M. de la Mata

Outcome of autoimmune hepatitis after liver transplantation.

BACKGROUND Recurrence of autoimmune hepatitis after liver transplantation is not rare, but there is little information about its time of onset, risk factors, response to treatment and prognosis. The aim of this study was to evaluate the rate of recurrence and outcome of autoimmune hepatitis after transplantation. METHODS The records of patients transplanted in eight centers in our country between 1984 and 1996 were retrospectively analyzed. RESULTS Forty-three of the 2331 (1.8%) recipients fulfilled diagnostic criteria of autoimmune hepatitis at the time of transplantation. Sixteen patients were excluded from evaluation. Nine (33%) of the 27 patients evaluated fulfilled criteria for recurrence of autoimmune hepatitis, with a mean time of recurrence after orthotopic liver transplantation of 2.6+/-1.5 years. Patients with recurrence had a longer follow-up time after transplantation (5.1 vs. 2.5 years, P=0.0012) and were receiving less immunosuppressive treatment. The estimated risk of recurrence of autoimmune hepatitis in the graft increased over time: 8% over the first year and 68% 5 years after transplantation. None of the seven patients with liver-kidney microsomal-positive antibodies recurred (P=0.059). Fifty percent of the patients failed to respond or responded only partially to therapy, although none of the patients have deteriorated clinically after 2.4+/-1.06 years of follow-up after recurrence. CONCLUSIONS Recurrence of autoimmune hepatitis in the graft is a common event with an incidence that increases over time as immunosuppression is reduced. Although response to treatment is poor, patient and graft survival do not appear to be decreased.

Diminished anticoagulant and fibrinolytic activity following liver transplantation

This study analyzed the coagulation changes in twenty patients after orthotopic liver transplantation. The procoagulant, anticoagulant, and fibrinolytic systems were studied during the first two postoperative weeks. Within the first postoperative day all extrinsic and intrinsic pathway factors became normal except factors IX, VII, and X, which recovered within the next 24 hr. Of interest are the changes in factor VIII, which reached a high concentration with an increase in its antigenic fraction during the study. However, coagulation inhibitors showed a different pattern. In fact, antithrombin III (AT-III) and protein C (PC) needed from 7 to 14 days to reach normal values. Total protein S (TPS) and free protein S (FPS) did not recover until day 7, whereas heparin cofactor II (HC-II) remained at subnormal levels throughout the study. Thrombin-antithrombin III complex (TAT) values were strikingly elevated in the immediate postoperative period. Fibrinolysis parameters showed plasminogen (PL) levels in the normal range until day 4. Antiplasmin (AP) followed a curve parallel to that of plasminogen but its levels were higher during this observation period. Similarly the initial elevation in plasminogen activator inhibitor 1 endothelial type (PAI-1) levels remained high until days 4 and 7. In summary, it can be concluded that during the postoperative phase after OLT a hypercoagulable state is developed as a result of diminished anticoagulant and fibrinolytic activity. This coagulation might be a nontechnical factor contributing to the thrombotic vascular complications of some liver recipients.

Control of blood pressure in liver transplant recipients.

Background Increased blood pressure (BP) is common after liver transplantation. However, there is scarce information on its control. Methods In this prospective, cross-sectional, multicenter study, we determined BP according to the recommended international standards in 921 liver transplant patients during one routine outpatient visit to assess their grade of control of BP. At the time of the study, 490 patients had been previously diagnosed with arterial hypertension and were receiving antihypertensive treatment, and 431 were not previously diagnosed as hypertensive. Results In the hypertensive group, arterial hypertension was uncontrolled (BP >140/90 mm Hg [>130/80 in diabetics]) in 158 (32%) patients and controlled in 332 (68%) patients. In a multivariate analysis, only diabetes was identified as a significant predictor of uncontrolled hypertension. Among patients not previously diagnosed as hypertensive, BP was increased in 106 (25%) and normal in 325 (75%). On multivariate analysis, the only variable independently associated with increased BP in this group was metabolic syndrome. Conclusion BP is not adequately controlled in a noticeable percentage of liver transplant patients, especially in subjects with diabetes or metabolic syndrome.

Model for end-stage liver disease can predict very early outcome after liver transplantation.

Postoperative Model for End-stage Liver Disease (MELD) values have never been assessed to predict very early (<1 week) death after liver transplantation (OLT). We retrospectively reviewed 275 consecutive OLTs performed in 252 recipients reported in a prospective database. We calculated the MELD score (pre-MELD) and consecutive postoperative MELD (post-MELD) scores computed daily during the first postoperative week and on days 15 and 30 after OLT. Post-MELD scores from nonsurviving recipients displayed on a scatterplot of immediate probability of death were adjusted to the best goodness-of-fit curve, and, finally, depicted graphically as a receiver operating characteristic (ROC) curve. Nonsurviving recipients showed higher post-MELD scores: day 1: 23.5 versus 16.6 (P = .05); day 3: 25.1 versus 12.5 (P = .000); day 5: 25.7 versus 11.8 (P = .000); and day 7: 22.1 versus 10.2 (P = .000). Overall comparisons were performed using a time-dependent general linear regression model, revealing higher post-MELD scores for nonsurviving recipients, irrespective of postoperative time (P = .002). The best goodness-of-fit curve was displayed when adjusting to a theoretical exponential regression curve calculated as follows: Probability of dying within the first week (%) = 3.36 x e(0.079 x (post-MELD)) (r = .89; P = .000). The area under the ROC curve was 0.783 (95% confidence interval, 0.630-0.935; P = .001). The model had a positive predictive value of 82.3%, a negative predictive value of 33.1%, and an accuracy of 79.2%. In conclusion, this study corroborated the suggestion that the MELD score may serve as a reliable tool to assess very early death after OLT.

