Corticoterapia con intención de rescate en pacientes con hepatitis autoinmune severa: ¿el trasplante hepático es evitable?

Resumen: Introducción: La hepatitis autoinmune es una enfermedad cuya presentación clínica inicial puede manifestarse de diversas formas, siendo su presentación aguda con aumento de los niveles de bilirrubina, caída de la función biosintética y necrosis masiva/submasiva o cirrosis en la histología, marcadores de severidad de la misma. La decisión de iniciar tratamiento con corticoides en este escenario resulta un desafío en la práctica clínica. Los objetivos del presente trabajo fueron evaluar el grado de respuesta al tratamiento, los predictores de respuesta, y la supervivencia global y libre de trasplante en pacientes cuyo debut clínico fue de forma aguda y severa. Resultados: Fueron incluidos 33 pacientes con bilirrubina total mayor a 2.5 mg/dl, sin tratamiento previo (naive), que cumplían criterios diagnósticos según el grupo internacional de hepatitis autoinmune. El 97% eran mujeres con una mediana de edad de 52 años, el 58% se encontraba en etapa de cirrosis con un MELD promedio de 24, y el 15% presentaba una necrosis masiva/submasiva en la muestra de biopsia hepática. En 27 casos se inició corticoterapia. El 66.7 % evolucionó con remisión completa, 14.8 % con remisión parcial, y en 18.5% hubo falla al tratamiento corticoideo. La colesterolemia basal y la presencia de encefalopatía hepática fueron predictores de no respuesta al tratamiento corticoideo, mientras que el MELD pre-tratamiento y la colesterolemia basal fueron las variables estadísticamente significativas asociadas a falla en el rescate del trasplante hepático. En los pacientes tratados con corticoides, la supervivencia global y libre de trasplante a 5 años en función del MELD (<25 vs ≥ 25) fue del 90% vs 60% respectivamente. Conclusión: Las altas tasas supervivencia logradas bajo tratamiento médico que fueron evidenciadas en esta serie reafirman la necesidad de priorizar el uso de corticoides en pacientes con hepatitis autoinmune aguda y severa.

Abstract: Introduction: Autoimmune hepatitis can initially manifest itself in various clinical ways. Its acute presentation with increased levels of bilirubin, fall of biosynthetic function and massive/submassive necrosis or cirrhosis in histology, is a marker of severity of it. The decision to start corticosteroid treatment in this scenario is a challenge in clinical practice. The objectives of this work were to assess the degree of response to treatment, response predictors, and overall and transplant-free survival in patients whose clinical debut was acute and severe. Results: 33 patients with total bilirubin greater than 2.5 mg/dL, without prior (naive) treatment, who met diagnostic criteria according to the international autoimmune hepatitis group, were included. 97% were women with a median age of 52, 58% were in the cirrhosis stage with an average MELD of 24, and 15% had massive/submassive necrosis in the liver biopsy sample. In 27 cases treatment with cortiocosteroids was initiated, 66.7% evolved with complete remission, 14.8% with partial remission, and in 18.5% there was failure of corticosteroid treatment. Basal cholesterol and the presence of hepatic encephalopathy were predictors of non-response to corticosteroid treatment, while pre-treatment MELD and basal cholesterol were the statistically significant variables associated with liver transplant rescue failure. In patients treated with corticosteroids, overall and transplant-free survival at 5 years based on MELD (<25 vs ≥ 25) was 90% vs 60% respectively. Conclusion: The high survival rates achieved under medical treatment that were demonstrated in this series reaffirm the need to prioritize the use of corticosteroids in patients with acute and severe autoimmune hepatitis.

