Ali A. Ayoub

Surgically produced congenital diaphragmatic hernia in fetal rabbits.

Animal models of congenital diaphragmatic hernia (CDH) still are indispensable for the evolution of knowledge related to this disease and to fetal surgery in general. The lamb has provided the most reliable experimental design thus far. Considering the possible advantages of using rabbits (rather than lambs) namely lower costs, no need of special veterinary facilities, smaller body size, year-round availability, higher number of fetuses per pregnancy, and shorter gestational period, a successful model of CDH was developed in fetal rabbits. Sixteen pregnant New Zealand rabbits underwent hysterotomy and fetal operation. Group 1 (6 does) underwent surgery on gestational day 20 and group 2 (10 does) on gestational day 24 or 25. The normal full gestation time is 31 to 33 days. In group 1, the CDH was created by transabdominal puncture and dilatation of the fetal diaphragm. In group 2, the CDH was created through open thoracotomy, either left or right. The fetuses were delivered by cesarean section on gestational day 30. The overall fetal survival rate was 0 for group 1 and 70% for group 2. All operated fetuses in group 2 that were born alive had CDH. The histological morphometric examinations (radial alveolar count after sustained lung expansion) of the normal and operated fetuses in group 2 showed pulmonary hypoplasia in all the lungs on the same side as the CDH (statistical analysis was performed using the Neuman-Keuls test and analysis of variance; the significance level was set at .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Hepatic venous reconstruction in pediatric living‐related donor liver transplantation – Experience of a single center

Abstract:  In pediatric patients submitted to living related liver transplantation, hepatic venous reconstruction is critical because of the diameter of the hepatic veins and the potential risk of twisting of the graft over the line of the anastomosis. The aim of the present study is to present our experience in hepatic venous reconstruction performed in pediatric living related donor liver transplantation. Fifty‐four consecutive transplants were performed and two methods were utilized for the reconstruction of the hepatic vein: direct anastomosis of the orifice of the donor left or left and middle hepatic veins and the common orifice of the recipient left and middle hepatic veins (group 1–26 cases), and wide triangular anastomosis after creating a wide triangular orifice in the recipient inferior vena cava at the confluence of all the hepatic veins with an additional longitudinal incision in the inferior angle of the orifice (group 2–28 cases). In group 1, eight patients were excluded because of graft problems in the early postoperative period and five among the remaining 18 patients (27.7%) presented stricture at the site of the hepatic vein anastomosis. All these patients had to be submitted to two or three sessions of balloon dilatations of the anastomoses and in four of them a metal stent had to be placed. The liver histopathological changes were completely reversed by the placement of the stent. Among the 28 patients of the group 2, none of them presented hepatic vein stenosis (p = 0.01). The results of the present series lead to the conclusion that hepatic venous reconstruction in pediatric living donor liver transplantation must be preferentially performed by using a wide triangulation on the recipient inferior vena cava, including the orifices of the three hepatic veins. In cases of stenosis, the endovascular dilatation is the treatment of choice followed by stent placement in cases of recurrence.

Mycophenolate mofetil promotes prolonged improvement of renal dysfunction after pediatric liver transplantation: experience of a single center.

Abstract:  Few studies have evaluated the long‐term use of MMF in liver transplanted children with renal dysfunction. The aim of this study is to report the experience of a pediatric transplantation center on the efficacy and security of long‐term use of a MMF immunosuppressant protocol with reduced doses of CNIs in stable liver transplanted children with renal dysfunction secondary to prolonged use of CsA or Tac. Between 1988 and 2003, 191 children underwent OLT and 11 patients developed renal dysfunction secondary to CNIs toxicity as evaluated by biochemical renal function parameters. The interval between liver transplantation and the introduction of the protocol varied from one to 12 yr. Renal function was evaluated by biochemical parameters in five phases: immediately prior to MMF administration; 3, 6, 12 and 24 months after the introduction of MMF. Among the patients, nine of them (82%) showed improvement of renal function parameters in comparison with the pretreatment values. The two patients that did not show any improvement were patients in whom the interval of time between OLT and the introduction of MMF was longer. All parameters of liver function remained unchanged. No episodes of acute or chronic rejection or increases in infection rates during the period were detected. Two patients developed transitory diarrhea and leukopenia that were reverted with reduction of MMF dosage. In conclusion, in liver transplanted pediatric patients with CNI‐induced chronic renal dysfunction, the administration of MMF in addition to reduced doses of CNIs promotes long‐term improvement in renal function parameters with no additional risks.

