Alvise Maffei Faccioli

Epstein-Barr virus-associated post-transplant lympho-proliferative disease of donor origin in liver transplant recipients

BACKGROUND/AIMS Post-transplant lymphoproliferative disease, a potential complication of solid organ transplantation, occurs in about 3% of orthotopic liver transplant recipients. We report the genetic and virological characterization of two cases of post-transplant lymphoproliferative disease that occurred early (4 and 6 months) after orthotopic liver transplant as large-cell non-Hodgkins lymphomas located at the hepatic hilum. METHODS Lymphomatous tissues were analyzed for clonality and presence of Epstein-Barr virus (EBV) sequences by Southern blot, polymerase chain reaction, and in situ hybridization techniques. RESULTS The tumors in both cases were sustained by a clonal proliferation of B lymphocytes containing type A EBV DNA. Moreover, in situ hybridization with a digoxigenin-labeled EBV-specific probe evidenced a strong nuclear signal in most of the neoplastic cells. DNA microsatellite analysis at three different loci detected alleles of donor origin in both tumor samples, suggesting that the neoplastic B cells were of donor origin. CONCLUSIONS EBV-infected donor B lymphocytes might be responsible for intragraft post-transplant lymphoproliferative disease in orthotopic liver transplant recipients. As 20 to 30% of post-transplant lymphomas involve the graft itself, donor-derived post-transplant lymphoproliferative disease might be more frequent than presently appreciated. Prospective studies are needed to assess its real incidence and identify possible risk factors.

Effect of Ursodeoxycholic Acid Administration on Bile Duct Proliferation and Cholestasis in Bile Duct Ligated Rat

The origin, mechanism, and significance of the bile duct proliferation (BDP) associated with cholestasis remain unexplained. This study examined the effect of oral administration of ursodeoxycholic acid (UDCA) on both BDP and cholestasis in the rat. After bile duct ligation, male Sprague-Dawley rats were treated for 30 days with either UDCA (5 mg/day) (group A) or saline solution (group B). Animals were sacrificed at day 30. The serum activity of aminotransferase (ALT, AST), alkaline phosphatase, and γ-glutamyltransferase (GGT) was significantly lower (P<0.01) in the UDCA-treated rats. Total serum bilirubin and total serum bile acids were lower (P<0.001) in group A. Moreover, the control of BA in bile was reduced also (P<0.02). Conversely, serum cholesterol levels were not different between the two groups. Histological examination showed that the number of ductular cells in the portal areas was significantly (P<0.001) reduced in UDCA-treated as compared to saline-treated rats. The replication activity, assessed as the number of bromodeoxyuridine-positive cells, was also significantly lower in treated animals (33±11 vs 64±22 per 1000 cells;P<0.001). Lobular bile ductules were three times larger in group B, and extrahepatic duct measurements confirmed this increase in size of the larger biliary ducts (P<0.001). These findings demonstrate that UDCA reduces BDP in response to BD ligation. Although the mechanism(s) of this effect is still hypothetical, UDCA may reduce the level of irritating bile salts such as chenodeoxycholic acid and lithocolate and increase periductular bile acid recirculation. These data support the beneficial effect of UDCA treatment in chronic cholestatic disease.

Infrahepatic Terminolateral Cavo–Cavostomy as a Rescue Technique in Complicated “Modified” Piggyback Liver Transplantation

Orthotopic liver transplantation is a well-known and widely applied codified procedure. Milestones of the standard technique are the use of the veno– venous bypass (1, 2), and the resection, en bloc with the liver, of the retrohepatic vena cava (3–5). Since its original description by Starzl (3–4), many modifications of the original technique have been suggested to reduce risks and time and to make the technique more flexible. Also, the graft caval implant has undergone gradual evolution through the introduction of variants that render the surgical procedure more adaptable toward problems. These techniques apply the dissection of the recipient liver from the vena cava during hepatectomy (6); then the graft implant may be performed preserving the recipient vena cava, according to the piggyback procedure (7, 8), anastomosing the donor’s suprahepatic vena cava and a “cuff” made out of the recipient’s suprahepatic veins, or, as described by some authors (9), using a side-to-side cavo–caval anastomosis after stitching the donor’s suprahepatic caval stumps. In both cases, the remnant of the donor’s infrahepatic vena cava must be ligated. Since 1992 we have used a modified piggyback technique, by performing an end-to-side cavo– caval anastomosis between the suprahepatic donor’s vena cava and the recipient’s vena cava, using the caudally enlarged hole of the common left and middle suprahepatic veins stump, after stitching the recipient’s right suprahepatic vein (10). Also by this technique, the remnant of the donor’s infrahepatic vena cava must be ligated. A drawback of these techniques may be either hepatic venous outflow obstruction because of stenosis or kinking of the caval anastomosis, or obstruction of the recipient’s inferior vena cava (11). We report a case of hepatic venous outflow obstruction at liver reperfusion because of kinking of the caval anastomosis. The stenosis was overcome performing an end-to-side cavo–caval anastomosis using the infrahepatic stump of the donor’s vena cava.

