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Amoxicillin-clavulanate is the most common drug involved in drug-induced liver injury and the single most frequently prescribed product leading to hospitalization for drug-induced liver disease in Spain. The liver damage most frequently associated with amoxicillin-clavulanate is cholestasic type. The latency period between first intake and onset of symptoms is 3-4 weeks on average. A 76-year-old man developed fever, pruritus, and jaundice 3 weeks after having completed treatment with amoxicillin-clavulanate. Liver function tests showed cholestasic hepatitis (up to 50.75 mg/dL of total serum bilirubin level). The ultrasound-guided liver biopsy revealed severe canalicular cholestasis and portal and lobular eosinophilic infiltrates. Prednisone and ursodeoxycholic acid therapy were then prescribed. The patient became symptom-free with normal liver function tests. Amoxicillin-clavulanate can cause hepatocellular, cholestasic, or mixed liver injury. The presence of eosinophilic infiltrates in the liver biopsy and the clinical signs of hypersensitivity in some of the cholestasic cases suggest a pathophysiological immunoallergic mechanism. For this reason, corticosteroid treatment should be considered for patients with severe cholestasic liver injury.

Introduction: Percutaneous stenting is established in the palliation of malignant biliary obstruction. We examined the indications, success rate, complications, and long-term postoperative course of patients undergoing this procedure., Methods: All patients undergoing percutaneous transhepatic cholangiography (PTC) and metal stenting over a 12-month period in a tertiary referral center were studied. Data regarding diagnosis, number and type of procedures, complications, and survival were collected from multidisciplinary case notes and general practitioner records., Results: There were 21 patients of median age 70 (mean, 71; range, 54-93), 56.5% (11) had pancreatic cancer and 33% (7) cholangiocarcinoma. The mean number of PTC procedures was 2.43 and mean length of stay in hospital 20.66 days (range, 3-99). Serum bilirubin fell post drainage from 397 to 226 (μmol/L; p < 0.001) on discharge, however, in 19% (4) there was no significant reduction. Complications included cholangitis (19%) and acute pancreatitis (10%). Mortality was high and 9 patients (43%) died within 30 days, of whom 2 died in the hospital (1 from ascending cholangitis and another from pneumonia). The median time between discharge and death was 25 days (mean, 59.1 days) and no patient was alive after 193 days., Conclusions: The prognosis following PTC stenting of malignant biliary obstruction is extremely poor despite adequate drainage. The procedure can lead to significant morbidity and a lengthy hospital stay. Patient selection is therefore of paramount importance and an expedient treatment protocol and early return home recommended.

Progressive familial intrahepatic cholestasis (PFIC) type 1, 2 and 3 are due to mutations in ATP8B1, ABCB11 and ABCB4, respectively. Each of these genes encodes a hepatocanalicular transporter, which is essential for the proper formation of bile. Mutations in ABCB4 can result in progressive cholestatic disease, while mutations in ATP8B1 and ABCB11 can result both in episodic cholestasis, referred to as benign recurrent intrahepatic cholestasis (BRIC) type 1 and 2, as well as in progressive cholestatic disease. This suggests a clinical continuum and these diseases are therefore preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. Similarly PFIC type 3 is designated as ABCB4 deficiency. Heterozygous mutations in each of these transporters can also be associated with intrahepatic cholestasis of pregnancy. This review summarizes the pathophysiology, clinical features and current as well as future therapeutic options for progressive familial- and benign recurrent intrahepatic cholestasis as well as intrahepatic cholestasis of pregnancy., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Cholestatic hepatitis is a life-threatening recurrent pattern of hepatitis C virus (HCV) in immunosuppressed patients, for which curative treatment has not yet been established. We report the successful treatment of cholestatic hepatitis in a 59-year-old man who had undergone right lobe living donor liver transplantation (LDLT) for liver cirrhosis (LC) caused by HCV. Following uneventful surgery and an uncomplicated posttransplant clinical course, there was an abrupt increase in total bilirubin in comparison to aminotransferase on postoperative day (POD) 60 (total bilirubin 16.2 mg/dl, alanine aminotransferase 100 U/l, HCV-RNA 390 kIU/ml). The histological findings of the liver tissue showed lymphocyte infiltration in the periportal zone and severe cholestasis. Considering the clinical course, cholestatic hepatitis was strongly suspected and pegylated interferon and ribavirin therapy was started immediately, resulting in not only a viral response, but minimal progression of fibrosis. This case serves to demonstrate that early diagnosis and timely initiation of optimal antiviral therapy is essential for the resolution of cholestatic hepatitis C.

