancer.

To investigate how the liver adapts to chronic obstructive cholestasis, liver samples from infants with early- and late-stage cholestasis were analyzed for changes in the levels of hepatocyte transporters and nuclear receptors. At early-stage cholestasis, most canalicular transporters and sinusoidal uptake transporters were downregulated, including bile salt export pump (BSEP, ABCB11), multidrug resistant protein 3 (MDR3, ABCB4), multidrug-resistant associated protein 2 (MRP2, ABCC2), sodium-dependent taurocholate cotransporting polypeptide (NTCP, SLC10A1), organic anion transporter (OATP, SLCO1A2), and nuclear receptor farnesoid X receptor (FXR, NR1H4). At late-stage cholestasis, FXR-BSEP levels returned to normal, MDR3 and MDR1 (ABCB1) were upregulated, and MRP-2 was downregulated. In addition, alternative sinusoidal efflux transporters, organic solute transporter alpha/beta (OSTalpha/beta) and MRP4 were upregulated, and pregnane X receptor (PXR, NR1I2) levels decreased. Cytochrome enzyme P450 7A1 was markedly downregulated at both early and late-stage cholestasis. An analysis of the long-term prognosis of 18 patients revealed lower PXR and constitutive androstane receptor (CAR, NR1I3) levels in the poor prognosis group. In conclusion, at long-term cholestasis, hepatocyte bile efflux was through sinusoidal and canalicular transporters, with FXR-BSEP levels maintained and PXR downregulated. Low PXR and CAR levels were associated with poor prognosis.

Objective: To study the role of gene polymorphisms of cytochrome P4501B1 (CYP1B1) in exon 2 codon 119(G-T) and exon 3 codon 432(C-G) in intrahepatic cholestasis of pregnancy (ICP)., Methods: Gene polymorphisms of CYP1B1 in exon 2 codon 119 and exon 3 codon 432 were detected with Allele-specific polymerase chain reaction (ASA-PCR) and di-allele-specific-amplification with artificially modified primer (diASA-AMP) techniques in a case-control study, which included 100 ICP patients and 100 healthy pregnant women as controls., Results: (1) The ICP patients had higher frequency of allele T on codon 119 of CYP1B1 gene than the controls (P < 0.05). Significant differences of frequencies were found in genotype GG, GT and TT between the ICP patients and the controls (P > 0.05). Compared to the wide-type GG, the ICP risks of the women with genotype TT homozygous and GT heterozygous increased by 3.6 and 2.435 times, respectively. (2) No genotype GG was found in this study. There were no significant differences between the ICP patients and the controls in the genotype distributions (CC and CG) and allele frequencies (C and G) of CYP1B1 polymorphism in exon 3 codon 432 (P > 0.05)., Conclusion: Gene polymorphism of CYP1B1 in exon 2 codon 119 may be associated with the risk of ICP. The mutation of CYP1B1 gene increases the risk of ICP. The gene polymorphism of CYP1B1 in exon 3 codon 432 is not associated with the risk of ICP.

Background: Bile duct injury after hepatic artery thrombosis (HAT) in liver transplantation is believed to be caused by ischemia predominantly. We aimed to define the involvement of bile secretory dysfunction in the pathogenesis of liver injury after HAT., Methods: In a murine model, the main hepatic artery, the extrahepatic peribiliary plexus, or both arterial connections to the liver were interrupted (n=5 for each group). After 1, 14, or 28 days, hepatobiliary function was assessed by analysis of bile transporter expression, serum bile acids and bilirubin, and hepatic ATP content. In addition, cellular injury was assessed by light microscopy and biochemical markers., Results: There were no signs of hepatobiliary dysfunction or injury in sham-operated animals or in mice with interruption of the hepatic artery or the extrahepatic peribiliary plexus alone. However, as early as 24 hr after complete dearterialization, bile transporter expression was significantly reduced and intrahepatic cholestasis started to progress the following weeks. Histologic studies at 28 days after complete dearterialization showed severe hepatobiliary injury., Conclusions: This study indicates that arterial blood supply is critical for normal bile secretion. Bile duct injury after complete arterial deprivation is preceded by a loss of bile secretory function and subsequent intrahepatic cholestasis.