Living Related Donor Liver Transplantation in Children

OBJECTIVE The objective of this study was to report our experience with pediatric orthotopic liver transplantation (OLT) with living related donors. METHODS We performed a retrospective chart analysis of 121 living related donor liver transplantations (LRDLT) from June 1998 to June 2010. RESULTS Indications were biliary atresia (BA; n = 81), primary sclerosing cholangitis (n = 5), α-1 antitrypsin deficiency (n = 4); cholestasis (n = 9), fulminant hepatic failure (n = 8), autoimmune hepatitis (n = 2), Alagille syndrome (n = 4), hepatoblastoma (n = 3), tyrosinemia (n = 2), and congenital hepatic fibrosis (n = 3). The age of the recipients ranged from 7-174 months (median, 22) and the weights ranged from 6-58 kg (median, 10). Forty-nine children (40.5%) weighed ≤10 kg. The grafts included the left lateral segment (n = 108), the left lobe (n = 12), and the right lobe (n = 1). The donors included 71 mothers, 45 fathers, 2 uncles, 1 grandmother, 1 grandfather, and 1 sister with a median age of 29 years (range, 16-53 ys) and a median weight of 68 kg (range, 47-106). Sixteen patients (12.9%) required retransplantation, most commonly due to hepatic artery thrombosis (HAT; n = 13; 10.7%). The other complications were biliary stenosis (n = 25; 20.6%), portal vein thrombosis (PVT; n = 11; 9.1%), portal vein stenosis (n = 5; 4.1%), hepatic vein stenosis (n = 6; 4.9%), and lymphoproliferative disorders (n = 8; 6.6%). The ultimate survival rate of recipients was 90.3% after 1 year and 75.8% after 3 years. Causes of early death within 1 month were HAT (n = 6), PVT (n = 2), severe graft dysfunction (n = 1), sepsis (n = 1), and intraoperative death in children with acute liver failure (n = 2). Causes of late deaths included lymphoproliferative disease (n = 3), chronic rejection (n = 2), biliary complications (n = 3), and recurrent disease (n = 3; hepatoblastoma and primary sclerosing cholangitis). CONCLUSIONS Despite the heightened possibility of complications (mainly vascular), LRDLT represented a good alternative to transplantation from cadaveric donors in pediatric populations. It was associated with a high survival ratio.

Sirolimus in pediatric liver transplantation: a single-center experience.

BACKGROUND AND AIMS Liver transplantation (OLT) in children has seen significant improvements in recent years. Long-term immunosuppressive strategies have focused on avoiding the risks of long-term immunosuppression, particularly nephrotoxicity, de novo malignancy and late infections. Since its introduction in renal transplantation in 1999, sirolimus (SRL) has been used by an increasing number of liver transplant centers. The aim of this study was to review the experience using SRL in pediatric liver transplant recipients at a single center. METHODS Between 1989 and 2006, 318 children underwent OLT including 13 who were converted to SRL therapy because of tacrolimus-related side effects. The indications were posttransplant lymphoproliferative disease (PTLD; n = 11), nephrotoxicity (n = 1), and de novo autoimmune hepatitis (n = 1). One patient with PTLD previously concurrently displayed chronic rejection. SRL dosages ranged between 0.4 and 5 mg/d. The median duration of follow-up was 18 months. RESULTS PTLD recurred in 1 patient. There were no episodes of acute rejection. One child developed hyperlipidemia that resolved with diet and medication. CONCLUSIONS Conversion from tacrolimus to SRL in selected pediatric liver transplant recipients is safe. Children with PTLD may benefit from immunosuppression with SRL after liver transplantation.

Successful treatment of de novo autoimmune hepatitis and cirrhosis after pediatric liver transplantation.

