Damiano Patrono

Matrix metalloproteinase inhibition protects rat livers from prolonged cold ischemia–warm reperfusion injury

Matrix metalloproteinases (MMPs) have been implicated in the hepatic injury induced after cold ischemia–warm reperfusion (CI‐WR), by altering the extracellular matrix (ECM), but their precise role remains unknown. The hepatic MMP expression was evaluated after 2 conditions of CI (4°C for 24 and 42 hours: viable and nonviable livers) followed by different periods of WR, using isolated perfused rat livers. CI‐WR induced moderate changes in hepatic MMP transcript levels not influenced by CI duration, whereas gelatinase activities accumulated in liver effluents. Therefore, the protective effect of a new phosphinic MMP inhibitor, RXP409, was tested after prolonged CI. RXP409 (10 μM) was added to the University of Wisconsin solution, and livers were preserved for 42 hours (4°C), then reperfused for 1 hour in Krebs solution (37°C), containing 20% erythrocytes. Liver viability parameters were recorded, and the extent of cell necrosis was evaluated on liver biopsies, using trypan blue nuclear uptake. Treatment with RXP409 significantly improved liver function (transaminase release and bile secretion) and liver injury. In particular, the MMP inhibitor significantly modified the extent of cell death from large clusters of necrotic hepatocytes as found in control livers (2%–60% of liver biopsies; mean, 26% ± 9%) to isolated necrotic hepatocytes as found in treated livers (0.2%–12%; mean, 3% ± 2%) (P < 0.05). Conclusion: These data demonstrate that MMPs, by altering the ECM, play a major role in liver CI‐WR injury leading to extensive hepatocyte necrosis and that their inhibition might prove to be a new strategy in improving preservation solutions. (HEPATOLOGY 2007.)

Warm ischemia‐reperfusion injury is decreased by tacrolimus in steatotic rat liver

Ischemia‐reperfusion (I‐R) injury is poorly tolerated by fatty livers, most probably secondary to reduced cellular adenosine triphosphate (ATP) levels. We investigated the effectiveness of tacrolimus pretreatment on fatty liver I‐R injury in obese Zucker rats. Tacrolimus (0.3 mg/kg, intravenously) was injected 24 hours before a 75‐minute ischemic period and rats were sacrificed 6 hours later. Tacrolimus modified the response to I‐R observed in obese Zucker rats, when compared to nontreated obese rats: a significant reduction in hepatocyte necrosis was associated with a significant increase in hepatocyte apoptosis. In addition, cell necrosis and apoptosis were significantly and inversely correlated in lean nontreated and treated obese Zucker rats following I‐R. Tacrolimus also significantly increased the hepatic ATP levels, reduced in nontreated obese rats, toward values found in lean Zucker rat livers. This protective effect of tacrolimus was further confirmed in vivo by a significantly improved survival following pretreatment with tacrolimus, 24 hours prior to ischemia. In conclusion, in obese Zucker rat livers, tacrolimus pretreatment reversed the I‐R injury toward the one found in lean Zucker rats. The correlations between ATP levels and the opposite changes in necrosis and apoptotic pathways strongly suggest a cause‐effect relationship between tacrolimus and changes in ATP levels. Liver Transpl 12:217–225, 2006.

Combined antifungal therapy, iron chelation and surgical resection as treatment of hepatic zygomycosis in a patient with haematological malignancy.

We describe the case of a 19‐year‐old boy with acute leukaemia who developed primary hepatic zygomycosis. The patient presented with febrile neutropenia and severe abdominal tenderness. Despite the administration of antibiotics and liposomal Amphotericin‐B (L‐AmB), the CT scan demonstrated an increase in the size of liver lesions. A wide surgical resection was carried out and liver specimens demonstrated a branching, filamentous fungus that was identified as Rhizomucor pusillus by both phenotypic and molecular methods. The patient was treated with L‐AmB combined with posaconazole, and deferasirox was subsequently added given the potential synergistic effect of this iron chelator in combination with L‐AmB. Three months after surgical intervention, an allogeneic stem‐cell transplantation was successfully carried out. The present case confirms that an early surgical management combined with antifungal agents is crucial to optimise the outcome of patients with zygomycosis and the use of deferasirox is a promising alternative.

Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation.