Sickle cell hepatopathy is a well-documented entity that ranges from the self-limiting hepatic right upper quadrant syndrome to the potentially lethal intrahepatic cholestasis and acute hepatic sequestration syndromes. We describe a 26-year-male with homozygous sickle cell disease who had this unique hepatic presentation and was documented to have characteristic findings of cholestasis, portal inflammation and sinusoidal dilatation on histopathology.

Unlabelled: Intrahepatic cholangiocarcinoma typically presents in an advanced stage in which treatment options are limited. In an effort to recapitulate key biological and clinical features of the progressive disease, we established a novel rat model based on bile duct inoculation of rat cholangiocyte cell lines in different stages of tumor progression. Our BDEneu cell line, which is highly tumorigenic, originated from an immortalized rat cholangiocyte cell line (BDE1 cells) that was stably transfected to constitutively overexpress mutationally activated rat neu oncogene. Our less aggressive tumorigenic BDEsp cholangiocyte cell line was derived from the spontaneous in vitro neoplastic transformation of the same parent BDE1 cell line. Unlike BDEneu cells, BDEsp cells expressed wild-type c-neu and exhibited in vitro growth rates intermediate between those of BDEneu and BDE1 cholangiocytes. Cyclooxygenase-2 and activated Akt were significantly overexpressed in BDEsp cells over those of BDE1 cells, and at higher levels than those expressed in BDEneu cells. Only BDEneu cells overexpressed activated p185(neu), which was associated with a significant increase in phospho-p44/42 mitogen-activated protein kinase (MAPK). Mucin 1 (MUC1) messenger RNA (mRNA), an indicator of cholangiocarcinoma cell progression, was also significantly overexpressed in BDEneu cells over that of BDEsp cells. BDEneu cells inoculated into the bile duct of isogenic rats resulted over a 21- to 26-day period in rapid exponential cholangiocarcinoma tumor growth within liver, paralleled by increases in bile duct obstruction and gross peritoneal metastases. Under comparable conditions, BDEsp cells yielded only small nonmetastatic intrahepatic cholangiocarcinomas without bile duct obstruction., Conclusions: A novel model of cholangiocarcinoma progression mimicking progressive development of the advanced human disease has been established, which may serve as a powerful preclinical platform to study cholangiocarcinoma progression and for rapidly testing treatment approaches.

Background: Intrahepatic neonatal cholestasis can be the initial manifestation of a very heterogeneous group of illnesses of different etiologies., Aim: To evaluate and compare clinical and laboratory data among intrahepatic neonatal cholestasis groups of infectious, genetic-endocrine-metabolic and idiopathic etiologies., Methods: The study evaluated retrospectively clinical and laboratory data of 101 infants, from March 1982 to December 2005, 84 from the State University of Campinas Teaching Hospital, Campinas, SP, Brazil, and 17 from the Child's Institute of the University of São Paulo, SP, Brazil. The inclusion criteria consisted of: jaundice beginning at up to 3 months of age and hepatic biopsy during the 1st year of life. It had been evaluated: clinical findings (gender, age, birth weight, weight during the first medical visit, stature at birth, jaundice, acholia/hipocholia, choluria, hepatomegaly and splenomegaly) and laboratorial (ALT, AST, FA, GGT, INR)., Results: According to diagnosis, patients were classified into three groups: group 1 (infectious) n = 24, group 2 (genetic-endocrine-metabolic) n = 21 and group 3 (idiopathic) n = 56. There were no significant differences in relation to the variables: age, gender, stature at birth, jaundice, acholia/hipocholia, choluria, hepatomegaly, splenomegaly, AST, ALT, ALP, GGT, DB and albumin. Significant differences were observed in relation to the following variables: birth weight and weight during the first medical visit. Birth weight of group 1 was lower in relation group 2 and 3. Weight during the first medical visit followed the same pattern. There was a statistically significant difference in relation to the INR, as the patients of the group 2 presented higher values in relation to groups 2 and 3, despite the median was still pointing out normal values., Conclusions: There were no significant differences in relation to age, gender, stature at birth, jaundice, acholia/hipocholia, choluria, hepatomegaly, splenomegaly, AST, ALT, ALP, GGT, BD and albumin. Birth weight and the weight during the first medical visit were lower in the group with infectious etiology. In addition, a significant difference in INR reflected impaired coagulation of patients of the group of the genetic-endocrine-metabolic disease.

