A real-world experience of SARS-CoV-2 infection in a tertiary referral centre of Montréal: Unexpected low prevalence and low mortality.

BACKGROUND: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with chronic liver disease (CLD) and liver transplant (LT) recipients remains a concern. The aim of this study was to report the impact of coronavirus disease 2019 (COVID-19) infection among patients at the tertiary health care centre Centre hospitalier de l'Université de Montréal (CHUM) during the first wave of the SARS-CoV-2 pandemic. METHODS: This real-world, retrospective cohort included all patients admitted to our liver unit and/or seen as an outpatient with CLD with or without cirrhosis and/or LT recipients who tested positive to SARS-CoV-2 infection. Cases were considered positive as defined by the detection of SARS-CoV-2 by reverse-transcription polymerase chain reaction (RT-PCR) on nasopharyngeal swabs. RESULTS: Between April 1 and July 31, 2020, 5,637 were admitted to our liver unit and/or seen as outpatient. Among them, 42 were positive for SARS-CoV-2. Twenty-two patients had CLD without cirrhosis while 16 patients had cirrhosis at the time of the infection (13, 2, and 1 with Child-Pugh A, B, and C scores, respectively). Four were LT recipients. Overall, 15 of 42 patients (35.7%) were hospitalized; among them, 7 of 42 (16.7%) required respiratory support and 4 of 42 (9.5%) were transferred to the intensive care unit. Only 4 of 42 (9.5%) patients died: 2 with CLD without cirrhosis and 2 with CLD with cirrhosis. Overall survival was 90.5%. CONCLUSION: This real-world study demonstrates an unexpectedly low prevalence and low mortality in the context of SARS-CoV-2 infection among patients with CLD with or without cirrhosis and LT recipients.

Identification of new donor variables associated with graft survival in a single-center liver transplant cohort.

We currently face the more widespread use of marginal livers for organ transplantation. Therefore, it is imperative to adequately identify the factors affecting early and late graft survival in that setting. The objective of this study was to determine the donor variables associated with graft survival in the liver transplant program of the University of Montreal. We retrospectively studied the survival of 634 grafts transplanted into 634 recipients between 1990 and 2008. The variables associated with 1- and 5-year graft survival were identified with the Cox proportional hazards regression model. The donor population was characterized by a mean age of 45.24 ± 18.15 years; 52.8% had at least 1 of the currently recognized extended criteria donor factors. The recipients had a mean age of 52.51 ± 10.80 years and a mean Child-Pugh score of 9.58 ± 2.32. Liver grafts were considered inadequate with respect to their gross appearance in 16 cases (2.5%). The 1- and 5-year graft survival rates were 78.7% and 71.1%, respectively. According to a Cox regression multivariate analysis, the independent determining factors associated with graft survival were (1) the graft appearance (P < 0.001 at 1 and 5 years), (2) the donor partial pressure of oxygen/fraction of inspired oxygen ratio (P = 0.005 at 1 year and P < 0.005 at 5 years), and (3) the donor hemoglobin level (P = 0.008 at 1 year and P = 0.005 at 5 years). In conclusion, the gross graft appearance, the presence of donor lung diffusion abnormalities, and the donor hemoglobin levels were significantly associated with graft survival. These observations, if they are confirmed, could improve our ability to select marginal organs.

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 >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.

Fulminant hepatitis induced by lamotrigine.

Anticonvulsant hypersensitivity syndrome (AHS) is a potentially life-threatening adverse drug reaction presenting with fever, skin eruptions, and internal organ involvement. We describe a case of AHS with fulminant hepatitis that occurred two weeks after introduction of lamotrigine in a 40-year-old female patient with a recently diagnosed bipolar disorder, no pre-existent systemic organ involvement, and no other medication. Lamotrigine was introduced at a dosage of 25 mg daily and increased to 50 mg daily 12 days later. The patient had favorable evolution with cessation of lamotrigine and supportive treatment. This report suggests that AHS with fulminant hepatitis may occur idiosyncratically, independent of dosage, titration and comedication with other potentially hepatotoxic drugs.

