Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rejection is still a major problem in liver transplantation: 50-70% of patients present at least one acute episode, while 5-15% develop chronic rejection. Acute rejection is suggested by clinical signs and abnormal laboratory test results, but only histological signs on biopsy specimens are adequately specific. The three most frequent elementary lesions are a portal infiltrate, bile duct alterations and endothelial inflammation. Several systems have been forwarded to classify the degree of rejection. Chronic rejection is characterized by a progressive reduction in the number of interlobular bile ducts. It does not respond to available immunosuppressive drugs and thus requires retransplantation. Prophylactic immunosuppression is usually based on the triple-drug combination cyclosporine/azathioprine/corticosteroids. The orthoclone OKT3 and FK506 have recently been proposed for prophylactic use in this setting. Treatment of liver graft recipients with cyclosporine carries a number of specific disadvantages, particularly with regard to gastrointestinal interactions (delayed intestinal absorption in patients with cholestasis, bile derivation, diarrhea or receiving cholestyramine; possibility of a sharp increase in blood cyclosporine levels when the Kehr drain is clamped), and drug interactions (cyclosporine metabolization of CP450-IIIA accounts for most such interactions). The results of radioimmunoassay and TDx must be interpreted with care, and HPLC remains the reference technique in borderline cases. Cyclosporine is hepatotoxic in about 20% of cases, generally giving rise to cholestasis. This toxicity is dose-dependent and therefore diminishes when the dosage is reduced. Most groups initially treat rejection with corticosteroids. The response to treatment is generally evaluated in terms of liver function tests.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Hepatic allograft rejection. Diagnostic and therapeutic aspects]. 149 85

We reviewed 37 living related liver transplantations (LRLT) performed by our department during the last 27 months on children with end-stage liver disease. The patients were 15 boys and 22 girls aged 7 months to 15 years with biliary atresia (27), cryptogenic cirrhosis (3), Budd-Chiari syndrome (2), progressive intrahepatic cholestasis (2), protoporphyria (1), Wilson's disease (1), and fulminant hepatitis (1). The donors were 14 fathers and 23 mothers. Grafts were made from the left lateral segment (19), left lateral segment with partial S4 (11), left lobe (6), and right lobe (1). After graft harvesting all donors resumed normal liver function and normal life. The recipient underwent total hepatectomy with preservation of the inferior vena cava. FK506 and low-dose steroids were used for immunosuppression. The survival rate was 90% (27/30) in elective cases and 57% (4/7) in emergency cases. Six recipients had functioning grafts but died of extrahepatic complications. Hepatic vein stenosis occurred in 3 cases at 3 months after LRLT and was successfully treated by balloon dilatation. Portal vein stenosis occurred in 1 case at 8 months after LRLT and was also safely dilated. We incurred no hepatic artery thrombosis after introducing microsurgery techniques. Among 12 viral, 5 bacterial, and 3 fungal postoperative infections, 1 Candida pneumonia and 1 EBV-associated lymphoma were lethal. Three patients with ABO-blood group compatible grafts and one with an incompatible graft developed acute rejection, which was controlled in evey case by steroid bolus and/or increasing the dose of FK506. There were no definite episodes of rejection in ABO-identical cases. Children with moderate growth retardation (> or = -1.5 SD of normal growth) caught up in growth soon after LRLT, but those with severe retardation (<-1.5 SD) were slow to attain age-normal height. Appropriate timing, meticulous surgical procedures, and comprehensive management of complications are crucial for successful outcome with LRLT. LRLT is a promising option for alleviating the shortage of livers for pediatric transplantation and may be regarded as an independent modality to supplement cadaver donation.
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PMID:Living related liver transplantation in children. 751 49