Objective: To determine maternal outcome as antenatal and postnatal complications and neonatal outcome as birth weight, morbidity and mortality in triplet gestation., Study Design: Observational study., Place and Duration of Study: Mother and Child Health (MCH) Centre, Pakistan Institute of Medical Sciences, Islamabad from May 2000 to April 2006., Patients and Methods: All the patients with triplet pregnancy beyond 28 weeks gestation, who delivered at the study place during above period were included in the study. The primary outcome measures were frequency of maternal complications and neonatal birth, weight and morbidity. Secondary outcome measures included the frequency of assisted conception in the studied cohort., Results: Eighteen women had triplet pregnancy beyond 28 weeks. Nine were booked, 6 non-booked and 3 of them were referred. Mean duration of gestation was 237.8 days (33.8 weeks). The antenatal complications were preterm delivery in 50%, hypertension in 50%, anemia in 44.4% and obstetric cholestasis in 5.6%. Eight patients (44.4%) suffered postpartum hemorrhage. One patient had peripartum hysterectomy and later expired in intensive care unit after three weeks. Maternal mortality ratio was 5.6%. Fifty five percent women had induction of ovulation with Clomiphene, while none had In Vitro Fertilization (IVF) or Intracytoplasmic Insemination (ICSI) or received gonadotrophins. Fifteen sets of triplets were delivered abdominally. Mean birth weights of 1st, 2nd and 3rd triplet were 1651, 1640 and 1443 grams respectively. Five sets of triplets (27.8%) had more than 25% discordance for birth weight. The mean Apgar scores of the babies at 1 and 10 minutes after birth were 6.0 and 8.0, 5.6 and 7.5; and 5.2 and 7.0 respectively. Of the 54 infants, 18 required Neonatal Intensive Care Unit (NICU) admission and 14 were admitted in nursery. Two died shortly after birth. Total perinatal mortalities were 13 including 4 cases of intra-uterine demise. Three babies suffered from jaundice, 7 had sepsis and 8 had respiratory distress syndrome., Conclusion: Triplet gestation had a high rate of fetomaternal complications. Majority had history of assisted conception.

We report the case of a 68-year-old African woman who presented with jaundice, hepatomegaly and anasarca. Clinical investigation disclosed severe intrahepatic cholestasis, nephrotic syndrome, erythrocytosis and hypoglycemia. Diagnosis of systemic AL amyloidosis was established by percutaneous liver biopsy. Bone marrow biopsy showed 32% of myeloma cells. The patient started treatment with melphalan and prednisolone, but liver function deteriorated and she died in hepatic failure complicated by septic shock three weeks after the diagnosis. We present possible explanations for the unusual clinical and laboratory findings, which required a multidisciplinary approach and posed challenging problems in differential diagnosis and management.

Biochemical cholestasis after liver transplantation is common and often has no clinical significance if biliary anastomosis strictures and leaks have been excluded. There is no agreed upon definition for severe cholestasis, but it is associated with a worse mortality. There has been little evaluation on risk factors, but these include cryoprecipitate and platelet transfusion intraoperatively, nonidentical blood group, suboptimal graft appearance, inpatient status before transplant, and bacteremia within the first month. Associated causes considered as early (<6 months) include ischemia-reperfusion injury, primary nonfunction, small-for-size graft syndrome, infection, drugs and acute cellular rejection. Late causes include hepatic artery thrombosis, chronic rejection, biliary complications, recurrent viral and cholestatic disease, and posttransplant lymphoproliferative disorder.