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.

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.

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 > or =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 Pugh's 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.

Recurrent hepatitis C post-transplantation: where are we now and where do we go from here? A report from the Canadian transplant hepatology workshop.

Approximately 400 liver transplants are performed in Canada every year and close to 6000 per year in the United States. Forty per cent to 45% of all liver transplants are performed for patients with underlying hepatitis C virus (HCV)-related liver disease. These patients have a different natural history, new complication risks and different treatment efficacy than nontransplant HCV patients. Every effort must be made to identify those patients at highest risk for progressive liver disease post-transplant. Recurrent HCV is an Achilles' heel to transplant hepatology. The true natural history of this disease is only starting to unravel and many questions remain unanswered on the optimal management of these patients after liver transplantation. The present report summarizes the literature and ongoing research needs that are specific to HCV-related liver transplantation.

Poor prediction of the glomerular filtration rate using current formulas in de novo liver transplant patients.

The utility of formulas estimating glomerular filtration rate (GFR) in liver transplant patients has not been well described. The purpose is to determine the correlation between the radionuclide GFR (rGFR) with formulas commonly used to estimate GFR. This study represented a secondary outcome measure of a multicenter randomized trial comparing the effectiveness of two immunosuppressive regimens in adult liver transplant patients (n=148). A total of 68 rGFR were measured, 33 at baseline and at 35 at three months after transplantation. GFR was estimated using 1/Scr and Cockcroft-Gault, MDRD, and Nankivell equations. At both time points assessed, all correlations with rGFR were poor: 1/Scr (r: 0.17 and 0.25), Cockcroft-Gault (r: 0.31 and 0.35), MDRD (r: 0.27 and 0.35), and Nankivell (r: 0.11 and 0.20). Accepted formulas to estimate GFR correlate poorly with rGFR during the first three months after liver transplantation. Recalibration of these formulas is required to improve the estimation of GFR in liver transplant patients.

Brain death diagnoses and evaluation of the number of potential organ donors in Quebec hospitals.

PURPOSE: Faced with our inability to respond to the growing number of Quebec patients waiting for organ transplants, we sought to determine the number of potential organ donors (OD) in acute care hospitals. METHODS: A retrospective chart review of all acute care, in-hospital deaths in Quebec in the year 2000 was undertaken. Hospital record librarians provided statistics and completed questionnaires on each chart after applying exclusion and inclusion criteria. RESULTS: There were 24,702 acute care in-hospital deaths reported by 83 hospitals participating in the study on a voluntary basis. Analyzing 2,067 files meeting inclusion criteria, we identified 348 potential OD (1.4% of deaths). In hospitals not providing tertiary adult trauma care, the potential donor rate was 0.99% of all deaths. There were 4.5 times more potential donors in tertiary care adult trauma centers. Brain death was formally diagnosed in 268/348 patients, and organ donation discussed as an option with 230/268 families. Consent for donation was given in 70% of cases, although not all these patients proved to be suitable after evaluation. There were 125 actual donors in Quebec in the year 2000 (18 per million population). CONCLUSIONS: The gap between used and potential donors can be explained by several factors including failure to approach families for organ donation, family refusal, incomplete neurological assessment of patients, and medical unsuitability of some consented donors. There is room for improvement in the identification of potential donors and in the presentation of organ donation as an end of life option to families.

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 13-37), and the median time to death was 30 months (95% confidence interval 28-53). 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.

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 m(2); P < 0.001) with and was seen at month 6 (75.4 vs. 69.5 mL/min/1.73 m(2); 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.

Early steroid withdrawal after liver transplantation: the Canadian tacrolimus versus microemulsion cyclosporin A trial: 1-year follow-up.

Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (micro-CsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n = 71) or micro-CsA (n = 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone