Francine Roggen

Transjugular intrahepatic portosystemic shunt after adult liver transplantation: experience in eight patients.

BACKGROUND Transjugular intrahepatic portosystemic shunting (TIPS) has become an effective treatment for the complications of portal hypertension. We assessed the feasibility and outcome of TIPS in liver transplant recipients. METHODS During the period from December 1992 to January 1998, eight adults presenting recurrent hepatitis C virus (five patients) and hepatitis B virus (one patient) infection, veno-occlusive disease (one patient), and secondary biliary cirrhosis (one patient) had TIPS because of refractory ascites (five patients), bleeding esophageal varices (one patient), refractory hepatic hydrothorax (one patient), retransplantation (two patients), and redo-biliary surgery (one patient). RESULTS In two patients, the procedure was difficult due to cavo-caval implantation. Ascites, hydrothorax, and variceal bleeding were controlled in all patients. Moderate to severe encephalopathy developed in four patients; two patients had worsening of their existing encephalopathy. Three of five patients treated with cyclosporine needed a drastic dose reduction due to the development of severe side effects. No long-term survivor developed shunt stenosis or occlusion. Two patients did moderately well at 6 and 14 months, respectively; the former died due to chronic rejection while waiting for a retransplantation. Three did well at 14, 36, and 28 months, respectively; the latter patient died of liver failure 32 months after TIPS. One jaundiced patient died after 1.5 months due to necrotic pancreatitis. Two patients died after 4 and 8.5 months, respectively, due to liver failure; the latter was doing well until 7 months after TIPS. CONCLUSIONS TIPS is feasible in transplant recipients in cases of decompensated allograft cirrhosis, of allograft veno-occlusive disease or when retransplantation or redo-biliary surgery are scheduled in the presence of portal hypertension. At transplantation, the surgeon should keep in mind the eventuality of a later TIPS procedure. Close immunosuppression monitoring is warranted because modified metabolization of cyclosporine (and probably tacrolimus) may cause serious side effects.

Liver transplantation and HBsAg-positive postnecrotic cirrhosis : adequate immunoprophylaxis and delta virus co-infection as the significant determinants of long-term prognosis

BACKGROUND/AIMS The place of liver transplantation in hepatitis B viral (HBV)-related diseases remains controversial because of the high rate of reinfection. The aim of this study was to define the determinants of long-term prognosis after transplantation. METHODS Fifty-eight patients were transplanted during the period February 1984-September 1996. Six patients died during the early (< 3 months) posttransplant period from causes unrelated to HBV infection. All 52 long-term (> 3 months) survivors were evaluated in relation to the mode of presentation, viral replication at time of transplantation, absence of hepatocellular cancer at time of transplantation and use of adequate immunoprophylaxis (IP). Adequate immunoprophylaxis, defined as maintenance of anti-HBs levels over 100 mUI/ml, was introduced in December 1989. Intention-to-treat IP analysis compared patients transplanted before and after this date. The median follow-up was 74 months (range 4 to 131). Forty-seven patients (90%) had a minimal follow-up of 3 years. RESULTS Five-year actuarial survival rates of 58 patients and of 52 long-term survivors were 72 +/- 6% and 80 +/- 6%, respectively. Univariate analysis showed that delta co-infection (n = 25) significantly improved survival (p < 0.001) [96 +/- 4% vs 63 +/- 10% in HBV patients (n = 27) at 5 years] as did absence of hepatocellular cancer (n = 36) (p = 0.020) [89 +/- 5% vs 61 +/- 12% in 16 non-cancer patients]. IP, however, significantly influenced 5-year survival in the HBV-patient group (n = 17) (p = 0.001) [85 +/- 10% vs 30 +/- 14% in 10 patients without IP). Multivariate analysis selected delta co-infection (p = 0.002) and IP (p = 0.01) as the significant determinants of prognosis independently influencing survival. Uni- and multivariate analyses showed that survival without reinfection was significantly influenced by IP (p = 0.002) [73 +/- 8% (n = 31) versus 33 +/- 12% in 15 non-treated patients). CONCLUSIONS Delta virus co-infection and immunoprophylaxis are the most important prognostic factors after transplantation for postnecrotic HBsAg-positive cirrhosis. Transplantation can be proposed as a therapeutic tool only if life-long adequate adjuvant therapy can be achieved. Under this condition good results can even be obtained if there is viral replication at the time of transplantation.

