Evaluation of Anti-HBs serum levels and pharmacokinetic profile after intravenous administration of Niuliva, a new hepatitis B immunoglobulin, following liver transplantation.

PURPOSE: We assessed whether trough anti-hepatitis B surface antigen (HBs) serum levels considered to be protective (>100 IU/L) were maintained in liver transplanted patients after 6 months of uninterrupted treatment with Niuliva, a new intravenous HBIg. METHODS: Twenty patients, aged 18-70 years, who had undergone liver transplantation due to HBV-related liver disease at least 1 year before inclusion were enrolled in a prospective, open-label, uncontrolled, multicenter clinical study. A fixed monthly dose of 5,000 IU of study medication was administered intravenously for 6 months. RESULTS: After the second infusion, all mean values of anti-HBs and 95% CIs were above the limit of 100 IU/L considered to be protective. The percentages of success ranged between 95% (95% CI 75.1%-99.9%) and 100% (95% CI 86.1%-100%). Mean values and 95% CI of in vivo recovery of anti-HBs at 15-30 minutes after each infusion showed overlaps between all intervals, which indicated that significant differences were not present in the recovery of post infusion anti-HBs in vivo. There were no recurrences of HBV infection during the study. There were no seroconversions in patients previously negative to hepatitis C virus or HIV. No serious adverse events related to the study medication were observed. CONCLUSIONS: Serum levels of anti-HBs after using Niuliva in patients who had undergone liver transplantation were protective in 95%-100% of cases after the study period. This new HBIg showed the expected pharmacokinetic profile and was well tolerated and safe.

Response to a vaccination schedule with 4 doses of 40 microg against hepatitis B virus in cirrhotic patients evaluated for liver transplantation.

We conducted a retrospective study to evaluate the response to recombinant hepatitis B vaccine after 4 intramuscular doses (40 microg) administered at 0, 1, 2, and 6 months in 157 cirrhotic patients who were liver transplant candidates. Seventeen nonresponders were revaccinated with the same schedule. We studied the association between the following variables and the vaccine response: age, gender, etiology of cirrhosis, diabetes, severity of liver disease (Child-Pugh class and Model for End-Stage Liver Disease [MELD] score), and the number of administered doses. The response rates were: 1 dose, 40% (2/5); 2 doses, 0% (0/7); 3 doses, 32.7% (16/49); and 4 doses, 31.3% (30/96) of patients. The median hepatitis B surface antibody (anti-HBs) titer was 45 mU/mL (range, 11-620 mU/mL). The response rate to revaccination was 41.2% (median anti-HBs titer, 88 mU/mL; range, 18-190 mU/mL). Diabetics showed a lower response rate than nondiabetic patients (17.2% vs 35.3%; P = .046). No association was observed between the response rate to vaccine and the other variables. In conclusion, the response rate to hepatitis B vaccine reached a little more than 30% in cirrhotic patients who received 3 or 4 doses. No higher response rate was observed among patients who received 4 doses. Diabetes was associated with a lower response rate. Anti-HBs seroconversion rates were not associated with the other variables. Revaccination may significantly increase the response rate to hepatitis B vaccine in cirrhotic patients, and may be considered in nonresponders after the third dose. Early vaccination against HBV should be considered in such patients.

Prevalence of hepatitis A and B markers and vaccine indication in cirrhotic patients evaluated for liver transplantation in Spain.

Vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV) is generally recommended for patients with chronic liver disease and those evaluated for liver transplantation in the absence of immunity. HAV and HBV infections after liver transplantation are frequent and associated with a worse prognosis. The data suggest that the number of patients with chronic liver disease without naturally acquired immunity against HAV and HBV is substantial, and that new vaccination strategies are needed. The aim of this study was to determine the level of immunity from hepatitis A and B infections and the need for HBV and HAV vaccination among cirrhotic patients evaluated for liver transplantation. We studied HBV and HAV serological markers (HbsAg, anti-HBc, anti-HBs, IgG anti-HAV) in 451 cirrhotic patients evaluated for liver transplantation to investigate the association with gender, age, and etiology of cirrhosis. Negative HBV markers were observed in 57% of patients with 43% displaying one positive HBV marker: HBsAg (+), 9.5%; anti-HBc (+)/anti-HBs (-), 11.5%; anti-HBc (-)/anti-HBs(+), 4.2%; anti-HBc(+)/anti-HBs(+), 17.7%. HBV vaccine indication established in 68.5% of patients was greater among women and hepatitis C virus-negative patients. No differences were observed in age or cause of cirrhosis. HAV vaccination indicated in 6.7% of patients (IgG anti-HVA-negative) was greater among patients with negative HBV markers (9.3% vs 3.3%, P = .018) and younger patients (25.3% of patients

Factors that predict survival in patients with cirrhosis considered for liver transplantation.

