Prolonged Cholestasis Research Articles

Clinical and pathological characteristics of Alagille syndrome in Chinese children

Alagille syndrome (AS) is regarded as the most common cause of chronic cholestasis in childhood associated with specific phenotypic features in western countries. This study was undertaken to investigate the significance of AS in Chinese children with chronic cholestasis and to describe its clinical and histological features. From October 2004 to January 2007, 157 children who presented with conjugated jaundice from less than 3 months of age were admitted to a tertiary hospital in Shanghai. Investigations of the heart, spine, eyes and kidneys were conducted in 13 children who experienced prolonged cholestasis beyond 1 year of age after exclusion of biliary atresia and familial progressive intrahepatic cholestasis type 1 or 2. In patients with interlobular bile duct paucity, AS was diagnosed if 3 or more of the following 5 major features were present: cardiac murmur, posterior embryotoxon, butterfly-like vertebrae, renal abnormalities and characteristic faces. In patients without interlobular bile duct paucity or who did not receive liver biopsy, 4 or more features were required for the diagnosis. Of the 13 children, 6 were diagnosed with AS at ages ranging from 1 year and 7 months to 3 years and 11 months. Jaundice was noticed in early infancy and then pruritus developed in all the 6 patients, of whom 5 presented with acholic stool and 4 had been misdiagnosed as having presumed biliary atresia by hepatobiliary scintigraphy or laparoscopic cholangiography. Biochemical examinations demonstrated increased concentration of total bile acid and hyperlipidemia. Interlobular bile duct paucity was demonstrated histologically in 5 patients who received liver biopsy. Vertebral abnormalities, heart murmur, characteristic faces and failure to thrive were found in all the 6 patients. Two patients had evidence of renal involvement. Micropenis, empty scrotum, and gall stone were seen in 1 patient. AS is also an important cause of prolonged cholestasis in Chinese children. It is difficult to differentiate AS from biliary atresia. Liver biopsy and spine X-ray may be helpful in the early detection of AS.

Randomized Placebo-Controlled Trial on the Effect of Corticosteroid on Prolonged Cholestasis due to Acute Hepatitis A

Aim and objective: To determine the efficacy and safety profile of corticosteroid on the clinical course of prolonged intrahepatic cholestasis due to acute hepatitis A. Method: We prospectively studied patients of acute hepatitis A with prolonged cholestasis (more than 12 weeks with debilitating symptoms in the form of anorexia, weight loss and pruritis disturbing night sleep) over a period of five years. The patients were randomly assigned to two groups of ursodeoxycholic acid and prednisolone (Group A) and ursodeoxycholic acid and placebo (Group B). They were assessed for cumulative mean decrease in bilirubin at day 3, 7 and then weekly till normalization of bilirubin. Quality of life was assessed in both groups on the basis of pruritis, anorexia, performance status improvement and work hour loss in days. Results: Out of 84 patients of acute hepatitis A, 21 patients had prolonged cholestatic hepatitis. Eleven patients (group A) were given ursodeoxycholic acid and prednisolone. Ten patients (group B) wer...

Disseminated Herpes Simplex Infection in a Neonate

Herpes simplex virus (HSV) infection in a newborn is commonly due to HSV 2 and less commonly due to HSV 1.1,2 Mixed HSV 1 & 2 infection in newborn is rarely reported.3 Neonatal HSV infection can present as- a) Localized skin, eye and mouth (SEM) affection; b) Central nervous system (CNS) disease or c)Disseminated disease.1,4,5 We report an unusual case of HSV infection in a neonate due both HSV 1 & HSV 2. It led to initial manifestation just like septicemia and ultimately prolonged cholestasis that responded to acyclovir therapy.

Mode d’entrée psychiatrique dans la maladie de Wilson : à propos d’un cas à début tardif

Mode d’entrée psychiatrique dans la maladie de Wilson : à propos d’un cas à début tardif

Innate Immune Response and Hepatic Inflammation

Inflammation is a pathogenic component of various types of acute and chronic liver diseases, and it contributes to progressive liver damage and fibrosis. Cells of the innate immune system initiate and maintain hepatic inflammation though mediator production as a result of their activation by pathogen-derived products recognized by pattern recognition receptors. Innate immune cells, particularly dendritic cells, have a pivotal role in sensing pathogens and initiating adaptive immune responses by activation and regulation of T-lymphocyte responses. Although the liver provides a "tolerogenic" immune environment for antigen-specific T-cells, activation of Kupffer cells, recruited macrophages, and inflammatory cells results in production of cytokines and chemokines that can lead to prolonged inflammation, hepatocyte damage, and/or cholestasis. The specificity of Toll-like receptors and the mechanisms of innate immune cell activation are discussed in relation to acute and chronic liver injury including viral, alcoholic, nonalcoholic, and drug-induced hepatitis.