NK ACTIVITY DURING GRAFT-VERSUS-HOST DISEASE AND GRAFT-REJECTION IN RATS FOLLOWING INTESTINAL SEMIALLOGENIC AND ALLOGENIC TRANSPLANTATION WITH OR WITHOUT MESENTERIC LYMPHADENECTOMY

Graft-versus-host disease (GVHD) and graft rejection are major problems following intestinal transplantation (IT). Natural killer (NK) cells may be important effector cells in both conditions. In this study, Sprague-Dawley (SD) or SD-Brown Norway (BN) F rat intestine was transplanted into BN recipients with and without associated graft mesenteric lymphadenectomy (GML). Cyclosporine (15 mg/kg day) was administered to all animals. Pieces of the intestinal graft were examined 4 days posttransplant and again at death. NK activity calculated using intestinal intraepithelial lymphocytes (IL) was determined utilizing an 18-hr cytotoxic assay assessing 51Cr release and the results are reported as lytic units. YAC-1 cells were used as the target. NK activity was reduced 4 days after IT both in native (8.02±0.64) and in grafted bowel (3.14±1.51), with histological evidence of rejection as compared with that of control bowel in ungrafted rats (21.1±2.14). Survival was increased, on mean, a total of 6 days with the addition of GML in both semiallogenic and allogenic transplanted rats. At the time of death, the NK activity in the native bowel had increased (17.1±3.02) and histologic evidence of GVHD was present. These data suggest that: (1) NK cells are important in GVHD and (2) both semiallogenic and allogenic transplants survive longer if they are combined with GML (P<0.05 and P<0.01, respectively).

A rare surgical case of metachronous double carcinoma of the biliary tract

We report on a rare case of metachronous double carcinoma of the biliary tract, occurring in a 65-year-old male. The patient was admitted to the hospital with jaundice in March 2004. Ultrasonography, computed tomography (CT) and magnetic resonance imaging (MRI) scans of the abdomen showed a minimally dilated intrahepatic biliary tree with normal-appearing choledocus. Obstruction of the common hepatic duct was revealed by endoscopic retrograde cholangiopancreatography (ERCP). The patient underwent a resection of the middle third of the extrahepatic duct and cholecystectomy (cholangiocarcinoma, pT1N0M0), with the surgical margins of resection showing as negative. After 2 years, during follow-up, the findings of a positron emission tomography (PET)-CT scan suggested a possible cholangiocarcinoma of the distal part of the biliary tract; CT and MRI scanning of the abdomen showed mild dilatation of the distal common hepatic duct; an ERCP showed mild dilatation of the retropancreatic remnant of the biliary tree with endoluminal defects. Eventually the patient underwent pancreaticoduodenectomy. The histopathological diagnosis of the resected specimen confirmed a cholangiocarcinoma; 10 lymph nodes were negative (pT1N0M0). At 6 months post-op after the second operation the patient is progressing well with no signs of recurrence. Patients with cholangiocarcinoma – in whom survival is prolonged with surgical resection – should undergo careful follow-up for both recurrence and second primary cancer. PET scanning seems to play the most important diagnostic role.

Arteroportal fistulas between the accessory right hepatic, gastroduodenal and superior mesenteric arteries and portal vein: a difficult technical problem to overcome in liver transplantation.

Background. Fistulous communications between the accessory right hepatic (ARHA), gastroduodenal (GD), and superior mesenteric (SMA) arteries and the portal vein (PV) may represent a contraindication for liver transplantation (LT). Material. A patient with HCV-related liver cirrhosis and progressive liver decompensation underwent preoperative LT work-up. Doppler ultrasound (DU), Angiography and MRI revealed arteroportal fistulas (APF) and diversion of mesenteric-splenoportal flow through spontaneous splenorenal shunts (SSRS) in the systemic circulation. The patient was transplanted and the ARHA and GDA were distally sectioned; the HA was anastomosed to the donor HA; the superior mesenteric vein (SMV) was detached from the splenopancreatic venous bed by sectioning and ligating the Henle trunk, by ligating an posterior-inferior pancreatic vein and, finally, by positioning an iliac vein interposition graft between the SMV and the donor PV. The postanastomotic SMV trunk and recipient PV were ligated below and above the pancreatic head, respectively. Results. Reperfusion and late liver function were good. DU and MRI studies showed an effective portal flow and the maintenance of a normal splenopancreatic vein outflow through the SSRS. Discussion. APF represent a serious clinical problem, particularly in patients who need LT. The persistence of arterial flow into the PV is dangerous for the long-term liver function. A particular surgical strategy, strictly tailored to the hemodynamic conditions, has to be planned. Conclusions. Extrahepatic multiple APF would no longer to represent a contraindication to LT, although this claim needs to be confirmed in the light of further experience and a longer-term follow-up.