Perhaps no condition associated with chronic cholestasis is less understood than vanishing bile duct syndrome, a term that refers loosely to the group of acquired disorders associated with progressive destruction and disappearance of the intrahepatic bile ducts and, ultimately, cholestasis. Although the array of insults resulting in poor bile flow is vast, most adult patients who have chronic cholestasis have either primary biliary cirrhosis (or primary sclerosing cholangitis; in some cases, however, a cause cannot be identified. This article reviews the multiple causes, postulated pathophysiology, clinical features, and treatment options for this syndrome.

Liver involvement in Hodgkin's lymphoma is common and is caused by hepatic infiltration, biliary obstruction by lymphoma, hepatitis, sepsis or complications of chemotherapeutic treatment. Jaundice caused by the vanishing bile duct syndrome related to Hodgkin's lymphoma is very rare. The mechanism is poorly understood but a paraneoplastic effect seems most likely as liver biopsy samples show cholestasis in the absence of lymphoma cells. Despite adequate treatment almost all reported patients died of liver failure or disease progression. Disease progression is explained partly by the difficulties encountered in the administration of potential hepatotoxic chemotherapy in severely cholestatic patients. We describe a 17-year-old man with vanishing bile duct syndrome and Hodgkin's lymphoma who was treated successfully with chemotherapy. The markedly elevated serum bilirubin levels completely normalized. Our case demonstrates that although dosing of chemotherapy in this situation can be very difficult, a good clinical outcome is possible, which makes the attempt at curative treatment worthwhile.

Background: There are unresolved issues regarding the security of liver transplantation with non-heart-beating donors (NHBDs). Recently, an increased incidence of biliary complications, mainly intrahepatic ischemic-type biliary strictures, has been described after controlled NHBDs., Methods: We studied the incidence and risk factors for biliary complications among uncontrolled NHBDs recipients compared with a large population of HBD recipients., Results: Overall, 16.8% of patients in the HBD group and 41.7% of patients in the NHBD group suffered any type of biliary complication (P=0.66). However, the incidence of nonanastomotic biliary strictures was significantly greater in the NHBD group (P<0.001). Multivariate analysis showed that independent risk factors for nonanastomotic strictures were hepatic artery thrombosis (relative risk; 98.7) and receiving a liver from a NHBD (relative risk; 47.1)., Conclusions: If this type of donors is accepted as a source of liver organs, the high incidence of biliary complications should be considered and efforts should be made to decrease ischemic injury.

Background: Hodgkin lymphoma (HL)-related vanishing bile duct syndrome (VBDS) and idiopathic cholestasis (IC) are rare conditions that often lead to liver failure and death. The available literature consists primarily of case reports, resulting in little clarity as to the clinical course and ideal treatment for this disease., Material and Methods: We performed a literature search from which we identified all published cases of HL-related VBDS or IC, and created a database of detailed presentation, treatment, and outcome information for all patients. Patient and disease factors were analyzed for an association with overall survival and liver failure-free survival. A case presentation introduces this analysis., Results: Thirty-seven cases of HL-related VBDS/IC were identified. Median follow-up was 7 months; 1-year OS and liver failure-free survival (LFFS) are 43% and 41%, respectively. Sixty-five percent of the patients died while 30% were alive with normal or near-normal stable liver function and no evidence of recurrent HL at last evaluation. Of the 20 patients without residual HL following therapy, 12 (60%) achieved liver failure-free survival. On univariate analysis, factors significantly associated with improved liver failure-free survival were stage I/II HL (p=0.02), a complete response of HL (p=0.0002), and delivery of radiotherapy (pB0.0001). Two patients received chemotherapy without radiation and survived with recovery of liver function., Discussion: HL-related VBDS/IC is potentially reversible and not uniformly fatal, with 30% of presenting patients demonstrating good lymphoma and liver outcomes after definitive therapy for HL. As a complete response of HL provides the only possibility of recovering liver function, patients with this disease should proceed to definitive treatment of HL as soon as feasible.