We report our experience in 17 pediatric orthotopic liver transplant (OLT) patients converted from cyclosporine (CsA) to FK506 for intractable acute and chronic rejection. FK506 was initiated orally at a dose of 0.3 mg/kg/day in most patients; the dose was then adjusted to achieve serum levels of 0.5-1.5 ng/ml. Azathioprine was discontinued and low-dose prednisone maintained. The median time between liver transplantation and FK506 conversion was 41 months. Patients have been treated for an average of 14.8 +/- 9.6 months. Six patients were converted for acute rejection and 11 for chronic rejection, i.e., vanishing bile duct syndrome (VBDS). After FK506 conversion, the actual patient and graft survival was 88% and 82%, respectively, in the group as a whole. Two patients died, one of chronic active hepatitis C and the other of lymphoma. Three patients, all with VBDS, did not respond to FK506 and therefore required retransplantation. The serum bilirubin is currently normal in 14 patients and the serum transaminases < 100 IU/ml in 12. The mean bilirubin pre-FK506 of patients successfully converted to FK506 was 4.2 mg/dl compared to 11.8 mg/dl in patients who failed conversion. Major complications included nephrotoxicity, neurotoxicity, and lymphoma. The mean glomerular filtration rate (GFR) of 97 +/- 29 mls/min/1.73m2 prior to FK506 conversion dropped to 51 +/- 20 mls/min/1.73m2 (p = 0.0001) after a mean of 13.6 months of FK506 therapy. Three patients have developed B-cell lymphomas; two of them responded to decreased immunosuppression and one died. We conclude that intractable liver graft rejection in children is most successfully reversed if FK506 is instituted before cholestasis becomes pronounced.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The treatment of intractable rejection with tacrolimus (FK506) in pediatric liver transplant recipients. 754 34

We report two cases of recurrence of primary biliary cirrhosis (PBC) in the transplanted liver whilst maintained on a FK506-based immunosuppressive regime, the first to be described. One patient experienced symptoms in association with the development of cholestasis. In both there was a persistence of serological markers of PBC and liver histology revealed florid bile duct destruction and a granulomatous reaction.
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PMID:Recurrence of primary biliary cirrhosis after liver transplantation following FK506-based immunosuppression. 768 92

Multivisceral transplantation, combined liver-intestine transplantation, and isolated small bowel transplantation are very similar procedures that were first developed in the 1950s. If the viscera can be conceptualized as a cluster of grapes hanging from its arterial stems, the three procedures are characterized by virtually identical vascular anastomoses, with exclusion or inclusion of as many viscera (grapes) as necessary; however, these procedures languished for nearly four decades because of the imperfect immunosuppressive regimens of the 1960s, 1970s, and 1980s. Finally, after the development of FK506, pediatric patients may undergo intestinal transplantation with the hope for long-term survival. These procedures are reserved for TPN-dependent children with permanent intestinal insufficiency. Candidacy for transplantation is also predicated on development of potentially fatal TPN complications such as cholestasis, recurrent sepsis, or thrombosis of access sites. Since 1990, 32 pediatric patients have undergone intestinal transplantation at the University of Pittsburgh, with an overall survival of 65%. Immunosuppression has been accomplished with a combination of corticosteroids, FK506, and prostaglandin E1. Although GVHD has not been a major problem, most patients have experienced rejection episodes requiring intensification of immunosuppression with a steroid bolus, a steroid recycle, an increase in FK506 dosage, or addition of OKT3. CMV has caused little morbidity, but EBV-related PTLD has affected 20% of all patients. It has not been possible to discontinue immunosuppression in the face of PTLD without engendering severe small intestinal rejection. Other problems have included recurrent sepsis, intestinal dysmotility, and persistent food avoidance. Future therapeutic trends are likely to include the performance of combined bone marrow-visceral transplant to induce a chimeric tolerogenic state and to lessen the need for long-term immunosuppression.
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PMID:Small bowel transplantation in infants and children. 769 29

Orthotopic liver transplantation (OLT) has been used with increasing frequency as a definitive treatment for end-stage liver disease. Whereas the spectrum of pathology in the early posttransplant period is well documented, the clinicopathologic features of patients with late hepatic dysfunction are less clearly defined. In a series of 100 OLTs we identified 12 patients with progressive liver dysfunction 4 months after transplantation. Four patients succumbed rapidly to fulminant hepatitis 4 to 6 months following transplantation, three of whom had recurrent hepatitis B infection. One patient lost two successive grafts owing to hepatitis C. Liver biopsies were diagnostic for hepatitis in all cases. The outcome of the remaining eight patients with late hepatic dysfunction was grim. Their clinical courses were notable for intractable and progressive cholestasis. Five patients died and two others required retransplantation. Only one patient responded to increased immunosuppression with FK506. Ductopenia was a common feature of liver biopsies in these cases, but severe ductopenia (vanishing bile duct syndrome) was seen in the liver biopsies of only four patients. In contrast, occlusive arteriopathy and secondary ischemic changes were ubiquitous. In summary, the liver biopsy is a useful adjunct in the diagnosis of late OLT dysfunction, particularly in distinguishing recurrent viral hepatitis from chronic graft rejection. Centrilobular ischemic changes occur frequently in chronic rejection, whereas ductopenia may be difficult to document consistently.
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PMID:Clinicopathologic features of late hepatic dysfunction in orthotopic liver transplants. 850 42