Quality control of the European Liver Transplant Registry: results of audit visits to the contributing centers

Background. The number of registries is increasing, but few of them perform reliability audits by comparing the data contained in the database with data contained in hospital charts. Methods. The European Liver Transplant Registry (ELTR) cocoordinating committee appointed an independent team to check the reliability of data contained in ELTR. Centers were selected at random. Ten percent of each center’s files were selected at random, and 25 items per file were checked during the site visits. The rates of completeness and inconsistencies and the agreement between ELTR and charts were established. We also assessed the correlation between the quality of data and the visited centers’ activity. Results. Seven hundred thirty-four files from 21 centers have been audited between June 1998 and June 2001. The rate of ELTR completeness was 95%, and the rate of consistency between charts and ELTR was 98%. The agreement between the ELTR and charts review was very good for all conditions (kappa value ≤0.81). However, comparisons of rates between items indicated that specific items, mostly cause of death or graft failure and patient outcome, should be targeted for improvement. No significant correlation was found between the quality of data and the experience of visited centers. The mean (min–max) and median cost per audited file were EUR 60 (8–150) and EUR 44, respectively. Conclusion. The results of audit visits indicate that ELTR data are reliable, and the scientific results of ELTR can be considered credible and representative of liver transplantation in Europe. The method could serve as a model for auditing a registry.

Tacrolimus monotherapy in liver transplantation: one-year results of a prospective, randomized, double-blind, placebo-controlled study.

Background:Minimal immunosuppression (IS) is desirable in organ transplantation to reduce side effects and to promote the process of tolerance induction. Material and Methods:Between February 2000 and September 2004, 156 adults (>15 years old) receiving a primary liver graft were enrolled in a prospective, randomized, double-blind, placebo-controlled, investigator-driven single-center study comparing tacrolimus (TAC)-placebo (PL) and TAC-low-dose, short-term (64 days) steroid (ST) IS. There were no exclusion criteria at moment of randomization. All patients had a 12-month follow-up (range, 12–84). Results:Three- and 12-month patient survival rates were 93.6% and 87.2% in the TAC-PL group and 98.7% and 94.7% in TAC-ST group (P = 0.096 and P = 0.093, respectively). Three- and 12-month graft survival rates were 92.3% and 85.9% versus 97.4% and 92.3% (P = 0.14 and 0.13, respectively). By 3 and 12 months, rejection treatment had been given in 20.5% (16 pts) and 23% (18 pts) of TAC-PL patients and in 12.7% (10 pts) and 20.5% (16 pts) of TAC-ST patients (P = 0.20 and 0.54). Corticosteroid-resistant rejection (CRR) at 3 and 12 months was recorded in 12.8% (10 pts) of TAC-PL patients and 3.8% (3 pts) of TAC-ST patients (P = 0.04). When considering the 145 patients transplanted without artificial organ support (n = 145), CRR at 3 and 12 months was recorded in 8.8% (6/68 pts) of TAC-PL patients and in 3.9% (3/77 pts) of TAC-ST patients (P = 0.22). Vanishing bile duct syndrome was diagnosed in 1 (1.2%) TAC-PL patient and 4 (5.1%) TAC-ST patients (P = 0.17). By 1 year, 78.2% (61/78) of TAC-PL patients and 82% (64/78) of TAC-ST patients were on TAC monotherapy (P = 0.54). When considering 67 TAC-PL and 74 TAC-ST survivors, rates of monotherapy were 91% (61 pts) and 86.5% (64 pts) (P = 0.39). At 1 year, 62.5% (42 pts) of TAC-PL survivors and 64.9% (48 pts) of TAC-ST survivors were on low-dosage (<6 ng/mL) TAC monotherapy (P 0.79). Conclusion:TAC monotherapy can be achieved safely without compromising graft nor patient survival in a primary, even unselected, adult liver transplant population. The higher incidence of early CRR in the TAC-PL group related to the significantly higher number of patients transplanted while being on artificial organ support. In such condition, this monodrug immunosuppressive strategy needs to be adapted. TAC monotherapy strategy should lay the basis for further large scale minimization studies in liver transplantation.

Validation of a liquid chromatography-mass spectrometric assay for tacrolimus in liver biopsies after hepatic transplantation: correlation with histopathologic staging of rejection.

The aims of this work were both to validate a sensitive and specific method to quantify tacrolimus (TAC) in liver biopsies after hepatic transplantation and to evaluate the predictive value of either tissue or blood TAC concentrations for rejection in 146 adult patients under a TAC-based immunosuppression. Trough blood levels were monitored daily during the hospital stay by immunoassay. Liver biopsies were routinely performed at day 7 posttransplantation. The tissue assay was developed by liquid chromatography-mass spectrometry. The limit of quantification was 5 pg/mg, with intra- and interassay precision ranging from 3.9% to 14.3% and 4.7% to 15.9%, respectively. The extraction efficiency was approximately 80%. TAC found in liver biopsies ranged from less than 5 up to 387 pg/mg. Blood TAC levels ranged from 2.7 to 19.3 ng/mL. Tissue levels displayed excellent correlation with liver histopathologic BANFF rejection score, whereas blood levels did not. Clinically significant rejections (BANFF scores ≥6) were characterized by mean TAC tissue and blood concentration of 13.1 pg/mg and 7.6 ng/mL, respectively, whereas these mean values became, respectively, 74.9 pg/mg (P < 0.05) and 7.1 ng/mL (not significant) for nonclinically significant rejection episodes (BANFF <6). In this study, hepatic tissue TAC concentrations were distributed in a wider range and displayed a significantly better correlation with the severity of the organ rejection than predose blood levels. A tissue TAC concentration less than 30 pg/mg is 89% sensitive and 98% specific to discriminate clinically significant cellular rejection. Further studies are required to better understand the factors affecting TAC distribution within liver tissue (such as carrier proteins and cytochrome genetic polymorphism, liver function, age, hepatic blood flow, type of organ transplanted, time posttransplantation) and to define its value in the treatment of liver allograft rejection.