Vanishing bile duct syndrome (VBDS) refers to a group of disorders characterized by prolonged cholestasis as a result of destruction and disappearance of intrahepatic bile ducts. Multiple etiologies have been indentified including infections, neoplastic disorders, autoimmune conditions and drugs. The natural history of this condition is variable and may involve resolution of cholestasis or progression with irreversible damage. VBDS is extremely rare in human immunodeficiency virus (HIV)-infected patients and anti-retroviral therapy has never been implicated as a cause. We encountered a young pregnant female with HIV and VBDS secondary to anti-retroviral therapy. Here, we report her clinical course and outcome.

Introduction: Little is known about the epidemiology, causes and outcomes of neonatal cholestasis in the Asian population beyond Japan and Taiwan., Methods: This was a prospective, observational study on patients with neonatal cholestasis who were referred to the University of Malaya Medical Centre, Malaysia, between November 1996 and May 2004., Results: Biliary atresia (BA) (29 percent) and idiopathic neonatal hepatitis (38 percent) were the two commonest causes of neonatal cholestasis (n is 146) that were referred. Out of the 39 patients (27 percent of the total) who died at the time of review, 35 succumbed to end-stage liver disease. Three of the four patients (three BA, one progressive familial intrahepatic cholestasis [PFIC]) who had a living-related liver transplant (LT) died after the surgery (two BA, one PFIC). Six (four percent) of the remaining 107 survivors had liver cirrhosis. The overall four-year survival rates for patients with native liver and LT as well as those with native liver alone for all cases of neonatal cholestasis were 72 percent and 73 percent, respectively, while the respective survival rates for BA were 38 percent and 36 percent., Conclusion: BA and idiopathic neonatal hepatitis are important causes of neonatal cholestasis in Malaysian infants. In Malaysia, the survival rate of patients with neonatal cholestasis, especially BA, is adversely affected by the lack of a timely LT.

Purpose of Review: Lipid emulsions containing fish oils have been proposed to improve parenteral nutrition associated cholestasis (PNAC), a very serious complication of prolonged parenteral nutrition occurring particularly in infants and children with intestinal failure. Here, we summarize current data., Recent Findings: The cause of PNAC is multifactorial. Prevention is possible by appropriate management, surgical procedures, infection prevention, and optimal parenteral nutrition management. Plausible hypotheses and experimental data support potential benefits of fish oils for treatment and prevention of PNAC. Improvement of PNAC over weeks and months has been reported in observational case studies in part of the children who received parenteral lipids with fish oil, but similar improvements also occurred by withholding or reducing standard lipid emulsions. No controlled trials are available that would allow final conclusions on efficacy and safety of fish oil-based emulsions in PNAC. Concerns exist regarding possible untoward effects and an inadequate supply of n-6 fatty acids with parenteral fish oil only. First data from controlled trials with mixed lipid emulsions containing partly fish oil suggest safety in infants and children and some possible benefits for liver function., Summary: The observed improvement of PNAC on parenteral lipids with fish oil deserves further exploration. No controlled trials are available, nutritional adequacy and safety of 100% fish oil emulsions are not adequately documented, and currently their use cannot be considered standard care. First data on mixed lipid emulsions with some fish oil are encouraging, and their effects in PNAC should also be explored.

Background: In the present experimental study, we analyzed the role of Rho-kinase during obstructive cholestasis by studying the effect of the Rho-kinase inhibitor Y-27632 on hepatic CXC chemokine formation, leukocyte recruitment and hepatocellular damage., Materials and Methods: C57BL/6 mice underwent bile duct ligation (BDL) to induce obstructive cholestasis. Mice were pretreated with Y-27632 (1 and 10mg/kg) or the vehicle PBS. Sham-operated animals served as controls. After 12h, hepatic accumulation of leukocytes and sinusoidal perfusion were determined using intravital fluorescence microscopy. Hepatocellular damage was monitored by measuring serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). CXC chemokines in the liver were analyzed by ELISA., Results: Administration of 10mg/kg of Y-27632 protected against cholestasis-induced hepatocellular damage indicated by a more than 87% reduction of ALT and AST in BDL mice. Moreover, this Rho-kinase inhibitor significantly decreased BDL-induced production of CXC chemokines by 44-83% and leukocyte recruitment by 60%. Finally, treatment with Y-27632 restored sinusoidal perfusion in cholestatic animals., Conclusions: Our findings indicate that the Rho-kinase signaling pathway plays a key role in the pathophysiology of cholestatic liver injury. Thus, targeting Rho-kinase activity may represent a new therapeutic approach in the treatment of inflammation and liver injury in cholestatic liver diseases.