OBJECTIVE: To identify prognostic factors for survival at 6 and 12 months in patients evaluated for liver transplantation using Child-Pugh (CP) classification and the Model for End-Stage Liver Disease (MELD) score. METHODS: We evaluated 144 patients with cirrhosis who were candidates for liver transplantation. We excluded patients with hepatocellular carcinoma, recent liver recipients, and patients who died because of factors unrelated to liver disease. The studied variables were age and sex; prothrombin time; platelet count; albumin, cholesterol, bilirubin, creatinine, and serum sodium concentrations; CP classification and MELD score; and the presence of ascites, encephalopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, and previous variceal bleeding. Data were processed using statistical software (SPSS version 13.0). RESULTS: Of the 144 patients, 27 (18.7%) did not survive because of complications of liver disease. Univariate analysis showed the most significant factors to be sex, prothrombin time, bilirubin and albumin levels; ascites, encephalopathy, CP classification, and MELD score. At Cox regression analysis, only CP classification proved to be a valid predictor of survival in our cohort. The lowest survival according to CP classification at 6 and 12 months corresponded to stage C and to MELD scores higher than 15. CONCLUSIONS: Child-Pugh classification is an independent prognostic factor for recipient survival. Stage C in the CP classification and a MELD score higher than 15 were strongly related to worse survival. Both scores must be taken into consideration for adequate evaluation of liver transplantation for candidates.

Results of liver transplantation at the Cuban Center for Medical and Surgical Research.

From July 4, 1999, when a liver transplantation program was started in Cuba, to December 30, 2007, we performed 125 procedures in 115 patients. The most frequent reasons for transplantation were cirrhosis caused by hepatitis C virus (29%) and alcoholic cirrhosis (17.2%). Two patients received simultaneous liver-kidney transplants. Sixty-seven patients were males, and the patient ages ranged from 12 to 74 years. The average surgical time was 6 hours, and cold ischemia time was 4 to 14 hours. The average blood consumption was 1630 mL; 2900 mL of plasma and 8 units of platelets were used in 7 cases. Immunosuppression was mainly cyclosporine, mycophenolate mofetil, and prednisone. Acute cellular rejections were treated in almost all cases with 3 doses of methylprednisolone. The most frequent complications were biliary (15%), hepatic arterial thrombosis (6%), postsurgical bleeding (8%), acute cellular rejection (20%), and ductopenic rejection (2%). The overall 1-year survival was 74.7%.

Gastrointestinal complications in liver transplant recipients: MITOS study.

INTRODUCTION: Liver transplant recipients frequently suffer gastrointestinal (GI) complications but their prevalence and their influence on quality of life remain unknown. OBJECTIVE: The objective of this study was to asses the prevalence, impact on quality of life, and management of GI complications in liver transplant recipients. PATIENTS AND METHODS: This was an epidemiologic, cross-sectional, multicenter study. Four hundred seventeen liver recipients were recruited in 14 centers. A questionnaire was filled for every patient. RESULTS: The median age of the patients was 55 years. The median time since transplantation was 4.1 +/- 4 years. Whereas 19.2% presented some GI disease before transplantation, 49.4% showed this type of complication after transplantation. Diarrhea was the most prevalent GI complication, and anorexia was the GI disorder that affected patients daily activities the most frequently. GI complications were more frequent among female patients, subjects with pretransplantation hiatal hernia, and those readmitted after transplantation. Of the patients with GI complications, 70.9% received pharmacological treatment (89.7% with gastric protectors). Immunosuppressive therapy was also modified because of GI complications. Immunosuppressive drug dose was reduced in 18.1%, transiently stopped in 3.4%, and definitively stopped in 3.4% of cases. The drug most frequently changed was mycophenolate mofetil: dose reduction, 23.6%; transient withdrawal, 5.7%; and definitive withdrawal, 6.6%. CONCLUSIONS: The prevalence of GI complications in the liver transplant population was approximately 50%. GI complications showed a significant impact on the quality of life of the patients. They were related to female gender, to pretransplantation GI pathology, and posttransplantation hospital admission. These complications were frequently managed with pharmacological therapy or with changes in immunosuppressive therapy.