Introduction: The wide use of infertility drugs and assisted reproduction has resulted in 4- to 5-fold increase in the incidence of triplet pregnancies, which carry an extremely high risk of maternal complications and adverse perinatal outcome. In Hungary, reduction of multifetal pregnancies is available for all pregnant women with multifetal gestation since 1998. The goal of the procedure is to ensure better outcome for surviving fetuses. Counseling of pregnant patients should include the maternal and fetal risks of triplet gestation without multifetal pregnancy reduction., Aim: To assess the risk of maternal complications, stillbirth, perinatal and neonatal mortality rates, and risk of neonatal morbidity in non-reduced triplets in a large case series, representing the Hungarian triplet population., Methods: The study population consisted of triplets delivered between July 1st, 1990 and June 30th, 2006, at the 1st Department of Obstetrics and Gynecology. All three fetuses had to be alive on the 18th-week ultrasound scan to be eligible., Results: Out of the 122 cases, 8 (6.6%) ended in midtrimester miscarriage, 114 (93.4%) ended in delivery. There were no maternal deaths. The most common antepartum maternal complications were pregnancy-induced hypertension (16.7%), gestational diabetes mellitus (18.4%), thrombocytopenia (20.2%), anemia (16.7%) and intrahepatic cholestasis (9.7%). Preterm labor requiring tocolysis occurred in 57.9%, preterm premature rupture of membranes in 32.5%. Prophylactic cerclage was performed in 15.8% of cases, and 69.3% of patients received steroid prophylaxis. The mean gestational age at delivery was 32.3 +/- 3.2 weeks. The rates of very early (<28 weeks) and early (<32 weeks) preterm deliveries were 8.8% and 42.1%, respectively. The mean 5-minute Apgar score was 9.2 +/- 0.8, and the mean birth weight at delivery was 1664 +/- 506 g. 38.0% of infants were very low birth weight (<1500 g). Stillbirth, crude perinatal mortality and corrected perinatal mortality rates were 23.4 per thousand, 64.3 per thousand and 27.4 per thousand, respectively. 11.7 per thousand of infants had some major congenital anomaly. 54.4% of infants required ventilation or oxygen therapy or both. The most common neonatal complication were respiratory distress (17.1%), transitory tachypnea (5.2%), sepsis or pneumonia (25.5%), intraventricular hemorrhage (4.3%) and jaundice (11.4%)., Conclusions: Both the maternal and neonatal risks should be considered when patients with triplets are counseled before the decision to continue the triplet gestation or to choose multifetal pregnancy reduction is made.

Citrin is a liver-type mitochondrial aspartate-glutamate carrier encoded by the SLC25A13 gene, and its deficiency causes adult-onset type II citrullinemia and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). Here, the authors investigated clinical findings in Korean infants with NICCD and performed mutation analysis on the SLC25A13 gene. Of 47 patients with neonatal cholestasis, three infants had multiple aminoacidemia (involving citrulline, methionine, and arginine) and galactosemia, and thus were diagnosed as having NICCD. Two of these three showed failure to thrive. The laboratory findings showed hypoproteinemia and hyperammonemia, and liver biopsies revealed micro-macrovesicular fatty liver and cholestasis. The three patients each harbored compound heterozygous 1,638-1,660 dup/ S225X mutation, compound heterozygous 851del4/S225X mutation, and heterozygous 1,638-1,660 dup mutation, respectively. With nutritional manipulation, liver functions were normalized and catch-up growth was achieved. NICCD should be considered in the differential diagnosis of cholestatic jaundice in Korean infants.

The Mirizzi's syndrome is an unusual complication of long-standing gallstone disease that occurs in 0.7% to 1.4% of all cholecystectomies performed. It was originally described as an obstruction of the proximal bile duct secondary to external compression by a large stone located in the Hartmann pouch or secondary to local inflammatory changes. In recent years, extension of Mirizzi's eponym has been used to define obstructive jaundice induced by different grades of compression and erosion of the bile duct wall by a stone, which can evolve to a complete cholecystocholedocal fistula, with compression and dilatation of the proximal bile duct by the stone. Herein we present a case of Mirizzi's syndrome type II with a gastric antrum erosion associated, in highlighting the essential of the pre-operative diagnosis by endoscopic retrograde cholangiography (ERC) or MR cholangiography, to avoid iatrogenic injuries of the bile ducts, because the syndrome has been cited as a trap in the surgery gallstones. This case is an example that the natural history of Mirizzi's syndrome cannot stop with the compression or the cholecysto-biliary fistula, but it may result in a complex fistula with the neighbouring digestive organs.

