Ignacio García

Clinical and histological efficacy of pegylated interferon and ribavirin therapy of recurrent hepatitis C after liver transplantation

Treatment of recurrent hepatitis C in liver transplant is controversial. The aim of our study was to evaluate the clinical and histological efficacy of pegylated interferon alpha 2b (PEG‐IFN) and ribavirin therapy of recurrent hepatitis C after liver transplantation (LT). We prospectively included 47 liver transplant patients with: 1) a positive test for hepatitis C virus (HCV)‐ribonucleic acid (RNA) in serum; 2) alanine aminotransferase (ALT) >45 UI/mL; and 3) a liver biopsy showing chronic hepatitis without rejection in the previous 2 months. Patients received PEG‐IFN (1.5 μg/kg/week) and ribavirin (800‐1,000 mg/day) for 12 months. Follow‐up was based on biochemical (ALT), virological (RNA‐HCV), and histological (liver biopsy) examinations. Follow‐up lasted a minimum of 6 months after the end of antiviral therapy. Sustained virological response (SVR) was achieved in 23% of the patients. A total of 33 (70%) patients had normalized ALT levels at the end of therapy. Inflammatory portal and lobular score declined significantly in patients with SVR (P < 0.05) but not in nonresponder patients. Fibrosis did not change significantly in either group. SVR was significantly associated with low γ‐glutamyltransferase GGT (P = 0.04) and HCV‐RNA levels (P = 0.03), a virological response at 12 weeks (P = 0.002) and patients compliance (P = 0.04). Ten (21%) patients were withdrawn prematurely due to adverse effects. In conclusion, Therapy with PEG‐IFN and ribavirin achieved SVR and a significant histological improvement in 23% of liver transplant recipients with chronic hepatitis C. Toxicity is an important drawback of this therapy. Liver Transpl 12:1805‐1812, 2006.

Successful treatment of mucor infection after liver or pancreas-kidney transplantation.

BACKGROUND Mucormycosis is a rare and opportunistic infection usually associated with hematologic diseases, diabetes mellitus, renal failure, solid tumors, and organ transplantation. METHODS We present five cases of mucor infection after transplantation (three after a series of 750 orthotopic liver transplantation and two after a series of 13 simultaneous pancreas-kidney transplantation in patients with type 1 diabetes) subjected to medical and surgical treatment and analyze the factors related to the development of this infection. RESULTS The clinical forms were two cutaneous (laparotomy wound or prior surgical drain site), two rhino-maxillary, and one pulmonary. As risk factors for mucormycosis all patients had pre- or posttransplantation diabetes, and showed at least one episode of acute rejection that required aggressive immunosuppression (2-7 g of methylprednisolone; also three patients were treated with antithymocyte globulin [ATG] monoclonal antibody [orthoclone and/or OKT3]). We also found renal failure, acidosis, malnutrition, and Candida and cytomegalovirus infections as factors related to mucor infection. Diagnosis of fungal infection was confirmed by exudate or fluid culture in three cases and by biopsy in two. All patients were treated with liposomal amphotericin B (from 3.5 to 5.6 g of total dose) and resection until the surgical margins were free of infection. All patients survived after this severe infection. CONCLUSIONS With an early diagnosis of mucormycosis by clinical findings, culture, or tissue biopsy, and aggressive treatment consisting of administration of liposomal amphotericin B and surgical resection of all infected tissue, excellent results are achieved.

Steroid withdrawal is safe and beneficial in stable cyclosporine-treated liver transplant patients

BACKGROUND In the immunosuppression of orthotopic liver transplant recipients, steroids are used despite their unspecific action and long-term side effects. Few studies have been carried out on steroid withdrawal and many aspects remain to be elucidated. METHODS A prospective study was performed to analyse the effect of steroid withdrawal on 86 patients with stable graft function, more than 1 year after orthotopic liver transplant. Thirty patients had chronic hepatitis in the graft. Seventy-two continued with cyclosporine (CsA) and 14 with CsA-azathioprine (AZA) therapy. The follow-up was 23.2 +/- 8.1 months (range 12-52 months). A paired t-test was used for statistical analysis. RESULTS No acute or chronic rejection occurred, and steroids were not reinstituted. There were no changes in serum transaminase levels, but bilirubin levels decreased (p < 0.01). At the end of the follow-up, we found improvements in blood pressure in hypertensive patients (systolic 156.1 +/- 8.4 mmHg vs. 139.4 +/- 8.7 mmHg, p < 0.001); body weight (72 +/- 13.5 kg vs. 70.8 +/- 13 kg, p < 0.05); serum cholesterol (211.3 +/- 42 mg/dl vs. 191.6 +/- 43.5 mg/dl, p < 0.001) and bone mineral density in lumbar spine (0.823 +/- 0.13 g/cm2 vs. 0.893 +/- 0.135 g/cm2, p < 0.001). Four of ten diabetic patients were no longer insulin-dependent and insulin requirements decreased in the remaining six. No significant biochemical changes were found in patients with hepatitis in the graft, and we found an improvement in inflammatory activity in the nine biopsied patients. CONCLUSIONS Steroid withdrawal with CsA monotherapy is feasible, safe and beneficial in patients who have stable liver graft function 1 year after orthotopic liver transplant. We consider that AZA therapy is not necessary unless drastic reduction of CsA levels is required because of renal dysfunction.

