Enrique Fraga

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.

Effect of PGE1 on TNF-α status and hepatic d-galactosamine-induced apoptosis in rats

Prostaglandin E1 has hepatoprotective properties in several clinical and experimental models of liver dysfunction. Hepatotoxicity induced by D‐galactosamine (D‐GalN) is a suitable animal model of human acute hepatic failure. The aim of the study was to investigate if prostaglandin E1 (PGE1) protection against hepatic D‐GalN‐induced apoptosis was related to tumour necrosis factor‐α (TNF‐α) content in serum. This cytokine is associated with in vitro apoptosis and general inflammatory disorders. In this study, PGE1 was administered 30 min before D‐GalN to rats. In other experiments, several doses of TNF‐α were administered 15 min after PGE1 to D‐GalN‐treated rats. Several parameters related to apoptosis and necrosis were measured by flow cytometry, gel electrophoresis, biochemical analysis, and optical and electron microscopy. Tumour necrosis factor‐α was quantified by competitive enzyme‐linked immunosorbent assay (ELISA). PGE1 by itself did not modify the cell cycle of hepato‐cytes and liver toxicity, but increased TNF‐α in serum in comparison with the control group. D‐Galactosamine increased the percentage of hepatocytes in apoptosis and in the S phase of the cell cycle, and decreased those in G0/G1. Such an increase of hepatocytes in apoptosis was correlated with a higher number of apoptotic bodies and DNA fragmentation in liver than control samples. Also, D‐GalN increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and TNF‐α in serum compared with the control group. Pre‐administration of PGE1 to D‐GalN‐treated rats reduced all the parameters of apoptosis and necrosis in liver, and increased additionally TNF‐α content in serum. In those experiments where low doses of TNF‐α were administered to PGE1 and D‐GalN‐treated rats an inverse relationship appeared between TNF‐α and ALT content in serum. In conclusion, the protective effects of PGE1 on D‐GalN‐induced apoptosis may be linked to its capacity to modulate cell division and/or its immunomodulatory activity. In this sense, our experimental results suggest that TNF‐α could be involved in protection or exacerbation of liver damage in relation to the pathophysiological status of the liver.

Orthotopic liver transplantation after subacute liver failure induced by therapeutic doses of ibuprofen

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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.

S-nitrosation of proteins during d-galactosamine-induced cell death in human hepatocytes

Nitric oxide (NO) participates in the cell death induced by d-Galactosamine (d-GalN) in hepatocytes, and NO-derived reactive oxygen intermediates are critical contributors to protein modification and hepatocellular injury. It is anticipated that S-nitrosation of proteins will participate in the mechanisms leading to cell death in d-GalN-treated human hepatocytes. In the present study, d-GalN-induced cell death was related to augmented levels of NO production and S-nitrosothiol (SNO) content. The biotin switch assay confirmed that d-GalN increased the levels of S-nitrosated proteins in human hepatocytes. S-nitrosocysteine (CSNO) enhanced protein S-nitrosation and altered cell death parameters that were related to S-nitrosation of the executioner caspase-3. Fifteen S-nitrosated proteins participating in metabolism, antioxidative defense and cellular homeostasis were identified in human hepatocytes treated with CSNO. Among them, seven were also identified in d-GalN-treated hepatocytes. The results here reported underline the importance of the alteration of SNO homeostasis during d-GalN-induced cell death in human hepatocytes.

Cardiovascular morbidity and mortality after liver transplantation: The protective role of Mycophenolate Mofetil

Cardiovascular (CV) diseases are recognized longterm causes of death after liver transplantation (LT). The objective of this multicenter study was to analyze the prevalence and the evolution of CV risk factors and CV morbidity and mortality in 1819 LT recipients along 5 years after LT. The influence of baseline variables on survival, morbidity, and mortality was studied. There was a continuous and significant increase of the prevalence of all the CV risk factors (except smoking) after LT. CV diseases were the fourth cause of mortality in the 5 years after LT, causing 12% of deaths during the follow‐up. Most CV events (39%) occurred in the first year after LT. Preexisting CV risk factors such as age, pre‐LT CV events, diabetes, metabolic syndrome, and hyperuricemia, and mycophenolate‐free immunosuppressive therapy, increased post‐LT CV morbidity and mortality. The development of new‐onset CV risk factors after LT, such as dyslipidemia and obesity, independently affected late CV morbidity and mortality. Tacrolimus and steroids increased the risk of posttransplant diabetes, whereas cyclosporine increased the risk of arterial hypertension, dyslipidemia, and metabolic syndrome. In conclusion, CV complications and CV mortality are frequent in LT recipients. Preexisting CV risk factors, immunosuppressive drugs, but also the early new onset of obesity and dyslipidemia after LT play an important role on late CV complications. A strict metabolic control in the immediate post‐LT period is advisable for improving CV risk of LT recipients. Liver Transplantation 23 498–509 2017 AASLD.

