Denis Marleau

Evaluation of renal function in liver transplant recipients receiving daclizumab (Zenapax), mycophenolate mofetil, and a delayed, low-dose tacrolimus regimen vs. a standard-dose tacrolimus and mycophenolate mofetil regimen: A multicenter randomized clinical trial

Posttransplant chronic renal failure, secondary to calcineurin inhibitor agents, is emerging as a major problem in liver transplantation. We report a randomized clinical trial comparing daclizumab, delayed low‐dose tacrolimus (target trough level 4‐8 ng/mL, starting day 4‐6), Investigational Arm (n = 72), to standard tacrolimus induction/maintenance dosing, Standard Arm (n = 76), with mycophenolate mofetil and tapering corticosteroids in both study arms. The end‐points were renal function indicated by the Modification of Diet in Renal Disease (MDRD). There was no significant difference in patient survival (86.6% Investigational Arm vs. 92.9% Standard Arm; P = 0.21) or acute rejection (23.2% vs. 27.7%, respectively; P = 0.68). Statistically significant differences in median glomerular filtration rate (GFR) were found in favor of the Investigational Arm. With the CG equation, the GFR at the end of the first week was 110.7 vs. 89.6 mL/min (P = 0.019) without significant differences thereafter. With the MDRD, statistically significant differences extended to the first posttransplant month (86.8 vs. 70.1 mL/min/1.73 m2; P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m2; P = 0.038). In conclusion, delayed low‐dose tacrolimus, in combination with daclizumab and mycophenolate mofetil, preserves early renal function post–liver transplantation without the cost of increased acute rejection. (Liver Transpl 2005;11:1064–1072.)

Coagulation Defects Do Not Predict Blood Product Requirements During Liver Transplantation

Background. In our experience, correction of coagulation defects with plasma transfusion does not decrease the need for intraoperative red blood cell (RBC) transfusions during liver transplantation. On the contrary, it leads to a hypervolemic state that result in increased blood loss. A previous study has shown that plasma transfusion has been associated with a decreased 1-year survival rate. The aim of this prospective study was to evaluate whether anesthesiologists could reduce RBC transfusion requirements during liver transplantation by eliminating plasma transfusion. Methods. Two hundred consecutive liver transplantations were prospectively studied over a 3-year period. Patients were divided into two groups: low starting international normalized ratio (INR) value <1.5 and high INR ≥1.5. Low central venous pressure was maintained in all patients before the anhepatic phase. Coagulation parameters were not corrected preoperatively or intraoperatively in the absence of uncontrollable bleeding. Phlebotomy and auto transfusion of blood salvaged were used following our protocol. Independent variables were analyzed in both univariate and multivariate fashion to find a link with RBC transfusions or decreased survival rate. Results. The mean number of intraoperative RBC units transfused was 0.3±0.8. Plasma, platelet, albumin, and cryoprecipitate were not transfused. In 81.5% of the patients, no blood product was used during their transplantation. The average final hemoglobin (Hb) value was 91.2±15.0 g/L. There were no differences in transfusional rate, final Hb, or bleeding between two groups (low or high INR values). The overall 1-year survival rate was 85.6%. Logistic regression showed that avoidance of plasma transfusion, phlebotomy, and starting Hb value were significantly linked to liver transplantation without RBC transfusion. The need for intraoperative RBC transfusion and Pughs score were linked to the decreased 1-year survival rate. Conclusion. The avoidance of plasma transfusion was associated with a decrease in RBC transfusions during liver transplantation. There was no link between coagulation defects and bleeding or RBC or plasma transfusions. Previous reports indicating that it is neither useful nor necessary to correct coagulation defects with plasma transfusion before liver transplantation seem further corroborated by this study. We believe that this work also supports the practice of lowering central venous pressure with phlebotomy to reduce blood loss, during liver dissection, without any deleterious effect.