Objective: To investigate the clinical and laboratory features of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and to characterize the molecular basis and prognosis of this disease., Methods: Twenty-six patients with NICCD were collected because of idiopathic intrahepatic cholestasis and jaundice. The diagnosis was made by routine laboratory data collection, tandem mass spectrometry (MS-MS) and gas chromatography mass spectrometry (GC-MS) analyses. SLC25A13 gene mutation was analyzed by using polymerase chain reaction (PCR), direct DNA sequencing and restriction fragment length polymorphism analyses. The patients were followed up for nearly 2 years., Results: The NICCD patients showed low birth weight and the average onset of jaundice was 29 days. Laboratory data showed liver dysfunction, hyperbilirubinemia, hypoproteinemia, high levels of alpha-fetoprotein, prolonged prothrombin time, hypoglycemia and hyperammonemia. MS-MS analysis of the blood samples revealed specific elevation of citrulline, methionine, threonine, tyrosine and elevation of free carnitine, short-chain and long-chain acylcarnitines. GC-MS analysis of the urine samples showed elevated 4-hydroxyl phenyllactic acid and 4-hydroxyl phenylpyruvic acid. Twelve different mutations were identified, including 4 novel mutations, i.e., G386V, R467X, K453R and 1192-1193delT. Forty-four mutated alleles were identified in the 52 alleles (84.6% ). Among them, 851del4, 1638ins23 and IVS6+5G>A mutations were the most frequent mutations, accounting for 40.9%, 20.5% and 11.4% of the total alleles examined respectively. Five of the 26 patients have not been recovered, including 4 died and 1 accepted liver transplantation. No obvious relationship was found between the genotype and phenotype in NICCD., Conclusion: The 851del4, 1638ins23 and IVS6+5G>A mutations are the hot-spot mutations in Chinese NICCD patients. Some NICCD patients have poor prognosis.

The use of over-the-counter supplements is commonplace in today's health conscious society. We present an unusual case of intrahepatic cholestasis caused by vitamin A intoxication. The patient consumed one Herbalife shake with two multivitamin tablets of the same brand for 12 years. When calculated this equated to more than the recommended daily allowance for vitamin A consumption. Deranged liver function tests were consistent with a cholestatic process. Liver biopsy was obtained and revealed features pathognomonic of vitamin A toxicity, without the usual fibrosis. When the supplements were ceased, his jaundice and alkaline phosphatase completely normalized. This case highlights the importance of health care providers documenting non-prescribed dietary supplements and considering them in the etiology of cholestatic liver disease., (Copyright 2009 Elsevier Inc. All rights reserved.)

Heterotopic tissue of the pancreas can be found in 1-2% of autopsies. The main locations are stomach, duodenum, jejunum, Meckel's diverticulum, and ileum. Less frequently it is observed in the liver, gallbladder, common bile duct, and papilla of Vateri. We report the first case of heterotopic pancreatic tissue in the bifurcation of the bile duct mimicking a Klatskin's tumour. The case is discussed based on the current literature.

The AMPLATZER Vascular Plug (AVP; AGA Medical, USA) is designed to provide optimal embolization of peripheral veins and arteries through single-device occlusion. There are no reported cases of the AVP's being used to prevent bile leak. We report the successful use of the AVP within the liver to prevent intraperitoneal bile leak following inadvertent subcapsular stent deployment.

Ventricular assist devices have been shown to be effective in advanced heart failure selected patients. They often have borderline end-organ function, what facilitates organ dysfunction. Liver failure is difficult to manage and leads to increased morbidity and mortality. We report a case of ductular cholestasis, an unusual cholestatic hepatic failure with untractable coagulopathy, developed during the use of a magnetic levitation centrifugal pump, implanted as a bridge to heart transplantation, in a patient with cardiogenic shock (as an end-stage disease of idiopathic dilated cardiomyopathy). We discussed the pathophysiology of this entity and the possible related factors, including the assist device. Preemptive interventions have been advocated as the primary way of treatment. Preoperative optimization of heart function and avoidance of visceral hypoperfusion and sepsis may play a major role.

Purpose: Dependence on total parenteral nutrition in intestinal failure or short bowel syndrome patients can lead to many complications. The most significant complication is progressive liver injury leading to liver failure. This study assesses the potential of hepatocyte growth factor (HGF) in modulating the hepatic response in a rat cholestatic liver injury model., Methods: Female Sprague-Dawley rats were divided into 3 groups: control (n = 5), chronic liver injury (alpha-naphtylisocyocyanate [ANIT] every 3.5 days at 75 mg/kg; n = 5), and chronic liver injury plus HGF (ANIT + HGF at 250 microg kg(-1) d(-1); n = 5). The rats initially underwent massive (80%) small bowel resections. Seven days later, they were given intraperitoneal injections of saline (control) or ANIT and implantation of an osmotic minipump for continuous intravenous saline or HGF. Intraperitoneal saline or ANIT injections were subsequently administered every 3.5 days to create a chronic cholestatic model. After 14 days, the animals were euthanized, and liver biopsies were obtained. The liver biopsies were evaluated by histology, immunofluorescence staining for interleukin-6 and tumor necrosis factor alpha, and assessment of apoptosis by terminal dUTP-transferase-mediated nick end labeling (TUNEL) technique., Results: In this chronic liver injury model, HGF did not effect the grade of inflammation. However, HGF did induce retention of the ductal structures and avoided ductal proliferation, damage, and evidence of primary sclerosing cholangitis (P < .05). Hepatocyte growth factor induced less interleukin-6 (P < .011) and tumor necrosis factor alpha (P < .01) expression. Apoptotic activity was also significantly less in the HGF group (P < .01)., Conclusion: Hepatocyte growth factor preserved the hepatic ductal system, modulated the hepatic inflammatory response, and reduced the apoptotic index in this chronic cholestatic liver injury model. It may diminish or prevent liver damage in patients with total parenteral nutrition-induced liver injury., (Copyright 2010 Elsevier Inc. All rights reserved.)