Systemic mastocytosis results in the accumulation of mast cells in various tissues. We report a rare case of systemic mastocytosis presenting with cholestatic liver disease. Our patient was a 60-year-old African-American woman who presented with diarrhea, weight loss, hepatosplenomegaly and cholestatic pattern of serum liver chemistry tests. Immunohistological stains with mast-cell tryptase and CD117 antibodies performed on the liver-biopsy tissue showed prominent mast cells. Subsequently, bone-marrow biopsy and small-bowel biopsies also showed mast-cell infiltration confirming the diagnosis of systemic mastocytosis. The patient underwent treatment with imatinib mesylate without response. Her disease transformed into acute myeloid leukemia and she ultimately died from sepsis. This case underscores the importance of including rare conditions like systemic mastocytosis in the differential diagnosis of cholestatic disorders.

Benign recurrent intrahepatic cholestasis is a rare hereditary disorder characterised by recurrent episodes ofcholestasis. We report the case of a young male patient with benign recurrent intrahepatic cholestasis who presented to us with recurrent cholestatic jaundice and pruritus with negative work up for all possible aetiologies and a liver biopsy consistent with intrahepatic cholestasis. He improved on treatment with ursodeoxycholic acid and ondansterone and is doing well on follow up.

Background: Subacute nonsuppurative cholangitis (cholangitis lenta) is an uncommon yet important histological finding in liver biopsies from pediatric liver transplant recipients. The histopathological features include proliferation of bile ductules at the edges of portal tracts, inspissated bile within dilated bile ductules, absence of acute inflammation within ducts or ductules, and normal structure of interlobular bile ducts., Objective: To describe the histopathology and clinical outcomes of pediatric liver transplant recipients with subacute nonsuppurative cholangitis., Materials and Methods: This is a retrospective analysis involving review of medical records and analysis of liver-biopsy specimens by a pathologist blinded to clinical diagnosis. We identified 9 pediatric patients meeting the criteria for nonsuppurative cholangitis. These patients were compared with a control group of patients with biliary obstruction., Results: Liver histopathology clearly distinguishes subacute nonsuppurative cholangitis from biliary obstruction and other causes of posttransplant cholestasis. Clinical biochemistry cannot reliably distinguish between the 2, although statistically significant differences existed in levels of serum total and direct bilirubin, alanine aminotransferase, and alkaline phosphatase. The rate of proven bacterial or fungal infection in the study group was 100% in contrast to a rate of 54.5% in the control group (P < .05). Graft and patient survival were similarly poor., Conclusions: : Finding subacute nonsuppurative cholangitis suggests the presence of severe local or systemic infection in liver-transplant recipients, and its recognition is important for clinical management.

Objective: Lipoprotein metabolism in FIC1 deficiency due to ATP8B1 mutations has never been studied sufficiently. This study was performed to investigate the detailed lipoprotein metabolism in benign recurrent intrahepatic cholestasis (BRIC) caused by FIC1 deficiency., Patients and Methods: Lipoprotein profile and major lipoprotein regulators such as lecithin:cholesterol acyltransferase (LCAT), hepatic triglyceride lipase (HTGL), lipoprotein lipase, and cholesteryl ester transfer protein in a Japanese patient with BRIC were serially examined during a bout of cholestasis. Liver expression of farnesoid X receptor (FXR), which suppresses high-density lipoprotein (HDL) generation, was also examined., Results: Hypercholesterolemia and lipoprotein X accumulation were never observed throughout this study. When the cholestasis was severe, triglyceride-rich low-density lipoprotein (LDL) accounted for most of the plasma lipoproteins whereas HDL was hardly detectable. Concurrently, activities of all regulators were decreased, together with decreases of the serum parameter for liver protein synthesis. In particular, suppressions of LCAT and HTGL activities were severe and greatly contributed to the appearance of triglyceride-rich LDL. As the cholestasis improved, this LDL gradually transformed into normal LDL with the recoveries of LCAT and HTGL activities. The activities of all regulators for the last 1 to 2 months were normal but HDL remained depleted. His liver showed low FXR expression compared with control livers., Conclusions: The present study showed an appearance of triglyceride-rich LDL due to suppressions of LCAT and HTGL activities and a depletion of HDL that is not able to be explained by lipoprotein regulators or FXR in our patient.