Liver transplantation for incidental cholangiocarcinoma: Analysis of the Canadian experience

Cholangiocarcinoma is a biliary tumor, which not infrequently complicates primary sclerosing cholangitis. It carries a poor prognosis and, with the exception of carefully selected individuals in research protocols, contraindicates orthotopic liver transplantation. There has been some suggestion that cholangiocarcinomas incidentally discovered at the time of transplantation carry a better prognosis. The goal of this retrospective study was to perform a national review of outcomes after liver transplantation in Canadian recipients found to have incidental cholangiocarcinoma in their explanted native liver. Six of the seven liver transplant centers in Canada provided clinical and follow‐up information on all liver transplant recipients found to have incidental cholangiocarcinoma in their explants. The diagnosis or suspicion of cholangiocarcinoma prior to transplantation were exclusion criteria for this study. Ten individuals with cholangiocarcinoma were transplanted between 1996 and 2003. The median duration of follow‐up was 28 months. Eight of the 10 had PSC. All of the tumors were stage I or II. The 3‐year survival for these patients was 30%. The median time to recurrence was 26 months (95% confidence interval 13uu‐uu37), and the median time to death was 30 months (95% confidence interval 28uu‐uu53). In conclusion, although early survival of patients transplanted for incidental cholangiocarcinoma appears good, intermediate‐ and long‐term survival rates are not better than for individuals historically transplanted with known cholangiocarcinoma. Aggressive investigation for cholangiocarcinoma is mandated. Incidentally found tumours remain a difficult treatment problem, and prospective adjuvant chemo‐, radio‐, and immunotherapies should be investigated. (Liver Transpl 2005;11:1412–1416.)

Treatment of chronic bleeding from gastric antral vascular ectasia (GAVE) with estrogen-progesterone in cirrhotic patients: an open pilot study.

Objective:Gastric antral vascular ectasia (GAVE) is a rare cause of chronic bleeding in cirrhotic patients. Treatment of GAVE with surgical or nonsurgical portal decompression, β-blockers, or endoscopic therapy provides disappointing results. In the present study, we evaluated the efficacy of estrogen-progesterone therapy, which has been reported to control chronic bleeding in gastrointestinal vascular malformations, such as Osler-Weber Rendu disease or angiodysplasia, in GAVE-related chronic bleeding.Methods:Six cirrhotic patients who bled chronically from GAVE were included. Three had alcoholic cirrhosis, two cryptogenic cirrhosis, and one primary biliary cirrhosis. Grade 1 esophageal varices were noted in four patients. Bleeding could not be controlled by β-blockers, and endoscopic therapy was not considered given the extension of the antral vascular lesions.Results:Before the start of therapy, transfusion requirements averaged 3.5 units/month over a 1.5–11 month period of observation. Patients were then treated with a combination of ethynil estradiol 30 μg and noretisterone 1.5 mg daily. During follow-up (range 3–12 months), bleeding did not recur in four patients; in one patient, treatment with estrogen progesterone decreased the need for transfusions from 4 units/month to 1.4 unit/month; this patient stopped the treatment inadvertently after 6 months and severe anemia recurred with a need for 4 units of blood in the following month; reintroduction of the treatment resulted in an increase of hemoglobin levels without the need for blood transfusions during the following 4 months. In the last patient, a 5-month treatment did not improve chronic bleeding.Conclusion:The present study suggests that estrogen-progesterone therapy is useful in the treatment of chronic bleeding related to GAVE; however, these findings require confirmation by a controlled trial.

MELD score and blood product requirements during liver transplantation: no link.