The main goal of our study was to evaluate cirrhosis course on one year. The study was prospective and longitudinal from January 2005 to December 2006 in the center of hepatology and gastro-enterology of CHU Gabriel Touré. The patients had one year follow up and examinated every three months. In this study 57 patients were included. Mean age was 41,5 + 15,3 years. Ascite and jaundice were the main clinical signs respectively 70.2% and 54.4%. Ascite or its increase was the most complication in 67.5% of cases (p = 0.002). The global mortality was 82.5% and it was high in the three first months, caused by hepatocellular carcinoma, digestive bleeding and hepatic encephalopathy respectively 33.3%, 27.3% and 15.2%. Abdomen pain, ascite and jaundice have an predictive value for high mortality (p between 3.10-3 et 10-7). Early examination, therapeutic observance and good management of cirrhosis complications could reduce the mortality.

We report two Malaysian siblings with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). The younger sibling, a six-month-old Chinese girl, presented with prolonged neonatal jaundice, and was investigated for biliary atresia. Urine metabolic screen showed the presence of urinary-reducing sugars, and she was treated with a lactose-free formula. NICCD was suspected based on the clinical history, examination and presence of urinary citrulline. Mutation study of the SLC25A13 gene showed the compound heterozygotes, 851del4 and IVS16ins3kb, which confirmed the diagnosis of NICCD in the patient and her three-year-old female sibling, who also had unexplained neonatal cholestasis. Long-term dietary advice, medical surveillance and genetic counselling were provided to the family. The diagnosis of NICCD should be considered in infants with unexplained prolonged jaundice. DNA-based genetic testing of the SLC25A13 gene may be performed to confirm the diagnosis retrospectively. An awareness of this condition may help in early diagnosis using appropriate metabolic and biochemical investigations, thus avoiding invasive investigations in infants with neonatal cholestasis caused by NICCD.

Purpose: Intestinal failure (IF)-associated liver disease (IFALD) complicates the treatment of children with IF receiving parenteral nutrition (PN). We hypothesized that prevention or resolution of IFALD was possible in most children and that this would result in improved outcomes., Methods: We reviewed prospectively gathered data on all children referred to the intestinal rehabilitation and transplantation center at our institution. Total bilirubin level (TB) was used as the marker for IFALD. Patients were grouped based on TB at referral and at subsequent inpatient stays and outpatient visits. Standard treatment consisted of cycling of PN, limiting lipid infusion, enteral stimulation, use of ursodeoxycholic acid, and surgical intervention when necessary. Outcomes such as mortality, dependence on PN, and need for transplantation were assessed. Statistical analyses were performed using Fisher's exact, Mann-Whitney U, and Wilcoxon signed rank tests., Results: Ninety-three patients with intestinal failure and on PN were treated at our center from 2003 to 2009. Median age at referral was 5 months (0.5-264 months). Prematurity was a complicating factor in 63 patients and necrotizing enterocolitis was the most common diagnosis. Eighty-two children had short bowel syndrome, whereas the remaining 11 had extensive motility disorders. 97% of children required significant alteration of their PN administration. At referral, 76 of 93 children had TB 2.0 mg/dL or higher, and 17 had TB below 2.0 mg/dL. TB normalized in 57 of 76 children with elevated TB at referral, and TB remained elevated in 19. Normalization of TB was associated with a mortality of 5.2%, and transplantation was needed in 5.2%. Conversely, when TB remained elevated, mortality was 58% (P = .0002 vs TB normalized), and transplantation occurred in 58% owing to failure of surgical and medical rehabilitation., Conclusions: Most children referred for treatment of IF have IFALD. A dedicated IF rehabilitation program can reverse IFALD in many children, and this is associated with improved outcome., (Copyright 2010 Elsevier Inc. All rights reserved.)