Background/aims: Cholangiocarcinoma represents a serious complication of primary sclerosing cholangitis. Ursodeoxycholic acid may possibly influence the incidence of cholangiocarcinoma in man. The aim of this study was to evaluate the incidence rate of cholangiocarcinoma in a large group of primary sclerosing cholangitis patients after long-time treatment with ursodeoxycholic acid., Patients and Methods: From May 1987 up to May 2005 a total of 150 patients with primary sclerosing cholangitis but without evidence of cholangiocarcinoma at entry were included in the study. All patients were treated with ursodeoxycholic acid and controls were performed in at least yearly intervals., Results: The median treatment time of the 150 patients was 6.4 years. Altogether five patients developed a cholangiocarcinoma during treatment yielding a rate of 3.3%. The patients developed 0.58 cholangiocarcinoma per 100 patient-years in years 0-2.5, 0.59 cholangiocarcinoma in years 2.5-8.5, and no cholangiocarcinoma thereafter up to 18 years after entry into the study. The Kaplan-Meier estimate of cholangiocarcinoma incidence during ursodeoxycholic acid treatment reached a plateau after 8.3 years., Summary and Conclusion: The annual incidence rate of cholangiocarcinoma in primary sclerosing cholangitis treated with ursodeoxycholic acid is lower than expected and decreases with time of treatment.

The strictures of bilitary tree may occur as a result of benign and malignant pathologies of liver and pancreas. The benign stricture of biliary tree are usually results of the surgery and if it is possible the endoscopic methods should be implemented in this group of patients. In case of the stricture of biliary tree in the course of the chronic pancreatitis a surgery should be chosen, because the widening and endoscopic stenting don't allow the long term removal of stricture. In course of cholangitis sclerosans endoscopic treatment is to ensure bile flow. The treatment of malignant stricture of biliary tree depends on the early diagnosis, placement and the extension of malignant lesion. Among the patients who are qualified to radical treatment, the surgical treatment should be applied. Palliative surgical treatment is usually used in laparotomy, when the non-removable tumor was diagnosed. In case of disqualification of the patient from surgical treatment in palliative treatment of malignant stricture of biliary tree, the method of choice is the endoscopic treatment and in case of failure from the pericotaneous drainage should be applied. The palliative endoscopic treatment usually is based on widening the stricture and putting into bilitary tree the plastic stent or more effective selfplacing metal ones, which are usually more effective, The achievement of long lasting medical effects after application of endoscopic methods relies on the cause leading to extrahepatic cholestasis and the extension of common bile structure. In most cases they do have character of urgent or palliative treatment. The study shows some of the treatment methods and the combination of different techniques, which may be used in case of bile flow obstruction because of the stricture of biliary tree. The final choice of treatment method is based on the clinical condition of a patient and the availability of the method and experience at using it.

We clarified the clinical features of NICCD (neonatal intrahepatic cholestasis caused by citrin deficiency) by retrospective review of symptoms, management and long-term outcome of 75 patients. The data were generated from questionnaires to paediatricians in charge of the patients. Thirty of the patients were referred to hospitals before 1 month of age because of positive results in newborn screening (hypergalactosaemia, hypermethioninaemia, and hyperphenylalaninaemia). The other 45, the screen-negative patients, were referred to hospitals with suspected neonatal hepatitis or biliary atresia because of jaundice or discoloured stool. Most of the screen-negative patients presented before 4 months of age, and 11 had failure to thrive. Laboratory data showed elevated serum bile acid concentrations, hypoproteinaemia, low levels of vitamin K-dependent coagulation factors and hypergalactosaemia. Hypoglycaemia was detected in 18 patients. Serum amino acid analyses showed significant elevation of citrulline and methionine concentrations. Most of the patients were given a lactose-free and/or medium-chain triglyceride-enriched formula and fat-soluble vitamins. Symptoms resolved in all but two of the patients by 12 months of age. The two patients with unresolved symptoms suffered from progressive liver failure and underwent liver transplantation before their first birthday. Another patient developed citrullinaemia type II (CTLN2) at age 16 years. It is important to recognize that NICCD is not always a benign condition.