Acute liver failure in a patient with multiple sclerosis treated with interferon-β

Sir Acute liver failure (ALF) is a rare but frequently fatal disorder, defined by the onset of coagulopathy and encephalopathy within 1 26 weeks of presentation, without underlying liver disease [1]. The mortality rate reaches 60 90%, depending on the grade of encephalopathy, and urgent liver transplantation is recommended when criteria are fulfilled (King’s College and Clichy criteria). We report an uncommon case of ALF requiring liver transplant occurring five years after starting interferon-b treatment in a patient with multiple sclerosis (MS). A 39-year-old woman with jaundice and malaise was admitted to our unit. She had relapsing MS, diagnosed 10 years earlier and had been receiving interferon-b (Betaferon, Schering) for five years at a dose of 25 mcg subcutaneously every two days, without any serious adverse event so far. There was no history of alcohol or paracetamol abuse, and without concomitant medications during the last five years. At admission her mental status was normal, without signs of encephalopathy or fever. The liver function tests at presentation were as follows: AST 1609 U/L, ALT 1082 U/L, GGT 175 U/L, ALP 176 U/L, total bilirubin 10.4 mg/dL, prothrombin activity 26% and factor V 26%. The values of other parameters such as glucose, BUN, creatinin, sodium, potassium, amylase, total protein, albumin, ceruloplasmin, copper, a-1-antitrypsin and a-fetoprotein were normal. All serum viral markers of HCV, HBV, HAV and systemic viruses (CMV, Herpes, Epstein-Barr) were negative. Autoimmune profile demonstrated positivity for ANA and SMA antibodies with a titre of 1:1260 and 1:160, respectively. Abdominal ultrasound examination showed normal liver size and no features of portal hypertension. The administration of interferon-b was discontinued, and the patient started on steroid treatment (methyl prednisolone 1 mg/kg weight i.v.). After 10 days, liver function tests improved partially (AST 101 UI/L, ALT 214 UI/L, bilirubin 15.4 mg/dL, prothrombin activity 23.7%, factor V 23.6%), but abdominal ultrasound showed presence of ascites and hepatic atrophy. At day 13 after admission the patient developed decreased level of consciousness and asterixis. Liver transplant was performed 24 h later, and the explant showed massive hepatic necrosis without specific aetiological features. The outcome of the patient was satisfactory and she was discharged 20 days after OLT with normal graft function. An association between MS and other autoimmune disorders has already been reported (thyroiditis, myasthenia gravis and rheumatoid arthritis). Some authors have suggested that the prevalence of AIH in MS patients is nearly 10 times higher than in the general population through similar B-cellmediated mechanisms [2]. The treatment of AIH includes steroids and azathioprine. On the other hand, interferon-b is considered as the gold standard treatment for MS, but abnormal liver function tests are reported in up to 36% of patients, based on postmarketing studies [3]. Several cases of AIH [4,5] or acute liver injury requiring liver transplantation [6] have been recorded in patients with MS treated with interferon-b. Although interferon-b treatment is safe and generally well tolerated, patients should be frequently monitored in order to detect eventual deterioration of liver function.

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.

Altered Underlying Renal Tubular Function in Patients With Chronic Hepatitis B Receiving Nucleos(t)ide Analogs in a Real-World Setting: The MENTE Study.

Background: Cases of renal tubular dysfunction have been reported in patients with hepatitis B and in patients with human immunodeficiency virus who are undergoing tenofovir treatment. However, little is known about the impact on tubular function in patients with chronic hepatitis B (CHB) under long-term use of entecavir (ETV) and tenofovir disoproxil fumarate (TDF). We evaluated markers of renal tubular function and bone turnover in patients with CHB treated with ETV or TDF. Patients and Methods: A multicenter, cross-sectional study was performed on markers of renal tubular function and bone turnover in hepatitis B virus–monoinfected patients on long-term treatment with Entecavir or Tenofovir (the MENTE study). The analyzed parameters were: retinol-binding protein/creatinine, neutrophil gelatinase-associated lipocalin/creatinine, excretion of phosphates, uric acid excretion, glomerular filtrate, protein/creatinine, albumin/creatinine, serum creatinine, phosphate, CTX, P1NP, vitamin D, and parathormone. Results: A total of 280 patients (ETV: 89, TDF: 69, control: 122) were included in this study. The TDF group was associated with altered levels of retinol-binding protein (RBP)/creatinine (TDF 25% vs. 7% ETV and control; P<0.001). Protein/creatinine, uric acid excretion, P1NP1, and parathormone were higher in the TDF group. The proportion of patients with serum phosphate <2.5 mg/dL was higher in both the ETV and the TDF groups compared with the control. The multivariate analysis showed that the use of TDF was independently associated with a higher risk of altered excretion of RBP/creatinine (4.4; interquartile range: 1.4 to 14; P=0.013). Conclusions: We found an independent association between TDF use and altered RBP excretion. This finding indicates subclinical tubular damage. Because tubular dysfunction can precede the decline of renal function, close monitoring of RBP levels in patients with CHB on nucleos(t)ide analog treatment must be performed for early detection of TDF-related renal toxicity. In this study, these differences in tubular function were not associated with concomitant changes in markers of bone turnover.

Impacto del sistema MELD en la selección de candidatos para trasplante hepático

La tasa de mortalidad en la lista de espera de trasplante hepático se sitúa en España en torno al 10%. Sin embargo, este porcentaje puede aumentar en un 5-10% más si se añaden las exclusiones de esta lista por gravedad extrema y muy baja probabilidad de sobrevivir al trasplante, y los pacientes con hepatocarcinoma (CHC) que progresan y rebasan los límites de extensión aceptados. No existe un consenso bien definido sobre los criterios de distribución de órganos, es decir, sobre la gestión de la lista de espera, que pasa a ser un factor determinante de la tasa de mortalidad pretrasplante. Frente al modelo de priorizar a los pacientes más graves, que reduciría la mortalidad pretrasplante, se propone la selección de los candidatos con mayores probabilidades de supervivencia. La defensa de cualquiera de estas estrategias introduce sesgos de índole ética de difícil evaluación. No hay en definitiva un modelo universalmente aceptado para la distribución de donantes, de tal modo que algunos centros optan por seguir un criterio cronológico en el que, respetando el grupo sanguíneo, los pacientes son trasplantados de acuerdo con el orden de inclusión.