Etiopathogenesis and prognosis of centrilobular necrosis in hepatic grafts

The incidence, contributing etiopathogenetic factors, and prognostic significance of centrilobular necrosis were investigated in 270 hepatic transplants to 215 immunosuppressed patients in whom 837 biopsies were performed. Twenty-six (9.6%) grafts demonstrated centrilobular necrosis in one or more biopsy specimens. The immunological, clinical, histopathological, and evolutionary features of this patient group (group A) were compared with a control group of patients who had undergone 92 consecutive transplants with no necrosis (group B). Group A was younger (p < 0.01), had a higher average of warm and cold-ischemia time (p < 0.05), a higher incidence (p < 0.001) and earlier appearance of acute rejection episodes (p < 0.01), and a closer association with evolution to chronic rejection (A: 53.8% vs B: 13.1%, p < 0.001). Survival rates for grafts and patients with necrosis at 12 and 30 months were significantly lower (p < 0.001). The 26 grafts were distributed into three chronological subgroups according to when necrosis appeared: (1) First week--All these grafts were lost (four through primary graft nonfunction and one due to protal recurrent thrombosis); (2) Second week--seven grafts with associated acute rejection, with three evolving to chronic rejection; (3) After the second week (116 +/- 82 days)--five with isolated necrosis, two with associated acute rejection, four with associated ductopenia, and three with associated acute rejection and ductopenia. In 11 grafts the necrosis persisted and evolved to chronic rejection. In conclusion, these findings indicate that centrilobular necrosis is a histopathological sign associated with poor prognosis in most hepatic grafts.(ABSTRACT TRUNCATED AT 250 WORDS)

Advanced donor age increases the risk of severe recurrent hepatitis C after liver transplantation

The association between donor age and the severity of recurrent hepatitis C and, whether there is any donor age above which severity of recurrence increases significantly, were analyzed. A total of 131 liver grafts of hepatitis C virus (HCV)‐infected recipients were selected for the study. Distribution of donor age was compared between grafts with and without severe recurrence. The risk of developing severe recurrence as well as the hepatitis‐free, severe hepatitis‐free and HCV‐related graft survival was compared between different donor age groups. Mean donor age was higher for grafts with severe recurrence (P = 0.007). The risk of developing severe recurrence within 2 years post‐transplant increased with donors aged ≥50 years (RR = 1.34) and donors aged ≥70 years (RR = 1.61). Five‐year severe hepatitis‐free survival rates decreased progressively when donor age was over 50 years (P < 0.001). The study shows 50 and 70 years as the donor age cut‐off points above which the evolution of HCV‐infected recipients worsens.

Choledochocholedochostomy conversion to hepaticojejunostomy due to biliary obstruction in liver transplantation.

Abstract. Choledochocholedochostomy with tutor (CC-T) or without (CC) is the technique of choice for biliary reconstruction in orthotopic liver transplantation (OLT), however, its rate of complications is high and does not decrease significantly over the years. Biliary obstruction is the most frequent complication and surgical treatment frequently involves conversion to hepaticojejunostomy (H-J). Out of 412 patients (448 OLTs) analyzed retrospectively, 74 (18%) presented biliary complications and 25 (6%) required conversion to H-J because of biliary obstruction, generally due to anastomotic stenosis (17 patients, 68%). Sixteen out of the 25 presented after the first 3 months, and in two patients, stenosis was secondary to arterial thrombosis. Anastomotic stenosis was more frequent in the CC group than in the CC-T group (9.9% versus 2.6%, p < 0.05). Sixteen patients (64%) underwent percutaneous dilatations, but the response was only transitory. There were no postoperative deaths. At the follow-up, three (12%) of the 17 surviving patients presented episodes of cholangitis which required percutaneous dilatations (1), revision of the H-J (1), or conversion to hepaticojejunoduodenostomy (1). Mean survival of patients with H-J was 70.9%, and the actuarial survival rate was 68% at 5 years. This does not differ from the actuarial survival in our series of transplanted patients (65%). CC or CC-T (in selected cases) is an adequate biliary reconstruction for OLT, in spite of the fact that a small number of patients will require conversion to H-J. H-J is an excellent technique of rescue in cases of biliary obstruction that are not possible to resolve by percutaneous dilatations.