Use of high-risk liver donors for urgent and elective liver transplantation.

ORGAN SHORTAGE is now the main factor limiting the growth of orthotopic liver transplantation (OLT). There is an increasing gap between need and transplantation in both the United States and in Europe. Moreover, the number of patients who benefit from this procedure has been broadened, resulting in patients who are less ill. To assure the best possible outcome, the pioneering transplant clinicians applied strict criteria when selecting potential donors, based on arbitrary medical grounds. This policy has resulted in the refusal of many potential donors, while deaths on waiting lists continue to constitute an unfortunate scenario. The use of high-risk or marginal donors is the most viable short-term means to boost the organ supply. Expansion of the liver donor pool calls for new organselection criteria. The use of older donor livers has been the most “liberalized” criterion. Other criteria such as longer hypotension and cold ischemia times, high-dose inotropic drug use, ICU stay, and morbid obesity status have recently been expanded. We have also reported the influence of unstable and hypernatremic liver donors on graft and patient survival. However, the relationship between these criteria and recipient status is poorly understood. Networks of organ-sharing worldwide aim to providing equity and efficacy of organ distribution, giving highest priority to patients most urgently in need. One major issue in organ allocation concerns which of the following options would contribute most to saving lives and improving longterm survival: (1) allocating organs according to sequence on the waiting list; (2) avoiding the confluence of risk factors from recipients and those from donors; or (3) reserving higher risk organs for higher risk recipients.

Tacrolimus exposure after liver transplantation in randomized controlled trials: too much for too long.

We read with great interest the randomized controlled trial (RCT) by De Simone et al. (1), which evaluated the combination of tacrolimus and everolimus after liver transplantation (LT). They demonstrated that glomerular filtration rate decreased less at 12 months with everolimus and reduced tacrolimus, compared to a conventional tacrolimus based regimen, while rejection rates were similar. Although these results are promising we are very concerned about what is meant by ‘‘conventional exposure to tacrolimus’’ in RCT, and its potential implications on clinical practice and patients’ safety.

Liver Retransplantation in HIV‐Infected Patients: A Prospective Cohort Study

Information regarding liver retransplantation in HIV‐infected patients is scant. Data from 14 HIV‐infected patients retransplanted between 2002 and 2011 in Spain (6% retransplantation rate) were analyzed and compared with those from 157 matched HIV‐negative retransplanted patients. In HIV‐infected patients, early (≤30 days) retransplantation was more frequently indicated (57% vs. 29%; p = 0.057), and retransplantation for HCV recurrence was less frequently indicated (7% vs. 37%; p = 0.036). Survival probability after retransplantation in HIV‐positive patients was lower than in HIV‐negative patients, 42% versus 64% at 3 years, although not significantly (p = 0.160). Among HIV‐infected patients, those with undetectable HCV RNA at retransplantation and those with late (>30 days) retransplantation showed better 3‐year survival probability (80% and 67%, respectively), similar to that in their respective HIV‐negative counterparts (72% and 70%). In HIV‐infected and HIV‐negative patients, 3‐year survival probability in those with positive HCV RNA at retransplantation was 22% versus 65% (p = 0.008); in those with early retransplantation, 3‐year survival probability was 25% versus 56% (p = 0.282). HIV infection was controlled with antiretroviral therapy after retransplantation. In conclusion, HIV‐infected patients taken as a whole have unsatisfactory survival after liver retransplantation, although patients with undetectable HCV RNA at retransplantation or undergoing late retransplantation show a more favorable outcome.