Successful Treatment With Selective and Transplenic Artery Embolization for Small-for-Size Syndrome: A Case Report

Small-for-size graft or small-for-size syndrome (SFSS) has emerged as an important clinical problem. SFSS is associated with high morbidity and poor prognosis, and many questions remain unanswered regarding its pathogenesis and treatment of SFSS (1–5). We report a liver graft recipient who developed clinical evidence of prolonged cholestasis and intractable ascites after a small-for-size right lobe living donor liver transplantation (LDLT) and who was successfully treated with a new procedure: selective splenic artery embolization using an interventional approach. The liver graft weighed 846 g, which was 56% of the recipient’s standard liver graft, and 0.90% of his body weight. After LDLT, serum total bilirubin remained at a high level, and the daily ascitic fluid volume increased to more than 2000 mL. The patient was initially treated with a steroid pulse therapy for possible acute rejection. However, a liver biopsy demonstrated no histologic features of acute rejection. A computed tomography scan showed congestion of liver segments of V and VIII, and both Doppler ultrasonography and a venacavography revealed lack of patency of the anastomosis between V5/V8 and interior vena cava indicating an outflow block of the segment V and VIII anastomosis. The Doppler ultrasonogram also showed that the portal vein system was dilated and with a very high flow velocity in the portal vein (60–70 cm/s), indicating portal overperfusion. The liver biopsy was also consistent with portal overperfusion liver injury. Our new procedure, selective and transsplenic artery embolization (TSAE) by interventional technique reduced promptly the flow velocity of portal vein from 60–70 cm/s to 20 cm/s. Serum total bilirubin level decreased from 242 μmol/L to 69.7umol/L by 2 weeks and to 30.2 μmol/L at 1 month after TSAE; the daily ascites fluid volume decreased dramatically to less than 500 mL 2 weeks after TSAE. We suggest that selective splenic artery embolization is a technically simple procedure for the treatment of portal overperfusion injury in SFSS. LuNan Yan ZheYu Chen Wentao Wang Wusheng Lu Qiang Lu Weixia Cheng Tianfu Wen Mingqing Xu Jiayin Yang Liver Transplantation Division Department of Surgery West China Hospital Sichuan University Medical School Chengdu, China

Mesenchymal Stem Cells Over-expressing Hepatocyte Growth Factor Improve Small-for-size Liver Grafts Regeneration

Ischemia-reperfusion (I/R) associated with small-for-size liver transplantation (SFSLT) impairs liver graft regeneration. Mesenchymal stem cells (MSCs) have the capability, under specific conditions, of differentiating into hepatocytes. Hepatocyte growth factor (HGF) has potent anti-apoptotic and mitogenic effects on hepatocytes during liver injury, and has been utilized in many experimental and clinical applications. In this study, we implanted HGF-expressing MSCs into liver grafts via the portal vein, using a 30% small-for-size rat liver transplantation model. HGF, c-met expression, hepatic injury and liver regeneration were assessed after liver transplantation. Our study demonstrated that MSCs over-expressing HGF prevented liver failure and reduced mortality in rats after SFSLT. These animals also exhibited improved liver function and liver weight recovery during the early post-transplantation period. Using green fluorescent protein (GFP) gene as a marker, we demonstrated that the engrafted cells and their progeny incorporated into remnant livers and produced albumin. These findings suggest that MSCs genetically modified to over-express HGF and implanted in the liver graft, may offer a novel approach to promoting liver regeneration after small-for-size transplantations.

Small-for-Size Syndrome Secondary to Outflow Block of the Segments V and VIII Anastomoses—Successful Treatment With Trans-splenic Artery Embolization: A Case Report

Despite the rapid expansion of living donor liver transplantation (LDLT) in the adult population over the last few years, small-for-size syndrome (SFSS) has emerged as an important clinical problem. We have herein reported a patient who developed clinical evidence of prolonged cholestasis and intractable ascites after a small-for-size right lobe LDLT. The SFSS was attributed to outflow block of segments V and VIII anastomoses with severe portal overperfusion injury. It was successfully treated by reduction of portal pressure and blood flow after trans-splenic arterial ligation. We recommend that trans-splenic artery embolization, a technically simple procedure, be applied to treat portal overperfusion injury in SFSS.