Recipient Factors as Determinants of Mortality after Adult Liver Transplantation

Abstract. The factors that can influence the outcome of orthotopic liver transplantation (OLT) are numerous. The purpose of this study was to determine the effects of recipient preoperative factors on patient mortality. Between April 1986 and April 1998 a total of 600 OLTs were performed in our institution. We retrospectively reviewed our first 203 consecutive primary adult OLTs with at least 4 years of follow-up. A case-control comparison was performed between survivors and nonsurvivors, and differences in recipient variables were studied for their correlation with patient mortality. A logistic regression analysis was also performed. Mortality was significantly increased among those with fulminant hepatic failure (FHF) (66.6%, p= 0.003), primary cancer (63.1%, p= 0.018), females (46.1%, p= 0.043), encephalopathy grade IV (72.7%, p= 0.012), recipients under respiratory support (69.2%, p= 0.031), and ABO-incompatible transplants (80%, p= 0.05). FHF, primary cancer, and female gender were the only variables that had a significant association with mortality in the logistic regression analysis. A higher incidence of prolonged respiratory support, bacterial and fungal infections, pneumonia, and chronic rejection contributed to the lower outcome observed in females. These results stress the need for continuous evaluation of the selection criteria of candidates for OLT suffering from primary cancer and FHF. The impact of recipient gender on mortality warrants further analysis but suggests that in the future more attention must be paid to the influence of this factor on the final outcome of OLT.

Clinical significance of hepatitis C virus (HCV) infection in liver transplant recipients. Role of serology and HCV RNA detection.

Hepatitis C virus (HCV) infection was studied in 60 liver transplant recipients. Antibodies to HCV were tested by both a second-generation ELISA test and a four-recombinant immunoblot assay (4-RIBA) just before the transplant and every three months thereafter. HCV RNA detection was performed by polymerase chain reaction (PCR) at least three times after the transplant in all the patients. Thirty-nine patients tested negative by ELISA before LT (group A), 14 patients tested positive by both serological tests (group B), and seven tested positive only by ELISA (group C). Posttransplant hepatitis was diagnosed in 11/14 in group B in comparison with 3/39 in group A (P<0.001) and 1/7 in group C (P<0.05). HCV RNA was detected in the sera of 14/14 patients in group B but in only 1/7 in group C and 6/39 in group A. Only 2/15 patients developed posttransplant hepatitis in the absence of HCV RNA detection. These data suggest that HCV is the major cause of hepatitis after LT. Patients HCV seropositive by RIBA test before the transplant formed a group of high-risk patients for developing viremia and hepatitis afterwards.

Treatment of mucor infection after liver or pancreas–kidney transplantation

MUCORMYCOSIS is a rare and opportunistic infection most commonly caused by Rhizopus, Rhizomucor, and Cunninghamella species. This infection is usually associated with hematologic disease, diabetes mellitus, renal failure, organ transplantation, and solid tumors. We only found eight reported cases of mucor infection after orthotopic liver transplantation (OLT), but none after simultaneous pancreas-kidney transplantation (SPKT). The aim of this study is to present our five cases of mucor infection mucormycosis after OLT or SPKT.

Liver transplantation in patients with Budd-Chiari syndrome

Patients with Budd-Chiari syndrome (obstruction of the hepatic veins) and associated hepatic insufficiency may be candidates for orthotopic liver transplantation (OLT). In our series of 405 OLT patients, 3 were transplanted due to Budd-Chiari syndrome (0.7%). The indication for liver transplantation in these patients was severe hepatic insufficiency (chronic in two and acute in the third one). Morphologic study of the obstructions revealed apparently different causes, including thrombi, membranous webs in hepatic veins, and hydatid cyst compression. The surgical technique employed in these transplantations was similar to that for other etiologies. Due to its implications for the future course of OLT, it is important to determine the exact etiology of Budd-Chiari syndrome in the pretransplant period and to treat the patients with early and long-term anticoagulant therapy to avoid syndrome recurrence.