Cyclosporine (CsA) and tacrolimus (FK506) have recently been reported to inhibit canalicular transport of bile acids in vitro and thereby possibly induce cholestasis. A relative reduction of chenodeoxycholic acid (CDCA) has been observed after liver transplantation when CsA is used as immunosuppressant. We tested the hypothesis that CsA induces cholestasis and reduces CDCA secretion as compared with treatment with monoclonal antibodies (OKT3), and that CsA differs from FK506 with regard to its effects on biliary lipid secretion. Bile flow, biliary lipid secretion rates, and biliary bile acid composition were determined during the first 10 days after transplantation in 29 liver transplant recipients. Two prospective randomized studies were performed that compared CsA and OKT3 and compared CsA- and FK506-based regimens. In study 1, bile acid output averaged 0.75+/-0.15 micromol/min in the CsA I group and 0.54+/-0.11 micromol/min in the OKT3 group on postoperative day 1. Bile flow and bile acid output then increased, and there was no significant difference between the two groups. The relative proportion of CDCA decreased to the same extent in both groups. In study 2, mean bile acid outputs on postoperative day 1 were 0.57+/-0.26 micromol/min and 0.55+/-0.15 micromol/min in the CsA 2 and FK506 groups, respectively. The following increase in bile acid secretion was significantly larger in the FK506 group. After transplantation, the relative proportion of CDCA decreased with time in both groups, but the reduction was more rapid in the FK506 group. In conclusion, CsA did not inhibit bile secretion during short-term treatment after liver transplantation. Compared with patients given CsA-based treatment, patients with FK506-based treatment recovered bile secretion more rapidly.
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PMID:Secretion and composition of bile after human liver transplantation: studies on the effects of cyclosporine and tacrolimus. 952 Dec 19

A 43-year-old man underwent living related-donor renal transplantation because of chronic renal failure in 1991. During the transplant period, both donor and recipient were seronegative for hepatitis B surface antigen (HBsAg). The donor was seropositive for antibody to hepatitis B surface antigen (anti-HBs) due to hepatitis B virus (HBV) vaccination. After transplantation, FK506 and methylprednisolone had been administered to the patient as immunosuppressants. In 1993, HBsAg appeared in his serum. His alanine aminotransferase level elevated gradually during 1995 and then in 1996, general fatigue, ascites and jaundice developed. At this time his serum was positive for hepatitis B e antibody, contained more than 100000 Meq/mL HBV-DNA and 100% precore mutant. Despite subsequent intensive therapy, liver dysfunction progressed and this patient died of hepatic failure 2 months following admission. At autopsy, the liver exhibited cholestasis, fibrosis extending from the portal tracts, mild inflammation and hepatocytes with a ground-glass appearance. In addition, HBsAg and hepatitis B core antigens had accumulated in the hepatocytes. Consequently, the final diagnosis was fibrosing cholestatic hepatitis (FCH) due to precore mutant HBV infection contracted after renal transplantation. It is unclear when and where the recipient liver became HBV infected. Nevertheless, after renal transplantation, while receiving immunosuppressive drugs, HBV appeared to have the potential to cause hepatic failure and FCH may have been a fatal complication for the recipient.
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PMID:Fibrosing cholestatic hepatitis after living related-donor renal transplantation. 987 Aug 1