We herein describe the case of a 30-year-old woman who experienced high fever during the puerperal period and was diagnosed with pheochromocytoma. Acute inflammatory syndrome, as indicated by the elevated serum levels of interleukin-6 (IL-6), and cholestatic liver dysfunction were observed. Since this condition resolved before the operation, it was probably caused by massive central necrosis within the tumor. The IL-6 production from the tumor cells was confirmed by immunohistochemistry. When a case of pheochromocytoma accompanied with acute inflammatory syndrome is encountered, the possibility that the tumor itself might produce some cytokines should be considered, even in the presence of massive necrosis within the tumor.

Unlabelled: OBJECTIVES, SETTING AND PATIENTS: With complete case referral for prolonged parenteral nutrition (PN) beyond term equivalent, serving a stable population of 1.25 million people, we describe the long-term outcome and survival of patients referred to an intestinal failure (IF) nutrition support team over the first 8 years of existence at a regional paediatric centre, and extrapolate to potential numbers of national home parenteral nutrition (HPN) cases and intestinal transplantation data., Design and Outcome Measures: Retrospective analysis detailing patient demographics, interventions, use of HPN, occurrence of intestinal failure-associated liver disease (IFALD), and outcomes of enteral adaptation, survival, and referral for and receipt of organ transplantation., Results: 23 patients were referred over 8 years, 20 being PN dependent within the neonatal period. Diagnoses included short bowel syndrome (SBS) (18), neuromuscular abnormalities (4) and congenital enterocyte disorder (1). 12 696 days of PN were delivered with 314 confirmed episodes of sepsis at a median of 12 episodes per patient. 144 central venous catheters (CVCs) were required at a median of four per patient. IFALD occurred in 17 (73%) patients, with 10 (44%) referred for transplant assessment. Thirteen (56%) children received HPN. Overall mortality was 44%. A significant predictor for survival in the SBS group was residual bowel >40 cm (82% vs 28%, p = 0.049)., Conclusions: Survival for IF at 56% was lower than reported from non-UK supra-regional centres, and nationally collected data, possibly reflecting pre-selected referral populations. Data from regional centres with complete ascertainment may be important both when counselling parents and when planning regional and national HPN and IF specialist services.

Citrin deficiency is a disorder with two phenotypes: neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD), and adult-onset type II citrullinaemia (CTLN2). NICCD presents in the first few weeks of life with prolonged cholestasis and metabolic abnormalities including aminoacidaemia (notably citrulline, tyrosine, threonine, arginine and methionine) and galactosuria. Symptoms resolve within the first year of life, thus making a diagnosis difficult after this time. Although patients subsequently remain generally healthy, some may develop more severe symptoms of CTLN2, characterized by neurological changes, one or more decades later. To date more than 400 cases have been reported, almost all from East Asia (mainly Japan). Here we describe the first two cases of NICCD in infants from the UK, one of caucasian origin and one of Pakistani origin. Both showed typical clinical and biochemical changes with a diagnosis confirmed by the presence of previously unreported mutations in the SLC25A13 gene. The presence of citrin deficiency in other ethnic groups means that NICCD needs to be considered in the diagnosis of any neonate with an unexplained cholestasis. We discuss both the difficulties in diagnosing these patients in populations where very few DNA mutations have been identified and the problems faced in the management of these patients. These findings also raise the possibility of adults with CTLN2 in whom a diagnosis has yet to be made.

Idiopathic adulthood ductopenia (IAD) is a chronic cholestatic liver disease of unknown etiology characterized by adult onset, an absence of autoantibodies, inflammatory bowel disease, and a loss of interlobular bile ducts. In the present report, a case fulfilling the IAD criteria is described. A 19-year-old man was admitted to the hospital for persistent elevation of transaminases and alkaline phosphatase without clinical symptoms. Viral hepatitis markers and autoantibodies were absent. The patient had a normal extrahepatic biliary tree and had no evidence of inflammatory bowel disease. A liver biopsy specimen showed absence of interlobular bile ducts from 58% of the portal tracts. He was diagnosed with IAD and was treated with ursodeoxycholic acid.