We report five cases with unusual causes of intrahepatic cholestasis, including consumption of Teucrium polium (family Lamiaceae) in the form of tea, Stauffer's syndrome, treatment with tamoxifen citrate for breast cancer, infection with Coxiella Burnetii (acute Q fever), and infection with Brucella melitensis (acute brucellosis).

Adult-onset citrullinemia (CTLN2) is a rare hereditary metabolic disorder characterized by highly increased concentration of citrulline and ammonia in the plasma, which is ascribed to a deficiency of argininosuccinate synthetase (ASS), one of the urea cycle enzymes mainly located in the liver. Neurological manifestation in CTLN2 patients closely resemble those of hepatic encephalopathy and in the past, most patients usually followed rapidly deteriorating clinical courses and died of severe brain edema within a few years after onset. However, in 1995 the first CTLN2 patient who was successfully treated by living-related liver transplantation was reported and since then more than 30 patients had underwent this operation in our country, showing good outcomes. No primary defect had not been found within ASS gene locus, but the causative gene of this disorder is now identified as the "citrin gene", which might act as a aspartate/glutamate transporter in mitochondria. Different phenotypes are seen in the individuals with a citrin deficiency: neonatal intrahepatic cholestasis, juvenile-onset chronic pancreatitis and hepatocellular carcinoma without cirrhosis can precede the appearance of CTLN2. The precise pathogenesis of this disease that includes the relationship between the mutations of citrin gene and a deficiency of hepatic ASS activity remains unclear.

Background: Stauffer syndrome, a very rare paraneoplastic syndrome, refers to reversible intrahepatic cholestasis in the setting of an abdominal malignancy., Case: A 60-year-old female with a past medical history of uterine leiomyosarcoma status post radical hysterectomy, presented three months later with right upper quadrant abdominal pain. Laboratory evaluation revealed intrabdominal cholestasis and ultrasound of the abdomen showed an echogenic solid mass consistent with a metastatic leiomyosarcoma, and it was felt that her hyperbilirubinemia was due to Stauffer syndrome. However, three days later, blood culture grew gram negative bacilli, and CT scan of the abdomen revealed multiple mesenteric masses with air bubbles consistent with an abdominal abscess. The abscess was drained under CT-scan guidance and her cholestasis gradually came back to nearly normal., Conclusion: The case highlights the importance of considering infectious etiologies and Stauffer syndrome in the differential diagnosis of liver dysfunction in patients with intraabdominal malignancies.

Adult-onset citrullinemia (CTLN2) is a rare hereditary metabolic disorder characterized by highly increased concentration of citrulline and ammonia in the plasma, which is ascribed to a deficiency of argininosuccinate synthetase (ASS), one of the urea cycle enzymes mainly located in the liver. Neurological manifestation in CTLN2 patients closely resemble those of hepatic encephalopathy and in the past, most patients usually followed rapidly deteriorating clinical courses and died of severe brain edema within a few years after onset. However, in 1995 the first CTLN2 patient who was successfully treated by living-related liver transplantation was reported and since then more than 30 patients had underwent this operation in our country, showing good outcomes. No primary defect had not been found within ASS gene locus, but the causative gene of this disorder is now identified as the "citrin gene", which might act as a aspartate/glutamate transporter in mitochondria. Different phenotypes are seen in the individuals with a citrin deficiency: neonatal intrahepatic cholestasis, juvenile-onset chronic pancreatitis and hepatocellular carcinoma without cirrhosis can precede the appearance of CTLN2. The precise pathogenesis of this disease that includes the relationship between the mutations of citrin gene and a deficiency of hepatic ASS activity remains unclear.