BACKGROUND In renal tubular cells, cytochrome P4503A enzyme and adenosine triphosphate-binding cassette transporter activities result in intracellular drug or metabolite exposure variability, depending on genetic polymorphisms. Our aim was to establish whether long-term renal function is affected by genetic polymorphisms in biotransformation enzymes and drug transporters of the donor after kidney transplantation. MATERIALS AND METHODS The study was conducted in a selected cohort of 97 kidney recipients. Genotyping of donors was performed on renal biopsy samples obtained before transplantation. Serum creatinine levels and Cockcroft-Gault estimated glomerular filtration rate were considered 1 y after transplantation and at the last follow-up. RESULTS Long-term function was significantly better in recipients of an organ from donors carrying the ABCB1 1199A mutated allele (median and range creatinine values were 1.1 mg/dL [0.8-1.5mg/dL] in case of at least one ABCB1 1199A allele versus 1.5 mg/dL [0.7-3.7 mg/dL] for homozygous carriers of wild-type allele, P < 0.01). ABCB1 1199G>A polymorphism and donor age had an independent impact on both serum creatinine and estimated glomerular filtration rate. Unlike donor age, the mutated ABCB1 1199A allele was found to have a protective effect on renal function. CONCLUSIONS Donor age and ABCB1 1199G>A polymorphism affect long-term renal function after transplantation. Analysis of genetic factors offers a promising approach to calcineurin inhibitor toxicity risk assessment.

Liver transplantation after severe hepatic trauma: a sustainable practice. A single-center experience and review of the literature

Severe hepatic trauma is a rare indication for liver transplantation (LT). We report our single‐center experience of LT for hepatic trauma. Four new cases are discussed in light of a literature review in order to depict the pathways leading from hepatic trauma to LT and to assess the outcomes of this practice. LT is generally indicated in case of uncontrollable hemorrhage, acute liver failure, or post‐traumatic late sequelae. Hepatic vessels thrombosis, sepsis, major hepatic resections, and a late referral are factors associated with the progression toward irreversible liver failure. Considering all reported cases, early patient and graft survival reached 68% and 62%, respectively, but in the last decade both have improved to 84%. LT after severe hepatic trauma is a sustainable practice considering the current good outcomes and the ineluctable death of these patients without LT.

Use of PlasmaJet ™ System in Patients Undergoing Abdominal Lipectomy following Massive Weight Loss Resulting from Bariatric Surgery: Early Experience

Background: Abdominoplasty has become a popular operation among patients seeking body contouring surgery due to the recent development of laparoscopic procedures in bariatric surgery and the epidemic diffusion of obesity. The wide surface of dissection is responsible for common postoperative complications such as seroma and hematoma. Methods: PlasmaJet™ system (PJS), a high energy flow of ionized gas, can be used to stop capillary bleeding from blood and lymph vessels. We tested the PJS in a prospective series of 15 consecutive patients undergoing abdominoplasty after bariatric surgery-induced weight loss. Results: 14 women underwent abdominoplasty with the PlasmaJet™ system after a mean weight loss of 48 kg (range 37-53). Mean operative time was 73 min (range 60-87). There was no postoperative complication. Mean fluid output from drains was 351.1 ml/patient (range 60 to 568), and drains were removed at a mean time of 4.8 days (range 3 to 6). Conclusion: These results are in favor of the efficacy of the PJS in reducing the amount of fluid production, and the rate of postoperative complications. However, this should be confirmed in a randomized trial comparing the PJS with standard technique.

Left-sided portal hypertension: Successful management by laparoscopic splenectomy following splenic artery embolization

INTRODUCTION Left-sided portal hypertension is a rare clinical condition most often associated with a pancreatic disease. In case of hemorrhage from gastric fundus varices, splenectomy is indicated. Commonly, the operation is carried out by laparotomy, as portal hypertension is considered a relative contraindication to laparoscopic splenectomy (LS). Although some studies have reported the feasibility of the laparoscopic approach in the setting of cirrhosis-related portal hypertension, experience concerning LS in left-sided portal hypertension is lacking. PRESENTATION OF CASE A 39-year-old man was admitted to the Emergency Department for haemorrhagic shock due to acute hemorrhage from gastric fundus varices. Diagnostic work up revealed a chronic pancreatitis-related splenic vein thrombosis causing left-sided portal hypertension with gastric fundus varices and splenic cavernoma. Following splenic artery embolization (SAE), the case was successfully managed by LS. DISCUSSION The advantages of laparoscopic over open splenectomy include lower complication rate, quicker recovery and shorter hospital stay. Splenic artery embolization prior to LS has been used to reduce intraoperative blood losses and conversion rate, especially in complex cases of splenomegaly or cirrhosis-related portal hypertension. We report a case of complicated left-sided portal hypertension managed by LS following SAE. In spite of the presence of large varices at the splenic hilum, the operation was performed by laparoscopy without any major intraoperative complication, thanks to the reduced venous pressure achieved by SAE. CONCLUSION Splenic artery embolization may be a valuable adjunct in case of left-sided portal hypertension requiring splenectomy, allowing a safe dissection of the splenic vessels even by laparoscopy.