Ictericia secundaria a metástasis pancreática de sarcoma de partes blandas / Obstructive jaundice secondary to pancreatic metastases of a soft-tissue sarcoma

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Morbidity and mortality in liver retransplantation.

INTRODUCTION: The incidence of orthotopic liver retransplantation (re-OLT) ranges from 6% to 11%. The most frequent causes of early re-OLT are allograft failure, uncontrolled acute rejection, and vascular complications. MATERIALS AND METHODS: A retrospective study of 512 orthotopic liver transplants (OLTs) in 482 patients over 15 years. RESULTS: The incidence of re-OLT was 6.6%, with a higher percentage of men requiring re-OLT than first-time OLT (75.0% vs 63.0%, P < .05). The reasons for re-OLT were thrombosis 21.7%, aneurysm 6.5%, stenosis 3.2%, primary nonfunction (PNF) 21.7%, and chronic rejection or recurrence of the initial disease 40.4%. Complications included PNF (22.0%), acute renal failure (65.6%), postoperative infection (87.5%), and adult respiratory distress syndrome (9.4%; P < .05). No differences were seen in the incidence of septicemia or postoperative hemorrhage. The average survival was much lower in re-OLT (21.8 days) compared with OLT (194.5 days; P < .05). The mortality rates in re-OLT were 100% for primary biliary cirrhosis, 85.7% for HCV, 50% for alcoholic cirrhosis, and 20% for HBV. A direct association between the Model for End-stage Liver Disease (MELD) score and the number of complications was present. DISCUSSION: There was a greater requirement for re-OLT in men and those patients transplanted due to hepatitis B virus cirrhosis and fulminant hepatitis (P < .05). The re-OLT patients had no greater incidence of sepsis compared with the OLT patients, although they did have a greater incidence of primary graft dysfunction, acute renal failure, adult respiratory distress syndrome, and postoperative infection (P < .05). The MELD was a good parameter for predicting graft evolution. Re-OLT in patients with primary biliary cirrhosis and hepatitis C virus was associated with a high degree of mortality.

Early postoperative response of cytokines in liver transplant recipients.

We evaluated the early postoperative response of several cytokines (IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma) prior to liver transplantation (T(0)) as well as 1, 6, and 12 hours and 1, 2, 3, 5, and 7 days afterward. Cytokine concentrations were correlated with serum levels of bilirubin as a predictor of postoperative complications. Cytokine levels were determined in plasma samples from 16 liver transplant recipients (13 men, 3 women) aged 43 to 61 years. IL-6 and IL-10 reached their maximum concentrations 1 hour after transplantation. Each increase in IL-6 correlated to a rise in IL-10. IL-2, IL-4, TNF-alpha, and IFN-gamma had a particular time-course for each patient studied. Bilirubin fell to almost normal values but not in cases of postoperative complications, where IL-6 showed values four times higher compared to those of liver transplant recipients who did not show postoperative complications. IL-6 and IL-10 plasma concentrations and serum bilirubin level might be useful as a predictive factor of postoperative complications in liver transplant recipients.

Cancers of new appearance in liver transplant recipients: incidence and evolution.

OBJECTIVE: To investigate the incidence, time of appearance, treatment, and evolution of tumors appearing in liver transplant recipients at our hospital. MATERIAL AND METHODS: We undertook a retrospective analysis of our series of liver transplants between 1990 and 2005. Patients who died during the immediate postoperative period were excluded. RESULTS: Of the 515 patients, 25 died during the immediate postoperative period and therefore had no occasion to develop neoplasms. Of the remaining 490, 32 developed cancers (6.5%). The average age was 55.4 +/- 7.17 years. The reasons for transplant were alcoholic cirrhosis (n = 15), hepatitis C virus (2), hepatitis B virus (n = 1), alcoholic and viral cirrhosis (n = 7), primary biliary cirrhosis (n = 1), and cryptogenic cirrhosis (n = 1). Four patients developed multiple neoplasms. Most of the tumors were cutaneous: nine basal cell and six squamous cell carcinomas. Other locations were the lung, urothelium, stomach, thyroid, and brain. Eight patients presented metastasis at the time of diagnosis. The average tumor-free period was 3.36 years. Nine patients died as a result of the tumor. DISCUSSION: Patients with a liver transplant have a high risk of developing cancers as a result of the immunosuppression treatment, which is lifelong. Nevertheless, other factors can be involved, such as infection by cytomegalovirus or the original diagnosis leading to transplantation. The risk for developing cancers is significantly greater than in the general population, with a higher tendency to recurrence and later development of second neoplasms.