Background: The biliary cast syndrome (BCS) is a frequent problem following liver transplantation. The pathogenesis of this complication is not well understood. Previous research has demonstrated that the soluble form of MICA (sMICA) is significantly higher in patients with chronic liver disease and hepatocellular carcinoma (HCC) than in healthy volunteers. The aim of this study is to investigate the possible involvement of sMICA in the formation of BCS after liver transplantation., Methods: Serum soluble MICA was retrospectively evaluated in pre- and post-transplant sera from 133 consecutive primary liver transplant patients and in sera from 88 healthy volunteers using sandwich ELISA. Normal distribution of serum sMICA was described by the data obtained from healthy population and sMICA concentration that was greater than the upper bound 95% normal range was considered as high levels of sMICA. Patient records were reviewed to identify patients who developed BCS., Results: The results demonstrated that 37.6% of patients with end-stage liver diseases had significantly higher pre-transplant serum sMICA than in healthy population. 34.4% of recipients with post-transplant high levels of sMICA developed BCS. In contrast, 17.3% of patients with post-transplant normal levels of sMICA developed BCS. The risk of BCS development is significantly associated with the presence of post-transplant high levels of sMICA (P=0.0365). Further analysis disclosed that patients with decreased post-transplant sMICA following liver transplantation had a lower incidence rate of BCS than those with remained high levels of sMICA after transplantation (10.5% vs. 38.7%, P=0.0302). Furthermore, log-rank test showed that BCS occurrence was significantly associated with dynamic changes of sMICA among different groups (P=0.0188)., Conclusions: Biliary cast syndrome is more likely to develop in recipients who have post-transplant high levels of sMICA. The data suggested that sMICA might have some immunologic effect on BCS development following liver transplant. Monitoring of serum sMICA could have a prognostic value in assessment of patients with liver transplantation.

Background: Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) is a novel inborn error of metabolism due to dysfunction of citrin protein, and much more information about this new disease is still needed for its clinical management., Aims: To investigate in detail the clinical and laboratory features of NICCD., Patients: 13 NICCD subjects in mainland of China diagnosed in our department since 2006., Methods: The anthropometric parameters of the patients at birth were compared with controls, representative biochemical changes and metabolome findings were investigated cross-sectionally, and mutations in the causative gene SLC25A13 were analyzed by protocols established previously., Results: The patients showed reduced birth weight, length and ponderal index. Main clinical manifestations consisted of jaundice, hepato/hepatosplenomegaly and steatohepatosis on ultrasonography. Biochemical analysis revealed intrahepatic cholestasis, delayed switch of AFP to albumin, and elevated triglyceride, total cholesterol and LDL-cholesterol together with reduced HDL-cholesterol. Metabolome findings included co-existence of markers for galactosemia and tyrosinemia in urine, and elevated Cit, Met, Thr, Tyr, Lys, Arg and Orn in blood. Mutations of 851-854del, IVS6+5G>A, 1638-1660dup, A541D, IVS16ins3kb, R319X and G333D were detected in the gene SLC25A13., Conclusions: The diagnosis of NICCD cannot be established based just on the numerous but non-specific clinical manifestations and biochemical changes. The relatively specific metabolome features provide valuable tools for its screening and diagnosis, while SLC25A13 mutation analysis should be taken as one of the reliable tools for the definitive diagnosis. The body proportionality at birth, steatohepatosis on ultrasonography, delayed switch of AFP to albumin, dyslipidemia pattern, urinary metabolome features and the novel mutation G333D expanded the clinical spectrum of NICCD.

Aim: Bilirubin overload caused by haemolysis of transfused blood and breakdown of extravasated blood constitutes an important causative factor of jaundice in trauma patients. Intravenous infusions of large amounts of unconjugated bilirubin (UCB) block biliary phospholipid secretion and produce canalicular membrane lesions in pigs, putatively because of enhanced cytotoxicity of bile. Severe intrahepatic cholestasis is the functional end result. The aim of the study was to investigate whether bilirubin ditaurate (BDT) overload, which also inhibits biliary phospholipid secretion, also induces intrahepatic cholestasis., Methods: Six pigs were infused with 2.8 g of BDT for 150 min. Six control pigs were infused with albumin sham solution for 150 min. Bile samples were analysed for bile acid- and phospholipid-secretion rates. Bile and serum samples were analysed for bilirubin concentration. Liver biopsies were obtained for scanning electron microscopic studies (SEM)., Results: Biliary bile acid secretion fell by 7.7% and biliary phospholipid secretion rate fell by 88% after BDT infusion. Thus, infusion of BDT for 150 min did not cause intrahepatic cholestasis. SEM showed some variability in the size of canalicular membrane microvilli, but no evidence of gross destruction., Conclusion: BDT overload markedly lowers biliary phospholipid secretion. In contrast to UCB, BDT does not induce canalicular membrane damage nor cause intrahepatic cholestasis. Sustained, marked inhibition of phospholipid secretion does therefore not adequately explain UCB-induced cholestasis. Accumulation of UCB in the canalicular membrane may be the important factor in the pathogenesis of canalicular membrane lesions and intrahepatic cholestasis during UCB overload.