Resumo: Introdução: A hepatite autoimune é uma doença cuja apresentação clínica inicial pode se manifestar de várias formas, sendo sua apresentação aguda com níveis elevados de bilirrubina, descida na função biossintética e necrose maciça/submassiva ou cirrose em histologia, marcadores de gravidade dela. A decisão de iniciar o tratamento corticosteroide nesse cenário é um desafio na prática clínica. Os objetivos deste trabalho foram avaliar o grau de resposta ao tratamento, preditores de resposta e sobrevida geral e livre de transplantes em pacientes cuja estréia clínica foi aguda e grave. Resultados: Foram incluídos 33 pacientes com bilirrubina total superior a 2,5 mg/dL, sem tratamento prévio (ingênuo), que atendiam aos critérios diagnósticos segundo o grupo internacional de hepatite autoimune. 97% eram mulheres com idade mediana de 52 anos, 58% estavam em estágio de cirrose com um MELD médio de 24, e 15% tinham necrose maciça/submassiva na amostra de biópsia hepática. Em 27 casos foi iniciado o tratamento médico e, em 6 casos, o transplante de fígado foi alcançado sem terapia prévia. 66,7% evoluíram com remissão completa, 14,8% com remissão parcial e, em 18,5%, houve falha no tratamento corticosteroide. O colesterol basal e a presença de encefalopatia hepática foram preditores de não resposta ao tratamento corticosteroide, enquanto o meld pré-tratamento e o colesterol basal foram as variáveis estatisticamente significativas associadas à falha de resgate do transplante de fígado. Em pacientes tratados com corticosteroides, a sobrevida geral e livre de transplante aos 5 anos com base no MELD (<25 vs ≥ 25) foi de 90% vs 60%, respectivamente. Conclusão: As altas taxas de sobrevivência alcançadas sob tratamento médico demonstrado nesta série reafirmam a necessidade de priorizar o uso de corticosteroides em pacientes com hepatite autoimune aguda e grave.

Agomelatina: fallo hepático fulminante en paciente con hígado graso / Agomelatine: fulminant liver failure in a patient with fatty liver

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[Hepatocellular carcinoma within Milan criteria and beyond: outcomes of liver transplantation in a single Argentinian institution]. / Hepatocarcinoma dentro y fuera de los criterios de Milán: resultados de un centro de trasplante hepático en la Argentina.

Hepatocellular carcinoma (HCC) recurrence following liver transplantation is associated to bad prognosis. We retrospectively analyzed the data of 95 patients who underwent liver transplantation for HCC. Recurrence rate and variables associated with recurrence were reviewed. According to the findings on the explanted livers they were divided in two groups: Milan (M) 67% and non-Milan (NM) 33%. Global recurrence rate, and M-group and NM-group recurrence rates were 19%; 12% and 32%, respectively (P = 0.001). Although in the univariate analysis we found some factors associated to recurrence (hemocromathosis, year of transplant, bilobar distribution, vascular invasion and previous chemoembolization), they were not independent predictors of recurrence in the multivariate analysis. Actuarial survival in cirrhotic patients with and without HCC at 1, 3 and 5 years was 86% and 91% (NS), 77% and 88% (NS), and 67% and 86% (P = 0.002), respectively; whereas actuarial survival of the M and NM groups was 86% and 71%; 82% and 61%, and 78% and 58%, respectively (P = 0.02). We had a satisfactory five-year global survival in our series even though one third of our patients grafted for HCC were outside Milan criteria.

[Hepatitis E: an infrequent virus or an unfrecuently investigated agent?]. / Hepatitis E: un virus infrecuente o un agente infrecuentemente pensado?

Two cases of hepatitis E that were assisted in our Unit of Hepatology and Liver Transplantation are described in this article. The first patient had prior hepatic involvement and therefore a more severe course, whereas the second case, with normal liver function, only developed a self-limited acute hepatitis.

Hepatocarcinoma dentro y fuera de los criterios de Milán: resultados de un centro de trasplante hepático en la Argentina. / [Hepatocellular carcinoma within Milan criteria and beyond: outcomes of liver transplantation in a single Argentinian institution].