Impact of non-congestive graft size in living donor liver transplantation: New indicator for additional vein reconstruction in right liver graft

Addition of the middle hepatic vein (MHV) or reconstruction of its tributaries to increase noncongestive graft volume is expected to improve graft function in right liver living donor liver transplantation (LDLT). However, the relationship between noncongestive graft volume and graft function after transplantation has not been clarified and definitive criteria for the reconstruction of MHV tributaries have yet to be established. We analyzed 29 right liver LDLT cases. The noncongestive graft weight was calculated as the total weight of the graft regions drained by hepatic veins reconstructed without postoperative occlusion. We calculated the noncongestive graft-to-recipient weight ratio (ncGRWR) by comparing it to the GRWR. Indocyanine green (ICG) clearance results on days 1 and 3 were significantly correlated with ncGRWR, but not with GRWR. Patients were then divided into 2 groups based on ncGRWR: lower than the median (L-ncGRWR group) and above the median (H-ncGRWR group). ICG clearance in the H-ncGRWR group was significantly better on days 1 and 3. For a different analysis, the patients were again divided into 2 groups, those with and without prolonged cholestasis after transplantation. ncGRWR was significantly lower in patients with prolonged cholestasis, and 7 of 9 patients with an ncGRWR value lower than 0.65 suffered from prolonged cholestasis. Our results demonstrated that the noncongestive volume of a right liver graft has a significant association with early graft function. Further, ncGRWR can play a key role in preoperative determination for additional vein reconstruction of MHV tributaries. When the estimated ncGRWR value with reconstruction of only the right hepatic vein (RHV) (+ inferior right hepatic vein [IRHV]) is less than 0.65, additional vein reconstruction of MHV tributaries should be planned.

Plasmapheresis and corticosteroid treatment for persistent jaundice after successful drainage of common bile duct stones by endoscopic retrograde cholangiography

Prolonged cholestasis is a very rare complication of endoscopic retrograde cholangiography (ERC). Only few cases with this complication are reported in the English literature. We report persisting cholestatic jaundice in a 73-year old man after successful therapeutic ERC for choledocholithiasis. Serologic tests for viral and autoimmune hepatitis were all negative. A second-look ERC was normal also. He denied any medication except for prophylaxis given intravenous 1 g ceftriaxone prior to the ERC procedure. After an unsuccessful trial with ursodeoxycholic acid and cholestyramine for 2 wk, this case was efficiently treated with corticosteroids and plasmapheresis. His cholestatic enzymes became normal and intense pruritus quickly resolved after this treatment which lasted during his follow-up period. We discussed the possible mechanisms and treatment alternatives of intrahepatic cholestasis associated with the ERC procedure.

Prolonged cholestasis following successful removal of common bile duct stones: Beware patients on estrogen therapy

There are various well described forms of chronic cholestatic jaundice in adults, such as autoimmune cholangitis, drug-induced cholangitis and intrahepatic cholestasis of pregnancy. We present two cases of prolonged cholestasis following removal of gallstones at endoscopic retrograde cholangiopancreatography (ERCP) and subsequent clear cholangiography. Both patients were taking oral estrogens at the time of presentation, which were subsequently withdrawn. The first case responded rapidly to corticosteroid treatment, and the second case had a much slower resolution with ursodeoxycholic acid. Both cases highlighted the significance of estrogen-induced cholestasis in female patients with protracted jaundice following ERCP and removal of intra-ductal stones. After oral estrogens are discontinued, a short course of steroids needs to be considered.

Prolonged cholestasis following successful removal of common bile duct stones: Beware patients on estrogen therapy

有在成年人的长期的胆汁郁积的黄疸的各种各样的很好描述的形式，例如自体免疫的胆管炎，导致药的胆管炎和怀孕的肝内胆汁郁积。我们在场胆石在的延长胆汁郁积追随者移动的二个盒子内视镜后退 cholangiopancreatography (ERCP ) 和随后的清楚的胆管造影术。两个病人在表示的时候正在拿口头的雌激素，它随后被撤退。第一个盒子对皮质甾治疗很快作出回应，并且第二个盒子与 ursodeoxycholic 酸有一个慢得多的决定。两个盒子与延长黄疸追随者 ERCP 和 intra-ductal 石头的移动在女病人加亮导致雌激素的胆汁郁积的意义。在口头的雌激素被中止以后，类固醇的一堂短功课需要被考虑。