Background. Orthotopic liver transplantation has been traditionally associated with major blood loss and the need for allogenic blood product transfusions. In recent years, improvements in surgical and anesthetic techniques have greatly decreased the amount of blood products transfused. We have published a median of 0 for all intraoperative blood products transfused. Some authors argue that these results could be possible merely because of the relatively healthy cohort in terms of model of end-stage liver disease (MELD) score. The MELD score could be adjusted by some conditions (hepatocellular carcinoma, hemodialysis, hepatopulmonary syndrome, and amyloidosis) and was not adjusted in these series. The goal of this work was to verify the MELD score according to US standards and to find any link between the MELD score and the transfusion rate. Method. Three hundred fifty consecutive liver transplantations were studied. The MELD score was adjusted according to US standards. Patients were divided into two groups according to the median of the MELD score. Blood loss and transfusion rate were determined for these two groups. Logistic regression models were used to find any link with transfusion of red blood cell (RBC) units. Result. The MELD score before adjusting was 19±9 and 22±10 after. A mean of 0.5±1.3 RBC units/patient intraoperative were transfused with 80.6% of cases without any blood products. There was no difference for the blood loss (999±670 mL vs. 1017±885 mL) or the transfusion rate (0.4±1.2 vs. 0.5±1.4 RBC/patient) between two groups of MELD (<21 or ≥21) or any of its component (creatinine, bilirubin, and international normalized ratio). The logistic regression analysis found that only two variables were linked to RBC transfusion; starting hemoglobin value and phlebotomy. Conclusion. In this series, the MELD score was as high as US series and did not predict blood losses and blood product requirement during liver transplantation. If the MELD system has to be implemented to prioritize orthotopic liver transplantation, it should be revisited, and the starting hemoglobin value should be added to the equation.

Interface hepatitis is associated with a high incidence of late graft fibrosis in a group of tightly monitored pediatric orthotopic liver transplantation patients

Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long‐term problem after liver transplantation. The aim of this study was to characterize our group of post–orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval −28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid‐resistant rejection, acute rejection later than 3 months post‐OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)‐positive serology with a CMV‐negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non–organ‐specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow‐up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes. Liver Transpl 14:946–955, 2008.

Systemic and hepatic hemodynamics after variceal hemorrhage: Effects of propranolol and placebo

Hepatic and systemic hemodynamics were measured in 19 cirrhotic patients with variceal bleeding enrolled in a controlled trial of propranolol for the prevention of rebleeding. The patients were studied on three separate occasions. The first study was performed before randomization within 24 h of the bleeding episode, once hemodynamic stabilization had been achieved. The second study was performed after 10 days of treatment, and the third after 6 mo without rebleeding. Propranolol dosage was titrated according to blood levels. Wedged and free hepatic venous pressures and the hepatic venous pressure gradient were recorded. Hepatic blood flow and cardiac output were also measured. Before treatment, the groups of patients treated with propranolol (n = 11) or placebo (n = 8) were comparable according to clinical, biochemical, and hemodynamic parameters. After 10 days, hepatic venous pressure gradient decreased similarly in the two groups (-20% in the propranolol group, -25% in the placebo group). Cardiac output fell only in the propranolol group (-40%). Hepatic blood flow remained unchanged in either group. After 6 mo, hepatic venous pressure gradient remained lower than the values from the first (within 24 h of bleeding) study in both the propranolol group (n = 5) and the placebo group (n = 6). Our results suggest that portal pressure increases shortly after hemorrhage with a return to baseline values 10 days later, and that propranolol does not further magnify these changes. Spontaneous changes in hepatic hemodynamics after variceal hemorrhage must be taken into account when evaluating the effect of pharmacologic agents on portal pressure.

Extraction of 125I-Albumin Microaggregates from Portal Blood: An index of functional portal blood supply in cirrhotics