The main determinant of bile formation is an osmotic filtration process resulting from active transport of bile acids and other osmotic solutes (glutathion). Most of the membrane transporters ensuring bile formation have now been identified. The expression of these membrane transporters is regulated through transcriptional and post-traductional mechanisms. Transcriptional regulation is under the control of nuclear receptors activated by ligands such as bile acids, which act as endogenous steroids synthesized from cholesterol in hepatocytes. Cholestatic liver diseases comprise genetic diseases resulting from the complex interaction between genetic and environmental factors. Monogenic cholestatic diseases recently identified illustrate the key role of membrane transporters in biliary function. Bile acids and inflammatory mediators are potent modulators of transporters and nuclear receptor genes and thus trigger an adaptative response to cholestasis. The extent of this adaptative response could explain the compelling phenotypic variability of cholestatic diseases in childhood and adults. The first-line medical treatment is currently ursodeoxycholic acid and in case of failure of this medical treatment, liver transplantation is required. Recent progress in the molecular pathogenesis of bile formation and cholestatic liver diseases is expected to provide the design of drugs targeted to the molecular abnormalities typical of cholestatic diseases.

We report a case of a 21-year-old pregnant woman with an early onset of intrahepatic cholestasis of pregnancy with very high aminotransferases activity and bilirubin concentration. Viral and autoimmune hepatitis, and other possible causes of liver function impairment were excluded. Treatment with ursodeoxycholic acid improved biochemical markers. The patient delivered a healthy female neonate by caesarean section. Neonatal and postoperative courses were uneventful.

Severe acute hepatitis of unknown etiology is difficult to treat and often progresses to subacute fulminant hepatitis or late-onset hepatic failure. A 45-year-old well-nourished, healthy man had progressive fatigue and his liver function tests showed severe liver dysfunction. The etiology of sever acute cholestatic hepatitis was unknown. The liver function tests normalized gradually, which excluded high persistent total bilirubin after starting on predonine. A liver biopsy showed chronic active hepatitis with mild fibrosis (A2, F1). Oral Inchinko-to, a Chinese herbal medicine, at 7.5 g daily was prescribed. The treatment was effective with no adverse effects. We present a successfully treated case and discuss hepatoprotective and choleretic effects of Inchinko-to.

We describe a 71-year-old man with an inflammatory tumor arising in segment 5 of the liver. The patient was admitted because of acute pain in the right upper quadrant of the abdomen and fever. Initial laboratory tests revealed the following: serum alkaline phosphatase concentration, 634 IU/L; serum gamma glutamic transpeptidase concentration, 1,378 IU/L; serum C-reactive protein concentration, 0.89 mg/dL; and total bilirubin concentration, 8.9 mg/dL. Abdominal ultrasonography, computed tomography (CT), and magnetic resonance imaging showed a mass, 3 cm in diameter, in segment 5 of the liver. Magnetic resonance cholangiopancreatography showed a lesion of moderate-to-high signal intensity on T2-weighted images of segment 5. Endoscopic retrograde cholangiopancreatography revealed a common bile duct stone. The intrahepatic bile ducts of segment 5 could not be visualized after the use of contrast material. Endoscopic sphincterotomy was performed to remove the common bile duct stone. Antibiotics were administered soon after stone removal, and fever gradually resolved. Positron emission tomography revealed hot spots in segment 5 of the liver. Three weeks after discharge, the patient was readmitted with an acute pain in the right upper quadrant of the abdomen. Abdominal ultrasonography, CT, and magnetic resonance imaging showed enlargement of this area. Inflammatory changes of segment 5 due to cholangitis with intrahepatic bile duct stones was diagnosed. Because malignant disease could not be completely ruled out, segment 5 of the liver was resected. Macroscopic examination of the resected specimen revealed a gray, fibrotic, solid tumor associated with intrahepatic bile duct stones. Microscopic examination of the tumor showed proliferation of spindle-shaped myofibroblastic cells in a mixed myxoedematous, dense fibrotic stroma, associated with infiltration by various acute and chronic inflammatory cells. The postoperative course was uneventful, and the patient was discharged on postoperative day 16.

Background: The link between microcirculatory disturbance and hepatocellular dysfunction remains unknown. The present study was designed to examine the key event of warm ischemia reperfusion (WIR) injury with subsequent cholestasis., Methods: A left lobar 70% ischemia and reperfusion rat model was used in this study. The portal vein and hepatic artery to the left lateral lobe of the liver were subjected to 20 min of warm ischemia followed by 60 min of reperfusion to collect bile and to measure its constituents., Results: The hepatocellular injury was increased significantly in livers exposed to WIR, as judged by serum alanine aminotransferase. This event coincided with decreased bile production and biliary concentration of glutathione (GSH), suggesting impaired bile salts-independent bile flow, while biliary phospholipids and bile salts were not decreased. Additionally, hepatic adenosine triphosphate and GSH were not decreased after WIR. Since the biliary GSH, which is a major driving force for bile salts-independent bile flow, is excreted from hepatocytes into the bile via multidrug resistance protein 2 (Mrp2), we examined whether intracellular localization of Mrp2 occurred. Immunohistochemical analyses revealed hepatocellular Mrp2 was retrieved from bile canalicular membrane into the pericanalicular cytoplasm in the post-warm ischemic livers. Microcirculatory disturbance in livers exposed to 20 min of warm ischemia improved to levels comparable to controls., Conclusion: Mrp2 internalization, observed in this study, may play an important determinant of cholestasis in the post-warm ischemic livers.