Liver Transplantation for Hepatocellular Carcinoma Within Milan Criteria in Patients With Model For End-Stage Liver Disease Score Below 15: The Impact of the Etiology of Cirrhosis on Long-Term Survival

BACKGROUND Liver transplantation (OLT) is the gold standard therapy for patients with cirrhosis complicated by hepatocellular carcinoma (HCC) within Milan Criteria (MC). We evaluated the impact of the etiology of the underlying liver disease on long-term outcomes of patients undergoing OLT for HCC within MC having a Model for End-stage Liver Disease (MELD) score < 15. METHODS From November 2002 to December 2009, we performed 203 primary OLTs from brain-dead donors in recipients with HCC and cirrhosis with biochemical MELD scores below 15. We excluded 31 patients outside MC on the explant pathology of the native liver. The remaining 172 were divided into 3 groups according to the etiology of the underlying cirrhosis: hepatitis C virus-positive (HCV+; n = 78; 45%), hepatitis B virus-positive (HBV+; n = 65; 38%) and other indications (n = 29; 17%). The groups were compared for donor and recipient features, donor-recipient match, and transplant variables. The study endpoint was long-term patient survival. RESULTS The groups were similar, except for a greater prevalence of hepatitis B core antibody-positive grafts in the HBV+ group and less frequent HCC bridging procedures in the other indications group. After a median follow-up of 72 months, HCC recurrence was observed in 8 (4.7%) patients (6 HCV+, 2 other indications), 5 of whom died. Overall 5-year patient survival of 82%, revealed significant differences among groups: 98.3% in HBV+, 67.1% in HCV+, and 85.8% in other indications (HBV+ vs other indications: P = .01; HBV+ vs HCV+: P = .0001; HCV+ vs other indications: P = NS). In the HCV+ group, recurrent HCV hepatitis was the most frequent cause of death. Upon multivariate analysis, HBV positivity in the recipient was an independent predictor of better patient survival (hazard ratio = 0.10, 95% confidence interval 0.02-0.64, P = .013). CONCLUSIONS Etiology of the underlying cirrhosis significantly influenced the long-term survival after OLT of patients with HCC within MC and MELD < 15. It should be taken into account in estimation of survival benefit.

Liver transplantation with an uncommon full right hemiliver graft after hydatid cysts resection: Case report and review of the literature

Because of widespread organ shortage, the transplant community has been exploiting more and more so‐called “extended criteria” donors. In this scenario, liver grafts harboring benign tumors or large cysts represent an infrequent but potentially valuable source of viable grafts. We depict a challenging case of liver transplantation performed using a graft harboring two large Echinococcus granulosus hydatid cysts in close proximity with the hilar plate and complicated by cystobiliary communication. Although liver transplantation using grafts with hydatid cyst has been rarely reported (three published cases), our case was peculiar as one of the cysts was located close to the hilum and was ruptured into the left hepatic duct. The graft was finally accepted taking into account the low risk profile of the recipient, the good quality and size of the remnant liver parenchyma, and only after complete resection of the cysts was achieved. Although the recipient had a complication due to biliary confluence necrosis, at 10‐months follow‐up he is in good health with normal hepatic function, and a graft that could have been otherwise discarded was successfully used. The decision process along with technical and management issues are discussed.

Peri-hepatic gauze packing for the control of haemorrhage during liver transplantation: A retrospective study

BACKGROUND Albeit accepted in the trauma setting, use of peri-hepatic gauze packing has been rarely reported during liver transplantation. AIMS To assess the results of packing in liver transplantation. METHODS We reviewed clinical characteristics, intraoperative events and postoperative outcome of consecutive adult liver transplantation recipients between 2003 and 2013. Patients treated with packing were compared to no-packing patients and to matched controls selected using a propensity score. RESULTS Of 1396 recipients, 107 were treated with packing for peri-hepatic bleeding (76.6%), allograft damage (12.1%) or partial outflow obstruction (11.2%). Urgent reoperation for ongoing haemorrhage was required in 6 (5.6%). Correction of haemodynamic and coagulation parameters was constantly achieved. Overall, patient (90% vs. 98%, p<0.001) and graft (83.2% vs. 94.7%, p<0.001) 3-month survival was significantly reduced in packing patients. However, after matching, no significant difference was observed in patient (89.3% vs. 95.2%, p=0.12) and graft (83.5% vs. 92.2%, p=0.06) 3-month survival. Patient survival was associated with recipient age (HR 2.59; p=0.04) and donor age × recipient MELD (HR 2.04; p=0.02), but not with packing (HR 1.81; p=0.29). CONCLUSIONS In our experience, packing was a valuable adjunct to conventional means of haemostasis during liver transplantation and, after accounting for confounding covariates, was not associated with inferior outcomes.