Correlation between the radiologic and histologic size of hepatocellular carcinoma in patients eligible for liver transplantation.

Hepatocellular carcinoma is the most prevalent primary hepatic tumor. Early diagnosis and staging is of paramount importance to obtain favorable survivals. So far, there is no general agreement on the most appropriate imaging technique to detect the tumor for correlation between pretransplant radiologic and pathologic size of the tumor, which remains inadequate. With greater clinical experience and increasing accuracy of imaging methods, magnetic resonance (MR) appears to be the most accurate method, yielding a correlation in 67% of cases.

Ictericia obstructiva en varón de 22 años / Obstructive jaundice in 22 years old man

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Lack of association of recipient MCP-1 gene promoter polymorphism with acute graft rejection after orthotopic liver transplantation.

Acute graft rejection after orthotopic liver transplantation (OLT) is associated with leukocyte infiltration of the graft. Monocyte chemoattractant protein-1 (MCP-1) is a beta-chemokine involved in the attraction and accumulation of mononuclear granulocytes toward sites of inflammation. A biallelic polymorphism (G/A) at position -2518 of the MCP-1 gene has been described. Cells obtained from individuals with the GG or AG genotypes have been found to produce more MCP-1 than those obtained from individuals with the AA genotype. The goal of this study was to assess the possible association between this polymorphism and susceptibility to acute graft rejection after OLT. One hundred fifty Caucasian liver transplant recipients from the South of Spain underwent genotyping using a polymerase chain reaction (PCR) amplification followed by restriction fragment length polymorphism (RFLP). No significant differences were observed when patients with versus without acute rejection episodes were compared for the distribution of -2518 MCP-1 genotypes. The present study supports the lack of involvement of polymorphism at position -2518 (A/G) of the MCP-1 gene on the susceptibility to acute allograft rejection among OLT recipients.

Mycotic pseudoaneurysms after liver transplantation.

The most frequent etiology of visceral artery aneurysms is arteriosclerosis, but vascular manipulation during hepatic transplantation may also cause a mycotic pseudoaneurysm. Treatment with embolization, stents or percutaneous thrombin injection have been recommended but surgical revascularization is indicated when interventional techniques fail. A 43-year-old man with hepatitis C virus cirrhosis who underwent orthotopic liver transplantation from a cadaveric donor was treated with cyclosporine, mycophenolate, and steroids and was discharged from hospital at 35 days. Two months later he was readmitted with a febrile syndrome. Abdominal computed tomography showed necrosis of hepatic segments IV, V, and VI. Magnetic resonance imaging and angiography revealed partial thrombosis of the hepatic artery and stenosis of the portal anastomosis secondary to an aneurysm of the hepatic artery. A few hours after the radiological diagnosis, the patient suffered a bout of upper gastrointestinal bleeding and shock. Emergency surgery revealed a mycotic pseudoaneurysm of the common hepatic artery, which had ruptured into the bile tract with hemobilia. The liver graft was removed because of severe necrosis of the right liver. The patient died awaiting a new liver transplantation.

Glutathione S-transferase T1 genetic mismatch is a risk factor for de novo immune hepatitis in liver transplantation.

Glutathione S-transferase T1 (GSTT1) is a drug metabolizing enzyme abundantly expressed in liver and kidney cells; it is encoded by a single gene that is absent in 20% of the Caucasian population. Our group found that some liver transplantation patients developed de novo immune hepatitis (IH) and that all of them had anti-GSTT1 antibodies. The main objective of this study was to analyze the influence of a GSTT1 mismatch between donor and recipient in the immune response and the outcome of the graft. We confirmed that only under one of the four possible genetic combinations (null recipient/positive donor) is an alloimmune response triggered with production of anti-GSTT1 antibodies. Therefore, we conclude that this genetic mismatch can be considered a risk factor for de novo IH.