Liver transplantation for hepatocellular cancer : UCL experience in 137 adult cirrhotic patients. Alpha-foetoprotein level and locoregional treatment as refined selection criteria.

Liver transplantation (LT) is a validated treatment for selected cirrhotics with hepatocellular cancer (HCC). A retrospective single center study including 137 recipients having proven HCC was done to refine inclusion criteria for LT as well as to look at impact of locoregional treatment (LRT) on outcome. At pre‐LT imaging, 42 (30.6%) patients were Milan criteria (MC)‐OUT; 28 (20.4%) were University of California San Francisco criteria (UCSFC)‐OUT. Pre‐LT LRT was performed in 109 (79.6%) patients. Multivariate analysis identified four factors to be independently predictive of recurrence: tumour number >3, AFP level ≥400 ng/ml, microvascular invasion and rejection needing anti‐lymphocytic antibodies. When considering pre‐transplant variables only, AFP level ≥400 ng/ml (HR = 5.13; P < 0.0001) was the unique risk factor for recurrence; conversely, application of LRT was protective (HR = 0.42; P = 0.04). MC‐IN patients having LRT (n = 79) had the best 5‐year tumour‐free survival (TFS) (91.6%). MC‐IN patients without LRT (n = 16) and MC‐OUT patients with LRT (n = 30) had similar good TFS (72.7% vs.77.5%); finally MC‐OUT patients without LRT (n = 12) had the worst results (45.0%; vs. 1st group: P < 0.0001). Immediate pre‐LT AFP and aggressive pre‐transplant LRT strategy, especially in MC‐OUT patients, are both important elements to further expand inclusion criteria without compromising long‐term results of HCC liver recipients.

Use of anti-HBc positive allografts in adult liver transplantation: toward a safer way to expand the donor pool

The use of livers from anti‐hepatitis B core (HBc) positive donors can alleviate donor shortage. Nineteen of 367 (6%) adults receiving anti‐HBc positive allografts [three were hepatitis B antigen (HBsAg) negative, hepatitis B antibody (HBsAb) positive; four were HBsAg positive and 12 were not exposed to hepatitis B viral (HBV) infection] were retrospectively reviewed. In HBsAg negative recipients, immunoprophylaxis (IP) was guided by viral serology and immunohistochemistry (IH) of day 0 and day 7 liver biopsies. If IH was negative, IP was stopped. None of three HBsAg negative, HBsAb positive recipients infected; one (replicating) of four HBsAg positive recipients reinfected and seven of eight (87.5%) HBsAg, HBsAb negative recipients, who did not receive long‐term IP, infected after a median time of 2 years (range 1–5); one patient died of liver failure. Four HBsAg, HBsAb negative recipients, receiving life‐long IP, remained infection free. Anti‐HBc positive donor livers must be directed selectively first to HBsAg positive recipients, next to recipients having HBV antibodies and finally to HBV‐naive recipients. Identification of both donor and recipient risk factors for HBV infection before transplantation allows indiscriminate use of antiviral prophylaxis. The necessity for IP therapy should be guided by HBV‐DNA testing of donor liver tissue and serum. IH of early liver biopsies is an unreliable marker for predicting antiviral treatment requirements.

Cavocaval adult liver transplantation and retransplantation without venovenous bypass and without portocaval shunting: a prospective feasibility study in adult liver transplantation.