Hepatocellular carcinoma (HCC) recurrence following liver transplantation is associated to bad prognosis. We retrospectively analyzed the data of 95 patients who underwent liver transplantation for HCC. Recurrence rate and variables associated with recurrence were reviewed. According to the findings on the explanted livers they were divided in two groups: Milan (M) 67

and non-Milan (NM) 33

. Global recurrence rate, and M-group and NM-group recurrence rates were 19

; 12

and 32

, respectively (P = 0.001). Although in the univariate analysis we found some factors associated to recurrence (hemocromathosis, year of transplant, bilobar distribution, vascular invasion and previous chemoembolization), they were not independent predictors of recurrence in the multivariate analysis. Actuarial survival in cirrhotic patients with and without HCC at 1, 3 and 5 years was 86

and 91

(NS), 77

and 88

(NS), and 67

and 86

(P = 0.002), respectively; whereas actuarial survival of the M and NM groups was 86

and 71

; 82

and 61

, and 78

and 58

, respectively (P = 0.02). We had a satisfactory five-year global survival in our series even though one third of our patients grafted for HCC were outside Milan criteria.

Hepatitis E: un virus infrecuente o un agente infrecuentemente pensado? / [Hepatitis E: an infrequent virus or an unfrecuently investigated agent?].

Two cases of hepatitis E that were assisted in our Unit of Hepatology and Liver Transplantation are described in this article. The first patient had prior hepatic involvement and therefore a more severe course, whereas the second case, with normal liver function, only developed a self-limited acute hepatitis.

Hepatitis E: un virus infrecuente o un agente infrecuentemente pensado? / [Hepatitis E: an infrequent virus or an unfrecuently investigated agent?].

Two cases of hepatitis E that were assisted in our Unit of Hepatology and Liver Transplantation are described in this article. The first patient had prior hepatic involvement and therefore a more severe course, whereas the second case, with normal liver function, only developed a self-limited acute hepatitis.

Hepatocarcinoma dentro y fuera de los criterios de Milán: resultados de un centro de trasplante hepático en la Argentina / [Hepatocellular carcinoma within Milan criteria and beyond: outcomes of liver transplantation in a single Argentinian institution].

Hepatocellular carcinoma (HCC) recurrence following liver transplantation is associated to bad prognosis. We retrospectively analyzed the data of 95 patients who underwent liver transplantation for HCC. Recurrence rate and variables associated with recurrence were reviewed. According to the findings on the explanted livers they were divided in two groups: Milan (M) 67

. Global recurrence rate, and M-group and NM-group recurrence rates were 19

, respectively (P = 0.001). Although in the univariate analysis we found some factors associated to recurrence (hemocromathosis, year of transplant, bilobar distribution, vascular invasion and previous chemoembolization), they were not independent predictors of recurrence in the multivariate analysis. Actuarial survival in cirrhotic patients with and without HCC at 1, 3 and 5 years was 86

(NS), and 67

(P = 0.002), respectively; whereas actuarial survival of the M and NM groups was 86

, and 78

, respectively (P = 0.02). We had a satisfactory five-year global survival in our series even though one third of our patients grafted for HCC were outside Milan criteria.

Hypercoagulability in patients with chronic noncirrhotic portal vein thrombosis.