Mycophenolate mofetil for drug-induced vanishing bile duct syndrome

Amoxicillin/clavulanate is associated with liver injury, mostly of a cholestatic pattern. While outcomes are usually benign, progression to cirrhosis and death has been reported. The role of immunosuppressive therapy for patients with a protracted course is unclear. We report the case of an elderly patient who developed prolonged cholestasis secondary to amoxicillin/clavulanate. Vanishing bile duct syndrome was confirmed by sequential liver biopsies. The patient responded to prednisone treatment, but could not be weaned off corticosteroids, even when azathioprine was added. Complete withdrawal of both prednisone and azathioprine was possible by using mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor. Sustained remission has been maintained for more than 3 years with low-dose mycophenolate mofetil.

Restoration of Bile Ducts in Drug-induced Vanishing Bile Duct Syndrome Due to Zonisamide

Prolonged drug-induced cholestasis may be due to destruction and disappearance of bile ducts, sometimes referred to as vanishing bile duct syndrome. Although some of these cases progress to fibrosis, cirrhosis, and liver failure, others improve with time. We report a case of a 35-year-old man who developed vanishing bile duct syndrome after ingestion of zonisamide, an antiepileptic drug that is also prescribed for weight loss. His liver biopsy showed complete absence of bile ducts 3 weeks after starting treatment. There was no ductular reaction. The drug was stopped and a follow-up biopsy 3 months later showed strands of intermediate hepatobiliary cells at the periphery of the portal tracts that extended into lobules; these structures lacked lumina and expressed biliary cytokeratins, CK7 and CK19. A third biopsy, 7 months later, showed the presence of ductules with lumina located within portal tracts. Intermediate hepatobiliary cells were rare; although sparse clusters of hepatocytes with membrane staining for CK7 were present. Cholestasis and levels of bilirubin improved over time. The histologic features in this case document the sequence of events in restoration of the biliary tree after loss of bile ducts, which seems to be a process of maturation of intermediate hepatobiliary cells that arise from a proliferative compartment at the porto-hepatic interface.

Prolonged cholestasis after raloxifene and fenofibrate interaction: A case report.

Assigning causality in drug-induced liver injury is challenging particularly when more than one drug could be responsible. We report a woman on long-term therapy with raloxifen who developed acute cholestasis shortly after starting fenofibrate. The picture evolved into chronic cholestasis. We hypothesized that an interaction at the metabolic level could have triggered the presentation of hepatotoxicity after a very short time of exposure to fenofibrate in this patient. The findings of an overexpression of vascular endothelial growth factor in the liver biopsy suggest that angiogenesis might play a role in the persistence of toxic cholestasis.

Does co‐infection with multiple viruses adversely influence the course and outcome of sporadic acute viral hepatitis in children?

This study looked at the frequency of co-infection with multiple hepatotropic viruses and the effect of such infection on the course and outcome of acute sporadic viral hepatitis (AVH) and fulminant hepatic failure (FHF) in children. Consecutive children up to 15 years of age presenting with AVH or FHF between January 1998 and July 2002 were evaluated prospectively. The following viral markers were assessed in all children: immunoglobulin M (IgM) anti-hepatitis A virus (HAV), IgM anti-hepatitis E virus (HEV), hepatitis B surface antigen (HBsAg), IgM anti-hepatitis B core (HBc), and anti-hepatitis C virus (HCV). A total of 149 children were included in the study, 122 with AVH and 27 with FHF. Co-infection with multiple viruses was detected in 30 (24.6%) AVH patients (A+E in 24, A+B in three, and E+B, A+C and A+E+B in one each) and seven (26%) FHF patients (A+E in five, and A+B and E+B in one each). The majority of single infections were due to HAV (AVH 70/92, FHF 14/20) followed by HEV (AVH 9/92, and FHF 5/20). HEV infection was associated with infection with another agent in 88% of patients with AVH (odds ratio 53, 95% confidence interval 15-186, P<0.0001). Frequency of anicteric state, prolonged cholestasis, relapsing hepatitis, ascites, hemolysis and mortality rates were similar in the single and multiple infection groups for both AVH and FHF patients. Co-infection with multiple viruses is observed in one-quarter of patients with sporadic AVH in childhood. Such infection does not produce a more severe disease. HEV positivity is a strong marker for multiple infections.