Mecanismos de lesión hepatocelular

Cell death is a process accompanying many physiological and pathological situations in organisms. The first cell death pattern that was identified was cell necrosis, described by Virchow in 1871. It was subsequently seen that cell death was an integral part of normal cell and tissue differentiation mechanisms in superior organisms. In this respect early embryological studies revealed that cell death processes were required to model organisms in their final configuration. Morphogenesis systematically entails the removal and generation of new cell and tissue structures. A similar phenomenon is encountered during metamorphosis in invertebrates and inferior vertebrates, where massive tissue involution and cell clearance are coordinately developed physiological processes. This cell death process, designated apoptosis, was characterized by Kerr in 1965. Cell apoptosis and necrosis can be differentiated by a number of both morphological and biochemical parameters. Apoptosis is a controlled removal of the involved cell with no relevant changes in cell metabolism. This process is characterized by the sequential activation of a number of proteases known as caspases, which affect cysteine-aspartate bonds in the substrate. Caspase activation entails DNA fragmentation and cell architecture changes, associated with morphological changes such as nuclear DNA condensation, decreased cell volume, and the generation of apoptotic bodies with no intracellular contents release. Necrosis results from an extreme disruption of cell balance dramatically affecting cell metabolism with a drastic decrease in cell energy contents in the form of adenosine triphosphate (ATP), ion contents changes, increased mitochondrial and cell volume, and intracellular protease activation. This process ultimately leads to a disruption of cell membranes, and release of cell contents, which promotes a secondary inflammatory response. In the liver cell apoptosis usually has a focal distribution, whereas necrosis shows a regional distribution. Despite a clear-cut differentiation between apoptosis and necrosis, both types of cell death usually coexist in the liver, because one stimulus may induce apoptosis or necrosis depending on cell type involved, exposure extent, cell metabolic status, and the integrity of the machinery involved in cell death. In this sense a number of authors have suggested that apoptosis and necrosis are no separate processes but the opposing ends in only one cell mechanism designated necrapoptosis (1). Mitochondriagenerated ATP contents are a key factor in the regulation of apoptosis or necrosis induction during the process of cell death. In this respect a lesion involving a few mitochondria may be solved by autophagia of altered organelles. If more mitochondria are involved, and an adequate amount of proapoptotic factors is released while intracellular ATP levels remain, the cell undergoes apoptosis. If the cell undergoes a severe lesion, the dramatic reduction of ATP contents will not allow for many enerMechanisms of liver cell injury

Liver Transplantation for Hepatocellular Carcinoma: Results of a Multicenter Study With Common Priorization Criteria

OBJECTIVE To evaluate the results of liver transplantation (OLT) performed for hepatocellular carcinoma (HCC) among a multicenter cohort of patients with predefined common inclusion and priorization criteria. PATIENTS AND METHODS Over a 5-year period (January 2002-December 2006), 199 HCC patients underwent OLT in four centers in Andalusia. The morphological (Milan) inclusion criteria were priorized in two consecutive periods, according to the Model for End-stage Liver Disease score: group I, 53 patients (HCC < 2 cm = 24 points; > or = 2 cm or multinodular = 29 points) and group II, 146 cases (HCC < 3 cm without priorization; HCC > or = 3 cm or multinodular = 18 points). RESULTS Among the 199 HCCs, 186 (93.5%) subjects were transplanted and 13 (6.5%) were excluded. There were 18 cases (9.7%) where the diagnosis was incidental and 168 were known HCC cases; 144 (85.7%) complied with the Milan criteria (Milan+); 24 (14.3%) exceeded there criteria (Milan-). According to preoperative imaging, the number of nodules and tumor mean sizes among the excluded-Milan+ and Milan- groups-were 1.8/5.3 cm, 1.4/3.5 cm, and 2.3/6.7 cm, respectively (P < .001). Percutaneous treatment during listing was delivered to 55% of the excluded cases: 49% of Milan+ and 96% of Milan-. The median time on the list was 88 days for known HCC (53 days for group I, and 97 days for group II), and 172 days for the incidental HCCs. Staging (pTNM) was correct in 64% of cases: 23% were understaged and 13% were overstaged. Overall mortality within the first 90 days was 9%, and transplant patient survival at 5 years was 61%. No differences were observed in survival rates between both study periods, although there were differences between the Milan+ (65%) and Milan- (23%) groups (P < .04). In addition, the difference in the recurrence rates was also significant between the Milan+ (7%), Milan- (24%), and the incidental (25%) groups (P < .02). CONCLUSIONS A common priorization policy of HCC for OLT based on morphological criteria results in a low exclusion rate on the waiting lists (6.5%). The Milan criteria are still a good cutoff to stratify the risk of recurrence, despite preoperative tumor staging being correct in only two-thirds of cases.

Factores pronósticos de complicaciones postoperatorias en el trasplante hepático

OBJECTIVES the postoperative evolution of patients submitted to orthotopic liver transplant (OLT) is frequently associated with the appearance of different types of complications such as renal failure, graft rejection, infections, and neurological disorders. These complications are the most significant causes of early morbidity and mortality in patients undergoing OLT. The purpose of the present study was the identification of factors related to the different postoperative complications after OLT. EXPERIMENTAL DESIGN a prospective study was carried out. PATIENTS seventy-eight variables were analyzed in 32 consecutive patients undergoing OLT. The factors independently associated with the appearance of postoperative complications were identified using a stepwise logistic regression analysis. RESULTS the multivariate analysis showed that malondialdehyde and creatinine pretransplant serum levels were associated with the development of renal dysfunction. The pretransplant levels of haemoglobin and the units of platelets administered during surgery were prognostic factors of infections. Acute graft rejection was predicted by ?-glutamyl transpeptidase and total bilirubin serum levels. The pretransplant sodium and glutaredoxin levels in serum were associated with neurological complications. CONCLUSIONS we propose these markers for the identification of high-risk patients allowing an early surveillance and/or treatment to improve morbidity and survival in patients submitted to OLT.