BACKGROUND & AIMS: Although they have normal liver histology and function, patients with chronic noncirrhotic nontumoral portal vein thrombosis (NC-PVT) frequently have abnormal results from coagulation tests. We investigated the significance of these results. METHODS: We analyzed blood samples collected from 50 stable patients with NC-PVT secondary to a thrombophilic disorder (32%) or local factor (32%), or that was idiopathic (36%). We measured endogenous thrombin potential (ETP) with and without thrombomodulin, prothrombin time, activated partial thromboplastin time, coagulation factors (I, II, V, VII, VIII, IX, X, XI, and XII), antithrombin, proteins C and S, von Willebrand factor (vWF) antigen, vWF ristocetin cofactor, a disintegrin and metalloprotease with thrombospondin type 1 motifs 13 antigen, D-dimer, plasmin-antiplasmin complex, prothrombin fragment F1+2, activated factor VII, and clot lysis time. Samples from 50 age- and sex-matched healthy individuals were evaluated as controls. RESULTS: Compared with controls, patients with NC-PVT had significant increases in prothrombin time and activated partial thromboplastin time; they had significant reductions in levels of procoagulant factors II, V, VII, IX, X, XI, and XII, and the anticoagulants antithrombin, protein C, and protein S. The patients had increased levels of factor VIII and vWF antigen. Irrespective of etiology, patients with NC-PVT had a significant increase in ETP with thrombomodulin and higher levels of factor VIIa, prothrombin fragment F1+2, D-dimer, and plasmin-antiplasmin complex than controls, indicating in vivo activation of coagulation and fibrinolysis. CONCLUSIONS: Patients with NC-PVT have hypercoagulability that is independent of the underlying etiology, based on in vitro analyses of thrombin-generation capacity and increased levels of biomarkers in blood samples. Further studies are required to determine if activation of hemostasis increases the risk for thrombotic events.

Von Willebrand factor levels predict clinical outcome in patients with cirrhosis and portal hypertension.

BACKGROUND AND AIMS: Endothelial dysfunction is a major determinant of the increased hepatic vascular tone of cirrhotic livers. Von Willebrand factor (vWF), P-selectin and 8-iso-PGF2α (isoprostanes), surrogate markers of endothelial dysfunction, are increased in patients with cirrhosis. This study was aimed at exploring in patients with cirrhosis and portal hypertension the relation of these endothelial factors with systemic and hepatic haemodynamics and their possible clinical prognostic value. METHODS: 42 consecutive patients with cirrhosis and portal hypertension had measurement of the hepatic venous pressure gradient (HVPG), cardiopulmonary pressures and vWF, P-selectin and isoprostane levels in blood samples from hepatic and peripheral veins. Patients were followed up to 2 years, death or liver transplantation and any clinical event were recorded. RESULTS: vWF, P-selectin and isoprostanes were increased in patients with cirrhosis compared with controls (p<0.001). vWF levels significantly correlated with HVPG, Child-Pugh score and MELD. Cox model analysis disclosed an independent indirect association of peripheral vWF with survival free of portal hypertension-related events and of transplantation. The vWF cut-off value of 216 U/dl (Youden index) disclosed two different populations of patients with cirrhosis with a highly different probability of survival free of portal hypertension-related events and transplantation (87% vs 22%, p=0.001). The prognostic role of vWF persisted after adjusting for parameters of liver dysfunction and for HVPG. CONCLUSIONS: In patients with cirrhosis and portal hypertension vWF levels correlate with liver function and HVPG and independently predict clinical outcome.

Paroxysmal nocturnal hemoglobinuria in Budd-Chiari syndrome: findings from a cohort study.

BACKGROUND/AIMS: A well recognized cause of Budd-Chiari syndrome (BCS) is paroxysmal nocturnal hemoglobinuria (PNH). PNH is an acquired disorder of hematopoietic stem cells, characterized by intravascular hemolysis and venous thrombosis. Testing for this hematological disorder should be considered in all BCS patients. METHODS: Using data from the EN-Vie study, a multi-center study of 163 patients with BCS, we investigated the relationship between BCS and PNH in 15 patients with combined disease and compared the results to 62 BCS patients in whom PNH was excluded. RESULTS: Median follow-up for the study group (n=77) was 20 months (range 0-44 months). BCS patients with PNH presented with a significantly higher percentage of additional splanchnic vein thrombosis (SVT) as compared to BCS patients without PNH (47% vs. 10%, p=0.002). During follow-up, type and frequency of interventions for BCS was similar between both groups. Six patients with BCS and PNH were successfully treated with a transjugular intrahepatic portosystemic shunt (TIPS). Of 15 patients with PNH, six underwent allogenic stem cell transplantation after diagnosis of BCS. PNH was successfully cured in five cases. There was no significant difference in survival between BCS patients with and without PNH. CONCLUSIONS: This study shows that despite a higher frequency of additional SVT, short-term prognosis of BCS patients with PNH does not differ from BCS patients without PNH. Treatment with TIPS can be safely performed in patients with PNH. Stem cell transplantation appears to be a feasible treatment option for PNH in BCS patients.