Intractable Pruritus in Patients With Hepatitis C Virus

Intractable pruritus is one of the most common symptoms of chronic liver disease, especially experienced by patients with prolonged cholestasis. It can become the most distressing symptom in patients affected by chronic liver disease, causing a reduction in quality of life, interfering with daily activities, and leading to sleep deprivation or contributing to psychological disturbances up to suicide ideation. Therefore, pruritus that does not respond to medical therapy is an indication for liver transplantation. We treated nine patients with hepatitis C virus affected by intractable pruritus with the molecular adsorbent recirculating system. In each patient, liver function, renal function, and hemodynamic variables were evaluated before and after the treatment. Before undergoing the treatment each patient underwent abdominal ultrasound or computed tomography scan to exclude organic causes for pruritus. We observed a decrease in total bilirubin, creatinine, and bile acids together with a significant improvement in Visual Analog Scale for staging of pruritus in all the patients. Due to the small number of patients the results were not significant.

Incidence and risk factors for the development of prolonged and severe intrahepatic cholestasis after liver transplantation

Predictive factors for intrahepatic cholestasis after orthotopic liver transplantation (OLT) have not yet been established. We sought to identify the incidence and risk factors associated with prolonged severe intrahepatic cholestasis (PSIC) after OLT. We assessed 428 consecutive patients undergoing their first OLT. PSIC was diagnosed if a serum bilirubin concentration was greater than 100 micromol/L and/or a 3-fold increase of alkaline phosphatase occurred within the first month after OLT and was sustained for at least 1 week in the absence of biliary complications. Multivariable logistic regression identified factors independently associated with PSIC. PSIC developed in 107 patients (25%). Independent risk factors by multivariable analysis were intraoperative transfusion of cryoprecipitate and platelets; nonidentical blood group status; suboptimal organ appearance; inpatient status before transplantation; and bacteraemia in the first month after transplantation. In contrast, acute liver failure, older age, and higher levels of serum sodium and serum potassium were all associated with a reduced likelihood of developing PSIC in the first month. There were 47 deaths in the PSIC group (44%) as opposed to 65 deaths in the non-PSIC group (20%) after OLT. A poor preoperative clinical status in conjunction with a suboptimal graft was associated with PSIC after OLT. Avoidance of suboptimal livers and ABO nonidentical grafts for young patients with poor synthetic function and for pretransplant inpatients may lessen this complication and reduce the associated early mortality.

Prolonged cholestasis associated with short-term use of celecoxib

Drug-induced liver injury due to celecoxib, a first generation Cox-2 inhibitor, has been rarely reported. We describe one case of severe and prolonged cholestasis after treatment with celecoxib for 12 days in a young woman with no evidence of other causes of liver disease or allergy. Jaundice lasted for 3 months, pruritus and abnormal liver biochemistry persisted for 18 months after stopping the drug. Liver biopsy specimens showed a cholestatic pattern of liver injury with only minimal mononuclear infiltrate in the portal tracts. This case report supports the notion that celecoxib may cause bland, long term cholestasis.

INTRACTABLE PRURITUS IN PATIENTS WITH HCV. PERSONAL EXPERIENCE

Intractable pruritus is one of the most common symptoms of chronic liver disease, especially experienced by patients with prolonged cholestasis. It can become the most distressing symptom in patients affected by chronic liver disease, causing a reduction in quality of life, interfering with daily activities and leading to sleep deprivation or contributing to psychological disturbances up to suicide ideation. Therefore non-responding to medical therapy pruritus is an indication for liver transplantation. MARS is an extracorporeal AHF support system method using albumin-enriched dyalisate to facilitate the removal of albumin-bound toxins. Veno-venous access (double-lumen catheter type) was used for blood supply. Intravenous heparin was used for blood anticoagulation for the maintenance of the extracorporeal circuit. Blood flow rate was 150250 mL/min, depending on the hemodynamic situation of the patient. Blood passed through an albumin non-permeable, high flux dialysis membrane. The clinical improvement was evaluated primarily through Child Pugh Score,MELD. In each patient, liver function (AST,GGT, total and direct bilirubin, coagulation, ammoniemia, albuminemia, serum bile acid), kidney function (creatinine, sodium, potassium, azotemia, diuresis/h), arterial pressure were evaluated before and after the treatment. Before each treatment patients underwent to abdominal ultrasound or CT scanner to exlude organic causes for the pruritus.