Portal and hepatic indicator dilution curves (IDC) were obtained after injection of a mixture of 51Cr-labeled red blood cells ([51Cr]RBC) and 125I-albumin microaggregates (125I-AMA) into the cranial mesenteric artery in dogs. The extraction (E) of 125I-AMA from portal blood was measured during one passage through the hepatic reticuloendothelial system. Using [51Cr]RBC as a vascular reference substance, E-125I-AMA was calculated by comparing simultaneous [51Cr]RBC and 125I-AMA portal and hepatic IDC, and was expressed as percentage of 125I-AMA flowing through the portal vein. In 44 experiments (15 dogs), the colloid was almost completely extracted (E-125I-AMA = 92.3 +/- 1.0% (mean +/- SE)). This approach was applied in 15 patients with severe portal hypertension undergoing combined umbilicoportal, hepatic vein, and superior mesenteric artery catheterization. Eleven patients had alcoholic cirrhosis (AC) and 4 patients had idiopathic noncirrhotic portal hypertension (IPH). Using [51Cr]RBC-IDC, the portal fraction of hepatic blood flow varied between 34.1 and 100% (mean 62.6%) in AC patients and between 56.5 and 91.2% (mean 74.2%) in IPH patients. E-125I-AMA varied from 5.2 to 100% (mean 45.1%) in AC patients, although normal values were obtained in IPH patients (mean 93.2%). In all patients the extraction of Indocyanine green (E-ICG) was calculated using a continuous infusion for the estimation of hepatic blood flow. E-ICG was decreased in AC patients (mean 22.1%), although normal values were obtained in IPH patients (mean 49.5%). A highly significant correlation was found between E-125I-AMA and E-IGC (r = 0.977, P less than 0.001). Also, a significant correlation was found in all patients between E-125I-AMA and the relative clearance of ICG (r = 0.906, P less than 0.001). The correlations between the extraction or clearance of substances removed by two different cell population suggest that their decreases are mainly due to changes in liver microcirculation. In cirrhotics, the decreased E-125I-AMA can be related to part of portal blood bypassing Kupffer cells (intrahepatic portohepatic shunts) and/or to sinusoidal changes responsible for ineffective phagocytosis. Thus, E-125I-AMA can be used as an estimation of the functional portal blood supply to the liver in cirrhotics. Using portal and hepatic IDC after injection of [51Cr]RBC and 125I-AMA into the superior mesenteric artery, the portal fraction of hepatic blood flow and the functional portal blood supply can be estimated simultaneously in patients with portal hypertension before portacaval shunts.

Liver transplantation for hepatic epithelioid hemangioendothelioma: The Canadian multicentre experience

INTRODUCTION Hepatic epithelioid hemangioendothelioma (HEHE) is a rare entity. At the present time, there is no standardized effective therapy. Liver transplantation (LT) has emerged as a treatment for this rare tumour. OBJECTIVE To evaluate the outcome of liver transplantation for HEHE at eight centres across Canada. METHODS The charts of patients who were transplanted for HEHE at eight centres across Canada were reviewed. RESULTS A total of 11 individuals (eight women and three men) received a LT for HEHE. All LTs were performed between 1991 and 2005. The mean (+/- SD) age at LT was 38.7+/-13 years. One patient had one large liver lesion (17 cm x 14 cm x 13 cm), one had three lesions, one had four lesions and eight had extensive (five or more) liver lesions. One patient had spleen involvement and two had involved lymph nodes at the time of transplantation. The mean duration of follow-up was 78+/-63 months (median 81 months). Four patients (36.4%) developed recurrence of HEHE with a mean time to recurrence of 25+/-25 months (median 15.6 months) following LT. The calculated survival rate following LT for HEHE was 82% at five years. CONCLUSIONS The results of LT for HEHE are encouraging, with a recurrence rate of 36.4% and a five-year survival rate of 82%. Further studies are needed to help identify patients who would benefit most from LT for this rare tumour.

Hyperglobulinemia in alcoholic cirrhosis. Relationship with portal hypertension and intrahepatic portal-systemic shunting as assessed by Kupffer cell uptake.

The relative importance of portal hypertension and intrahepatic portal-systemic shunting in the pathogenesis of hyperglobulinemia is examined in 31 alcoholic cirrhotic patients and 6 patients with idiopathic portal hypertension. The degree of portal hypertension was evaluated by combined umbilicoportal and hepatic vein catheterization and the intrahepatic portal-systemic shunting was assessed by the Kupffer uptake of [125I]albumin microaggregates during a single passage through the liver. All patients had comparable severe portal hypertension and most had bled from ruptured varices; however, no demonstrable relationship could be found between portal hypertension and hyperglobulinemia. Elevated levels of serum gammaglobulins and immunoglobulins (mainly IgG) were observed only in cirrhotic patients, particularly those with markedly altered Kupffer cell uptake. It is concluded that intrahepatic portal systemic shunting as evaluated by the Kupffer cell uptake is more important than the collateral circulation secondary to portal hypertension in the pathogenesis of hyperglobulinemia in alcoholic cirrhotic patients.