Prognostic value of acute hemodynamic response to i.v. propranolol in patients with cirrhosis and portal hypertension.

BACKGROUND/AIMS: Cirrhotic patients chronically treated with beta-blockers who achieve a decrease of hepatic venous pressure gradient (HVPG) > or =20% from baseline or to < or =12 mmHg have a marked reduction of first bleeding or re-bleeding. However, two HVPG measurements are needed to evaluate response. This study was aimed at investigating the predictive role of acute HVPG response to i.v. propranolol for bleeding and survival. METHODS: We retrospectively studied 166 cirrhotic patients with varices with HVPG response to i.v. propranolol (0.15 mg/kg). All patients subsequently received non-selective beta-blockers to prevent first bleeding (n=78) or re-bleeding (n=88). RESULTS: Thirty-seven patients developed a portal hypertension-related bleeding over 2 years of follow-up. Decrease (12%) in HVPG was the best cut-off for bleeding risk discrimination. This parameter was used to classify patients in responders (n=95) and non-responders (n=71). In primary prophylaxis (54 responders vs. 24 non-responders) the actuarial probability of bleeding was half in responders than in non-responders (12% vs. 23% at 2 years; ns). In secondary prophylaxis (41 responders vs. 47 non-responders) a good hemodynamic response was also significantly and independently associated with a 50% decrease in the probability of re-bleeding (23% at 2 years vs. 46% in non-responders; p=0.032) and a better survival (95% vs. 65%; p=0.003). CONCLUSION: The evaluation of acute HVPG response to i.v. propranolol before initiating secondary prophylaxis for variceal bleeding is a useful tool in predicting the efficacy of non-selective beta-blockers. If adequately validated, this might be a more cost-effective strategy than the chronic evaluation of HVPG response and might be useful to guide therapeutic decisions in these patients.

Pregnancy in women with known and treated Budd-Chiari syndrome: maternal and fetal outcomes.

BACKGROUND/AIMS: Budd-Chiari syndrome (BCS) mainly affects women of childbearing age. We aimed to clarify whether pregnancy, a thrombotic risk factor, should be contraindicated in patients with known and treated BCS. METHODS: A retrospective study of pregnancy in women with known and treated BCS. RESULTS: Sixteen women had 24 pregnancies. Nine women had undergone surgical or radiological treatment. Anticoagulation was administered during 17 pregnancies. Seven fetuses were lost before gestation week 20. Deliveries occurred between week 20 and 31 in two patients, week 32 and 36 in eleven and after week 37 in four. There was one stillbirth, but 16 infants did well. Factor II gene mutation was a factor for a poor outcome of pregnancies. In two patients, symptomatic thrombosis recurred during pregnancy or postpartum. All patients were alive after a median follow-up of 34 months after the last delivery. Bleeding at delivery, although non-lethal, occurred only on anticoagulation therapy. CONCLUSIONS: When known and treated BCS is well controlled, pregnancy should not be contraindicated as maternal outcome, and fetal outcome beyond gestation week 20, are good. The risk-benefit ratio of anticoagulant therapy needs to be further clarified. Patients should be fully informed of the persistent risks of such pregnancies.

TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.