Background. The original method of liver transplantation (LT) included recipient inferior vena cava (IVC) resection and the use of extracorporeal venovenous bypass (VVB). Refinements in technique permit transplantation to be done with IVC preservation and without VVB use. Material and Methods. Between November 1993 and November 2000, 202 consecutive grafts were performed in 188 adults (≥16 years of age). Twelve patients (6.4%) received two and three retransplants (re-LT). Split grafting was performed 19 times (19 of 202 grafts, 9.4%). Risk factors included United Network of Organ Sharing status I (n=30, 16%), previous right upper abdominal surgery (n=32, 17.1%), caudate lobe encirclement of IVC (n=65, 32.2%), IVC (n=24, 11.9%), and splanchnic venous modification (n=58, 30.9%), transjugular intrahepatic portosystemic stent shunt (n=34, 16.8%), giant (>5 kg) liver tumor (n=6, 3%), septic necrosis of the caudate lobe (n=1, 0.5%), and previous cavocaval (n=13, 6.4%) or classical LT (n=5, 2.5%). Results. IVC preservation, avoidance of IVC cross clamping and of VVB use were possible in 98.9%, 93%, and 99.5% of 183 primary LT and in 89.5%, 84.2%, and 89.5% of 19 re-LT. Temporary portocaval shunting was never applied. Perioperative mortality was 1.2%. There was no allotransfusion in 73 (36%) grafts and 45 (22%) patients were immediately extubated. Permanent hepatic vein and caval problems were encountered in three (1.5%) grafts. One patient needed stent placement to treat IVC stenosis. Actual 3- and 12-month patient survival for whole, re-LT, and right-lobe split LT groups were 94.7%, 94.1%, 94.7%, 88.2%, 94.1%, and 89%. Three-month graft survival rates for these groups were 92.6%, 94.7%, and 84.2%. Conclusions. LT with IVC preservation and without VVB use and portocaval shunting is possible in nearly all primary transplants and in the majority of re-LT.

Hematochezia and congenital extrahepatic portocaval shunt with absent portal vein: successful treatment by liver transplantation.

Congenital absence of the portal vein is a very rare condition. An exceptional case of successful liver transplantation in an adult with incapacitating hematochezia without any signs of impaired liver function is presented. The patient was born at 38 weeks of gestation. He first presented with an episode of hematochezia at 6 years of age. Clinical examination at that time showed congestive hemorrhoids. After that he had several severe episodes of hematochezia, causing incapacitating anemia. Angiography revealed a significant splanchnic venous anomaly corresponding to type I congenital extrahepatic portocaval shunt (CEPSh). An enormous venous collector connected to the left internal iliac vein and inferior vena cava (IVC) replaced the absent portal vein. Huge venous collaterals surrounded the bladder (Figure 1A, B). Biochemical examination revealed severe anemia, elevated international normalized ratio, and normal ammonium and albumin levels. Colonoscopy showed significant rectocolic varicosities. There were no signs of portal hypertension. Repeated ultrasonography examinations showed progressive shrinking of the liver volume. Local control of the bleeding was not considered as a therapeutic option due to the size of the ano-recto-colonic varices and due to the fact that the venous pelvic collaterals were draining into the IVC through several large vessels (Figure 1B). Despite the absence of any functional liver disturbance, the lower gastrointestinal tract bleeds, the incapacitating anemia that interfered severely with his job as a baker, and the ultrasonography findings all led to the decision to perform a liver transplantation to normalize his splanchnic venous

Is minimal, [almost] steroid-free immunosuppression a safe approach in adult liver transplantation? Long-term outcome of a prospective, double blind, placebo-controlled, randomized, investigator-driven study

Objective:To investigate the safety of minimal immunosuppression (IS) in liver transplantation (LT). Background:The lack of long-term follow-up studies, including pathologic data, has led to a protean handling of IS in LT. Methods:Between February 2000 and September 2004, 156 adults were enrolled in a prospective, randomized, double-blind, placebo-controlled minimization trial comparing tacrolimus placebo (TAC-PLAC) and TAC short-term steroid (TAC-STER) IS. All patients had a minimum clinical, biochemical, and histological follow-up of 5 years. Results:Five-year actual patient and graft survival rates in TAC-PLAC and TAC-STER groups were 78.1% and 82.1% (P = 0.89) and 74.2% and 76.9% (P = 0.90), respectively. Five-year biopsies were available in 112 (89.6%) of 125 survivors. Twelve patients refused a biopsy because of their excellent evolution; tissue material was insufficient in 1 patient; 11 had normal liver tests; and 2 patients had developed alcoholic and secondary biliary cirrhosis. Histology was normal in 44 (39.3%) patients; 35 (31.3%) had disease recurrence. The remaining biopsies showed nonspecific chronic hepatitis (14.3%), mild inflammatory infiltrates (10.7%), and steatosis (3.5%). All findings were equally distributed between both groups. In each group, 3 patients (4.8%) presented with acute cellular rejection after the first year and only 1 (0.9%) TAC-PLAC patient developed chronic rejection after IS withdrawal because of pneumonitis. Arterial hypertension, diabetes mellitus, renal insufficiency, hypercholesterolemia, gout, and obesity were equally low in both groups. Conclusions:Excellent long-term results can be obtained under minimal IS and absence of steroids. TAC-based monotherapy is feasible in most adult liver recipients until 5 years of follow-up.