Abstract: Over a 15‐yr period of observation, among the 205 children who underwent liver transplantations, one of them developed a particular type of late graft dysfunction with clinical and histological similarity to autoimmune hepatitis. The patient had α1‐antitrypsin deficiency and did not previously have autoimmune hepatitis or any other autoimmune disease before transplantation. Infectious and surgical complications were excluded. After repeated episodes of unexplained fluctuations of liver function tests and liver biopsies demonstrating reactive or a biliary pattern, without any corresponding alteration of percutaneous cholangiography, a liver‐biopsy sample taken 4 yr after the transplant showed active chronic hepatitis progressing to cirrhosis, portal lymphocyte aggregates, and a large number of plasma cells. At that time, autoantibodies (gastric parietal cell antibody, liver–kidney microsomal antibody, and anti‐hepatic cytosol) were positive and serum IgG levels were high. Based on these findings of autoimmune disease, a diagnosis of ‘de novo autoimmune hepatitis’ was made. The treatment consisted of reducing the dose of cyclosporine, reintroduction of corticosteroids, and addition of mycophenolate mofetil. After 19 months of treatment, a new liver‐biopsy sample showed marked reduction of portal and lobular inflammatory infiltrate, with regression of fibrosis and of the architectural disruption. At that time, serum autoantibodies became negative. The last liver‐biopsy sample showed inactive cirrhosis and disappearance of interface hepatitis and of plasma cell infiltrate. Presently, 9 yr after the transplantation, the patient is doing well, with normal liver function tests and no evidence of cirrhosis. Her immunosuppressive therapy consists of tacrolimus, mycophenolate mofetil, and prednisolone. In conclusion, the present case demonstrates that de novo autoimmune hepatitis can appear in liver‐transplant patients despite appropriate anti‐rejection immunosuppression, and triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone could sustain the graft and prevent retransplantation.

Multiple clinical presentations of lymphoproliferative disorders in pediatric liver transplant recipients: a single-center experience.

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naïve prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.

Posterior reversible encephalopathy syndrome after liver transplantation in children: a rare complication related to calcineurin inhibitor effects.

Santos MM, Tannuri ACA, Gibelli NE, Ayoub AA, Maksoud‐Filho JG, Andrade WC, Velhote MCP, Silva MM, Pinho ML, Miyatani HT, Suzuki L, Tannuri U. Posterior reversible encephalopathy syndrome after liver transplantation in children: A rare complication related to calcineurin inhibitor effects.
Pediatr Transplantation 2011: 15:157–160.

Which is the best technique for hepatic venous reconstruction in pediatric living-donor liver transplantation? Experience from a single center

BACKGROUND/PURPOSE The introduction of the piggyback technique for reconstruction of the liver outflow in reduced-size liver transplants for pediatric patients has increased the incidence of hepatic venous outflow block (HVOB). Here, we proposed a new technique for hepatic venous reconstruction in pediatric living-donor liver transplantation. METHODS Three techniques were used: direct anastomosis of the orifice of the donor hepatic veins and the orifice of the recipient hepatic veins (group 1); triangular anastomosis after creating a wide triangular orifice in the recipient inferior vena cava at the confluence of all the hepatic veins (group 2); and a new technique, which is a wide longitudinal anastomosis performed at the anterior wall of the inferior vena cava (group 3). RESULTS In groups 1 and 2, the incidences of HVOB were 27.7% and 5.7%, respectively. In group 3, no patient presented HVOB (P = .001). No difference was noted between groups 2 and 3. CONCLUSIONS Hepatic venous reconstruction in pediatric living-donor liver transplantation must be preferentially performed by using a wide longitudinal incision at the anterior wall of the recipient inferior vena cava. As an alternative technique, triangulation of the recipient inferior vena cava, including the orifices of the 3 hepatic veins, may be used.

An alternative method of arterial reconstruction in pediatric living donor liver transplantation with the recipient right gastroepiploic artery

Abstract:  The classical method for arterial reconstruction in pediatric living donor liver transplantation using left lateral segment consists of end‐to‐end anastomosis between the donor left hepatic artery and the recipient right hepatic artery. In the present case, an intra‐operative hepatic artery thrombosis occurred because of extensive intima wall dissection of the recipient hepatic artery. The patient was a 6‐yr‐old boy with fulminant hepatic failure, who underwent living donor partial liver transplantation with left lateral segment from his father. The graft was irrigated by a left hepatic artery and an accessory left hepatic artery from gastric artery, both arteries with diameter of <2 mm. These arteries were anastomosed to the recipient right and left hepatic arteries, respectively. Before performing the bile duct reconstruction it was noted that these anastomoses were occluded by clots of blood. An extensive subintimal dissection of the recipient hepatic artery was the cause of this problem. The creation of a new anastomosis by using a more proximal part of this artery without subintimal dissection was judged impossible. Then, the right gastroepiploic artery was mobilized and an anastomosis was performed with the donor left hepatic artery in an end‐to‐end fashion. Arterial blood flow to the graft was established successfully and the patients postoperative recovery was excellent. Fifteen days after the transplantation, an angiotomography demonstrated a good hepatic arterial blood flow. The patient is now alive and well, 4 months after the transplantation. In conclusion, the method of hepatic graft arterialization described here is an important option for patients who undergo living donor or split liver transplantation.