BACKGROUND & AIMS: Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder secondary to hepatic venous outflow obstruction. Small series of BCS patients indicate that transjugular intrahepatic portosystemic shunt (TIPS) may be useful. However, the influence of TIPS on patient survival and factors that predict the outcome of TIPS in BCS patients remain unknown. METHODS: One hundred twenty-four consecutive BCS patients treated with TIPS in 6 European centers between July 1993 and March 2006 were followed until death, orthotopic liver transplantation (OLT), or last clinical evaluation. RESULTS: Prior to treatment with TIPS, BCS patients had a high Model of End Stage Liver Disease and high Rotterdam BCS prognostic index (98% of patients at intermediate or high risk) indicating severity of liver dysfunction. However, 1- and 5-year OLT-free survival were 88% and 78%, respectively. In the high-risk patients, 5-year OLT-free survival was much better than that estimated by the Rotterdam BCS index (71% vs 42%, respectively). In the whole population, bilirubin, age, and international normalized ratio for prothrombin time independently predicted 1-year OLT-free survival. A prognostic score with a good discriminative capacity (area under the curve, 0.86) was developed from these variables. Seven out of 8 patients with a score >7 died or underwent transplantation vs 5 out of 114 patients with a score <7. CONCLUSIONS: Long-term outcome for patients with severe BCS treated with TIPS is excellent even in high-risk patients, suggesting that TIPS may improve survival. Furthermore, we identified a small subgroup of BCS patients with poor prognosis despite TIPS who might benefit from early OLT.

The impact of JAK2 and MPL mutations on diagnosis and prognosis of splanchnic vein thrombosis: a report on 241 cases.

Myeloproliferative diseases (MPDs) represent the commonest cause of splanchnic vein thrombosis (SVT), including Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT), but their diagnosis is hampered by changes secondary to portal hypertension, while their influence in the outcome of SVT remains unclear. We assessed the diagnostic and prognostic value of JAK2 and MPL515 mutations in 241 SVT patients (104 BCS, 137 PVT). JAK2V617F was found in 45% of BCS and 34% of PVT, while JAK2 exon 12 and MPL515 mutations were not detected. JAK2V617F was found in 96.5% of patients with bone marrow (BM) changes specific for MPD and endogenous erythoid colonies, but also in 58% of those with only one feature and in 7% of those with neither feature. Stratifying MPD diagnosis first on JAK2V617F detection would have avoided BM investigations in 40% of the patients. In BCS, presence of MPD carried significantly poorer baseline prognostic features, required hepatic decompression procedures earlier, but had no impact on 5-year survival. Our results suggest that JAK2V617F testing should replace BM investigations as initial test for MPD in patients with SVT. Underlying MPD is associated with severe forms of BCS, but current therapy appears to offset deleterious effects of MPD on the medium-term outcome.

How common is delayed cyclosporine absorption following liver transplantation?

The mean time to peak absorption of cyclosporine (CsA) in liver transplant patients is approximately 2 hours, but in some patients the peak occurs later. The goal of this study was, therefore, to investigate the incidence of delayed absorption in 27 de novo liver transplant recipients receiving CsA > or =10 mg/kg/day (C(2) monitoring) and in 15 maintenance patients. Patients were categorized as 'normal' absorbers (C(2) exceeding C(4) and C(6)) or 'delayed' absorbers (C(4) or C(6) exceeding C(2)), and as 'good' (>800 ng/mL at C(0), C(2), C(4), or C(6)) or 'poor' absorbers (C(0), C(2), C(4) and C(6) <800 ng/mL) on the day of study. Among de novo patients, 15 (56%) had 'normal' CsA absorption and 12 (44%) 'delayed' absorption. Good CsA absorption occurred in 16 patients (59%) and poor absorption in 11 (41%). The proportion of poor absorbers was similar in patients with normal (6/15, 40%) or delayed (5/12, 42%) absorption. Among the 12 delayed absorbers, 11 had peak CsA concentration at C(4). Mean C(0) level was significantly higher in delayed absorbers (282 +/- 96 ng/mL) than in normal absorbers (185 +/- 88 ng/mL; P = .01). Delayed absorbers reverted to normal absorption (C(2) > C(4)) after a median of 6 days from the day of study, and no cases of delayed absorption were found among maintenance patients. In conclusion, almost 50% of the patients had delayed CsA absorption early posttransplant; around half of these exhibited normal CsA exposure. Measurement of C(4) in addition to C(2) differentiates effectively between delayed and poor absorbers of CsA such that over- or underimmunosuppression can be avoided.