Liver transplantation for hilar cholangiocarcinoma: Spanish experience.

INTRODUCTION: Palliative treatment for nondisseminated irresectable hilar cholangiocarcinoma (HCC) carries a 0% 5-year survival rate. The role of orthotopic liver transplantation (OLT) in these patients is controversial because the survival rate is lower than that for other indications for transplantation and the lack of available donor organs. The aim of this paper was to review the Spanish experience in OLT for HCC and identify prognostic factors for survival. METHODS: We retrospectively reviewed 36 patients undergoing OLT for HCC over 13 years. RESULTS: The actuarial survival rate at 1, 3, and 5 years was 82%, 53%, and 30%, respectively. The main cause of death was tumor recurrence (53%). In the univariate analysis, the factors for a poor prognosis were vascular invasion (P<.001) namely 0% survival at 3 years when present versus 63% and 35% at 3 and 5 years, respectively, when it was not; and stages III to IVA (P<.05), namely 15% survival at 5 years versus 47% for stages I to II. Lymph node and perineural invasion also reduce survival. In the multivariate analysis, the factors for poor prognosis included vascular invasion (P<.01) and stages III to IVA (P<.01). CONCLUSION: OLT for nondisseminated irresectable HCC has higher survival rates at 3 and 5 years than palliative treatments, especially with initial stage tumors, which means that more information is needed to better select cholangiocarcinoma patients for transplantation.

Liver transplantation for peripheral cholangiocarcinoma: Spanish experience.

INTRODUCTION: Palliative treatment for nondisseminated unresectable peripheral cholangiocarcinoma (PCC) carries a 0% 5-year survival rate. The role of orthotopic liver transplantation (OLT) in these patients is controversial because the survival rate is lower than with other indications for transplantation and the lack of available donor organs. The aim of this paper was to review the Spanish experience in OLT for PCC to identify prognostic factors for survival. METHODS: We retrospectively reviewed 23 patients undergoing OLT in Spain for PCC over a period of 13 years. RESULTS: The actuarial survival rates were 77%, 65%, and 42% at 1, 3, and 5 years, respectively. The main cause of death was tumor recurrence (35%). Prognotic factors for an adverse outcome were pTNM classification (P<.05) in the univariate analysis and perineural invasion (P<.05) and stages III or IVA (P<.05) in the multivariate analysis. CONCLUSIONS: OLT for nondisseminated irresectable PCC displays higher survival rates at 3 and 5 years than palliative treatments, especially for tumors in the initial stages, which means that more information is needed to help better select PCC patients for transplantation.

Results of an upper endoscopy protocol in liver transplant candidates.

OBJECTIVE: our aims is to understand endoscopic findings from a preoperative systematic study of patients with hepatic cirrhosis who were candidates for transplantation and their impact on a protocol for primary and secondary prophylaxis of variceal haemorrhage. PATIENTS AND METHODS: this study involves a retrospective evaluation of upper digestive tract lesions detected before inclusion and a prospective evaluation of new episodes of variceal haemorrhage, associated mortality rates, and factors that are likely to be involved in the development of this condition. Primary prophylaxis with beta-blockers was considered indicated in cases of varices of grande II or greater or with signs associated with increased risk. Secondary prophylaxis was essentially always associated with medical and endoscopic treatment. RESULTS: of 134 patients, there were 9 deaths, with a median time on the waiting list of 3 months. Of all patients, 33.6% presented with high risk oesophageal varices, 11.2 % with gastric varices, 42.6% with portal hypertensive gastropathy, and 26.9% with peptic lesions. Primary prophylaxis was indicated in 33 of 90 patients, and was initiated in almost half of the cases as a results of the study. Optimum fulfiment of the pre-established objectives was 75.3%. The incidence of new haemorrhagic events due to varices was 10.4% and accounted for almost half of the deaths during the monitoring period. The only statistically significant predictive factors were the presence of gastrict varices and previous history. CONCLUSION: upper endoscopy should play a role in the preoperative examination of liver transplant candidates due to the significant impact it has on subsequent management.