Fibrosing cholestatic hepatitis (FCH) is a variant of viral hepatitis reported in hepatitis B virus or hepatitis C virus infected liver, renal or bone transplantation recipients and in leukemia and lymphoma patients after conventional cytotoxic chemotherapy. FCH constitutes a well-described form of fulminant hepatitis having extensive fibrosis and severe cholestasis as its most characteristic pathological findings. Here, we report a case of a 49-year-old patient diagnosed with small-cell lung cancer who developed this condition following conventional chemotherapy-induced immunosuppression. This is the first reported case in the literature of FCH after conventional chemotherapy for a solid tumor. In addition to a detailed report of the case, a physiopathological examination of this potentially life-threatening condition and its treatment options are discussed.

Two clinical phenotypes for citrin deficiency (CD) have been reported. One is adult-onset citrullinemia type II (CTLN2) and another is neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). A child with CD and who had failure to thrive (FTT) and dyslipidemia as main clinical manifestations is reported here. Both the weight-and length-for-age at 18 months dropped below the 3rd percentile in the corresponding WHO anthropometry percentile charts, while blood biochemical analysis revealed dramatically increased triglyceride and total cholesterol, together with reduced HDL-cholesterol. Inquiries revealed his aversion to rice and fondness for fish since the age of one year, a peculiar habit which could not be corrected. Since the age of two years, the peculiar diet became more obvious, and slightly increased citrulline and threonine levels were detected on blood amino acid analysis. At the age of two years and five months he was suspected to have CD. Since then, he has been fed in accordance with his own food preferences, and FTT improved gradually, with weight-for-age, in particular, recovering beyond the 3rd percentile at three years of age, and dyslipidemia was also ameliorated gradually. SLC25A13 gene analysis revealed a homozygote of 851del4, and CD was thus confirmed. Diet survey at four years and seven months revealed a fondness for high-protein and low-carbohydrate foods, such as seafood, meat, eggs and milk. This child presented with FTT and dyslipidemia as main clinical manifestations and this was a novel CD phenotype different from NICCD and CTLN2.

Introduction: The causes of intrahepatic cholestasis include cholestatic viral hepatitis, primary biliary cirrhosis, benign recurrent cholestasis, primary sclerosing cholangitis and sepsis. During sepsis, proinflammatory cytokines and nitric oxide cause cholestasis by impairing hepatocellular and ductal bile formation., Case Outline: We report a 48-year-old woman who was admitted to hospital due to malaise, jaundice, fever and pain in the neck. Physical examination revealed jaundice, tachycardia (pulse rate was 120/min), hypotension 90/60 mm Hg. Laboratory findings showed normocytic normochromic anaemia, inflammatory syndrome and abnormal liver function tests indicating cholestasis and hepatocellular necrosis. Abdominal ultrasonography detected hepatosplenomegaly. Chest computed tomography showed bronchopneumonic infiltrates. Percutaneous liver biopsy was performed using a Menghini needle of 1.4 mm. Pathohystological analysis of the liver tissue confirmed reactive, intrahepatic cholestasis. Blood cultures isolated Staphylococcus aureus. After the diagnosis was established the treatment with broad-spectrum antibiotics was carried out, resulting in the improvement of general condition of the patient, regression of inflammatory syndrome, disappearance of cholestasis and regression of pulmonary infiltrates. Abdominal ultrasonography after antibiotic treatment did not show hepatosplenomegaly., Conclusion: Concerning patients with cholestasis of uncertain origin, we should always think of sepsis as a possible cause in order to start antibiotic treatment in time.

Background: Cholangiocarcinoma (CC), the most common biliary tract malignancy, is frequently seen in advanced unresectable stages and is typically localized extrahepatically. Early diagnosis is unusual because of nonspecific symptoms. Painless jaundice is usually the first sign of tumor., Method: We present a patient with a CC (Klatskin tumor) with a complete biliary drainage by an aberrant bile duct without jaundice., Results: A 67-year-old woman presented with persisting elevation of liver parameters. Diagnostic tests showed a Klatskin tumor type II. A curative right hepatic trisegmentectomy was performed after liver volume augmentation by preoperative vein embolization., Conclusions: A direct drainage of the right posterior bile duct into the common bile duct as an aberrant hepatic duct is a rare variation and is present in less than 5% of the population. In case of persistently perturbed liver function tests, an aberrant bile duct can cover up severe intrahepatic cholestasis and even obscure the diagnosis of a Klatskin tumor. Up to now it has not been described in the literature.