Pediatric donor (PD) livers have been allocated to adult transplant recipients in certain situations despite size discrepancies. We compared data on adults (age > or = 19 years) who underwent primary liver transplantation using livers from either PDs (age < 13 years; n = 70) or adult donors (ADs; age > or = 19 years; n = 1,051). We also investigated the risk factors and effect of prolonged cholestasis on survival in the PD group. In an attempt to determine the minimal graft volume requirement, we divided the PD group into 2 subgroups based on the ratio of donor liver weight (DLW) to estimated recipient liver weight (ERLW) at 2 different cutoff values: less than 0.4 (n = 5) versus 0.4 or greater (n = 56) and less than 0.5 (n = 21) versus 0.5 or greater (n = 40). The incidence of hepatic artery thrombosis (HAT) was significantly greater in the PD group (12.9%) compared with the AD group (3.8%; P =.0003). Multivariate analysis showed that preoperative prothrombin time of 16 seconds or greater (relative risk, 3.206; P =.0115) and absence of FK506 use as a primary immunosuppressant (relative risk, 4.477; P =.0078) were independent risk factors affecting 1-year graft survival in the PD group. In the PD group, transplant recipients who developed cholestasis (total bilirubin level > or = 5 mg/dL on postoperative day 7) had longer warm (WITs) and cold ischemic times (CITs). Transplant recipients with a DLW/ERLW less than 0.4 had a trend toward a greater incidence of HAT (40%; P <.06), septicemia (60%), and decreased 1- and 5-year graft survival rates (40% and 20%; P =.08 and.07 v DLW/ERLW of 0.4 or greater, respectively). In conclusion, the use of PD livers for adult recipients was associated with a greater risk for developing HAT. The outcome of small-for-size grafts is more likely to be adversely affected by longer WITs and CITs. The safe limit of graft volume appeared to be a DLW/ERLW of 0. 4 or greater.
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PMID:Safety and risk of using pediatric donor livers in adult liver transplantation. 1115 Apr 22

Polycystic liver disease (PLD) may provoke massive hepatomegaly and severe physical and social handicaps. Data on orthotopic liver transplantation (OLT) for PLD are rare and conflicting. Conservative surgery (resection or fenestration) is indicated for large single cysts, but its value for small diffuse cysts is questionable. In addition, conservative surgery is not devoid of morbidity and mortality. OLT offers the prospect of a fully curative treatment, but controversy remains because those patients usually have preserved liver function. Thus, we reviewed our experience with OLT for PLD. Sixteen adult women underwent OLT for small diffuse PLD between 1990 and 1999. Mean age was 45 years (range, 34 to 56 years). Fourteen patients had combined liver and kidney cystic disease, but only 1 patient required combined liver and kidney transplantation, whereas 13 patients underwent OLT alone. Two patients had isolated PLD. Indications for transplantation were massive hepatomegaly causing physical handicaps (n = 16), social handicaps (n = 16), malnutrition (n = 4), and cholestasis and/or portal hypertension (n = 5). OLT caused no technical difficulty in 15 of 16 patients (surgery duration, 6.8 hours; range, 5 to 8 hours), with blood transfusions of 7.9 units (range, 0 to 22 units). One patient who underwent attempted liver-mass reduction pre-OLT died of bleeding and pulmonary emboli. Native liver weight was 10 to 20 kg. Posttransplantation immunosuppression consisted of cyclosporine or FK506, azathioprine, and steroids (discontinued at 3 months). Morbidity included biliary stricture (2 patients), revision for bleeding and hepatitis (1 patient), pneumothorax and subphrenic collection (1 patient), and tracheostomy (1 patient). One patient died of lung cancer 6 years posttransplantation. Both patient and graft survival rates are 87.5% (follow-up, 3 months to 9 years). Of 15 patients who underwent OLT alone, only 1 patient needed a kidney transplant 4 years after OLT. Kidney function has remained satisfactory in the other patients despite the use of cyclosporine or FK506 (last follow-up creatinine level, 1.55 mg/dL; range, 0.80 to 2.85 mg/dL). OLT had a dramatic impact on daily quality of life, enabling these patients to go back to a fully active life style. OLT offers the chance of a definitive treatment in patients with extensive, small, diffuse PLD that has evolved into severely handicapping hepatomegaly. In contrast to previous studies, combined liver and kidney transplantation is rarely needed. Patient symptoms and chances of definitive palliation offered by OLT must be balanced against the risks of transplantation and lifelong commitment to immunosuppression.
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PMID:Liver transplantation for polycystic liver disease. 1124 66


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